Phantom Limb Pain

Electromagn Biol Med.  2011 Sep;30(3):115-27.

Phantom pain reduction by low-frequency and low-intensity electromagnetic fields.

Bókkon I, Till A, Grass F, Erdöfi Szabó A.

Source

Doctoral School of Pharmaceutical and Pharmacological Sciences, Semmelweis University , Budapest , Hungary.

Abstract

Although various treatments have been presented for phantom pain, there is little proof supporting the benefits of pharmacological treatments, surgery or interventional techniques, electroconvulsive therapy, electrical nerve stimulation, far infrared ray therapy, psychological therapies, etc. Here, we report the preliminary results for phantom pain reduction by low-frequency and intensity electromagnetic fields under clinical circumstances. Our method is called as Electromagnetic-Own-Signal-Treatment (EMOST). Fifteen people with phantom limb pain participated. The patients were treated using a pre-programmed, six sessions. Pain intensity was quantified upon admission using a 0-10 verbal numerical rating scale. Most of the patients (n = 10) reported a marked reduction in the intensity of phantom limb pain. Several patients also reported about improvement in their sleep and mood quality, or a reduction in the frequency of phantom pain after the treatments. No improvements in the reduction of phantom limb pain or sleep and mood improvement were reported in the control group (n = 5). Our nonlinear electromagnetic EMOST method may be a possible therapeutic application in the reduction of phantom limb pain. Here, we also suggest that some of the possible effects of the EMOST may be achieved via the redox balance of the body and redox-related neural plasticity. Case Report Med.  2011;2011:130751. Epub 2011 May 11.

Phantom limb pain: low frequency repetitive transcranial magnetic stimulation in unaffected hemisphere.

Di Rollo A, Pallanti S.

Source

Department of Psychiatry, University of Florence, 50134 Florence, Italy.

Abstract

Phantom limb pain is very common after limb amputation and is often difficult to treat. The motor cortex stimulation is a valid treatment for deafferentation pain that does not respond to conventional pain treatment, with relief for 50% to 70% of patients. This treatment is invasive as it uses implanted epidural electrodes. Cortical stimulation can be performed noninvasively by repetitive transcranial magnetic stimulation (rTMS). The stimulation of the hemisphere that isn’t involved in phantom limb (unaffected hemisphere), remains unexplored. We report a case of phantom limb pain treated with 1 Hz rTMS stimulation over motor cortex in unaffected hemisphere. This stimulation produces a relevant clinical improvement of phantom limb pain; however, further studies are necessary to determine the efficacy of the method and the stimulation parameters. Clin Neurophysiol.  2003 Aug;114(8):1521-30.

Repetitive transcranial magnetic stimulation of the parietal cortex transiently ameliorates phantom limb pain-like syndrome.

Töpper R, Foltys H, Meister IG, Sparing R, Boroojerdi B.

Source

Department of Neurology, Universitätsklinikum Aachen, Pauwelsstrasse 30, RWTH D-52057 Aachen, Germany.

Abstract

OBJECTIVE:

Phantom pain is linked to a reorganization of the partially deafferented sensory cortex. In this study we have investigated whether the pain syndrome can be influenced by repetitive transcranial magnetic stimulation (rTMS).

METHODS:

Two patients with a longstanding unilateral avulsion of the lower cervical roots and chronic pain in the arm were studied. As a control the acute effects of rTMS (15 Hz, 2 s duration) on pain were studied in 4 healthy subjects. Pain intensity was assessed with the Visual Analogue Scale.

RESULTS:

Stimulation of the contralateral parietal cortex led to a reproducible reduction in pain intensity lasting up to 10 min. Stimulation of other cortical areas produced only minor alterations in the severity of the pain. Both 1 and 10 Hz rTMS trains applied to the contralateral parietal cortex on weekdays for 3 consecutive weeks did, however, not lead to permanent changes in the pain intensity. Experimentally induced pain (cold water immersion of the right hand) in normal subjects was not influenced by rTMS.

CONCLUSIONS:

These results do not favor the use of rTMS in the treatment of phantom limb pain. The results, however, support the concept that phantom pain is due to a dysfunctional activity in the parietal cortex. The transient rTMS-induced analgesic effect may be due to a temporary interference with the cerebral representation of the deafferented limb.

Periodontitis

Stomatologiia (Mosk). 2000;79(6):16-9.

Use of transcutaneous laser biostimulation of blood and a running alternating magnetic field in preparing periodontitis patients for surgery.

[Article in Russian]

Lepilin AV, Bulkina NV, Bogomolova NV, Raigorodskii IuM.

A total of 103 patients with exacerbation of chronic generalized periodontitis of moderate and high severity were treated using running alternating magnetic field generated by ATOS device and transcutaneous laser biostimulation of the blood. These treatment modalities accelerated preoperative treatment and allowed performing the operations on the periodontal tissues in the optimal status under conditions of improved defense forces of the organism.

Stomatologiia (Mosk). 2003;82(4):20-4.

Magnetic laser therapy in the treatment of apical periodontitis.

[Article in Russian]

Giliazetdinova IuA, Vinnichenko AV, Vinnichenko IuA.

A new method for the treatment of apical periodontitis, making use of Optodan laser, differs from the known method by more rapid periapical tissue regeneration, which is paralleled by high antiinflammatory effect of magnetic laser therapy at early stages of treatment.

Perineal Healing in Maternity Patients

Georgian Med News. 2006 Sep;(138):71-3

Application of magnet laser radiation to stimulate healing of perineum injuries in the maternity patients.

[Article in Russian]

  • Rzakulieva LM,
  • Israfilbeili SG,
  • Gasymova G.

The study is aimed at developing the new complex effective method of treatment with an application of magnet laser radiation as a stimulating aid in healing of perineum injuries in the maternity patients. 86 maternity patients with perineotomy and/or episiotomy were studied in treatment. The injury on the perineum was conventionally treated by antiseptics in 40 maternity patients (control group); the magnet laser therapy (MLT) by means of device “MILTA” was applied to 46 maternity patients in concomitantly with the conventional methods. The therapeutic effect was based on the combined influence of the constant magnetic field and impulsive laser radiation of the red and infra-red range on the body. The patients reported less discomfort during MLT, which promotes the decrease of pain intensity and hyperaemia instantly after 2-3 procedures. We have not observed any sutures divergence in the maternity patients who received MLT, in comparison to the control group where full divergence of sutures was registered in 2.5%, and partial–in 7.5%. The proposed complex method of treatment with the application of MLT improves the process of the healing considerably, promotes the rapid disappearance of inflammatory signs and renders analgesic effect.

Periarthritis Humeroscapularis

Vopr Kurortol Fizioter Lech Fiz Kult. 1994 Jul-Aug;(4):9-12.

The combined use of electromagnetic decimeter waves and deresinated naphthalan in patients with vertebrogenic humeroscapular periarthrosis (its experimental and clinical validation).

[Article in Russian]

Musaev AV, Guse?nova SG, Mamedov AP.

Abstract

Physicochemical and experimental studies on pond snail neuron were made to validate combined or simultaneous usage of decimeter microwaves and deresinified naphthalane. Clinical and neurophysiological trials in 133 patients with vertebrogenic scapulohumeral periarthritis revealed that the above treatment is clinically beneficial and corrects functional activity of segmental-peripheral neuromotor system.

Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):34-8.

The cerebral hemodynamics in patients with humeroscapular periarthritis under the influence of decimeter waves and deresinated naphthalan.

[Article in Russian]

Musaev AV, Guse?nova SG.

Abstract

110 patients with scapulohumeral periarthritis of vertebrogenic origin were exposed to decimetric waves or received salt-free naphthalan. There were also patients who got combined treatment with decimetric waves and salt-free naphthalan. REG recorded positive shifts in cerebral hemodynamics due to these factors utilization.

Peptic – Duodenal Ulcer

Zh Nevropatol Psikhiatr Im S S Korsakova. 1993;93(6):50-2.

A psychoautonomic syndrome in duodenal peptic ulcer patients and its correction by magnetic puncture using an alternating magnetic field.

[Article in Russian]

Kravtsova TIu, Rybolovtsev EV, Shutov AA.

