Oncology

Technol Health Care. 2011;19(6):455-67.

Solid Ehrlich tumor growth treatment by magnetic waves.

Ali FM, El Gebaly RH, El Hag MA, Rohaim AM.

Source 

Department of Biophysics, Faculty of Science, Cairo University, Giza, Egypt. 

Abstract 

In this work the retardation of Ehrlich tumor growth implanted in mice was studied by employing 4.5 Hz magnetic field. Eighty female Balb/c mice were used, twenty as normal group; the other sixty mice were inoculated with Ehrlich tumor, then they were divided equally into three groups namely A, B and C. Group A (control group) animals were not exposed to the magnetic field. The tumors in the thigh of the animals of group B were exposed to 4.5 Hz, 2 Gauss square wave magnetic field by using a small solenoid connected to a power square wave generator. Group C animals were whole body exposed inside a large solenoid to 4.5 Hz, 2 Gauss square wave magnetic field. Both groups B and C were exposed for a period of 2 weeks at a rate 2 hours per day. Tumor volume, survival period, histological examination and dielectric relaxation of the tumor were measured to investigate the activity of the tumor of the exposed and the unexposed animals. The results indicated that exposing the tumor tissue to 4.5 Hz square wave magnetic field for 2 weeks at a rate 2 hours/day inhibited tumor growth and increased the survival period of the animals. However, group B showed more improvements than did group C. This was attributed to some distortions in the square waveform in the large solenoid (group C). By comparing data from current and previous work, it was concluded that the use of magnetic waves showed better results over previously published work using amplitude modulated electromagnetic waves with the same frequency. 

/Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106. doi: 10.1517/13543784.2011.583236. Epub 2011 May 9. 

Tumor treating fields: concept, evidence and future.

Pless M, Weinberg U.

Source 

Medical Oncology, Department of Internal Medicine, and Tumor Center, Kantonsspital Winterthur, Brauerstrasse, Switzerland. miklos.pless@ksw.ch 

Abstract 

INTRODUCTION: Local control is fundamental, both for the curative as well as the palliative treatment of cancer. Tumor treating fields (TTFields) are low intensity (1 ? 2 V/cm), intermediate frequency (100 ? 200 kHz) alternating electric fields administered using insulated electrodes placed on the skin surrounding the region of a malignant tumor. TTFields were shown to destroy cells within the process of mitosis via apoptosis, thereby inhibiting tumor growth. TTFields have no effect on non-dividing cells. 

AREAS COVERED: This article reviews in vitro and in vivo preclinical studies, demonstrating the activity of TTFields both as a monotherapy as well as in combination with several cytotoxic agents. Furthermore, it summarizes the clinical experience with TTFields, mainly in two indications: one in recurrent glioblastoma multiforme: in a large prospective randomized Phase III trial TTFields was compared with best standard care (including chemotherapy): TTFields significantly improved median overall survival (OS) compared with standard therapy (7.8 vs 6.1 months) for the patients treated per protocol. Importantly, quality of life was also better in the TTFields group. The second indication was a Phase II study in second-line non-small cell lung cancer, where TTFields was administered concomitantly with pemetrexed. This combination resulted in an excellent median OS of 13.8 months. Interestingly, the progression-free survival (PFS) within the area of the TTFields was 28, however, outside the TTFields the PFS was only 22 weeks. 

EXPERT OPINION: The proof of concept of TTFields has been well demonstrated in the preclinical setting, and the clinical data seem promising in various tumor types. The side effects of TTFields were minimal and in general consisted of skin reaction to the electrodes. There are a number of ways in which TTFields could be further evaluated, for example, in combination with chemotherapy, as a maintenance treatment, or as a salvage therapy if radiotherapy or surgery is not possible. While more clinical data are clearly needed, TTFields is an emerging and promising novel treatment concept. 

Electromagn Biol Med. 2010 Dec;29(4):132-43. 

Bioelectromagnetic field effects on cancer cells and mice tumors.

Berg H, Günther B, Hilger I, Radeva M, Traitcheva N, Wollweber L.

Source 

Laboratory Bioelectrochemistry, Beutenberg Campus, Jena, Germany. 

Abstract 

We present possibilities and trends of ELF bioelectromagnetic effects in the mT amplitude range on cancer cells and on mice bearing tumors. In contrast to invasive electrochemotherapy and electrogenetherapy, using mostly needle electrodes and single high-amplitude electropulses for treatment, extremely low-frequency (ELF) pulsating electromagnetic fields (PEMF) and sinusoidal electromagnetic fields (SEMF) induce tumor cell apoptosis, inhibit angiogenesis, impede proliferation of neoplastic cells, and cause necrosis non invasively, whereas human lymphocytes are negligibly affected. Our successful results in killing cancer cells-analyzed by trypan blue staining or by flow cytometry-and of the inhibition of MX-1 tumors in mice by 15-20?mT, 50?Hz treatment in a solenoid coil also in the presence of bleomycin are presented in comparison to similar experimental results from the literature. In conclusion, the synergistic combinations of PEMF or SEMF with hyperthermia (41.5°C) and/or cancerostatic agents presented in the tables for cells and mice offer a basis for further development of an adjuvant treatment for patients suffering from malignant tumors and metastases pending the near-term development of suitable solenoids of 45-60?cm in diameter, producing >20?mT in their cores.  Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2010 Oct;27(5):1128-32.

Focusing properties of picosecond electric pulses in non-invasive cancer treatment.

[Article in Chinese] Long Z, Yao C, Li C, Mi Y, Sun C.

Source 

State Key Laboratory of Power Transmission Equipment & System Security and New Technology, Chongqing University, Chongqing 400044, China. longzaiquan@foxmail.com 

Abstract 

In the light of optical theory, we advanc an ultra-wideband impulse radiating antenna (IRA) which is composed of an ellipsoidal reflector and a cone radiator. The high-intensity ultra-short electric pulses radiated by IRA can be transferred into the deep target in tissue non-invasively and be focused effectively. With the focused picosecond electric pulses, the organelles (mitochondria) transmembrane potential shall change to collapse under which the tumor cells will be targetly induced to apoptosis, so the method of non-invasive treatment of tumors would be achieved. Based on the time-domain electromagnetic field theory, the propagation characteristics of picosecond electric pulses were analyzed with and without the context of biological tissue, respectively. The results show that the impulse characteristics of input pulse were maintained and the picosecond electric pulses can keep high resolution in target areas. Meanwhile, because of the dispersive nature of medium, the pulse amplitude of the pulses will attenuate and the pulse width will be broadened. 

BMC Cancer. 2010 Apr 24;10:159. 

Anti-proliferative effect of extremely low frequency electromagnetic field on preneoplastic lesions formation in the rat liver.

Jiménez-García MN, Arellanes-Robledo J, Aparicio-Bautista DI, Rodríguez-Segura MA, Villa-Treviño S, Godina-Nava JJ. 

Department of Physics Center of Research and Advanced Studies of the National Polytechnic Institute, Mexico City, Mexico. jj@fis.cinvestav.mx 

Abstract 

BACKGROUND: Recently, extremely low frequency electromagnetic fields (ELF-EMF) have been studied with great interest due to their possible effects on human health. In this study, we evaluated the effect of 4.5 mT-120 Hz ELF-EMF on the development of preneoplastic lesions in experimental hepatocarcinogenesis. 

METHODS: Male Fischer-344 rats were subjected to the modified resistant hepatocyte model and were exposed to 4.5 mT – 120 Hz ELF-EMF. The effects of the ELF-EMF on hepatocarcinogenesis, apoptosis, proliferation and cell cycle progression were evaluated by histochemical, TUNEL assay, caspase 3 levels, immunohistochemical and western blot analyses. 

RESULTS: The application of the ELF-EMF resulted in a decrease of more than 50% of the number and the area of gamma-glutamyl transpeptidase-positive preneoplastic lesions (P = 0.01 and P = 0.03, respectively) and glutathione S-transferase placental expression (P = 0.01). The number of TUNEL-positive cells and the cleaved caspase 3 levels were unaffected; however, the proliferating cell nuclear antigen, Ki-67, and cyclin D1 expression decreased significantly (P < or = 0.03), as compared to the sham-exposure group. 

CONCLUSION: The application of 4.5 mT-120 Hz ELF-EMF inhibits preneoplastic lesions chemically induced in the rat liver through the reduction of cell proliferation, without altering the apoptosis process. 

Cell Biochem Biophys. 2009;55(1):25-32. Epub 2009 Jun 18. 

Evaluation of the potential in vitro antiproliferative effects of millimeter waves at some therapeutic frequencies on RPMI 7932 human skin malignant melanoma cells.

Beneduci A. 

Department of Chemistry, University of Calabria, Via P. Bucci, Cubo 17/D, Arcavacata di Rende (CS), Italy.beneduci@unical.it 

Abstract 

The potential antiproliferative effects of low power millimeter waves (MMWs) at 42.20 and 53.57 GHz on RPMI 7932 human skin melanoma cells were evaluated in vitro in order to ascertain if these two frequencies, comprised in the range of frequency used in millimeter wave therapy, would have a similar effect when applied in vivo to malignant melanoma tumours. Cells were exposed for 1 h exposure/day and to repeated exposure up to a total of four treatments. Plane wave incident power densities <1 mW/cm(2) were used in the MMWs-exposure experiments so that the radiations did not cause significant thermal effects. Numerical simulations of Petri dish reflectivity were made using the equations for the reflection coefficient of a multilayered system. Such analysis showed that the power densities transmitted into the aqueous samples were < or = 0.3 mW/cm(2). Two very important and general biological endpoints were evaluated in order to study the response of melanoma cells to these radiations, i.e. cell proliferation and cell cycle. Herein, we show that neither cell doubling time nor the cell cycle of RPMI 7932 cells was affected by the frequency of the GHz radiation and duration of the exposure, in the conditions above reported. 

— ———————————————————————————— 

Bioelectrochemistry. 2010 Oct;79(2):257-60. Epub 2010 Mar 10. 

Electroporation and alternating current cause membrane permeation of photodynamic cytotoxins yielding necrosis and apoptosis of cancer cells.

Traitcheva N, Berg H. 

Institute of Plant Physiology “M. Popov,” Bulgarian Acad. of Sciences, Sofia, Bulgaria. 

Abstract 

In order to increase the permeability of cell membranes for low doses of cytostatic drugs, two bioelectrochemical methods have been compared: (a) electric pore formation in the plasma membranes by single electric impulses (electroporation), and (b) reordering of membrane structure by alternating currents (capacitively coupled). These treatments were applied to human leukemic K-562 cells and human lymphoma U-937 cells, yielding apoptotic and necrotic effects, determined by flow cytometry. Additional cell death occurs after exposure to light irradiation at wavelengths lambda > 600 nm, of cells which were electroporated and had incorporated actinomycin-C or daunomycin (daunorubicin). It is observed that drug uptake after an exponentially decaying electroporation pulse of the initial field strength Eo=1.4 kV/cm and pulse time constants in the time range 0.5-3 ms is faster than during PEMF-treatment, i.e., application of an alternating current of 16 kHz, voltage U<100 V, I=55 mA, and exposure time 20 min. However, at the low a.c. voltage of this treatment, more apoptotic and necrotic cells are produced as compared to the electroporation treatment with one exponentially decaying voltage pulse. Thus, additional photodynamic action appears to be more effective than solely drugs and electroporation as applied in clinical electrochemotherapy, and more effective than the noninvasive pulsed electromagnetic fields (PEMFs), for cancer cells in general and animals bearing tumors in particular. 

Arch Biochem Biophys. 2010 May;497(1-2):82-9. Epub 2010 Mar 24. 

Nanosecond pulsed electric fields stimulate apoptosis without release of pro-apoptotic factors from mitochondria in B16f10 melanoma.

Ford WE, Ren W, Blackmore PF, Schoenbach KH, Beebe SJ. 

Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA. 

Abstract 

Nanosecond pulsed electric fields (nsPEFs) eliminates B16f10 melanoma in mice, but cell death mechanisms and kinetics of molecular events of cell death are not fully characterized. Treatment of B16f10 cells in vitro resulted in coordinate increases in active caspases with YO-PRO-1 uptake, calcium mobilization, decreases in mitochondria membrane potential with decreases in forward light scatter (cell size), increases in ADP/ATP ratio, degradation of actin cytoskeleton and membrane blebbing. However, there was no mitochondrial release of cytochrome c, AIF or Smac/DIABLO or generation of reactive oxygen species. Phosphatidylserine externalization was absent and propidium iodide uptake was delayed in small populations of cells. The results indicate that nsPEFs rapidly recruit apoptosis-like mechanisms through the plasma membrane, mimicking the extrinsic apoptosis pathway without mitochondrial amplification yet include activation of initiator and executioner caspases. nsPEFs provide a new cancer therapy that can bypass cancer-associated deregulation of mitochondria-mediated apoptosis in B16f10 melanoma. 

J Physiol Pharmacol. 2010 Apr;61(2):201-5. 

Pulsating electromagnetic field stimulation prevents cell death of puromycin treated U937 cell line.

Kaszuba-Zwoinska J, Wojcik K, Bereta M, Ziomber A, Pierzchalski P, Rokita E, Marcinkiewicz J, Zaraska W, Thor P. 

Department of Pathophysiology, Jagiellonian University Medical College, Cracow, Poland. jkaszuba@cm-uj.krakow.pl 

Abstract

Aim of study was to verify whether pulsating electromagnetic field (PEMF) can affect cancer cells proliferation and death. U937 human lymphoid cell line at densities starting from 1 x 10(6) cells/ml to 0.0625 x 10(6) cells/ml, were exposed to a pulsating magnetic field 50 Hz, 45+/-5 mT three times for 3 h per each stimulation with 24 h intervals. Proliferation has been studied by counting number of cells stimulated and non-stimulated by PEMF during four days of cultivation. Viability of cells was analyzed by APC labeled Annexin V and 7-AAD (7-amino-actinomycin D) dye binding and flow cytometry. Growing densities of cells increase cell death in cultures of U937 cells. PEMF exposition decreased amount of cells only in higher densities. Measurement of Annexin V binding and 7-AAD dye incorporation has shown that density-induced cell death corresponds with decrease of proliferation activity. PEMF potentiated density-induced death both apoptosis and necrosis. The strongest influence of PEMF has been found for 1 x 10(6)cells/ml and 0.5 x 10(6) cells/ml density. To eliminate density effect on cell death, for further studies density 0.25 x 10(6) cells/ml was chosen. Puromycin, a telomerase inhibitor, was used as a cell death inducer at concentration 100 microg/ml. Combined interaction of three doses of puromycin and three fold PEMF interaction resulted in a reduced of apoptosis by 24,7% and necrosis by 13%. PEMF protects U937 cells against puromycin- induced cell death. PEMF effects on the human lymphoid cell line depends upon cell density. Increased density induced cells death and on the other hand prevented cells death induced by puromycin. 

Int J Radiat Biol. 2010 Feb;86(2):79-88. 

Growth of injected melanoma cells is suppressed by whole body exposure to specific spatial-temporal configurations of weak intensity magnetic fields.

Hu JH, St-Pierre LS, Buckner CA, Lafrenie RM, Persinger MA. 

Department of Biology, Laurentian University, Sudbury, Ontario, Canada. 

Abstract 

PURPOSE: To measure the effect of exposure to a specific spatial-temporal, hysiologically-patterned electromagnetic field presented using different geometric configurations on the growth of experimental tumours in mice. 

METHODS: C57b male mice were inoculated subcutaneously with B16-BL6 melanoma cells in two blocks of experiments separated by six months (to control for the effects of geomagnetic field). The mice were exposed to the same time-varying electromagnetic field nightly for 3 h in one of six spatial configurations or two control conditions and tumour growth assessed. 

RESULTS: Mice exposed to the field that was rotated through the three spatial dimensions and through all three planes every 2 sec did not grow tumours after 38 days. However, the mice in the sham-field and reference controls showed massive tumours after 38 days. Tumour growth was also affected by the intensity of the field, with mice exposed to a weak intensity field (1-5 nT) forming smaller tumours than mice exposed to sham or stronger, high intensity (2-5 microT) fields. Immunochemistry of tumours from those mice exposed to the different intensity fields suggested that alterations in leukocyte infiltration or vascularisation could contribute to the differences in tumour growth. 

CONCLUSIONS: Exposure to specific spatial-temporal regulated electromagnetic field configurations had potent effects on the growth of experimental tumours in mice. 

Melanoma Res. 2009 Aug 26. [Epub ahead of print] 

Histopathology of normal skin and melanomas after nanosecond pulsed electric field treatment.

Chen X, James Swanson R, Kolb JF, Nuccitelli R, Schoenbach KH. 

Department of Hepatobiliary Surgery, the First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China bFrank Reidy Research Center for Bioelectrics cDepartment of Biological Sciences, Old Dominion University, Norfolk, Virginia, USA. 

Abstract 

Nanosecond pulsed electric fields (nsPEFs) can affect the intracellular structures of cells in vitro. This study shows the direct effects of nsPEFs on tumor growth, tumor volume, and histological characteristics of normal skin and B16-F10 melanoma in SKH-1 mice. A melanoma model was set up by injecting B16-F10 into female SKH-1 mice. After a 100-pulse treatment with an nsPEF (40-kV/cm field strength; 300-ns duration; 30-ns rise time; 2-Hz repetition rate), tumor growth and histology were studied using transillumination, light microscopy with hematoxylin and eosin stain and transmission electron microscopy. Melanin and iron within the melanoma tumor were also detected with specific stains. After nsPEF treatment, tumor development was inhibited with decreased volumes post-nsPEF treatment compared with control tumors (P<0.05). The nsPEF-treated tumor volume was reduced significantly compared with the control group (P<0.01). Hematoxylin and eosin stain and transmission electron microscopy showed morphological changes and nuclear shrinkage in the tumor. Fontana-Masson stain indicates that nsPEF can externalize the melanin. Iron stain suggested nsPEF caused slight hemorrhage in the treated tissue. Histology confirmed that repeated applications of nsPEF disrupted the vascular network. nsPEF treatment can significantly disrupt the vasculature, reduce subcutaneous murine melanoma development, and produce tumor cell contraction and nuclear shrinkage while concurrently, but not permanently, damaging peripheral healthy skin tissue in the treated area, which we attribute to the highly localized electric fields surrounding the needle electrodes. 

Cancer Biol Ther. 2009 Sep;8(18):1756-62. Epub 2009 Sep 17. 

Static magnetic fields impair angiogenesis and growth of solid tumors in vivo.

Strelczyk D, Eichhorn ME, Luedemann S, Brix G, Dellian M, Berghaus A, Strieth S. 

Walter-Brendel-Center for Experimental Medicine (WBex), Campus Grosshadern, University of Munich (LMU), Munich, Germany. 

Abstract 

Exposure to static magnetic fields (SMFs) results in a reduced blood flow in tumor vessels as well as in activation and adherence of platelets. Whether this phenomenon may have a significant functional impact on tumors has not been investigated as yet. The aim of our study was to evaluate the effects of prolonged exposure to SMFs on tumor angiogenesis and growth. Experiments were performed in dorsal skinfold chamber preparations of Syrian Golden hamsters bearing syngenic A-Mel-3 melanomas. On 3 d following tumor cell implantation one group of animals was immobilized and exposed to a SMF of 586 mT for three h. Control animals were immobilized for the same duration without SMF exposure. Using in vivo-fluorescence microscopy the field effects on tumor angiogenesis and microcirculation were analyzed for seven days. Tumor growth was assessed by repeated planimetry of the tumor area during the observation period. Exposure to SMFs resulted in a significant retardation of tumor growth ( approximately 30%). Furthermore, histological analysis showed an increased peri- and intratumoral edema in tumors exposed to SMFs. Analysis of microcirculatory parameters revealed a significant reduction of functional vessel density, vessel diameters and red blood cell velocity in tumors after exposure to SMFs compared to control tumors. These changes reflect retarded vessel maturation by antiangiogenesis. The increased edema after SMF exposure indicates an increased tumor microvessel leakiness possibly enhancing drug-uptake. Hence, SMF therapy appears as a promising new anticancer strategy-as an inhibitor of tumor growth and angiogenesis and as a potential sensitizer to 

J Exp Clin Cancer Res. 2009 Apr 14;28:51. 

Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach.

Barbault A, Costa FP, Bottger B, Munden RF, Bomholt F, Kuster N, Pasche B.  Cabinet Médical, Avenue de la Gare 6, Lausanne, Switzerland. alexandre.barbault@gmail.com

Abstract  PURPOSE:Because in vitro studies suggest that low levels of electromagnetic fields may modify cancer cell growth, we hypothesized that systemic delivery of a combination of tumor-specific frequencies may have a therapeutic effect. We undertook this study to identify tumor-specific frequencies and test the feasibility of administering such frequencies to patients with advanced cancer. PATIENTS AND METHODS:We examined patients with various types of cancer using a noninvasive biofeedback method to identify tumor-specific frequencies. We offered compassionate treatment to some patients with advanced cancer and limited therapeutic options. RESULTS:We examined a total of 163 patients with a diagnosis of cancer and identified a total of 1524 frequencies ranging from 0.1 Hz to 114 kHz. Most frequencies (57-92%) were specific for a single tumor type. Compassionate treatment with tumor-specific frequencies was offered to 28 patients. Three patients experienced grade 1 fatigue during or immediately after treatment. There were no NCI grade 2, 3 or 4 toxicities. Thirteen patients were evaluable for response. One patient with hormone-refractory breast cancer metastatic to the adrenal gland and bones had a complete response lasting 11 months. One patient with hormone-refractory breast cancer metastatic to liver and bones had a partial response lasting 13.5 months. Four patients had stable disease lasting for +34.1 months (thyroid cancer metastatic to lung), 5.1 months (non-small cell lung cancer), 4.1 months (pancreatic cancer metastatic to liver) and 4.0 months (leiomyosarcoma metastatic to liver). CONCLUSION: Cancer-related frequencies appear to be tumor-specific and treatment with tumor-specific frequencies is feasible, well tolerated and may have biological efficacy in patients with advanced cancer. J Ethnopharmacol. 2009 Jun 22;123(2):293-301. Epub 2009 Mar 24.

Induction of apoptosis in human hepatocarcinoma SMMC-7721 cells in vitro by flavonoids from Astragalus complanatus.

Hu YW, Liu CY, Du CM, Zhang J, Wu WQ, Gu ZL. 

Department of Pharmacology, Medical College of Soochow University, 199 RenAi Road, Suzhou 215123, PR China. 

Abstract

AIM OF THE STUDY: Flavonoids extracted from the seeds of Astragalus complanatus R.Br. reduce the proliferation of many cancer cells. The present study was carried out to evaluate the effects of these flavonoids from Astragalus complanatus (FAC) on human hepatocarcinoma cell viability and apoptosis and to investigate its mechanisms of action in SMMC-7721 cells. 

MATERIALS AND METHODS: Cell viability was measured using the MTT assay. To detect apoptotic cells, SMMC-7721 cells treated with FAC were stained with Hoechst 33258 and subjected to agarose gel electrophoresis. Quantitative detection of apoptotic cells was performed by flow cytometry. The effects of FAC on apoptosis and cell cycle regulatory genes and proteins in SMMC-7721 cells were examined using an S series apoptosis and cell cycle gene array and Western blot analysis. 

RESULTS: The growth of SMMC-7721 and HepG2 cells was inhibited by treatment with FAC. Cell death induced by FAC was characterized by nuclear condensation and DNA fragmentation. Moreover, the cell cycle was arrested in the G0/G1 and S phases in FAC-treated SMMC-7721 cells. A sub-G1 peak with reduced DNA content was also formed. The activity of caspase-3 was significantly increased following FAC treatment. Microarray data indicated that the expression levels of 76 genes were changed in SMMC-7721 cells treated with FAC: 35 genes were up-regulated and 41 were down-regulated. Western blot analysis showed that caspase-3, caspase-8, Bax, P21, and P27 protein levels in SMMC-7721 cells were increased after 48 h of FAC treatment, while cyclinB1, cyclinD1, CDK1, and CDK4 protein levels were decreased. 

CONCLUSIONS: These results suggest that FAC may play an important role in tumor growth suppression by inducing apoptosis in human hepatocarcinoma cells via mitochondria-dependent and death receptor-dependent apoptotic pathways. 

Anticancer Res. 2008 Jul-Aug;28(4B):2245-51. 

Effect of steep pulsed electric field on proliferation, viscoelasticity and adhesion of human hepatoma SMMC-7721 cells.

Song G, Qin J, Yao C, Ju Y. 

Department of Bioengineering, College of Bioengineering, Ministry of Education of China, Chongqing University, Chongqing, PR China. 

song@cqu.edu.cn 

Abstract 

It has been proven that steep pulsed electric field (SPEF) can directly kill tumor cells and plays an important role in anticancer treatment. The biorheological mechanisms, however, that destroy tumor cells are almost unknown. To resolve this issue, here, an SPEF generator was used to assess the effects of high- and low-dose SPEF on the proliferation of human hepatoma SMMC-7721 cells by MTT assay, and on the viscoelasticity, adhesion of SMMC-7721 cells to endothelial cells by micropipette aspiration technique. Viability and proliferation of SPEF-treated SMMC-7721 cells were significantly inhibited. Cell cycle analysis indicated that SPEF arrested the cell cycle progression of SMMC-7721 cells at the G0/G1 transition to the S-phase. Viscoelastic data fitted by a standard linear solid model showed that viscoelasticity of SMMC-7721 cells changed after treatment with SPEF. Moreover, the adhesive force of low-dose SPEF-treated SMMC-7721 cells to endothelial cells markedly decreased compared to that of control cells. These results suggest that the suppressant effects of SPEF on the proliferation of SMMC-7721 cells appeared to be mediated, at least in part, through arresting cell cycle progression and altering the viscoelastic and adhesive properties of the cells, which provides a novel biorheological mechanism for the antitumor therapy of SPEF.

  The Effect of Intense Subnanosecond Electrical Pulses on Biological Cells Schoenbach, K.H. Shu Xiao Joshi, R.P. Camp, J.T. Heeren, T. Kolb, J.F. Beebe, S.J.
Old Dominion Univ., Norfolk;  This paper appears in: Plasma Science, IEEE Transactions on
Publication Date: April 2008
Volume: 36, Issue: 2, Part 1
On page(s): 414-422
Location: Eindhoven, Netherlands,
ISSN: 0093-3813
INSPEC Accession Number: 9921271
Digital Object Identifier: 10.1109/TPS.2008.918786
Current Version Published: 2008-04-08        AbstractNanosecond electrical pulses have been successfully used to treat melanoma tumors by using needle arrays as pulse delivery systems. Reducing the pulse duration of intense electric field pulses from nanoseconds into the subnanosecond range will allow us to use wideband antennas to deliver the electromagnetic fields into tissue with a spatial resolution in the centimeter range. To explore the biological effect of intense subnanosecond pulses, we have developed a generator that provides voltage pulses of 160 kV amplitude, 200 ps rise time, and 800 ps pulse width. The pulses are delivered to a cylindrical Teflon chamber with polished flat electrodes at either end. The distance between the electrodes is variable and allows us to generate electric fields of up to 1 MV/cm in cell suspensions. The pulses have been applied to B16 (murine melanoma) cells, and the plasma membrane integrity was studied by means of trypan blue exclusion. For pulse amplitudes of 550 kV/cm, approximately 50% of the cells took up trypan blue right after pulsing, whereas only 20% were taking it up after 1 h. This indicates that the plasma membrane in a majority of the cells affected by the pulses recovers with a time constant of about 1 h. The cells that show trypan blue uptake after this time suffer cell death through apoptosis. Evaluation of the experimental results and molecular dynamics modeling results indicate that with a pulse duration of 800 ps, membrane charging and nanopore formation are the dominant bioelectric effects on B16 cells. This information has been used in a continuum model to estimate the increase in membrane permeability and, consequently, the increase in pore size caused by repetitive pulsing.

Conf Proc IEEE Eng Med Biol Soc. 2008;2008:1044-7. 

Experiment and mechanism research of SKOV3 cancer cell apoptosis induced by nanosecond pulsed electric field.

Yao C, Mi Y, Hu X, Li C, Sun C, Tang J, Wu X. 

State Key Laboratory of Power Transmission Equipment & System Security and New Technology, Chongqing University, Chongqing 400044, China. 

Abstract 

This paper studies the apoptosis of human ovarian carcinoma cell Line (SKOV3) induced by the nanosecond pulsed electric field (10kV/cm, 100ns, 1 Hz) and its effect on intracellular calcium concentration ([Ca2+]i). These cells were doubly marked by Annexin V-FITC/PI, and the apoptosis rate was analyzed with flow cytometry. After AO/EB staining the morphological changes were observed under fluorescent microscope, and their ultrastructural changes were observed under scanning electron microscope (SEM). With Fluo-3/AM as calcium fluorescent marker, laser scanning confocal microscope (LSCM) was used to detect the effect of nsPEF on [Ca2+]i and the source of Ca2+. The results showed that the early apoptosis rate of the treatment group was (22.21+/-2.71)%, significantly higher than that of the control group (3.04+/-0.44)% (P<0.01). The typical features of apoptotic cell have been observed by fluorescent microscope and SEM. It is proved that nsPEF can induce apoptosis of SKOV3 cells and result in distinct increase in [Ca2+]i (P0.01), which was independent of extracellular calcium concentration (P>0.05). Since nsPEF can penetrate cell membrane due to its high frequency components, one of the mechanisms of nsPEF-induced apoptosis may be that activating intracellular calcium stores can increase the [Ca2+]i, and consequently, the apoptotic signal pathway can be induced. 

Apoptosis. 2007 Sep;12(9):1721-31. 

Nanosecond pulsed electric fields induce apoptosis in p53-wildtype and p53-null HCT116 colon carcinoma cells.

Hall EH, Schoenbach KH, Beebe SJ. 

Center for Pediatric Research, Children’s Hospital of the King’s Daughters, Department of Physiological Sciences, Eastern Virginia Medical School, PO Box 1980, Norfolk, VA 23501-1980, USA. 

Abstract 

Non-ionizing radiation produced by nanosecond pulsed electric fields (nsPEFs) is an alternative to ionizing radiation for cancer treatment. NsPEFs are high power, low energy (non-thermal) pulses that, unlike plasma membrane electroporation, modulate intracellular structures and functions. To determine functions for p53 in nsPEF-induced apoptosis, HCT116p53(+/+) and HCT116p53(-/-) colon carcinoma cells were exposed to multiple pulses of 60 kV/cm with either 60 ns or 300 ns durations and analyzed for apoptotic markers. Several apoptosis markers were observed including cell shrinkage and increased percentages of cells positive for cytochrome c, active caspases, fragmented DNA, and Bax, but not Bcl-2. Unlike nsPEF-induced apoptosis in Jurkat cells (Beebe et al. 2003a) active caspases were observed before increases in cytochrome c, which occurred in the presence and absence of Bax. Cell shrinkage occurred only in cells with increased levels of Bax or cytochrome c. NsPEFs induced apoptosis equally in HCT116p53(+/+) and HCT116p53(-/-) cells. These results demonstrate that non-ionizing radiation produced by nsPEFs can act as a non-ligand agonist with therapeutic potential to induce apoptosis utilizing mitochondrial-independent mechanisms in HCT116 cells that lead to caspase activation and cell death in the presence or absence of p-53 and Bax.  Hell J Nucl Med. 2007 May-Aug;10(2):95-101.

Anticancer effects on leiomyosarcoma-bearing Wistar rats after electromagnetic radiation of resonant radiofrequencies.

Avdikos A, Karkabounas S, Metsios A, Kostoula O, Havelas K, Binolis J, Verginadis I, Hatziaivazis G, Simos I, Evangelou A. 

Source 

Laboratory of Physiology, Unit of Environmental Physiology, Faculty of Medicine, University of Ioannina, Greece. 

Abstract 

In the present study, the effects of a resonant low intensity static electromagnetic field (EMF), causing no thermal effects, on Wistar rats have been investigated. Sarcoma cell lines were isolated from leiomyosarcoma tumors induced in Wistar rats by the subcutaneous (s.c) injection of 3,4-benzopyrene. Furthermore, smooth muscle cells (SMC) were isolated from the aorta of Wistar rats and cultivated. Either leiomyosarcoma cells (LSC) or SMC were used to record a number of characteristic resonant radiofrequencies, in order to determine the specific electromagnetic fingerprint spectrum for each cell line. These spectra were used to compose an appropriate algorithm, which transforms the recorded radiofrequencies to emitted ones. The isolated LSC were cultured and then exposed to a resonant low intensity radiofrequency EMF (RF-EMF), at frequencies between 10 kHz to 120 kHz of the radiowave spectrum. The exposure lasted 45 consecutive minutes daily, for two consecutive days. Three months old female Wistar rats were inoculated with exposed and non-exposed to EMF LSC (4 x 10(6) LCS for animal). Inoculated with non-exposed to EMF cells animals were then randomly separated into three Groups. The first Group was sham exposed to the resonant EMF (control Group-CG), the second Group after the inoculation of LSC and appearance of a palpable tumor mass, was exposed to a non-resonant EMF radiation pattern, for 5 h per day till death of all animals (experimental control Group-ECG). The third Group of animals after inoculation of LSC and the appearance of a palpable tumor mass, was exposed to the resonant EMF radiation for 5 h per day, for a maximum of 60 days (experimental Group-I, EG-I). A fourth Group of animals was inoculated with LSC exposed to EMF irradiation and were not further exposed to irradiation (experimental Group-II, EG-II). Tumor induction was 100% in all Groups studied and all tumors were histologically identified as leiomyosarcomas. In the case of the EG-I, a number of tumors were completely regretted (final tumor induction: 66%). Both Groups of animals inoculated with exposed or non-exposed to the EMF LSC, (EG-I and EG-II, respectively) demonstrated a significant prolongation of the survival time and a lower tumor growth rate, in comparison to the control Group (CG) and the experimental control Group (ECG). However, the survival time of EG-I animals was found to be significantly longer and tumor growth rate significantly lower compared to EG-II animals. In conclusion, our results indicate a specific anticancer effect of resonant EMF irradiation. These results may possibly be attributed to (a) the duration of exposure of LSC and (b) the exposure of the entire animal to this irradiation. 

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007 Feb;24(1):230-4. 

Biological effects and their applications in medicine of pulsed electric fields.

[Article in Chinese] 

Huang H, Song G, Wang G, Sun C. 

Key Laboratory for Biomnechanics & Tissue Engineering of the State Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China. 

Abstract

Pulsed electric fields can induce various kinds of biological effects that are essentially different from the normal electric fields, especially the interactions of Nanosecond Pulsed electric field (nsPEF) with cells. The biological effects of different pulsed electric fields on cell membranes, cytoplasmic matrixes, cell growth are introduced in this paper. Based on these effects, some applications of pulsed electric fields in cancer therapy, gene therapy, and delivery of drugs are reviewed in details. 

Biochem Biophys Res Commun. 2006 May 5;343(2):351-60. Epub 2006 Mar 10. 

Nanosecond pulsed electric fields cause melanomas to self-destruct.

Nuccitelli R, Pliquett U, Chen X, Ford W, James Swanson R, Beebe SJ, Kolb JF, Schoenbach KH. 

Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA. yaochenguo@cqu.edu.cn 

Abstract

We have discovered a new, drug-free therapy for treating solid skin tumors. Pulsed electric fields greater than 20 kV/cm with rise times of 30 ns and durations of 300 ns penetrate into the interior of tumor cells and cause tumor cell nuclei to rapidly shrink and tumor blood flow to stop. Melanomas shrink by 90% within two weeks following a cumulative field exposure time of 120 micros. A second treatment at this time can result in complete remission. This new technique provides a highly localized targeting of tumor cells with only minor effects on overlying skin. Each pulse deposits 0.2 J and 100 pulses increase the temperature of the treated region by only 3 degrees C, ten degrees lower than the minimum temperature for hyperthermia effects. 

Bioelectromagnetics. 2006 May;27(4):258-64. 

Effect of millimeter wave irradiation on tumor metastasis.

Logani MK, Szabo I, Makar V, Bhanushali A, Alekseev S, Ziskin MC. 

Richard J. Fox Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, PA 19140, USA. mlogani@temple.edu 

Abstract

One of the major side effects of chemotherapy in cancer treatment is that it can enhance tumor metastasis due to suppression of natural killer (NK) cell activity. The present study was undertaken to examine whether millimeter electromagnetic waves (MMWs) irradiation (42.2 GHz) can inhibit tumor metastasis enhanced by cyclophosphamide (CPA), an anticancer drug. MMWs were produced with a Russian-made YAV-1 generator. Peak SAR and incident power density were measured as 730 +/- 100 W/kg and 36.5 +/- 5 mW/cm(2), respectively. Tumor metastasis was evaluated in C57BL/6 mice, an experimental murine model commonly used for metastatic melanoma. The animals were divided into 5 groups, 10 animals per group. The first group was not given any treatment. The second group was irradiated on the nasal area with MMWs for 30 min. The third group served as a sham control for group 2. The fourth group was given CPA (150 mg/kg body weight, ip) before irradiation. The fifth group served as a sham control for group 4. On day 2, all animals were injected, through a tail vein, with B16F10 melanoma cells, a tumor cell line syngeneic to C57BL/6 mice. Tumor colonies in lungs were counted 2 weeks following inoculation. CPA caused a marked enhancement in tumor metastases (fivefold), which was significantly reduced when CPA-treated animals were irradiated with MMWs. Millimeter waves also increased NK cell activity suppressed by CPA, suggesting that a reduction in tumor metastasis by MMWs is mediated through activation of NK cells. 

Bioelectromagnetics. 2006 Apr;27(3):226-32. 

Effect of extremely low frequency electromagnetic fields (ELF-EMF) on Kaposi’s sarcoma-associated herpes virus in BCBL-1 cells.

Pica F, Serafino A, Divizia M, Donia D, Fraschetti M, Sinibaldi-Salimei P, Giganti MG, Volpi A. 

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy. 

pica@uniroma2.it 

Abstract

Association between extremely low frequency electromagnetic fields (ELF-EMF) and human cancers is controversial, and few studies have been conducted on their influence on oncogenic viruses. We studied the effects of 1 mT, 50 Hz sine waves, applied for 24-72 h, on Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV or HHV-8) in BCBL-1, a latently infected primary effusion lymphoma (PEL) cell line. ELF-EMF exposure did not affect the growth and viability of BCBL-1 cells, either stimulated or not with TPA. The total amount of KSHV DNA detected in ELF-EMF exposed cultures not stimulated with TPA did not differ from that of the unexposed controls (P = ns). However, in the presence of TPA stimulation, total KSHV DNA content was found higher in ELF-EMF exposed than in control BCBL-1 cultures (P = .024) at 72 h exposure, but not earlier. Viral DNA increase significantly correlated with increased mean fluorescence intensity/cell for the lytic antigen gp K8.1A/B (P < .01), but not with percentage of gp K8.1A/B-positive cells or of cells containing virions. Viral progeny produced under ELF-EMF exposure consisted mainly of defective viral particles. 

Conf Proc IEEE Eng Med Biol Soc. 2006;1:6370-2. 

Outlook for the use of focused shock waves and pulsed electric fields in the complex treatment of malignant neoplasms.

Garilevich BA, Andrianov YV, Olefir YV, Zubkov AD, Rotov AE. 

Central Air Force Clinical Hosp., Moscow, Russia. 

medic-air@mtu-net.ru 

Abstract

The experimental studies the synchronous action of electric field microsecond range with amplitude within the range of 1-7 kV/sm and shock waves with pressure before 100 MPa on cells membrane permeability of the mouse’s ascitic tumors in vitro have shown the intensification the efficiency of the forming the irreversible pores under synchronous action. Thereby, enabling the electric field in the compression phase of shock wave pulse which can essentially reduce the electric field intensity required for breakdown cell membrane. In usual condition at amplitude of electric field, specified above, electric breakdown membrane carries basically reversible nature. At the same time in the pressure field tension phase of shock-wave pulse reversible pores, created by electric field, can grow before sizes, under which wholeness membrane is not restored. Under simultaneous action on cellular suspension the shock wave and electric field with moderate intensity cells survival is reduced in 5 once in contrast with occuring at different time’s action, and in 10 once in contrast with checking. The most sensitive to influence by under study fields are cells in phase of the syntheses DNA, preparation to fission and in phase of the mitosis. Thereby, continuation of the studies on use synchronous action shock waves and pulsed electric fields in complex treatment of the tumors introduces perspectiv 

Bioelectromagnetics. 2006 Jan;27(1):64-72. 

Effects of pulsed magnetic stimulation on tumor development and immune functions in mice.

Yamaguchi S, Ogiue-Ikeda M, Sekino M, Ueno S. 

Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Japan. 

chikko@medes.m.u-tokyo.ac.jp 

Abstract

We investigated the effects of pulsed magnetic stimulation on tumor development processes and immune functions in mice. A circular coil (inner diameter = 15 mm, outer diameter = 75 mm) was used in the experiments. Stimulus conditions were pulse width = 238 micros, peak magnetic field = 0.25 T (at the center of the coil), frequency = 25 pulses/s, 1,000 pulses/sample/day and magnetically induced eddy currents in mice = 0.79-1.54 A/m(2). In an animal study, B16-BL6 melanoma model mice were exposed to the pulsed magnetic stimulation for 16 days from the day of injection of cancer cells. A tumor growth study revealed a significant tumor weight decrease in the stimulated group (54% of the sham group). In a cellular study, B16-BL6 cells were also exposed to the magnetic field (1,000 pulses/sample, and eddy currents at the bottom of the dish = 2.36-2.90 A/m(2)); however, the magnetically induced eddy currents had no effect on cell viabilities. Cytokine production in mouse spleens was measured to analyze the immunomodulatory effect after the pulsed magnetic stimulation. tumor necrosis factor (TNF-alpha) production in mouse spleens was significantly activated after the exposure of the stimulus condition described above. These results showed the first evidence of the anti-tumor effect and immunomodulatory effects brought about by the application of repetitive magnetic stimulation and also suggested the possible relationship between anti-tumor effects and the increase of TNF-alpha levels caused by pulsed magnetic stimulation. 

Clin Cancer Res. 2005 Oct 1;11(19 Pt 2):7093s-7103s. 

Application of high amplitude alternating magnetic fields for heat induction of nanoparticles localized in cancer.

Ivkov R, DeNardo SJ, Daum W, Foreman AR, Goldstein RC, Nemkov VS, DeNardo GL. 

Triton BioSystems, Inc., Chelmsford, Massachusetts 01824, USA. rivkov@tritonbiosystems.com 

Abstract

OBJECTIVE: Magnetic nanoparticles conjugated to a monoclonal antibody can be i.v. injected to target cancer tissue and will rapidly heat when activated by an external alternating magnetic field (AMF). The result is necrosis of the microenvironment provided the concentration of particles and AMF amplitude are sufficient. High-amplitude AMF causes nonspecific heating in tissues through induced eddy currents, which must be minimized. In this study, application of high-amplitude, confined, pulsed AMF to a mouse model is explored with the goal to provide data for a concomitant efficacy study of heating i.v. injected magnetic nanoparticles. 

METHODS: Thirty-seven female BALB/c athymic nude mice (5-8 weeks) were exposed to an AMF with frequency of 153 kHz, and amplitude (400-1,300 Oe), duration (1-20 minutes), duty (15-100%), and pulse ON time (2-1,200 seconds). Mice were placed in a water-cooled four-turn helical induction coil. Two additional mice, used as controls, were placed in the coil but received no AMF exposure. Tissue and core temperatures as the response were measured in situ and recorded at 1-second intervals. 

RESULTS: No adverse effects were observed for AMF amplitudes of < or = 700 Oe, even at continuous power application (100% duty) for up to 20 minutes. Mice exposed to AMF amplitudes in excess of 950 Oe experienced morbidity and injury when the duty exceeded 50%. 

CONCLUSION: High-amplitude AMF (up to 1,300 Oe) was well tolerated provided the duty was adjusted to dissipate heat. Results presented suggest that further tissue temperature regulation can be achieved with suitable variations of pulse width for a given amplitude and duty combination. These results suggest that it is possible to apply high-amplitude AMF (> 500 Oe) with pulsing for a time sufficient to treat cancer tissue in which magnetic nanoparticles have been embedded. 

Anticancer Res. 2005 Mar-Apr;25(2A):1023-8. 

Frequency and irradiation time-dependant antiproliferative effect of low-power millimeter waves on RPMI 7932 human melanoma cell line.

Beneduci A, Chidichimo G, De Rose R, Filippelli L, Straface SV, Venuta S. 

Department of Chemistry, University of Calabria, 87036 Arcavacata di Rende (CS), Italy. beneduci@unical.it 

Abstract

The biological effects produced by low power millimeter waves (MMW) were studied on the RPMI 7932 human melanoma cell line. Three different frequency-type irradiation modes were used: the 53.57-78.33 GHz wide-band frequency range, the 51.05 GHz and the 65.00 GHz monochromatic frequencies. In all three irradiation conditions, the radiation energy was low enough not to increase the temperature of the cellular samples. Three hours of radiation treatment, applied every day to the melanoma cell samples, were performed at each frequency exposure condition. The wide-band irradiation treatment effectively inhibited cell growth, while both the monochromatic irradiation treatments did not affect the growth trend of RPMI 7932 cells. A light microscopy analysis revealed that the low-intensity wide-band millimeter radiation induced significant morphological alterations on these cells. Furthermore, a histochemical study revealed the low proliferative state of the irradiated cells. This work provides further evidence of the antiproliferative effects on tumor cells induced by low power MMW in the 50-80 GHz frequency range of the electromagnetic spectrum. 

Bioelectromagnetics. 2005 Jan;26(1):10-9. 

Effect of millimeter waves on natural killer cell activation.

Makar VR, Logani MK, Bhanushali A, Kataoka M, Ziskin MC. 

Richard J Fox Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, PA 19140, USA. 

Abstract

Millimeter wave therapy (MMWT) is being widely used for the treatment of many diseases in Russia and other East European countries. MMWT has been reported to reduce the toxic effects of chemotherapy on the immune system. The present study was undertaken to investigate whether millimeter waves (MMWs) can modulate the effect of cyclophosphamide (CPA), an anticancer drug, on natural killer (NK) cell activity. NK cells play an important role in the antitumor response. MMWs were produced with a Russian-made YAV-1 generator. The device produced modulated 42.2 +/- 0.2 GHz radiation through a 10 x 20 mm rectangular output horn. Mice, restrained in plastic tubes, were irradiated on the nasal area. Peak SAR at the skin surface and peak incident power density were measured as 622 +/- 100 W/kg and 31 +/- 5 mW/cm2, respectively. The maximum temperature elevation, measured at the end of 30 min, was 1 degrees C. The animals, restrained in plastic tubes, were irradiated on the nasal area. CPA injection (100 mg/kg) was given intraperitoneally on the second day of 3-days exposure to MMWs. All the irradiation procedures were performed in a blinded manner. NK cell activation and cytotoxicity were measured after 2, 5, and 7 days following CPA injection. Flow cytometry of NK cells showed that CPA treatment caused a marked enhancement in NK cell activation. The level of CD69 expression, which represents a functional triggering molecule on activated NK cells, was increased in the CPA group at all the time points tested as compared to untreated mice. However, the most enhancement in CD69 expression was observed on day 7. A significant increase in TNF-alpha level was also observed on day 7 following CPA administration. On the other hand, CPA caused a suppression of the cytolytic activity of NK cells. MMW irradiation of the CPA treated groups resulted in further enhancement of CD69 expression on NK cells, as well as in production of TNF-alpha. Furthermore, MMW irradiation restored CPA induced suppression of the cytolytic activity of NK cells. Our results show that MMW irradiation at 42.2 GHz can up-regulate NK cell functions. 

Bioelectromagnetics. 2004 Oct;25(7):516-23. 

Combined millimeter wave and cyclophosphamide therapy of an experimental murine melanoma.

Logani MK, Bhanushali A, Anga A, Majmundar A, Szabo I, Ziskin MC. 

Richard J. Fox Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. 

mlogani@temple.edu 

Abstract

The objective of the present studies was to investigate whether millimeter wave (MMW) therapy can increase the efficacy of cyclophosphamide (CPA), a commonly used anti-cancer drug. The effect of combined MMW-CPA treatment on melanoma growth was compared to CPA treatment alone in a murine model. MMWs were produced with a Russian made YAV-1 generator. The device produced 42.2 +/- 0.2 GHz modulated wave radiation through a 10 x 20 mm rectangular output horn. The animals, SKH-1 hairless female mice, were irradiated on the nasal area. Peak SAR and incident power density were measured as 730 +/- 100 W/kg and 36.5 +/- 5 mW/cm2, respectively. The maximum skin surface temperature elevation measured at the end of 30 min irradiation was 1.5 degrees C. B16F10 melanoma cells (0.2 x 10(6)) were implanted subcutaneously into the left flank of mice on day 1 of the experiment. On days 4-8, CPA was administered intraperitoneally (30 mg/kg/day). MMW irradiation was applied concurrently with, prior to or following CPA administration. A significant reduction (P < .05) in tumor growth was observed with CPA treatment, but MMW irradiation did not provide additional therapeutic benefit as compared to CPA alone. Similar results were obtained when MMW irradiation was applied both prior to and following CPA treatment. 

Biofizika. 2004 May-Jun;49(3):545-50. 

A comparison of the effects of millimeter and centimeter waves on tumor necrosis factor production in mouse cells.

[Article in Russian] 

Sinotova OA, Novoselova EG, Glushkova OV, Fesenko EE. 

Abstract

The effects of millimeter (40 GHz) and centimeter (8.15-18.00 GHz) low-intensity waves on the production of tumor necrosis factor (TNE) in macrophages and lymphocytes from exposed mice as well as in exposed isolated cells were compared. It was found that the dynamics of TNF secretory activity of cells varies depending on the frequency and duration of exposure. The application of millimeter waves induced a nonmonotonous course of the dose-effect curve for TNF changes in macrophages and splenocytes. Alternately, a stimulation and a decrease in TNF production were observed following the application of millimeter waves. On the contrary, centimeter waves provoked an activation in cytokine production. It is proposed that, in contrast to millimeter waves, the single application of centimeter waves to animals (within 2 to 96 h) or isolated cells (within 0.5 to 2.5 h) induced a much more substantial stimulation of immunity. 

Bioelectromagnetics. 2004 Oct;25(7):503-7. 

Differences in lethality between cancer cells and human lymphocytes caused by LF-electromagnetic fields.

Radeva M, Berg H. 

Labor Bioelectrochemistry (Campus Beutenberg, Jena) of the Saxonian Academy of Sciences, Leipzig, Germany. 

Abstract

The lethal response of cultured cancer cells lines K-562, U-937, DG-75, and HL-60 were measured directly after a 4 h exposure to a pulsating electromagnetic field (PEMF, sinusoidal wave form, 35 mT peak, 50 Hz) [Traitcheva et al. (2003): Bioelectromagnetics 24:148-158] and 24 h later, to determine the post-exposure effect. The results were found to depend on the medium, pH value, conductivity, and temperature. From these experiments, suitable conditions were chosen to compare the vitality between K-562 cells and normal human lymphocytes after PEMF treatment and photodynamic action. Both agents enhance necrosis synergistically for diseased as well as for healthy cells, but the lymphocytes are more resistant. The efficacy of PEMF on the destruction of cancer cells is further increased by heating (hyperthermia) of the suspension up to 44 degrees C or by lowering the pH-value (hyperacidity) to pH 6.4. Similar apoptosis and necrosis can be obtained using moderate magnetic fields (B < or = 15 mT 50/60 Hz), but this requires longer treatment of at least over a week. PEMF application combined with anticancer drugs and photodynamic therapy will be very effective. 

Bioelectromagnetics. 2004 Sep;25(6):466-73. 

Millimeter wave-induced suppression of B16 F10 melanoma growth in mice: involvement of endogenous opioids.

Radzievsky AA, Gordiienko OV, Szabo I, Alekseev SI, Ziskin MC. 

Center for Biomedical Physics, Temple University Medical School, Philadelphia, Pennsylvania 19140, USA. aradziev@temple.edu 

Abstract

Millimeter wave treatment (MMWT) is widely used in Eastern European countries, but is virtually unknown in Western medicine. Among reported MMWT effects is suppression of tumor growth. The main aim of the present “blind” and dosimetrically controlled experiments was to evaluate quantitatively the ability of MMWT to influence tumor growth and to assess whether endogenous opioids are involved. The murine experimental model of B16 F10 melanoma subcutaneous growth was used. MMWT characteristics were: frequency, 61.22 GHz; average incident power density, 13.3 x 10(-3) W/cm2; single exposure duration, 15 min; and exposure area, nose. Naloxone (1 mg/kg, intraperitoneally, 30 min prior to MMWT) was used as a nonspecific blocker of opioid receptors. Five daily MMW exposures, if applied starting at the fifth day following B16 melanoma cell injection, suppressed subcutaneous tumor growth. Pretreatment with naloxone completely abolished the MMWT-induced suppression of melanoma growth. The same course of 5 MMW treatments, if started on day 1 or day 10 following tumor inoculations, was ineffective. We concluded that MMWT has an anticancer therapeutic potential and that endogenous opioids are involved in MMWT-induced suppression of melanoma growth in mice. However, appropriate indications and contraindications have to be developed experimentally before recommending MMWT for clinical usage. 

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2004 Aug;21(4):546-8. 

Effects of steep pulsed electric fields on cancer cell proliferation and cell cycle.

[Article in Chinese] 

Yao C, Sun C, Mi Y, Xiong L, Hu L, Hu Y. 

Key Lab of High Voltage Engineering and Electrical New Technology, Ministry of Education, Chongqing University, Chongqing 400044, China. 

Abstract

To assess study the cytocidal and inhibitory effects of steep pulsed electric fields (SPEFs) on ovarian cancer cell line SKOV3, the cancer cell suspension was treated by SPEFs with different parameters (frequency, pulse duration, peak value of voltage). Viability rate and growth curves of two test groups (high dosage and low dosage of SPEFs) and one control group were also measured. The DNA contents and cell cycle were analyzed by flow cytometry (FCM). Different dosing levels of SPEFs exerted obviously different effects on cancer cell viability. With the enhancement of each pulse parameter, the viability rate was promoted and the inhibitory effect on the proliferation of treated cells was more evident. The cells exposed to SPEFs grew slower than the control. The ratio of S+G2/M phase cells was decreased, which restrained the DNA synthesis and division, but the ratio of G0/G1 phase cells was increased in the treated groups. It was also indicated that the SPEFs blocked the cell transition from G0/G1 phase to S+G2/M phase. There was a significant difference in cell cycle between treated group and control group (P<0.01). Lethal effects of SPEFs were represented by inhibiting the cancer cell proliferation at the cell level and by influencing the cell cycle at the DNA level.

Physiol Meas. 2004 Aug;25(4):1077-93.

Nanosecond pulsed electric fields modulate cell function through intracellular signal transduction mechanisms.

Beebe SJ, Blackmore PF, White J, Joshi RP, Schoenbach KH. 

Center for Pediatric Research, Eastern Virginia Medical School, Children’s Hospital for The King’s Daughters, Norfolk, VA, USA. sbeebe@chkd.com 

These studies describe the effects of nanosecond (10-300 ns) pulsed electric fields (nsPEF) on mammalian cell structure and function. As the pulse durations decrease, effects on the plasma membrane (PM) decrease and effects on intracellular signal transduction mechanisms increase. When nsPEF-induced PM electroporation effects occur, they are distinct from classical PM electroporation effects, suggesting unique, nsPEF-induced PM modulations. In HL-60 cells, nsPEF that are well below the threshold for PM electroporation and apoptosis induction induce effects that are similar to purinergic agonistmediated calcium release from intracellular stores, which secondarily initiate capacitive calcium influx through store-operated calcium channels in the PM. NsPEF with durations and electric field intensities that do or do not cause PM electroporation, induce apoptosis in mammalian cells with a well-characterized phenotype typified by externalization of phosphatidylserine on the outer PM and activation of caspase proteases. Treatment of mouse fibrosarcoma tumors with nsPEF also results in apoptosis induction. When Jurkat cells were transfected by electroporation and then treated with nsPEF, green fluorescent protein expression was enhanced compared to electroporation alone. The results indicate that nsPEF activate intracellular mechanisms that can determine cell function and fate, providing an important new tool for probing signal transduction mechanisms that modulate cell structure and function and for potential therapeutic applications for cancer and gene therapy.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2004 Jun;21(3):433-5.

Effect of steep pulsed electric fields on survival of tumour-bearing mice.

[Article in Chinese] 

Yao C, Sun C, Xiong L, Mi Y, Liao R, Hu L, Hu Y. 

College of Electrical Engineering, Chongqing University, Chongqing, 400044, China. 

To investigate the lethal effect of steep pulsed electric fields (SPEFs) on cancer cells and the life-prolonging effect of SPEFs on the survival of tumour-bearing mice, this study was carried out with the use of SPEFs to treat 40 BALB/C mice inoculated by cervical cancer. The lethal effect on cancer cells and the life-prolonging effect on tumour-bearing mice were examined and compared between the experiment group and control group. The survival periods of the experiment group and control group were 52.05 days and 33.03 days, respectively. There was a significant difference in survival curve between the two groups. The results confirmed the inhibitiory effect and lethal effect of SPEFs on cancer cells. SPEFs can prolong the survival period of tumour-bearing mice.

Ann Biomed Eng. 2003 Jan;31(1):80-90.

Viability of cancer cells exposed to pulsed electric fields: the role of pulse charge.

Krassowska W, Nanda GS, Austin MB, Dev SB, Rabussay DP. 

Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA. wanda.krassowska@duke.edu 

The goal of this study was to collect a comprehensive set of data that related lethal effects of electric fields to the duration of the pulse. Electric pulses of different strengths and durations were applied to a suspension of HEp-2 cells (epidermoid carcinoma of the human larynx) using a six-needle electrode array connected through an autoswitcher to a square wave generator. Pulse durations varied from 50 micros to 16 ms and the ranges of electric field were adjusted for each duration to capture cell viabilities between 0% and 100%. After pulsation, cells were incubated for 44 h at 37 degrees C, and their viability was measured spectrophotometrically using an XTT assay. For each pulse duration (d), viability data were used to determine the electric field that killed half of the cells (E50). When plotted on logarithmic axes, E50 vs. d was a straight line, leading to a hyperbolic relationship: E50=const/d. This relationship suggests that the total charge delivered by the pulse is the decisive factor in killing HEp-2 cells.

Vopr Onkol. 2003;49(6):748-51.

Experience with turbulent magnetic field as a component of breast cancer therapy.

[Article in Russian] 

Letiagin VP, Protchenko NV, Rybakov IuL, Dobrynin IaV. 

N.N. Blokhin Center for Oncology Research, Russian Academy of Medical Sciences, Zdorovje Research Center, Moscow. 

No adverse side-effects were reported in an investigation of the antitumor effect of turbulent magnetic field (TMF) carried out as a component of preoperative chemoradiotherapy for breast cancer at the Center’s Clinic. The study group included 114 patients with locally advanced tumors(T3, N1-N3, M0). According to the clinical, roentgenological and histological evidence on the end-results, the procedure was highly effective. Also, it was followed by shorter and less extensive postoperative lymphorrhea. 

Bioelectromagnetics. 2003 Feb;24(2):148-50. 

ELF fields and photooxidation yielding lethal effects on cancer cells.

Traitcheva N, Angelova P, Radeva M, Berg H. 

Laboratory of Bioelectrochemistry, Institute of Virology, FSU, Jena, Germany. 

Abstract

The lethal effect on human cancer cells was studied under three types of treatment: A) an ELF pulsed sinusoidal of 50 Hz electromagnetic field (PEMF) with amplitudes between 10 and 55 mT; B) the field and a cytostatic agent (actinomycin-C); and C) the field, the cytostatic agent, which has a photodynamic effect, and exposure to a halogen lamp. The results show a decreasing vitality of human K-562 and U-937 cancer cells in suspension with each additional treatment. Combination with other parameters as hyperthermia and/or hyperacidity could yield high killing rates by this noninvasive method. 

Technol Cancer Res Treat. 2002 Feb;1(1):71-82. 

Enhancing the effectiveness of drug-based cancer therapy by electroporation (electropermeabilization).

Rabussay DP, Nanda GS, Goldfarb PM. 

Genetronics, Inc., 11199 Sorrento Valley Road, San Diego CA 92121, USA. dietmarr@genetronics.com 

Abstract

Many conventional chemotherapeutic drugs, as well as DNA for cancer gene therapy, require efficient access to the cell interior to be effective. The cell membrane is a formidable barrier to many of these drugs, including therapeutic DNA constructs. Electropermeabilization (EP, often used synonymously with “electroporation”) has become a useful method to temporarily increase the permeability of the cell membrane, allowing a broad variety of molecules efficient access to the cell interior. EP is achieved by the application of short electrical pulses of relatively high local field strength to the target tissue of choice. In cancer therapy, EP can be applied in vivo directly to the tumor to be treated, in order to enhance intracellular uptake of drugs or DNA. Alternatively, EP can be used to deliver DNA into cells of healthy tissue to achieve longer-lasting expression of cancer-suppressing genes. In addition, EP has been used in ex vivo therapeutic approaches for the transfection of a variety of cells in suspension. In this paper, we communicate results related to the development of a treatment for squamous cell carcinomas of the head and neck, using electropermeabilization to deliver the drug bleomycin in vivo directly into the tumor cells. This drug, which is not particularly effective as a conventional therapeutic, becomes highly potent when the intracellular concentration is enhanced by EP treatment. In animal model experiments we found a drug dose of 1 U/cm(3) tumor tissue (delivered in 0.25 mL of an aqueous solution/cm3 tumor tissue) and an electrical field strength of 750 V/cm or higher to be optimal for the treatment of human squamous cell tumors grown subcutaneously in mice. Within 24-48 hours, the majority of tumor cells are rapidly destroyed by this bleomycin-electroporation therapy (B-EPT). This raises the concern that healthy tissue may be similarly affected. In studies with large animals we showed that normal muscle and skin tissue, normal tissue surrounding major blood vessels and nerves, as well as healthy blood vessels and nerves themselves, are much less affected than tumor tissue. Normal tissues did show acute, focal, and transitory effects after treatment, but these effects are relatively minor under standard treatment conditions. The severity of these effects increases with the number of electric pulse cycles and applied voltage. The observed histological changes resolved 20 to 40 days after treatment or sooner, even after excessive EP treatment. Thus, B-EPT is distinct from other ablative therapies, such as thermal, cryo, or photodynamic ablation, which equally affect healthy and tumor tissue. In comparison to surgical or radiation therapy, B-EPT also has potential as a tissue-sparing and function-preserving therapy. In clinical studies with over 50 late stage head and neck cancer patients, objective tumor response rates of 55-58%, and complete tumor response rates of 19-30% have been achieved. 

Bioelectromagnetics. 2002 Dec;23(8):578-85. 

Influence of 1 and 25 Hz, 1.5 mT magnetic fields on antitumor drug potency in a human adenocarcinoma cell line.

Ruiz-Gómez MJ, de la Peña L, Prieto-Barcia MI, Pastor JM, Gil L, Martínez-Morillo M. 

Laboratory of Radiobiology, Department of Radiology and Physical Medicine, Faculty of Medicine, University of Málaga, Teatinos, Málaga, Spain. 

Abstract

The resistance of tumor cells to antineoplastic agents is a major obstacle during cancer chemotherapy. Many authors have observed that some exposure protocols to pulsed electromagnetic fields (PEMF) can alter the efficacy of anticancer drugs; nevertheless, the observations are not clear. We have evaluated whether a group of PEMF pulses (1.5 mT peak, repeated at 1 and 25 Hz) produces alterations of drug potency on a multidrug resistant human colon adenocarcinoma (HCA) cell line, HCA-2/1(cch). The experiments were performed including (a) exposures to drug and PEMF exposure for 1 h at the same time, (b) drug exposure for 1 h, and then exposure to PEMF for the next 2 days (2 h/day). Drugs used were vincristine (VCR), mitomycin C (MMC), and cisplatin. Cell viability was measured by the neutral red stain cytotoxicity test. The results obtained were: (a) The 1 Hz PEMF increased VCR cytotoxicity (P < 0.01), exhibiting 6.1% of survival at 47.5 microg/ml, the highest dose for which sham exposed groups showed a 19.8% of survival. For MMC at 47.5 microg/ml, the % of survival changed significantly from 19.2% in sham exposed groups to 5.3% using 25 Hz (P < 0.001). Cisplatin showed a significant reduction in the % of survival (44.2-39.1%, P < 0.05) at 25 Hz and 47.5 microg/ml, and (b) Minor significant alterations were observed after nonsimultaneous exposure of cells to PEMF and drug. The data indicate that PEMF can induce modulation of cytostatic agents in HCA-2/1(cch), with an increased effect when PEMF was applied at the same time as the drug. The type of drug, dose, frequency, and duration of PEMF exposure could influence this modulation. 

Biofizika. 2002 Mar-Apr;47(2):376-81. 

Immunomodulating effect of electromagnetic waves on production of tumor necrosis factor in mice with various rates of neoplasm growth.

[Article in Russian] 

Glushkova OV, Novoselova EG, Sinotova OA, Vrublevskaia VV, Fesenko EE. 

Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290 Russia. 

Abstract

The effects of low-density centimeter waves (8.15-18 GHz, 1 microW/cm2, 1 h daily for 14 days; MW) on tumor necrosis factor production in macrophages of mice with different growth rate of a cancer solid model produced after hypodermic injection of Ehrlich carcinoma ascites cells into hind legs were studied. After irradiation, an increase in the concentration of tumor necrosis factor in immunocompetent cells of healthy and, specially, of tumor-bearing animals was observed; and the effect of stimulation was higher upon exposure of mice carrying rapidly growing tumors. We suggest that the significant immunomodulating effect of low-density microwaves can be utilized for tumor growth suppression. 

Biofizika. 2001 Jan-Feb;46(1):131-5. 

Effect of centimeter m

Cell Biol. Int. 2002;26(7):599-603.

Extremely low frequency (ELF) pulsed-gradient magnetic fields inhibit malignant tumour growth at different biological levels.

Zhang X, Zhang H, Zheng C, Li C, Zhang X, Xiong W.

Source 

Biomedical Physics Unit, Department of Physics, Wuhan University, Wuhan, 430072, China. 

Abstract 

Extremely low frequency (ELF) pulsed-gradient magnetic field (with the maximum intensity of 0.6-2.0 T, gradient of 10-100 T.M(-1), pulse width of 20-200 ms and frequency of 0.16-1.34 Hz treatment of mice can inhibit murine malignant tumour growth, as seen from analyses at different hierarchical levels, from organism, organ, to tissue, and down to cell and macromolecules. Such magnetic fields induce apoptosis of cancer cells, and arrest neoangiogenesis, preventing a supply developing to the tumour. The growth of sarcomas might be amenable to such new method of treatment. 

icrowaves and the combined magnetic field on the tumor necrosis factor production in cells of mice with experimental tumors.

[Article in Russian] 

Novoselova EG, Oga? VB, Sorokina OV, Novikov VV, Fesenko EE. 

Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290 Russia. 

Abstract

The effect of fractionated exposure to low-intensity microwaves (8.15-18 GHz, 1 microW/cm2, 1.5 h daily for 7 days) and combined weak magnetic field (constant 65 1 microT; alternating–100 nT, 3-10 Hz) on the production of tumor necrosis factor in macrophages of mice with experimental solid tumors produced by transplantation of Ehrlich ascites carcinoma was studied. It was found that exposure of mice to both microwaves and magnetic field enhanced the adaptive response of the organism to the onset of tumor growth: the production of tumor necrosis factor in peritoneal macrophages of tumor-bearing mice was higher than in unexposed mice.

J Photochem Photobiol B. 2001 Nov 1;64(1):21-6.

Photodynamic effect on cancer cells influenced by electromagnetic fields.

Pang L, Baciu C, Traitcheva N, Berg H. 

Institute of Physics, Nankai University, Nankai, PR China. 

The synergism of low-frequency electromagnetic field treatment and photodynamic effect on killing of human cancer cells is presented. The weak pulsating electromagnetic field (PEMF) generated by Helmholtz coils in the mT range influences the permeability of cell membranes for photosensitizers. Several types of sensitizers were excited by visible light during incorporation without and with two kinds of PEMF treatment. In the first part suitable photosensitizers were selected in the absorption range between 400 and 700 nm against human myeloid leukaemia K562 and human histiocytic lymphoma U937 cells by treatment of PEMF consisting of rectangular pulse groups. In the second part amplitude and frequency dependencies were measured using sinuous PEMF and white light with the result that after 12 min the PEMF treatment enhanced photodynamic effectivity by more than 40% over the control value. Taking into account the influence of many parameters, an additional optimization will be possible by photodynamic PEMF synergism for an increased drug delivery in general. 

Bioelectromagnetics. 2001 Oct;22(7):503-10. 

Pulsed electromagnetic fields affect the intracellular calcium concentrations in human astrocytoma cells.

Pessina GP, Aldinucci C, Palmi M, Sgaragli G, Benocci A, Meini A, Pessina F. 

Institute of General Physiology and Nutritional Science, University of Siena, Italy. pessina@unisi.it 

Abstract

Experiments assessed whether long term exposure to 50 Hz pulsed electromagnetic fields with a peak magnetic field of 3 mT can alter the dynamics of intracellular calcium in human astrocytoma U-373 MG cells. Pretreatment of cells with 1.2 microM substance P significantly increased the [Ca(2+)](i). The same effect was also observed when [Ca(2+)](i) was evaluated in the presence of 20 mM caffeine. After exposure to electromagnetic fields the basal [Ca(2+)](i) levels increased significantly from 143 +/- 46 nM to 278 +/- 125 nM. The increase was also evident after caffeine addition, but in cells treated with substance P and substance P + caffeine we observed a [Ca(2+)](i) decrease after exposure. When we substituted calcium-free medium for normal medium immediately before the [Ca(2+)](i) measurements, the [Ca(2+)](i) was similar to that measured in the presence of Ca(2+). In this case, after EMFs exposure of cells treated with substance P, the [Ca(2+)](i), measured without and with addition of caffeine, declined from 824 +/- 425 to 38 +/- 13 nM and from 1369 +/- 700 to 11 +/- 4 nM, respectively, indicating that electromagnetic fields act either on intracellular Ca(2+) stores or on the plasma membrane. Moreover the electromagnetic fields that affected [Ca(2+)](i) did not cause cell proliferation or cell death and the proliferation indexes remained unchanged after exposure. 

Cell Biol Int. 2002;26(7):599-603.

Extremely low frequency (ELF) pulsed-gradient magnetic fields inhibit malignant tumour growth at different biological levels.

Zhang X, Zhang H, Zheng C, Li C, Zhang X, Xiong W.

Source

Biomedical Physics Unit, Department of Physics, Wuhan University, Wuhan, 430072, China.

Abstract

Extremely low frequency (ELF) pulsed-gradient magnetic field (with the maximum intensity of 0.6-2.0 T, gradient of 10-100 T.M(-1), pulse width of 20-200 ms and frequency of 0.16-1.34 Hz treatment of mice can inhibit murine malignant tumour growth, as seen from analyses at different hierarchical levels, from organism, organ, to tissue, and down to cell and macromolecules. Such magnetic fields induce apoptosis of cancer cells, and arrest neoangiogenesis, preventing a supply developing to the tumour. The growth of sarcomas might be amenable to such new method of treatment.

Cell Mol Biol (Noisy-le-grand). 2001;47 Online Pub:OL115-7. 

Inhibition of proliferation of human lymphoma cells U937 by a 50 Hz electromagnetic field.

Glück B, Güntzschel V, Berg H. 

Laboratory Cell Culture, Institute of Virology, Friedrich-Schiller-University Jena, Germany. i6glbr@rz.uni-jena.de 

Abstract

Weak pulsating electromagnetically induced fields (PEMF) by Helmholtz coils changes cell metabolism, if cells are treated with a certain range of frequency and amplitude. The influence on proliferation of human histiocytic lymphoma cells U937 has been studied applying a sinusoidal 50 Hz field with amplitudes of the flux density B = 0.3 to 4.7 mT for 4 days. No difference between experiment and control was found in the region 0.3 and 2 mT. However, stronger fields (> or =2.5 mT) inhibit cell division. Fields > or =3.5 mT treatment kill > or =80% of the cell number at the beginning (1.5 x 10(5)/ml). This effect may be an electromagnetocally induced cell death as the first step for a non-invasive application on cell proliferation process. 

Laryngoscope. 2001 Jan;111(1):52-6. 

Electroporation therapy for head and neck cancer including carotid artery involvement.

Allegretti JP, Panje WR. 

Department of Otolaryngology, Rush-Presbyterian-St Luke’s Medical Center, Rush Medical College, Chicago, Illinois 60612, USA. 

Abstract

OBJECTIVES: Electroporation therapy with intralesional bleomycin (EPT) is a novel, technically simple outpatient technique in which high-voltage electric impulses delivered into a neoplasm transiently increase cell membrane permeability to large molecules, including cytotoxic agents, causing localized progressive necrosis. Unlike many laser ablation methods, EPT can treat bulky tumors (>2 cm) with complete penetration. Our recent publication confirms an excellent response rate in the use of EPT in a clinical trial. STUDY 

DESIGN, PATIENTS, AND METHODS: Following our initial prospective study report in 1998, we have followed our entire initial cohort (10 patients) of patients with head and neck cancer beyond 24-months follow-up. Additionally, we have used this approach to treat four additional patients (total: 9 males/5 females) with upper aerodigestive tract squamous cell carcinoma, including three with internal carotid artery (ICA) involvement up to or within the skull base. Two patients underwent preoperative balloon test occlusion with cerebral perfusion studies followed by carotid embolization. EPT was then done safely at least 2 weeks later to avoid the temporary hypercoagulable state. 

RESULTS: Within the overall cohort (14 patients) 6 patients had a complete response, 6 had a partial response, and 2 did not respond (overall 85.7% response rate). Both patients with ICA involvement had a partial or complete response to treatment; neither patient had a hemorrhagic or neurologic complication. Overall, 13 of the 14 patients were treated for persistent or recurrent head and neck cancer. Two of the four patients with early recurrent stage tumors had no evidence of recurrence after EPT with an average follow-up of 31.5 months. The overall early stage tumor group had four complete responders out of five (80%). On the contrary, only 2 of 9 patients with advanced recurrent stage tumors were disease-free at 18 months. Morbidity was low for early stage tumors, but higher for advanced tumors with complications, including poor wound healing, dysphagia, and osteomyelitis. There were no treatment-related deaths. 

CONCLUSION: We found EPT to be safe and efficacious in patients with head and neck cancer, even with internal carotid artery involvement. Patients with early stage recurrences have the potential for prolonged survival beyond 2 years without the morbidity of surgery and radiation or toxicity of systemic chemotherapy. Because of its superb access qualities even for bulky tumors, EPT is a potential method of delivery for other tumoricidal agents such as in genetic-altering schemes.

Vopr Onkol. 2000;46(4):469-72.

Use of artificial magnetic field for rehabilitation of children with malignant tumors.

[Article in Russian] 

Kiselev AV, Grushina TI. 

N.N. Blokhin Center for Oncology Research, Russian Academy of Medical Sciences, Moscow. 

Local complications of standard intravenous injections for chemotherapy and due to error of administration were compared in 400 patients (200 of them children) and general wound pathologies described. Treatment for wounds included two modalities: standard medication and alternating or pulsating magnetic field. Magnetic therapy proved highly effective: wound healing was 3-3.5 times faster while duration of treatment–2-3 times shorter than in standard procedure. Clinically-verified partial adhesion-related intestinal obstruction was eliminated by magnetic procedure in 18 children after combined treatment for lymphosarcoma involving the ileum. 

Bioelectromagnetics. 2000 Feb;21(2):112-21. 

Effects of PEMF on a murine osteosarcoma cell line: drug-resistant (P-glycoprotein-positive) and non-resistant cells.

Miyagi N, Sato K, Rong Y, Yamamura S, Katagiri H, Kobayashi K, Iwata H. 

Department of Orthopaedic Surgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. 

Abstract 

After pulsed exposure of Dunn osteosarcoma cells (nonresistant cells) to Adriamycin (ADR) at increasing concentrations and single-cell cloning of surviving cells, ADR-resistant cells were obtained. These resistant cells expressed P-glycoprotein and had resistance more than 10 times that of their nonresistant parent cells. Compared to the nonresistant cells not exposed to pulsing electromagnetic fields (PEMF) in ADR-free medium, their growth rates at ADR concentrations of 0.01 and 0.02 micrograms/ml, which were below IC50, were 83.0% and 61.8%, respectively. On the other hand, in the nonresistant cells exposed to PEMF (repetition frequency, 10 Hz; rise time, 25 microsec, peak magnetic field intensity, 0.4-0.8 mT), the growth rate was 111.9% in ADR-free medium, 95.5% at an ADR concentration of 0.01 micrograms/ml, and 92.2% at an ADR concentration of 0.02 micrograms/ml. This promotion of growth by PEMF is considered to be a result of mobilization of cells in the non-proliferative period of the cell cycle due to exposure to PEMF. However, at ADR concentrations above the IC50, the growth rate tended to decrease in the cells not exposed to PEMF. This may be caused by an increase in cells sensitive to ADR resulting from mobilization of cells in the non-proliferative period to the cell cycle. The growth rate in the resistant cells exposed to PEMF was significantly lower than that in the non-exposed resistant cells at all ADR concentrations, including ADR-free culture (P</=0.0114). Therefore, this study suggests that PEMF promotes the growth of undifferentiated cells but progressively suppresses the growth of more differentiated cells, i.e., PEMF controls cell growth depending on the degree of cell differentiation. This study also shows the potentiality of PEMF as an adjunctive treatment method for malignant tumors 

J Physiol Biochem. 1999 Jun;55(2):79-83. 

Growth modification of human colon adenocarcinoma cells exposed to a low-frequency electromagnetic field.

Ruiz Gómez MJ, Pastor Vega JM, de la Peña L, Gil Carmona L, Martínez Morillo M. 

Departamento de Radiología y Medicina Física, Facultad de Medicina, Universidad de Málaga, Teatinos, Spain. mjrg@uma.es 

Abstract

The influence of variable low-intensity, low-frequency electromagnetic fields on culture cells is investigated. Human colon adenocarcinoma cells were exposed to a rectangular and variable magnetic field (1 and 25 Hz; 1.5 mT peak). Cultures were exposed to a dose for 15 and 360 minutes, and after 24 hours incubation, cell viability was measured with neutral red stain. The group treated for 15 minutes showed a statistically significant increase in cell growth with 1 Hz (p < 0.002) and 25 Hz (p < 0.003). In contrast, a significant decrease in cell growth was found in those cultures treated with 1 Hz for 360 minutes (p < 0.02). The effects reported could be influenced by the magnetic field frequency and the exposure time.

Am J Physiol. 1997 May;272(5 Pt 2):R1677-83.

Electrical fields enhance growth of cancer spheroids by reactive oxygen species and intracellular Ca2+.

Wartenberg M, Hescheler J, Sauer H. 

Institute for Neurophysiology, University of Cologne, Germany. 

A single electrical field pulse (500 V/m) with a duration of 60 s increased tumor outgrowth over a postpulse period of 24 h. RNA staining with acridine orange showed a rise in RNA content in pulsed spheroids, indicating stimulation of cell cycle activity. The electropulse induced an intracellular Ca2+ concentration ([Ca2+]i) transient that started approximately 40 s after the onset of the electrical field. Neither the presence of extracellular Ni2+ (0.5 mM) nor the absence of extracellular Ca2+ impeded the [Ca2+]i rise. It was, however, totally blocked by thapsigargin (1 microM), indicating that the initial Ca2+ response is due to Ca2+ release from intracellular stores. The [Ca2+]i transient was paralleled by an increase in reactive oxygen species (ROS), as revealed using 2′,7′-dichlorofluorescein diacetate as an indicator. The radical scavengers N-acetyl-L-cysteine (NAC)(20 mM) and dehydroascorbate (5 mM) inhibited both ROS production and the [Ca2+]i transient during electrical field treatment. The mitogenic activation was dependent on the rise in [Ca2+]i because inhibition of Ca2+ release during electrical field treatment by addition of either thapsigargin or NAC to the incubation medium abolished the observed effect. We conclude that a single, direct current electrical field pulse induces production of ROS, which in turn mediate Ca2+ release from intracellular stores and activate cell cycle activity in multicellular spheroids. 

Anticancer Res. 1997 May-Jun;17(3C):2083-8. 

Enhanced potency of daunorubicin against multidrug resistant subline KB-ChR-8-5-11 by a pulsed magnetic field.

Liang Y, Hannan CJ Jr, Chang BK, Schoenlein PV. 

Department of Radiology, Research and Nuclear Medicine, Medical College of Georgia, Augusta 30912, USA. 

Abstract

Tumor cell resistance to many unrelated anticancer drugs is a major obstacle during cancer chemotherapy. One mechanism of drug resistance is thought to be due to the efflux of anticancer drugs caused by P-glycoprotein. In recent years, magnetic fields have been found to enhance the potency of anticancer drugs, with favorable modulation of cancer therapy. In this study, KB-ChR-8-5-11, a multidrug resistant (MDR) human carcinoma subline, was used as a model to evaluate the ability of pulsed magnetic fields (PMF) to modulate the potency of daunorubicin (DNR) in vivo and to determine the appropriate order of exposure to drugs and PMF using an in vitro cytotoxicity assay. Solenoid coils with a ramped pulse current source were used at 250 pulses per second for both in vivo and in vitro experiments. For the in vivo study, KB-ChR-8-5-11 cells were inoculated into thymic Balbc-nu/nu female mice. Treatment was begun when the average tumor volume reached 250-450 mm3. Treatment consisted of whole body exposure to PMF for one hour, followed immediately by intravenous (i.v.) injection of 8 mg/kg DNR designated as day 0, and repeated on days 7 and 14. Among the various groups, significant differences in the tumor volume were found between PMF + saline and PMF + DNR groups (p = 0.0107) at 39 days and 42 days (p = 0.0101). No mice died in the PMF alone group, and no toxicity attributable to PMF was found during the experimental period. For the in vitro studies, the sulforhodamine blue (SRB) cytotoxicity assay was used to determine the effect of the sequence which cells are exposed to PMF and/or DNR. Cells were exposed to PMF either before (pre-PMF) or after (post-PMF) drug was added. Results showed that the IC50 was significantly different between controls and pre-PMF + DNR groups (P = 0.0096, P = 0.0088). The IC50 of the post-PMF + DNR group was not found to be significantly different from control groups. Thus, the data in this report demonstrates that PMF enhanced the potency of DNR against KB-ChR-8-5-11 xenograft in vivo, while the efficacy of DNR was potentiated in vitro by PMF exposure only when PMF exposure occurred in the presence of drug. The data in vitro suggest that the mechanism by which PMFs modulate DNR’s potency may be by inhibition of the efflux pump, P-glycoprotein. Further work to determine conditions for maximum modulation of drug potency by PMFs is warranted. 

Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997 May;17(5):286-8. 

Effect of acupoint irradiation with Q-wave millimeter microwave on peripheral white blood cells in post-operational treatment with chemotherapy in stomach and colorectal cancer patients.

[Article in Chinese] 

Wu JG, Huang WZ, Wu BY. 

Oncology Department of Second Ningde District Hospital, Fujian. 

Abstract

OBJECTIVE: To explore the biological effect of Q-wave millimeter microwave (QWMM). 

METHODS: The QWMM was used to irradiate the acupoints Xuehai (Sp10) and Geshu (B17) in treating post-operational and chemotherapy treated stomach cancer and colorectal cancer patients. The effect of irradiation on chemotherapy affected peripheral white blood cells was observed. 62 cases (stomach cancer 42, colorectal cancer 20) in total were divided into two groups: group A, 21 cases (stomach cancer 15, colorectal cancer 6) the irradiation began 10 days after operation, and on the 16th day the chemotherapy combined with irradiation started. Group B had 41 cases (stomach cancer 27, colorectal cancer 14), in which the irradiation began immediately after the occurrence of chemotherapy induced peripheral WBC reduction, which persisted for at least 12 days. 

RESULTS: The effective rate for the group A and B was 85.7% (18/21) and 73.2% (30/41) respectively. The total effective rate of the two groups was 77.4% (48/62). The effective rate of group A was significantly higher than that of group B, P < 0.01. 

CONCLUSION: GWMM irradiation at acupoints could promote the hematopoietic function of bone marrow, and the irradiation performed 1 week before chemotherapy yielded even better protection on bone marrow.

Bioelectromagnetics 1996;17(5):358-63.

Exposure to strong static magnetic field slows the growth of human cancer cells in vitro.

Raylman RR, Clavo AC, Wahl RL. 

University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor, USA. 

Proposals to enhance the amount of radiation dose delivered to small tumors with radioimmunotherapy by constraining emitted electrons with very strong homogeneous static magnetic fields has renewed interest in the cellular effects of prolonged exposures to such fields. Past investigations have not studied the effects on tumor cell growth of lengthy exposures to very high magnetic fields. Three malignant human cell lines, HTB 63 (melanoma), HTB 77 IP3 (ovarian carcinoma), and CCL 86 (lymphoma: Raji cells), were exposed to a 7 Tesla uniform static magnetic field for 64 hours. Following exposure, the number of viable cells in each group was determined. In addition, multicycle flow cytometry was performed on all cell lines, and pulsed-field electrophoresis was performed solely on Raji cells to investigate changes in cell cycle patterns and the possibility of DNA fragmentation induced by the magnetic field. A 64 h exposure to the magnetic field produced a reduction in viable cell number in each of the three cell lines. Reductions of 19.04 +/- 7.32%, 22.06 +/- 6.19%, and 40.68 +/- 8.31% were measured for the melanoma, ovarian carcinoma, and lymphoma cell lines, respectively, vs. control groups not exposed to the magnetic field. Multicycle flow cytometry revealed that the cell cycle was largely unaltered. Pulsed-field electrophoresis analysis revealed no increase in DNA breaks related to magnetic field exposure. In conclusion, prolonged exposure to a very strong magnetic field appeared to inhibit the growth of three human tumor cell lines in vitro. The mechanism underlying this effect has not, as yet, been identified, although alteration of cell growth cycle and gross fragmentation of DNA have been excluded as possible contributory factors. Future investigations of this phenomenon may have a significant impact on the future understanding and treatment of cancer.

J Cell Biochem. 1993 Apr;51(4):387-93.

Beneficial effects of electromagnetic fields.

Bassett CA. 

Bioelectric Research Center, Columbia University, Riverdale, New York 10463. 

Selective control of cell function by applying specifically configured, weak, time-varying magnetic fields has added a new, exciting dimension to biology and medicine. Field parameters for therapeutic, pulsed electromagnetic field (PEMFs) were designed to induce voltages similar to those produced, normally, during dynamic mechanical deformation of connective tissues. As a result, a wide variety of challenging musculoskeletal disorders have been treated successfully over the past two decades. More than a quarter million patients with chronically ununited fractures have benefitted, worldwide, from this surgically non-invasive method, without risk, discomfort, or the high costs of operative repair. Many of the athermal bioresponses, at the cellular and subcellular levels, have been identified and found appropriate to correct or modify the pathologic processes for which PEMFs have been used. Not only is efficacy supported by these basic studies but by a number of double-blind trials. As understanding of mechanisms expands, specific requirements for field energetics are being defined and the range of treatable ills broadened. These include nerve regeneration, wound healing, graft behavior, diabetes, and myocardial and cerebral ischemia (heart attack and stroke), among other conditions. Preliminary data even suggest possible benefits in controlling malignancy.

In Vivo. 1991 Jan-Feb;5(1):39-40.

Effect of a 9 mT pulsed magnetic field on C3H/Bi female mice with mammary carcinoma. A comparison between the 12 Hz and 460 Hz frequencies.

Bellossi A, Desplaces A. 

Laboratoire de Biophysique, Faculte de Medecine, Rennes, France. 

In a previous experiment, the exposure of tumoral C3H/Bi female mice to a 9 mT, 460 Hz pulsed magnetic field led to an increase in the length of survival in the late period of the disease; this might be due to a hampered metastatic process. In the present study 27 controls and 52 exposed mice were treated with the same protocol (a 10-minute exposure, 3 non-consecutive days a week, from 2-3 weeks after the tumors appeared until death) but with a 12 Hz PMF. In this experiment the 12 Hz PMF appeared to increase length of survival times in the early period of the disease.

Sov Med. 1991;(7):25-7.

The assessment of the efficacy of the effect of a rotational magnetic field on the course of the tumor process in patients with generalized breast cancer.

[Article in Russian] 

Bakhmutskii NG, Pyleva TA, Frolov VE, Sinitskii DA, Ripa IM. 

The efficacy of rotational magnetic field generated by a “Magnitoturbotron” unit was evaluated in 51 women with advanced breast cancer. The effect resulted from an action on the patient’s body by modulated rotational magnetic field changing in cycles according to induction. A significant response was achieved in 27 of 51 patients. There was no hemopoiesis suppression, negative functional shifts. The unit is recommended for introduction in a combined treatment of breast cancer.

Jpn J Cancer Res. 1990 Sep;81(9):956-61.

Treatment of experimental tumors with a combination of a pulsing magnetic field and an antitumor drug.

Omote Y, Hosokawa M, Komatsumoto M, Namieno T, Nakajima S, Kubo Y, Kobayashi H. 

Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo. 

We investigated the effects of a combination treatment involving a pulsing magnetic field (PMF) and an antitumor drug, mitomycin C (MMC), on two experimental tumors (fibrosarcoma KMT-17 and hepatocellular carcinoma KDH-8) in WKA rats, paying attention to possible potentiation of the therapeutic effect of the antitumor drug. PMF was obtained using a system generating a pulsed current in a solenoid coil. On day 7 after tumor implantation into the right thighs of rats, the region of the tumor was exposed to PMF (frequency 200 Hz, mean magnetic flux density 40 gauss) for 1 h immediately after iv injection of MMC at a dose of 1 mg/kg. Survival rates at day 90 of KMT-17 implanted rats were 0% (0/10) in the non-treated group, 34% (4/12) in the MMC-treated group, 47% (6/13) in the PMF-treated group and 77% (10/13) in the MMC/PMF combination group. The increase of life span (ILS) of KDH-8-implanted rats in the combination therapy group was significantly prolonged (%ILS 17.6%) compared with that in the MMC-treated (%ILS 3.4%) and PMF-treated (%ILS 7.6%) groups. By using cultured cells of the above two lines of tumor, the therapeutic effects of MMC and PMF were also determined from the cell colony-forming efficiency in soft agar. The colony-forming efficiencies of both cell lines were significantly suppressed in the combination therapy group compared with those in the other single therapy groups. The present results indicate that PMF exhibited a potentiation of the antitumor effect of mitomycin C.

Nippon Geka Gakkai Zasshi. 1988 Aug;89(8):1155-66.   

An experimental attempt ot potentiate therapeutic effects of combined use of pulsing magnetic fields and antitumor agents.

[Article in Japanese] 

Omote Y. 

First Department of Surgery, Asahikawa Medical College, Japan. 

With a view to examining the possible clinical applicability of pulsing magnetic fields (PMF), we investigated the effects of weak, non-heat inducing, PMF on DNA synthesis and sensitivity of cancer cells to antitumor agents. Leukemic T-cells (Molt-4) and a pancreatic ductal adenocarcinoma (solid tumor) transplanted in a Syrian golden hamster were used for the in vitro experiment and in vivo experiment respectively. In order to evaluate the effects of PMF on the DNA synthesis of cancer cells and the incorporation of antitumor agent into cancer cells, cultured cells or solid tumor were exposed to PMF generated by a solenoid coil immediately after 3H-or 14C-thymidine and 3H-methotrexate administration respectively. Thymidine uptake was found to increase by exposure to PMF, as did also 3H-methotrexate uptake by leukemic T-cells. Following exposure to PMF immediately after administration of methotrexate or mitomycin C, antitumor activity in both cells was increased. From these results it appears that the incorporation of antitumor agents into the cells increases by eddy current stimulation induced by PMF, and that the cell cycle shifts from the non-proliferative to proliferative phase, resulting in increased antitumor activity.

Anticancer Res. 1987 May-Jun;7(3 Pt B):391-3.

Tumoricidal cells increased by pulsating magnetic field.

Malter M, Schriever G, Kuhnlein R, Suss R. 

Repeated applications of pulsed magnetic fields (right-angle waves, 50 Hz = 135 Gauss, 2 Hz = 262 Gauss) significantly enhanced the number and the tumoricidal activity of nonparenchymal liver cells. The transplantable mouse leukemia L1210 used as a tumor model was not significantly influenced, either directly or during Cyclophosphamide treatment

Vopr Onkol. 1980;26(1):28-34.

Morphological criteria of lung cancer regression under the effect of magnetotherapy.

[Article in Russian] 

Ogorodnikova LS, Gairabed’iants NG, Ratner ON, Chirvina ED, Sem LD. 

The complex investigation (histological, histochemical, morphological, electrone microscopy) of lung cancerous tumors from 20 patients, subjected preoperatively to the action of magnetic fields enhancing the antitumor resistance by developing general nonspecific adaptation reactions: activation and training, has revealed a number of morphological changes which indicate a marked antitumor effect of magnetic fields. These changes were maximum manifest after 20-30 sessions. High-differentiated adenocarcinoma proved to be mostly sensitive to the magnetic field action. 

Nitric Oxide

Logo of oximed

Oxid Med Cell Longev. 2017; 2017: 2181942. Published online 2017 Sep 12. doi:  10.1155/2017/2181942 PMCID: PMC5613626

Benign Effect of Extremely Low-Frequency Electromagnetic Field on Brain Plasticity Assessed by Nitric Oxide Metabolism during Poststroke Rehabilitation

Natalia Cicho,

corresponding author

 1 Piotr Czarny, 2 Micha Bijak, 1 Elbieta Miller, 3 , 4 Tomasz liwiski, 5 Janusz Szemraj, 2 and Joanna Saluk-Bijak 11Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, Lodz, Poland 2Department of Medical Biochemistry, Medical University of Lodz, Mazowiecka 6/8, Lodz, Poland 3Department of Physical Medicine, Medical University of Lodz, Pl. Hallera 1, Lodz, Poland 4Neurorehabilitation Ward, III General Hospital in Lodz, Milionowa 14, Lodz, Poland 5Department of Molecular Genetics, Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Pomorska 141/143, Lodz, Poland

corresponding author

Corresponding author. Natalia Cicho: lp.zdol.inu.loib@nohcic.ailatan Academic Editor: Tanea T. Reed Author information Article notes Copyright and License information Received 2017 May 12; Revised 2017 Jul 2; Accepted 2017 Aug 14. Copyright © 2017 Natalia Cicho et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nitric oxide (NO) is one of the most important signal molecules, involved in both physiological and pathological processes. As a neurotransmitter in the central nervous system, NO regulates cerebral blood flow, neurogenesis, and synaptic plasticity. The aim of our study was to investigate the effect of the extremely low-frequency electromagnetic field (ELF-EMF) on generation and metabolism of NO, as a neurotransmitter, in the rehabilitation of poststroke patients. Forty-eight patients were divided into two groups: ELF-EMF and non-ELF-EMF. Both groups underwent the same 4-week rehabilitation program. Additionally, the ELF-EMF group was exposed to an extremely low-frequency electromagnetic field of 40Hz, 7mT, for 15min/day. Levels of 3-nitrotyrosine, nitrate/nitrite, and TNF? in plasma samples were measured, and NOS2 expression was determined in whole blood samples. Functional status was evaluated before and after a series of treatments, using the Activity Daily Living, Geriatric Depression Scale, and Mini-Mental State Examination. We observed that application of ELF-EMF significantly increased 3-nitrotyrosine and nitrate/nitrite levels, while expression of NOS2 was insignificantly decreased in both groups. The results also show that ELF-EMF treatments improved functional and mental status. We conclude that ELF-EMF therapy is capable of promoting recovery in poststroke patients.

1. Introduction

Cardiovascular diseases, including ischemic stroke (IS), are a serious problem of the modern age, killing 4 million people each year in Europe [1]. Stroke is caused by ischemia of brain tissue. Brain structure damage occurring during ischemia/reperfusion is due to the generation of significant amounts of reactive oxygen species and inflammatory mediators [2]. Damage to brain tissue as a result of a stroke cannot be undone. However, the most important part of poststroke therapy is immediate and long-term rehabilitation, considering the enormous plasticity of the brain [3]. Although extremely low-frequency electromagnetic field (ELF-EMF) therapy is not a standard treatment in the poststroke rehabilitation, some authors suggest its increased positive effect on patients [4]. ELF-EMF treatment is based on regeneration, osteogenesis, analgesics, and anti-inflammatory action. Its biological effect is related to processes of ion transport, cell proliferation, apoptosis, protein synthesis, and changes in the transmission of cellular signals [5]. The regenerative and cytoprotective effect of ELF-EMF is based on mechanism associated with nitric oxide induction, collateral blood flow, opioids, and heat shock proteins [6].

Nitric oxide (NO) is an unstable, colourless, water-soluble gas with a short half-life (3–6sec). The compound has one unpaired electron, which makes it a highly reactive free radical. It is characterized by the multiplicity of action in the body, in both physiological and pathological conditions [7]. Synthesis of NO in the organism is catalysed by nitric oxide synthase (NOS), occurring in three isoforms: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS), encoded by different genes whose expression is subject to varying regulation. The constituent isoforms of NOS are eNOS and nNOS, whose activity is associated with concentration of calcium ions and the level of calmodulin in a cell, as well as with hypoxia, physical activity, and the level of certain hormones, that is, oestrogens [8]. In contrast, because it is closely related with the calmodulin, iNOS does not require a high concentration of calcium ions but is regulated by various endogenous and exogenous proinflammatory factors [9].

The two-stage synthesis of NO consists of the oxidation of L-arginine to N-hydroxy-L-arginine and, under the influence of NOS and oxygen, formation of L-citrulline and release of NO. All isoforms of NOS require the same cofactors: nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), tetrahydrobiopterin (BH4), iron protoporphyrin IX (heme), and O2[7].

Nitric oxide is one of the most important signal molecules, involved in both physiological and pathological processes. One of the major functions of NO is as a potent vasodilation, increasing the blood flow and regulation of blood pressure, which has been used in clinical practice for many years. Deficiency of this compound is observed in various disorders of many systems: cardiovascular, gastrointestinal, respiratory, and genitourinary [10]. The beneficial effects of NO lie in its platelet inhibition, macrophage cytotoxicity (antibacterial, antiviral, and antiparasitic), and protection of the mucosal lining of the digestive system. On the other hand, excessive expression of iNOS can be disadvantageous, for example, during sepsis. The adverse action of NO is associated with the production of superoxide anions and subsequent generation of peroxynitrite and hydroxyl radicals, which are highly toxic [11].

In the central nervous system, NO as a neurotransmitter regulates cerebral blood flow, as well as neurogenesis and synaptic plasticity. Furthermore, neuronal death is caused by high concentrations of NO by caspase-dependent apoptosis process and promotion of inflammation. Elevated levels of nitric oxide promote necrosis by energy depletion. On the basis of these mechanisms, NO is involved in the etiology of many neurological diseases, such as major depression, schizophrenia, epilepsy, anxiety, and drug addiction [12].

Our study was designed to investigate the effect of ELF-EMF on the metabolism of NO, as a signal molecule in the central nervous system, in the rehabilitation of acute poststroke patients.

2. Materials and Methods

2.1. Blood Sample Collection

Blood samples were collected into CPDA1-containing tubes (Sarstedt, Nümbrecht, Germany). Immediately upon doing so, a portion of the sample was frozen at 80°C and the rest of the samples centrifuged to isolate the plasma (15min, 1500g) at 25°C. Blood samples were collected twice, at an interval of 14 days before and after a standard 10 sessions of therapy. For additional analysis of 3-nitrotyrosine levels, the blood samples were collected three times, at an interval of 28 days: before treatment, after 10 treatments, and after 20 treatments. All blood samples were taken in the morning (between 7am and 9am) under patient fasting condition and stored using the same protocol.

2.2. Subject Presentation

Forty-eight poststroke patients were enrolled in the study. Participants were randomly divided into two groups: ELF-EMF (n = 25) and non-ELF-EMF (n = 23). Patients with metal and/or electronic implants (pacemakers, etc.) were excluded from the ELF-EMF group, for safety reasons. The ELF-EMF group had already undergone ELF-EMF therapy with specific parameters (40Hz frequency, magnetic induction of 5mT (B), rectangular and bipolar waveforms) (Figure 1), which was conducted using a Magnetronic MF10 generator (EiE Elektronika i Elektromedycyna, Otwock, Poland). The parameters were selected on the basis of the fact that low-intensity stimuli improve the vital functions of the body. In addition, rectangular pulses are more intense than sinusoidal and trapezoid, while bipolar pulses show more range of changes than unipolar pulses [13]. The ELF-EMF and non-ELF-EMF groups were treated for the same amount of time (15minutes). The non-ELF-EMF subjects were given only sham exposure. The pelvic girdle of the patients was exposed to the electromagnetic field, because exposure of the head to ELF-EMF can affect the activation of the epilepsy focus in the brain. The same therapeutic program was used for both subject groups. This consisted of aerobic exercise (30min), neurophysiological routines (60min), and psychological therapy (15min). Poststroke patients with moderate stroke severity according to NIHSS scores of 4.9 ±3.1 in the ELF-EMF group (aged 48.8 ±7.7) and 5.4 ±2.9 (aged 44.8 ±8.0) in the non-ELF-EMF group were enrolled in the study. Table 1 shows the clinical and demographic characteristics. Participants with haemorrhagic stroke, dementia, chronic or significant acute inflammatory factors, decreased consciousness, and/or neurological illness other than stroke in their medical prestroke history were excluded. The subjects had undergone neurorehabilitation for 4 weeks in Neurorehabilitation Ward III of the General Hospital in Lodz, Poland, as well as internal and neurological examinations. The Bioethics Committee of the Faculty of Biology and Environmental Protection of The University of Lodz, Poland, approved the protocol with resolution numbers 28/KBBN-U/II/2015 and 13/KBBN-U/II/2016. All participants provided written informed consent prior to participation. Depression was screened in both groups using the Geriatric Depression Scale (GDS). Cognitive status was estimated in a Mini-Mental State Examination (MMSE), and functional status using the Barthel Index of Activities of Daily Living (ADL). The GDS, ADL, and MMSE were administered either on the same day as the blood sampling or on the afternoon before.

Figure 1

Figure 1 ELF-EMF description. B=5mT; T = 1.3sec.

Table 1

Table 1 Clinical demographic characteristics.

2.3. Magnetronic MF10 Devices

ELF-EMF therapy was performed by a Magnetronic MF10 generator as per accepted guidelines. This device is able to produce pulses in rectangular, trapezoid, and sinusoidal shapes. The pulses were applied using an AS-550 applicator (EiE, Otwock, Poland), which has the following properties: 550 mm in diameter, 270mm in length, and 5 layers of 187 turns of 1.45mm twin-parallel wires. Magnetic induction was set at 5mT. The electromagnetic field intensity was not uniformed; its distribution is vertical, while the induction coils are set horizontally. Induction of the electromagnetic field of 5mT is present at the geometric center of the applicator, and the value increases in the proximity to the surface about 7mT. Other factors that could affect EMF were eliminated (electronic measuring instruments occurring in rehabilitation room and other electronic equipment).

2.4. Immunodetection of 3-Nitrotyrosine by c-ELISA

Levels of 3-NT-containing proteins in plasma were determined using a modified c-ELISA method, as described by Khan et al. [14]. 96-well microtiter plates were coated with nitro-fibrinogen (nitro-Fg) (1mg/mL) and kept overnight at 4°C. Concentrations of nitrated proteins inhibiting the binding of anti-nitrotyrosine antibodies were assessed from the standard curve (10–100nM nitro-Fg equivalents) and expressed as nitro-Fg equivalents [15].

2.5. Nitrate/Nitrite Estimation

Plasma samples were diluted twice before the measurement of nitrate/nitrite concentration using a Nitrate/Nitrite Colorimetric Assay Kit (Cayman Chemical Company, USA), based on the two-step Griess method. In the first step, the nitrate is converted to nitrite with nitrate reductase, while in the second step, after addition of the Griess reagent, the nitrite is converted to a deep purple azo compound. The absorbance measurement was performed at 540nm in a 96-well microplate reader (SPECTROstarNano, BMG Labtech, Ortenberg, Germany) [16].