86 duodenal ulcer patients were diagnosed to have serious psychovegetative disorders. Among other treatment, the patients were exposed to AMF puncture of biologically active points. The puncture produced optimization of the function of cerebral (suprasegmental) vegetative structures, promoted a regress of vegetative dystonia clinical symptoms and speeded up ulcer healing.

Vopr Kurortol Fizioter Lech Fiz Kult. 1994 Jan-Feb;(1):22-4.

The use of magnetic puncture in patients with duodenal peptic ulcer.

[Article in Russian]

Kravtsova TIu, Rybolovlev EV, Kochurov AP.

Sixty-six patients with duodenal ulcer were found to have apparent shifts in psychovegetative correlations. The patients underwent puncture with alternating magnetic field of active biological points responsible for general adaptation (E 36, G 14, VB 20) and gastroduodenal function (E 20, T 9, T 8). The treatment improved emotional, personality and vegetative regulation. The symptoms declined and ulcer healed more rapidly.

PEMF vs / or combined with Laser Therapy

J Maxillofac Oral Surg. 2014 Dec;13(4):451-7. doi: 10.1007/s12663-013-0551-2. Epub 2013 Jul 26.

Radiodensitometric Assessment of the Effect of Pulsed Electromagnetic Field Stimulation Versus Low Intensity Laser Irradiation on Mandibular Fracture Repair: A Preliminary Clinical Trial.

Refai H1, Radwan D1, Hassanien N1.

Author information

  • 1Department of Oral and Maxillofacial Surgery, Faculty of Oral and Dental Medicine, Cairo University, Cairo, Egypt.

Abstract

PURPOSE:

Closed reduction of mandibular fractures usually entails a relatively long period of immobilization, with the subsequent delay of rehabilitation. Therefore, shorter immobilization period with various approaches to protect or enhance bone healing have been investigated. The aim of this study was to analyze the effects of pulsed electromagnetic field (PEMF) and low intensity laser irradiation (LILI) on the fracture healing process, through radiodensitometric assessment of the bone callus.

PATIENTS AND METHODS:

Eighteen patients with mandibular fractures at the tooth bearing area participated in this prospective study. They were treated by closed reduction using maxillo-mandibular fixation (MMF) and were consecutively assigned into 1 of 3 groups. In group A, the fracture sites were exposed to PEMF for 2 h daily for 12 days. In group B, the fracture sites were exposed to LILI on the tenth and twelfth postoperative days (2 sessions of 6 min per day 2 h apart). The fracture sites in group C acted as controls. MMF was maintained for 2 weeks in group A and 4 weeks in groups B and C. The bone fracture healing was evaluated clinically by investigating the union of the fractured segments and radiographically using computerized densitometry. The union of the fractured segments was tested by manual manipulation and the occlusion was assessed upon removal of MMF. Standardized digital panoramic radiographs were performed for each patient, immediately postoperatively as well as at 2 and 4 weeks. The digital images were manipulated using the IDRISI software. A rectangular area of 10 × 15 mm was drawn along the center of the fracture line. The obtained densitometry values were expressed in gray levels from 0 to 256. The collected data were then tabulated and statistically analyzed.

RESULTS:

After releasing the MMF, the bimanual mobility test of the fractured segments in all patients showed stability of the segments. The preinjury occlusion was maintained in all patients. The postoperative radiographs of all patients revealed good bony alignment of the bony segments. In all groups, comparison between the study intervals with respect to both means and changes percentages of the bone density values showed insignificant differences. At 2nd postoperative week, the mean bone density at the fracture sites decreased by 4.74, 6.6 and 27.89 % in groups A, B and C respectively. The period from the 2nd to the 4th postoperative weeks showed increase in the bone density by 1.49, 1.95 and 14.12 % in groups A, B and C respectively. Insignificant difference was found between the means of bone densities of group A and B throughout the study intervals. On the other hand, both groups showed insignificant difference with group C immediately postoperative and significant increase in bone density at the 2nd and 4th postoperative weeks.

CONCLUSIONS:

Short period immobilization of mandibular fractures for 2 weeks supplemented with PEMF is recommended. Further studies are needed to evaluate the efficacy of LILI as a supplement to reduce the mandibular fracture immobilization period.

Pelvic Pain – Endometriosis – UTI – Fibroids

BJU Int. 2005 Apr;95(6):838-41.

Sacral magnetic stimulation in non-inflammatory chronic pelvic pain syndrome.

Leippold T, Strebel RT, Huwyler M, John HA, Hauri D, Schmid DM.

Department of Urology, University Hospital Zurich, Switzerland.

Abstract

OBJECTIVES: To prospectively evaluate sacral magnetic high-frequency stimulation as a treatment option for patients with non-inflammatory chronic pelvic pain syndrome (CPPS, category IIIB).

PATIENTS AND METHODS: Fourteen men with CPPS IIIB were treated with high-frequency sacral magnetic stimulation, with 10 treatment sessions once a week for 30 min at a frequency of 50 Hz. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and quality-of-life index were determined before and after treatment.

RESULTS: All patients tolerated the stimulation well and 12 of 14 reported agreeable sensations during stimulation. There were no complications; only one patient did not complete the treatment course. The mean (range) total NIH-CPSI score did not change with treatment, at 27 (18-38) before and 27 (4-40) after treatment. Moreover, there was no sustained effect on the mean scores for pain, micturition complaints or quality of life.

CONCLUSIONS: High-frequency sacral magnetic stimulation in patients with CPPS IIIB only reduces pain during stimulation, with no sustained relief of symptoms. Therefore, intermittent sacral magnetic stimulation cannot be recommended as a treatment option for CPPS IIIB.

Urol Nefrol (Mosk). 1996 Sep-Oct;(5):10-4.

Magnetic-laser therapy in inflammatory and posttraumatic lesions of the urinary system.

[Article in Russian]

Loran OB, Kaprin AD, Gazimagomedov GA.

The authors discuss disputable problem of renal and ureteral tissue after trauma or inflammation. These cause irreversible morphological changes in the tissue. Poor results of the standard therapy urged the authors to try magnetic-laser therapy in urological clinic. The technique has been developed on experimental animal models. The resultant morphological characteristics of ureteral wall and parenchyma support the validity of magnetic-laser therapy in urological practice.

Vopr Kurortol Fizioter Lech Fiz Kult. 1996 Sep-Oct;(5):22-5.

The effect of a low-frequency magnetic field on the clinico-immunological indices of patients with chronic inflammatory diseases of the organs of the female genital system.

[Article in Russian]

Markina LP, Iarustovskaia OV, Alisultanova LS, Derevnina NA, Gontar’ EV.

Low-frequency magnetic field generated by the vaginal inductor used in 120 females with chronic genital inflammation promoted a decrease in leukocytosis, elevation of total population of T-lymphocytes, inhibition of high proliferative activity in PHA test. However, marked immunocorrection was not reached.

Clin Exp Obstet Gynecol. 1995;22(4):350-4.

Analgesic properties of electromagnetic field therapy in patients with chronic pelvic pain.

Varcaccio-Garofalo G, Carriero C, Loizzo MR, Amoruso S, Loizzi P.

Institute of Obstetrics and Gynecology II Clinic, University of Bari, Italy.

Abstract

AIM: Demonstration of analgesic effects of electromagnetic field treatment in cases of chronic refractory pelvic pain.

STUDY DESIGN: Prospective non-controlled trial, 64 women complaining about pelvic pain of at least 6 months duration, resistant to standard therapies, submitted to electromagnetic field applications on both iliac regions by Thelf Systems apparatus by two applications daily lasting 2 hours each for 20-40 days. Control visit after 3 months.

RESULTS: Complete subsidence of pain in 39 cases (61%), in 15 patients (23%) relief during treatment, then mild endopelvic tension after a 3-month control; in 10 cases (16%) symptoms reduced only during application hours, unchanged at follow-up. Outcome of treatment appears to be independent of pre-existent psychosocial variables.

CONCLUSION: Magnetic therapy shows a real analgesic effect on pelvic pain, and seems to contribute to resolution of complex interactions between somatic nociceptive stimuli and psychosocial implications affecting pain perception in these patients.

Paroxysmal Dyskinesia

Pediatr Neurol. 2005 Apr;32(4):229-35.

Channelopathy: hypothesis of a common pathophysiologic mechanism in different forms of paroxysmal dyskinesia.

Margari L, Presicci A, Ventura P, Margari F, Perniola T.