2.6. Determination of NOS2 Expression in Whole Blood Samples

RNA was isolated from the frozen whole blood samples (?80°C), in accordance with the manufacturer’s protocol using TRI Reagent® (Sigma-Aldrich, USA). The aqueous phase was purified in accordance with the manufacturer’s protocol using an InviTrap Spin Universal RNA Mini Kit (Stratec Biomedical Systems, Germany). The purity and quantity of isolated RNA were assessed using a Synergy HTX Multi-Mode Microplate Reader equipped with a Take3 Micro-Volume Plate and connected to a PC running Gen5 Software (BioTek Instruments Inc., Winooski, VT, USA). Isolated RNA (20ng/L) was transcribed onto cDNA with a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems™, Waltham, MA, USA). Quantitative assays were executed using a TaqMan Hs01075529_m1 probe for human NOS2 genes and an Hs02786624_g1 for endogenous control, which was GAPDH (Life Technologies). Reactions were carried out using a TaqMan Universal Master Mix II, without UNG (Life Technologies) in a BioRad CFX96 real-time PCR system (BioRad Laboratories, Hercules, CA, USA), all in accordance with the manufacturers’ protocols. Relative expression of NOS2 was obtained using the equation 2Ct, where Ct is the threshold cycle (Ct) value for the target gene minus Ct values obtained for the housekeeping gene GAPDH [17].

2.7. Determination of TNF?

Measurements of human tumour necrosis factor alpha (TNF?) in plasma samples were made with a Human TNF? ELISA development kit (MABTECH, Cincinnati, OH, USA), in accordance with the manufacturer’s protocol. The combination of two coating antibodies (TNF3 and TNF4) were used for the analysis. The absorbance was measured at 450nm, and TNF?.

2.8. Data Analysis

Biochemical and clinical data were expressed as mean ±SD. All measurements were executed in duplicate. Output value (100%) was determined for each measured parameter of each patient before treatment. Data from tests performed on the same study subjects after therapy constituted a percentage of the output value. Percentage values were presented as mean ± SD. Statistical analyses were performed using the Statistica 12 statistical software (StaftSoft Inc.). A Shapiro-Wilk test was used to analyse for normality. A paired Student t-test was used to the calculate differences between the values obtained for subjects before and after therapy, whereas unpaired Student t-test or Mann–Whitney U tests were used to determine differences between the ELF-EMF and non-ELF-EMF groups. p values of 0.05 were accepted as statistically significant for all analyses.

3. Results

Our comparative analysis demonstrated an increased level of 3-nitrotyrosine (3-NT) (p< 0.05) (Figure 2) and an elevated nitrate/nitrite concentration (p < 0.01) (Figure 3) in the plasma of patients from the ELF-EMF group. The gain in the 3-NT level was significantly higher with an increased amount of sessions (Figure 2). In the non-ELF-EMF group, we saw that the effect of rehabilitation on nitrative stress was largely weaker and not statistically significant (p > 0.05) (Figures (Figures22 and and3).3). The 3-NT level increased more in the ELF-EMF group than in the non-ELF-EMF after 10 treatments (68% versus 17%, p < 0.05) (Figure 2). The level of nitrate/nitrite in the non-ELF-EMF group even decreased after 10 treatments (although not statistically significantly) (Figure 3).

Figure 2

Figure 2 The comparison of 3-NT levels in plasma proteins obtained from the ELF-EMF group versus those from the non-ELF-EMF group. Statistical significance between the ELF-EMF and non-ELF-EMF groups: B versus D (p < 0.05).

Figure 3

Figure 3 The comparison of nitrate/nitrite levels in plasma proteins obtained from the ELF-EMF group versus those from the non-ELF-EMF group. Statistical significance between ELF-EMF and non-ELF-EMF groups: B versus D (p < 0.05).

In the next set of experiments, we determined the effect of magnetotherapy on gene expression in the whole blood samples of NOS2 mRNA. Its expression was unmeasurable in 35% of subjects from both the ELF-EMF and non-ELF-EMF groups. We observed a statistically insignificant decrease in the level of NOS2 mRNA expression after treatment in both the ELF-EMF and non-ELF-EMF groups (Figure 4).

Figure 4

Figure 4 The comparison of NOS2 mRNA expression obtained from the ELF-EMF group versus that from the non-ELF-EMF group.

Subsequently, we determined the concentration of proinflammatory cytokine TNF?. We found that the concentration of TNF? was comparable before treatment in both the ELF-EMF and non-ELF-EMF-groups. The cytokine level did not change in either groups after rehabilitation (Figure 5).

Figure 5

Figure 5 The comparison of TNF? levels in plasma proteins obtained from the ELF-EMF group versus those from the non-ELF-EMF group.

The ADL, MMSE, and GDS were used to evaluate the functional and mental status of poststroke patients undergoing rehabilitation. We demonstrated that treatment using ELF-EMF improves their clinical parameters, particularly in cognitive and psychosomatic functions.

Motor abilities estimated by ADL score changed at similar levels in both groups, with the observed improvement being statistically significant in all rehabilitated patients (p < 0.001) (Table 2).

Table 2

Table 2 Clinical parameters: ADL, MMSE, and GDS measured in the ELF-EMF and non-ELF-EMF groups. Data presented as the delta of a clinimetric scale before and after the standard series of treatments ADL=the increase of ADL; MMSE= the 

The baseline MMSE values before treatment in both groups were comparable, but statistically different (p < 0.05) after rehabilitation. After 2 weeks of rehabilitation, MMSE parameters improved markedly in the ELF-EMF group (p = 0.002), while a small increase in the non-ELF-EMF group was not statistically significant (p = 0.2) (Table 2).

Depression syndrome expressed by GDS improved significantly in both groups after rehabilitation. However, the GDS value reached about a 60% lower result in the ELF-EMF group than in the non-ELF-EMF group (p = 0.018), starting from a similar base level in both groups (p > 0.05) (Table 2).

4. Discussion

In this study, we provide the evidence that application of extremely low-frequency electromagnetic field increases nitric oxide generation and its metabolism, as well as improving the effectiveness of poststroke ischemic patients’ treatments.

Ischemic stroke is one of the major causes of morbidity and mortality in the world’s population and is one of the main causes of long-term disability. The mechanisms of neurological function recovery after brain injury associated with neuroplasticity (cortical reorganization) are still insufficiently understood. Poststroke neurorehabilitation is designed to provide external stimuli, improving the effectiveness of compensatory plasticity [19].

In the central nervous system, NO is both a pre- and postsynaptic signal molecule. The activity of NO is associated with a cGMP-mediated signalling cascade. The presynaptic excitatory action of NO is related to the phosphorylation of synaptophysin by the cGMP-dependent protein kinase G (PKG) pathway and the subsequent potentates of glutamatergic neurotransmission [20]. On the other hand, NO causes a neurotransmission inhibition through gamma-aminobutyric acid- (GABA-) ergic synaptic communication. It is associated with ion exchange and regulation of membrane excitation [2122]. Moreover, NO as an important vasodilation factor mediates neurovascular coupling. The enlargement of vessel diameter is caused by increasing metabolic consumption as a result of neuronal activity. Neurovascular coupling maintains functional and structural brain integrity [23].

This study was designed to investigate the impact of ELF-EMF on the metabolism of nitric oxide in the rehabilitation of acute poststroke patients.

In our study, we demonstrate that poststroke rehabilitation increases the level of 3-NT and nitrate/nitrite concentrations. Due to its vasodilating and proangiogenic effects, NO serves as a protective function during cerebral ischemia. Su et al. investigated the role of simvastatin-regulated TRPV1 receptors (transient receptor potential vanilloid type 1) in NO bioavailability, activation of eNOS, and angiogenesis in mice. They demonstrated that simvastatin causes an influx of calcium ions through the TRPV1-TRPA1 (transient receptor potential ankyrin 1) pathway, which then causes activation of CaMKII (Ca2+/calmodulin-dependent protein kinase II). This then enhances the formation of the TRPV1-eNOS complex, which also includes CaMKII, AMPK (5AMP-activated protein kinase), and Akt (protein kinase B), which leads to activation of eNOS, production of NO, and thus the promotion of endothelial angiogenesis [24]. There have been numerous reports of the protective effects of NO against inflammation and oxidative stress [25]. Transgenic eNOS-deficient mice demonstrated a more extensive infarct of the middle cerebral artery (MCA), compared to controls [26]. NO effects on the regulation of endothelial integrity, anti-inflammatory and anti-apoptotic effects, as well as maintenance of cerebral blood flow, inhibition of platelet aggregation, and reduction of leukocyte adhesion [2527]. Khan et al. studied structurally different NO donors as agents of cerebrovascular protection in experimentally induced stroke in rats. They showed that NO donors promote cerebral blood flow through S-nitrosylation and may be an effective drug for acute stroke [2829].

Furthermore, Greco et al. proved the protective effect of nitroglycerin (donors of NO) on cerebral damage induced by MCA occlusion in Wistar rats. They observed a significant reduction in stroke volume in preinjected rats compared to their control group, which confirms the protective effect of nitroglycerin in vivo. They speculated that the mechanism of action is associated with the generation of a complex chain of phenomena, triggering activation of apoptosis and subsequent activation of antiapoptotic responses [30].

The biological action of ELF-EMF is still being investigated. It is suggested that ELF-EMF has an impact on the physicochemical properties of water, the liquid crystal structure generated by cholesterol, and its derivatives [3132]. Changes in ion balance caused by ELF-EMF appeal to the structure of tissue with piezoelectric and magnetostrictive properties, free radicals, diamagnetic molecules, and uncompensated magnetic spins of paramagnetic elements [33]. Therefore, ELF-EMF causes depolarization of cells having the ability to spontaneously depolarize, predominantly through Ca2+ influx [34]. In our previous study, we investigated the effect of ELF-EMF on oxidative stress in patients after ischemic stroke. We demonstrated that ELF-EMF causes activation of antioxidant enzymes [35], which leads to reduction of the oxidative modification of plasma protein (this is detailed in an article published in Advances in Clinical and Experimental Medicine). As a highly reactive molecule, NO can also regulate the level of oxidative stress. Through the covalent interaction, NO influences the activity of various enzymes. Mechanisms of this modulation can be varied: NO reacts with coenzymes and active centers containing metal ions and interacts with cysteine residues of proteins [36].

In the current study, we observed that in the ELF-EMF group, the level of plasma 3-NT was increased (Figure 2). The formation of 3-NT in protein molecules occurs in vivo by the action of nitrating agents on the polypeptide chain. The formation of 3-NT is mainly attributed to NO and superoxide anions (O2??), which react rapidly to form peroxynitrite (ONOO?). This is one of the major oxidizing and nitrating agents produced in vivo in acute and chronic inflammation, as well as in ischemia/reperfusion. Endothelial cells, macrophages, and neutrophils release large amounts of NO and O2?. Thus, increased amounts of NO contribute to the creation of 3-NT [37].

To investigate the effect of ELF-EMF on NO metabolism, we determined nitrate/nitrite concentrations in plasma. We showed that in the ELF-EMF group, the level of nitrate/nitrite compounds in plasma increased after treatment (Figure 3), and these results correspond with the data presented by Chung et al. [38]. The authors investigated the effects of ELF-EMF (60Hz, 2mT) on the level of NO, biogenic amines, and amino acid neurotransmitters in the hippocampus, cortex, thalamus, cerebellum, and striatum in rats. They found a significant increase in NO concentration in the hippocampus, thalamus, and striatum. Moreover, ELF-EMF also caused a change in the level of biogenic amines and amino acid neurotransmitters in the brain. However, the observed effect and range were different, depending on the brain area. Balind et al. determined the effect of ELF-EMF (50Hz, 0.5mT) on oxidative stress in gerbils with induced cerebral ischemia. They measured the level of NO using the Griess reagent and showed an increased level of NO, provoked by electromagnetic fields. Moreover, ELF-EMF reduces oxidative stress generated during cerebral ischemia, thus leading to a decrease in the damaged brain tissue [39].

NO is produced from L-arginine with the involvement of nitric oxide synthase. Three NOS isoforms are expressed in different tissues. Although, in the blood, only NOS2 is expressed, in 35% of the subjects in both the ELF-EMF and non-ELF-EMF groups, mRNA expression of NOS2 was under detection. In the remaining patients, the expression of NOS2 had not significantly changed after treatment. The NOS2 gene in fact encodes for iNOS, which is primarily activated during inflammation. In order to exclude deeper inflammation, we measured the concentration of TNF?, one of the main proinflammatory cytokines. TNF? is a pleiotropic cytokine that is involved in nearly all phenomena of inflammatory responses: initiating chemokine synthesis, promoting the expression of adhesion molecules, promoting the maturation of dendritic cells, and inducing the production of inflammatory mediators and other proinflammatory cytokines [40]. TNF? stimulates collagenase synthesis in synovial fibroblasts and synovial cartilage chondrocytes and activates osteoclasts, leading to joint cartilage damage, hypertrophy, bone resorption and erosion, and angiogenesis. It also activates monocytes and macrophages, enhancing their cytotoxicity and stimulating cytokine production. Chemokines and growth factors are responsible for T cell proliferation, proliferation and differentiation of B lymphocytes, and the release of inflammatory cytokines by the lymphocytes. Moreover, in the hypothalamus, TNF? stimulates prostaglandin E and IL-1 synthesis [41]. Pena-Philippides et al. investigated the effect of pulsed electromagnetic fields on injury size and neuroinflammation in mice after middle cerebral artery occlusion (MCAO). They found, using magnetic resonance imaging (MRI), that EMF reduced infarct size, as well as changed expression of genes encoding pro- and anti-inflammatory cytokines in the hemisphere with ischemic injury. After EMF exposure, genes encoding IL-1 and TNF superfamily were downregulated, while IL-10 expression was upregulated. Thus, the authors suggested that application of EMF to poststroke patients could have been beneficial through anti-inflammatory effect and reduction of injury size [42].

On the basis of our results, we suggest that the observed increase in NO level is associated with nNOS and/or eNOS activities, but not with iNOS expression. Our research is consistent with evidence shown by Cho et al., who established that ELF-EMF (60Hz, 2mT) increased the expression and activation of nNOS in rat brains [43].

The activities of nNOS and eNOS depend on calcium ions. There are many reports that the biological effect of ELF-EMF is related to the control of calcium channels [4448]. In view of these findings, the observed mechanism of increased NO generation and metabolism may be associated with calcium-ion flux.

Additionally, we noticed that ELF-EMF treatment enhances the effectiveness of poststroke rehabilitation (Table 2). Some researchers suggest that electromagnetic fields have a beneficial effect on ischemic/reperfusion injury, and in some places, therapeutic programs using ELF-EMF are considered to be standard therapy for poststroke patients [4950]. The beneficial effects of ELF-EMF include the following: improvement in the transport of cellular and mitochondrial membranes; normalization of blood rheological values; counteraction of tissue oxidation; intensification of regenerative processes; stimulation of axon growth in undamaged neurons; intensification of neuronal dissociation and differentiation; reduction of stress-induced emotional reactions and free radicals; acceleration of the return of fibre function in functional disorders; reduction of periapical scarring; and increase of the level of energetic substances in the brain tissue and erythrocytes [4853]. Grant et al. estimated the impact of low-frequency pulsed electromagnetic field on cerebral ischemia in rabbit. They observed using MRI that exposure to electromagnetic field caused extenuation of cortical ischemia oedema and reduction of neuronal injury in cortical area [54].

In conclusion, ELF-EMF therapy increases the metabolism and generation of NO, which has both neuroprotective and cytotoxic properties. An increase in NO level is probably associated with nNOS and/or eNOS activities, but not with iNOS expression, which increases mainly during inflammation. We suggested that in poststroke patients, NO demonstrated a protective effect due to significant improvement in patient functional status. Thus, our studies promote the validity of this method in poststroke rehabilitation therapy.

Acknowledgments

This study was supported by the Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz (no. 506/1136), and Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz (no. B161100000004601), and Grants for Young Scientists and PhD Students, Faculty of Biology and Environmental Protection, University of Lodz (B1611000001145.02).

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

References

1. Townsend N., Wilson L., Bhatnagar P., Wickramasinghe K., Rayner M., Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. European Heart Journal. 2016;37(42):3232–3245. doi: 10.1093/eurheartj/ehw334. [PubMed][Cross Ref] 2. Li X., Su L., Zhang X., et al. Ulinastatin downregulates TLR4 and NF-kB expression and protects mouse brains against ischemia/reperfusion injury. Neurological Research. 2017;13:1–7. doi: 10.1080/01616412.2017.1286541. [PubMed] [Cross Ref] 3. Klarner T., Barss T. S., Sun Y., Kaupp C., Loadman P. M., Zehr E. P. Long-term plasticity in reflex excitability induced by five weeks of arm and leg cycling training after stroke. Brain Sciences. 2016;6(4) doi: 10.3390/brainsci6040054.[PMC free article] [PubMed] [Cross Ref] 4. Cheng Y., Dai Y., Zhu X., et al. Extremely low-frequency electromagnetic fields enhance the proliferation and differentiation of neural progenitor cells cultured from ischemic brains. Neuroreport. 2015;26(15):896–902. doi: 10.1097/WNR.0000000000000450. [PubMed] [Cross Ref] 5. Cichon N., Olejnik A. K., Miller E., Saluk J. The multipotent action of magnetic fields. Biologia. 2016;71(10):1103–1110. 6. Robertson J. A., Thomas A. W., Bureau Y., Prato F. S. The influence of extremely low frequency magnetic fields on cytoprotection and repair. Bioelectromagnetics. 2007;28(1):16–30. doi: 10.1002/bem.20258. [PubMed] [Cross Ref] 7. Kumar S., Singh R. K., Bhardwaj T. R. Therapeutic role of nitric oxide as emerging molecule. Biomedicine & Pharmacotherapy. 2017;85:182–201. doi: 10.1016/j.biopha.2016.11.125. [PubMed] [Cross Ref] 8. Alderton W. K., Cooper C. E., Knowles R. G. Nitric oxide synthases: structure, function and inhibition. The Biochemical Journal. 2001;357, Part 3:593–615.[PMC free article] [PubMed] 9. Li H., Poulos T. L. Structure-function studies on nitric oxide synthases. Journal of Inorganic Biochemistry. 2005;99:293–305. doi: 10.1016/j.jinorgbio.2004.10.016.[PubMed] [Cross Ref] 10. Lei J., Vodovotz Y., Tzeng E., Billiar T. R. Nitric oxide, a protective molecule in the cardiovascular system. Nitric Oxide. 2013;35:175–185. doi: 10.1016/j.niox.2013.09.004. [PubMed] [Cross Ref] 11. Rasool M., Ashraf M. A., Malik A., et al. Comparative study of extrapolative factors linked with oxidative injury and anti-inflammatory status in chronic kidney disease patients experiencing cardiovascular distress. PLoS One. 2017;12(2, article e0171561) doi: 10.1371/journal.pone.0171561. [PMC free article] [PubMed][Cross Ref] 12. Kozlov A. V., Bahrami S., Redl H., Szabo C. Alterations in nitric oxide homeostasis during traumatic brain injury. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 2017 doi: 10.1016/j.bbadis.2016.12.020. In press. [PubMed] [Cross Ref] 13. Mika T. In: Metodyka Magnetoterapii. Mika T., Kasprzak W., editors. Wydawnictwo Lekarskie PZWL. Warszawa: Fizykoterapia; 2013. pp. 337–339. 14. Khan J., Brennan D. M., Bradley N., Gao B., Bruckdorfer R., Jacobs M., Part 2 3-Nitrotyrosine in the proteins of human plasma determined by an ELISA method. The Biochemical Journal. 1998;330:795–801. [PMC free article] [PubMed] 15. Kolodziejczyk J., Saluk-Juszczak J., Wachowicz B. L-Carnitine protects plasma components against oxidative alterations. Nutrition. 2011;27(6):693–699. doi: 10.1016/j.nut.2010.06.009. [PubMed] [Cross Ref] 16. Declèves A. É., Jadot I., Colombaro V., et al. Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: an old friend with new assets. Experimental Physiology. 2016;101(1):193–206. doi: 10.1113/EP085333. [PubMed][Cross Ref] 17. Bobi?ska K., Szemraj J., Czarny P., Ga?ecki P. Expression and activity of metalloproteinases in depression. Medical Science Monitor. 2016;22:1334–1341.[PMC free article] [PubMed] 18. Désy O., Carignan D., Caruso M., de Campos-Lima P. O. Methanol induces a discrete transcriptional dysregulation that leads to cytokine overproduction in activated lymphocytes. Toxicological Sciences. 2010;117(2):303–313. doi: 10.1093/toxsci/kfq212. [PubMed] [Cross Ref] 19. Allman C., Amadi U., Winkler A. M., et al. Ipsilesional anodal tDCS enhances the functional benefits of rehabilitation in patients after stroke. Science Translational Medicine. 2016;8(330):p. 330re1. doi: 10.1126/scitranslmed.aad5651.[PMC free article] [PubMed] [Cross Ref] 20. Wang H. G., Lu F. M., Jin I., et al. Presynaptic and postsynaptic roles of NO, cGK, and RhoA in long-lasting potentiation and aggregation of synaptic proteins. Neuron. 2005;45:389–403. doi: 10.1016/j.neuron.2005.01.011. [PubMed] [Cross Ref] 21. Yang Y. R., Jung J. H., Kim S. J., et al. Forebrain-specific ablation of phospholipase C?1 causes manic-like behavior. Molecular Psychiatry. 2017 doi: 10.1038/mp.2016.261. [PubMed] [Cross Ref] 22. Fekete C. D., Goz R. U., Dinallo S., et al. In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex. The Journal of Comparative Neurology. 2017;525(5):1291–1311. doi: 10.1002/cne.24137. [PubMed] [Cross Ref] 23. Ungvari Z., Tarantini S., Hertelendy P., et al. Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience. 2017;39(1):33–42. doi: 10.1007/s11357-017-9964-z. [PMC free article] [PubMed] [Cross Ref] 24. Su K. H., Lin S. J., Wei J., et al. The essential role of transient receptor potential vanilloid 1 in simvastatin-induced activation of endothelial nitric oxide synthase and angiogenesis. Acta Physiologica (Oxford, England) 2014;212(3):191–204. doi: 10.1111/apha.12378. [PubMed] [Cross Ref] 25. Cirino G., Fiorucci S., Sessa W. C. Endothelial nitric oxide synthase: the Cinderella of inflammation? Trends in Pharmacological Sciences. 2003;24:91–95. doi: 10.1016/S0165-6147(02)00049-4. [PubMed] [Cross Ref] 26. Huang Z., Huang P. L., Ma J., et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. Journal of Cerebral Blood Flow and Metabolism. 1996;16:981–987. doi: 10.1097/00004647-199609000-00023.[PubMed] [Cross Ref] 27. Li H., Forstermann U. Nitric oxide in the pathogenesis of vascular disease. The Journal of Pathology. 2000;190:244–254. doi: 10.1002/(SICI)1096-9896(200002)190:3<244::AID-PATH575>3.0.CO;2-8. [PubMed] [Cross Ref] 28. Khan M., Jatana M., Elango C., Paintlia A. S., Singh A. K., Singh I. Cerebrovascular protection by various nitric oxide donors in rats after experimental stroke. Nitric Oxide. 2006;15(2):114–124. doi: 10.1016/j.niox.2006.01.008. [PubMed][Cross Ref] 29. Khan M., Sekhon B., Giri S., et al. S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. Journal of Cerebral Blood Flow and Metabolism. 2005;25:177–192. doi: 10.1038/sj.jcbfm.9600012. [PubMed] [Cross Ref] 30. Greco R., Amantea D., Blandini F., et al. Neuroprotective effect of nitroglycerin in a rodent model of ischemic stroke: evaluation of Bcl-2 expression. International Review of Neurobiology. 2007;82:423–435. doi: 10.1016/S0074-7742(07)82024-1.[PubMed] [Cross Ref] 31. Sulpizio M., Falone S., Amicarelli F., et al. Molecular basis underlying the biological effects elicited by extremely low-frequency magnetic field (ELF-MF) on neuroblastoma cells. Journal of Cellular Biochemistry. 2011;112:3797–3806. doi: 10.1002/jcb.23310. [PubMed] [Cross Ref] 32. Yi G., Wang J., Wei X., et al. Effects of extremely low-frequency magnetic fields on the response of a conductance-based neuron model. International Journal of Neural Systems. 2014;24(1, article 1450007) doi: 10.1142/S0129065714500075. [PubMed][Cross Ref] 33. Brisdelli F., Bennato F., Bozzi A., Cinque B., Mancini F., Iorio R. ELF-MF attenuates quercetin-induced apoptosis in K562 cells through modulating the expression of Bcl-2 family proteins. Molecular and Cellular Biochemistry. 2014;397(1-2):33–43. doi: 10.1007/s11010-014-2169-1. [PubMed] [Cross Ref] 34. Morgado-Valle C., Verdugo-Díaz L., García D. E., Morales-Orozco C., Drucker-Colín R. The role of voltage-gated Ca2+ channels in neurite growth of cultured chromaffin cells induced by extremely low frequency (ELF) magnetic field stimulation. Cell and Tissue Research. 1998;291(2):217–230. [PubMed] 35. Cichon N., Bijak M., Miller E., Saluk J. Extremely low-frequency electromagnetic field (ELF-EMF) reduces oxidative stress and improves functional and psychological status in ischemic stroke patients. Bioeletromagtetics. 2017;38(5):386–396. doi: 10.1002/bem.22055. [PubMed] [Cross Ref] 36. Wink D. A., Miranda K. M., Espey M. G., et al. Mechanisms of the antioxidant effects of nitric oxide. Antioxidants & Redox Signaling. 2001;3(2):203–213. doi: 10.1089/152308601300185179. [PubMed] [Cross Ref] 37. Ronson R. S., Nakamura M., Vinten-Johansen J. The cardiovascular effects and implications of peroxynitrite. Cardiovascular Research. 1999;44:47–59. [PubMed] 38. Chung Y. H., Lee Y. J., Lee H. S., et al. Extremely low frequency magnetic field modulates the level of neurotransmitters. The Korean Journal of Physiology and Pharmacology. 2015;19(1):15–20. doi: 10.4196/kjpp.2015.19.1.15. [PMC free article][PubMed] [Cross Ref] 39. Rauš B. S., Selakovi? V., Radenovi? L., Proli? Z., Jana? B. Extremely low frequency magnetic field (50 Hz, 0.5 mT) reduces oxidative stress in the brain of gerbils submitted to global cerebral ischemia. PLoS One. 2014;9(2, article e88921) doi: 10.1371/journal.pone.0088921. [PMC free article] [PubMed] [Cross Ref] 40. Wu P., Jia F., Zhang B., Zhang P. Risk of cardiovascular disease in inflammatory bowel disease. Experimental and Therapeutic Medicine. 2017;13(2):395–400. doi: 10.3892/etm.2016.3966. [PMC free article] [PubMed] [Cross Ref] 41. Godos J., Biondi A., Galvano F., et al. Markers of systemic inflammation and colorectal adenoma risk: meta-analysis of observational studies. World Journal of Gastroenterology. 2017;23(10):1909–1919. doi: 10.3748/wjg.v23.i10.1909.[PMC free article] [PubMed] [Cross Ref] 42. Pena-Philippides J. C., Yang Y., Bragina O., Hagberg S., Nemoto E., Roitbak T. Effect of pulsed electromagnetic field (PEMF) on infarct size and inflammation after cerebral ischemia in mice. Translational Stroke Research. 2014;5(4):491–500. doi: 10.1007/s12975-014-0334-1. [PubMed] [Cross Ref] 43. Cho S. I., Nam Y. S., Chu L. Y., et al. Extremely low-frequency magnetic fields modulate nitric oxide signaling in rat brain. Bioelectromagnetics. 2012;33(7):568–574. doi: 10.1002/bem.21715. [PubMed] [Cross Ref] 44. Walleczek J. Electromagnetic field effects on cells of the immune system: the role of calcium signaling. The FASEB Journal. 1992;6:3177–3185. [PubMed] 45. Grassi C., D’Ascenzo M., Torsello A., et al. Effects of 50 Hz electromagnetic fields on voltage-gated Ca2+ channels and their role in modulation of neuroendocrine cell proliferation and death. Cell Calcium. 2004;35:307–315. doi: 10.1016/j.ceca.2003.09.001. [PubMed] [Cross Ref] 46. Piacentini R., Ripoli C., Mezzogori D., Azzena G. B., Grassi C. Extremely low-frequency electromagnetic fields promote in vitro neurogenesis via upregulation of Cav1-channel activity. Journal of Cellular Physiology. 2008;215:129–139. doi: 10.1002/jcp.21293. [PubMed] [Cross Ref] 47. Gobba F., Malagoli D., Ottaviani E. Effects of 50 Hz magnetic fields on fMLP-induced shape changes in invertebrate immunocytes: the role of calcium ion channels. Bioelectromagnetics. 2003;24:277–282. doi: 10.1002/bem.10102. [PubMed][Cross Ref] 48. Craviso G. L., Choe S., Chatterjee P., Chatterjee I., Vernier P. T. Nanosecond electric pulses: a novel stimulus for triggering Ca2+ influx into chromaffin cells via voltage-gated Ca2+ channels. Cellular and Molecular Neurobiology. 2010;30:1259–1265. doi: 10.1007/s10571-010-9573-1. [PubMed] [Cross Ref] 49. Sieroñ A., Cieslar G. Use of magnetic fields in medicine – 15 years of personal experience. Wiadomo?ci Lekarskie. 2003;56:434–441. [PubMed] 50. Wolda?ska-Oko?ska M., Czernicki J. Effect of low frequency magnetic fields used in magnetotherapy and magnetostimulation on the rehabilitation results of patients after ischemic stroke. Przegla?d Lekarski. 2007;64(2):74–77. [PubMed] 51. Capone F., Dileone M., Profice P., et al. Does exposure to extremely low frequency magnetic fields produce functional changes in human brain? Journal of Neural Transmission (Vienna) 2009;116(3):257–265. doi: 10.1007/s00702-009-0184-2.[PubMed] [Cross Ref] 52. Miecznik A., Czernicki J., Krukowska J. Influence of magnetic field of different characteristics on blood pressure in patients with back pain syndromes and hypertensive disease. Acta Bio-Optica et Informatica Medica. 2001;7(1-2):9–13. 53. Di Lazzaro V., Capone F., Apollonio F., et al. A consensus panel review of central nervous system effects of the exposure to low-intensity extremely low-frequency magnetic fields. Brain Stimulation. 2013;6(4):469–476. doi: 10.1016/j.brs.2013.01.004.[PubMed] [Cross Ref] 54. Grant G., Cadossi R., Steinberg G. Protection against focal cerebral ischemia following exposure to a pulsed electromagnetic field. Bioelectromagnetics. 1994;15(3):205–216. [PubMed]

Measurements of human tumour necrosis factor alpha (TNF?) in plasma samples were made with a Human TNF? ELISA development kit (MABTECH, Cincinnati, OH, USA), in accordance with the manufacturer’s protocol. The combination of two coating antibodies (TNF3 and TNF4) were used for the analysis. The absorbance was measured at 450nm, and TNF? concentration was expressed as pg/mL [18].

NIH Bioelectromagnetics Applications in Medicine

PANEL MEMBERS AND CONTRIBUTING AUTHORS

Beverly Rubik, Ph.D.–Chair

Robert O. Becker, M.D.

Robert G. Flower, M.S.

Carlton F. Hazlewood, Ph.D.

Abraham R. Liboff, Ph.D.

Jan Walleczek, Ph.D.

Overview

Bioelectromagnetics (BEM) is the emerging science that studies how living organisms interact with electromagnetic (EM) fields. Electrical phenomena are found in all living organisms. Moreover, electrical currents exist in the body that are capable of producing magnetic fields that extend outside the body. Consequently, they can be influenced by external magnetic and EM fields as well. Changes in the body’s natural fields may produce physical and behavioral changes. To understand how these field effects may occur, it is first useful to discuss some basic phenomena associated with EM fields.

In its simplest form, a magnetic field is a field of magnetic force extending out from a permanent magnet. Magnetic fields are produced by moving electrical currents. For example, when an electrical current flows in a wire, the movement of the electrons through the wire produces a magnetic field in the space around the wire (fig. 1). If the current is a direct current (DC), it flows in one direction and the magnetic field is steady. If the electrical current in the wire is pulsing, or fluctuating–such as in alternating current (AC), which means the current flow is switching directions–the magnetic field also fluctuates. The strength of the magnetic field depends on the amount of current flowing in the wire; the more current, the stronger the magnetic field. An EM field contains both an electrical field and a magnetic field. In the case of a fluctuating magnetic or EM field, the field is characterized by its rate, or frequency, of fluctuation (e.g., one fluctuation per second is equal to 1 hertz [Hz], the unit of frequency).

A field fluctuating in this fashion theoretically extends out in space to infinity, decreasing in strength with distance and ultimately becoming lost in the jumble of other EM and magnetic fields that fill space. Since it is fluctuating at a certain frequency, it also has a wave motion (fig. 2). The wave moves outward at the speed of light (roughly 186,000 miles per second). As a result, it has a wavelength (i.e., the distance between crests of the wave) that is inversely related to its frequency. For example, a 1-Hz frequency has a wavelength of millions of miles, whereas a 1-million-Hz, or 1-megahertz (MHz), frequency has a wavelength of several hundred feet, and a 100-MHz frequency has a wavelength of about 6 feet.

All of the known frequencies of EM waves or fields are represented in the EM spectrum, ranging from DC (zero frequency) to the highest frequencies, such as gamma and cosmic rays. The EM spectrum includes x rays, visible light, microwaves, and television and radio frequencies, among many others. Moreover, all EM fields are force fields that carry energy through space and are capable of producing an effect at a distance. These fields have characteristics of both waves and particles. Depending on what types of experiments one does to investigate light, radio waves, or any other part of the EM spectrum, one will find either waves or particles called photons.

A photon is a tiny packet of energy that has no measurable mass. The greater the energy of the photon, the greater the frequency associated with its waveform. The human eye detects only a narrow band of frequencies within the EM spectrum, that of light. One photon gives up its energy to the retina in the back of the eye, which converts it into an electrical signal in the nervous system that produces the sensation of light.

Table 1 shows the usual classification of EM fields in terms of their frequency of oscillation, ranging from DC through extremely low frequency (ELF), low frequency, radio frequency (RF), microwave and radar, infrared, visible light, ultraviolet, x rays, and gamma rays. For oscillating fields, the higher the frequency, the greater the energy.

Endogenous fields (those produced within the body) are to be distinguished from exogenous fields (those produced by sources outside the body). Exogenous EM fields can be classified as either natural, such as the earth’s geomagnetic field, or artificial (e.g., power lines, transformers, appliances, radio transmitters, and medical devices). The term electropollution refers to artificial EM fields that may be associated with health risks.

In radiation biophysics, an EM field is classified as ionizing if its energy is high enough to dislodge electrons from an atom or molecule. High-energy, high-frequency forms of EM radiation, such as gamma rays and x rays, are strongly ionizing in biological matter. For this reason, prolonged exposure to such rays is harmful. Radiation in the middle portion of the frequency and energy spectrum–such as visible, especially ultraviolet, light–is weakly ionizing (i.e., it can be ionizing or not, depending on the target molecules).

Although it has long been known that exposure to strongly ionizing EM radiation can cause extreme damage in biological tissues, only recently have epidemiological studies and other evidence implicated long-term exposure to nonionizing, exogenous EM fields, such as those emitted by power lines, in increased health hazards. These hazards may include an increased risk in children of developing leukemia (Bierbaum and Peters, 1991; Nair et al., 1989; Wilson et al., 1990a).

However, it also has been discovered that oscillating nonionizing EM fields in the ELF range can have vigorous biological effects that may be beneficial and thus nonharmful (Becker and Marino, 1982; Brighton and Pollack, 1991). This discovery is a cornerstone in the foundation of BEM research and application.

Specific changes in the field configuration and exposure pattern of low-level EM fields can produce highly specific biological responses. More intriguing, some specific frequencies have highly specific effects on tissues in the body, just as drugs have their specific effects on target tissues. The actual mechanism by which EM fields produce biological effects is under intense study. Evidence suggests that the cell membrane may be one of the primary locations where applied EM fields act on the cell. EM forces at the membrane’s outer surface could modify ligand-receptor interactions (e.g., the binding of messenger chemicals such as hormones and growth factors to specialized cell membrane molecules called receptors), which in turn would alter the state of large membrane molecules that play a role in controlling the cell’s internal processes (Tenforde and Kaune, 1987). Experiments to establish the full details of a mechanistic chain of events such as this, however, are just beginning.

Another line of study focuses on the endogenous EM fields. At the level of body tissues and organs, electrical activity is known to exhibit macroscopic patterns that contain medically useful information. For example, the diagnostic procedures of electroencephalography (EEG) and electrocardiography are based on detection of endogenous EM fields produced in the central nervous system and heart muscle, respectively. Taking the observations in these two systems a step further, current BEM research is exploring the possibility that weak EM fields associated with nerve activity in other tissues and organs might also carry information of diagnostic value. New technologies for constructing extremely sensitive EM transducers (e.g., magnetometers and electrometers) and for signal processing recently have made this line of research feasible.

Recent BEM research has uncovered a form of endogenous EM radiation in the visible region of the spectrum that is emitted by most living organisms, ranging from plant seeds to humans (Chwirot et al., 1987, Mathew and Rumar, in press, Popp et al., 1984, 1988, 1992). Some evidence indicates that this extremely low-level light, known as biophoton emission, may be important in bioregulation, membrane transport, and gene expression. It is possible that the effects (both beneficial and harmful) of exogenous fields may be mediated by alterations in endogenous fields. Thus, externally applied EM fields from medical devices may act to correct abnormalities in endogenous EM fields characteristic of disease states. Furthermore, the energy of the biophotons and processes involving their emission as well as other endogenous fields of the body may prove to be involved in energetic therapies, such as healer interactions.

At the cutting edge of BEM research lies the question of how endogenous body EM fields may change as a result of changes in consciousness. The recent formation and rapid growth of a new society, the International Society for the Study of Subtle Energies and Energy Medicine, is indicative of the growing interest in this field._

Figure 3 illustrates several types of EM fields of interest in BEM research.

Medical Applications of Bioelectromagnetics

Medical research applications of BEM began almost simultaneously with Michael Faraday’s discovery of electromagnetic induction in the late 1700s. Immediately thereafter came the famous experiments of the 18th-century physician and physicist Luigi Galvani, who showed with frog legs that there was a connection between electricity and muscle contraction. This was followed by the work of Alessandro Volta, the Italian physicist whose investigation into electricity led him to correctly interpret Galvani’s experiments with muscle, showing that the metal electrodes and not the tissue generated the current. From this early work came a plethora of devices for the diagnosis and treatment of disease, using first static electricity, then electrical currents, and, later, frequencies from different regions of the EM spectrum. Like other treatment methods, certain devices were seen as unconventional at first, only to become widely accepted later. For example, many of the medical devices that make up the core of modern, scientifically based medicine, such as x-ray devices, at one time were considered highly experimental.

Most of today’s medical EM devices use relatively large levels of electrical, magnetic, or EM energy. The main topic of this chapter, however, is the use of the nonionizing portion of the EM spectrum, particularly at low levels, which is the focus of BEM research.

Nonionizing BEM medical applications may be classified according to whether they are thermal (heat producing in biologic tissue) or nonthermal. Thermal applications of nonionizing radiation (i.e., application of heat) include RF hyperthermia, laser and RF surgery, and RF diathermy.

The most important BEM modalities in alternative medicine are the nonthermal applications of nonionizing radiation. The term nonthermal is used with two different meanings in the medical and scientific literature. Biologically (or medically) nonthermal means that it “causes no significant gross tissue heating”; this is the most common usage. Physically (or scientifically) nonthermal means “below the thermal noise limit at physiological temperatures.” The energy level of thermal noise is much lower than that required to cause heating of tissue; thus, any physically nonthermal application is automatically biologically nonthermal.

All of the nonthermal applications of nonionizing radiation are nonthermal in the biological sense. That is, they cause no significant heating of tissue. Some of the newer, unconventional BEM applications are also physically nonthermal. A variety of alternative medical practices developed outside the United States employ nonionizing EM fields at nonthermal intensities. For instance, microwave resonance therapy, which is used primarily in Russia, employs low-intensity (either continuous or pulse-modulated), sinusoidal microwave radiation to treat a variety of conditions, including arthritis, ulcers, esophagitis, hypertension, chronic pain, cerebral palsy, neurological disorders, and side effects of cancer chemotherapy (Devyatkov et al., 1991). Thousands of people in Russia also have been treated by specific frequencies of extremely low-level microwaves applied at certain acupuncture points.

The mechanism of action of microwave resonance therapy is thought to involve modifications in cell membrane transport or production of chemical mediators or both. Although a sizable body of Russian-language literature on this technique already exists, no independent validation studies have been conducted in the West. However, if such treatments prove to be effective, current views on the role of information and thermal noise (i.e., order and disorder) in living systems, which hold that biological information is stored in molecular structures, may need revision. It may be that such information is stored at the level of the whole organism in the endogenous EM field, which may be used informationally in biological regulation and cellular communication (i.e., not due to energy content or power intensity). If exogenous, extremely low-level nonionizing fields with energy contents well below the thermal noise limit produce biological effects, they may be acting on the body in such a way that they alter the body’s own field. That is to say, biological information would be altered by the exogenous EM fields.

The eight major new (or “unconventional”) applications of nonthermal, nonionizing EM fields are as follows:

1. Bone repair.

2. Nerve stimulation.

3. Wound healing.

4. Treatment of osteoarthritis.

5. Electroacupuncture.

6. Tissue regeneration.

7. Immune system stimulation.

8. Neuroendocrine modulations.

These applications of BEM and the evidence for their efficacy are discussed in the following section.

Research Base

Applications 1 through 5 above have been clinically tested and are in limited clinical use. On the basis of existing animal and cellular studies, applications 6 through 8 offer the potential for developing new clinical treatments, but clinical trials have not yet been conducted.

Bone Repair

Three types of applied EM fields are known to promote healing of nonunion bone fractures (i.e., those that fail to heal spontaneously):

* Pulsed EM fields (PEMFs) and sinusoidal EM fields (AC fields).

* DC fields.

* Combined AC-DC magnetic fields tuned to ion-resonant frequencies (these are extremely low-intensity, physically nonthermal fields) (Weinstein et al., 1990).

Approval of the U.S. Food and Drug Administration (FDA) has been obtained on PEMF and DC applications and is pending for the AC-DC application. In PEMF and AC applications, the repetition frequencies used are in the ELF range (Bassett, 1989). In DC applications, magnetic field intensities range from 100 microgauss to 100 gauss (G), and electric currents range from less than 0.1 microampere to milliamperes (Baranowski and Black, 1987)._ FDA approval of these therapies covers only their use to promote healing of nonunion bone fractures, not to accelerate routine healing of uncomplicated fractures.

Efficacy of EM bone repair treatment has been confirmed in double-blind clinical trials (Barker et al., 1984; Sharrard, 1990). A conservative estimate is that as of 1985 more than 100,000 people had been treated with such devices (Bassett et al., 1974, 1982; Brighton et al., 1979, 1981; Goldenberg and Hansen, 1972; Hinsenkamp et al., 1985).

Stimulation and Measurement of Nerve Activity

These applications fall into the following seven categories:

1. Transcutaneous electrical nerve stimulation (TENS). In this medical application, two electrodes are applied to the skin via wires attached to a portable electrical generating device, which may be clipped to the patient’s belt (Hagfors and Hyme, 1975). Perhaps more than 100 types of FDA-approved devices in this category are currently available and used in physical therapy for pain relief. All of them operate on the same basis.

2. Transcranial electrostimulation (TCES). These devices are similar to the TENS units. They apply extremely low currents (below the nerve excitation threshold) to the brain via two electrodes applied to the head and are used for behavioral/psychological modification (e.g., to reduce symptoms of depression, anxiety, and insomnia) (Shealy et al., 1992). A recent meta-analysis covering at least 12 clinical trials selected from more than 100 published reports found that TCES can alleviate anxiety disorders (Klawansky et al., 1992). With support from the National Institutes of Health (NIH), TCES is under evaluation for alleviation of drug dependence.

3. Neuromagnetic stimulation. In this application, which has both diagnostic and therapeutic uses, a magnetic pulse is applied noninvasively to a part of the patient’s body to stimulate nerve activity. In diagnostic use, a pulse is applied to the cerebral cortex, and the patient’s physiological responses are monitored to obtain a dynamic picture of the brain-body interface (Hallett and Cohen, 1989). As a treatment modality, it is being used in lieu of electroshock therapy to treat certain types of affective disorder (e.g., major depression) and seizures (Anninos and Tsagas, 1991). Neuromagnetic stimulation also is used in nerve conduction studies for conditions such as carpal tunnel syndrome.

4. Electromyography. This diagnostic application detects electrical potentials associated with muscle contraction. Specific electrical patterns have been associated with certain abnormal states (e.g., denervated muscle). This method, along with electromyographic biofeedback, is being used to treat carpal tunnel syndrome and other movement disorders.

5. Electroencephalography. This neurodiagnostic application detects brainwaves. Coupled with EEG biofeedback it is used to treat a variety of conditions, such as learning disabilities, attention deficit and hyperactivity disorders, chronic alcoholism, and stroke.

6. Electroretinography. This diagnostic application monitors electrical potentials across the retina to assess eye movements. This is one of the few methods available for noninvasive monitoring of rapid eye movement sleep.

7. Low-energy emission therapy. This application uses an antenna positioned in the patient’s mouth to administer amplitude-modulated EM fields. It has been shown to affect the central nervous system, and pilot clinical studies show efficacy in treating insomnia (Hajdukovic et al., 1992) and hypertension (Pasche et al., 1989).

Soft-tissue Wound Healing

The following studies have demonstrated accelerated healing of soft-tissue wounds using DC, PEMF, and electrochemical modalities:

* When wound healing is abnormal (retarded or arrested), electric or magnetic field applications may trigger healing to occur. A review of several reports indicates that fields may be useful in this regard (Lee et al., 1993; Vodovnik and Karba, 1992).

* PEMFs have been used clinically to treat venous skin ulcers. Results of several double-blind studies showed that PEMF stimulation promotes cell activation and cell proliferation through an effect on the cell membrane, particularly on endothelial cells (Ieran et al., 1990; Stiller et al., 1992).

* ELF and RF fields are applied to accelerate wound healing. Since skin wounds have unique electrical potentials and currents, stimulation of these electrical factors by a variety of exogenous EM fields can aid in the healing process by causing dedifferentiation (i.e., conversion to a more primitive form) of the nearby cells followed by accelerated cell proliferation (O’Connor et al., 1990).

* An electrochemical treatment that provides scarless regenerative wound healing uses electricity solely to introduce active metallic ions, such as silver, into the tissue. The electric field plays no role itself (Becker, 1987, 1990, 1992).

* PEMF increases the rate of formation of epithelial (skin) cells in partially healed wounds (Mertz et al., 1988).

* AC EM fields promote the repair of injured vascular networks (Herbst et al., 1988).

* EM devices have been patented for treating atherosclerotic lesions (i.e., small blood clots that build up on the walls of arteries and cause cardiovascular disease) and to control tissue growth (Gordon, 1986; Liboff et al., 1992b).

Osteoarthritis

In a recent clinical trial using a double-blind, randomized protocol with placebo control, osteoarthritis (primarily of the knee) treated noninvasively by pulsed 30-Hz, 60-G PEMFs showed the treatment group improved substantially more than the placebo group (Trock et al., 1993). It is believed that applied magnetic fields act to suppress inflammatory responses at the cell membrane level (O’Connor et al., 1990).

Electroacupuncture

Electrical stimulation via acupuncture needles is often used as an enhancement or replacement for manual needling. Clinical benefits have been demonstrated for the use of electrical stimulation (electrostimulation) in combination with acupuncture as well as for electrostimulation applied directly to acupuncture points.

As an enhancement of acupuncture, a small-scale study showed electrostimulation with acupuncture to be beneficial in the treatment of post-operative pain (Christensen and Noreng, 1989). Other controlled studies have shown good success in using electrostimulation with acupuncture in the treatment of chemotherapy-induced sickness in cancer patients (Dundee and Ghaly, 1989). In addition, electrical stimulation with acupuncture was recently shown to be beneficial in the treatment of renal colic (Lee et al., 1992).

As a replacement for acupuncture, electrostimulation applied in a controlled study to acupuncture points by a TENS unit was effective in inducing uterine contractions in postterm pregnant women (Dunn and Rogers, 1989). Further, research with rats has shown that electrostimulation at such points can enhance peripheral motor nerve regeneration (McDevitt et al., 1987) and sensory nerve sprouting (Pomeranz et al., 1984).

Regeneration

Animal research in this area indicates that the body’s endogenous EM fields are involved in growth processes and that modifications of these fields can lead to modest regeneration of severed limbs (Becker, 1987; Becker and Spadero, 1972; Smith, 1967). Russian research and clinical applications, along with studies now under way in the United States, indicate that low-intensity microwaves apparently stimulate bone marrow stem cell division and may be useful in enhancing the effects of chemotherapy by maintaining the formation and development, or hematopoiesis, of various types of blood cells (Devyatkov et al., 1991).

The following studies are also relevant to the use of BEM for regeneration:

* PEMF applications to promote peripheral nerve regeneration (Orgel et al., 1992; Sisken, 1992).

* The “diapulse” method of using pulsed, high-frequency EM fields for human wrist nerve regeneration (Wilson et al., 1974).

* DC applications to promote rat spinal cord regeneration (Fehlings et al., 1992; Hurlbert and Tator, 1992).

* Swedish work showing that BEM promotes rat sciatic nerve regeneration (Kanje and Rusovan, 1992; Rusovan and Kanje, 1991, 1992; Rusovan et al., 1992).

Immune System

During the past two decades, the effects of EM exposure on the immune system and its components have been extensively studied. While early studies indicated that long-term exposure to EM fields might negatively affect the immune system, there is promising new research showing that applied EM fields may be able to beneficially modulate immune responses. For example, studies with human lymphocytes show that exogenous EM or magnetic fields can produce changes in calcium transport (Walleczek, 1992) and cause mediation of the mitogenic response (i.e., the stimulation of the division of cellular nuclei; certain types of immune cells begin to divide and reproduce rapidly in response to certain stimuli, or mitogens). This finding has led to research investigating the possible augmentation by applied EM fields of a type of immune cell population called natural killer cells, which are important in helping the body fight against cancer and viruses (Cadossi et al., 1988a, 1988b; Cossarizza et al., 1989a, 1989b, 1989c).

Potential Neuroendocrine Modulations

Low-level PEMFs have typically been shown to suppress levels of melatonin, which is secreted by the pineal gland and is believed to regulate the body’s inner clock (Lerchl et al., 1990; Wilson et al., 1990b). Melatonin, as a hormone, is oncostatic (i.e., it stops cancer growth). Thus, if melatonin can be suppressed by certain magnetic fields, it also may be possible to employ magnetic fields with different characteristics to stimulate melatonin secretion for the treatment of cancer. Other applications may include use of EM fields to affect melatonin secretion to normalize circadian rhythms in people with jet lag and sleep cycle disturbances.

Table 2 provides an overview of selected citations to the refereed literature for these applications.

Future Research Opportunities

Although to date there is an extensive base of literature on the use of BEM for medical applications, the overall research strategy into this phenomenon has been quite fragmented. Because of BEM’s potential for the treatment of a wide range of conditions, an integrated research program is needed that includes both basic and clinical research in BEM. These two approaches should be pursued vigorously and simultaneously along parallel tracks.

Basic research is needed to refine or develop new BEM technologies with the aim of establishing the fundamental knowledge about the body’s endogenous EM fields and how they interact with clinically applied EM fields. A basic understanding of the BEM of the human body might provide insight into the scientific bioenergetic or bioinformational principles by which other areas of alternative medicine, such as homeopathy, acupuncture, and energetic therapies, may function. Furthermore, fundamental knowledge of BEM principles in the human body, in conjunction with psychophysiological states, might help facilitate understanding of mind-body regulation.

Clinical research, including preclinical assessments, is also essential, with the aim of bringing the most promising BEM treatments and diagnostics from limited use into widespread use as quickly as possible. Although a number of BEM devices show promise as new diagnostics or therapeutics, they must be tested on humans to show exactly when they are effective and when they are not. Moreover, measures of clinical effectiveness and safety are required for FDA approval of BEM medical devices. Ultimately, knowledge about the safety of new BEM medical devices can be ascertained only from the appropriate clinical trials.

Basic

The current status of basic research in BEM may be summarized as follows:

* Nonionizing, nonthermal exogenous EM fields exert measurable bioeffects in living organisms. In general, the organism’s response to applied EM fields is highly frequency specific and the dose-response curve is nonlinear (i.e., application of an additional amount of the EM field does not elicit a response of equal magnitude; the response eventually diminishes no matter how additional EM stimuli are applied). Extremely weak EM fields may, at the proper frequency and site of application, produce large effects that are either clinically beneficial or harmful.

* The cell membrane has been proposed as the primary site of transduction of EM field bioeffects. Relevant mechanisms may include changes in cell-membrane binding and transport processes, displacement or deformation of polarized molecules, modifications in the conformation of biological water (i.e., water that comprises organisms), and others.