Child Neuropsychiatric Service, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.

Paroxysmal dyskinesias are a rare heterogeneous group of neurologic disorders, characterized by transient sudden choreoathetoid or dystonic attacks without loss of consciousness. This study reports a family with six affected members in three generations, and two sporadic cases of paroxysmal dyskinesia. Familial cases of paroxysmal dyskinesia are affected by idiopathic long-lasting paroxysmal exertion-induced dyskinesia and the sporadic cases by idiopathic short-lasting paroxysmal kinesigenic dyskinesia. Familial cases also suffer from epilepsy, mainly of generalized type, with benign outcome; one sporadic case is affected by migraine. Results presented in this neurophysiologic study include electromyography, somatosensory evoked potentials by median nerve stimulation, somatosensory evoked potentials by posterior tibial nerve stimulation, motor evoked potentials by magnetic transcranial cortical stimulation, visual evoked potentials, brainstem auditory evoked potentials, blink reflex, reflex H, and electroencephalography. The clinical and neurophysiologic findings presented here suggest a condition of hyperexcitability at the muscular and brain level, perhaps as a result of an ion channel disorder, which is in agreement with reports in the literature.

Parkinson’s Disease

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Neural Regen Res. 2016 Dec; 11(12): 1888–1895. doi:  10.4103/1673-5374.195277 PMCID: PMC5270416

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

Fabio Guerriero, M.D., Ph.D.1,2,* and Giovanni Ricevuti1,21Department of Internal Medicine and Medical Therapy, Section of Geriatrics, University of Pavia, Pavia, Italy 2Azienda di Servizi alla Persona, Istituto di Cura Santa Margherita of Pavia, Pavia, Italy *Correspondence to: Fabio Guerriero, ti.aivapidatisrevinu@10oreirreug.oibaf.

Author contributions: All authors contributed to developing the concepts, designing the structure, and writing/revising the manuscript, and approved the final version before submission and agree to be accountable. Author information ? Article notes ? Copyright and License information ? Accepted 2016 Nov 25. Copyright : © Neural Regeneration Research This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs) stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer’s disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.Keywords: electromagnetic fields, Alzheimer’s disease, transcranial magnetic stimulation, autoimmunity, immunomodulation

Introduction

The etiology of neurodegenerative diseases is multifactorial. Genetic polymorphisms, increasing age and environmental cues are recognized to be primary risk factors. Although different neuronal cell populations are affected across diverse neurodegenerative disorders, hallmark protein modifications is a common feature that supports the differential disease diagnosis and provides a mechanistic basis to gauge disease progression (Bossy-Wetzel et al., 2004).

It is becoming increasingly clear that, particularly for chronic neurodegenerative disorders occurring late in life, a complex combination of risk factors can initiate disease development and modify proteins that have a physiological function into ones with pathological roles via a number of defined mechanisms (Moreno-Gonzalez and Soto, 2011).

Amyloid-beta plaques and tau protein tangles – hallmarks of the pathology – are most likely a non-specific result of the disease process, rather than a cause (Lee et al., 2007). A large body of evidence supports the direct contribution of inflammation in the development and progression of neurodegeneration (Tweedie et al., 2007). A common denominator in the occurrence of different pathogenic mechanisms is oxidative stress accompanied by redox dysregulation, which have a role in mitochondrial dysfunction, toxicity, missignalling by calcium, glial cell dysfunction and neuroinflammation itself. Each of these can influence one another at multiple different levels, and hence oxidative stress can both be secondary to them as well as have a primary part in their initiation (von Bernhardi and Eugenin, 2012).

In the last years, evidence are remarkably revealing that Alzheimer’s disease (AD) has an autoimmune component (D’Andrea, 2005). In older patients the presence of anti-neuronal autoantibodies in the serum frequently occurs; if blood-brain barrier (BBB) dysfunction comes up, these autoantibodies are able to reach their targets and determine deleterious effect (D’Andrea, 2003). In fact, a profound change in BBB permeability has been observed in AD. In these patients amyloid deposits have been observed in microvessels and this overload is associated with degenerating endothelium (decreased mitochondrial content, increased pinocytotic vesicles), damaged smooth muscle cells and pericytes, and basement membrane changes (focal necrosis, reduplication, increased collagen content, disintegrating) (Thomas et al., 1996; Wardlaw et al., 2003). All these components strengthen the possibility that the ‘major pathological role of amyloid in AD may be to inflict vascular damage’ and hence, impair BBB function (Franzblau et al., 2013; Attems and Jellinger, 2014).

Immunoglobulins (IGs) have been detected in serum, cerebrospinal fluid and amyloid plaques of patients with AD. IGs are associated with vessel-associated amyloid, which has been linked to a faulty BBB (Franzblau et al., 2013). As a consequence, the presence of neuronal autoantibodies associated with a BBB dysfunction seems to be a relevant part of AD neuropathology (Attems and Jellinger, 2014).

Additional data about relationship between autoimmune diseases (e.g., thyroid dysfunction, diabetes) and AD has been proven. In fact, patients with AD have a significant increase in the values of anti-thyroglobulin and anti-microsomial autoantibodies compared to healthy controls (Genovesi et al., 1996).

Moreover, typical features of autoimmunity have been associated with both AD and diabetes (e.g., high levels of advanced glycation end products and their receptor have been detected in tissues and in the circulation in both disease) (Mruthinti et al., 2006).

In summary, these data in the context of the underlying mechanisms of many autoimmune diseases indicated that AD has proven autoimmune mechanisms, which provide a link between vascular pathology (altered BBB function) and neuronal cell death. Furthermore, according to these data, BBB dysfunction precedes neuronal degeneration and dementia (Rhodin and Thomas, 2001).

Electromagnetic Brain Stimulation and Immunomodulation in Neurodegenerative Diseases

Over the past decades, neuroscientists and clinicians have been exploring the properties of the brain’s electromagnetic activity for both diagnostic and therapeutic purposes. In the 1990s, research on electromagnetic radiation was motivated by the need to better understand the potential harmful effects of environmental magnetic fields (Bennett, 1995; Bracken and Patterson, 1996); actually, it is becoming increasingly clear that interactions between magnetic fields and biological systems deserve to be studied in their own right because these interactions appear to be fundamental to life processes and could represent a therapeutic agent in several diseases.

In our opinion, one of the more striking observations related to the effects of EMFs on biological systems concerns the presence of a “window effect,” showing that biological effects occur only at particular combinations of frequency and field intensity (Panagopoulos and Margaritis, 2010). These effects have been reported especially for changes in calcium ion flux in cells and tissues. Related window effects are reports of signal-specific quantitative and qualitative response to EMFs in several different tissues (Azanza and del Moral, 1994).

ELF-EMFs interact readily with the central nervous system (CNS). While the high-frequency EMFs encountered in industry can expose workers to an increased risk of AD (Hakansson et al., 2003), amyotrophic lateral sclerosis and multiple sclerosis (MS) (Johansen, 2004), EMFs of weak and very weak intensity can exert interesting and proven therapeutic effects on the CNS (Sandyk, 1992; Sandyk and Iacono, 1994; Boggio et al., 2012). The level of radiation is typically in the range of 1 millitesla (mT) in most studies.

Transcranial magnetic brain stimulation (TMS) is a commonly-used neurostimulation and a neuromodulation technique, based on the principle of electromagnetic induction of an electrical field in the brain. This field can be of sufficient magnitude and density to depolarize neurons, and when TMS pulses are applied repetitively they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation, even beyond the duration of the train of stimulation (Fregni and Pascual-Leone, 2007; Ridding and Rothwell, 2007).

The last decade has seen a rapid increase in the applications of TMS to study cognition, neurobehavioral relations and the pathophysiology of several neurologic and psychiatric disorders. Evidence has accumulated that demonstrates that TMS provides a valuable tool for modulating brain activity in a specific, distributed, cortico-subcortical network through control and manipulation of cognition, neuromotoricity and behavior (George et al., 2007; Guerriero et al., 2015).

Since the immune system plays a primary role in the control of many diseases and tumor growth, many laboratories have investigated the influence of ELF-EMF stimulation on blood mononuclear cells, various cellular components and cellular processes; other studies have examined electromagnetic effects on specific genes expressions and signal transduction pathways, but the experimental data obtained are currently controversial (Cossarizza et al., 1993; Onodera et al., 2003).