* The physical mechanisms by which EM fields may act on biomolecules are far too complex to discuss here. However, the following references propose such physical mechanisms: Grundler et al., in press; Liboff, 1985, 1991; and Liboff et al., 1991.

* Endogenous nonthermal EM fields ranging from DC to the visible spectral region may be intimately involved in regulating physiological and biochemical processes.

Consequently, the following pressing needs should be addressed in developing a basic BEM research program:

* Standardized protocols for measuring dosages for therapeutically applied EM fields should be established and followed uniformly in BEM research. Protocols are needed for characterizing (i.e., defining and measuring) EM field sources (both exogenous and endogenous) and EM parameters of biological subjects. Such variables must be characterized in greater detail than is commonly practiced in clinical research. Artifacts caused by ambient EM fields in the laboratory environment (e.g., from power lines and laboratory equipment) must be avoided.

* In general, a balanced, strategic approach to basic research–including studies in humans, animals, and cells along with theoretical modeling and close collaboration with other investigators in alternative medicine–will produce the most valuable results in the long run.

* Many independent parameters characterize nonthermal nonionizing EM fields, including pulsed vs. nonpulsed and sinusoidal vs. other waveforms; frequency; phase; intensity (as a function of spatial position); voltage; and current. If multiple fields are combined, these parameters must be specified for each component. Additional parameters necessary for characterizing the medical application of EM fields include the site of application and the time course of exposure. All of these can be experimentally varied, producing an enormous range of possibilities. To date, there has been little systematic research to explore the potential biological effects of this vast array of applied field parameter characteristics.

Clinical

Clinical trials of BEM-based treatments for the following conditions may yield useful results relatively soon: arthritis, psychophysiological states (including drug dependence and epilepsy), wound healing and regeneration, intractable pain, Parkinson’s disease, spinal cord injury, closed head injury, cerebral palsy (spasticity reduction), learning disabilities, headache, degenerative conditions associated with aging, cancer, and acquired immunodeficiency syndrome (AIDS).

EM fields may be applied clinically as the primary therapy or as adjuvant therapy along with other treatments in the conditions listed above. Effectiveness can be measured via the following clinical markers:

* In arthritis, the usual clinical criteria, including decrease of pain, less swelling, and thus a greater potential for mobility.

* In psychophysiological problems, relief from symptoms of drug withdrawal and alleviation of depressive anxiety and its symptoms.

* In epilepsy, return to greater normality in EEG, more normal sleep patterns, and reduction in required drug dosages.

* In wound healing and regeneration, repair of soft tissue and reduction of collagenous tissue in scar formation; regrowth via blastemal (primitive cell) formation and increase in tensile strength of surgical wounds; alleviation of decubitus chronic ulcers (bedsores); increased angiogenesis (regrowth of vascular tissue such as blood vessels); and healing of recalcitrant (i.e., unresponsive to treatment) chronic venous ulcers.

For instance, a short-term, double-blind clinical trial of magnetic field therapy could be based on the protocol of Trock et al. (1993) for osteoarthritis of the knee or elbow. This protocol is as follows:

* A suitable patient population is divided into treatment and control groups. Individual assignments are coded and remain unknown to patients, clinicians, and operators until treatment and assessment are complete.

* Pretreatment clinical markers are assessed by clinicians or by patients themselves or both.

* Treatments consist of 3 to 5 half-hour sessions each week for a total of 18 treatments over 5-6 weeks.

* During treatment, each patient inserts the affected limb into the opening of a Helmholtz coil (a solenoid about 12 inches in diameter and 6 inches long) and rests while appropriate currents are applied to the coil via a preset program.

* The treatment is noninvasive and painless; the patient feels nothing; there is no measurable transfer of heat to the patient.

* The control group follows the same procedure except that, unknown to operator and patient, a “dummy” apparatus (altered internally so that no current flows in the coil) is used.

* Patients’ posttreatment clinical markers are assessed.

* Appropriate data reduction (scoring of assessments, decoding of the treatment and control groups, and statistical analysis) is performed.

Clinical trials of BEM-based treatments for a variety of other conditions could follow a similar general outline.

Key Issues

Certain key issues or controversies surrounding BEM have inhibited progress in this field. These issues fall into several distinct areas: medical controversy, scientific controversy, barriers, and other issues.

Medical Controversy

A number of uncharacterized “black box” medical treatment and diagnostic devices–some legal and some illegal–have been associated with EM medical treatment. Whether they operate on the basis of BEM principles is unknown. Among these devices are the following: radionics devices, Lakhovsky multiple-wave oscillator, Priore’s machine, Rife’s inert gas discharge tubes, violet ray tubes, Reich’s orgone energy devices, EAV machines, and biocircuit devices. There are at least six alternative explanations for how these and other such devices operate: (1) They are ineffectual and are based on erroneous application of physical principles. (2) They may be operating on BEM principles, but they are uncharacterized. (3) They may operate on acoustic principles (sound or ultrasound waves) rather than BEM. (4) In the case of diagnostic devices, they may work by focusing the intuitive capacity of the practitioner. (5) In the case of long-distance applications, they may operate by means of nonlocal properties of consciousness of patient and practitioner. (6) They may be operating on the energy of some domain that is uncharacterized at present.

A recent survey (Eisenberg et al., 1993) showed that about 1 percent of the U.S. population used energy healing techniques that included a variety of EM devices. Indeed, more of the respondents in this 1990 survey used energy healing techniques than used homeopathy and acupuncture in the treatment of either serious or chronic disease. In addition to the use of devices by practitioners, a plethora of consumer medical products that use magnetic energy are purported to promote relaxation or to treat a variety of illnesses. For example, for the bed there are mattress pads impregnated with magnets; there are magnets to attach to the site of an athletic injury; and there are small pelletlike magnets to place over specific points on the body. Most of these so-called therapeutic magnets, also called biomagnets, come from Japan. However, no known published journal articles demonstrating effectiveness via clinical trials exist.

Some of the medical modalities discussed in this report, although presently accepted medically or legally in the United States, have not necessarily passed the most recent requirements of safety or effectiveness. FDA approval of a significant number of BEM-based devices, primarily those used in bone repair and neurostimulation, was “grandfathered.” That is, medical devices sold in the United States prior to the Medical Device Law of the late 1970s automatically received FDA approval for use in the same manner and for the same medical conditions for which they were used prior to the law’s enactment. Grandfathering by the FDA applies not only to BEM devices but to all devices covered by the Medical Device Law. However, neither the safety nor the effectiveness of grandfathered devices is established (i.e., they are approved on the basis of a “presumption” by the FDA, but they usually remain incompletely studied). Reexamination of devices in use, whether grandfathered or not, may be warranted.

There are three possible ways of resolving controversies associated with BEM and its application: (1) elucidating the fundamental principles underlying the device, or at least the historical basis for the development of the device; (2) conducting properly designed case control studies and clinical trials to validate effects that have been reported or claimed for BEM-based treatments; and (3) increasing the medical community’s awareness of well-documented, controlled clinical trials that indicate the effectiveness of specific BEM applications (see table 2).

Scientific Controversy

Some physicists claim that low-intensity, nonionizing EM fields have no bioeffects other than resistive (joule) heating of tissue. One such argument is based on a physical model in which the only EM field parameter considered relevant to biological systems is power density (Adair, 1991). The argument asserts that measurable nonthermal bioeffects of EM fields are “impossible” because they contradict known physical laws or would require a “new physics” to explain them.

However, numerous independent experiments reported in the refereed-journal research literature conclusively establish that nonthermal bioeffects of low-intensity EM fields do indeed exist. Moreover, the experimental results lend support to certain new approaches in theoretical modeling of the interactions between EM fields and biological matter. Most researchers now feel that BEM bioeffects will become comprehensible not by forsaking physics but rather by developing more sophisticated, detailed models based on known physical laws, in which additional parameters (e.g., frequency, intensity, waveform, and field directionality) are taken into account.

Barriers

The following barriers to BEM research exist:

* Members of NIH review panels in medical applications might not be adequately knowledgeable about alternative medical practices or BEM. This is the most serious barrier.

* Funding in BEM research is weighted heavily toward the study of hazards of EM fields; there is little funding for potential beneficial medical applications or the study of basic mechanisms of EM interactions with life processes. Also, the bulk of EM field research is administered by the Department of Defense and the Department of Energy, agencies with missions unrelated to medical research. The small amount of BEM work funded by NIH thus far has addressed mostly the hazards of EM fields. In late 1993 the National Institute of Environmental Health Sciences issued requests for grant application in the areas of (1) cellular effects of low-frequency EM fields and (2) effects of 60-Hz EM fields in vivo. The latter project is concerned solely with safety in power line and appliance exposures. However, the former apparently does not rule out the investigation of possible beneficial effects from low-frequency fields, although the focus is clearly on assessing previously reported effects of 60-Hz EM fields on cellular processes.

* Regulatory barriers to making new BEM devices available to practitioners are formidable. The approval process is slow and exorbitantly expensive even for conventional medical devices.

* Barriers in education include the following: (1) basic education in biological science is weak in physics, (2) undergraduate-and graduate-level programs in BEM are virtually nonexistent, and (3) multidisciplinary training is lacking in medicine and biology.

* The mainstream scientific and medical communities are basically conservative and respond to emerging disciplines, such as BEM, with reactions ranging from ignorance and apathy to open hostility. Consequently, accomplished senior researchers may not be aware of the opportunities for fruitful work in (or in collaboration with others in) BEM, while junior researchers may be reluctant to enter a field perceived by some as detrimental to career advancement.

Other Issues

Other key issues that need to be considered in developing a comprehensive research and development agenda for BEM include the following:

* Separate studies prepared for the Office of Technology Assessment, the National Institute of Occupational Safety and Health, and the Environmental Protection Agency have recommended independently that research on fundamental mechanisms of EM field interactions in humans receive high priority (Bierbaum and Peters, 1991; Nair et al., 1989; U.S. EPA, 1991). Moreover, a 1985 report prepared by scientists at the Centers for Devices and Radiological Health recommended that future research on EM field interactions with living systems “be directed at exploring beneficial medical applications of EMR (electromagnetic radiation) modulation of immune responses” (Budd and Czerski, 1985).

* Elucidation of the physical mechanisms of BEM medical modalities is the single most powerful key to developing efficient and optimal clinical intervention. Even a relatively small advance beyond present knowledge of fundamental mechanisms would be of considerable practical value. In addition, progress in the development of a mechanistic explanation of the effects of alternative medicine could increase its acceptability in the eyes of mainstream medicine and science.

* BEM potentially offers a powerful new approach to understanding the neuroendocrine and immunological bases of certain major medical problems (e.g., wound healing, cancer, and AIDS). However, substantial funding and time are required to perform the basic research needed in developing this approach.

* BEM may provide a comprehensive biophysical framework grounded in fundamental science, through which many alternative medical practices can be studied. BEM offers a promising starting point for scientifically exploring various traditional alternative medical systems (Becker and Marino, 1982).

Basic Research Priorities

The most fruitful topics for future basic research investigations of BEM may include the following:

* Developing assay methods based on EM field interactions in cells (e.g., for potassium transport, calcium transport, and cytotoxicity). These assays could then be applied to existing studies of such phenomena in cellular systems.

* Developing BEM-based treatments for osteoporosis, on basis of the large body of existing work on EM bone repair and other research (e.g., Brighton et al., 1985; Cruess and Bassett, 1983; Liboff et al., 1992a; MadroZero, 1990; Magee et al., 1991; Skerry et al., 1991). NASA researchers have already expressed interest in collaborative work to develop BEM treatments for weightlessness-induced osteoporosis.

* Measuring neurobiochemical changes in the blood in response to microcurrent skin stimulation in animals or humans with different frequencies, waveforms, and carrier waves. Such measurements should be made for preclinical evaluation of neurostimulation devices.

* Furthering studies of mechanisms of EM field interactions in cells and tissues with emphasis on coherent or cooperative states and resonant phenomena in biomolecules; and on coherent brainwave states and other long-range interactions in biological systems.

* Studying the role of water as a mediator in biological interactions with emphasis on the quantum EM aspects of its conformation (i.e., “structure,” as implied in some forms of homeopathy). The response of biologic water to EM fields should be studied experimentally. A novel informational capacity of water in relation to EM bioeffects may provide insights into homeopathy and healer interactions (i.e., “laying on of hands”).

* Studying in detail the role of the body’s internally generated (endogenous) EM fields and the body’s other natural electromagnetic parameters (see the “Manual Healing Methods” chapter). Knowledge of such processes should be applied to develop novel diagnostic methods and to understand alternative medical treatments such as acupuncture, electroacupuncture, and biofield therapies. Furthermore, exploratory research on the role of the body’s energy fields in relation to the role of states of consciousness in health and healing should be launched.

* Establishing a knowledge base (an intelligent database) to provide convenient access to all significant BEM work in both basic and clinical research.

* Performing systematic reviews as well as meta-analytic reviews of existing BEM studies to identify the frequency and quality of research concerning BEM as well as most promising clinical end points for BEM treatments in humans.

Summary

Just as exposure to high-energy radiation has unquestioned hazards, radiation has long been a key weapon in the fight against many types of cancers. Likewise, although there are indications that some EM fields may be hazardous, there is now increasing evidence that there are beneficial bioeffects of certain low-intensity nonthermal EM fields.

In clinical practice, BEM applications offer the possibility of more economical and more effective diagnostics and new noninvasive therapies for medical problems, including those considered intractable or recalcitrant to conventional treatments. The sizable body of recent work cited in this chapter has established the feasibility of treatments based on BEM, although the mainstream medical community is largely unaware of this work.

In biomedical research, BEM can provide a better understanding of fundamental mechanisms of communication and regulation at levels ranging from intracellular to organismic. Improved knowledge of fundamental mechanisms of EM field interactions could lead directly to major advances in diagnostic and treatment methods.

In the study of other alternative medical modalities, BEM offers a unified conceptual framework that may help explain how certain diagnostic and therapeutic techniques (e.g., acupuncture, homeopathy, certain types of ethnomedicine, and healer effects) may produce results that are difficult to understand from a more conventional viewpoint. These areas of alternative medicine are currently based entirely on empirical (i.e., experimentation and observation rather than theory) and phenomenological (i.e., the classification and description of any fact, circumstance, or experience without any attempt at explanation) approaches. Thus, their future development could be accelerated as a scientific understanding if their mechanisms of action are ascertained.

References

Adair, R.K. 1991. Constraints on biological effects of weak extremely low-frequency electromagnetic fields. Physical Review 43:1039-1048.

Adey, W.R. 1992. Collective properties of cell membranes. In B. Norden and C. Ramel, eds. Interaction Mechanisms of Low-level Electromagnetic Fields in Living Systems. Symposium, Royal Swedish Academy of Sciences, Stockholm (pp. 47-77). Oxford University Press, New York.

Adey, W.R., and A.F. Lawrence, eds. 1984. Nonlinear Electrodynamics in Biological Systems (conference proceedings). Plenum Press, New York.

Albertini, A., P. Zucchini, G. Nocra, R. Carossi, and A. Pierangeli. 1990. Effect of PEMF on irreversible ischemic injury following coronary artery occlusion in rats. Transactions of Bioelectrical Repair and Growth Society 10:20.

Anninos, P.A., and N. Tsagas. 1991. Magnetic stimulation in the treatment of partial seizures. Int. J. Neurosci. 60:141-171.

Baranowski, T.J., and J. Black. 1987. Stimulation of osteogenesis. In M. Blank and E. Findl, eds. Mechanistic Approaches to Interactions of Electric and Electromagnetic Fields With Living Systems (pp. 399-416). Plenum Press, New York.

Barker, A.T., R.A. Dixon, W.J.W. Sharrard, and M.L. Sutcliffe. 1984. Pulsed magnetic field therapy for tibial non-union: interim results of a double-blind trial. Lancet. 1 (8384):994-996.

Bassett, C.A.L. 1989. Fundamental and practical aspects of therapeutic uses of pulsed electromagnetic fields (PEMFs). CRC Critical Reviews in Biomedical Engineering 17:451-529.

Bassett, C.A.L., S.N. Mitchell, and S.R. Gaston. 1982. Pulsing electromagnetic field treatment in ununited fractures and failed arthrodoses. JAMA 247:623-628.

Bassett, C.A.L., R.D. Pawluk, and A.A. Pilla. 1974. Augmentation of bone repair by inductively coupled electromagnetic fields. Science 184:575-577.

Becker, R.O. 1987. The effect of electrically generated silver ions on human cells. Proceedings of 1st International Conference on Gold and Silver in Medicine, Bethesda, Md., May 13-14, pp. 227-243.

Becker, R.O. 1990. A technique for producing regenerative healing in humans. Frontier Perspectives 1(2):1-2.

Becker, R.O. 1992. Effect of anodally generated silver ions on fibrosarcoma cells. Electro-and Magnetobiology 11:57-65.

Becker, R.O., and A.A. Marino. 1982. Electromagnetism and Life. State University of New York Press, Albany, New York.

Becker, R.O., and J.A. Spadero. 1972. Electrical stimulation of partial limb regeneration in mammals. Bull. N.Y. Acad. Med. 48:627-641.

Bierbaum, P.J., and J.M. Peters, eds. 1991. Proceedings of the Scientific Workshop on the Health Effects of Electric and Magnetic Fields on Workers. Cincinnati, Ohio, January 30-31. National Institute of Occupational Safety and Health (NIOSH) Report No. 91-111. NTIS Order No. PB-91-173-351/A13. National Technical Information Service, Springfield, Va.

Blank, M., ed. 1993. Electricity and Magnetism in Biology and Medicine. Proceedings of the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19, 1992. San Francisco Press, Inc., San Francisco.

Blank, M., and E. Findl, eds. 1987. Mechanistic Approaches to Interactions of Electric and Electromagnetic Fields With Living Systems. Plenum Press, New York.

Brayman, A., and M. Miller. 1989. Proportionality of 60-Hz electric field bioeffect severity to average induced transmembrane potential magnitude in a root model system. Radiat. Res. 117:207-213.

Brayman, A., and M. Miller. 1990. 60-Hz electric field exposure inhibits net apparent H-ion excretion from excised roots of Zea mays L. Radiat. Res. 123:22-31.

Brighton, C.T., J. Black, Z.B. Friedenberg, J.L. Esterhai, L. Day, and J.F. Connally. 1981. A multicenter study of the treatment of nonunion with constant direct current. J. Bone Joint Surg. (Br.) 63A:2-12.

Brighton, C.T., J. Black, and S.R. Pollack, eds. 1979. Electrical Properties of Bone and Cartilage: Experimental Effects and Clinical Applications. Grune and Stratton, Inc., New York.

Brighton, C.T., M.J. Katz, S.R. Goll, C.E. Nichols, and S.R. Pollack. 1985. Prevention and treatment of sciatic denervation disuse osteoporosis in the rat tibia with capacitively coupled electrical stimulation. Bone 6:87-97.

Brighton, C.T., and S.R. Pollack, eds. 1991. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Brown, H.D., and S.K. Chattpadhyay. 1991. EM-field effect upon properties of NADPH-cytochrome P-450 reductase with model substrates. Cancer Biochem. Biophys. 12(3):211-215.

Budd, R.A., and P. Czerski. 1985. Modulation of mammalian immunity by electromagnetic radiation. J. Microw. Power Electromagn. Energy 20:217-231.

Cadossi, R., G. Emilia, and G. Torelli. 1988a. Lymphocytes and pulsing magnetic fields. In A.A. Marino, ed. Modern Bioelectricity. Marcel Dekker, Inc., New York.

Cadossi, R., R. Iverson, V.R. Hentz, P. Zucchini, G. Emilia, and G. Torelli. 1988b. Effect of low-frequency low-energy pulsing electromagnetic fields on mice undergoing bone marrow transplantation. International Journal of Immunopathology and Pharmacology 1:57-62.

Chen, J., and O.P. Gandhi. 1989. RF currents in an anatomically based model of a human for plane-wave exposures (20-100 MHz). Health Phys. 57(1):89-98.

Christensen, P.A., and M. Noreng. 1989. Electroacupuncture and postoperative pain. Br. J. Anaesth. 62:258-262.

Chwirot, W.B. 1988. Ultraweak photon emission and anther meiotic cycle in Larix europaea (experimental investigation of Nagl and Popp’s electromagnetic model of differentiation). Experientia 44:594-599.

Chwirot, W.B., R.S. Dygdala, and S. Chwirot. 1987. Quasi-monochromatic-light-induced photon emission from microsporocytes of larch shows oscillating decay behavior predicted by the electromagnetic model of differentiation. Cytobios 47:137-146.

Cohen, M.M., A. Kunska, J.A. Astemborsky, and D. McCulloch. 1986. The effect of low-level 60-Hz electromagnetic fields on human lymphoid cells. Circ. Res. 172:177-184.

Cossarizza, A., D. Monti, F. Bersani, et al. 1989a. Extremely low-frequency pulsed electromagnetic fields increase cell proliferation in lymphocytes from young and aged subjects. Biochem. Biophys. Res. Commun. 160:692-698.

Cossarizza, A., D. Monti, F. Bersani, et al. 1989b. Extremely low-frequency pulsed electromagnetic fields increase interleukin-2 (IL-2) utilization and IL-2 receptor expression in mitogen-stimulated human lymphocytes from old subjects. FEBS Lett. 248:141-144.

Cossarizza, A., D. Monti, P. Sola, et al. 1989c. DNA repair after irradiation in lymphocytes exposed to low-frequency pulsed electromagnetic fields. Radiat. Res. 118:161-168.

Cruess, R.L., and C.A.L. Bassett. 1983. The effect of pulsing electromagnetic fields on bone metabolism in experimental disuse osteoporosis. Clin. Orthop. 173:245-250.

De Loecker, W., P.H. Delport, and N. Cheng. 1989. Effects of pulsed electromagnetic fields on rat skin metabolism. Biochim. Biophys. Acta 982:9-14.

Devyatkov, N.D., Y.V. Gulyaev, et al. 1991. Digest of Papers. International Symposium on Millimeter Waves of Non-Thermal Intensity in Medicine. Cosponsored by Research and Development Association “ISTOK” and Research Institute of U.S.S.R. Ministry of Electronic Industry (“ORION”). Moscow, October 3-6. (In Russian.)

Dundee, J.W., and R.G. Ghaly. 1989. Acupuncture prophylaxis of cancer chemotherapy-induced sickness. J. R. Soc. Med. 82:268-271.

Dunn, P.A., and D. Rogers. 1989. Transcutaneous electrical nerve stimulation at acupuncture points in the induction of uterine contractions. Obstet. Gynecol. 73:286-290.

Easterly, C. 1982. Cardiovascular risk from exposure to static magnetic fields. American Industrial Hygiene Association Journal 43:533-539.

Eisenberg, D.M., R.C. Kessler, C. Foster, et al. 1993. Unconventional medicine in the United States: prevalence, costs, and patterns of use. N. Engl. J. Med. 328:246-252.

Fehlings, M.G., R.J. Hurlbert, and C.H. Tator. 1992. An examination of direct current fields for the treatment of spinal cord injury. Paper presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Feinendegen, L.E. and H. Muhlensiepen. 1987. In vivo enzyme control through a strong stationary magnetic field: The case of thymidine kinase in mouse bone marrow cells. Int. J. Radiat. Biol. 52(3):469-479.

Foxall, P.J.D., G.H. Neild, F.D. Thompson, and J.K. Nicholson. 1991. High-resolution NMR spectroscopy of fluid from polycystic kidneys suggests reversed polarity of cyst epithelial cells. Journal of the American Society of Nephrology 2(3):252.

Goldenberg, D.M., and H.J. Hansen. 1972. Electric enhancement of bone healing. Science 175:1118-1120.

Goodman, R., L. Wei, J. Xu, and A. Henderson. 1989. Exposures of human cells to low-frequency electromagnetic fields results in quantitative changes in transcripts. Biochim. Biophys. Acta 1009:216-220.

Gordon, R.T. 1986. Process for the Treatment of Atherosclerotic Lesions. U.S. Patent No. 4,622,953, November 18.

Grande, D.A., F.P. Magee, A.M. Weinstein, and B.R. McLeod. 1991. The effect of low-energy combined AC and DC magnetic fields on articular cartilage metabolism. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Greene, J.J., W.J. Skowronski, J.M. Mullins, and R.M. Nardone. 1991. Delineation of electric and magnetic field effects of extremely low frequency electromagnetic radiation on transcription. Biomedical and Biophysical Research Communications 174(2):742-749.

Grundler, W., F. Kaiser, F. Keilmann, and J. Walleczek. In press. Mechanisms of electromagnetic interaction with cellular systems. Naturwissenschaften. From a workshop sponsored by the Deutsche Forschungsgemeinschaft (DFG) at the Max-Planck-Institut fhr Festk`rperforschung, Stuttgart, Germany, September 11-12.

Guy, A.W. 1987. Dosimetry association with exposure to non-ionizing radiation: very low frequency to microwaves. Health Phys. 53(6):569-584.

Hagfors, N.R., and A.C. Hyme. 1975. Method and structure of preventing and treating ileus, and reducing acute pain by electrical pulse stimulation. U.S. Patent No. 3,911,930, October 14.

Hajdukovic, R., M. Mitler, B. Pasche, and M. Erman. 1992. Effects of low-energy emission therapy (LEET) on sleep structure (abstract). Sleep Research 21:206.

Hallett, M., and L.G. Cohen. 1989. Magnetism: a new method for stimulation of nerve and brain. JAMA 262 (4):538-541.

Herbst, E., B.F. Sisken, and H.Z. Wang. 1988. Assessment of vascular network in rat skin flaps subjected to sinusoidal EMFs using image analysis techniques. Transactions of the 8th Annual Meeting of the Bioelectrical Repair and Growth Society. Washington, D.C., October 9-12.

Hinsenkamp, M., J. Ryaby, and F. Burny. 1985. Treatment of nonunion by pulsing electromagnetic fields: European multicenter study of 308 cases. Reconstr. Surg. Traumatol. 19:147-151.

Horton, P., J.T. Ryaby, F.P. Magee, and A.M. Weinstein. 1992. Stimulation of specific neuronal differentiation proteins in PC12 cells by combined AC/DC magnetic fields. Presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Huraki, Y., N. Endo, M. Takigawa, A. Asada, H. Takahashe, and F. Suzuki. 1987. Enhanced responsiveness to parathyroid hormone and induction of functional differentiation of cultured rabbit costal chondrocytes by a pulsed electromagnetic field. Biochim. Biophys. Acta 931:94-110.

Hurlbert, R.J., and C.H. Tator. 1992. Effect of disc vs. cuff electrode configuration on tolerance of the rat spinal cord to DC stimulation. Paper presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Ieran, M., S. Zaffuto, M. Bagnacani, M. Annovi, A. Moratti, and R. Cadossi. 1990. Effect of low-frequency pulsing electromagnetic fields on skin ulcers of venous origin in humans: a double-blind study. J. Orthop. Res. 8:276-282.

Im, M.J., and J.E. Hoopes. 1991. Effects of electrical stimulation on ischemia/reperfusion injury in rat skin. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Kanje, M., and A. Rusovan. 1992. Reversal of the stimulation of magnetic field exposure on regeneration of the rat sciatic nerve by a Ca2+ antagonist. Paper presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Klawansky, S., A. Yueng, C. Berkey, N. Shah, C. Zachery, and T.C. Chalmers. 1992. Meta-analysis of randomized control trials of the efficacy of cranial electrostimulation in treating psychological and physiological conditions. Report of the Technology Assessment Group, Department of Health Policy and Management, Harvard University School of Public Health, August 28.

Kraus, W. 1992. The treatment of pathological bone lesion with nonthermal, extremely low frequency electromagnetic fields. Bioelectrochemistry and Bioenergetics 27:321-339.

Lee, R.C., D.J. Canaday, and H. Doong. 1993. A review of the biophysical basis for the clinical application of electric fields in soft tissue repair. J. Burn Care Rehabil. 14:319-335.

Lee, Y.H., W.C. Lee, M.T. Chen, et al. 1992. Acupuncture in the treatment of renal colic. J. Urol. 147:16-18.

Lerchl, A., K.O. Nonaka, K.A. Stokkan, and R.J. Reiter. 1990. Marked rapid alterations in nocturnal pineal serotonin metabolism in mice and rats exposed to weak intermittent magnetic fields. Biochem. Biophys. Res. Commun. 169:102-108.

Liboff, A.R. 1985. Geomagnetic cyclotron resonance in living cells. J. of Biol. Phys. 13:99-104.

Liboff, A.R. 1991. The cyclotron resonance hypothesis: experimental evidence and theoretical constraints. In C. Ramel and B. Norden, eds. Interaction Mechanisms of Low-Level Electromagnetic Fields With Living Systems. Oxford University Press, London, pp. 130-147.

Liboff, A.R., B.R. McLeod, and S.D. Smith. 1991. Resonance transport in membranes. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Liboff, A.R., B.R. McLeod, and S.D. Smith. 1992a. Techniques for Controlling Osteoporosis Using Noninvasive Magnetic Fields. U.S. Patent No. 5,100,373, March 31.

Liboff, A.R., B.R. McLeod, and S.D. Smith. 1992b. Method and Apparatus for Controlling Tissue Growth with an Applied Fluctuating Magnetic Field, U.S. Patent No. 5,123,898, June 23.

Liboff, A.R., R.A. Rinaldi, eds. 1974. Electrically mediated growth mechanisms in living systems. Ann. N.Y. Acad. Sci. 238(October 11).

Liburdy, R.P., and T.S. Tenforde. 1986. Magnetic field-induced drug permeability in liposome vesicles. Radiat. Res. 108:102-111.

MadroZero, A. 1990. Influence of magnetic fields on calcium salts crystal formation: an explanation of the “pulsed electromagnetic field” technique for bone healing. J. Biomed. Eng. 12:410-412.

Magee, F.P., A.M. Weinstein, R.J. Fitzsimmons, D.J. Baylink, and B.R. McLeod. 1991. The use of low-energy combined AC and DC magnetic fields in the prevention of osteopenia. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Marino, A.A., ed. 1988. Modern Bioelectricity. Marcel Dekker, Inc., New York.

Marron, M.T., E.M. Goodman, P.T. Sharpe, and B. Greenebaum. 1988. Low-frequency electric and magnetic fields have different effects on the cell surface. FEBS Lett. 230(1-2):13-16.

Mathew, R., and S. Rumar. The non-exponential decay pattern of the weak luminescence from seedlings in Cicer arietinum L. stimulated by pulsating electric fields. Experientia. In press.

McDevitt, L., P. Fortner, and B. Pomeranz. 1987. Application of weak electrical field to the hindpaw enhances sciatic motor-nerve regeneration in the adult rat. Brain Res. 416:308-314.

Mertz, P.M., S.C. Davis, and W.H. Eaglstein. 1988. Pulsed electrical stimulation increases the rate of epithelialization in partial thickness wounds. Transactions of the 8th Annual Meeting of the Bioelectrical Repair and Growth Society, Washington, D.C., October 9-12.

Miklavcic, D., S. Rebersek, G. Sersa, et al. 1991. Nonthermal antitumor effect of electrical direct current on murine fibrosarcoma SA-1 tumor model. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Nair, I., M.G. Morgan, and H.K. Florig. 1989. Biological Effects of Power Frequency Electric and Magnetic Fields (Background Paper). Office of Technology Assessment, Report No. OTA-BP-E-53. U.S. Government Printing Office, Washington, D.C.

O’Connor, M.E., R.H.C. Bentall, and J.C. Monahan, eds. 1990. Emerging Electromagnetic Medicine conference proceedings. Springer-Verlag, New York.

O’Connor, M.E., and R.H. Lovely, eds. 1988. Electromagnetic Fields and Neurobehavioral Function. Alan R. Liss, Inc., New York.

Omote, Y., M. Hosokawa, M. Komatsumoto, et al. 1990. Treatment of experimental tumors with a combination of a pulsing magnetic field and an antitumor drug. Jpn. J. Cancer Res. 81:956-961.

Onuma, E., and S. Hui. 1988. Electric field-directed cell shape changes, displacement, and cytoskeletal reorganization are calcium dependent. J. Cell Biol. 106:2067-2075.

Orgel, M.G., R.J. Zienowicz, B.A. Thomas, and W.H. Kurtz, 1992. Peripheral nerve transection injury: the role of electromagnetic field therapy. Paper presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Papatheofanis, F.J., and B.J. Papatheofanis. 1989. Acid and alkaline phosphase activity in bone following intense magnetic field irradiation of short duration. Int. J. Radiat. Biol. 55(6):1033-1035.

Pasche, B., T.P. Lebet, A. Barbault, C. Rossel, and N. Kuster. 1989. Electroencephalographic changes and blood pressure lowering effect of low energy emission therapy (abstract). Bioelectromagnetics Society Proceedings, F-3-5.

Phillips, J.L., and L. McChesney. 1991. Effect of 72-Hz pulsed magnetic field exposure on macromolecular synthesis in CCRF-CEM cells. Cancer Biochem. Biophys. 12:1-7.

Pollack, S.R., C.T. Brighton, D. Plenkowski, and N.J. Griffith. 1991. Electromagnetic Method and Apparatus for Healing Living Tissue. U.S. Patent No. 5,014,699, May 14.

Pomeranz, B., M. Mullen, and H. Markus. 1984. Effect of applied electrical fields on sprouting of intact saphenous nerve in adult rat. Brain Res. 303:331-336.

Popp, F.A., A.A. Gurwitsch, H. Inaba, et al. 1988. Biophoton emission (multiauthor review). Experientia 44:543-600.

Popp, F.A., K.H. Li, and Q. Gu, eds. 1992. Recent Advances in Biophoton Research and Its Applications. World Scientific Publishing Co., Singapore and New York.

Popp, F.A., W. Nagl, K.H. Li, et al. 1984. Biophoton emission: new evidence for coherence and DNA as source. Cell Biophys. 6:33-52.

Ramel, C., and B. Norden, eds. 1991. Interaction Mechanisms of Low-Level Electromagnetic Fields With Living Systems. Oxford University Press, London.

Rodemann, H.P., K. Bayreuther, and G. Pfleiderer. 1989. The differentiation of normal and transformed human fibroblasts in vitro is influenced by electromagnetic fields. Exp. Cell Res. 182:610-621.

Rosenthal, M., and G. Obe. 1989. Effects of 50-Hz electromagnetic fields on proliferation and on chromosomal alterations in human peripheral lymphocytes untreated or pretreated with chemical mutagens. Mutat. Res. 210:329-335.

Rusovan, A., and M. Kanje. 1991. Stimulation of regeneration of the rat sciatic nerve by 50-Hz sinusoidal magnetic fields. Exp. Neurol. 112:312-316.

Rusovan, A., and M. Kanje. 1992. D600, a Ca2+ antagonist, prevents stimulation of nerve regeneration by magnetic fields. NeuroReport 3:813-814.

Rusovan, A., M. Kanje, and K.H. Mild. 1992. The stimulatory effect of magnetic fields on regeneration of the rat sciatic nerve is frequency dependent. Exp. Neurol. 117:81-84.

Ryaby, J.T., D.A. Grande, F.P. Magee, and A.M. Weinstein. 1992. The effect of combined AC/DC magnetic fields on resting articular cartilage metabolism. Presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Sharrard, W.J.W. 1990. A double-blind trial of pulsed electromagnetic fields for delayed union of tibial fractures. J. Bone Joint Surg. (Br.) 72B:347-355.

Shealy, N., R. Cady, D. Veehoff, et al. 1992. Neuro-chemistry of depression. American Journal of Pain Management 2:31-36.

Short, W.O., L. Goodwill, C.W. Taylor, et al. 1992. Alteration of human tumor cell adhesion by high-strength static magnetic fields. Invest. Radiol. 27:836-840.

Sisken, B.F. 1992. Nerve regeneration: implications for clinical applications of electrical stimulation. Paper presented at the 1st World Congress for Electricity and Magnetism in Biology and Medicine, Orlando, Fla., June 14-19.

Skerry, T.M., M.J. Pead, M.J., and L.E. Lanyon. 1991. Modulation of bone loss during disuse by pulsed electromagnetic fields. J. Orthop. Res. 9:600-608.

Smith, S.D. 1967. Induction of partial limb regeneration in Arana pipicus by galvanic stimulation. Anat. Rec. 158:89-97.

Stiller, M.J., G.H. Pak, J.L. Shupack, S. Thaler, C. Kenny, and L. Jondreau. 1992. A portable pulsed electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a double-blind placebo-controlled clinical trial. Br. J. Dermatol. 127:147-154.

Subramanian, M., C.H. Sutton, B. Greenebaum, and B.F. Sisken. 1991. Interaction of electromagnetic fields and nerve growth factor on nerve regeneration in vitro. In C.T. Brighton and S.R. Pollack, eds. Electromagnetics in Medicine and Biology. San Francisco Press, Inc., San Francisco.

Takahashi, K., I. Kaneko, and E. Fukada. 1987. Influence of pulsing electromagnetic field on the frequency of sister-chromatid exchanges in cultural mammalian cells. Experientia 43:331-332.

Tenforde, T.S., and W.T. Kaune. 1987. Interaction of extremely low frequency electric and magnetic fields with humans. Health Phys. 53:585-606.

Thomas, J.R., J. Schrot, and A.R. Liboff. 1986. Low-intensity magnetic fields alter operant behavior in rats. Bioelectromagnetics 7:349.

Trock, D.H., A.J. Bollet, R.H. Dyer, Jr., L.P. Fielding, W.K. Miner, and R. Markoll. 1993. A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis. J. Rheumatol. 20:456-460.

U.S. Environmental Protection Agency. 1991. Evaluation of the Potential Carcinogenicity of Electromagnetic Fields. Report #EPA/600/6-90/05B. Unreleased preliminary draft (March).

Vodovnik, L., and R. Karba. 1992. Treatment of chronic wounds by means of electric and electromagnetic fields. Part 1: literature review. Med. Biol. Eng. and Comput. (May):257-266.

Walleczek, J. 1992. Electromagnetic field effects on cells of the immune system: the role of calcium signalling. FASEB Lett. 6:3177-3185.

Weinstein, A.M., B.R. McLeod, S.D. Smith, and A.R. Liboff. 1990. Ion resonance-tuned electromagnetic fields increase healing rate in ostectomized rabbits. Abstracts of 36th Annual Meeting of Orthopedic Research, February 5-8, 1990, New Orleans.

Wijk, R.V., and D.H.J. Schamhart. 1988. Regulatory aspects of low-intensity photon emission. Experientia 44:586-593.

Wilson, B.W., R.G. Stevens, and L.E. Anderson, eds. 1990a. Extremely Low Frequency Electromagnetic Fields: The Question of Cancer. Battelle Press, Columbus, Ohio.

Wilson, B.W., C.W. Wright, J.E. Morris, et al. 1990b. Evidence for an effect of ELF electromagnetic fields on human pineal gland function. J. Pineal Res. 9:259-269.

Wilson, D.H., P. Jagdeesh, P.P. Newman, and D.G.F. Harriman. 1974. The effects of pulsed electromagnetic energy on peripheral nerve regeneration. Ann. N.Y. Acad. Sci. 238:575-585.

Yen-Patton, G.P.A., W.F. Patton, D.M. Beer, and B.S. Jacobson. 1988. Endothelial cell response to pulsed electromagnetic fields: stimulation of growth rate and angiogenesis in vitro. J. Cell. Physiol. 134:37-46.

Table 1. Electromagnetic Spectrum

Frequency range (Hz)* Classification Biological effect

0 Direct current Nonionizing

0 – 300 Extremely low frequency Nonionizing

300 – 104 Low frequency Nonionizing

104 – 109 Radio frequency Nonionizing

109 – 1012 Microwave and radar bands Nonionizing

1012 – 4 x 1014 Infrared band Nonionizing

4 x 1014 – 7 x 1014 Visible light Weakly ionizing

7 x 1014 – 1018 Ultraviolet band Weakly ionizing

1018 – 1020 X rays Strongly ionizing

Over 1020 Gamma rays Strongly ionizing

* Division of the EM spectrum into frequency bands is based on conventional but arbitrary usage in various disciplines.

Table 2. Selected Literature Citations on Biomedical Effects of Nonthermal EM Fields

Frequency range of EM fields

Location or type of bioeffect_

DC_ELF, including sinusoidal, pulsed, and mixed_

RF and microwave_

IR, visible, and UV light_

Review articles and monographs___

Bone and cartilage, including treatments for bone repair and osteoporosis_Brighton et al., 1981;

Baranowsi & Black, 1987;

Papatheofanis, 1989_Bassett et al., 1982;

Barker et al., 1984;

Brighton et al., 1985;

Hinsenkamp et al., 1985;

Huraki et al., 1987;

Bassett, 1989;

MadroZero, 1990;

Sharrard, 1990;

Grande et al., 1991;

Magee et al., 1991;

Pollack et al., 1991;

Skerry et al., 1991;

Ryaby et al., 1992___Brighton et al., 1979__

Soft tissue, including wound healing, regeneratrion, and vascular­tissue effects_Becker, 1987;

Becker, 1990;

Becker, 1992;

Vodovnik & Karba, 1992_Gordon, 1986;

Herbst et al., 1988;

Mertz et al., 1988;

Yen­Patton et al., 1988;

Albertini et al., 1990;

Ieran et al., 1990;

Im & Hoopes, 1991;

Kraus, 1992;

Liboff et al., 1992b;

Stiller et al., 1992;

Vodovnik & Karba, 1992_Devyatkov et al., 1991__Vodovnik & Karba, 1992__

Neural tissue, including nerve growth and regeneration__Wilson et al., 1974;

Rusovan & Kanje, 1991;

Subramanian et al., 1991;

Horton et al., 1992;

Rusovan & Kanje, 1992;

Rusovan et al., 1992_____

Neural stimulation effects, including TENS and TCES__Hagfors & Hyme, 1975;

Hallett & Cohen, 1989;

Anninos & Tsagas, 1991;

Klawansky et al., 1992_____

Psychophysiological and behavioral effects___Pasche et al., 1989;

Devyatkov et al., 1991;

Hajdukovic et al., 1992_Thomas et al., 1986_O’Connor & Lovely, 1988__

Electroacupuncture_McDevitt et al., 1987_Pomeranz et al., 1984;

Christensen & Noreng, 1989;

Dundee & Ghaly, 1989;

Lee et al., 1992_____

Neuroendocrine effects, including melatonin modifications_Feinendegen & Muhlensiepen, 1987_Lerchl et al., 1990;

Wilson et al., 1990a, 1990b___O’Connor & Lovely, 1988__

Immune system effects__Cadossi et al., 1988a;

Cadossi et al., 1988b;

Cossarizza et al., 1989a;

Cossarizza et al., 1989b;

Rosenthal & Obe, 1989;

Phillips & McChesney, 1991;

Walleczek, 1992_____

Arthritis treatments__Grande et al., 1991;

Trock et al., 1993_Devyatkov et al., 1991____

Cellular and subcellular effects, including effects on cell membrane, genetic system, and tumors_Easterly, 1982;

Liburdy & Tenforde, 1986;

Foxall et al., 1991;

Miklavcic et al., 1991;

Short et al., 1992_Cohen et al., 1986;

Takahashi et al., 1987;

Adey, 1992;

Marron et al., 1988;

Onuma & Hui, 1988;

Brayman & Miller, 1989;

Cossarizza et al., 1989a, 1989b;

De Loecker et al., 1989;

Goodman et al., 1989;

Rodemann et al., 1989;

Brayman & Miller, 1990;

Lerchl et al., 1990;

Omote et al., 1990;

Greene et al., 1991;

Liboff et al., 1991_Guy, 1987;

Chen & Ghandi, 1989;

Brown & Chattpadhyay, 1991;

Devyatkov et al., 1991__Adey & Lawrence, 1984;

Marino, 1988;

Blank & Findl, 1987;

Ramel & Norden, 1991;

Grundler et al., in press__

Endogenous EM fields, including biophotons__Mathew & Rumar, in press_Mathew & Rumar, in press_Popp et al., 1984;

Chwirot et al., 1987;

Chwirot, 1988;

Popp et al., 1988_Wijk & Schamhart, 1988;

Popp et al., 1992__

Note: Reports listed in table 2 are selected from refereed medical and scientific journals, multiauthor monographs, conference proceedings, and patents. See References for identification of sources. This is a representative selection from a large body of relevant sources and is not meant to be exhaustive or definitive.

A more detailed introduction to the field of BEM and an overview of research progress is available in the following monographs and conference proceedings: Adey, 1992; Adey and Lawrence, 1984; Becker and Marino, 1982; Blank, 1993; Blank and Findl, 1987; Brighton and Pollack, 1991; Brighton et al., 1979; Liboff and Rinaldi, 1974; Marino, 1988; O’Connor et al., 1990; O’Connor and Lovely, 1988; Popp et al., 1992; and Ramel and Norden, 1991.

Gauss is a unit of magnetic flux density. For comparison, a typical magnet used to hold papers vertically on a refrigerator is 200 G.

Neurosurgical Outcomes

Vopr Kurortol Fizioter Lech Fiz Kult. 1999 Nov-Dec;(6):27-30.

Multilevel magnetic and electrical stimulation in the combined treatment of neurosurgical patients.

[Article in Russian]

Tyshkevich TG, Bersnev VP, Ponomarenko GN.

The program of rehabilitation of neurosurgical patients with effective physical methods (multilayer magnetic and electric stimulation, scanning laser therapy, QHF therapy) has been used in 265 patients with functional disorders because of nervous affection. The program reduced the treatment duration and improved the quality of treatment of neurosurgical patients.

Neuropathy – Neuropathic Pain

J Neurosurg. 2018 May 18:1-12. doi: 10.3171/2017.12.JNS171333. [Epub ahead of print]

Added value of multiple versus single sessions of repetitive transcranial magnetic stimulation in predicting motor cortex stimulation efficacy for refractory neuropathic pain.

Pommier B1,2, Quesada C3,2, Fauchon C2, Nuti C1,2, Vassal F1, Peyron R4,2.

Author information

1 Service de Neurochirurgie. 2 INSERM U1028, UMR5292 Intégration Centrale de la Douleur chez l’Homme Centre de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1 & Université Jean Monnet, Saint-Etienne, France. 3 Centre d’Evaluation et de Traitement de la Douleur, Centre Hospitalier Régional Universitaire, Saint-Etienne; and. 4 Service de Neurologie.

Abstract

OBJECTIVE Selection criteria for offering patients motor cortex stimulation (MCS) for refractory neuropathic pain are a critical topic of research. A single session of repetitive transcranial magnetic stimulation (rTMS) has been advocated for selecting MCS candidates, but it has a low negative predictive value. Here the authors investigated whether multiple rTMS sessions would more accurately predict MCS efficacy. METHODS Patients included in this longitudinal study could access MCS after at least four rTMS sessions performed 3-4 weeks apart. The positive (PPV) and negative (NPV) predictive values of the four rTMS sessions and the correlation between the analgesic effects of the two treatments were assessed. RESULTS Twelve MCS patients underwent an average of 15.9 rTMS sessions prior to surgery; nine of the patients were rTMS responders. Postoperative follow-up was 57.8 ± 15.6 months (mean ± standard deviation). Mean percentage of pain relief (%R) was 21% and 40% after the first and fourth rTMS sessions, respectively. The corresponding mean durations of pain relief were respectively 2.4 and 12.9 days. A cumulative effect of the rTMS sessions was observed on both %R and duration of pain relief (p < 0.01). The %R value obtained with MCS was 35% after 6 months and 43% at the last follow-up. Both the PPV and NPV of rTMS were 100% after the fourth rTMS session (p = 0.0045). A significant correlation was found between %R or duration of pain relief after the fourth rTMS session and %R at the last MCS follow-up (R2 = 0.83, p = 0.0003). CONCLUSIONS Four rTMS sessions predicted MCS efficacy better than a single session in neuropathic pain patients. Taking into account the cumulative effects of rTMS, the authors found a high-level correlation between the analgesic effects of rTMS and MCS.

KEYWORDS:

%R MCS = percentage of pain relief following MCS; %R rTMS = percentage of pain relief following rTMS; LEP = laser evoked potential; MCS; MCS = motor cortex stimulation; MEP = motor evoked potential; NPV = negative predictive value; NRS = Numerical Rating Scale; PPV = positive predictive value; ROC = receiver operating characteristic; SSEP = somatosensory evoked potential; central pain; motor cortex stimulation; neuropathic pain; rTMS; rTMS = repetitive transcranial magnetic stimulation; repetitive transcranial magnetic stimulation Oncotarget. 2017 Jan 3;8(1):1110-1116. doi: 10.18632/oncotarget.13584.

The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy.

Liu H1,2, Zhou J3, Gu L1, Zuo Y2.

Author information

1 Department of Anesthesiology, Jiangsu Cancer Hospital, Jiangsu 210009, China. 2 Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan 610041, China. 3 Department of Rehabilitation, West China Hospital, Sichuan University, Sichuan 610041, China.

Abstract

Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord. Rats were subjected to CCI with or without pulsed electromagnetic field (PEMF) therapy. It was found that CCI induced neural cell degeneration while PEMF promoted nerve regeneration as documented by Nissl staining. CCI shortened the hind paw withdrawal latency (PWL) and hind paw withdrawal threshold (PWT) and PEMF prolonged the PWL and PWT. In addition, CCI lowers the expression of HCN1 and HCN2 mRNA and PEMF cannot restore the expression of HCN1 and HCN2 mRNA. Our results indicated that PEMF can promote nerve regeneration and could be used for the treatment of neuropathic pain.

KEYWORDS:

chronic constriction injury (CCI); hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN); pulsed electromagnetic field (PEMF)

Logo of plosone

PLoS One. 2013; 8(4): e61414. Published online 2013 Apr 18. doi:  10.1371/journal.pone.0061414 PMCID: PMC3630223 PMID: 23637830

Therapeutic Effects of 15 Hz Pulsed Electromagnetic Field on Diabetic Peripheral Neuropathy in Streptozotocin-Treated Rats

Tao Lei,# 1 Da Jing,# 1 Kangning Xie,# 1 Maogang Jiang, 1 Feijiang Li, 1 Jing Cai, 2 Xiaoming Wu, 1 Chi Tang, 1Qiaoling Xu, 3 Juan Liu, 1 Wei Guo, 1 Guanghao Shen, 1 , * and Erping Luo 1 , * Maria Rosaria Scarfi, Editor 1 School of Biomedical Engineering, Fourth Military Medical University, Xi’an, China, 2 Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China, 3 School of Nursing, Fourth Military Medical University, Xi’an, China, National Research Council, Italy, #Contributed equally. * E-mail: moc.361@nehshg (GS); moc.liamtoh@oulgnipre (EL) Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: DJ GS EL TL KX. Performed the experiments: TL MJ FL JC. Analyzed the data: TL MJ. Contributed reagents/materials/analysis tools: XW CT QX JL WG. Wrote the paper: TL KX. Author information ? Article notes ? Copyright and License information ? Disclaimer Received 2012 Dec 11; Accepted 2013 Mar 8. Copyright © 2013 Lei et al This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

Abstract

Although numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) have a neuroprotective role in patients with diabetic peripheral neuropathy (DPN), the application of PEMF for clinic is still controversial. The present study was designed to investigate whether PEMF has therapeutic potential in relieving peripheral neuropathic symptoms in streptozotocin (STZ)-induced diabetic rats. Adult male Sprague–Dawley rats were randomly divided into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with 15 Hz PEMF exposure group (DM+PEMF) which were subjected to daily 8-h PEMF exposure for 7 weeks and diabetes mellitus with sham PEMF exposure group (DM). Signs and symptoms of DPN in STZ-treated rats were investigated by using behavioral assays. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed. During a 7-week experimental observation, we found that PEMF stimulation did not alter hyperglycemia and weight loss in STZ-treated rats with DPN. However, PEMF stimulation attenuated the development of the abnormalities observed in STZ-treated rats with DPN, which were demonstrated by increased hind paw withdrawal threshold to mechanical and thermal stimuli, slighter demyelination and axon enlargement and less VEGF immunostaining of sciatic nerve compared to those of the DM group. The current study demonstrates that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. It is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN.

Introduction

Diabetic peripheral neuropathy (DPN) is generally considered to be one of the most common complications of diabetes mellitus, affecting both types of diabetes equally [1][3]. Studies suggest that about 30% of patients with diabetes mellitus are affected by DPN and 16–26% of diabetic patients experience chronic pain [4].