The mechanisms by which ELF-EMFs elicit cellular responses are somewhat still unknown, and it is still unclear which cellular components mediate these fields’ effects. However, there are several hypotheses to explain EMF interaction with the living matter.

It is assumed that some type of initial interaction occurs at the level of the cell membrane and that specific signal amplification processes carry the membrane-mediated effect into the cell (Frey, 1993). Molecular studies of the membrane signaling processes have shown, for example, that the involved cells can use mechanisms such as intracellular second-messenger (e.g., Ca2+, cyclic adenosine monophosphate [cAMP], cyclic guanosine monophosphate [cGMP]) cascades, positive feedback, and linear membrane channel-gating (Grundler et al., 1992). Some of the most important calcium-related processes such as synaptic neurotransmitter and synthesis and release and levels of cAMP (Matthews and Gersdorff, 1996), essential for the functioning of the neurons that are influenced by EMFs (Rosen, 1992). In addition, amplification via calcium flux could also provide the means by which the membrane-mediated effects of EMFs could be carried into the cell (Karabakhtsian et al., 1994).

As described below, EMFs proved to exert a certain immune function modulation. Modulation of neural activity by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative and neuropsychiatric disorders reducing their severity and, possibly, their onset.

Thus, in the next sections we will address the influence of ELF-EMFs on autoimmunity and immune cells, supposing that ELF-EMF may act on the basis of mechanisms centered on immunomodulation. This could have particular relevance for the treatment of neurodegenerative disorders, such as AD.

Low-frequency Electromagnetic Fields Stimulation and Autoimmunity

Regarding a possible relationship between EMF and autoimmunity, the researches conducted by Sandyk and colleagues deserve great interest. In the 1990s, Sandyk amply demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on axonal and synaptic neurotransmission (Sandyk and Iacono, 1993; Sandyk and Dann, 1995). Weekly treatment administered for years with very weak ELF-EMFs can alter the clinical course of chronic progressive MS, arresting progression of the disease for as long as four years (Sandyk, 1995a, 1997). This observation prompts the hypothesis that, in addition to effects on axonal and synaptic neurotransmission, effects may also be exerted on the autoimmune mechanisms responsible for demyelination.

Other proposals that to use pulsed ELF-EMFs of a few mT aims to modify the autoimmune pathology of the disease by eliciting profound membrane changes (Bistolfi, 2002) (the so-called Marinozzi effect) (Marinozzi et al., 1982) in the MS plaque cells.

While the action of ELF fields of a few pT is characterized by an improvement in neurotransmission, the use of ELF fields of a few mT aims to exert an action of local immunomodulation on the cells of the MS plaque through the induction of the Marinozzi effect. It therefore follows that the targets of ELF fields in the mT range will be the plaque cells (T-lymphocytes, macrophagic monocytes, microglia cells and dendritic cells), those cells disseminated in the seemingly normal nervous tissue (macrophages and microglia cells) (Bistolfi, 2007).

More specifically, the target should be the plasma membrane of these cells, which is almost always carpeted with microvilli and protrusions of various types. Since the plasma membrane is central to the relationships among immune cells (Lassmann et al., 2007) and since the plasma membrane itself is the elective target of ELF-EMF, a possible induction of the Marinozzi effect could slow down the activity of autoimmune cells in the plaque. It may determine an effect of local (on the brain) or regional immunomodulation (on the entire CNS) (Baureus Koch et al., 2003).

In far 1998, Richards et al. (1998) expressed the hope that electromagnetic fields might find application in the therapy of MS, both to manage symptoms and to achieve long-term effects by eliciting beneficial changes in the immune system and in nerve regeneration.

Our personal hypothesis is that – as observed in MS – similar effects could be present and relevant during EMF brain stimulation in patients with other CNS neurodegenerative disorders and be responsible for their therapeutic effect.

Low-frequency Electromagnetic Fields Stimulation and Immunomodulation

ELF-EMF effects on macrophages, nitric oxide and heat shock proteins

Macrophages are responsible for eliminating infectious agents and other cellular debris (Tintut et al., 2002). The recruitment of monocytes/macrophages to inflammatory sites and neoplastic tissues and their activation therein is crucial to the success of an immune reaction, in part because further cell migration is intimately related to leukocyte function. Resting macrophages have low levels of phagocytic activity and become fully active through the binding of pathogens or by local cytokine release. Once activated, macrophages exhibit an increased level of phagocytic activity and an increased production of reactive oxygen species (ROS) enabling the killing of microbes within phagosomes. The first step is the phagocytosis of the infectious agent, which is then transferred to the phagosome where it is killed by ROS and reactive nitrogen oxide species. The main protagonist of this process is nitric oxide (NO), which in turn induces the formation of cGMP, which in turn triggers a cascade of intracellular signaling. In the other hand, ROS also act as a signaling molecule and targets a wide range of physiological pathways. Activation of these cellular pathways also causes the secretion of inflammatory cytokines including IL-1b and TNF-alpha (Laskin and Laskin, 2001). Therefore when stimulated with bacterial toxins, NO and ROS stimulate cells to synthesize heat shock proteins (HSPs) (Polla et al., 1996).

Several studies have shown the effect of ELF-EMFs on macrophages. Kawczyk-Krupka and colleagues aimed to determine the effect of ELF-EMFs on the physiological response of phagocytes to an infectious agent. Human monocytic leukemia cell lines were cultured and 50 Hz, 1 mT EMF was applied for 4–6 hours to cells induced with Staphylococcus aureus. The growth curve of exposed bacteria was lower than the control, while field application increased NO levels. The increase was more prominent for Staphylococcus aureus-induced cells and appeared earlier than the increase in cells without field application (Kawczyk-Krupka et al., 2002). Increased cGMP levels in response to field application were closely correlated with increased NO levels (Azanza and del Moral, 1994).

Another study on mouse macrophages after short-term (45 minutes) exposure to 50 Hz EMF at 1.0 mT showed a significant uptake of carboxylated latex beads in macrophages, suggesting EMFs stimulate the phagocytic activity of their macrophages (Frahm et al., 2006). Tetradecanoylphorbol acetate (TPA) was used as positive control to prove the activating capacity of cells, as TPA is known to activate the protein kinase C and induce cellular processes including pinocytosis and phagocytosis (Laskin et al., 1980). On the basis of these data, ELF-EMF seems to potentially play a role in decreasing the growth rate of bacteria and other pathogens eliminated by phagocytosis.

A significant increase of free radical production has been observed after exposure to 50 Hz electromagnetic fields at a flux density of 1 mT to mouse macrophages (Aktan, 2004). To elucidate whether NADPH- or NADH-oxidase functions are influenced by EMF interaction, the flavoprotein inhibitor diphenyleneiodonium chloride (DPI) was used. EMF-induced free radical production was not inhibited by DPI, whereas TPA-induced free radical production was diminished by approximately 70%. Since DPI lacks an inhibitory effect in EMF-exposed cells, 50 Hz EMF stimulates the NADH-oxidase pathway to produce superoxide anion radicals, but not the NADPH pathway. Furthermore, the oscillation in superoxide anion radical release in mouse macrophages suggests a cyclic pattern of NADH-oxidase activity (Rollwitz et al., 2004).

An important aspect of these phagocytic cells is that they produce high levels of free radicals in response to infection, and the effect of ELF-EMF on free radicals has been widely proposed as a probable direct mechanism for the action of ELF-EMF on the living systems (Simko and Mattsson, 2004).

NO, a free radical, is an intra-cellular and inter-cellular signaling molecule and it constitutes an important host defense effector for the phagocytic cells of the immune system. It is synthesized by NO synthase, which has two major types: “constitutive” and “inducible”. Inducible nitric oxide synthase (iNOS) is particularly expressed in macrophages and other phagocytic cells that are stimulated during an immune response to infection (Aktan, 2004). Although high concentration of NO can be beneficial as an antibacterial and antitumor agent, an excess of NO can be fatal and can lead to cell injury. For example the excessive activity of iNOS has detrimental effects on oligodendrocytes, cells responsible for the myelination of neuron in the CNS (Klostergaard et al., 1991). The roles of NO in the pathophysiology of disease are still being defined, but there is a growing body of evidence that the neutralization of iNOS activity may have a therapeutic value (Parmentier et al., 1999).