DPN is characterized by aberrant symptoms of stimulus-evoked pain including allodynia and hyperalgesia [5], and it often leads to mood and sleep disturbance, and thus can substantially impair the quality and expectancy of life [6][7]. Therefore, it imposes a huge burden on both individuals and society, and represents a major public health problem. However, beyond the careful management of the diabetes itself via glycemic control and pain relief for neuropathy, no treatment for DPN exists [8][9]. Potential toxicity, poor tolerability and ineffectiveness for some percent of diabetic patients are major disadvantages of the current therapeutic options. For this reason, there is a need to explore other non-pharmacological novel therapeutic modalities with efficacy and safety, particularly when diabetic patients require a combined treatment with an oral antidiabetic drug to prevent the development of DPN.

Numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) are able to modify some parameters of nerve function in diabetic patients [10][11], and a voluminous amount of literature has suggested that PEMF can stimulate nerve growth, regeneration, and functional recovery of nerves in cells in vitro or in animal models with nerve disease [12][16]. However, the application of PEMF for clinic is still controversial [17]. Therefore, more research is needed to confirm the therapeutic effects of PEMF on DPN and then to justify the applicability of PEMF for clinical practice. Since few studies have examined the effects of PEMF on neuropathy induced by diabetes mellitus in animals at present, this study aimed to test whether PEMF has therapeutic potential in relieving diabetes-induced neuropathy in animals.

Streptozotocin (STZ)-induced diabetic rat model has been used extensively as a model of DPN to demonstrate many abnormalities observed in patients with DPN and to assess the efficacies of potential therapeutic interventions [18][20]. Diabetic rats develop tactile allodynia and hyperalgesia to mechanical or thermal stimuli in the hind paws two or three weeks after STZ injection [5][21][22]. In the current study, we examined the effects of whole-body exposure to 15 Hz PEMF whose peak magnetic flux density (MFD) was approximately 1.6×10?3 T on improving signs and symptoms of DPN in STZ-treated rats by using behavioral assays. The PEFM was generated by a modified Helmholtz coils and the exposure duration was 8 hours everyday, 6 days a week for 7 weeks. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed seven weeks after PEMF stimulation. Moreover, the potential action mechanism of PEMF on DPN was preliminarily investigated.

Methods

Experimental Diabetes

Thirty adult male Sprague–Dawley rats, weighting 350±20 g, were provided by Animal Center of the Fourth Military Medical University and housed in a room (Animal Center of the Fourth Military Medical University, Xi’an, China) with controlled temperature (23±1°C), relative humidity (50?60%), and alternately light-dark cycle (12 h/12 h), with access to standard pellet and clean water. Diabetes mellitus was induced by an intraperitoneal injection of STZ (Sigma Chemicals, St. Louis, MO, USA) at 45 mg/kg in freshly prepared 0.1 mM citrate buffer (pH 4.5) after an overnight fast [23]. Confirmation of hyperglycemia was made three days after STZ injection, and only STZ-treated rats whose glucose concentration of the tail venous blood measured by OneTouch SureStep Plus glucometer (Lifescan, Milpitas, CA, USA) was higher than 20 mM were considered as qualified diabetic models [24]. Six rats were excluded from the study after confirmation of success of diabetic models because of low blood glucose levels. The rest of rats were randomized into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with sham PEMF exposure group (DM), diabetes mellitus with PEMF exposure group (DM+PEMF) which were subjected to whole-body exposure to PEMF 8 hours (09:00–17:00) everyday, 6 days a week for 7 weeks. Although the same PEMF apparatus was employed in DM group, the PEMF stimulation was not activated. PEMF stimulation was carried out the next day after confirmation of hyperglycemia. The current study was performed in adherence to the National Institutes of Health guidelines for the use of experimental animals, and all animal protocols were approved by the Committee for Ethical Use of Experimental Animals of the Fourth Military Medical University.

PEMF Apparatus

Three identical coils with coil diameters of 800 mm constituted the PEMF stimulation apparatus (the modified Helmholtz coils). The coils were in series connection and placed coaxially with a distance of 304 mm apart (Fig. 1A). Each coil was made up of enameled coated copper wire with 0.8 mm diameter. The assembly of three identical coils significantly upgraded the uniformity of MFD by decreasing the deviation of the MFD between the central reference point (origin, center of the middle coil) and other areas in the magnetic field [25].

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g001.jpg

Open in a separate windowFigure 1Schematic drawing of PEMF exposure system and PEMF pulse protocol.

(A) Modified Helmholtz coils consisted of three identical coils with diameters of 800 mm which were in series connection and mounted coaxially at a distance of 304 mm apart. Two cubic plastic rat cages whose length was along O–Y direction (Origin is the center of the middle coil, O–X direction is the axial direction of the coil and the coordinate system meets right-hand rule) were put in the center of every two neighboring coils and cages were supported by stands to let the activities of rats restrict on the XY plane. The modified Helmholtz coils were wired to the GHY-III pulse generator. (B) The pulse stimulator (GHY-III) generated an open-circuit voltage waveform of PEMF with a repetitive burst frequency at 15 Hz (burst width, 5 ms; burst wait, 60 ms; pulse width, 0.2 ms; pulse wait, 0.02 ms; pulse rise and fall time: 0.3 µs, 2.0 µs).

The MFD value along the O–X direction (axial direction of the coil, the coordinate system meets right-hand rule) is expressed as:

equation image
An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e002.jpg
An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e003.jpg
An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e004.jpg
An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e005.jpg

Where  is the permeability of vacuum, I is the current through the coils, R is the radius of the coils,  is the distance between the central coil and the outside coil,  is the abscissa relative to origin, N is the number of turns of the outside coil, and k×N is the number of turns of the middle coil. By setting the parameters ?=?0.7601R and k?=?0.5315, the second and fourth derivative of B(x) will become zero at the position of origin and then the maximum uniformity of the MFD will be obtained [25]. In the present study, we set the number of turns of the two outside coils as 500. Therefore, the number of turns of the central coil has been determined as 266. Besides, the distance between the central coil and the outside coil was approximately 304 mm. The modified Helmholtz coils were wired to a pulse generator (GHY-III, FMMU, Xi’an, China; China Patent no.ZL02224739.4) which produced a PEMF signal (Fig. 1A). The open-circuit voltage waveform of the PEFM consisted of a pulsed burst (burst width, 5 ms; burst wait, 60 ms; pulse width, 0.2 ms; pulse wait, 0.02 ms; pulse rise and fall time: 0.3 µs, 2.0 µs ) repeated at 15 Hz (Fig. 1B). The reason for selecting this particular waveform was that it had been proven to be effective in diabetes-induced diseases in our previous studies which were performed by our study group over a long period of time [26][30].

Two cubic plastic rat cages containing rats in PEFM group were put in the center of every two neighboring coils (the length of the cage was along O-Y direction) and cages were supported by stands to let the activities of rats restrict on the XY plane which had higher intensity and better uniformity of MFD (Fig. 1A). Moreover, whole body exposure to PEMF for rats was applied eight hours everyday. The distribution of the peak MFD was measured by using a Gaussmeter (Model 455 DMP Gaussmeter, Lake Shore Cryotronics, USA), and the measurement result was (1.6±0.1)×10?3 T (average ± standard deviation) in the exposure area (cage: 50 cm long, 20 cm wide and 15 cm high).

A small resistor of 2 ? was placed in series with the modified Helmholtz coils. The voltage drop across the resistor was observed with an oscilloscope (Agilent 6000 Series, Agilent Technologies, Inc., Santa Clara, CA). Peak value of voltage drop was observed to calculate the peak value of current in the coils so as to obtain the peak value of MFD. In order to make the distribution of MFD in the modified Helmholtz coils more intuitive, the finite element engineering software called COMSOL Multiphysics (v4.3 COMSOL AB, Burlington, MA, USA) was applied to simulate the three dimensional distribution of the MFD in the modified Helmholtz coils when the current in the coils reached peak value (approximately 1.5A). A physics-controlled mesh setting whose element size is coarse was employed to avoid memory overflow caused by too many mesh elements. By establishing the geometric model, setting boundary conditions, meshing models and obtaining numerical solutions, the distributions of MFD of modified Helmholtz coils are shown in Fig. 2. We can find that the MFD on rats’ behavior plane (XY plane) was uniform and the peak MFD was about 1.6×10?3 T which approximately coincided with the practical measurement result ((1.6±0.1)×10?3 T).

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g002.jpg

Open in a separate windowFigure 2The three dimensional distribution of peak MFD at XY plane (the activity plane of rats) of modified Helmholtz coils and two dimensional distribution of peak MFD on O–X and O–Y cut line of XY plane when the current in the coils reached peak value (approximately 1.5 A).

(A) Three dimensional distribution of peak MFD at XY plane of modified Helmholtz coils whose homogeneous color (blue) indicates the peak MFD at XY plane was uniform and approximately 1.6×10?3 T and red arrows indicates the instantaneous direction of MFD. (B) Two dimensional distribution of peak MFD on O–X cut line of XY plane whose major parts at the activity plane of rats was uniform and approximately 1.6×10?3 T. (C) Two dimensional distribution of peak MFD on O–Y cut line of XY plane whose major parts at the activity plane of rats was uniform and approximately 1.6×10?3 T.

Evaluation of Mechanical Allodynia

Tactile allodynia was assessed by measuring the hind paw withdrawal threshold to the application of a calibrated series of 6 von Frey filaments (bending forces of 2, 4, 6, 8, 10 and 15 g) (Stoelting, Wood Dale, IL, USA) using a modification of the up-down method [31]. Rats were placed in acrylic cages with a wire grid ?oor and allowed to sit in a quiet room for 30 min before beginning the tests. Starting with the filament that has the lowest force (2 g), the filament was applied perpendicularly to the mid-plantar surface of hind paw with sufficient force to cause the filament to buckle slightly. Brisk withdrawal or hind paw flinching was considered as the positive response. Each filament was applied five times to each hind paw (for 6–8 s per stimulation, with a stimulus interval of 1–2 min). Minimum recording of five positive responses (50%) out of 10 stimulations for both paws was considered to be the mechanical withdrawal threshold (MWT) (in grams). Absence of a response (less than five withdrawals) prompted use of the next graded filament. The cut-off of a 15 g filament was selected as the upper limit for testing, since stiffer filaments tended to raise the entire limb rather than to buckle, substantially changing the nature of the stimulus. A significant decrease in the threshold of hind paw withdrawal in response to the mechanical stimulus was interpreted as indicating the presence of mechanical allodynia as compared to the baseline threshold.

Evaluation of Thermal Hyperalgesia

The thermal stimulation system (Commat, Ankara, Turkey) consisting of a clear plastic chamber (10×20×24 cm3) that sits on a clear smooth glass ?oor was used to assess thermal hyperalgesia by measuring nociceptive thermal threshold. Before beginning the test, rats were placed individually in the chamber and allowed approximately 30 min to acclimate to the testing environment. A radiant heat source (8 V, 50 W halogen bulb) mounted on a movable holder below a glass pane was positioned to deliver a thermal stimulus to the mid-plantar region of the hind paw. The intensity of the heat stimulus was maintained constant throughout all experiments. When the rat feels pain and withdraws its paw, a photocell detects interruption of a light beam re?ection, the infrared generator is automatically switched off, and the timer stops, determining the withdrawal threshold. Each rat was unilaterally tested three times at 3-min interval. The average of the three measurements was taken as thermal withdrawal threshold (TWT). In order to avoid excessive suffering of rats, the thermal source was automatically discontinued after 25 s (cut-off latency) if the rat fails to withdraw its paw. A significant decrease in the latency of hind paw withdrawal in response to the noxious thermal stimulus was interpreted as indicating the presence of thermal hyperalgesia as compared to the baseline latency.

Time Course for Measurements of Weight, Blood Glucose, Mechanical Allodynia and Thermal Hyperalgesia

The weights, blood glucose levels and responses to mechanical and thermal stimuli of all rats were evaluated prior to STZ administration, and there were no statistically significant differences for these parameters among three groups. Weights and blood glucose levels of all rats were regularly measured in the Friday morning (9:00–11:00) in weeks 0, 1, 3, 5 and 7 after PEMF stimulation. Mechanical allodynia and thermal hyperalgesia were evaluated at the Friday night (19:00–23:00) in weeks 0, 1, 3, 5 and 7 after PEMF stimulation. For these two tests, measurements were done by two experimenters who were not aware of the treatment groups respectively and responsible for each test until the study finished.

Ultrastructural Examination of Sciatic Nerve

Seven weeks after PEMF stimulation in STZ-treated rats with DPN, all rats were anesthetized by an intraperitoneal injection of 7% chloral hydrate solution (0.45 ml/100 g) prior to collecting the sciatic nerve [32]. The distal part of the sciatic nerve was dissected and post fixed by immersion in the fixative solution (2% paraformaldehyde, 2% glutaraldehyde, 0.1 M cacodylate buffer at pH 7.3) for 2 h at 4°C, and washed in 0.1 M cacodylate buffer, and osmicated for 4 h in 1% OsO4 (Fluka). Nerves were rinsed in 0.1 M cacodylate buffer, dehydrated and embedded in epoxy 812-Araldite (Polysciences). Ultra-thin sections (80 nm) were subsequently cut, collected on cellodincoated single slot grids and stained with uranyl acetate and lead citrate. Photographs were obtained using a transmission electron microscope (JEM-2000EX, Japan) operated at 80 keV.

Immunohistochemical Study for VEGF of Sciatic Nerve

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e006.jpg

The distal part of the sciatic nerve was dissected and post fixed by immersion in the fixative solution (10% paraformaldehyde), and routine paraffin embedding was performed. Longitudinal sections (12 m) of sciatic nerve were thaw-mounted onto Superfrost Plus Slides (VWR). Sections were washed with PBS, and then incubated in blocking buffer (10% normal goat serum, 0.2% Triton-X 100 in PBS) for 1 h at room temperature. Slides were incubated overnight at 4°C with primary antibodies (in blocking buffer): anti–VEGF (1:100; EMD Millipore, USA). Slides were washed and then incubated with goat anti-rabbit IgG (1:200; Jackson ImmunoResearch, USA) for 1 h at room temperature. Digital images were acquired using light microscope (ECLIPSE50i, Nikon, Japan).

Statistical Analysis

Statistical analyses were carried out using SPSS (version 14.0, SPSS, IL, USA). All values were expressed as means ± standard error of the mean (SEM). P<0.05 was considered statistically significant. Data sets (body weight, blood glucose level and mechanical and thermal withdrawal threshold) of time course study were analyzed by two-way repeated measures analysis of variance (ANOVA). All results were interpreted using the Greenhous–Geisser correction to reduce the probability of obtaining a significant result by chance alone. Between subject factors consisted of intervention (Control, DM and DM+PEMF) and within subject factors consisted of time (weeks 0, 1, 3, 5 and 7 after PEMF stimulation) resulted in a 3×5 ANOVA. Data was analyzed for intervention and time main effects. Bonferroni-adjusted pairwise comparisons were performed for multiple comparisons of the means between the groups. PEMF effect would be indicated by a significant main effect for intervention.

Results

Body Weight and Whole Blood Glucose Level

Two-way repeated measures ANOVA with a Greenhouse-Geisser correction determined that a significant main effect for time (F (2.109, 75.936)?=?9.502, P<0.001) was found for means of body weight throughout the time course. The body weight differed significantly between time points. Post hoc tests using the Bonferroni correction revealed that the mean body weight of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 3). After STZ injection, rats consistently lost weight. Although there was slightly less loss of the body weight in PEMF treated diabetic rats, no significant difference between DM+PEMF group and DM group was found (P>0.05). PEMF stimulation did not significantly affect the loss of body weight caused by diabetes.

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g003.jpg

Figure 3Trends of body weight in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Similarly, a significant main effect for time (F (1.841, 38.651)?=?92.331, P<0.001) was observed for average blood glucose level throughout the time course. The average blood glucose level differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the average blood glucose levels of DM group and DM+PEMF group were significantly higher than in the Control group (P<0.01) (Fig. 4). STZ administration caused a rapid elevation of average blood glucose levels (>500 mg/dl) within one week, which persisted for up to 7 weeks. Although the blood glucose levels were slightly lower in PEMF treated diabetic rats, there was no significant difference between DM+PEMF group and DM group (P>0.05). PEMF stimulation did not significantly affect the hyperglycemia caused by diabetes.

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g004.jpg

Figure 4Trends of blood glucose levels in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Effects of PEMF on Mechanical Allodynia

A significant main effect for time (F (2.975, 62.470)?=?176.065, P<0.001) was observed for MWT throughout the time course. MWT differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the MWT of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 5). There was a significant difference between DM+PEMF group and DM group (P<0.05) (Fig. 5). PEMF stimulation significantly prevented the development of hypersensitivity to mechanical stimulus in diabetic rats (Fig. 5).

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g005.jpg

Open in a separate windowFigure 5Trends of MWT in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group, #P<0.05, statistically significant compared to the DM group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Effects of PEMF on Thermal Hyperalgesia

A significant main effect for time (F (2.564, 53.840)?=?56.742, P<0.001) was observed for TWT. TWT differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the TWT of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 6). There was a significant difference between DM+PEMF group and DM group (P<0.05) (Fig. 6). PEMF stimulation significantly prevented the development of hypersensitivity to noxious thermal stimulus in diabetic rats (Fig. 6).

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g006.jpg

Figure 6Trends of TWT in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group, #P<0.05, statistically significant compared to the DM group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Electron Microscopy of Sciatic Nerve

Ultrastructural examination of sciatic nerve was obtained by using transmission electron microscopy after a 7-week experimental period in all rats. In Control group, myelinated fiber with normal structure and morphology was observed (Fig. 7A). In DM group, some evidences of axonal degeneration such as demyelination and axon enlargement were observed. Myelin sheath showed infolding, splitting, swelling and deformation, and layers were separated or disappeared (Fig. 7B). In DM+PEMF group, myelin sheath of sciatic nerve was abnormal, the densities of layer on myelin sheath were uneven and rarefaction, but the damage was slighter than in the DM group (Fig. 7C). Seven-week exposure to PEMF stimulation partially prevented the development of axonal degeneration in STZ-treated rats with DPN.

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g007.jpg

Open in a separate windowFigure 7Electron micrographs of sciatic nerves in Control, DM, and DM+PEMF groups after a 7-week experimental period in all rats (magnification: ×6000).

(A) Control group: Myelinated fiber had normal structure and morphology. Myelin sheath was in integrity and lined up in order. (B) DM group: Demyelination and axon enlargement were observed. Myelin sheath showed infolding, splitting, swelling and deformation, and layers were separated or disappeared. (C) DM+PEMF group: Myelin sheath of sciatic nerve was abnormal, the densities of layer on myelin sheath were uneven and rarefaction, but the damage was slighter than in the DM group.

Immunostaining for VEGF in Sciatic Nerve

After a 7-week experimental period, no VEGF immunostaining in sciatic nerve was seen in Control group (Fig. 8A). In contrast, diabetic rats with DPN showed intense VEGF immunostaining in sciatic nerve (Fig. 8B). Diabetic animals treated with PEMF stimulation showed less VEGF immunostaining intensity in sciatic nerve compared to that of the DM group (Fig. 8C).

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g008.jpg

Figure 8Immunohistochemical staining for VEGF in sciatic nerves in Control, DM and DM+PEMF groups after a 7-week experimental period in all rats (magnification: ×200).

(A) Control group: No VEGF immunostaining in sciatic nerve. (B) DM group: Intense VEGF immunostaining in sciatic nerve. (C) DM+PEMF group: Less VEGF immunostaining intensity in sciatic nerve compared to that of the DM group.

Discussion

Our data in the present study support the hypothesis that PEMF might play a therapeutic role in the development of DPN in STZ-treated rats. Efficacy was evaluated by the assessment of hypersensitivity using behavioral assays of neuropathic pain that included hind paw withdrawal threshold to non-noxious mechanical stimuli (mechanical allodynia) and thermal hind paw withdrawal latency to noxious heat stimuli (thermal hyperalgesia). In our experiments, 3 weeks after the STZ injection, rats with diabetes developed mechanical allodynia and thermal hyperalgesia, which is consistent with previous studies which demonstrated that DPN often comes alone with altered sensitivity by producing both allodynia and hyperalgesia both in STZ-induced diabetic animal models and diabetic patients [33][35]. Our results also revealed that application of PEMF attenuated the development of painful DPN. PEMF stimulation showed protective effects to non-noxious mechanical stimuli and noxious heat stimuli and caused an increase in hind paw withdrawal threshold to mechanical stimuli and response time to thermal pain compared to the diabetic rats with sham PEMF stimulation. Our findings are similar to a previous investigation which asserted that treatment with PEMF may prevent the development or may reverse the abnormalities observed in animal models for painful DPN [36]. Although different types of PEMF were employed by these two studies, the same anti-neuropathic pain efficacy emerged.

In the current investigation, a marked decrease in body weight of diabetic rats was observed on week 3 as compared to non-diabetic control rats. The reduction in body weight is probably related to the osmotic diuresis and dehydration induced by diabetic hyperglycemia [36][37]. Meanwhile, blood glucose level rose immediately after the STZ injection, reached quite a high level at first week, and then remained approximately at a stable value. The results of the current study have confirmed previous findings that blood glucose level is elevated and body weight is decreased in diabetic rats after STZ administration [38][39]. Our results also revealed that PEMF stimulation did not significantly prevent the weight loss caused by diabetes, which is consistent to a previous investigation [36]. However, contrary to the findings researched by Mert et al. [36], who observed that PEMF had efficacy in anti-hyperglycemia in diabetic rats, we found that the application of PEMF did not significantly alter hyperglycemia in diabetic rats during the whole experimental observation (7 weeks). This finding is consistent with the fact that the hematoxylin and eosin staining for pancreatic islets in diabetic rats with PEMF stimulation and sham PEMF stimulation showed similar atrophy and reduction in cell numbers (not illustrated) in the current study. The different effects of PEMF in hyperglycemia might be ascribed to the different types of PEMF adopted by Mert et al. and us. These inconsistent findings concerning PEMF effects on DPN often come from varying stimulation parameters and exposure durations [40].

Obviously, a prerequisite for a clear understanding of the pathophysiological mechanisms of neuropathic appearance and treatment is to know if there are definite structural changes in the nerve fibers and to what extent they exist in the patients or experimental animal models. The pathology of DPN is characterized by progressive nerve fiber loss [41]. Our morphological analysis was performed on the sciatic nerve because the common type of DPN associated with diabetes in humans is the loss of the distal region of long and large-diameter axons. In the present study, some evidences of axonal degeneration such as demyelination and axon enlargement were observed in STZ-treated rats with DPN. Similar results were also reported by other investigators [42][43]. The sciatic nerve degeneration associated with morphologic changes was confirmed by hyperalgesia and allodynia in diabetic rats with neuropathy in our study, which is consistent with the findings that pathological changes in diabetic rats with DPN are characteristically associated with altered pain sensitivity [44]. In addition to this, our morphological study of sciatic nerve revealed that long-term PEMF stimulation partially attenuated the development of axonal degeneration observed in STZ-treated rats with DPN, which appears to be seldom reported in animal models for DPN by other investigators.

Our findings demonstrate that diabetic rats with DPN express VEGF in peripheral nerves such as sciatic nerve, while adult and healthy rats did not express the VEGF. Similar findings were also revealed by a previous study [24]. Since it is known that angiogenesis takes primarily place in metabolically altered or in injured peripheral nerves and VEGF has demonstrated neurotrophic functions in both central and peripheral neurons [45][47], it is not surprising to find elevated levels of the most potent vascular growth substance in peripheral nerves of diabetic rats with DPN. Intriguingly, on the one hand, direct neuroprotective role for VEGF comes from both in vitro and in vivo studies [8], but on the other hand, a potential consequence of high levels of VEGF observed in diabetes will be enhanced vascular permeability which often results in the extravasation of plasma protein as well as the formation of lesions in peripheral nerves. This abnormal angiogenesis caused by up-regulated VEGF expression initiates chronic insidious progressive damage and loss in unmyelinated and myelinated peripheral nerve fibers [48]. The fact that sciatic nerve of diabetic rats with DPN over seven weeks’ PEMF stimulation showed less VEGF immunostaining might indicate that restitution of nerve function induced by PEMF stimulation leads to down-regulation for VEGF, what’s more, the down-regulated VEGF might in turn cause less damage to peripheral nerve fibers.

This present experimental study demonstrated that treatment with PEMF may attenuate the development of abnormalities observed in animal models for DPN. However, the underlying mechanism of PEMF on DPN is still ambiguous. Previous study reported that PEMF had an significant anti-hyperglycemia efficacy in diabetic rats, and this PEMF-induced reduction in blood glucose level could have a positive effect on nerve function that may result in diminished pain intensity [36]. However, the significant anti-hyperglycemia efficacy of PEMF stimulation was not observed in STZ-treated rats with DPN during the whole experimental observation (7 weeks) in our study. Therefore, we hypothesized that long-term PEMF stimulation would have direct corrective effects on injured nerves, which might lead to diminished pain intensity observed in present studies. Moreover, our hypothesis is supported by in vitro and in vivo studies which have indicated that PEMF stimulation can accelerate nerve conduction velocity and increase compound action potentials of sciatic nerve, enhance nerve growth factor levels, and reduce both oxidative damage and neuronal loss [13][15][16].

In summary, the results from our present study demonstrate that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. Moreover, it is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN. However, further research is required to elucidate the specific mechanisms of PEMF on DPN and to confirm the applicability of PEMF for clinical practice.

Acknowledgments

The authors would like to thank M. Ye (Department of Physiology, Xijing hospital, Fourth Military Medical University), H. Dong (Department of Pathology, Fourth Military Medical University) and X. Huang (Department of Immunology, Fourth Military Medical University) for their excellent technical assistance.

Funding Statement

This work was supported by grants from the National Natural Science Foundation of China (Grant no.31000491, 51077128, 31000381 and 31270889). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Go to:

References

1. Imperatore G, Knowler WC, Pettitt DJ, Kobes S, Bennett PH, et al. (2000) Segregation analysis of diabetic nephropathy in Pima Indians. Diabetes 49: 1049–1056. [PubMed] 2. Raine AE (1993) Epidemiology, development and treatment of end-stage renal failure in type 2 (non-insulin-dependent) diabetic patients in Europe. Diabetologia 36: 1099–1104. [PubMed] 3. Sima AA, Kamiya H (2006) Diabetic neuropathy differs in type 1 and type 2 diabetes. Ann N Y Acad Sci 1084: 235–249. [PubMed] 4. Jensen TS, Backonja MM, Hernandez JS, Tesfaye S, Valensi P, et al. (2006) New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 3: 108–119. [PubMed] 5. Rondon LJ, Privat AM, Daulhac L, Davin N, Mazur A, et al. (2010) Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain. J Physiol 588: 4205–4215. [PMC free article] [PubMed] 6. Sator-Katzenschlager SM, Schiesser AW, Kozek-Langenecker SA, Benetka G, Langer G, et al. (2003) Does pain relief improve pain behavior and mood in chronic pain patients? Anesth Analg 97: 791–797.[PubMed] 7. Schmader KE (2002) Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 18: 350–354. [PubMed] 8. Price SA, Dent C, Duran-Jimenez B, Liang Y, Zhang L, et al. (2006) Gene transfer of an engineered transcription factor promoting expression of VEGF-A protects against experimental diabetic neuropathy. Diabetes 55: 1847–1854. [PubMed] 9. Ziegler D (2008) Treatment of diabetic neuropathy and neuropathic pain: how far have we come?Diabetes Care 31 Suppl 2S255–261. [PubMed] 10. Szymborska-Kajanek A, Strzelczyk JK, Karasek D, Rawwash HA, Biniszkiewicz T, et al. (2010) Impact of low-frequency pulsed magnetic fields on defensin and CRP concentrations in patients with painful diabetic polyneuropathy and in healthy subjects. Electromagn Biol Med 29: 19–25. [PubMed] 11. Wrobel MP, Szymborska-Kajanek A, Wystrychowski G, Biniszkiewicz T, Sieron-Stoltny K, et al. (2008) Impact of low frequency pulsed magnetic fields on pain intensity, quality of life and sleep disturbances in patients with painful diabetic polyneuropathy. Diabetes Metab 34: 349–354. [PubMed] 12. Walker JL, Evans JM, Resig P, Guarnieri S, Meade P, et al. (1994) Enhancement of functional recovery following a crush lesion to the rat sciatic nerve by exposure to pulsed electromagnetic fields. Exp Neurol125: 302–305. [PubMed] 13. Mert T, Gunay I, Gocmen C, Kaya M, Polat S (2006) Regenerative effects of pulsed magnetic field on injured peripheral nerves. Altern Ther Health Med 12: 42–49. [PubMed] 14. Macias MY, Battocletti JH, Sutton CH, Pintar FA, Maiman DJ (2000) Directed and enhanced neurite growth with pulsed magnetic field stimulation. Bioelectromagnetics 21: 272–286. [PubMed] 15. Kim S, Im WS, Kang L, Lee ST, Chu K, et al. (2008) The application of magnets directs the orientation of neurite outgrowth in cultured human neuronal cells. J Neurosci Methods 174: 91–96. [PubMed] 16. Tasset I, Medina FJ, Jimena I, Aguera E, Gascon F, et al. (2012) Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington’s disease rat model: effects on neurotrophic factors and neuronal density. Neuroscience 209: 54–63. [PubMed] 17. Bril V, England J, Franklin GM, Backonja M, Cohen J, et al. (2011) Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 76: 1758–1765. [PMC free article] [PubMed] 18. Kim H, Sasaki T, Maeda K, Koya D, Kashiwagi A, et al. (2003) Protein kinase Cbeta selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons. Diabetes 52: 2102–2109. [PubMed] 19. Jolivalt CG, Jiang Y, Freshwater JD, Bartoszyk GD, Calcutt NA (2006) Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats. Diabetologia 49: 2775–2785. [PubMed] 20. Cameron NE, Tuck Z, McCabe L, Cotter MA (2001) Effect of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion, conduction velocity and nociception in experimental diabetes. Diabetologia 44: 1161–1169. [PubMed] 21. Berti-Mattera LN, Larkin B, Hourmouzis Z, Kern TS, Siegel RE (2011) NF-kappaB subunits are differentially distributed in cells of lumbar dorsal root ganglia in naive and diabetic rats. Neurosci Lett 490: 41–45. [PMC free article] [PubMed] 22. Yamamoto H, Shimoshige Y, Yamaji T, Murai N, Aoki T, et al. (2009) Pharmacological characterization of standard analgesics on mechanical allodynia in streptozotocin-induced diabetic rats. Neuropharmacology 57: 403–408. [PubMed] 23. Stevens MJ, Li F, Drel VR, Abatan OI, Kim H, et al. (2007) Nicotinamide reverses neurological and neurovascular deficits in streptozotocin diabetic rats. J Pharmacol Exp Ther 320: 458–464. [PubMed] 24. Samii A, Unger J, Lange W (1999) Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats. Neurosci Lett 262: 159–162. [PubMed] 25. Wang J, She S, Zhang S (2001) An improved Helmholtz coil and analysis of its magnetic field homogeneity. Rev Sci Instrum 20: 6–9. 26. Jing D, Cai J, Shen G, Huang J, Li F, et al. (2011) The preventive effects of pulsed electromagnetic fields on diabetic bone loss in streptozotocin-treated rats. Osteoporos Int 22: 1885–1895. [PubMed] 27. Jing D, Shen G, Huang J, Xie K, Cai J, et al. (2010) Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. Bone 46: 487–495. [PubMed] 28. Li C, Liu Z, Zhang R, Luo E, Shen G, et al. (2008) Therapeutical effect of pulse electricmagnetic field on postmenopausal osteoporosis. Chin J Osteoporos 14: 52–54. 29. Luo E, Shen G, Xie K, Wu X, Xu Q, et al. (2007) Alimentary hyperlipemia of rabbits is affected by exposure to low-intensity pulsed magnetic fields. Bioelectromagnetics 28: 608–614. [PubMed] 30. Yu L, Luo E, Han L (2004) Preventive effect of low intensity pulse electromagnetic fields on osteoporosis of ovariectomized rats. Chin J Clin Rehabil 8: 3590–3591. 31. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53: 55–63. [PubMed] 32. Chen RJ, Lin CC, Ju MS (2010) In situ transverse elasticity and blood perfusion change of sciatic nerves in normal and diabetic rats. Clin Biomech (Bristol, Avon) 25: 409–414. [PubMed] 33. Calcutt NA (2004) Experimental models of painful diabetic neuropathy. J Neurol Sci 220: 137–139.[PubMed] 34. Fox A, Eastwood C, Gentry C, Manning D, Urban L (1999) Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. Pain 81: 307–316. [PubMed] 35. Thomas PK (1997) Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 46 Suppl 2S54–57. [PubMed] 36. Mert T, Gunay I, Ocal I (2010) Neurobiological effects of pulsed magnetic field on diabetes-induced neuropathy. Bioelectromagnetics 31: 39–47. [PubMed] 37. Malcangio M, Tomlinson DR (1998) A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 76: 151–157. [PubMed] 38. Hoybergs YM, Biermans RL, Meert TF (2008) The impact of bodyweight and body condition on behavioral testing for painful diabetic neuropathy in the streptozotocin rat model. Neurosci Lett 436: 13–18. [PubMed] 39. Wuarin-Bierman L, Zahnd GR, Kaufmann F, Burcklen L, Adler J (1987) Hyperalgesia in spontaneous and experimental animal models of diabetic neuropathy. Diabetologia 30: 653–658. [PubMed] 40. Pieber K, Herceg M, Paternostro-Sluga T (2010) Electrotherapy for the treatment of painful diabetic peripheral neuropathy: a review. J Rehabil Med 42: 289–295. [PubMed] 41. Calcutt NA, Backonja MM (2007) Pathogenesis of pain in peripheral diabetic neuropathy. Curr Diab Rep 7: 429–434. [PubMed] 42. Liu GS, Shi JY, Lai CL, Hong YR, Shin SJ, et al. (2009) Peripheral gene transfer of glial cell-derived neurotrophic factor ameliorates neuropathic deficits in diabetic rats. Hum Gene Ther 20: 715–727.[PubMed] 43. Tan AM, Samad OA, Fischer TZ, Zhao P, Persson AK, et al. (2012) Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain. J Neurosci 32: 6795–6807. [PubMed] 44. Renno WM, Saleh F, Klepacek I, Al-Awadi F (2006) Talin immunogold density increases in sciatic nerve of diabetic rats after nerve growth factor treatment. Medicina (Kaunas) 42: 147–163. [PubMed] 45. Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 846: 219–228. [PubMed] 46. Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 19: 5731–5740. [PubMed] 47. Sondell M, Sundler F, Kanje M (2000) Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 12: 4243–4254. [PubMed] 48. Stevens MJ, Obrosova I, Cao X, Van Huysen C, Greene DA (2000) Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes 49: 1006–1015. [PubMed]


Neurosci Behav Physiol. 2010 Mar;40(3):347-50.

Non-pharmacological correction of impaired microcirculation in children with diabetic polyneuropathy.

Nikolaeva NV, Bolotova NV, Luk’yanov VF, Raigorodskii YM, Tkacheva EN.

Saratov State Medical University, Saratov, Russia.

Abstract

A total of 25 boys and 20 girls aged 5-17 years with type I diabetes mellitus and disease durations of 2-10 years were studied. All had diabetic polyneuropathy. The microcirculation was studied by laser Doppler flowmetry. Treatment consisted of using a running impulse magnetic field. This method was found to be effective in diabetic polyneuropathy with the running field along the limb towards the periphery at a run velocity (field modulation frequency) being a multiple of the nerve fiber spike conduction velocity.

Bioelectromagnetics. 2010 Jan;31(1):39-47.

Neurobiological effects of pulsed magnetic field on diabetes-induced neuropathy.

Mert T, Gunay I, Ocal I.

Faculty of Medicine, Department of Biophysics, Cukurova University, Balcali, Adana, Turkey.tufanmert@yahoo.com

Abstract

In the clinic, although several pharmacological agents or surgical procedures are used to treat diabetes and diabetes-induced neuropathic pain, their success has been limited. Therefore, development of different alternatives in treatments is very important. The purpose of this study was to determine the efficacy of pulsed magnetic field (PMF) in improving signs and symptoms of diabetic neuropathy. In this study, the effects of PMF treatment were investigated in Streptozotocin (STZ)-induced acute and chronic diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels and body weights. After STZ administration to rats, blood glucose level elevated and body weight decreased. Although PMF treatment did not affect changes in body weight, the blood glucose levels of PMF-treated diabetic rats exhibited a decrease during the treatments. Diabetic animals displayed marked decrease in mechanical thresholds and thermal latencies. While treatment of PMF partially restored the mechanical thresholds and thermal latency in acute diabetic rats, PMF caused a corrective effect on only mechanical threshold of chronic diabetic rats. These results suggested that treatment of PMF can potentially ameliorate the painful symptoms of diabetes, such as hyperalgesia and allodynia, by partially preventing the hyperglycemia. (c) 2009 Wiley-Liss, Inc.

Bioelectromagnetics. 2009 Sep;30(6):438-45.

Exposure of inhomogenous static magnetic field ceases mechanical allodynia in neuropathic pain in mice.

Antal M, László J.

Department of Anatomy, Histology, and Embriology, University of Debrecen, Debrecen, Hungary.

Abstract

Magnetic therapy as a self-care intervention has led to the conduct of numerous human trials and animal experiments. Results concerning the analgesic efficacy of magnetic exposure, however, are inconsistent. By using a magnetic device generating an inhomogeneous static magnetic field (iSMF), here we studied how the whole-body exposure to iSMF may influence the mechanical withdrawal threshold (MWT) of the hind paw in different stages of neuropathic pain evoked by partial ligation of the sciatic nerve in mice. It was found that iSMF exposure did not prevent the decrease of MWT in the first postoperative week. A 2-week long iSMF treatment that was started just after the nerve ligation elevated MWT values to a modest extent. However, the effectiveness of a daily exposure to iSMF was much more prominent when it was applied between postoperative days 15 and 28. In this case, MWT was already noticeably increased after the first treatment and it practically reached the control values by the end of the 2-week long exposure period. The results suggest that exposure to iSMF cannot prevent the development of mechanical allodynia, but can inhibit processes that maintain the increased sensitivity to mechanical stimuli in neuropathic pain.

Arch Phys Med Rehabil. 2009 Jul;90(7):1102-9.

Pulsed electromagnetic fields to reduce diabetic neuropathic pain and stimulate neuronal repair: a randomized controlled trial.

Weintraub MI, Herrmann DN, Smith AG, Backonja MM, Cole SP.

Department of Neurology, New York Medical College, Valhalla, NY, USA. miwneuro@pol.net

Abstract

OBJECTIVE: To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration.

DESIGN: Randomized, double-blind, placebo-controlled parallel study.

SETTING: Sixteen academic and clinical sites in 13 states.

PARTICIPANTS: Subjects (N=225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 h/d to feet for 3 months.

INTERVENTIONS: Nerve conduction testing was performed serially.

MAIN OUTCOME MEASURES: Pain reduction scores using a visual analog scale (VAS), the Neuropathy Pain Scale (NPS), and the Patient’s Global Impression of Change (PGIC). A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification.

RESULTS: Subjects (N=225) were randomized with a dropout rate of 13.8%. There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44% vs 31%; P=.04). There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS. Twenty-seven subjects completed serial biopsies. Twenty-nine percent of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (P=.04). Increases in distal thigh ENFD were significantly correlated with decreases in pain scores.

CONCLUSIONS: PEMF at this dosimetry was noneffective in reducing NP. However neurobiological effects on ENFD, PGIC and reduced itching scores suggest future studies are indicated with higher dosimetry (3000-5000 G), longer duration of exposure, and larger biopsy cohort.

Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(11):43-6.

Non-pharmacological treatment of microcirculation disturbance in children with diabetic polyneuropathy.

[Article in Russian]

Nikolaeva NV, Bolotova V, Luk’ianov VF, Ra?gorodski? IuM, Tkacheva EN.

Abstract

Twenty-five boys and 20 girls, aged 5-17 years, with diabetes mellitus type I and illness duration from 2 to 10 years have been studied. All of them suffered from diabetic neuropathy. Laser-Doppler flowmetry has been used. The treatment has been conducted using running impulse magnetic field. The efficacy of the influence of running field along the extremity with the velocity of run (frequency of field modulation) divisible by the impulse conduction velocity along the nerve fiber in diabetic polyneuropathy has been shown.

Altern Ther Health Med. 2006 Sep-Oct;12(5):42-9

Regenerative effects of pulsed magnetic field on injured peripheral nerves.

Mert T, Gunay I, Gocmen C, Kaya M, Polat S.

Department of Biophysics, University of Cukurova School of Medicine, Adana, Turkey.

Previous studies confirm that pulsed magnetic field (PMF) accelerates functional recovery after a nerve crush lesion. The contention that PMF enhances the regeneration is still controversial, however. The influence of a new PMF application protocol (trained PMF) on nerve regeneration was studied in a model of crush injury of the sciatic nerve of rats. To determine if exposure to PMF influences regeneration, we used electrophysiological recordings and ultrastructural examinations. After the measurements of conduction velocity, the sucrose-gap method was used to record compound action potentials (CAPs) from sciatic nerves. PMF treatment during the 38 days following the crush injury enhanced the regeneration. Although the axonal ultrastructures were generally normal, slight to moderate myelin sheath degeneration was noted at the lesion site. PMF application for 38 days accelerated nerve conduction velocity, increased CAP amplitude and decreased the time to peak of the CAP. Furthermore, corrective effects of PMF on. the abnormal characteristics of sensory nerve fibers were determined. Consequently, long-periodic trained-PMF may promote both morphological and electrophysiological properties of the injured nerves. In addition, corrective effects of PMF on sensory fibers may be considered an important finding for neuropathic pain therapy.

Diabetologia. 2005 May;48(5):817-23. Epub 2005 Apr 15.

Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy.

Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G, Scionti L.

Diabetes and Endocrinology Unit, Department of General Medicine, Vita-Salute San Raff aele University Hospital, Via Olgettina 60, 20132 Milan, Italy. bosi.emanuele@hsr.it

Abstract

AIMS/HYPOTHESIS: The largely unsatisfactory results reported for the pharmacological treatment of diabetic neuropathy has spurred the search for alternative therapies. The aim of this study was to evaluate the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) as a novel treatment for painful diabetic neuropathy.

METHODS: Patients (n=31) with painful neuropathy associated with decreased nerve conduction velocity (<40 m/s) and increased vibration perception threshold (>25 V) were enrolled in a randomised, double-blind, crossover study designed to compare the effects of FREMS with those of placebo. Each patient received two series of ten treatments of either FREMS or placebo in random sequence, with each series lasting no more than 3 weeks. The primary efficacy end point was the change in pain measured by a visual analogue scale (VAS).

RESULTS: FREMS induced a significant reduction in daytime and night-time VAS pain score (all p<0.02). Furthermore, FREMS induced a significant increase in sensory tactile perception, as assessed by monofilament; a decrease in foot vibration perception threshold, as measured by a biothesiometer; and an increase in motor nerve conduction velocity (all p<0.01). No significant changes were observed after placebo. Comparison of measurements at the 4-month follow-up with those at baseline revealed that a significant benefit persisted for all measures that showed an improvement at the end of treatment, with an additional improvement in quality of life evaluated by the Short Form-36 questionnaire (all p<0.05). No significant side effects were recorded during the study.

CONCLUSIONS/INTERPRETATION: FREMS is a safe and effective therapy for neuropathic pain in patients with diabetes and is able to modify some parameters of peripheral nerve function.

Neurorehabil Neural Repair. 2004 Mar;18(1):42-6.

Pulsed magnetic field therapy in refractory neuropathic pain secondary to peripheral neuropathy: electrodiagnostic parameters–pilot study.

Weintraub MI, Cole SP.

New York Medical College, Briarcliff Manor, New York 10510, USA.

CONTEXT: Neuropathic pain (NP) from peripheral neuropathy (PN) arises from ectopic firing of unmyelinated C-fibers with accumulation of sodium and calcium channels. Because pulsed electromagnetic fields (PEMF) safely induce extremely low frequency (ELF) quasirectangular currents that can depolarize, repolarize, and hyperpolarize neurons, it was hypothesized that directing this energy into the sole of one foot could potentially modulate neuropathic pain.

OBJECTIVE: To determine if 9 consecutive 1-h treatments in physician’s office (excluding weekends) of a pulsed signal therapy can reduce NP scores in refractory feet with PN.

DESIGN/SETTING/PATIENTS: 24 consecutive patients with refractory and symptomatic PN from diabetes, chronic inflammatory demyelinating polyneuropathy (CIDP), pernicious anemia, mercury poisoning, paraneoplastic syndrome, tarsal tunnel, and idiopathic sensory neuropathy were enrolled in this nonplacebo pilot study. The most symptomatic foot received therapy. Primary endpoints were comparison of VAS scores at the end of 9 days and the end of 30 days follow-up compared to baseline pain scores. Additionally, Patients’ Global Impression of Change (PGIC) questionnaire was tabulated describing response to treatment. Subgroup analysis of nerve conduction scores, quantified sensory testing (QST), and serial examination changes were also tabulated. Subgroup classification of pain (Serlin) was utilized to determine if there were disproportionate responses.

INTERVENTION: Noninvasive pulsed signal therapy generates a unidirectional quasirectangular waveform with strength about 20 gauss and a frequency about 30 Hz into the soles of the feet for 9 consecutive 1-h treatments (excluding weekends). The most symptomatic foot of each patient was treated.

RESULTS: All 24 feet completed 9 days of treatment. 15/24 completed follow-up (62%) with mean pain scores decreasing 21% from baseline to end of treatment (P=0.19) but with 49% reduction of pain scores from baseline to end of follow-up (P<0.01). Of this group, self-reported PGIC was improved 67% (n=10) and no change was 33% (n=5). An intent-to-treat analysis based on all 24 feet demonstrated a 19% reduction in pain scores from baseline to end of treatment (P=0.10) and a 37% decrease from baseline to end of follow-up (P<0.01). Subgroup analysis revealed 5 patients with mild pain with nonsignificant reduction at end of follow-up. Of the 19 feet with moderate to severe pain, there was a 28% reduction from baseline to end of treatment (P<0.05) and a 39% decrease from baseline to end of follow-up (P<0.01). Benefit was better in those patients with axonal changes and advanced CPT baseline scores. The clinical examination did not change. There were no adverse events or safety issues.

CONCLUSIONS: These pilot data demonstrate that directing PEMF to refractory feet can provide unexpected short term analgesic effects in more than 50% of individuals. The role of placebo is not known and was not tested. The precise mechanism is unclear yet suggests that severe and advanced cases are more magnetically sensitive. Future studies are needed with randomized placebo-controlled design and longer treatment periods.

Arch Phys Med Rehabil. 2003 May;84(5):736-46.

Static magnetic field therapy for symptomatic diabetic neuropathy: a randomized, double-blind, placebo-controlled trial.

Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G, Cohen JA, Page JC, Bromberg MB, Schwartz SL

Magnetic Research Group. Department of Neurology, New York Medical College, Valhalla, NY, USA. miwneuro@pol.net

OBJECTIVE: To determine if constant wearing of multipolar, static magnetic (450G) shoe insoles can reduce neuropathic pain and quality of life (QOL) scores in symptomatic diabetic peripheral neuropathy (DPN). DESIGN: Randomized, placebo-control, parallel study.

SETTING: Forty-eight centers in 27 states.

PARTICIPANTS: Three hundred seventy-five subjects with DPN stage II or III were randomly assigned to wear constantly magnetized insoles for 4 months; the placebo group wore similar, unmagnetized device.

INTERVENTION: Nerve conduction and/or quantified sensory testing were performed serially.

MAIN OUTCOME MEASURES: Daily visual analog scale scores for numbness or tingling and burning and QOL issues were tabulated over 4 months. Secondary measures included nerve conduction changes, role of placebo, and safety issues. Analysis of variance (ANOVA), analysis of covariance (ANCOVA), and chi-square analysis were performed.

RESULTS: There were statistically significant reductions during the third and fourth months in burning (mean change for magnet treatment, -12%; for sham, -3%; P<.05, ANCOVA), numbness and tingling (magnet, -10%; sham, +1%; P<.05, ANCOVA), and exercise-induced foot pain (magnet, -12%; sham, -4%; P<.05, ANCOVA). For a subset of patients with baseline severe pain, statistically significant reductions occurred from baseline through the fourth month in numbness and tingling (magnet, -32%; sham, -14%; P<.01, ANOVA) and foot pain (magnet, -41%; sham, -21%; P<.01, ANOVA).

CONCLUSIONS: Static magnetic fields can penetrate up to 20mm and appear to target the ectopic firing nociceptors in the epidermis and dermis. Analgesic benefits were achieved over time.

Fiziol Zh. 2003;49(2):85-90.

Use of low-power electromagnetic therapy in diabetic polyneuropathy.

[Article in Ukrainian]

Chebotar’ova LL, Chebotar’ov HIe.

Abstract

The clinical-electroneuromyography investigations were performed for objective evaluation of low-power electromagnetic therapy effectiveness in 12 patients with diabetic polyneuropaties. It is established that combination of low-power electromagnetic therapy using “ANET-UHF”, “ANET-SHF” apparatus (Ukraine) and low-power variable magnetic field using AMT apparatus (Ukraine) give the stable positive effects. The positive changes were confirmed by following: the decrease of neurological deficit and required insulin daily dose, nerve conduction velocity increase, increase of the muscle compound action potentials (muscle power) and peripheral outflow in some patients.

Neurosci Behav Physiol. 2003 Oct;33(8):745-52.

The use of pulsed electromagnetic fields with complex modulation in the treatment of patients with diabetic polyneuropathy.

Musaev AV, Guseinova SG, Imamverdieva SS.

Science Research Institute of Medical Rehabilitation, Baku, Azerbaidzhan.

Clinical and electroneuromyographic studies were performed in 121 patients with diabetic polyneuropathy (DPN) before and after courses of treatment with pulsed electromagnetic fields with complex modulation (PEMF-CM) at different frequencies (100 and 10 Hz). Testing of patients using the TSS and NIS LL scales demonstrated a correlation between the severity and frequency of the main subjective and objective effects of disease and the stage of DPN. The severity of changes in the segmental-peripheral neuromotor apparatus–decreases in muscle bioelectrical activity, the impulse conduction rate along efferent fibers of peripheral nerves, and the amplitude of the maximum M response–depended on the stage of DPN and the duration of diabetes mellitus. The earliest and most significant electroneuromyographic signs of DPN were found to be decreases in the amplitude of the H reflex and the Hmax/Mmax ratio in the muscles of the lower leg. Application of PEMF-CM facilitated regression of the main clinical symptoms of DPN, improved the conductive function of peripheral nerves, improved the state of la afferents, and improved the reflex excitability of functionally diverse motoneurons in the spinal cord. PEMF-CM at 10 Hz was found to have therapeutic efficacy, especially in the initial stages of DPN and in patients with diabetes mellitus for up to 10 years.

Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):38-41.

The use of combined methods of magnetoelectrotherapy in treating polyneuropathies.

[Article in Russian]

Shiman AG, Lobzin VS, Maksimov AV, Zabolokov IG.

A comparative evaluation by such parameters as alleviation of pain syndrome, improvement of peripheral resistance and vegetotrophic processes, a decline in pareses and sensory disorders has been performed in 3 groups of patients: group 1 underwent benzohexonium electrophoresis, group 2 benzohexonium electrophoresis in the magnetic field produced by the unit “Polyus-I” followed by low-frequency electrotherapy with bipolar impulse current, group 3 benzohexonium electrophoresis in the magnetic field from the unit “ADMT-Magnipuls” followed by low-frequency electrotherapy with bipolar impulse current. The best clinical and physiological results were reported in group 3 patients.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine–15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.

Lik Sprava. 1996 Oct-Dec;(10-12):155-8.

The medical effect of magnetic-laser therapy in patients with diabetic angiopathies of the lower extremities.

[Article in Ukrainian]

Shved MI, Dudnik AP.

Conventional antidiabetic therapy with insulin and sugar-lowering agents helps in achieving compensation of diabetes mellitus but fails to exert high effect on subjective and objective manifestations of diabetic microangiopathies of the lower extremities. A course of magnetic-laser therapy results in significant reduction of concentration of the lipid oxidation products as one of the pathogenetic mechanisms of diabetic microangiopathies, normalization of immunologic reactivity as well as attenuation of clinical manifestations of hemocirculatory disorders in the lower extremities and improvement of parameters of thermo- and rheovasography.

Klin Med (Mosk). 1996;74(5):39-41.

Magentotherapy in the comprehensive treatment of vascular complications of diabetes mellitus.

[Article in Russian]

Kirillov IB, Suchkova ZV, Lastushkin AV, Sigaev AA, Nekhaeva TI.