Some studies have focused on the potential toxicity of the ensuing high-output NO-synthesis serving as a mean to eliminate pathogens or tumor cells, but the expression of iNOS, contributes to local tissue destruction during chronic inflammation. NO increases the ability of monocytes to respond to chemotactic agents more effectively, and it is considered to be one of the principal effector molecules involved in macrophage-mediated cytotoxicity (Desai et al., 2003).

It has been observed that exposure to ELF-EMFs modifies both NOS and MCP-1 chemokine expression and that these modifications are related to each other and are furthermore mediated by increased NF-?B protein expression (Goodman et al., 1994). EMF represents a non-pharmacological inhibitor of NO and an inducer of MCP-1, the latter of which activates one of these molecules and leads to inhibition of the former and vice versa, establishing a mechanism that protects cells from excess stimulation and contributes to the regulation of cellular homeostasis (Biswas et al., 2001). Moreover in vitro study observed a slight decrease was observed in iNOS levels was observed in cells induced with Staphlococcus aureus after ELF-EMF stimulation (Azanza and del Moral, 1994).

HSPs are evolutionarily conserved proteins known to play a key role in cellular defense against the effect of stressors and their function in modulating apoptosis has been well assessed (Beere, 2004). Concerning the relationship between EMF stimulus and HSPs expressions, Goodman et al. (1994) first demonstrated that HSP expression was enhanced by exposure to electromagnetic fields. Tokalov and Gutzeit (2004) showed the effect of ELF-EMF on heat shock genes and demonstrated that even a low dose of ELF-EMF (10 mT) caused an increase in HSPs, especially hsp70, implying that the cell senses ELF-EMF as a physical stressor.

ELF-EMF stimulation and oxidative stress

Oxidative stress derives from two primary sources: 1) chronic ROS creation that is generated from the mitochondrial electron transport chain during normal cellular function; 2) high levels of acute ROS generation resulting from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, particularly associated with the activation of the CNS immune system (Barja, 1998). In both circumstances, oxidative stress comes up when an imbalance between ROS production and clearance of radical species occurs.

ROS have been implicated as second messengers that activate protein kinase cascades, although the means by which ROS regulate signal transduction remains unclear. ROS release and cytokine production, such as IL-1?, are common cell activation markers in immune relevant cells. ROS is involved in the activation of IL-1? signal transduction pathway (Li and Engelhardt, 2006). To neutralize the detrimental effects of ROS, cells have evolved a hierarchy of sophisticated antioxidant response mechanisms regulated by NF-E2-related factor 2 (Nrf2) transcription factor (Tasset et al., 2010).

Environmental factors including EMFs, stressors or diseases that augment the former or lower the latter can amplify and drive the process. Thus, in practical terms, oxidative stress is determined by excessive exposure to oxidant molecules when there is insufficient availability of antioxidant mechanisms, with the resulting free ROS oxidizing vulnerable cellular constituents, including proteins, nucleic acids and lipids, inducing microglial activation, inducing pro-inflammatory and suppressing anti-inflammatory cytokines and related signaling pathways and ultimately causing both synaptic and neuronal damage and dysfunction (Bonda et al., 2010). Whereas most environmental electromagnetic radiations cause oxidative stress in the brain (Sahin and Gumuslu, 2007), ELF-EMF seems to have an antioxidant and neuroprotective effect (Medina and Tunez, 2010).

As shown by Tunez et al. (2006), ELF-EMF induces the antioxidant pathway Nrf2, which is closely associated with its protective effect against neurotoxicity induced by 3-nitropropionic acid (3-NP) (Tunez et al., 2006). This effect may be due to the induction of Nrf2, increasing its concentration in the nucleus as a result, at least in part, on its translocation from the cytoplasm to the nucleus. These changes in antioxidant systems were associated with a reduction of cell and oxidative damage biomarkers. In fact given that Nrf2 regulates the expression of antioxidant protein systems, its decrease may plausibly be related to a reduction in antioxidant system levels. Thus, the depletion of Nrf2 showed that 3-NP induced a significant decrease in antioxidant enzyme activity in the striatum and an intense depletion of glutathione levels. This was accompanied by clear and intense oxidative damage characterized by lipid and protein oxidation, an increase in cell death and damage markers and neuronal loss. Thus, the reduction in Nrf2 in both cytoplasm and nucleus may have been due to significant cell loss induced by 3-NP (Tunez et al., 2006).

Animal studies have demonstrated that ELF-EMF exposure, in the form of TMS (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, can be neuroprotective (Tunez et al., 2006; Tasset et al., 2012). Administered prior to and after a toxic insult to the brain, for example in the systemic injection of 3-nitropropionic acid to induce an animal model of Huntington’s disease (Tunez and Santamaria, 2009), ELF-EMF can mitigate oxidative damage, elevate neurotrophic protein levels in brain and potentially augment neurogenesis (Arias-Carrion et al., 2004).

EMF 1.0 mT exposure of mouse macrophages showed a significant increase in extracellular IL-1b release after only 4 hours of exposure, which was continuously increased after 12–24 hours of exposure. This data suggests that EMF stimulation is able to increase cytokines in murine macrophages. Cossarizza and colleagues described the increased release of IL-2, IL-1, and IL-6 in peritoneal lymphocytes after long-term exposure to ELF-EMF (Cossarizza et al., 1989). On the other hand, investigation on cytokine production by Pessina et al. showed no effects after EMF on peritoneal blood cells (Pessina and Aldinucci, 1998).

Beyond these results, such studies reiterate the importance that the cellular effects of ELF-EMFs depend, in a large part, on their intensity and exposure time, as well as on the phenotype of the cellular target and interactions with intracellular structures. The level and timing of exposure can potentially be scheduled to optimize endogenous compensatory mechanisms following an adverse reaction.

ELF-EMF effects on pro-inflammatory chemokines

Chemokines are produced by a variety of cells including monocytes, T lymphocytes, neutrophils, fibroblasts, endothelial cells and epithelial cells (Murdoch and Finn, 2000). Chemokines play a relevant role in inflammatory events, such as trans-endothelial migration and accumulation of leucocytes at the site of damage. In addition, they modulate a number of biological responses, including enzyme secretion, cellular adhesion, cytotoxicity, T-cell activation and tissue regeneration (Zlotnik and Yoshie, 2000).

Since their discovery, chemokines have emerged as important regulators of leukocyte trafficking, and MCP-1, one of the best-studied chemokines, is known to exert multiple effects on target cells, such as increased cytosolic calcium levels, superoxide anion production, lysosomal enzyme release, production of anti-inflammatory cytokines and adhesion molecules in monocytes. MCP-1 is involved in the induction of polarized type Th2 responses and in the enhancement of IL-4 production. A possible feedback loop for Th2 activation would be the production of IL-4 and IL-13 by Th2, which stimulates MCP-1 production and leads to further recruitment of Th2 cells (Moser and Loetscher, 2001).

The fine control of inflammatory mediator levels is critical to neuronal homeostasis and health. For example, a deficiency in neuronal TGF-? signaling promotes neurodegeneration and AD, whereas augmented TGF-? can act as an anti-inflammatory cytokine and has potential neuroprotective action in AD and following other insults to the central nervous system (Ren et al., 1997).

Studies have shown the anti-inflammatory effects of ELF-EMF in vivo; for instance, Selvam used a coil system emitting a 5 Hz frequency to treat rats with rheumatoid arthritis for 90 minutes, producing significant anti-exhudative effects and resulting in the restoration of normal functional parameters (Vianale et al., 2008). This anti-inflammatory effect was reported to be partially mediated through the stabilizing action of ELF-EMF on cell membranes, reflected the restoration of intracellular Ca2+ levels in plasma lymphocytes (Selvam et al., 2007). Other investigators have suggested that ELF-EMF can interact with cells through mechanisms that involve extracellular calcium channels (Cho et al., 1999).

Moreover, incubating mononuclear cells with an iNOS inhibitor showed a significant reduction of iNOS and an increase of MCP-1 levels, and these effects are consistent with iNOS and MCP-1 level modifications observed in mononuclear cells exposed to ELF-EMF. Selective inhibition of the NF-?B signaling pathway by ELF-EMF may be involved in the decrease of chemokine production. If so, ELF-EMF exposure, interfering with many cellular processes, may be included in the plethora of stimuli that modulate NF-?B activation (including pro-inflammatory cytokines such as tumor necrosis factor-? and IL-1?, chemokines, phorbol 12-myristate 13-acetate, growth factors, lipopolysaccharide, ultraviolet irradiation, viral infection, as well as various chemical and physical stresses) (Vianale et al., 2008).