320 diabetes mellitus (DM) patients were exposed to impulsed magnetic field, 100 control DM patients received conservative therapy alone. 270 patients had microangiopathy, macroangiopathy was diagnosed in 50 patients. Good and satisfactory results of magnetotherapy in combination with conservative methods were achieved in 74% of patients versus 28% in control group. Metabolism stabilization resulted in some patients in reduced blood sugar. Use of magnetic field produced faster and longer response than conservative therapy.

Srp Arh Celok Lek. 1993 Aug-Dec;121(8-12):124-6.

Use of pulsating high-frequency electromagnetic fields in patients with diabetic neuropathies and angiopathies.

[Article in Serbian]

Vesovi?-Poti? V, Coni? S.

Belgrade Institute of Rehabilitation.

Abstract

High-frequency pulsating electromagnetic field therapy was carried out in 22 patients with diabetic polyneuropathy and angiopathy manifested on lower extremities (18 men, 4 women, aged 48.2 +/- 6.3 years; 10 insulin-dependent persons, and 12 on oral antidiabetic treatment). The aim of the study was to verify the effect of this therapy on symptoms, neurophysiological findings and peripheral circulation. The diagnose of diabetic polyneuropathy was based on the electromyographic examination of foot and calf muscles, measurement of motor nerve conduction velocity of peroneal and tibial nerve, and sensory nerve conduction velocity of sural nerve. Diagnosis of diabetic polyneuropathy was based on electromyographic examination of the foot and calf muscles, measurement of the motor nerve conduction velocity of peroneal and tibial nerves, and the sensory nerve conduction velocity of the sural nerve. Diagnosis of diabetic angiopathy was established by oscillometric examination, measurement of skin temperature and claudication distance. The same methods were used for the evaluation of the therapeutical effect of electromagnetic field. Significant improvement of symptoms, and of all registered parameters of peripheral circulation was established after the therapy, but there were no significant changes of neurophysiological parameters. Therefore, high-frequency pulsating electromagnetic field is recommended for the treatment of diabetic angiopathy. In patients with neuropathic changes it can be used as an introduction procedure, or as an additional procedure to physical agents which are commonly used in the treatment of peripheral nerve lesion.

Neuronal Effects

J Neural Eng. 2010 Aug;7(4):045003. Epub 2010 Jul 19.

Modulation of neuronal activity and plasma membrane properties with low-power millimeter waves in organotypic cortical slices.

Pikov V, Arakaki X, Harrington M, Fraser SE, Siegel PH.

Neural Engineering Program, Huntington Medial Research Institutes, Pasadena, CA, USA. pikov@hotmail.com

Abstract

As millimeter waves (MMWs) are being increasingly used in communications and military applications, their potential effects on biological tissue has become an important issue for scientific inquiry. Specifically, several MMW effects on the whole-nerve activity were reported, but the underlying neuronal changes remain unexplored. This study used slices of cortical tissue to evaluate the MMW effects on individual pyramidal neurons under conditions mimicking their in vivo environment. The applied levels of MMW power are three orders of magnitude below the existing safe limit for human exposure of 1 mW cm(-2). Surprisingly, even at these low power levels, MMWs were able to produce considerable changes in neuronal firing rate and plasma membrane properties. At the power density approaching 1 microW cm(-2), 1 min of MMW exposure reduced the firing rate to one third of the pre-exposure level in four out of eight examined neurons. The width of the action potentials was narrowed by MMW exposure to 17% of the baseline value and the membrane input resistance decreased to 54% of the baseline value across all neurons. These effects were short lasting (2 min or less) and were accompanied by MMW-induced heating of the bath solution at 3 degrees C. Comparison of these results with previously published data on the effects of general bath heating of 10 degrees C indicated that MMW-induced effects cannot be fully attributed to heating and may involve specific MMW absorption by the tissue. Blocking of the intracellular Ca(2+)-mediated signaling did not significantly alter the MMW-induced neuronal responses suggesting that MMWs interacted directly with the neuronal plasma membrane. The presented results constitute the first demonstration of direct real-time monitoring of the impact of MMWs on nervous tissue at a microscopic scale. Implication of these findings for the therapeutic modulation of neuronal excitability is discussed.

Bioelectromagnetics. 2010 Apr;31(3):180-90.

Millimeter wave effects on electrical responses of the sural nerve in vivo.

Alekseev SI, Gordiienko OV, Radzievsky AA, Ziskin MC.

Center for Biomedical Physics, Temple University Medical School, 3400 N. Broad Street, Philadelphia, PA 19140, USA.

Abstract

Millimeter wave (MMW, 42.25 GHz)-induced changes in electrical activity of the murine sural nerve were studied in vivo using external electrode recordings. MMW were applied to the receptive field of the sural nerve in the hind paw. We found two types of responses of the sural nerve to MMW exposure. First, MMW exposure at the incident power density >/=45 mW/cm(2) inhibited the spontaneous electrical activity. Exposure with lower intensities (10-30 mW/cm(2)) produced no detectable changes in the firing rate. Second, the nerve responded to the cessation of MMW exposure with a transient increase in the firing rate. The effect lasted 20-40 s. The threshold intensity for this effect was 160 mW/cm(2). Radiant heat exposure reproduced only the inhibitory effect of MMW but not the transient excitatory response. Depletion of mast cells by compound 48/80 eliminated the transient response of the nerve. It was suggested that the cold sensitive fibers were responsible for the inhibitory effect of MMW and radiant heat exposures. However, the receptors and mechanisms involved in inducing the transient response to MMW exposure are not clear. The hypothesis of mast cell involvement was discussed.

Radiat Res. 2009 Dec;172(6):725-36.

Altered calcium dynamics mediates P19-derived neuron-like cell responses to millimeter-wave radiation.

Titushkin IA, Rao VS, Pickard WF, Moros EG, Shafirstein G, Cho MR.

Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan Street, Chicago, IL 60607, USA.

Abstract

Intracellular calcium oscillations have long been recognized as a principal mediator of many vital cellular activities. Furthermore, Ca(2+) dynamics can be modulated by external physical cues, including electromagnetic fields. While cellular responses to low-frequency electric fields have been established, the possible non-thermal effects of millimeter-wave (MMW) radiation are still a subject of discussion and debate. We used mouse embryonic stem cell-derived neuronal cells and a custom-built 94 GHz applicator to examine in real time the altered Ca(2+) oscillations associated with MMW stimulation. MMW irradiation at 18.6 kW/m(2) nominal power density significantly increased the Ca(2+) spiking frequency in the cells exhibiting Ca(2+) activity. The N-type calcium channels, phospholipase C enzyme, and actin cytoskeleton appear to be involved in mediating increased Ca(2+) spiking. Reorganization of the actin microfilaments by a 94 GHz field seems to play a crucial role in modulating not only Ca(2+) activity but also cell biomechanics. Many but not all observed cellular responses to MMW were similar to thermally induced effects. For example, cell exposure to a 94 GHz field induced nitric oxide production in some morphologically distinct neuronal cells that could not be reproduced by thermal heating of the cells up to 42 degrees C. The highest observed average temperature rise in the MMW exposure chamber was approximately 8 degrees C above the room temperature, with possible complex non-uniform microscopic distribution of heating rates at the cell level. Our findings may be useful to establish quantitative molecular benchmarks for elucidation of nociception mechanisms and evaluation of potential adverse bioeffects associated with MMW exposure. Moreover, control of Ca(2+) dynamics by MMW stimulation may offer new tools for regulation of Ca(2+)-dependent cellular and molecular activities, for example, in tissue engineering applications.

Bioelectromagnetics. 1997;18(4):324-34.

Search for frequency-specific effects of millimeter-wave radiation on isolated nerve function.

Pakhomov AG, Prol HK, Mathur SP, Akyel Y, Campbell CB.

Microwave Bioeffects Branch, U.S. Army Medical Research Detachment of the Walter Reed Army Institute of Research, Brooks Air Force Base, San Antonio, Texas 78235-5324, USA.

Abstract

Effects of a short-term exposure to millimeter waves (CW, 40-52 GHz, 0.24-3.0 mW/cm2) on the compound action potential (CAP) conduction were studied in an isolated frog sciatic nerve preparation. CAPs were evoked by either a low-rate or a high-rate electrical stimulation of the nerve (4 and 20 paired pulses/s, respectively). The low-rate stimulation did not alter the functional state of the nerve, and the amplitude, latency, and peak latency of CAPs could stay virtually stable for hours. Microwave irradiation for 10-60 min at 0.24-1.5 mW/cm2, either at various constant frequencies or with a stepwise frequency change (0.1 or 0.01 GHz/min), did not cause any detectable changes in CAP conduction or nerve refractoriness. The effect observed under irradiation at a higher field intensity of 2-3 mW/cm2 was a subtle and transient reduction of CAP latency and peak latency along with a rise of the test CAP amplitude. These changes could be evoked by any tested frequency of the radiation; they reversed shortly after cessation of exposure and were both qualitatively and quantitatively similar to the effect of conventional heating of 0.3-0.4 degree C. The high-rate electrical stimulation caused gradual and reversible decrease of the amplitude of conditioning and test CAPs and increased their latencies and peak latencies. These changes were essentially the same with and without irradiation (2.0-2.7 or 0.24-0.28 mW/cm2), except for attenuation of the decrease of the test CAP amplitude. This effect was observed at both field intensities, but was statistically significant only for certain frequencies of the radiation. Within the studied limits, this effect appeared to be dependent on the frequency rather than on the intensity of the radiation, but this observation requires additional experimental confirmation.

Neurological

Altern Ther Health Med.  2011 Nov-Dec;17(6):22-8. Long-term Effects of Bio-electromagnetic-energyregulation Therapy on Fatigue in Patients With Multiple Sclerosis. Ziemssen T, Piatkowski J, Haase R. Abstract Background Electromagnetic-field therapy has beneficial short-term effects in multiple sclerosis (MS) patients with major fatigue, but long-term data are lacking. Primary Study Objectives To evaluate the long-term effects of a specific electromagnetic therapy device (Bio-Electromagnetic- Energy-Regulation [BEMER]) on MS-related fatigue, we designed a crossover control of a previously performed randomized controlled trial and a long-term open-label follow-up trial. Design and Setting: Crossover and open-label follow-up trials at a single neurological outpatient center. Participants Patients with relapsing-remitting MS who had major fatigue (N = 37 patients). Intervention After a previous randomized controlled trial (exposure to low-frequency pulsed magnetic fields for 8 min twice daily or to placebo treatment for 12 wk), a crossover from control to treatment for another 12 weeks, followed by an openlabel follow-up trial to 3 years, were done. Primary Outcome Measures The outcome criteria were the Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), German long version of the Center for Epidemiologic Studies Depression Scale (CES-D), Multiple Sclerosis Functional Scale (MSFC), and Expanded Disability Status Scale (EDSS). Results Patients previously on placebo during the randomized controlled trial experienced significant reductions in fatigue after crossing over to treatment. The MFIS and FSS scores were significantly lower in the open-label group than in the control subjects after follow-up. Participation in the open-label treatment was the strongest predictor of low fatigue outcome after followup. Electromagnetic-field therapy was well tolerated. Conclusions In this long-term study, a beneficial effect of long-term BEMER therapy on MS fatigue was demonstrated. Electromagnetic-field therapy may be a useful therapeutic modality in MS patients with severe fatigue.  J Recept Signal Transduct Res. 2010 Aug;30(4):214-26. Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects. Kovacic P, Somanathan R. Department of Chemistry, San Diego State University, San Diego, California, USA. pkovacic@sundown.sdsu.edu Abstract Electromagnetic fields (EMFs) played a role in the initiation of living systems, as well as subsequent evolution. The more recent literature on electrochemistry is documented, as well as magnetism. The large numbers of reports on interaction with living systems and the consequences are presented. An important aspect is involvement with cell signaling and resultant effects in which numerous signaling pathways participate. Much research has been devoted to the influence of man-made EMFs, e.g., from cell phones and electrical lines, on human health. The degree of seriousness is unresolved at present. The relationship of EMFs to reactive oxygen species (ROS) and oxidative stress (OS) is discussed. There is evidence that indicates a relationship involving EMFs, ROS, and OS with toxic effects. Various articles deal with the beneficial aspects of antioxidants (AOs) in countering the harmful influence from ROS-OS associated with EMFs. EMFs are useful in medicine, as indicated by healing bone fractures. Beneficial effects are recorded from electrical treatment of patients with Parkinson’s disease, depression, and cancer. J Altern Complement Med.  2009 May;15(5):507-11. Effect of BEMER magnetic field therapy on the level of fatigue in patients with multiple sclerosis: a randomized, double-blind controlled trial. Piatkowski J, Kern S, Ziemssen T. Source Neurological Outpatient Center Reichenbachstrasse, Dresden, Germany. Abstract OBJECTIVES: Electromagnetic field therapy has been reported to be beneficial in patients with multiple sclerosis (MS) with significant fatigue. This study was designed to evaluate the long-term effects of Bio-Electro-Magnetic-Energy-Regulation (BEMER) on MS-related fatigue. DESIGN: This was a monocenter, patient- and rater-blinded, placebo-controlled trial. PATIENTS: There were 37 relapsing-remitting patients with MS with significant fatigue in the study. INTERVENTION: The intervention consisted of BEMER magnetic field treatment for 8 minutes twice daily in comparison to placebo for 12 weeks. OUTCOME MEASURES: The primary outcome criterion was change in the Modified Fatigue Impact Scale (MFIS) between baseline and 12 weeks. The secondary outcome criteria were changes of the Fatigue Severity Scale (FSS), a general depression scale-long version (ADS-L), Multiple Sclerosis Functional Scale (MSFC), and the Expanded Disability Status Scale (EDSS). RESULTS: There was evidence of a significant difference of MFIS value (primary outcome criterion) after 12 weeks in favor of the verum group (26.84 versus 36.67; p = 0.024). In addition, FSS values were significantly lower in the verum group after 12 weeks (3.5 versus 4.7; p = 0.016). After 6 weeks’ follow-up, verum and placebo groups did not differ in experienced fatigue (MFIS, FSS). Regarding the subscales of the MFIS, there was a significant decrease in physical (p = 0.018) and cognitive (p = 0.041), but not in psychologic subscales only in the verum group regarding the timepoints baseline and 12 weeks. BEMER therapy was well tolerated. DISCUSSION: In this pilot study, we were able to demonstrate a beneficial effect of BEMER intervention on MS fatigue. As this was only a pilot study, trials with more patients and longer duration are mandatory to describe long-term effects. Biolectromagn Biol Med. 2007;26(4):305-9. The autistic syndrome and endogenous ion cyclotron resonance: state of the art. Crescentini F. Department of Bioelectromagnetic Research, I.R.P. L’Aquila, Pescara, Italy. The autistic syndrome is a multigenic disease whose expression is different according to the level of involvement of different structures in the central nervous system. The pathogenesis is unknown. No completely effective medical therapy has yet been demonstrated. Accepting the request of the families of eight autistic children in Lomazzo, Milan and Naples, we used ion cyclotron resonance (Seqex(R) therapy) therapeutic support after many other therapies had been already carried out on these patients. After regimens consisting of 20-30 treatments with ICR, improvements were noted in all cases. Int J Neurosci. 2006 Jul;116(7):775-826. Serotonergic mechanisms in amyotrophic lateral sclerosis. Sandyk R. The Carrick Institute for Clinical Ergonomics Rehabilitation, and Applied Neurosciences, School of Engineering Technologies State University of New York at Farmingdale, Farmingdale, New York 11735, USA. rsandyk@optonline.net Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.     Neuron. 2005 Jan 20;45(2):181-3.

Toward establishing a therapeutic window for rTMS by theta burst stimulation.

Paulus W.

Department of Clinical Neurophysiology, University of Goettingen, D-37075 Goettingen, Germany.

In this issue of Neuron, Huang et al. show that a version of the classic theta burst stimulation protocol used to induce LTP/LTD in brain slices can be adapted to a transcranial magnetic stimulation (TMS) protocol to rapidly produce long lasting (up to an hour), reversible effects on motor cortex physiology and behavior. These results may have important implications for the development of clinical applications of rTMS in the treatment of depression, epilepsy, Parkinson’s, and other diseases.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine-15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.

Adv Anat Embryol Cell Biol. 2003;173:III-IX, 1-77.

Electric field-induced effects on neuronal cell biology accompanying dielectrophoretic trapping.

Heida T.

University of Twente, Faculty of Electrical Engineering, Mathematics and Computer Science, Laboratory of Measurement and Instrumentation, Laboratory of Biomedical Engineering, P.O. Box 217, 7500 AE Enschede, The Netherlands. t.heida@el.utwente.nl

Abstract

Trapping neuronal cells may aid in the creation of the cultured neuron probe. The aim of the development of this probe is the creation of the interface between neuronal cells or tissue in a (human) body and electrodes that can be used to stimulate nerves in the body by an external electrical signal in a very selective way. In this way, functions that were (partially) lost due to nervous system injury or disease may be restored. First, a direct contact between cultured neurons and electrodes is created. This is realized using a microelectrode array (MEA) which can be fabricated using standard photolithographic and etching methods. Section 1 gives an overview of the human nervous system, methods for functional recovery focused on the cultured neuron probe, and the prerequisites for culturing neurons on a microelectrode array. An important aspect in the selective stimulation of neuronal cells is the positioning of cells or a small group of cells on top of each of the electrode sites of the MEA. One of the most efficient methods for trapping neuronal cells is to make use of di-electrophoresis (DEP). Dielectrophoretic forces are created when (polarizable) cells are located in nonuniform electric fields. Depending on the electrical properties of the cells and the suspending medium, the DEP force directs the cells towards the regions of high field strength (positive dielectrophoresis; PDEP) or towards regions of minimal field intensities (negative dielectrophoresis; NDEP). Since neurons require a physiological medium with a sufficient concentration of Na+, the medium conductivity is rather high (~ 1.6 S/m). The result is that negative dielectrophoretic forces are created over the entire frequency range. With the use of a planar quadrupole electrode sturcture negative forces are directed so that in the center of this structure cell can be collected. The process of trapping cortical rat neurons is described in Sect. 2 theoretically and experimentally. Medium and cell properties are frequency-dependent due to relaxation processes, which have a direct influence on the strength of the dielectrophorectic force. On the other hand, the nonideal material properties of the gold electrodes and glass substrate largely determine the electric field strength created inside the medium. Especially, the electrode-medium interface results in a significant loss of the imput signal at lower frequencies (< 1 MHz), and thus a reduction of the electric field strength inside the medium. Furthermore, due to the high medium conductivity, the electric field causes Joule heating. Local temperature rises result in local gradients in fluid density, which induces fluid flow. The electrode-medium interface and induced fluid flow are theoretically investigated with the use of modeling techniques such as finite elements modeling. Experimental and theoretical results agreed with each other on the occurrence of the effects described in this section. For the creation of the cultured neuron probe, preservation of cell viability during the trapping process is a prerequisite. Cell viability of dielectrophoretically trapped neurons has to be investigated. The membrane potential induced by the external field plays a crucial role in preservation of cell viability. The membrane can effectively be represented by a capaticance in parallel woth a low conductance; with increasing frequency and /or decreasing field strength the induced membrane potential decreases. At high induced membrane potentials ths representation for the membrane is no longer valid. At this point membrane breakdown occurs and the normally insulating membrane becomes conductive and permeable. The creation of electropores has been proposed in literature to be the cause of this high permeability state. Pores may grow or many small pores may be created which eventually may lead to membrane rupture, and thus cell death. Membrane breakdown may be reversible, but a chemical imbalance created during the high permeability state may still exist after the resealing of the membrane. This may cause cell death after several hours or even days after field application. Section 3 gives a detailed description of membrane breakdown. Since many investigations on electroporation of lipid bilayers and cell membranes are based on uniform electric fields, a finite element model is used to investigate induced membrane potentials in the nonuniform field created by the quadropole electrode structure. Modeling results are presented in cmbination with the results of breakdown experiments using four frequencies in the range from 100 kHz to 1MHz. Radomly positioned neuronals cells were exposed to stepwise increasing electric field strengths. The field strength at which membrane rupture occurred gives an indication of the maximum induced membrane potential. Due to the nonuniformity of the electric field, cell collapse was expected to be position-dependent. However, at 100 kHz cells collapsed at a break down level of about 0.4 V, in contradistinction to findings at higher frequencies where more variation in breakdown levels were found. Model simulations were able to explain the experimental results. For examining whether the neuronal cells trapped by dielectrophoresis were still viable after the trapping process, the frequency range was divided into two ranges. First, a high frequency (14 MHz) and a rather low signal amplitude (3 Vpp) were used to trap cells. At this high frequency the field-induced membrane potential is small according to the theoretical model, and therefore no real damage is expected. The experimental analysis included the investigation of the growth of the neurons, number and length of the processes (dendrites and axons), and the number of outgrowing (~ viable) versus nonoutgrowing (~ nonviable) neural cells. The experimental results agreed with the expectation. The effect of the use of driving signals with lower frequencies and/or higher amplitudes on cell viability was investigated using a staining method as described in the second part of Sect. 4. Survival chances are not directly linked to the estimated maximum induced membrane potential. The frequency of the dield plays an important role, decreasing frequency lowering the chance of survival. A lower frequency limit of 100 kHz is preferable at field strengths less than 80 k V/m, while with increasing field strength this limit shifts towards higher frequencies. The theoretical and experimental results presented in this review form the inception of the development of new electrode structures for trapping neuronal cells on top of each of the electrodes of the MEA. New ways to investigate cell properties and the phenomenon of electroporation using electrokinetic methods were developed that can be exploited in future research linking cell biology to technology.

Curr Opin Neurol. 2000 Aug;13(4):397-405.

Recent advances in amotrophic lateral sclerosis.

Al-Chalabi A, Leigh PN.

Department of Neurology, Guy’s King’s and St Thomas’ School of Medicine and Institute of Psychiatry, De Crespigny Park, London, UK.

The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.

Int J Neurosci. 1994 Jun;76(3-4):185-225.

Alzheimer’s disease: improvement of visual memory and visuoconstructive performance by treatment with picotesla magnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811.

Impairments in visual memory and visuoconstructive functions commonly occur in patients with Alzheimer’s disease (AD). Recently, I reported that external application of electromagnetic fields (EMF) of extremely low intensity (in the picotesla range) and of low frequency (in the range of 5Hz-8Hz) improved visual memory and visuoperceptive functions in patients with Parkinson’s disease. Since a subgroup of Parkinsonian patients, specifically those with dementia, have coexisting pathological and clinical features of AD, I investigated in two AD patients the effects of these extremely weak EMF on visual memory and visuoconstructive performance. The Rey-Osterrieth Complex Figure Test as well as sequential drawings from memory of a house, a bicycle, and a man were employed to evaluate the effects of EMF on visual memory and visuoconstructive functions, respectively. In both patients treatment with EMF resulted in a dramatic improvement in visual memory and enhancement of visuoconstructive performance which was associated clinically with improvement in other cognitive functions such as short term memory, calculations, spatial orientation, judgement and reasoning as well as level of energy, social interactions, and mood. The report demonstrates, for the first time, that specific cognitive symptoms of AD are improved by treatment with EMF of a specific intensity and frequency. The rapid improvement in cognitive functions in response to EMF suggests that some of the mental deficits of AD are reversible being caused by a functional (i.e., synaptic transmission) rather than a structural (i.e., neuritic plaques) disruption of neuronal communication in the central nervous system.

Acupunct Electrother Res. 1992;17(2):107-48.

Common factors contributing to intractable pain and medical problems with insufficient drug intake in areas to be treated, and their pathogenesis and treatment: Part I. Combined use of medication with acupuncture, (+) Qi gong energy-stored material, soft laser or electrical stimulation.

Omura Y, Losco BM, Omura AK, Takeshige C, Hisamitsu T, Shimotsuura Y, Yamamoto S, Ishikawa H, Muteki T, Nakajima H, et al.

Heart Disease Research Foundation, New York.

Most frequently encountered causes of intractable pain and intractable medical problems, including headache, post-herpetic neuralgia, tinnitus with hearing difficulty, brachial essential hypertension, cephalic hypertension and hypotension, arrhythmia, stroke, osteo-arthritis, Minamata disease, Alzheimer’s disease and neuromuscular problems, such as Amyotrophic Lateral Sclerosis, and cancer are often found to be due to co-existence of 1) viral or bacterial infection, 2) localized microcirculatory disturbances, 3) localized deposits of heavy metals, such as lead or mercury, in affected areas of the body, 4) with or without additional harmful environmental electro-magnetic or electric fields from household electrical devices in close vicinity, which create microcirculatory disturbances and reduced acetylcholine. The main reason why medications known to be effective prove ineffective with intractable medical problems, the authors found, is that even effective medications often cannot reach these affected areas in sufficient therapeutic doses, even though the medications can reach the normal parts of the body and result in side effects when doses are excessive. These conditions are often difficult to treat or may be considered incurable in both Western and Oriental medicine. As solutions to these problems, the authors found some of the following methods can improve circulation and selectively enhance drug uptake: 1) Acupuncture, 2) Low pulse repetition rate electrical stimulation (1-2 pulses/second), 3) (+) Qi Gong energy, 4) Soft lasers using Ga-As diode laser or He-Ne gas laser, 5) Certain electro-magnetic fields or rapidly changing or moving electric or magnetic fields, 6) Heat or moxibustion, 7) Individually selected Calcium Channel Blockers, 8) Individually selected Oriental herb medicines known to reduce or eliminate circulatory disturbances. Each method has advantages and limitations and therefore the individually optimal method has to be selected. Applications of (+) Qi Gong energy stored paper or cloth every 4 hours, along with effective medications, were often found to be effective, as Qigongnized materials can often be used repeatedly, as long as they are not exposed to rapidly changing electric, magnetic or electro-magnetic fields. Application of (+) Qi Gong energy-stored paper or cloth, soft laser or changing electric field for 30-60 seconds on the area above the medulla oblongata, vertebral arteries or endocrine representation area at the tail of pancreas reduced or eliminated microcirculatory disturbances and enhanced drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Int J Neurosci. 1991 Aug;59(4):259-62.

Age-related disruption of circadian rhythms: possible relationship to memory impairment and implications for therapy with magnetic fields.

Sandyk R, Anninos PA, Tsagas N.

Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461.

Disorganization of circadian rhythms, a hallmark of aging, may be related causally to the progressive deterioration of memory functions in senescence and possibly Alzheimer’s disease (AD). In experimental animals, disruption of circadian rhythms produces retrograde amnesia by interfering with the circadian organization of memory processes. The circadian system is known to be synchronized to external 24 h periodicities of ambient light by a neural pathway extending from the retina to the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. There is also evidence that the earth’s magnetic field is a time cue (“Zeitgeber”) of circadian organization and that shielding of the ambient magnetic field leads to disorganization of the circadian rhythms in humans. Since aging is associated with a delay of the circadian rhythm phase, and since light, which phase advances circadian rhythms, mimics the effects of magnetic fields on melatonin secretion, we postulate that application of magnetic fields might improve memory functions in the elderly as a result of resynchronization of the circadian rhythms. Moreover, since the circadian rhythm organization is more severely disrupted in patients with AD, it is possible that magnetic treatment might prove useful also in improving memory functions in these patients. If successful, application of magnetic fields might open new avenues in the management of memory disturbances in the elderly and possibly in AD.

Zh Nevropatol Psikhiatr Im S S Korsakova. 1990;90(7):108-12.

Regional cerebral angiodystonia in the practice of a neuropathologist and therapist.

[Article in Russian]

Pokalev GM, Raspopina LA.

Altogether 108 patients with regional cerebral angiodystonia were examined using rheoencephalography, measurements of temporal and venous pressure and functional tests (nitroglycerin and bicycle ergometry). Three variants of abnormalities connected with regional cerebral angiodystonia were distinguished: dysfunction of the inflow, derangement of the venous outflow, and initial functional venous hypertonia. The patients were treated with nonmedicamentous therapy (electroanalgesia, magnetotherapy, iontotherapy).

Rev Neurol. 2004 Feb 16-29;38(4):374-80.

Transcranial magnetic stimulation. Applications in cognitive neuroscience.

[Article in Spanish]

Calvo-Merino B, Haggard P.

Institute of Movement Neuroscience, University College, Londres, UK. b.calvo@ion.ucl.ac.uk

OBJECTIVE: In this review we trace some of the mayor developments in the use of transcranial magnetic stimulation (TMS) as a technique for the investigation of cognitive neuroscience. Technical aspects of the magnetic stimulation are also reviewed.

DEVELOPMENT: Among the many methods now available for studying activity of the human brain, magnetic stimulation is the only technique that allows us to interfere actively with human brain function. At the same time it provides a high degree of spatial and temporal resolution. Standard TMS applications (central motor conduction time, threshold and amplitude of motor evoked potentials) allow the evaluation of the motor conduction in the central nervous system and more complex TMS applications (paired pulse stimulation, silent period) permit study the mechanisms of diseases causing changes in the excitability of cortical areas. These techniques also allow investigation into motor disorder, epilepsy, cognitive function and psychiatric disorders.

CONCLUSIONS: Transcranial magnetic stimulation applications have an important place among the investigative tools to study cognitive functions and neurological and psychiatric disorders. Even so, despite the many published research and clinical studies, a systematic study about the possible diagnostic value and role in neurocognitive rehabilitation of TMS testing need to be realized to offer new possibilities of future applications.

Neuroreport. 2005 Nov 7;16(16):1849-1852.

Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex affects strategic decision-making.

Wout MV, Kahn RS, Sanfey AG, Aleman A.

aDepartment of Psychonomics, Helmholtz Research Institute, University of Utrecht bDepartment of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht cBCN NeuroImaging Center, Groningen, The Netherlands dDepartment of Psychology, University of Arizona, Tucson, Arizona, USA.

Although decision-making is typically seen as a rational process, emotions play a role in tasks that include unfairness. Recently, activation in the right dorsolateral prefrontal cortex during offers experienced as unfair in the Ultimatum Game was suggested to subserve goal maintenance in this task. This is restricted to correlational evidence, however, and it remains unclear whether the dorsolateral prefrontal cortex is crucial for strategic decision-making. The present study used repetitive transcranial magnetic stimulation in order to investigate the causal role of the dorsolateral prefrontal cortex in strategic decision-making in the Ultimatum Game. The results showed that repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex resulted in an altered decision-making strategy compared with sham stimulation. We conclude that the dorsolateral prefrontal cortex is causally implicated in strategic decision-making in healthy human study participants.

Trends Cogn Sci. 2005 Nov;9(11):503-5. Epub 2005 Sep 21.

Recharging cognition with DC brain polarization.

Wassermann EM, Grafman J.

Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Electrical direct current (DC) has been applied to the human head throughout history for various reasons and with claims of behavioral effects and clinical benefits. This technique has recently been rediscovered and its effects validated with modern quantitative techniques and experimental designs. Despite the very weak current used, DC polarization applied to specific brain areas can alter verbal fluency, motor learning and perceptual thresholds, and can be used in conjunction with transcranial magnetic stimulation. Compact and safe, this old technique seems poised to allow major advances cognitive science and therapy.

J ECT. 2005 Jun;21(2):88-95.

Transcranial magnetic stimulation in persons younger than the age of 18.

Quintana H.

Department of Psychiatry, Division of Child and Adolescent Psychiatry, Louisiana State University Health Science Center, School of Medicine, New Orleans, Louisiana 70112-2822, USA. Hquint@lsuhsc.edu

OBJECTIVES: To review the use of transcranial magnetic stimulation (single-pulse TMS, paired TMS, and repetitive TMS [rTMS]) in persons younger than the age of 18 years. I discuss the technical differences, as well as the diagnostic, therapeutic, and psychiatric uses of TMS/rTMS in this age group.

METHODS: I evaluated English-language studies from 1993 to August 2004 on nonconvulsive single-pulse, paired, and rTMS that supported a possible role for the use of TMS in persons younger than 18. Articles reviewed were retrieved from the MEDLINE database and Clinical Scientific index.

RESULTS: The 48 studies reviewed involved a total of 1034 children ages 2 weeks to 18 years; 35 of the studies used single-pulse TMS (980 children), 3 studies used paired TMS (20 children), and 7 studies used rTMS (34 children). Three studies used both single and rTMS. However, the number of subjects involved was not reported.

CONCLUSIONS: Single-pulse TMS, paired TMS, and rTMS in persons younger than 18 has been used to examine the maturation/activity of the neurons of various central nervous system tracts, plasticity of neurons in epilepsy, other aspects of epilepsy, multiple sclerosis, myoclonus, transcallosal inhibition, and motor cortex functioning with no reported seizure risk. rTMS has been applied to psychiatric disorders such as ADHD, ADHD with Tourette’s, and depression. Adult studies support an antidepressant effect from repetitive TMS, but there is only one study that has been reported on 7 patients that used rTMS to the left dorsal prefrontal cortex on children/adolescents with depression (5 of the 7 subjects treated responded). Although there are limited studies using rTMS (in 34 children), these studies did not report significant adverse effects or seizures. Repetitive TMS safety, ethical, and neurotoxicity concerns also are discussed.

Biol Psychiatry. 2005 Jun 15;57(12):1597-600.

Transcranial magnetic stimulation-evoked cortical inhibition: a consistent marker of attention-deficit/hyperactivity disorder scores in tourette syndrome.

Gilbert DL, Sallee FR, Zhang J, Lipps TD, Wassermann EM.

Division of Neurology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, OH 45229-3039, USA. d.gilbert@cchmc.org

BACKGROUND: Prior case-control studies using Transcranial Magnetic Stimulation (TMS) to probe the neural inhibitory circuitry of Attention Deficit Hyperactivity Disorder (ADHD), Tourette Syndrome (TS), and Obsessive Compulsive Disorder (OCD), have yielded conflicting results. Using regression analysis in TS patients with tics, ADHD, and/or OCD symptoms, all ranging from none to severe, we previously found that TMS-evoked short interval intracortical inhibition (SICI) correlated inversely with ADHD scores. We sought to validate this observation.

METHODS: We used regression to estimate the consistency of the association between ADHD symptom scores and TMS-evoked SICI at two separate visits in 28 children and adults with TS.

RESULTS: ADHD scores correlated significantly and consistently with SICI, particularly in patients not taking dopamine receptor blockers (r=.60 and r=.58). Hyperactivity, not inattention, scores accounted for ADHD-related variance in SICI.

CONCLUSIONS: SICI reliably reflects the severity of hyperactivity in children and adults with TS.

Child Adolesc Psychiatr Clin N Am. 2005 Jan;14(1):1-19, v.

Emerging brain-based interventions for children and adolescents: overview and clinical perspective.

Hirshberg LM, Chiu S, Frazier JA.

The NeuroDevelopment Center, 260 West Exchange Street, Suite 302, Providence, RI 02903, USA. lhirshberg@neruodevelopmentcenter.com

Electroencephalogram biofeedback (EBF), repetitive transcranial magnetic stimulation (rTMS), and vagal nerve stimulation (VNS) are emerging interventions that attempt to directly impact brain function through neurostimulation and neurofeedback mechanisms. This article provides a brief overview of each of these techniques, summarizes the relevant research findings, and examines the implications of this research for practice standards based on the guidelines for recommending evidence based treatments as developed by the American Academy of Child and Adolescent Psychiatry for attention deficit hyperactivity disorder (ADHD). EBF meets the “Clinical Guidelines” standard for ADHD, seizure disorders, anxiety, depression, and traumatic brain injury. VNS meets this same standard for treatment of refractory epilepsy and meets the lower “Options” standard for several other disorders. rTMS meets the standard for “Clinical Guidelines” for bipolar disorder, unipolar disorder, and schizophrenia. Several conditions are discussed regarding the use of evidence based thinking related to these emerging interventions and future directions.

Curr Med Res Opin. 2003;19(2):125-30.

Repetitive transcranial magnetic stimulation (rTMS): new tool, new therapy and new hope for ADHD.

Acosta MT, Leon-Sarmiento FE.

Department of Neurology, Children’s National Medical Center, Washington, DC, USA.

Attention-deficit hyperactivity disorder (ADHD) is the most common developmental disorder that is associated with environmental and genetic factors. Neurobiological evidence suggests that fronto-striatum-cerebellum circuit abnormalities, mainly in the right hemisphere, are responsible for most of the disturbed sensorimotor integration; dopamine seems to be the main neurochemical alteration underlying these morphological abnormalities. Different conventional treatments have been employed on ADHD; however, repetitive transcranial magnetic stimulation (rTMS), a new and useful option for the clinical/research investigation of several neuropsychiatric disorders involving dopamine circuits, has yet to be considered as a therapeutic tool and possible drug-free option for ADHD. Here the authors explore the available evidence that makes this tool a rational therapeutic possibility for patients with ADHD, calling attention to safety issues, while highlighting the potentials of such an approach and the new hope it may bring for patients, parents, researchers and clinicians. The authors advocate carefully conducted clinical trials to investigate efficacy, safety, cost-effectiveness and clinical utility of rTMS for ADHD patients – in comparison to both placebo and standard treatments.

Clin Neurophysiol. 2003 Nov;114(11):2036-42.

Disturbed transcallosally mediated motor inhibition in children with attention deficit hyperactivity disorder (ADHD).

Buchmann J, Wolters A, Haessler F, Bohne S, Nordbeck R, Kunesch E.

Department of Child and Adolescence Neuropsychiatry, Centre of Nerve Disease, University of Rostock, Gehlsdorfer Strasse 20, 18147 Rostock, Germany.

OBJECTIVE: The aim of this study was to investigate mechanisms of motor-cortical excitability and inhibition which may contribute to motor hyperactivity in children with attention deficit hyperactivity disorder (ADHD).

METHODS: Using transcranial magnetic stimulation (TMS), involvement of the motor cortex and the corpus callosum was analysed in 13 children with ADHD and 13 sex- and age-matched controls. Contralateral silent period (cSP) and transcallosally mediated ipsilateral silent period (iSP) were investigated.

RESULTS: Resting motor threshold (RMT), amplitudes of motor evoked potentials (MEP) and cSP were similar in both groups whereas iSP-latencies were significantly longer (p<0.05) and their duration shorter (p<0.01) in the ADHD group. For the ADHD group iSP duration tended to increase and iSP latency to decrease with age (n.s.). Conners-Scores did neither correlate with iSP-latencies and -duration nor with children’s age.

CONCLUSIONS: The shortened duration of iSP in ADHD children could be explained by an imbalance of inhibitory and excitatory drive on the neuronal network between cortex layer III-the projection site of transcallosal motor-cortical fibers-and layer V, the origin of the pyramidal tract. The longer iSP-latencies might be the result of defective myelination of fast conducting transcallosal fibers in ADHD. iSP may be a useful supplementary diagnostic tool to discriminate between ADHD and normal children.

J Child Neurol. 2001 Dec;16(12):891-4.

Subjective reactions of children to single-pulse transcranial magnetic stimulation.

Garvey MA, Kaczynski KJ, Becker DA, Bartko JJ.

Pediatric Movement Disorders Unit, Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1255, USA. garveym@intra.nimh.nih.gov

Single-pulse transcranial magnetic stimulation is a useful tool to investigate cortical function in childhood neuropsychiatric disorders. Magnetic stimulation is associated with a shock-like sensation that is considered painless in adults. Little is known about how children perceive the procedure. We used a self-report questionnaire to assess children’s subjective experience with transcranial magnetic stimulation. Normal children and children with attention-deficit hyperactivity disorder (ADHD) underwent transcranial magnetic stimulation in a study of cortical function in ADHD. Subjects were asked to rate transcranial magnetic stimulation on a 1 to 10 scale (most disagreeable = 1, most enjoyable = 10) and to rank it among common childhood events. Thirty-eight subjects completed transcranial magnetic stimulation; 34 said that they would repeat it. The overall rating for transcranial magnetic stimulation was 6.13, and transcranial magnetic stimulation was ranked fourth highest among the common childhood events. These results suggest that although a few children find transcranial magnetic stimulation uncomfortable, most consider transcranial magnetic stimulation painless. Further studies are necessary to confirm these findings.

Int J Neurosci. 1994 Jun;76(3-4):185-225.

Alzheimer’s disease: improvement of visual memory and visuoconstructive performance by treatment with picotesla range magnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811.

Impairments in visual memory and visuoconstructive functions commonly occur in patients with Alzheimer’s disease (AD). Recently, I reported that external application of electromagnetic fields (EMF) of extremely low intensity (in the picotesla range) and of low frequency (in the range of 5Hz-8Hz) improved visual memory and visuoperceptive functions in patients with Parkinson’s disease. Since a subgroup of Parkinsonian patients, specifically those with dementia, have coexisting pathological and clinical features of AD, I investigated in two AD patients the effects of these extremely weak EMF on visual memory and visuoconstructive performance. The Rey-Osterrieth Complex Figure Test as well as sequential drawings from memory of a house, a bicycle, and a man were employed to evaluate the effects of EMF on visual memory and visuoconstructive functions, respectively. In both patients treatment with EMF resulted in a dramatic improvement in visual memory and enhancement of visuoconstructive performance which was associated clinically with improvement in other cognitive functions such as short term memory, calculations, spatial orientation, judgement and reasoning as well as level of energy, social interactions, and mood. The report demonstrates, for the first time, that specific cognitive symptoms of AD are improved by treatment with EMF of a specific intensity and frequency. The rapid improvement in cognitive functions in response to EMF suggests that some of the mental deficits of AD are reversible being caused by a functional (i.e., synaptic transmission) rather than a structural (i.e., neuritic plaques) disruption of neuronal communication in the central nervous system.

Int J Neurosci. 1991 Aug;59(4):259-62.

Age-related disruption of circadian rhythms: possible relationship to memory impairment and implications for therapy with magnetic fields.

Sandyk R, Anninos PA, Tsagas N.

Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461.

Disorganization of circadian rhythms, a hallmark of aging, may be related causally to the progressive deterioration of memory functions in senescence and possibly Alzheimer’s disease (AD). In experimental animals, disruption of circadian rhythms produces retrograde amnesia by interfering with the circadian organization of memory processes. The circadian system is known to be synchronized to external 24 h periodicities of ambient light by a neural pathway extending from the retina to the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. There is also evidence that the earth’s magnetic field is a time cue (“Zeitgeber”) of circadian organization and that shielding of the ambient magnetic field leads to disorganization of the circadian rhythms in humans. Since aging is associated with a delay of the circadian rhythm phase, and since light, which phase advances circadian rhythms, mimics the effects of magnetic fields on melatonin secretion, we postulate that application of magnetic fields might improve memory functions in the elderly as a result of resynchronization of the circadian rhythms. Moreover, since the circadian rhythm organization is more severely disrupted in patients with AD, it is possible that magnetic treatment might prove useful also in improving memory functions in these patients. If successful, application of magnetic fields might open new avenues in the management of memory disturbances in the elderly and possibly in AD.

Clin EEG Neurosci. 2004 Jan;35(1):4-13.

Current status of the utilization of antileptic treatments in mood, anxiety and aggression: drugs and devices.

Barry JJ, Lembke A, Bullock KD.

Department of Psychiatry, Stanford University Medical Center, 401 Quarry Road MC 5723, Stanford, CA 94305, USA. jbarry@leland.stanford.edu

Interventions that have been utilized to control seizures in people with epilepsy have been employed by the psychiatric community to treat a variety of disorders. The purpose of this review will be to give an overview of the most prominent uses of antiepileptic drugs (AEDs) and devices like the Vagus Nerve Stimulator (VNS) and Transcranial Magnetic Stimulation (TMS) in the treatment of psychiatric disease states. By far, the most prevalent use of these interventions is in the treatment of mood disorders. AEDs have become a mainstay in the effective treatment of Bipolar Affective Disorder (BAD). The U.S. Food and Drug Administration has approved the use of valproic acid for acute mania, and lamotrigine for BAD maintenance therapy. AEDs are also effectively employed in the treatment of anxiety and aggressive disorders. Finally, VNS and TMS are emerging as possibly useful tools in the treatment of more refractory depressive illness.

Am J Psychiatry. 2004 Jan;161(1):93-8.

Low-field magnetic stimulation in bipolar depression using an MRI-based stimulator.

Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen BM, Renshaw PF.

Brain Imaging Center, McLean Hospital, Belmont, MA 02478, USA. mrohan@mclean.harvard.edu

OBJECTIVE: Anecdotal reports have suggested mood improvement in patients with bipolar disorder immediately after they underwent an echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) procedure that can be performed within clinical MR system limits. This study evaluated possible mood improvement associated with this procedure.

METHOD: The mood states of subjects in an ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief Affect Scale, a structured mood rating scale, immediately before and after an EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects with bipolar disorder, and actual EP-MRSI was administered to a comparison group of healthy subjects. The characteristics of the electric fields generated by the EP-MRSI scan were analyzed.

RESULTS: Mood improvement was reported by 23 of 30 bipolar disorder subjects who received the actual EP-MRSI examination, by three of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14 healthy comparison subjects who received actual EP-MRSI. Significant differences in mood improvement were found between the bipolar disorder subjects who received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects who received actual EP-MRSI, between the healthy subjects and the bipolar disorder subjects and to a lesser extent between the unmedicated bipolar disorder subjects and the bipolar disorder subjects who were taking medication. The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of depression (1-500 V/m) and also extended uniformly throughout the head, unlike the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train of monophasic trapezoidal gradient pulses, differed from that used in rTMS.

CONCLUSIONS: These preliminary data suggest that the EP-MRSI scan induces electric fields that are associated with reported mood improvement in subjects with bipolar disorder. The findings are similar to those for rTMS depression treatments, although the waveform used in EP-MRSI differs from that used in rTMS. Further investigation of the mechanism of EP-MRSI is warranted.

Psychiatry Res. 2004 Sep 30;128(2):199-202.

Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a case series of eight patients.

Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Lipski H, Januel D.

Unite de recherche clinique, secteur III de Ville Evrard, 5, Rue du Dr Delafontaine, Saint-Denis, 93200 France. urcve@free.fr

The aim of this study is to assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) as an add-on therapy in the treatment of manic bipolar patients. Eight patients were enrolled in an open trial. They received fast rTMS (five trains of 15 s, 80% of the motor threshold, 10 Hz) over the right dorsolateral prefrontal cortex (DLPFC). They were evaluated using the Mania Assessment Scale (MAS) and the Clinical Global Impression (CGI) at baseline and at day 14. All patients were taking medication during the treatment trial. There was a significant improvement of manic symptoms at the end of the trial. No side effects were reported. The results show a significant improvement of mania when patients are treated with fast rTMS over the right DLPFC. However, these results have to be interpreted with caution since they derive from an open case series and all the subjects were taking psychotropic medication during rTMS treatment. Double-blind controlled studies with a sham comparison condition should be conducted to investigate the efficiency of this treatment in manic bipolar disorders.

J Affect Disord. 2004 Mar;78(3):253-7.

Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation.

Michael N, Erfurth A.

Mood Disorders Unit, Department of Psychiatry, University of Muenster, Albert-Schweitzer-Str. 11, 48129 Muenster, Germany.

BACKGROUND: Transcranial magnetic stimulation (TMS) has been suggested for the treatment of a variety of CNS disorders including depression and mania.

METHODS: Nine bipolar (I) in-patients diagnosed with mania were treated with right prefrontal rapid TMS in an open and prospective study. Eight of nine patients received TMS as add-on treatment to an insufficient or only partially effective drug therapy.

RESULTS: During the 4 weeks of TMS treatment a sustained reduction of manic symptoms as measured by the Bech-Rafaelsen mania scale (BRMAS) was observed in all patients.

LIMITATIONS: Due to the open and add-on design of the study, a clear causal relationship between TMS treatment and reduction of manic symptoms cannot be established.

CONCLUSIONS: Our data suggest that right prefrontal rapid TMS is safe and efficacious in the add-on treatment of bipolar mania showing laterality opposed to the proposed effect of rapid TMS in depression.

Bipolar Disord. 2003 Feb;5(1):40-7.

Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy.

Nahas Z, Kozel FA, Li X, Anderson B, George MS.

Brain Stimulation Laboratory, Department of Psychiatry, Medical University of South Carolina, Charleston 29425, USA.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve depressive symptoms. We designed and carried out the following left prefrontal rTMS study to determine the safety, feasibility, and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD).

METHODS: We recruited and enrolled 23 depressed BPAD patients (12 BPI depressed state, nine BPII depressed state, two BPI mixed state). Patients were randomly assigned to receive either daily left prefrontal rTMS (5 Hz, 110% motor threshold, 8 sec on, 22 sec off, over 20 min) or placebo each weekday morning for 2 weeks. Motor threshold and subjective rating scales were obtained daily, and blinded Hamilton Rating Scale for Depression (HRSD) and Young Mania Rating Scales (YMRS) were obtained weekly.

RESULTS: Stimulation was well tolerated with no significant adverse events and with no induction of mania. We failed to find a statistically significant difference between the two groups in the number of antidepressant responders (>50% decline in HRSD or HRSD <10 – 4 active and 4 sham) or the mean HRSD change from baseline over the 2 weeks (t = -0.22, p = 0.83). Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment (t = 1.58, p = 0.13). The motor threshold did not significantly change after 2 weeks of active treatment (t = 1.11, p = 0.28).

CONCLUSIONS: Daily left prefrontal rTMS appears safe in depressed BPAD subjects, and the risk of inducing mania in BPAD subjects on medications is small. We failed to find statistically significant TMS clinical antidepressant effects greater than sham. Further studies are needed to fully investigate the potential role, if any, of TMS in BPAD depression.

CNS Drugs. 2002;16(1):47-63.

The Bech-Rafaelsen Mania Scale in clinical trials of therapies for bipolar disorder: a 20-year review of its use as an outcome measure.

Bech P.

Psychiatric Research Unit, WHO Collaborating Centre for Mental Health, Frederiksborg General Hospital, Hillerod, Denmark. pebe@fa.dk

Over the last two decades the Bech-Rafaelsen Mania Scale (MAS) has been used extensively in trials that have assessed the efficacy of treatments for bipolar disorder. The extent of its use makes it possible to evaluate the psychometric properties of the scale according to the principles of internal validity, reliability, and external validity. Studies of the internal validity of the MAS have demonstrated that the simple sum of the 11 items of the scale is a sufficient statistic for the assessment of the severity of manic states. Both factor analysis and latent structure analysis (the Rasch analysis) have been used to demonstrate this. The total score of the MAS has been standardised such that scores below 15 indicate hypomania, scores around 20 indicate moderate mania, and scores around 28 indicate severe mania. The inter-observer reliability has been found to be high in a number of studies conducted in various countries. The MAS has shown an acceptable external validity, in terms of both sensitivity and responsiveness. Thus, the MAS was found to be superior to the Clinical Global Impression scale with regard to responsiveness, and sensitivity has been found to be adequate, with the MAS able to demonstrate large drug-placebo differences. Based on pretreatment scores, trials of antimanic therapies can be classified into: (i) ultrashort (1 week) therapy of severe mania; (ii) short-term therapy (3 to 8 weeks) of moderate mania; (iii) short-term therapy of hypomanic or mixed bipolar states; and (iv) long-term (12 months) therapy of bipolar states. The responsiveness of MAS is such that the scale has been able to demonstrated that typical antipsychotics are effective as an ultrashort therapy of severe mania; that lithium and anticonvulsants are effective in the short-term therapy of moderate mania; and that atypical antipsychotics, electroconvulsive therapy (ECT) and transcranial magnetic stimulation seem to have promising effects in the short-term therapy of moderate mania. In contrast, the scale has been used to demonstrate that calcium antagonists (e.g. verapamil) are ineffective in the treatment of mania. MAS has also been used to add to the literature on the evidence-based effect of lithium as a short-term therapy for hypomania or mixed bipolar states and as a long-term therapy of bipolar states.

Altern Ther Health Med. 2006 Sep-Oct;12(5):42-9

Regenerative effects of pulsed magnetic field on injured peripheral nerves.

  • Mert T,
  • Gunay I,
  • Gocmen C,
  • Kaya M,
  • Polat S.

Department of Biophysics, University of Cukurova School of Medicine, Adana, Turkey.

Previous studies confirm that pulsed magnetic field (PMF) accelerates functional recovery after a nerve crush lesion. The contention that PMF enhances the regeneration is still controversial, however. The influence of a new PMF application protocol (trained PMF) on nerve regeneration was studied in a model of crush injury of the sciatic nerve of rats. To determine if exposure to PMF influences regeneration, we used electrophysiological recordings and ultrastructural examinations. After the measurements of conduction velocity, the sucrose-gap method was used to record compound action potentials (CAPs) from sciatic nerves. PMF treatment during the 38 days following the crush injury enhanced the regeneration. Although the axonal ultrastructures were generally normal, slight to moderate myelin sheath degeneration was noted at the lesion site. PMF application for 38 days accelerated nerve conduction velocity, increased CAP amplitude and decreased the time to peak of the CAP. Furthermore, corrective effects of PMF on. the abnormal characteristics of sensory nerve fibers were determined. Consequently, long-periodic trained-PMF may promote both morphological and electrophysiological properties of the injured nerves. In addition, corrective effects of PMF on sensory fibers may be considered an important finding for neuropathic pain therapy.

Bioelectromagnetics. 2005 Jan;26(1):20-7.

Pulsed electromagnetic fields induce peripheral nerve regeneration and endplate enzymatic changes.

De Pedro JA, Perez-Caballer AJ, Dominguez J, Collia F, Blanco J, Salvado M.

Department of Orthopaedics, University Hospital of Salamanca, Salamanca, Spain. jpedrom@usal.es

An experimental study was carried out in rats with the purpose of demonstrating the capacity of pulsed electromagnetic fields (PEMFs) to stimulate regeneration of the peripheral nervous system (PNS). Wistar and Brown Norway (BN) rats were used. Direct sciatic nerve anastomoses were performed after section or allograft interposition. Treatment groups then received 4 weeks of PEMFs. Control groups received no stimulation. The evaluation of the results was carried out by quantitative morphometric analysis, demonstrating a statistically significant increase in regeneration indices (P < 0.05) in the stimulated groups (9000 +/- 5000 and 4000 +/- 6000) compared to the non-stimulated groups (2000 +/- 4000 and 700 +/- 200). An increase of NAD specific isocitrate dehydrogenase (IDH) activity was found along with an increase in the activity of acetyl cholinesterase at the motor plate. The present study might lead to the search for new alternatives in the stimulation of axonal regenerative processes in the PNS and other possible clinical applications. 2004 Wiley-Liss, Inc.

Spine. 2003 Dec 15;28(24):2660-6.

Exposure to pulsed magnetic field enhances motor recovery in cats after spinal cord injury.

Crowe MJ, Sun ZP, Battocletti JH, Macias MY, Pintar FA, Maiman DJ.

Neuroscience Research Laboratories, The Clement J. Zablocki VA Medical Center, Milwaukee, WI 53295, USA. mcrowe@mcw.edu

STUDY DESIGN: Animal model study of eight healthy commercial cats was conducted.

OBJECTIVE: To determine whether pulsed electromagnetic field (PMF) stimulation results in improvement of function after contusive spinal cord injury in cats. SUMMARY OF

BACKGROUND DATA: PMF stimulation has been shown to enhance nerve growth, regeneration, and functional recovery of peripheral nerves. Little research has been performed examining the effects of PMF stimulation on the central nervous system and no studies of PMF effects on in vivo spinal cord injury (SCI) models have been reported.

MATERIALS AND METHODS: PMF stimulation was noninvasively applied for up to 12 weeks to the midthoracic spine of cats with acute contusive spinal cord injury. The injury was produced using a weight-drop apparatus. Motor functions were evaluated with the modified Tarlov assessment scale. Morphologic analyses of the injury sites and somatosensory-evoked potential measurements were conducted to compare results between PMF-stimulated and control groups.

RESULTS: There was a significant difference in locomotor recovery between the PMF-stimulated and control groups. Although not statistically significant, PMF-stimulated spinal cords demonstrated greater sparing of peripheral white matter and smaller lesion volumes compared to controls. Somatosensory-evoked potential measurements indicated that the PMF-stimulated group had better recovery of preinjury waveforms than the control group; however, this observation also was not statistically significant because of the small sample size.

CONCLUSIONS: This preliminary study indicates that pulsed magnetic fields may have beneficial effects on motor function recovery and lesion volume size after acute spinal cord injury.

J Neurosci Res. 1999 Jan 15;55(2):230-7.

Electromagnetic fields influence NGF activity and levels following sciatic nerve transection.

Longo FM, Yang T, Hamilton S, Hyde JF, Walker J, Jennes L, Stach R, Sisken BF.

Department of Neurology, UCSF/VAMC, San Francisco, California, USA. LFM@itsa.UCSF.edu

Pulsed electromagnetic fields (PEMF) have been shown to increase the rate of nerve regeneration. Transient post-transection loss of target-derived nerve growth factor (NGF) is one mechanism proposed to signal induction of early nerve regenerative events. We tested the hypothesis that PEMF alter levels of NGF activity and protein in injured nerve and/or dorsal root ganglia (DRG) during the first stages of regeneration (6-72 hr). Rats with a transection injury to the midthigh portion of the sciatic nerve on one side were exposed to PEMF or sham control PEMF for 4 hr/day for different time periods. NGF-like activity was determined in DRG, in 5-mm nerve segments proximal and distal to the transection site and in a corresponding 5-mm segment of the contralateral nonoperated nerve. NGF-like activity of coded tissue samples was measured in a blinded fashion using the chick DRG sensory neuron bioassay. Overall, PEMF caused a significant decrease in NGF-like activity in nerve tissue (P < 0.02, repeated measures analysis of variance, ANOVA) with decreases evident in proximal, distal, and contralateral nonoperated nerve. Unexpectedly, transection was also found to cause a significant (P=0.001) 2-fold increase in DRG NGF-like activity between 6 and 24 hr postinjury in contralateral but not ipsilateral DRG. PEMF also reduced NGF-like activity in DRG, although this decrease did not reach statistical significance. Assessment of the same nerve and DRG samples using ELISA and NGF-specific antibodies confirmed an overall significant (P < 0.001) decrease in NGF levels in PEMF-treated nerve tissue, while no decrease was detected in DRG or in nerve samples harvested from PEMF-treated uninjured rats. These findings demonstrate that PEMF can affect growth factor activity and levels, and raise the possibility that PEMF might promote nerve regeneration by amplifying the early postinjury decline in NGF activity.

Neurosci Behav Physiol. 1998 Sep-Oct;28(5):594-7.

Magnetic and electrical stimulation in the rehabilitative treatment of patients with organic lesions of the nervous system.

Tyshkevich TG, Nikitina VV.

A. L. Polenov Russian Science Research Neurosurgical Institute, St. Petersburg.

Studies were performed on 89 patients with organic lesions of the nervous system in which the leading clinical symptoms consisted of paralysis and pareses. Patients received complex treatment, including pulsed magnetic fields and an electrical stimulation regime producing multilevel stimulation. A control group of 49 patients with similar conditions was included, and these patients received only sinusoidal currents. Combined treatment with magnetic and electrical stimulation was more effective, as indicated by radiographic and electromyographic investigations.

Arch Otolaryngol Head Neck Surg. 1998 Apr;124(4):383-9.

Effect of pulsed electromagnetic stimulation on facial nerve regeneration.

Byers JM, Clark KF, Thompson GC.

Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.

OBJECTIVE: To determine if exposure to electromagnetic fields influences regeneration of the transected facial nerve in the rat.

DESIGN AND METHODS: The left facial nerve was transected in the tympanic section of the fallopian canal in 24 rats randomly assigned to 2 groups. The cut ends of the facial nerve were reapproximated without sutures within the fallopian canal to maximize the potential for regeneration. Rats in the experimental group (n= 12) were then exposed to pulsed electromagnetic stimulation (0.4 millitesla at 120 Hz) for 4 hours per day, 5 days per week, for 8 weeks. Rats in the control group (n=12) were handled in an identical manner without pulsed electromagnetic stimulation. Four other rats were given sham operations in which all surgical procedures were carried out except for the actual nerve transection. Two of these rats were placed in each group. Nerve regeneration was evaluated using electroneurography (compound action potentials), force of whisker and eyelid movements, and voluntary facial movements before and at 2-week intervals after transection. Histological evaluation was performed at 10 weeks after transection. Each dependent variable was analyzed using a 2-way analysis of variance with 1 between variable (groups) and 1 within repeated measures variable (days after transection).

RESULTS: Statistical analysis indicated that N1 (the negative deflection of depolarization phase of the muscle and/or nerve fibers) area, N1 amplitude, and N1 duration, as well as absolute amplitude of the compound action potentials, were all significantly greater 2 weeks after transection in the experimental than in the control group of rats. The force of eye and whisker movements after electrical stimulation was statistically greater in the experimental group of rats 4 weeks after transection. Voluntary eye movements in the experimental group were significantly better at 5 and 10 weeks, while whisker movements were better at 3 and 10 weeks. There was no statistical difference between the 2 groups for any histological variable.

CONCLUSION: Results of this study indicate that pulsed electromagnetic stimulation enhances early regeneration of the transected facial nerve in rats.

J Cell Biochem. 1993 Apr;51(4):387-93.

Beneficial effects of electromagnetic fields.

Bassett CA.

Bioelectric Research Center, Columbia University, Riverdale, New York 10463.

Selective control of cell function by applying specifically configured, weak, time-varying magnetic fields has added a new, exciting dimension to biology and medicine. Field parameters for therapeutic, pulsed electromagnetic field (PEMFs) were designed to induce voltages similar to those produced, normally, during dynamic mechanical deformation of connective tissues. As a result, a wide variety of challenging musculoskeletal disorders have been treated successfully over the past two decades. More than a quarter million patients with chronically ununited fractures have benefitted, worldwide, from this surgically non-invasive method, without risk, discomfort, or the high costs of operative repair. Many of the athermal bioresponses, at the cellular and subcellular levels, have been identified and found appropriate to correct or modify the pathologic processes for which PEMFs have been used. Not only is efficacy supported by these basic studies but by a number of double-blind trials. As understanding of mechanisms expands, specific requirements for field energetics are being defined and the range of treatable ills broadened. These include nerve regeneration, wound healing, graft behavior, diabetes, and myocardial and cerebral ischemia (heart attack and stroke), among other conditions. Preliminary data even suggest possible benefits in controlling malignancy.

Bioelectromagnetics. 1993;14(4):353-9.

Pretreatment of rats with pulsed electromagnetic field enhances regeneration of the sciatic nerve.

Kanje M, Rusovan A, Sisken B, Lundborg G.

Department of Animal Physiology, University of Lund, Sweden.

Regeneration of the sciatic nerve was studied in rats pretreated in a pulsed electromagnetic field (PEMF). The rats were exposed between a pair of Helmholtz coils at a pulse repetition rate of 2 pps at a field density of 60 or 300 microT. The PEMF treatment was then discontinued. After an interval of recovery, regeneration of the sciatic nerve was initiated by a crush lesion. Regeneration of sensory fibers was measured by the “pinch test” after an additional 3-6 days. A variety of PEMF pretreatments including 4 h/day for 1-4 days or exposure for 15 min/day during 2 days resulted in an increased regeneration distance, measured 3 days after the crush lesion. This effect could be demonstrated even after a 14-day recovery period. In contrast, pretreatment for 4 h/day for 2 days at 60 microT did not affect the regeneration distance. The results showed that PEMF pretreatment conditioned the rat sciatic nerve in a manner similar to that which occurs after a crush lesion, which indicates that PEMF affects the neuronal cell body. However, the mechanism of this effect remains obscure.

Brain Res. 1989 Apr 24;485(2):309-16.

Stimulation of rat sciatic nerve regeneration with pulsed electromagnetic fields.

Sisken BF, Kanje M, Lundborg G, Herbst E, Kurtz W.

Center for Biomedical Engineering, University of Kentucky, Lexington 40506.

The effects of pulsed electromagnetic fields (PEMF) on rat sciatic nerve regeneration after a crush lesion were determined. The rats were placed between a pair of Helmholtz coils and exposed to PEMF of frequency 2 Hz and magnetic flux density of 0.3 mT. A 4 h/day treatment for 3-6 days increased the rate of nerve regeneration by 22%. This stimulatory effect was independent of the orientation of the coils. Exposure times of 1 h/day-10 h/day were equally effective in stimulating nerve regeneration. Rats exposed to PEMF for 4 h/day for 7 days before crush, followed by 3 days after crush without PEMF, also showed significantly increased regeneration. This pre-exposure ‘conditioning’ effect suggests that PEMF influences regeneration indirectly.

J Hand Surg [Br]. 1984 Jun;9(2):105-12.

An experimental study of the effects of pulsed electromagnetic field (Diapulse) on nerve repair.

Raji AM.

This study investigates the effects of a pulsed electromagnetic field (PEMF) (Diapulse) on experimentally divided and sutured common peroneal nerves in rats. Evidence is presented to show that PEMF accelerates recovery of use of the injured limb and enhances regeneration of damaged nerves.

Clin Orthop Relat Res. 1983 Dec;(181):283-90.

Effect of weak, pulsing electromagnetic fields on neural regeneration in the rat.

Ito H, Bassett CA.

The short- and long-term effects of pulsed electromagnetic fields (PEMFs) on the rate and quality of peripheral nerve regeneration were studied. High bilateral transections of rat sciatic nerves were surgically approximated (a 1-mm gap was left) and shielded with a Silastic sleeve. Animals were exposed to PEMFs for two to 14 weeks after operation. Three groups of 20 rats each (control rats and rats undergoing 12- and 24-hour/day PEMF exposure) were killed at two weeks. Histologically, regenerating axons had penetrated the distal stump nearly twice as far in the PEMF-exposed animals as in the control animals. Return of motor function was judged two to 14 weeks after operation by the load cell-measured, plantar-flexion force produced by neural stimulation proximal to the transection site. Motor function returned earlier in experimental rats and to significantly higher load levels than in control rats. Nerves from animals functioning 12-14 weeks after operation had less interaxonal collagen, more fiber-containing axis cylinders, and larger fiber diameters in the PEMF-exposed group than in the control rats. Histologic and functional data indicate that PEMFs improve the rate and quality of peripheral nerve regeneration in the severed rat sciatic nerve by a factor of approximately two.

Paraplegia. 1976 May;14(1):12-20.

Experimental regeneration in peripheral nerves and the spinal cord in laboratory animals exposed to a pulsed electromagnetic field.

Wilson DH, Jagadeesh P.

Peripheral nerve section and suture was performed in 132 rats. Postoperatively half the animals were exposed to a pulsed electromagnetic field each day and half were kept as controls. Nerve conduction studies, histology and nerve fibre counts all indicated an increased rate of regeneration in the treated animals. A similar controlled study of spinal cord regeneration following hemicordotomy in cats has been started, and preliminary results indicate that when the animals are sacrificed three months after the hemicordotomy, the pulsed electromagnetic therapy has induced nerve fibre regeneration across the region of the scar.

Altern Ther Health Med. 2006 Sep-Oct;12(5):42-9

Regenerative effects of pulsed magnetic field on injured peripheral nerves.

Mert T, Gunay I, Gocmen C, Kaya M, Polat S.

Department of Biophysics, University of Cukurova School of Medicine, Adana, Turkey.

Previous studies confirm that pulsed magnetic field (PMF) accelerates functional recovery after a nerve crush lesion. The contention that PMF enhances the regeneration is still controversial, however. The influence of a new PMF application protocol (trained PMF) on nerve regeneration was studied in a model of crush injury of the sciatic nerve of rats. To determine if exposure to PMF influences regeneration, we used electrophysiological recordings and ultrastructural examinations. After the measurements of conduction velocity, the sucrose-gap method was used to record compound action potentials (CAPs) from sciatic nerves. PMF treatment during the 38 days following the crush injury enhanced the regeneration. Although the axonal ultrastructures were generally normal, slight to moderate myelin sheath degeneration was noted at the lesion site. PMF application for 38 days accelerated nerve conduction velocity, increased CAP amplitude and decreased the time to peak of the CAP. Furthermore, corrective effects of PMF on. the abnormal characteristics of sensory nerve fibers were determined. Consequently, long-periodic trained-PMF may promote both morphological and electrophysiological properties of the injured nerves. In addition, corrective effects of PMF on sensory fibers may be considered an important finding for neuropathic pain therapy.

Neurorehabil Neural Repair. 2004 Mar;18(1):42-6.

Pulsed magnetic field therapy in refractory neuropathic pain secondary to peripheral neuropathy: electrodiagnostic parameters–pilot study.

Weintraub MI, Cole SP.

New York Medical College, Briarcliff Manor, New York 10510, USA.

CONTEXT: Neuropathic pain (NP) from peripheral neuropathy (PN) arises from ectopic firing of unmyelinated C-fibers with accumulation of sodium and calcium channels. Because pulsed electromagnetic fields (PEMF) safely induce extremely low frequency (ELF) quasirectangular currents that can depolarize, repolarize, and hyperpolarize neurons, it was hypothesized that directing this energy into the sole of one foot could potentially modulate neuropathic pain.

OBJECTIVE: To determine if 9 consecutive 1-h treatments in physician’s office (excluding weekends) of a pulsed signal therapy can reduce NP scores in refractory feet with PN.

DESIGN/SETTING/PATIENTS: 24 consecutive patients with refractory and symptomatic PN from diabetes, chronic inflammatory demyelinating polyneuropathy (CIDP), pernicious anemia, mercury poisoning, paraneoplastic syndrome, tarsal tunnel, and idiopathic sensory neuropathy were enrolled in this nonplacebo pilot study. The most symptomatic foot received therapy. Primary endpoints were comparison of VAS scores at the end of 9 days and the end of 30 days follow-up compared to baseline pain scores. Additionally, Patients’ Global Impression of Change (PGIC) questionnaire was tabulated describing response to treatment. Subgroup analysis of nerve conduction scores, quantified sensory testing (QST), and serial examination changes were also tabulated. Subgroup classification of pain (Serlin) was utilized to determine if there were disproportionate responses.

INTERVENTION: Noninvasive pulsed signal therapy generates a unidirectional quasirectangular waveform with strength about 20 gauss and a frequency about 30 Hz into the soles of the feet for 9 consecutive 1-h treatments (excluding weekends). The most symptomatic foot of each patient was treated.

RESULTS: All 24 feet completed 9 days of treatment. 15/24 completed follow-up (62%) with mean pain scores decreasing 21% from baseline to end of treatment (P=0.19) but with 49% reduction of pain scores from baseline to end of follow-up (P<0.01). Of this group, self-reported PGIC was improved 67% (n=10) and no change was 33% (n=5). An intent-to-treat analysis based on all 24 feet demonstrated a 19% reduction in pain scores from baseline to end of treatment (P=0.10) and a 37% decrease from baseline to end of follow-up (P<0.01). Subgroup analysis revealed 5 patients with mild pain with nonsignificant reduction at end of follow-up. Of the 19 feet with moderate to severe pain, there was a 28% reduction from baseline to end of treatment (P<0.05) and a 39% decrease from baseline to end of follow-up (P<0.01). Benefit was better in those patients with axonal changes and advanced CPT baseline scores. The clinical examination did not change. There were no adverse events or safety issues.

CONCLUSIONS: These pilot data demonstrate that directing PEMF to refractory feet can provide unexpected short term analgesic effects in more than 50% of individuals. The role of placebo is not known and was not tested. The precise mechanism is unclear yet suggests that severe and advanced cases are more magnetically sensitive. Future studies are needed with randomized placebo-controlled design and longer treatment periods.

Arch Phys Med Rehabil. 2003 May;84(5):736-46.

Static magnetic field therapy for symptomatic diabetic neuropathy: a randomized double-blind, placebo-controlled trial.

Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G, Cohen JA, Page JC, Bromberg MB, Schwartz SL; Magnetic Research Group.

Department of Neurology, New York Medical College, Valhalla, NY, USA. miwneuro@pol.net

OBJECTIVE: To determine if constant wearing of multipolar, static magnetic (450G) shoe insoles can reduce neuropathic pain and quality of life (QOL) scores in symptomatic diabetic peripheral neuropathy (DPN).

DESIGN: Randomized, placebo-control, parallel study.

SETTING: Forty-eight centers in 27 states.

PARTICIPANTS: Three hundred seventy-five subjects with DPN stage II or III were randomly assigned to wear constantly magnetized insoles for 4 months; the placebo group wore similar, unmagnetized device.

INTERVENTION: Nerve conduction and/or quantified sensory testing were performed serially.

MAIN OUTCOME MEASURES: Daily visual analog scale scores for numbness or tingling and burning and QOL issues were tabulated over 4 months. Secondary measures included nerve conduction changes, role of placebo, and safety issues. Analysis of variance (ANOVA), analysis of covariance (ANCOVA), and chi-square analysis were performed.

RESULTS: There were statistically significant reductions during the third and fourth months in burning (mean change for magnet treatment, -12%; for sham, -3%; P<.05, ANCOVA), numbness and tingling (magnet, -10%; sham, +1%; P<.05, ANCOVA), and exercise-induced foot pain (magnet, -12%; sham, -4%; P<.05, ANCOVA). For a subset of patients with baseline severe pain, statistically significant reductions occurred from baseline through the fourth month in numbness and tingling (magnet, -32%; sham, -14%; P<.01, ANOVA) and foot pain (magnet, -41%; sham, -21%; P<.01, ANOVA).

CONCLUSIONS: Static magnetic fields can penetrate up to 20mm and appear to target the ectopic firing nociceptors in the epidermis and dermis. Analgesic benefits were achieved over time.

Neurosci Behav Physiol. 2003 Oct;33(8):745-52.

The use of pulsed electromagnetic fields with complex modulation in the treatment of patients with diabetic polyneuropathy.

Musaev AV, Guseinova SG, Imamverdieva SS.

Science Research Institute of Medical Rehabilitation, Baku, Azerbaidzhan.

Clinical and electroneuromyographic studies were performed in 121 patients with diabetic polyneuropathy (DPN) before and after courses of treatment with pulsed electromagnetic fields with complex modulation (PEMF-CM) at different frequencies (100 and 10 Hz). Testing of patients using the TSS and NIS LL scales demonstrated a correlation between the severity and frequency of the main subjective and objective effects of disease and the stage of DPN. The severity of changes in the segmental-peripheral neuromotor apparatus–decreases in muscle bioelectrical activity, the impulse conduction rate along efferent fibers of peripheral nerves, and the amplitude of the maximum M response–depended on the stage of DPN and the duration of diabetes mellitus. The earliest and most significant electroneuromyographic signs of DPN were found to be decreases in the amplitude of the H reflex and the Hmax/Mmax ratio in the muscles of the lower leg. Application of PEMF-CM facilitated regression of the main clinical symptoms of DPN, improved the conductive function of peripheral nerves, improved the state of la afferents, and improved the reflex excitability of functionally diverse motoneurons in the spinal cord. PEMF-CM at 10 Hz was found to have therapeutic efficacy, especially in the initial stages of DPN and in patients with diabetes mellitus for up to 10 years.

Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):38-41.

The use of combined methods of magnetoelectrotherapy in treating polyneuropathies.

[Article in Russian]

A comparative evaluation by such parameters as alleviation of pain syndrome, improvement of peripheral resistance and vegetotrophic processes, a decline in pareses and sensory disorders has been performed in 3 groups of patients: group 1 underwent benzohexonium electrophoresis, group 2 benzohexonium electrophoresis in the magnetic field produced by the unit “Polyus-I” followed by low-frequency electrotherapy with bipolar impulse current, group 3 benzohexonium electrophoresis in the magnetic field from the unit “ADMT-Magnipuls” followed by low-frequency electrotherapy with bipolar impulse current. The best clinical and physiological results were reported in group 3 patients.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine–15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.

Klin Med (Mosk). 1996;74(5):39-41.

Magentotherapy in the comprehensive treatment of vascular complications of diabetes mellitus.

[Article in Russian]

Kirillov IB, Suchkova ZV, Lastushkin AV, Sigaev AA, Nekhaeva TI.

320 diabetes mellitus (DM) patients were exposed to impulsed magnetic field, 100 control DM patients received conservative therapy alone. 270 patients had microangiopathy, macroangiopathy was diagnosed in 50 patients. Good and satisfactory results of magnetotherapy in combination with conservative methods were achieved in 74% of patients versus 28% in control group. Metabolism stabilization resulted in some patients in reduced blood sugar. Use of magnetic field produced faster and longer response than conservative therapy.

Vestn Oftalmol. 1990 Sep-Oct;106(5):54-7.

Effectiveness of magnetotherapy in optic nerve atrophy.  A preliminary study.

[Article in Russian]

Zobina LV, Orlovskaia LS, Sokov SL, Sabaeva GF, Konde LA, Iakovlev AA.

Magnetotherapy effects on visual functions (vision acuity and field), on retinal bioelectric activity, on conductive vision system, and on intraocular circulation were studied in 88 patients (160 eyes) with optic nerve atrophy. A Soviet Polyus-1 low-frequency magnetotherapy apparatus was employed with magnetic induction of about 10 mT, exposure 7-10 min, 10-15 sessions per course. Vision acuity of patients with its low (below 0.04 diopters) values improved in 50 percent of cases. The number of patients with vision acuity of 0.2 diopters has increased from 46 before treatment to 75. Magnetotherapy improved ocular hemodynamics in patients with optic nerve atrophy, it reduced the time of stimulation conduction along the vision routes and stimulated the retinal ganglia cells. The maximal effect was achieved after 10 magnetotherapy sessions. A repeated course carried out in 6-8 months promoted a stabilization of the process.

Int J Neurosci. 1998 Apr;93(3-4):239-50.

Treatment with AC pulsed electromagnetic fields normalizes the latency of the visual evoked response in a multiple sclerosis patient with optic atrophy.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Visual evoked response (VER) studies have been utilized as supportive information for the diagnosis of multiple sclerosis (MS) and may be useful in objectively monitoring the effects of various therapeutic modalities. Delayed latency of the VER, which reflects slowed impulse transmission in the optic pathways, is the most characteristic abnormality associated with the disease. Brief transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density are efficacious in the symptomatic treatment of MS and may also reestablish impulse transmission in the optic pathways. A 36 year old man developed an attack of right sided optic neuritis at the age of 30. On presentation he had blurring of vision with reduced acuity on the right and fundoscopic examination revealed pallor of the optic disc. A checkerboard pattern reversal VER showed a delayed latency to right eye stimulation (P100 = 132 ms; normal range: 95-115 ms). After he received two successive applications of AC pulsed EMFs of 7.5 picotesla flux density each of 20 minutes duration administered transcranially, there was a dramatic improvement in vision and the VER latency reverted to normal (P100= 107 ms). The rapid improvement in vision coupled with the normalization of the VER latency despite the presence of optic atrophy, which reflects chronic demyelination of the optic nerve, cannot be explained on the basis of partial or full reformation of myelin. It is proposed that in MS synaptic neurotransmitter deficiency is associated with the visual impairment and delayed VER latency following optic neuritis and that the recovery of the VER latency by treatment with pulsed EMFs is related to enhancement of synaptic neurotransmitter functions in the retina and central optic pathways. Recovery of the VER latency in MS patients may have important implications with respect to the treatment of visual impairment and prevention of visual loss. Specifically, repeated pulsed applications of EMFs may maintain impulse transmission in the optic nerve and thus potentially sustain its viability.

Altern Ther Health Med. 2003 Jul-Aug;9(4):38-48.

Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo-controlled trial.

Lappin MS, Lawrie FW, Richards TL, Kramer ED.

Energy Medicine Developments, (North America), Inc., Burke, Va., USA.

CONTEXT: There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure.

OBJECTIVE: To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life.

DESIGN: A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period. SETTING: The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ.

SUBJECTS: 117 patients with clinically definite MS.

INTERVENTION: Daily exposure to a small, portable pulsing electromagnetic field generator.

MAIN OUTCOME: The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite.

RESULTS: Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity.

CONCLUSIONS: Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.

Phys Med Rehabil Clin N Am. 1998 Aug;9(3):659-74.

Bioelectromagnetic applications for multiple sclerosis.

Richards TL, Lappin MS, Lawrie FW, Stegbauer KC.

Department of Radiology, University of Washington, Seattle, USA.

There are EM effects on biology that are potentially both harmful and beneficial. We have reviewed applications of EM fields that are relevant to MS. It is possible that EM fields could be developed into a reproducible therapy for both symptom management and long-term care for MS. The long-term care for MS would have to include beneficial changes in the immune system and in nerve regeneration.

Mult Scler. 2005 Jun;11(3):302-5.

Effect of pulsed magnetic field therapy on the level of fatigue in patients with multiple sclerosis–a randomized controlled trial.

Mostert S, Kesselring J.

Department of Neurology, Rehabilitation Centre, CH 7317 Valens, Switzerland.

Twenty-five multiple sclerosis patients, taking part in a rehabilitation program, were randomly assigned to treatment with pulsed magnetic field therapy (PMFT) or to sham therapy in order to study the additional effect of PMFT as part of a multimodal neurological rehabilitation program on fatigue. Patients demographic and disease specific characteristics were recorded. Level of fatigue was measured by fatigue severity scale (FSS) at entrance and discharge and with a visual analog scale (VAS) immediate before and after a single treatment session. The ‘Magnetic Cell Regeneration’ system by Santerra was used for PMFT. A single treatment lasted 16 minutes twice daily over 3-4 weeks and consisted of relaxed lying on a PMF mattress. Sham intervention was conducted in an identical manner with the PMF-device off. Patients and statistics were blinded. Level of fatigue measured by FSS was high at entrance in both treatment group (TG) and control group (CG) (5.6 versus 5.5). Over time of rehabilitation fatigue was reduced by 18% in TG and 7% in CG which was statistically not significant. There was a statistically significant immediate effect of the single treatment session which 18% reduction of fatigue measured by VAS in TG versus 11% in CG. Because of a high ‘placebo effect’ of simple bed rest, a only small and short lasting additional effect of PMFT and high costs of a PMF-device, we cannot recommend PMFT as an additional feature of a multimodal neurological rehabilitation program in order to reduce fatigue level of MS-patients.

Int J Neurosci. 1997 Nov;92(1-2):95-102.

Treatment with electromagnetic fields improves dual-task performance (talking while walking) in multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

Multiple sclerosis (MS) is associated with an increased risk of falling resulting from visual disturbances, difficulties with gait and balance, apraxia of gait and peripheral neuropathy. These factors often interact synergistically to compromise the patient’s gait stability. It has long been recognized that walking involves a cognitive component and that simultaneous cognitive and motor operations (dual-task) such as talking while walking may interfere with normal ambulation. Talking while walking reflects an example of a dual-task which is frequently impaired in MS patients. Impaired dual-task performance during walking may compromise the patient’s gait and explain why in some circumstances, MS patients unexpectedly lose their balance and fall. Frontal lobe dysfunction, which commonly occurs in MS patients, may disrupt dual-task performance and increase the risk of falling in these patients. This report concerns a 36 old man with remitting-progressive MS with an EDSS score of 5.5 who experienced marked increase in spasticity in the legs and trunk and worsening of his gait and balance, occasionally resulting in falling, when talking while walking. His gait and balance improved dramatically after he received two successive transcranial treatments, each of 45 minutes, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density. Simultaneously, there was improvement in dual-task performance to the extent that talking while walking did not adversely affect his ambulation. In addition, neuropsychological testing revealed an almost 5-fold increase in word output on the Thurstone’s Word-Fluency Test, which is sensitive to frontal lobe dysfunction. It is suggested that facilitation of dual-task performance during ambulation contributes to the overall improvement of gait and balance observed in MS patients receiving transcranial treatment with AC pulsed EMFs.

Int J Neurosci. 1997 Aug;90(3-4):177-85.

Treatment with electromagnetic fields reverses the long-term clinical course of a patient with chronic progressive multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

It is estimated that 10-20% of patients with multiple sclerosis (MS) have a chronic progressive (CP) course characterized by an insidious onset of neurological deficits followed by steady progression of disability in the absence of symptomatic remission. To date no therapeutic modality has proven effective in reversing the clinical course of CP MS although there are indications that prolonged treatment with picotesla electromagnetic fields (EMFs) alters the clinical course of patients with CP MS. A 40 year-old woman presented in December of 1992 with CP MS with symptoms of spastic paraplegia, loss of trunk control, marked weakness of the upper limbs with loss of fine and gross motor hand functions, severe fatigue, cognitive deficits, mental depression, and autonomic dysfunction with neurogenic bladder and bowel incontinence. Her symptoms began at the age of 18 with weakness of the right leg and fatigue with long distance walking and over the ensuing years she experienced steady deterioration of functions. In 1985 she became wheelchair dependent and it was anticipated that within 1-2 years she would become functionally quadriplegic. In December of 1992 she began experimental treatment with EMFs. While receiving regularly weekly transcortical treatments with AC pulsed EMFs in the picotesla range intensity she experienced during the first year improvement in mental functions, return of strength in the upper extremities, and recovery of trunk control. During the second year she experienced the return of more hip functions and recovery of motor functions began in her legs. For the first time in years she can now initiate dorsiflexion of her ankles and actively extend her knees voluntarily. Over the past year she started to show signs of redevelopment of reciprocal gait. Presently, with enough function restored in her legs, she is learning to walk with a walker and is able to stand unassisted and maintain her balance for a few minutes. She also regained about 80% of functions in the upper limbs and hands. Most remarkably, there was no further progression of the disease during the 4 years course of magnetic therapy. This patient’s clinical recovery cannot be explained on the basis of a spontaneous remission. It is suggested that pulsed applications of picotesla EMFs affect the neurobiological and immunological mechanisms underlying the pathogenesis of CP MS.

Int J Neurosci. 1997 Aug;90(3-4):145-57.

Resolution of sleep paralysis by weak electromagnetic fields in a patient with multiple sclerosis.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

Sleep paralysis refers to episodes of inability to move during the onset of sleep or more commonly upon awakening. Patients often describe the sensation of struggling to move and may experience simultaneous frightening vivid hallucinations and dreams. Sleep paralysis and other manifestations of dissociated states of wakefulness and sleep, which reflect deficient monoaminergic regulation of neural modulators of REM sleep, have been reported in patients with multiple sclerosis (MS). A 40 year old woman with remitting-progressive multiple sclerosis (MS) experienced episodes of sleep paralysis since the age of 16, four years prior to the onset of her neurological symptoms. Episodes of sleep paralysis, which manifested at a frequency of about once a week, occurred only upon awakening in the morning and were considered by the patient as a most terrifying experience. Periods of mental stress, sleep deprivation, physical fatigue and exacerbation of MS symptoms appeared to enhance the occurrence of sleep paralysis. In July of 1992 the patient began experimental treatment with AC pulsed applications of picotesla intensity electromagnetic fields (EMFs) of 5Hz frequency which were applied extracerebrally 1-2 times per week. During the course of treatment with EMFs the patient made a dramatic recovery of symptoms with improvement in vision, mobility, balance, bladder control, fatigue and short term memory. In addition, her baseline pattern reversal visual evoked potential studies, which showed abnormally prolonged latencies in both eyes, normalized 3 weeks after the initiation of magnetic therapy and remained normal more than 2.5 years later. Since the introduction of magnetic therapy episodes of sleep paralysis gradually diminished and abated completely over the past 3 years. This report suggests that MS may be associated with deficient REM sleep inhibitory neural mechanisms leading to sleep paralysis secondary to the intrusion of REM sleep atonia and dream imagery into the waking state. Pineal melatonin and monoaminergic neurons have been implicated in the induction and maintenance of REM sleep and the pathogenesis of sleep paralysis and it is suggested that resolution of sleep paralysis in this patient by AC pulsed applications of EMFs was related to enhancement of melatonin circadian rhythms and cerebral serotoninergic neurotransmission.

Int J Neurosci. 1997 Jun;90(1-2):59-74.

Immediate recovery of cognitive functions and resolution of fatigue by treatment with weak electromagnetic fields in a patient with multiple sclerosis.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering, Dix Hills, NY, USA.

Cognitive deficits are common among patients with multiple sclerosis (MS). The pathogenetic mechanisms underlying the cognitive impairment in MS are unknown and there is presently no effective therapeutic modality which has shown efficacy in improving cognitive deficits in MS. A 53 year old college professor with a long history of secondary progressive MS experienced, over the preceding year, noticeable deterioration in cognitive functions with difficulties in short and long term memory, word finding in spontaneous speech, attention and concentration span. Unable to pursue his academic activities, he was considering early retirement. Mental examination disclosed features of subcortical and cortical dementia involving frontal lobe, left hemispheric and right hemispheric dysfunction. Almost immediately following the extracerebral application of AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla intensity and a 4-Hz sinusoidal wave, the patient experienced a heightend sense of well being, which he defined as enhancement of cognitive functions with a feeling “like a cloud lifted off my head.” He reported heightend clarity of thinking and during the application of EMFs he felt that words were formed faster and he experienced no difficulty finding the appropriate words. His speech was stronger and well modulated and he felt “energized” with resolution of his fatigue. There was improvement in manual dexterity and handwriting and testing of constructional praxis demonstrated improvement in visuospatial, visuoperceptive and visuomotor functions. It is suggested that some of the cognitive deficits associated with MS, which are caused by synaptic disruption of neurotransmitter functions, may be reversed through pulsed applications of picotesla range EMFs.

Int J Neurosci. 1996 Oct;87(1-2):5-15.

Suicidal behavior is attenuated in patients with multiple sclerosis by treatment with electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

A marked decrease in the levels of serotonin (5-HT) and its metabolite (5-HIAA) has been demonstrated in postmortem studies of suicide victims with various psychiatric disorders. Depression is the most common mental manifestation of multiple sclerosis (MS) which accounts for the high incidence of suicide in this disease. CSF 5-HIAA concentrations are reduced in MS patients and nocturnal plasma melatonin levels were found to be lower in suicidal than in nonsuicidal patients. These findings suggest that the increased risk of suicide in MS patients may be related to decreased 5-HT functions and blunted circadian melatonin secretion. Previous studies have demonstrated that extracerebral applications of pulsed electromagnetic fields (EMFs) in the picotesla range rapidly improved motor, sensory, affective and cognitive deficits in MS. Augmentation of cerebral 5-HT synthesis and resynchronization of circadian melatonin secretion has been suggested as a key mechanism by which these EMFs improved symptoms of the disease. Therefore, the prediction was made that this treatment modality would result in attenuation of suicidal behavior in MS patients. The present report concerns three women with remitting-progressive MS who exhibited suicidal behavior during the course of their illness. All patients had frequent suicidal thoughts over several years and experienced resolution of suicidal behavior within several weeks after introduction of EMFs treatment with no recurrence of symptoms during a follow-up of months to 3.5 years. These findings demonstrate that in MS pulsed applications of picotesla level EMFs improve mental depression and may reduce the risk of suicide by a mechanism involving the augmentation of 5-HT neurotransmission and resynchronization of circadian melatonin secretion.

Int J Neurosci. 1996 Jul;86(1-2):79-85.

Effect of weak electromagnetic fields on body image perception in patients with multiple sclerosis.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Cerebellar ataxia is one of the most disabling symptoms of multiple sclerosis (MS) and also one of the least responsive to pharmacotherapy. However, cerebellar symptoms often improve dramatically in MS patients by brief, extracerebral applications of picotesla flux electromagnetic fields (EMFs). This report concerns two MS patients with chronic disabling ataxia who experienced rapid improvement in gait and balance after receiving a series of treatments with EMFs. To assess whether improvement in cerebellar gait is accompanied by changes in body image perception, a parietal lobe function, both patients were administered the Human Figure Drawing Test before and after a series of brief treatments with EMFs. Prior to application of EMFs these patients’ free drawings of a person showed a figure with a wide-based stance characteristic of cerebellar ataxia. After receiving a series of EMFs treatments both patients demonstrated a change in body image perception with the drawings of the human figure showing a normal stance. These findings demonstrate that in MS improvement in cerebellar symptoms by pulsed applications of picotesla EMFs is associated with changes in the body image.

Int J Neurosci. 1996 Jul;86(1-2):67-77.

Treatment with weak electromagnetic fields attenuates carbohydrate cravings in a patients with multiple sclerosis.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Pharmacological studies have implicated serotonergic (5-HT) neurons in the regulation of food intake and food preference. It has been shown that the urge to consume carbohydrate rich foods is regulated by 5-HT activity and that carbohydrate craving is triggered by 5-HT deficiency in the medical hypothalamus. Ingestion of carbohydrate foods stimulates insulin secretion which accelerates the uptake of tryptophan, the precursor of 5-HT and melatonin, into the brain and pineal gland, respectively. Thus, carbohydrate craving might be considered a form of “self medication” aimed at correcting an underlying dysfunction of cerebral 5-HT and pineal melatonin functions. A 51 year old woman with remitting-progressive MS experienced carbohydrate craving during childhood and adolescence and again in temporal association with the onset of her first neurological symptoms at the age of 45. Carbohydrate craving, which resembled the pattern observed in patients with seasonal affective disorder (SAD), was attenuated by a series of extracranial AC pulsed applications of picotesla (10(-12) Tesla) flux intensity electromagnetic fields (EMFs). It is suggested that AC pulsed EMFs applications activated retinal mechanisms which, through functional interactions with the medial hypothalamus, initiated an increased release of 5-HT and resynchronization of melatonin secretion ultimately leading to a decrease in carbohydrate craving. The occurrence of carbohydrate craving in early life may have increased the patient’s vulnerability to viral infection given the importance of 5-HT and melatonin in immunomodulation and the regulation of the integrity of the blood brain barrier. The recurrence of this craving in temporal relation to the onset of neurological symptoms suggests that 5-HT deficiency and impaired pineal melatonin functions are linked to the timing of onset of the clinical symptoms of the disease. The report supports the role of experimental factors in the pathophysiology of MS.

Int J Neurosci. 1995 Nov;83(1-2):81-92.

Resolution of dysarthria in multiple sclerosis by treatment with weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

It has been reported that 50% or more of patients diagnosed with multiple sclerosis (MS) exhibit speech impairment (dysarthria) which in some cases can be exceedingly disabling. Currently there is no effective medical treatment for the dysarthria of MS which occurs as a result of lesions to the cerebellum and its outflow tracts. It was reported recently that extracranial application of brief AC pulsed electromagnetic fields (EMFs) in the picotesla (pT) range intensity produced in patients with MS sustained improvement in motor functions including cerebellar symptomatology. This communication concerns two MS patients with a chronic progressive course who exhibited severe dysarthria which improved already during the initial treatment with pulsed EMFs and which resolved completely 3-4 weeks later. Since application of EMFs has been shown to alter: (a) the resting membrane potential and synaptic neurotransmitter release through an effect involving changes in transmembrane calcium flux; and (b) the secretion of pineal melatonin which in turn influences the synthesis and release of serotonin (5-HT) and gamma-amino butyric acid (GABA) in the cerebellum, it is suggested that the immediate improvement of the dysarthria occurred as a result of changes in cerebellar neurotransmitter functions particularly 5-HT and GABA rather than from remyelination.

Int J Neurosci. 1995 Jun;82(3-4):223-42.

Chronic relapsing multiple sclerosis: a case of rapid recovery by application of weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

A 54 year-old woman was diagnosed with multiple sclerosis (MS) in 1985 at the age of 45 after she developed diplopia, slurred speech, and weakness in the right leg. A Magnetic Resonance Imaging (MRI) scan obtained in 1985 showed several areas of plaque formation distributed in the periventricular white matter and centrum semiovale bilaterally. Coincident with slow deterioration in her condition since 1990 a second MRI scan was obtained in 1991 which showed a considerable increase in the number and size of plaques throughout both cerebral hemispheres, subcortical white matter, periventricularly and brainstem. In 1994, the patient received treatment with Interferon beta- 1b (Betaseron) for 6 months with no improvement in symptoms. However, following two successive extracranial applications of pulsed electromagnetic fields (EMFs) in the picotesla (pT) range each of 20 minutes duration the patient experienced an immediate improvement in symptoms most dramatically in gait, balance, speech, level of energy, swallowing, mood, and vision. On a maintenance program of 3 treatments per month the patient’s only symptom is mild right foot and leg weakness. The report points to the unique efficacy of externally applied pT range EMFs in the symptomatic treatment of MS, indicates a lack of an association between the extent of demyelinating plaques on MRI scan and rate and extent of recovery in response to EMFs, and supports the notion that dysfunction of synaptic conductivity due to neurotransmitter deficiency particularly of serotonin (5-HT) contributes more significantly to the development of MS symptoms than the process of demyelination which clinically seems to represent an epiphenomenon of the disease.

Int J Neurosci. 1994 Dec;79(3-4):199-212.

Weak electromagnetic fields attenuate tremor in multiple sclerosis.

Sandyk R, Dann LC.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

It has been estimated that about 75% of patients diagnosed with multiple sclerosis (MS) have tremor which can be exceedingly disabling. The most common tremor observed in patients with MS is a cerebellar intention tremor (‘kinetic tremor’) although postural tremor (‘static tremor’) is also common and often extremely incapacitating. Currently there is no effective medical treatment for the tremor of MS which, in some severe cases, may be abolished by stereotactic thalamotomy. It was reported recently that extracranial application of brief AC pulsed electromagnetic fields (EMFs) in the picotesla (pT) range produced improvement in motor and cognitive functions in patients with MS. The present communication concerns three MS patients with a chronic progressive course of the disease (mean age: 39.3 +/- 8.3 years; mean duration of illness: 11.3 +/- 3.2 years) in whom brief external applications of pulsed EMFs of 7.5 pT intensity reduced intention and postural tremors resulting in significant functional improvement. The report suggests that these extremely low intensity EMFs are beneficial also in the treatment of tremors in MS and that this treatment may serve as an alternative method to stereotactic thalamotomy in the management of tremor in MS. The mechanisms by which EMFs attenuate the tremors of MS are complex and are thought to involve augmentation of GABA and serotonin (5-HT) neurotransmission in the cerebellum and its outflow tracts.

Therapeutic effects of alternating current pulsed electromagnetic fields in multiple sclerosis.

Sandyk R. Dep. of Neuroscience, Institute for Biomedical Engineering and Rehab Services of Touro College, Dix Hills, New York.

Multiple sclerosis is the third most common cause of severe disability in patients between the ages of 15 and 50 years. The cause of the disease and its pathogenesis remain unknown. The last 20 years have seen only meager advances in the development of effective treatments for the disease. No specific treatment modality can cure the disease or alter its long-term course and eventual outcome. Moreover, there are no agents or treatments that will restore premorbid neuronal function. A host of biological phenomena associated with the disease involving interactions among genetic, environmental, immunologic, and hormonal factors, cannot be explained on the basis of demyelination alone and therefore require refocusing attention on alternative explanations, one of which implicates the pineal gland as pivotal. The pineal gland functions as a magnetoreceptor organ. This biological property of the gland provided the impetus for the development of a novel and highly effective therapeutic modality, which involves transcranial applications of alternating current (AC) pulsed electromagnetic fields flux density. This review summarizes recent clinical work on the effects of transcranially applied pulsed electromagnetic fields for the symptomatic treatment of the disease.

J In Biologic Effects of Light 1998 Symposium

Pulsing magnetic field effects on brain electrical activity in multiple sclerosis.

Richards TL, Acosta-Urquidi,

Multiple sclerosis (MS) is a disease of the central nervous system. Clinical symptoms include central fatigue, impaired bladder control, muscle weakness, sensory deficits, impaired cognition, and others. The cause of MS is unknown, but from histologic, immunologic, and radiologic studies, we know that there are demyelinated brain lesions (visible on magnetic resonance images) that contain immune cells such as macrophages and T-cells (visible on microscopic analysis of brain sections). Recently, a histologic study has also shown that widespread axonal damage occurs in MS along with demyelination. What is the possible connection between MS and bio-electromagnetic fields? We recently published a review entitled “Bio-electromagnetic applications for multiple sclerosis,” which examined several scientific studies that demonstrated the effects of electromagnetic fields on nerve regeneration, brain electrical activity (electro-encephalography), neurochemistry, and immune system components. All of these effects are important for disease pathology and clinical symptoms in multiple sclerosis (MS). EEG was measured in this study in order to test our hypothesis that the pulsing magnetic device affects the brain electrical activity, and that this may be a mechanism for the effect we have observed on patient-reported symptoms. The EEG data reported previously were measured only during resting and language conditions. The purpose of the current study was to measure the effect of the electromagnetic device on EEG activity during and after photic stimulation with flashing lights. After photic stimulation, there was a statistically significant increase in alpha EEG magnitude that was greater in the active group compared to the placebo group in electrode positions P3, T5, and O1 (analysis of variance p<.001, F=14, DF = 1,16). In the comparison between active versus placebo, changes measured from three electrode positions were statistically significantly even after multiple comparison correction.

Treatment with weak electromagnetic fiels improves fatigue associated with multiple sclerosis.

Sandyk R. NeuroCommunication Research Laboratories, Danbury, CT, USA

It is estimated that 75-90% of patients with multiple sclerosis (MS) experience fatigue at some point during the course of the disease and that in about half of these patients, subjective fatigue is a primary complaint. In the majority of patients fatigue is present throughout the course of the day being most prominent in the mid to late afternoon. Sleepiness is not prominent, but patients report that rest may attenuate fatigability. The pathophysiology of the fatigue of MS remains unknown. Delayed impulse conduction in demyelinated zones may render transmission in the brainstem reticular formation less effective. In addition, the observation that rest may restore energy and that administration of pemoline and amantadine, which increase the synthesis and release of monoamines, often improve the fatigue of MS suggest that depletion of neurotransmitter stores in damaged neurons may contribute significantly to the development of fatigue in these patients. The present report concerns three MS patients who experienced over several years continuous and debilitating fatigue throughout the course of the day. Fatigue was exacerbated by increased physical activity and was not improved by rest. After receiving a course of treatments with picotesla flux electromagnetic fields (EMFs), which were applied extracranially, all patients experienced improvement in fatigue. Remarkably, patients noted that several months after initiation of treatment with EMFs they were able to recover, after a short period of rest, from fatigue which followed increased physical activity. These observations suggest that replenishment of monoamine stores in neurons damaged by demyelination in the brainstem reticular formation by periodic applications of picotesla flux intensity EMFs may lead to more effective impulse conduction and thus to improvement in fatigue including rapid recovery of fatigue after rest.

Int J Neurosci. 1998 Jul;95(1-2):107-13.

Yawning and stretching–a behavioral syndrome associated with transcranial application of electromagnetic fields in multiple sclerosis.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Intracerebral administration of adrenocorticotropic hormone (ACTH) elicits in experimental animals a yawning stretching behavior which is believed to reflect an arousal response mediated through the septohippocampal cholinergic neurons. A surge in plasma ACTH levels at night and just prior to awakening from sleep is also associated in humans with yawning and stretching behavior. Recurrent episodes of uncontrollable yawning and body stretching, identical to those observed upon awakening from physiological sleep, occur in a subset of patients with multiple sclerosis (MS) during transcranial therapeutic application of AC pulsed electromagnetic fields of picotesla flux density. This behavioral response has been observed exclusively in young female patients who are fully ambulatory with a relapsing remitting course of the disease who also demonstrate a distinctly favorable therapeutic response to magnetic stimulation. ACTH is employed for the treatment of MS due to its immunomodulatory effects and a surge in its release in response to AC pulsed magnetic stimulation could explain some of the mechanism by which these fields improve symptoms of the disease.

Int J Neurosci. 1997 Jan;89(1-2):39-51.

Progressive cognitive improvement in multiple sclerosis from treatment with electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

It has long been recognized that cognitive impairment occurs in patients with multiple sclerosis (MS) particularly among patients with a chronic progressive course. MS is considered a type of “subcortical dementia” in which cognitive and behavioral abnormalities resemble those observed in patients with a frontal lobe syndrome. The Bicycle Drawing Test is employed for the neuropsychological assessment of cognitive impairment specifically that of mechanical reasoning and visuographic functioning. It also provides clues concerning the patient’s organizational skills which are subserved by the frontal lobes. Extracerebral pulsed applications of picotesla flux intensity electromagnetic fields (EMFs) have been shown to improve cognitive functions in patients with MS. I present three patients with long standing symptoms of MS who, on the initial baseline, pretreatment Bicycle Drawing Test, exhibited cognitive impairment manifested by omissions of essential details and deficient organizational skills. All patients demonstrated progressive improvement in their performance during treatment with EMFs lasting from 6-18 months. The improvement in cognitive functions, which occurred during the initial phases of the treatment, was striking for the changes in organizational skills reflecting frontal lobe functions. These findings demonstrate that progressive recovery of cognitive functions in MS patients are observed over time through continued administration of picotesla flux intensity EMFs. It is believed that the beneficial cognitive effects of these EMFs are related to increased synaptic neurotransmission and that the progressive cognitive improvement noted in these patients is associated with slow recovery of synaptic functions in monoaminergic neurons of the frontal lobe or its projections from subcortical areas.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine–15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.

Ann Neurol. 2005 Oct 20; [Epub ahead of print]

Altered plasticity of the human motor cortex in Parkinson’s disease.

Ueki Y, Mima T, Ali Kotb M, Sawada H, Saiki H, Ikeda A, Begum T, Reza F, Nagamine T, Fukuyama H.