Lymphocyte activity and electrotaxis: a possible link to ELF-EMF stimulation

Recent studies have shown that cells can directionally respond to applied electric fields, in both in vitro and in vivo settings, a phenomenon called electrotaxis. However, the exact cellular mechanisms for sensing electrical signals are still not fully well understood, and it is thus far unknown how cells recognize and respond to electric fields, although some studies have suggested that electro-migration of some cell surface receptors and ion channels in cells could be involved (Cortese et al., 2014). Directed cell migration is essential to numerous physiological processes including immune responses, wound healing, cancer metastasis and neuron guidance (Kubes, 2002). Normal blood lymphocytes and monocytes respond to a steady electric field in Transwell assays. All lymphocyte subsets, including naive and memory CD4+, CD8+ T cells and B cells migrated toward the cathode. Electrotaxisis highly directional and the uniform migration of circulating lymphocytes suggests that other leukocyte subsets (e.g., tissue memory cells) may undergo electrotaxis as well.

Lymphocytes respond to electric fields with activation of Erk-kinases and Akt, which are involved in chemo-attractant receptor signaling and in electrotactic signaling in other cells (Sotsios et al., 1999; Zhao et al., 2006). Activation of these pathways suggests that electrotaxis and chemotaxis engage common intracellular cell motility programs in responding lymphocytes. In fact, electric field exposure induces Erk1/2 and Akt activation in lymphocytes, consistent with the activation of the MAPK and PI3K signaling pathways implicated in coordinated cell motility. Furthermore, it has been proven that an applied electric field induced the electrotactic migration of endogenous lymphocytes to mouse skin (Lin et al., 2008). These data thus define electrotaxis andpotentially present an additional mechanism for the control of lymphocyte and monocyte migration.

ELF-EMFs can either inhibit or stimulate lymphocyte activity as a function not only of the exposure (Petrini et al., 1990), but also of the biological conditions to the cells are exposed, with mitogen-activated cells being more responsive than resting cells (Conti et al., 1986). To explain this ambivalence of the effects of ELF magnetic fields on the immune system, Marino and colleagues have presented the hypothesis that the biological effects of ELF magnetic fields are governed by non-linear laws, and that deterministic responses may therefore occur that are both real and inconsistent, thereby yielding two conflicting types of results (Marino et al., 2000). A particular role in the interaction of ELF-EMFs with lymphocytes seems to be played by the mobilization of intracellular Ca2+from the calciosomes and of extracellular Ca2+ through the membrane channels (Conti et al., 1985). The action of ELF-EMFs on lymphoid cells, however, can also be exerted on the functions of the plasma membrane: the duration of the ligand-receptor bond (Chiabrera et al., 1984), the clustering of membrane proteins (Bersani et al., 1997), the activity of enzymatic macro-molecules (Lindstrom et al., 2001), and the active ion pumps (Ca2+ ATPase and Na+ K+ATPase).

Conclusions

Several studies have shown that ELF-EMF exposure is able to activate primary monocytes and macrophages from different species and also in cell lines. This activation potential is comparable to the activation by certain chemicals resulting in physiologically relevant cellular responses.

In the past, several findings have demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on synaptic neurotransmission and autoimmunity (by determining cell membrane changes in plaques).

Moreover, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of numerous immunological reactions, such as increased ROS formation, in an enhanced phagocytic activity, and in an increased IL-1? release. Therefore, we can deduce that EMFs activate physiological functions of immune cells. However, the underlying mechanisms of interaction between EMF and immune system are still to be completely understood and need further studies at the molecular level.

Animal studies have demonstrated that ELF-EMF exposure, in the form of transcranial magnetic stimulation (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, has been seen to be neuroprotective (Sahin and Gumuslu, 2007; Medina and Tunez, 2010).

The effects of low flux density magnetic fields are exerted on altered functional states, in the sense of hyper- or hypo-function, rather than on normal functional states. The neurophysiological interpretation is that neurotransmission is favored at various sites: partially synapses, the cerebellum, and interhemisphere transcallosal connections, an idea which is strongly supported by the rapid regression seen in certain symptoms in patients with MS (Sandyk, 1995b). Based on all these evidences such effect could be attributed to the correction of perturbations of synaptic conductivity and immunomodulation (Bistolfi, 2007), resulting in clinical therapeutic effect as observed in neurodegenerative disorders such as AD (Mruthinti et al., 2006; Attems and Jellinger, 2014).

However, so far there is still no general agreement on the exact biological effect elicited by EMFs on the physical mechanisms that may be behind their interaction with biological systems. Of course the biological effects of EMFs are dependent on frequency, amplitude, timing and length of exposure, but are also related to intrinsic susceptibility and responsiveness of different cell types (Tenuzzo et al., 2006). Level and timing of exposure can be potentially scheduled to optimize endogenous compensatory mechanisms following an adverse challenge.

In the light of results reviewed here, we conclude that there is growing evidence of the potential role of EMFs in biological modulation of autoimmunity, immune functions and oxidative stress. As a consequence, the hypothesis that ELF-EMFs explicit their therapeutic effect through modulation of immune relevant cells is of clear interest, in particular in neurodegenerative diseases.

It is notable to underline that the effects of ELF-EMFs are not unique as they depend on their intensity, exposure time and cellular targets; further efforts towards more scheduled and well defined level and timing of exposure should be warranted.

Hence, it is necessary to proceed with substantial research on this issue, paying particular attention to the choice of the appropriate biological model and controlled experimental conditions.

Footnotes

Conflicts of interest: The authors report no conflicts of interest in this work. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

  • Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci. 2004;75:639–653. [PubMed]
  • Arias-Carrion O, Verdugo-Diaz L, Feria-Velasco A, Millan-Aldaco D, Gutierrez AA, Hernandez-Cruz A, Drucker-Colin R. Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions. J Neurosci Res. 2004;78:16–28. [PubMed]
  • Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer’s disease-lessons from pathology. BMC Med. 2014;12:206.[PMC free article] [PubMed]
  • Azanza MJ, del Moral A. Cell membrane biochemistry and neurobiological approach to biomagnetism. Prog Neurobiol. 1994;44:517–601. [PubMed]
  • Barja G. Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci. 1998;854:224–238. [PubMed]
  • Baureus Koch CL, Sommarin M, Persson BR, Salford LG, Eberhardt JL. Interaction between weak low frequency magnetic fields and cell membranes. Bioelectromagnetics. 2003;24:395–402. [PubMed]
  • Beere HM. “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci. 2004;117:2641–2651. [PubMed]
  • Bennett WR. Electromagnetic fields and power lines. Sci Am. 1995;2:68–77.
  • Bersani F, Marinelli F, Ognibene A, Matteucci A, Cecchi S, Santi S, Squarzoni S, Maraldi NM. Intramembrane protein distribution in cell cultures is affected by 50 Hz pulsed magnetic fields. Bioelectromagnetics. 1997;18:463–469. [PubMed]
  • Bistolfi F. Are microvilli and cilia sensors of electromagnetic fields? Physica Medica. 2002;XVIII:85–94.
  • Bistolfi F. Extremely low-frequency pulsed magnetic fields and multiple sclerosis: effects on neurotransmission alone or also on immunomodulation? Building a working hypothesis. Neuroradiol J. 2007;20:676–693. [PubMed]
  • Biswas SK, Sodhi A, Paul S. Regulation of nitric oxide production by murine peritoneal macrophages treated in vitro with chemokine monocyte chemoattractant protein 1. Nitric Oxide. 2001;5:566–579. [PubMed]
  • Boggio PS, Ferrucci R, Mameli F, Martins D, Martins O, Vergari M, Tadini L, Scarpini E, Fregni F, Priori A. Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimul. 2012;5:223–230. [PubMed]
  • Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA. Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology. 2010;59:290–294. [PubMed]
  • Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegeneration. Nat Med. 2004;10(Suppl):S2–9. [PubMed]
  • Bracken TD, Patterson RM. Variability and consistency of electric and magnetic field occupational exposure measurements. J Expo Anal Environ Epidemiol. 1996;6:355–374. [PubMed]
  • Chiabrera A, Grattarola M, Viviani R. Interaction between electromagnetic fields and cells: microelectrophoretic effect on ligands and surface receptors. Bioelectromagnetics. 1984;5:173–191. [PubMed]
  • Cho MR, Thatte HS, Silvia MT, Golan DE. Transmembrane calcium influx induced by ac electric fields. FASEB J. 1999;13:677–683. [PubMed]
  • Conti P, Gigante GE, Cifone MG, Alesse E, Fieschi C. Effect of electromagnetic field on two calcium dependent biological systems. J Bioelectr. 1985;4:227–236.
  • Conti P, Gigante GE, Cifone MG, Alesse E, Fieschi C, Bologna M, Angeletti PU. Mitogen dose-dependent effect of weak pulsed electromagnetic field on lymphocyte blastogenesis. FEBS Lett. 1986;199:130–134. [PubMed]
  • Cortese B, Palama IE, D’Amone S, Gigli G. Influence of electrotaxis on cell behaviour. Integr Biol. 2014;6:817–830. [PubMed]
  • Cossarizza A, Monti D, Bersani F, Paganelli R, Montagnani G, Cadossi R, Cantini M, Franceschi C. 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. 1989;248:141–144. [PubMed]
  • Cossarizza A, Angioni S, Petraglia F, Genazzani AR, Monti D, Capri M, Bersani F, Cadossi R, Franceschi C. Exposure to low frequency pulsed electromagnetic fields increases interleukin-1 and interleukin-6 production by human peripheral blood mononuclear cells. Exp Cell Res. 1993;204:385–387. [PubMed]
  • D’Andrea MR. Evidence linking neuronal cell death to autoimmunity in Alzheimer’s disease. Brain Res. 2003;982:19–30. [PubMed]
  • D’Andrea MR. Add Alzheimer’s disease to the list of autoimmune diseases. Med Hypotheses. 2005;64:458–463. [PubMed]
  • Desai A, Miller MJ, Huang X, Warren JS. Nitric oxide modulates MCP-1 expression in endothelial cells: implications for the pathogenesis of pulmonary granulomatous vasculitis. Inflammation. 2003;27:213–223.[PubMed]
  • Frahm J, Lantow M, Lupke M, Weiss DG, Simko M. Alteration in cellular functions in mouse macrophages after exposure to 50 Hz magnetic fields. J Cell Biochem. 2006;99:168–177. [PubMed]
  • Franzblau M, Gonzales-Portillo C, Gonzales-Portillo GS, Diamandis T, Borlongan MC, Tajiri N, Borlongan CV. Vascular damage: a persisting pathology common to Alzheimer’s disease and traumatic brain injury. Med Hypotheses. 2013;81:842–845. [PMC free article] [PubMed]
  • Fregni F, Pascual-Leone A. Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clini Prac Neurol. 2007;3:383–393. [PubMed]
  • Frey AH. Electromagnetic field interactions with biological systems. FASEB J. 1993;7:272–281. [PubMed]
  • Genovesi G, Paolini P, Marcellini L, Vernillo E, Salvati G, Polidori G, Ricciardi D, de Nuccio I, Re M. Relationship between autoimmune thyroid disease Rand Alzheimer’s disease. Panminerva Med. 1996;38:61–63.[PubMed]
  • George MS, Nahas Z, Borckardt JJ, Anderson B, Foust MJ, Burns C, Kose S, Short EB. Brain stimulation for the treatment of psychiatric disorders. Curr Opin Psychiat. 2007;20:250–254. discussion 247-259. [PubMed]
  • Goodman R, Blank M, Lin H, Dai R, Khorkava O, Soo L, Weisbrot D, Henderson A. Increased levels of hsp70 transcripts induced when cells are exposed to low frequency electro-magnetic fields. Bioelectrochem Bioenerg. 1994;33:115–120.
  • Grundler W, Kaiser F, Keilmann F, Walleczek J. Mechanisms of electromagnetic interaction with cellular systems. Naturwissenschaften. 1992;79:551–559. [PubMed]
  • Guerriero F, Botarelli E, Mele G, Polo L, Zoncu D, Renati P, Sgarlata C, Rollone M, Ricevuti G, Maurizi N, Francis M, Rondanelli M, Perna S, Guido D, Mannu P. An innovative intervention for the treatment of cognitive impairment-Emisymmetric bilateral stimulation improves cognitive functions in Alzheimer’s disease and mild cognitive impairment: an open-label study. Neuropsychiatr Dis Treat. 2015;11:2391–2404.[PMC free article] [PubMed]
  • Hakansson N, Gustavsson P, Johansen C, Floderus B. Neurodegenerative diseases in welders and other workers exposed to high levels of magnetic fields. Epidemiology. 2003;14:420–426. discussion 427-428. [PubMed]
  • Johansen C. Electromagnetic fields and health effects–epidemiologic studies of cancer, diseases of the central nervous system and arrhythmia-related heart disease. Scand J Work Environ Health. 2004;30(Suppl 1):1–30. [PubMed]
  • Karabakhtsian R, Broude N, Shalts N, Kochlatyi S, Goodman R, Henderson AS. Calcium is necessary in the cell response to EM fields. FEBS Lett. 1994;349:1–6. [PubMed]
  • Kawczyk-Krupka A, Sieron A, Shani J, Czuba ZP, Krol W. Biological effects of extremely low-frequency magnetic fields on stumlated macrophages J774-2 in cell culture. Electromagn Biol Med. 2002;21:141–153.
  • Klostergaard J, Leroux ME, Hung MC. Cellular models of macrophage tumoricidal effector mechanisms in vitro. Characterization of cytolytic responses to tumor necrosis factor and nitric oxide pathways in vitro. J Immunol. 1991;147:2802–2808. [PubMed]
  • Kubes P. The complexities of leukocyte recruitment. Semin Immunol. 2002;14:65–72. [PubMed]
  • Laskin DL, Laskin JD. Role of macrophages and inflammatory mediators in chemically induced toxicity. Toxicology. 2001;160:111–118. [PubMed]
  • Laskin DL, Laskin JD, Weinstein IB, Carchman RA. Modulation of phagocytosis by tumor promoters and epidermal growth factor in normal and transformed macrophages. Cancer Res. 1980;40:1028–1035.[PubMed]
  • Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210–218. [PubMed]
  • Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther. 2007;321:823–829. [PubMed]
  • Li Q, Engelhardt JF. Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase. J Biol Chem. 2006;281:1495–1505. [PubMed]
  • Lin F, Baldessari F, Gyenge CC, Sato T, Chambers RD, Santiago JG, Butcher EC. Lymphocyte electrotaxis in vitro and in vivo. J Immunol. 2008;181:2465–2471. [PMC free article] [PubMed]
  • Lindstrom E, Still M, Mattsson MO, Mild KH, Luben RA. ELF magnetic fields initiate protein tyrosine phosphorylation of the T cell receptor complex. Bioelectrochemistry (Amsterdam, Netherlands) 2001;53:73–78.[PubMed]
  • Marino AA, Wolcott RM, Chervenak R, Jourd’Heuil F, Nilsen E, Frilot C., 2nd Nonlinear response of the immune system to power-frequency magnetic fields. Am J Physiol Regul Integr Comp Physiol. 2000;279:R761–768. [PubMed]