Human Brain Research Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Interventional paired associative stimulation (IPAS) to the contralateral peripheral nerve and cerebral cortex can enhance the primary motor cortex (M1) excitability with two synchronously arriving inputs. This study investigated whether dopamine contributed to the associative long-term potentiation-like effect in the M1 in Parkinson’s disease (PD) patients. Eighteen right-handed PD patients and 11 right-handed age-matched healthy volunteers were studied. All patients were studied after 12 hours off medication with levodopa replacement (PD-off). Ten patients were also evaluated after medication (PD-on). The IPAS comprised a single electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 milliseconds (240 paired stimuli every 5 seconds for 20 minutes). The motor-evoked potential amplitude in the right abductor pollicis brevis muscle was increased by IPAS in healthy volunteers, but not in PD patients. IPAS did not affect the motor-evoked potential amplitude in the left abductor pollicis brevis. The ratio of the motor-evoked potential amplitude before and after IPAS in PD-off patients increased after dopamine replacement. Thus, dopamine might modulate cortical plasticity in the human M1, which could be related to higher order motor control, including motor learning. Ann Neurol 2006.

Int J Neurosci. 1999 Aug;99(1-4):139-49.

AC pulsed electromagnetic fields-induced sexual arousal and penile erections in Parkinson’s disease.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Bay Shore, NY 11706, USA.

Sexual dysfunction is common in patients with Parkinson’s disease (PD) since brain dopaminergic mechanisms are involved in the regulation of sexual behavior. Activation of dopamine D2 receptor sites, with resultant release of oxytocin from the paraventricular nucleus (PVN) of the hypothalamus, induces sexual arousal and erectile responses in experimental animals and humans. In Parkinsonian patients subcutaneous administration of apomorphine, a dopamine D2 receptor agonist, induces sexual arousal and penile erections. It has been suggested that the therapeutic efficacy of transcranial administration of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density in PD involves the activation of dopamine D2 receptor sites which are the principal site of action of dopaminergic pharmacotherapy in PD. Here, 1 report 2 elderly male PD patients who experienced sexual dysfunction which was recalcitrant to treatment with anti Parkinsonian agents including selegiline, levodopa and tolcapone. However, brief transcranial administrations of AC pulsed EMFs in the picotesla flux density induced in these patients sexual arousal and spontaneous nocturnal erections. These findings support the notion that central activation of dopamine D2 receptor sites is associated with the therapeutic efficacy of AC pulsed EMFs in PD. In addition, since the right hemisphere is dominant for sexual activity, partly because of a dopaminergic bias of this hemisphere, these findings suggest that right hemispheric activation in response to administration of AC pulsed EMFs was associated in these patient with improved sexual functions

Int J Neurosci. 1999 Apr;97(3-4):225-33.

Treatment with AC pulsed electromagnetic fields improves olfactory function in Parkinson’s disease.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Olfactory dysfunction is a common symptom of Parkinson’s disease (PD). It may manifest in the early stages of the disease and infrequently may even antedate the onset of motor symptoms. The cause of olfactory dysfunction in PD remains unknown. Pathological changes characteristic of PD (i.e., Lewy bodies) have been demonstrated in the olfactory bulb which contains a large population of dopaminergic neurons involved in olfactory information processing. Since dopaminergic drugs do not affect olfactory threshold in PD patients, it has been suggested that olfactory dysfunction in these patients is not dependent on dopamine deficiency. I present two fully medicated Parkinsonian patients with long standing history of olfactory dysfunction in whom recovery of smell occurred during therapeutic transcranial application of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density. In both patients improvement of smell during administration of EMFs occurred in conjunction with recurrent episodes of yawning. The temporal association between recovery of smell and yawning behavior is remarkable since yawning is mediated by activation of a subpopulation of striatal and limbic postsynaptic dopamine D2 receptors induced by increased synaptic dopamine release. A high density of dopamine D2 receptors is present in the olfactory bulb and tract. Degeneration of olfactory dopaminergic neurons may lead to upregulation (i.e., supersensitivity) of postsynaptic dopamine D2 receptors. Presumably, small amounts of dopamine released into the synapses of the olfactory bulb during magnetic stimulation may cause activation of these supersensitive receptors resulting in enhanced sense of smell. Interestingly, in both patients enhancement of smell perception occurred only during administration of EMFs of 7 Hz frequency implying that the release of dopamine and activation of dopamine D2 receptors in the olfactory bulb was partly frequency dependent. In fact, weak magnetic fields have been found to cause interaction with biological systems only within narrow frequency ranges (i.e., frequency windows) and the existence of such frequency ranges has been explained on the basis of the cyclotron resonance model.

Int J Neurosci. 1998 Sep;95(3-4):255-69.

Reversal of the bicycle drawing direction in Parkinson’s disease by AC pulsed electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

The Draw-a-Bicycle Test is employed in neuropsychological testing of cognitive skills since the bicycle design is widely known and also because of its complex structure. The Draw-a-Bicycle Test has been administered routinely to patients with Parkinson’s disease (PD) and other neurodegenerative disorders to evaluate the effect of transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density on visuoconstructional skills. A seminal observation is reported in 5 medicated PD patients who demonstrated reversal of spontaneous drawing direction of the bicycle after they received a series of transcranial treatments with AC pulsed EMFs. In 3 patients reversal of the bicycle drawing direction was observed shortly after the administration of pulsed EMFs while in 2 patients these changes were observed within a time lag ranging from several weeks to months. All patients also demonstrated a dramatic clinical response to the administration of EMFs. These findings are intriguing because changes in drawing direction do not occur spontaneously in normal individuals as a result of relateralization of cognitive functions. This report suggests that administration of AC pulsed EMFs may induce in some PD patients changes in hemispheric dominance during processing of a visuoconstructional task and that these changes may be predictive of a particularly favourable response to AC pulsed EMFs therapy.

Int J Neurosci. 1998 May;94(1-2):41-54.

Transcranial AC pulsed applications of weak electromagnetic fields reduces freezing and falling in progressive supranuclear palsy: a case report.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Dix Hills, NY 11746, USA.

Freezing is a common and disabling symptom in patients with Parkinsonism. It affects most commonly the gait in the form of start hesitation and sudden immobility often resulting in falling. A higher incidence of freezing occurs in patients with progressive supranuclear palsy (PSP) which is characterized clinically by a constellation of symptoms including supranuclear ophthalmoplegia, postural instability, axial rigidity, dysarthria, Parkinsonism, and pseudobulbar palsy. Pharmacologic therapy of PSP is currently disappointing and the disease progresses relentlessly to a fatal outcome within the first decade after onset. This report concerns a 67 year old woman with a diagnosis of PSP in whom freezing and frequent falling were the most disabling symptoms of the disease at the time of presentation. Both symptoms, which were rated 4 on the Unified Parkinson Rating Scale (UPRS) which grades Parkinsonian symptoms and signs from 0 to 4, with 0 being normal and 4 being severe symptoms, were resistant to treatment with dopaminergic drugs such as levodopa, amantadine, selegiline and pergolide mesylate as well as with the potent and highly selective noradrenergic reuptake inhibitor nortriptyline. Weekly transcranial applications of AC pulsed electromagnetic fields (EMFs) of picotesla flux density was associated with approximately 50% reduction in the frequency of freezing and about 80-90% reduction in frequency of falling after a 6 months follow-up period. At this point freezing was rated 2 while falling received a score of 1 on the UPRS. In addition, this treatment was associated with an improvement in Parkinsonian and pseudobulbar symptoms with the difference between the pre-and post EMF treatment across 13 measures being highly significant (p < .005; Sign test). These results suggest that transcranial administration AC pulsed EMFs in the picotesla flux density is efficacious in the treatment of PSP.

J Neurosci. 1998 Feb;93(1-2):43-54.

Reversal of a body image disorder (macrosomatognosia) in Parkinson’s disease by treatment with AC pulsed electromagnetic fields.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Macrosomatognosia refers to a disorder of the body image in which the patient perceives a part or parts of his body as disproportionately large. Macrosomatognosia has been associated with lesions in the parietal lobe, particularly the right parietal lobe, which integrates perceptual-sensorimotor functions concerned with the body image. It has been observed most commonly in patients with paroxysmal cerebral disorders such as epilepsy and migraine. The Draw-a-Person-Test has been employed in neuropsychological testing to identify disorders of the body image. Three fully medicated elderly Parkinsonian patients who exhibited, on the Draw-a-Person Test, macrosomatognosia involving the upper limbs are presented. In these patients spontaneous drawing of the figure of a man demonstrated disproportionately large arms. Furthermore, it was observed that the arm affected by tremor or, in the case of bilateral tremor, the arm showing the most severe tremor showed the greatest abnormality. This association implies that dopaminergic mechanisms influence neuronal systems in the nondominant right parietal lobe which construct the body image. After receiving a course of treatments with AC pulsed electromagnetic fields (EMFs) in the picotesla flux density applied transcranially, these patients’ drawings showed reversal of the macrosomatognosia. These findings demonstrate that transcranial applications of AC pulsed EMFs affect the neuronal systems involved in the construction of the human body image and additionally reverse disorders of the body image in Parkinsonism which are related to right parietal lobe dysfunction.

Int J Neurosci. 1997 Nov;92(1-2):63-72.

Speech impairment in Parkinson’s disease is improved by transcranial application of electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 52 year old fully medicated physician with juvenile onset Parkinsonism experienced 4 years ago severe “on-off” fluctuations in motor disability and debilitating speech impairment with severe stuttering which occurred predominantly during “on-off” periods. His speech impairment improved 20%-30% when sertraline (75 mg/day), a serotonin reuptake inhibitor, was added to his dopaminergic medications which included levodopa, amantadine, selegiline and pergolide mesylate. A more dramatic and consistent improvement in his speech occurred over the past 4 years during which time the patient received, on a fairly regular basis, weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Recurrence of speech impairment was observed on several occasions when regular treatments with EMFs were temporarily discontinued. These findings demonstrate that AC pulsed applications of picotesla flux density EMFs may offer a nonpharmacologic approach to the management of speech disturbances in Parkinsonism. Furthermore, this case implicates cerebral serotonergic deficiency in the pathogenesis of Parkinsonian speech impairment which affects more than 50% of patients. It is believed that pulsed applications of EMFs improved this patient’s speech impairment through the facilitation of serotonergic transmission which may have occurred in part through a synergistic interaction with sertraline.

Int J Neurosci. 1997 Oct;91(3-4):189-97.

Treatment with AC pulsed electromagnetic fields improves the response to levodopa in Parkinson’s disease.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 52 year old fully medicated Parkinsonian patient with severe disability (stage 4 on the Hoehn & Yahr disability scale) became asymptomatic 10 weeks after he received twice weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Prior to treatment with EMFs, his medication (Sinemet CR) was about 50% effective and he experienced end-of-dose deterioration and diurnal-related decline in the drug’s efficacy. For instance, while his morning medication was 90% effective, his afternoon medication was only 50% effective and his evening dose was only 30% effective. Ten weeks after introduction of treatment with EMFs, there was 40% improvement in his response to standard Sinemet medication with minimal change in its efficacy during the course of the day or evening. These findings demonstrate that intermittent, AC pulsed applications of picotesla flux density EMFs improve Parkinsonian symptoms in part by enhancing the patient’s response to levodopa. This effect may be related to an increase in the capacity of striatal DA neurons to synthesize, store and release DA derived from exogenously supplied levodopa as well as to increased serotonin (5-HT) transmission which has been shown to enhance the response of PD patients to levodopa. Since decline in the response to levodopa is a phenomenon associated with progression of the disease, this case suggests that intermittent applications of AC pulsed EMFs of picotesla flux density reverse the course of chronic progressive PD.

Int J Neurosci. 1997 Sep;91(1-2):57-68.

Reversal of cognitive impairment in an elderly parkinsonian patient by transcranial application of picotesla electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 74 year old retired building inspector with a 15 year history of Parkinson’s disease (PD) presented with severe resting tremor in the right hand, generalized bradykinesia, difficulties with the initiation of gait with freezing, mental depression and generalized cognitive impairment despite being fully medicated. Testing of constructional abilities employing various drawing tasks demonstrated drawing impairment compatible with severe left hemispheric dysfunction. After receiving two successive transcranial applications, each of 20 minutes duration, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density and frequencies of 5Hz and 7Hz respectively, his tremor remitted and there was dramatic improvement in his drawing performance. Additional striking improvements in his drawing performance occurred over the following two days after he continued to receive daily treatments with EMFs. The patient’s drawings were subjected to a Reliability Test in which 10 raters reported 100% correct assessment of pre- and post drawings with all possible comparisons (mean 2 = 5.0; p < .05). This case demonstrates in PD rapid reversal of drawing impairment related to left hemispheric dysfunction by brief transcranial applications of AC pulsed picotesla flux density EMFs and suggests that cognitive deficits associated with Parkinsonism, which usually are progressive and unaffected by dopamine replacement therapy, may be partly reversed by administration of these EMFs. Treatment with picotesla EMFs reflects a “cutting edge” approach to the management of cognitive impairment in Parkinsonism.

Int J Neurosci. 1997 Jun;90(1-2):75-86.

Treatment with weak electromagnetic fields restores dream recall in a parkinsonian patient.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Dix Hills, NY 11746, USA.

Absent or markedly reduced REM sleep with cessation of dream recall has been documented in numerous neurological disorders associated with subcortical dementia including Parkinson’s disease, progressive supranuclear palsy and Huntington’s chorea. This report concerns a 69 year old Parkinsonian patient who experienced complete cessation of dreaming since the onset of motor disability 13 years ago. Long term treatment with levodopa and dopamine (DA) receptor agonists (bromocriptine and pergolide mesylate) did not affect dream recall. However, dreaming was restored after the patient received three treatment sessions with AC pulsed picotesla range electromagnetic fields (EMFs) applied extracranially over three successive days. Six months later, during which time the patient received 3 additional treatment sessions with EMFs, he reported dreaming vividly with intense colored visual imagery almost every night with some of the dreams having sexual content. In addition, he began to experience hypnagogic imagery prior to the onset of sleep. Cessation of dream recall has been associated with right hemispheric dysfunction and its restoration by treatment with EMFs points to right hemispheric activation, which is supported by improvement in this patient’s visual memory known to be subserved by the right temporal lobe. Moreover, since DA neurons activate REM sleep mechanisms and facilitate dream recall, it appears that application of EMFs enhanced DA activity in the mesolimbic system which has been implicated in dream recall. Also, since administration of pineal melatonin has been reported to induce vivid dreams with intense colored visual imagery in normal subjects and narcoleptic patients, it is suggested that enhanced nocturnal melatonin secretion was associated with restoration of dream recall in this patient. These findings demonstrate that unlike chronic levodopa therapy, intermittent pulsed applications of AC picotesla EMFs may induce in Parkinsonism reactivation of reticular-limbic-pineal systems involved in the generation of dreaming.

Int J Neurosci. 1996 Nov;87(3-4):209-17.

Brief communication: electromagnetic fields improve visuospatial performance and reverse agraphia in a parkinsonian patient.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 73 year old right-handed man, diagnosed with Parkinson’s disease (PD) in 1982, presented with chief complaints of disabling resting and postural tremors in the right hand, generalized bradykinesia and rigidity, difficulties with the initiation of gait, freezing of gait, and mild dementia despite being fully medicated. On neuropsychological testing the Bicycle Drawing Test showed cognitive impairment compatible with bitemporal and frontal lobe dysfunction and on attempts to sign his name he exhibited agraphia. After receiving two successive treatments, each of 20 minutes duration, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla intensity and 5 Hz frequency sinusoidal wave, his drawing to command showed improvement in visuospatial performance and his signature became legible. One week later, after receiving two additional successive treatments with these EMFs each of 20 minutes duration with a 7 Hz frequency sinusoidal wave, he drew a much larger, detailed and visuospatially organized bicycle and his signature had normalized. Simultaneously, there was marked improvement in Parkinsonian motor symptoms with almost complete resolution of the tremors, start hesitation and freezing of gait. This case demonstrates the dramatic beneficial effects of AC pulsed picotesla EMFs on neurocognitive processes subserved by the temporal and frontal lobes in Parkinsonism and suggest that the dementia of Parkinsonism may be partly reversible.

Int J Neurosci. 1996 Mar;85(1-2):111-24.

Freezing of gait in Parkinson’s disease is improved by treatment with weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Freezing, a symptom characterized by difficulty in the initiation and smooth pursuit of repetitive movements, is a unique and well known clinical feature of Parkinson’s disease (PD). It usually occurs in patients with long duration and advanced stage of the disease and is a major cause of disability often resulting in falling. In PD patients freezing manifests most commonly as a sudden attack of immobility usually experienced during walking, attempts to turn while walking, or while approaching a destination. Less commonly it is expressed as arrest of speech or handwriting. The pathophysiology of Parkinsonian freezing, which is considered a distinct clinical feature independent of akinesia, is poorly understood and is believed to involve abnormalities in dopamine and norepinephrine neurotransmission in critical motor control areas including the frontal lobe, basal ganglia, locus coeruleus and spinal cord. In general, freezing is resistant to pharmacological therapy although in some patients reduction or increase in levodopa dose may improve this symptom. Three medicated PD patients exhibiting disabling episodes of freezing of gait are presented in whom brief, extracerebral applications of pulsed electromagnetic fields (EMFs) in the picotesla range improved freezing. Two patients had freezing both during “on” and “off” periods while the third patient experienced random episodes of freezing throughout the course of the day. The effect of each EMFs treatment lasted several days after which time freezing gradually reappeared, initially in association with “off” periods. These findings suggest that the neurochemical mechanisms underlying the development of freezing are sensitive to the effects of EMFs, which are believed to improve freezing primarily through the facilitation of serotonin (5-HT) neurotransmission at both junctional (synaptic) and nonjunctional neuronal target sites.

Int J Neurosci. 1998 Apr;93(3-4):239-50.

Treatment with AC pulsed electromagnetic fields normalizes the latency of the visual evoked response in a multiple sclerosis patient with optic atrophy.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Visual evoked response (VER) studies have been utilized as supportive information for the diagnosis of multiple sclerosis (MS) and may be useful in objectively monitoring the effects of various therapeutic modalities. Delayed latency of the VER, which reflects slowed impulse transmission in the optic pathways, is the most characteristic abnormality associated with the disease. Brief transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density are efficacious in the symptomatic treatment of MS and may also reestablish impulse transmission in the optic pathways. A 36 year old man developed an attack of right sided optic neuritis at the age of 30. On presentation he had blurring of vision with reduced acuity on the right and fundoscopic examination revealed pallor of the optic disc. A checkerboard pattern reversal VER showed a delayed latency to right eye stimulation (P100 = 132 ms; normal range: 95-115 ms). After he received two successive applications of AC pulsed EMFs of 7.5 picotesla flux density each of 20 minutes duration administered transcranially, there was a dramatic improvement in vision and the VER latency reverted to normal (P100= 107 ms). The rapid improvement in vision coupled with the normalization of the VER latency despite the presence of optic atrophy, which reflects chronic demyelination of the optic nerve, cannot be explained on the basis of partial or full reformation of myelin. It is proposed that in MS synaptic neurotransmitter deficiency is associated with the visual impairment and delayed VER latency following optic neuritis and that the recovery of the VER latency by treatment with pulsed EMFs is related to enhancement of synaptic neurotransmitter functions in the retina and central optic pathways. Recovery of the VER latency in MS patients may have important implications with respect to the treatment of visual impairment and prevention of visual loss. Specifically, repeated pulsed applications of EMFs may maintain impulse transmission in the optic nerve and thus potentially sustain its viability.

Int J Neurosci, 66(3-4):209-35 1992 Oct

Magnetic fields in the therapy of parkinsonism.

Sandyk R NeuroCommunication Research Laboratories, Danbury, CT 06811.

In a recent Editorial published in this Journal, I presented a new and revolutionary method for the treatment of Parkinson’s disease (PD). I reported that extracranial treatment with picoTesla magnetic fields (MF) is a highly effective, safe, and revolutionary modality in the symptomatic management of PD. My conclusion was based on experience gained following the successful treatment of over 20 Parkinsonian patients, two of whom had levodopa-induced dyskinesias. None of the patients developed side effects during a several month period of follow-up. In the present communication, I present two reports. The first concerns four Parkinsonian patients in whom picoTesla MF produced a remarkable and sustained improvement in disability. Three of the patients had idiopathic PD and the fourth patient developed a Parkinsonian syndrome following an anoxic episode. In all patients, treatment with MF was applied as an adjunct to antiParkinsonian medication. The improvement noted in these patients attests to the efficacy of picoTesla MF as an additional, noninvasive modality in the therapy of the disease. The second report concerns two demented Parkinsonian patients in whom treatment with picoTesla MF rapidly reversed visuospatial impairment as demonstrated by the Clock Drawing Test. These findings demonstrate, for the first time, the efficacy of these MF in the amelioration of cognitive deficits in Parkinson’s disease. Since Alzheimer’s pathology frequently coexists with the dementia of Parkinsonism, these observations underscore the potential efficacy of picoTesla MF in the treatment of dementias of various etiologies.

Neck Pain – Osteoarthritis – Whiplash

Best Pract Res Clin Rheumatol. 2007 Feb;21(1):93-108. Strategies for prevention and management of musculoskeletal conditions.  Neck pain. Jensen I, Harms-Ringdahl K. Department of Clinical Neuroscience, Section of Personal Injury Prevention, Karolinska Institutet, and Department of Physical Therapy, Karolinska University Hospital, Stockholm, Sweden. irene.jensen@ki.se The aim of this article was to summarise the existing evidence concerning interventions for non-specific neck pain. Neck-and-shoulder pain is commonly experienced by both adolescents and adults. Although the prevalence appears to vary among different nations, the situation is essentially the same, at least in the industrialised nations. Explanations for the wide variation in incidence and prevalence include various methodological issues. Back and neck disorders represent one of the most common causes for both short- and long-term sick leave and disability pension. Evidenced risk factors for the onset and maintenance of non-specific neck and back pain include both individual and work-related psychosocial factors. Based on the existing evidence different forms of exercise can be strongly recommended for at-risk populations, as well as for the acute and chronic non-specific neck pain patient. Furthermore, for symptom relief this condition can be treated with transcutaneous electric nerve stimulation, low level laser therapy, pulse electromagnetic treatment or radiofrequency denervation.

Pain. 2007 Jan;127(1-2):173-82. Epub 2006 Oct 18.

Pulsed radiofrequency adjacent to the cervical dorsal root ganglion in chronic cervical radicular pain: a double blind sham controlled randomized clinical trial.

Van Zundert J, Patijn J, Kessels A, Lamé I, van Suijlekom H, van Kleef M.

Department of Anesthesiology, Pain Management and Research Centre, University Hospital Maastricht, The Netherlands. janvanzundert@pandora.be

Abstract

Cervical radicular pain affects approximately 1 on 1000 adults per year. Although many treatment modalities are described in the literature, the available evidence for efficacy is not sufficient to allow definitive conclusions on the optimal therapy to be made. The effect of pulsed radiofrequency treatment for this type of patients was evaluated in a prospective audit that showed satisfactory pain relief for a mean period of 9.2 months, justifying a randomized sham controlled trial. Twenty-three patients, out of 256 screened, met the inclusion criteria and were randomly assigned in a double blind fashion to receive either pulsed radiofrequency or sham intervention. The evaluation was done by an independent observer. At 3 months the pulsed radiofrequency group showed a significantly better outcome with regard to the global perceived effect (>50% improvement) and visual analogue scale (20 point pain reduction). The quality of life scales also showed a positive trend in favor of the pulsed radiofrequency group, but significance was only reached in the SF-36 domain vitality at 3 months. The need for pain medication was significantly reduced in the pulsed radiofrequency group after six months. No complications were observed during the study period. These study results are in agreement with the findings of our previous clinical audit that pulsed radiofrequency treatment of the cervical dorsal root ganglion may provide pain relief for a limited number of carefully selected patients with chronic cervical radicular pain as assessed by clinical and neurological examination.

Rheumatol Int. 2005 Jun 29; [Epub ahead of print]

The effect of pulsed electromagnetic fields in the treatment of cervical osteoarthritis: a randomized, double-blind, sham-controlled trial.

Sutbeyaz ST, Sezer N, Koseoglu BF.

Ankara Physical Medicine and Rehabilitation Education and Research Hospital, Turk ocagi S No: 3 Sihhiye, Ankara, Turkey.

The purpose of this study was to evaluate the effect of electromagnetic field therapy (PEMF) on pain, range of motion (ROM) and functional status in patients with cervical osteoarthritis (COA). Thirty-four patients with COA were included in a randomized, double-blind study. PEMF was administrated to the whole body using a mat 1.8×0.6 m in size. During the treatment, the patients lay on the mat for 30 min per session, twice a day for 3 weeks. Pain levels in the PEMF group decreased significantly after therapy (p<0.001), but no change was observed in the placebo group. The active ROM, paravertebral muscle spasm and neck pain and disability scale (NPDS) scores improved significantly after PEMF therapy (p<0.001) but no change was observed in the sham group. The results of this study are promising, in that PEMF treatment may offer a potential therapeutic adjunct to current COA therapies in the future.

Pain Res Manag. 2005 Spring;10(1):21-32.

Treatment of whiplash-associated disorders–part I: Non-invasive interventions.

Conlin A, Bhogal S, Sequeira K, Teasell R.

St Joseph’s Health Centre, Parkwood Hospital, London, Canada.

BACKGROUND: A whiplash-associated disorder (WAD) is an injury due to an acceleration-deceleration mechanism at the neck. WAD represents a very common and costly condition, both economically and socially. In 1995, the Quebec Task Force published a report that contained evidence-based recommendations regarding the treatment of WAD based on studies completed before 1993 and consensus-based recommendations.

OBJECTIVE: The objective of the present article–the first installment of a two-part series on interventions for WAD–is to provide a systematic review of the literature published between January 1993 and July 2003 on noninvasive interventions for WAD using meta-analytical techniques.

METHODS OF THE REVIEW: Three medical literature databases were searched for identification of all studies on the treatment of WAD. Randomized controlled trials (RCTs) and epidemiological studies were categorized by treatment modality and analyzed by outcome measure. The methodological quality of the RCTs was assessed. When possible, pooled analyses of the RCTs were completed for meta-analyses of the data. The results of all the studies were compiled and systematically reviewed.

RESULTS: Studies were categorized as exercise alone, multimodal intervention with exercise, mobilization, strength training, pulsed magnetic field treatment and chiropractic manipulation. A total of eight RCTs and 10 non-RCTs were evaluated. The mean score of methodological quality of the RCTs was five out of 10. Pooled analyses were completed across all treatment modalities and outcome measures. The outcomes of each study were summarized in tables.

CONCLUSIONS: There exists consistent evidence (published in two RCTs) in support of mobilization as an effective noninvasive intervention for acute WAD. Two RCTs also reported consistent evidence that exercise alone does not improve range of motion in patients with acute WAD. One RCT reported improvements in pain and range of motion in patients with WAD of undefined duration who underwent pulsed electromagnetic field treatment. Conflicting evidence in two RCTs exists regarding the effectiveness of multimodal intervention with exercise. Limited evidence, in the form of three non-RCTs, exists in support of chiropractic manipulation. Future research should be directed toward clarifying the role of exercise and manipulation in the treatment of WAD, and supporting or refuting the benefit of pulsed electromagnetic field treatment. Mobilization is recommended for the treatment of pain and compromised cervical range of motion in the acute WAD patient.

J Med Eng Technol. 2002 Nov-Dec;26(6):253-8.

Comparison between the analgesic and therapeutic effects of a musically modulated electromagnetic field (TAMMEF) and those of a 100 Hz electromagnetic field: blind experiment on patients suffering from cervical spondylosis or cervical periarthritis.

Rigato M, Battisti E, Fortunato M, Giordano N.

Department of Physics, Section of Medical Physics University of Sienna, Italy. rigato@unisi.it

The analgesic-therapeutic efficacy and tolerability of a low-frequency electromagnetic field (ELF), modulated at a frequency of 100 Hz with a sinusoidal waveform and mean induction of a few gauss, has been demonstrated by the authors in numerous previous studies of various hyperalgic pathologies, particularly of the locomotor apparatus. In the present study, the authors tested a new type of all-inclusive field, denoted TAMMEF, whose parameters (frequency, intensity, waveform) are modified in time, randomly varying within the respective ranges, so that all the possible codes can occur during a single application. For the comparison, 150 subjects (118 women and 32 men, between 37 and 66 years of age) were enrolled. They were affected by cervical spondylosis (101 cases) or shoulder periarthritis (49 cases). Unbeknownst to them, they were randomly divided into three groups of 50 subjects. One group was exposed to the new TAMMEF, another group to the usual ELF, and the third group to simulated treatment. The results show that the effects of the new TAMMEF therapy are equivalent to those obtained with the ELF.

Cochrane Database Syst Rev. 2002;(1):CD003523.

Electromagnetic fields for the treatment of osteoarthritis.

Hulme J, Robinson V, DeBie R, Wells G, Judd M, Tugwell P.

Cochrane Collaborating Center, Center for Global Health, Institute of Population Health – University of Ottawa, 1 Stewart Street, Ottawa, Ontario, Canada, K1N 6N5. jhulme@uottawa.ca

BACKGROUND: As the focus for osteoarthritis (OA) treatment shifts away from drug therapy, we consider the effectiveness of pulsed electric stimulation which is proven to stimulate cartilage growth on the cellular level.

OBJECTIVES: 1)To assess the effectiveness of pulsed electric stimulation for the treatment of osteoarthritis (OA). 2) To assess the most effective and efficient method of applying an electromagnetic field, through pulsed electromagnetic fields (PEMF) or electric stimulation, as well as the consideration of length of treatment, dosage, and the frequency of the applications.

SEARCH STRATEGY: We searched PREMEDLINE, MEDLINE, HealthSTAR, CINAHL, PEDro, and the Cochrane Controlled Trials Register (CCTR) up to and including 2001. This included searches through the coordinating offices of the trials registries of the Cochrane Field of Physical and Related Therapies and the Cochrane Musculoskeletal Group for further published and unpublished articles. The electronic search was complemented by hand searches and experts in the area.

SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials that compared PEMF or direct electric stimulation against placebo in patients with OA.

DATA COLLECTION AND ANALYSIS: Two reviewers determined the studies to be included in the review based on inclusion and exclusion criteria (JH,VR) and extracted the data using pre-developed extraction forms for the Cochrane Musculoskeletal Group. The methodological quality of the trials was assessed by the same reviewers using a validated scale (Jadad 1996). Osteoarthritis outcome measures were extracted from the publications according to OMERACT guidelines (Bellamy 1997) and additional secondary outcomes considered.

MAIN RESULTS: Only three studies with a total of 259 OA patients were included in the review. Electrical stimulation therapy had a small to moderate effect on outcomes for knee OA, all statistically significant with clinical benefit ranging from 13-23% greater with active treatment than with placebo. Only 2 outcomes for cervical OA were significantly different with PEMF treatment and no clinical benefit can be reported with changes of 12% or less.

REVIEWER’S CONCLUSIONS: Current evidence suggests that electrical stimulation therapy may provide significant improvements for knee OA, but further studies are required to confirm whether the statistically significant results shown in these trials confer to important benefits.

Neurorehabilitation
Issue: Volume 17, Number 1 / 2002
Pages: 63 – 67
URL: Linking Options
Evaluation of electromagnetic fields in the treatment of pain in patients with lumbar radiculopathy or the whiplash syndrome Ch. Thuile A1 and M. Walzl A2 A1 International Society of Energy Medicine, Vienna, Austria A2 State Clinic of Neurology and Psychiatry, Graz, Austria Abstract: Back pain and the whiplash syndrome are very common diseases involving tremendous costs and extensive medical effort. A quick and effective reduction of symptoms, especially pain, is required. In two prospective randomized studies, patients with either lumbar radiculopathy in the segments L5/S1 or the whiplash syndrome were investigated. Inclusion criteria were as follows: either clinically verified painful lumbar radiculopathy in the segments L5/S1 and a Laségue’s sign of 30 degrees (or more), or typical signs of the whiplash syndrome such as painful restriction of rotation and flexion/extension. Exclusion criteria were prolapsed intervertebral discs, systemic neurological diseases, epilepsy, and pregnancy. A total of 100 patients with lumbar radiculopathy and 92 with the whiplash syndrome were selected and entered in the study following a 1:1 ratio. Both groups (magnetic field treatment and controls) received standard medication consisting of diclofenac and tizanidine, while the magnetic field was only applied in group 1, twice a day, for a period of two weeks. In patients suffering from radiculopathy, the average time until pain relief and painless walking was 8.2 – 0.5 days in the magnetic field group, and 11.7 – 0.5 days in controls p < 0.04). In patients with the whiplash syndrome, pain was measured on a ten-point scale. Pain in the head was on average 4.6 before and 2.1 after treatment in those receiving magnetic field treatment, and 4.2/3.5 in controls. Neck pain was on average 6.3/1.9 as opposed to 5.3/4.6, and pain in the shoulder/arm was 2.4/0.8 as opposed to 2.8/2.2 (p < 0.03 for all regions). Hence, magnetic fields appear to have a considerable and statistically significant potential for reducing pain in cases of lumbar radiculopathy and the whiplash syndrome. References: G.B.J. Andersson, The Epidemiology of Spinal Disorder, in: The Adult Spine: Principles and Practice, J.W. Frymoyer, ed., Raven Press, New York, 1991. V. Grosser, K. Seide and D. Wolter, Berufliche Belastungen und bandscheibenbedingte Erkrankungen der LWS: Derzeit-iger Kausalwissenstand in der Literatur? in: Berufskrankheit 2108: Kausalit¨at und Abgrenzungskriterien, D. Wolter and K. Seide, eds., Springer, Berlin, 1995, pp. 26-38.
Vopr Kurortol Fizioter Lech Fiz Kult. 1997 Sep-Oct;(5):25-6.

Experience in using saprogel mud in combination with a magnetic field in treating cervical osteochondrosis.

[Article in Russian]

Samutin NM.

Patients with cervical osteochondrosis were successfully treated with Deshembinskoe Lake [correction of Deshembinskaya] sapropel mud in combination with exposure to magnetic field. The details of this treatment regimen are described. Combination of pelotherapy with effects of the magnetic field proved beneficial for patients with cervical osteochondrosis.

J Rheumatol. 1994 Oct;21(10):1903-11.

The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.

Trock DH, Bollet AJ, Markoll R.

Department of Medicine, Danbury Hospital, CT.

Abstract

OBJECTIVE: We conducted a randomized, double blind clinical trial to determine the effectiveness of pulsed electromagnetic fields (PEMF) in the treatment of osteoarthritis (OA) of the knee and cervical spine.

METHODS: A controlled trial of 18 half-hour active or placebo treatments was conducted in 86 patients with OA of the knee and 81 patients with OA of the cervical spine, in which pain was evaluated using a 10 cm visual analog scale, activities of daily living using a series of questions (answered by the patient as never, sometimes, most of the time, or always), pain on passive motion (recorded as none, slight, moderate, or severe), and joint tenderness (recorded using a modified Ritchie scale). Global evaluations of improvement were made by the patient and examining physician. Evaluations were made at baseline, midway, end of treatment, and one month after completion of treatment.

RESULTS: Matched pair t tests showed extremely significant changes from baseline for the treated patients in both knee and cervical spine studies at the end of treatment and the one month followup observations, whereas the changes in the placebo patients showed lesser degrees of significance at the end of treatment, and had lost significance for most variables at the one month followup. Means of the treated group of patients with OA of the knee showed greater improvement from baseline values than the placebo group by the end of treatment and at the one month followup observation. Using the 2-tailed t test, at the end of treatment the differences in the means of the 2 groups reached statistical significance for pain, pain on motion, and both the patient overall assessment and the physician global assessment. The means of the treated patients with OA of the cervical spine showed greater improvement from baseline than the placebo group for most variables at the end of treatment and one month followup observations; these differences reached statistical significance at one or more observation points for pain, pain on motion, and tenderness.

CONCLUSION: PEMF has therapeutic benefit in painful OA of the knee or cervical spine.

J Rheumatol. 1993 Mar;20(3):456-60.

A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis.

Trock DH, Bollet AJ, Dyer RH Jr, Fielding LP, Miner WK, Markoll R.

Department of Medicine (Rheumatology), Danbury Hospital, CT 06810.

Abstract

OBJECTIVE: Further evaluation of pulsed electromagnetic fields (PEMF), which have been observed to produce numerous biological effects, and have been used to treat delayed union fractures for over a decade.

METHODS: In a pilot, double-blind randomized trial, 27 patients with osteoarthritis (OA), primarily of the knee, were treated with PEMF. Treatment consisted of 18 half-hour periods of exposure over about 1 month in a specially designed noncontact, air-coil device. Observations were made on 6 clinical variables at baseline, midpoint of therapy, end of treatment and one month later; 25 patients completed treatment.

RESULTS: An average improvement of 23-61% occurred in the clinical variables observed with active treatment, while 2 to 18% improvement was observed in these variables in placebo treated control patients. No toxicity was observed.

CONCLUSION: The decreased pain and improved functional performance of treated patients suggests that this configuration of PEMF has potential as an effective method of improving symptoms in patients with OA. This method warrants further clinical investigation.

J Rheumatol. 1993 Mar;20(3):456-60.

The Effect of Pulsed Electromagnetic Fields in the Treatment of Osteoarthritis of the Knee and Cervical Spine.  Report of Randomized, Double-Blind, Placebo Controlled Trials

Trock D. et.al.

Department of Medicine, Danbury Hospital, CT. J. of Rheumatology

From http://www.curatronic.com/scientific.html#1

OBJECTIVE. We conducted a randomized, double blind clinical trial to determine the effectiveness of pulsed electromagnetic fields (PEMF) in the treatment of osteoarthritis (OA) of the knee and cervical spine.

METHODS. A controlled trial of 18 half-hour active or placebo treatments was conducted in 86 patients with OA of the knee and 81 patients with OA of the cervical spine, in which pain was evaluated using a 10 cm visual analog scale, activities of daily living using a series of questions (answered by the patient as never, sometimes, most of the time, or always), pain on passive motion (recorded as none, slight, moderate, or severe), and joint tenderness (recorded using a modified Ritchie scale). Global evaluations of improvement were made by the patient and examining physician. Evaluations were made at baseline, midway, end of treatment, and one month after completion of treatment.

RESULTS. Matched pair t tests showed extremely significant changes from baseline for the treated patients in both knee and cervical spine studies at the end of treatment and the one month follow-up observations, whereas the changes in the placebo patients showed lesser degrees of significance at the end of treatment, and had lost significance for most variables at the one month follow-up. Means of the treated group of patients with OA of the knee showed greater improvement from baseline values than the placebo group by the end of treatment and at the one month follow-up observation. Using the 2-tailed t test, at the end of treatment the differences in the means of the 2 groups reached statistical significance for pain, pain on motion, and both the patient overall assessment and the physician global assessment. The means of the treated patients with OA of the cervical spine showed greater improvement from baseline than the placebo group for most variables at the end of treatment and one month follow-up observations; these differences reached statistical significance at one or more observation points for pain, pain on motion, and tenderness.

CONCLUSION. PEMF has therapeutic benefit in painful OA of the knee or cervical

Scand J Rehabil Med. 1992;24(1):51-9.

Low energy high frequency pulsed electromagnetic therapy for acute whiplash injuries.  A double blind randomized controlled study.

Foley-Nolan D. et.al.

Mater Hospital, Dublin, Ireland.

The standard treatment of acute whiplash injuries (soft collar and analgesia) is frequently unsuccessful. Pulsed electromagnetic therapy PEMT has been shown to have pro-healing and anti-inflammatory effects. This study examines the effect of PEMT on the acute whiplash syndrome. PEMT as described is safe for domiciliary use and this study suggests that PEMT has a beneficial effect in the management of the acute whiplash injury.

Orthopedics. 1990 Apr;13(4):445-51.

Pulsed high frequency (27MHz) electromagnetic therapy for persistent neck pain. A double blind, placebo-controlled study of 20 patients.

Foley-Nolan D, Barry C, Coughlan RJ, O’Connor P, Roden D.

Mater Misericordiae Hospital, Dublin, Ireland.

Abstract

In the majority of patients with neck pain, symptoms will resolve spontaneously or quite quickly in response to therapy. However, some patients’ symptoms persist for a long period, irrespective of therapy. In this study, 20 patients with persistent (greater than 8 weeks) neck pain were enrolled in a double blind, placebo-controlled trial of low energy, pulsed electromagnetic therapy (PEMT)–a treatment previously shown to be effective in soft tissue injuries. For the first 3-week period, group A (10 patients) received active PEMT units while group B (10 patients) received facsimile placebo units. After 3 weeks, both pain (visual analogue scale (P less than .023) and range of movement (P less than .002) had improved in the group on active treatment compared to the controls. After the second 3 weeks, during which both groups used active units, there were significant improvements in observed scores for pain and range of movement in both groups. PEMT, in the form described, can be used at home easily in the treatment of patients with neck pain. It is frequently successful and without side effects.

Minerva Anestesiol. 1989 Jul-Aug;55(7-8):295-9.

Pulsed magnetic fields.  Observations in 353 patients suffering from chronic pain.

[Article in Italian]

Di Massa A, Misuriello I, Olivieri MC, Rigato M.

Three hundred-fifty-three patients with chronic pain have been treated with pulsed electromagnetic fields. In this work the Authors show the result obtained in the unsteady follow-up (2-60 months). The eventual progressive reduction of benefits is valued by Spearman’s test. We noted the better results in the group of patients with post-herpetic pain (deafferentation) and in patients simultaneously suffering from neck and low back pain.

Arch Phys Med Rehabil. 1982 Oct;63(10):462-6.

Magnetic necklace: its therapeutic effectiveness on neck and shoulder pain.

Hong CZ, Lin JC, Bender LF, Schaeffer JN, Meltzer RJ, Causin P.

The effect of the magnetic necklace on chronic neck and shoulder pain was studied on 101 volunteers, 46 males and 55 females. A double-blind method was applied on 4 divided groups (with pain vs without pain matched with magnetic vs nonmagnetic necklace). All the subjects wore the necklace 24 hours per day for 3 weeks. Subjective evaluation from the subjects with pain, either with magnetic or nonmagnetic treatment, was performed before and 3 weeks after the necklace treatment, and revealed a significant placebo effect in terms of decrease in intensity or frequency of pain. The objective tests with electrodiagnostic procedures were done before the treatment and at 3 weekly intervals. The proximal conduction time of the ulnar nerve was significantly reduced by magnetic treatment in the subjects without pain but was not changed in the subjects with pain. There was no significant change in the excitation threshold of the suprascapular nerve in all subjects. The possible mechanism of magnetic effects on pain and the prospect of magnetotherapy for pain relief in physical medicine are discussed.

Natural Killer Cells

Int J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):1059-66.

Natural killer cell activity decreases in workers occupationally exposed to extremely low frequency magnetic fields exceeding 1 microT.

Gobba F, Bargellini A, Bravo G, Scaringi M, Cauteruccio L, Borella P.

Department of Public Health Sciences, University of Modena and Reggio Emilia, Modena, Italy. f.gobba@unimore.it

Abstract

In a preliminary study a reduction in natural killer (NK) cell activity in peripheral blood lymphocytes (PBL) was observed in a group of workers exposed to levels of extremely low frequency-magnetic fields (ELF-MF) exceeding 1 microT. This study was performed to confirm the results. In 121 workers engaged in various occupational activities, individual ELF-MF exposure was monitored for 2 work shifts. Exposure levels were calculated as time-weighted average (TWA). Subjects were classified as Low exposure (TWA < or = 0.2 microT), Medium exposure (TWA 0.21-0.99 microT), or Higher exposure (TWA > or = 1 microT). In higher exposure workers NK activity proved significantly reduced compared to low exposure,(p<0.01). In medium exposure a reduction was also observed, but the difference was not significant. Multivariate analysis also confirmed the relation between exposure and NK activity. It has been suggested that ELF might affect tumour progression by inducing changes in the immune system: due to the role played by NK activity in host defence against cancer, the interference with the NK cell activity observed in this study is in agreement with this hypothesis. Furthermore, an increased risk for some neurodegenerative disorders has been reported in some epidemiological studies in ELF-MF-exposed workers: changes in NK function were also described in these diseases. Our results, showing the effect on NK activity of exposure exceeding 1 microT, suggest a possible mechanism for ELF-MF effects. This could open new horizons regarding the adverse long-term effects of these fields.

Sci Total Environ. 2009 Jan 15;407(3):1218-23. Epub 2008 Sep 19.

Extremely low frequency-magnetic fields (ELF-EMF) occupational exposure and natural killer activity in peripheral blood lymphocytes.

Gobba F, Bargellini A, Scaringi M, Bravo G, Borella P.

Chair of Occupational Medicine, Department of Public Health Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41100, Modena (MO), Italy. f.gobba@unimore.it

Abstract

Extremely Low Frequency-Magnetic Fields (ELF-MF) are possible carcinogens to humans and some data suggest that they can act as promoters or progressors. Since NK cells play a major role in the control of cancer development, an adverse effect on ELF-MF on NK function has been hypothesized. We examined NK activity in 52 workers exposed to different levels of ELF-MF in various activities. Individual exposure was monitored during 3 complete work-shifts using personal dosimeters. Environmental exposure was also monitored. ELF-MF levels in the workers were expressed as Time-Weighted Average (TWA) values. NK activity was measured in peripheral blood lymphocytes (PBL). In the whole group the median occupational TWA was 0.21 microT. According to the TWA levels, workers were classified as low exposed (26 subjects, TWA < or =0.2 microT) and higher exposed workers (26 subjects; TWA >0.2 microT). In higher exposed workers, we observed a trend to reduce NK activity compared to low exposed, but the difference was not significant. Then we selected a subgroup of highest exposed workers (12 subjects; TWA >1 microT); no difference was observed between low and highest exposed subjects in the main personal variables. Considering both E:T ratios from 12:1 to 50:1 and Lytic Units, a significant reduction in NK activity was observed in the highest exposed workers compared to the low exposed. Multivariate analysis showed a significant negative correlation between exposure and LU, while no correlation was evidenced with other personal characteristics. ELF-MF are considered possible carcinogens, and existing data suggest that they can act as promoters. Due to the role of NK activity in host defence against cancer, the results obtained in this study in workers exposed to ELF-MF levels exceeding 1 microT are in agreement with this hypothesis, and support the need for further investigation in this field.

Electromagn Biol Med. 2006;25(2):79-85.

Suppression of natural killer cell activity on Candida stellatoidea by a 50 Hz magnetic field.

Canseven AG, Seyhan N, Mirshahidi S, Imir T.

Department of Biophysics, Gazi University Medical Faculty, Ankara, Turkey. canseven@gazi.edu.tr

Abstract

Exposure to electromagnetic fields (EMF) is ubiquitous for almost all individuals living in industrialized countries. Epidemiological and laboratory studies suggest that exposure to Extremely Low Frequency (ELF) EMF increase cancer risk. The immune system functions as one of the body’s main protective mechanisms, and Natural Killer (NK) cells are a subset of lymphocytes that can destroy several types of tumor cells. In this study, we investigated, NK cell activity after exposure to a 50 Hertz (Hz), 2 mT magnetic field generated by a Helmholtz Coil. Nineteen male, 10-12 week old guinea pigs were used, and NK cytotoxic activity of splenocytes was measured in vitro by natural anticandidial colorimetric index. The Mann-Whitney U test was applied for statistical analysis. NK cell cytotoxic activity was decreased in exposed compared to controls. Our data suggests that part of the immune system, the NK cell, can be suppressed by a 50 Hz magnetic field.

Radiats Biol Radioecol. 2003 Sep-Oct;43(5):531-4.

Activity of natural killer cells of the spleen of mice exposed to low-intensity of extremely high frequency electromagnetic radiation.

[Article in Russian]

Oga? VB, Novoselova EG, Cherenkov DA, Fesenko EE.

Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, 142290 Russia. ogay@mail.icb.psn.ru

Abstract

The dose dependence of natural killer (NK) cell activity from mouse spleen upon action of low-intensity millimeter waves in the exposure range from 5 to 96 hours was studied. It has found an increase of NK activity by 24 hours posttreatment that returned to normal level in a day after the cessation of the irradiation. Also the stimulation of isolated NK cell activity after millimeter waves treatment within 1 hour was revealed.

Biofizika. 1999 Jul-Aug;44(4):737-41.

Stimulation of murine natural killer cells by weak electromagnetic waves in the centimeter range.

[Article in Russian]

Fesenko EE, Novoselova EG, Semiletova NV, Agafonova TA, Sadovnikov VB.

Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.

Abstract

Irradiation with electromagnetic waves (8.15-18 GHz, 1 Hz within, 1 microW/cm2) in vivo increases the cytotoxic activity of natural killer cells of rat spleen. In mice exposed for 24-72 h, the activity of natural killer cells increased by 130-150%, the increased level of activity persisting within 24 h after the cessation of treatment. Microwave irradiation of animals in vivo for 3.5 and 5 h, and a short exposure of splenic cells in vitro did not affect the activity of natural killer cells.

Muscular Dystrophy

Neuromuscul Disord. 2004 Jan;14(1):39-45.

Changes in motor cortex excitability in fascioscapuloheral muscular dystrophy.

Di Lazzaro V, Oliviero A, Tonali PA, Felicetti L, De Marco MB, Saturno E, Pilato F, Pescatori M, Dileone M, Pasqualetti P, Ricci E.

Institute of Neurology, Universita Cattolica, Largo A. Gemelli 8, Rome 00168, Italy. vdilazzaro@rm.unicatt.it

Previous studies found that some patients with severe, early onset facioscapulohumeral muscular dystrophy (FSHD) present epilepsy and mental retardation. This suggests a functional involvement of central nervous system in severe FSHD. It is unknown whether minor functional changes of central nervous system are also present in less severe forms of FSHD. To investigate this, we examined the excitability of neuronal networks of the motor cortex with a range of transcranial magnetic stimulation paradigms in 20 FSHD patients with heterogeneous clinical severity and compared the data with that from 20 age-matched healthy individuals and from 6 age-matched patients with other muscle diseases. There was significantly less intracortical inhibition in FSHD patients (mean responses +/- SD reduced to 58.1+/-43.5% of the test size) than in controls (mean responses +/- SD reduced to 29.3+/-13.5% of the test size; P=0.025) and in patients with other muscle diseases (mean responses +/-SD, reduced to 30.6+/-11.7% of the test size; P=0.046). No significant difference was found between the control group and patients with other muscle diseases (P=0.970).

Muscle Nerve. 1998 May;21(5):662-4.Related Articles, Links

Functional involvement of cerebral cortex in Duchenne muscular dystrophy.

Di Lazzaro V, Restuccia D, Servidei S, Nardone R, Oliviero A, Profice P, Mangiola F, Tonali P, Rothwell JC.

Istituto di Neurologia, Universita Cattolica, Rome, Italy.

Transcranial stimulation was performed in 4 patients with Duchenne muscular dystrophy and 4 control subjects. The patients’ central motor conduction time was normal. The threshold for evoking electromyographic responses using electrical anodal stimulation was the same in both groups, but the threshold for stimulation with a circular magnetic coil at the vertex was higher in the patients. This is compatible with reduced cortical excitability that may be related to the deficiency of brain synaptic dystrophin.

Electroencephalogr Clin Neurophysiol. 1997 Aug;105(4):297-301.

Magnetic stimulation study in patients with myotonic dystrophy.

Oliveri M, Brighina F, La Bua V, Aloisio A, Buffa D, Fierro B.

Institute of Neuropsychiatry, University of Palermo, Italy.

To further define motor nervous system alterations in myotonic dystrophy (MD), motor potentials to transcranial and cervical magnetic stimulation (MEPs) were recorded from the right abductor pollicis brevis muscle in 10 patients with MD and in 10 healthy controls. Cortical and cervical latencies, central motor conduction time (CMCT), stimulus threshold intensity and cortical MEP amplitudes expressed both as absolute values and as %M were analysed. MEP cervical latency, absolute or relative amplitude and excitability threshold did not significantly differ in patients and controls. The mean cortical motor latency and CMCT were significantly prolonged in MD patients with respect to normal subjects. Moreover, CMCTs were found to be significantly related to stimulus threshold intensity (P = 0.03) and only marginally related to absolute cortical amplitude (P = 0.06). These findings are indicative of a central motor delay, also related to decreased excitability of motor neurons, in patients with MD. No correlations were found between individual neurophysiological parameters and age, duration of disease and clinical impairment. Our results suggest that magnetic stimulation studies can detect subclinical dysfunctions of the central motor system in MD patients, as one of the multisystemic manifestations of the disease, rather independent of the primitive muscle damage.