  • Marinozzi G, Benedetto A, Brandimarte B, Ripani M, Carpano S, Camporiondo MP. Effetti dei campi magnetici pulsanti su colture cellulari. Giorn Ital Oncol. 1982;2:87–100.
  • Matthews G, Gersdorff H. Calcium dependence of neurotransmitter release. Semin Neurosci. 1996;8:329–334.
  • Medina FJ, Tunez I. Huntington’s disease: the value of transcranial meganetic stimulation. Curr Med Chem. 2010;17:2482–2491. [PubMed]
  • Moreno-Gonzalez I, Soto C. Misfolded protein aggregates: mechanisms, structures and potential for disease transmission. Semin Cell Dev Biol. 2011;22:482–487. [PMC free article] [PubMed]
  • Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol. 2001;2:123–128. [PubMed]
  • Mruthinti S, Schade RF, Harrell DU, Gulati NK, Swamy-Mruthinti S, Lee GP, Buccafusco JJ. Autoimmunity in Alzheimer’s disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes. Curr Alzheimer Res. 2006;3:229–235. [PubMed]
  • Murdoch C, Finn A. Chemokine receptors and their role in inflammation and infectious diseases. Blood. 2000;95:3032–3043. [PubMed]
  • Onodera H, Jin Z, Chida S, Suzuki Y, Tago H, Itoyama Y. Effects of 10-T static magnetic field on human peripheral blood immune cells. Radiat Res. 2003;159:775–779. [PubMed]
  • Panagopoulos DJ, Margaritis LH. The identification of an intensity ‘window’ on the bioeffects of mobile telephony radiation. Int J Radiat Biol. 2010;86:358–366. [PubMed]
  • Parmentier S, Bohme GA, Lerouet D, Damour D, Stutzmann JM, Margaill I, Plotkine M. Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. Br J Pharmacol. 1999;127:546–552.[PMC free article] [PubMed]
  • Pessina GP, Aldinucci C. Pulsed electromagnetic fields enhance the induction of cytokines by peripheral blood mononuclear cells challenged with phytohemagglutinin. Bioelectromagnetics. 1998;19:445–451.[PubMed]
  • Petrini M, Polidori R, Ambrogi F. Effects of different low-frequency electro-magnetic fields on lymphocyte activation: at which cellular level? J Bioelectr. 1990;9:159–166.
  • Polla BS, Kantengwa S, Francois D, Salvioli S, Franceschi C, Marsac C, Cossarizza A. Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. Proc Natl Acad Sci U S A. 1996;93:6458–6463. [PMC free article] [PubMed]
  • Ren RF, Hawver DB, Kim RS, Flanders KC. Transforming growth factor-beta protects human hNT cells from degeneration induced by beta-amyloid peptide: involvement of the TGF-beta type II receptor. Brain Res Mol Brain Res. 1997;48:315–322. [PubMed]
  • Rhodin JA, Thomas T. A vascular connection to Alzheimer’s disease. Microcirculation. 2001;8:207–220. [PubMed]
  • Richards TL, Lappin MS, Lawrie FW, Stegbauer KC. Bioelectromagnetic applications for multiple sclerosis. Phys Med Rehabil Clin N Am. 1998;9:659–674. [PubMed]
  • Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nat Rev Neurosci. 2007;8:559–567.[PubMed]
  • Rollwitz J, Lupke M, Simko M. Fifty-hertz magnetic fields induce free radical formation in mouse bone marrow-derived promonocytes and macrophages. Biochim Biophys Acta. 2004;1674:231–238. [PubMed]
  • Rosen AD. Magnetic field influence on acetylcholine release at the neuromuscular junction. Am J Physiol. 1992;262:C1418–1422. [PubMed]
  • Sahin E, Gumuslu S. Immobilization stress in rat tissues: alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comp Biochem Physiol C Toxicol Pharmacol. 2007;144:342–347.[PubMed]
  • Sandyk R. Successful treatment of multiple sclerosis with magnetic fields. Int J Neurosci. 1992;66:237–250. [PubMed]
  • Sandyk R. Long term beneficial effects of weak electromagnetic fields in multiple sclerosis. Int J Neurosci. 1995a;83:45–57. [PubMed]
  • Sandyk R. Chronic relapsing multiple sclerosis: a case of rapid recovery by application of weak electromagnetic fields. Int J Neurosci. 1995b;82:223–242. [PubMed]
  • Sandyk R. Treatment with electromagnetic fields reverses the long-term clinical course of a patient with chronic progressive multiple sclerosis. Int J Neurosci. 1997;90:177–185. [PubMed]
  • Sandyk R, Iacono RP. Resolution of longstanding symptoms of multiple sclerosis by application of picoTesla range magnetic fields. Int J Neurosci. 1993;70:255–269. [PubMed]
  • Sandyk R, Iacono RP. Multiple sclerosis: improvement of visuoperceptive functions by picoTesla range magnetic fields. Int J Neurosci. 1994;74:177–189. [PubMed]
  • Sandyk R, Dann LC. Resolution of Lhermitte’s sign in multiple sclerosis by treatment with weak electromagnetic fields. Int J Neurosci. 1995;81:215–224. [PubMed]
  • Selvam R, Ganesan K, Narayana Raju KV, Gangadharan AC, Manohar BM, Puvanakrishnan R. Low frequency and low intensity pulsed electromagnetic field exerts its antiinflammatory effect through restoration of plasma membrane calcium ATPase activity. Life Sci. 2007;80:2403–2410. [PubMed]
  • Simko M, Mattsson MO. Extremely low frequency electromagnetic fields as effectors of cellular responses in vitro: possible immune cell activation. J Cell Biochem. 2004;93:83–92. [PubMed]
  • Sotsios Y, Whittaker GC, Westwick J, Ward SG. The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes. J Immunol. 1999;163:5954–5963. [PubMed]
  • Tasset I, Medina FJ, Jimena I, Aguera E, Gascon F, Feijoo M, Sanchez-Lopez F, Luque E, Pena J, Drucker-Colin R, Tunez I. Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington’s disease rat model: effects on neurotrophic factors and neuronal density. Neuroscience. 2012;209:54–63. [PubMed]
  • Tasset I, Perez-De La Cruz V, Elinos-Calderon D, Carrillo-Mora P, Gonzalez-Herrera IG, Luna-Lopez A, Konigsberg M, Pedraza-Chaverri J, Maldonado PD, Ali SF, Tunez I, Santamaria A. Protective effect of tert-butylhydroquinone on the quinolinic-acid-induced toxicity in rat striatal slices: role of the Nrf2-antioxidant response element pathway. Neurosignals. 2010;18:24–31. [PubMed]
  • Tenuzzo B, Chionna A, Panzarini E, Lanubile R, Tarantino P, Di Jeso B, Dwikat M, Dini L. Biological effects of 6 mT static magnetic fields: a comparative study in different cell types. Bioelectromagnetics. 2006;27:560–577. [PubMed]
  • Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–171. [PubMed]
  • Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL. Monocyte/macrophage regulation of vascular calcification in vitro. Circulation. 2002;105:650–655. [PubMed]
  • Tokalov SV, Gutzeit HO. Weak electromagnetic fields (50 Hz) elicit a stress response in human cells. Environ Res. 2004;94:145–151. [PubMed]
  • Tunez I, Santamaria A. Model of Huntington’s disease induced with 3-nitropropionic acid. Rev Neurol. 2009;48:430–434. [PubMed]
  • Tunez I, Drucker-Colin R, Jimena I, Medina FJ, Munoz Mdel C, Pena J, Montilla P. Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3-nitropropionic model of Huntington’s disease. J Neurochem. 2006;97:619–630. [PubMed]
  • Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007;4:378–385. [PubMed]
  • Vianale G, Reale M, Amerio P, Stefanachi M, Di Luzio S, Muraro R. Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production. Br J Dermatol. 2008;158:1189–1196. [PubMed]
  • von Bernhardi R, Eugenin J. Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal. 2012;16:974–1031. [PubMed]
  • Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806–812. [PubMed]
  • Zhao M, Song B, Pu J, Wada T, Reid B, Tai G, Wang F, Guo A, Walczysko P, Gu Y, Sasaki T, Suzuki A, Forrester JV, Bourne HR, Devreotes PN, McCaig CD, Penninger JM. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature. 2006;442:457–460. [PubMed]
  • Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–127. [PubMed]

Articles from Neural Regeneration Research are provided here courtesy of Medknow Publications Behav Brain Funct. 2015; 11: 26.  Published online 2015 Sep 7. doi: 10.1186/s12993-015-0070-z

Mechanisms and therapeutic applications of electromagnetic therapy in Parkinson’s disease.

Maria Vadalà, Annamaria Vallelunga, Lucia Palmieri, Beniamino Palmieri, Julio Cesar Morales-Medina, and Tommaso Iannitti corresponding author Department of General Surgery and Surgical Specialties, University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy
Department of Medicine and Surgery, Centre for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy
Department of Nephrology, University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy
Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
Maria Vadalà, Email: moc.liamg@aladav.yram.
Contributor Information.
corresponding authorCorresponding author. Author information   Article notes  Copyright and License information
Received 2015 Jan 5; Accepted 2015 Jul 22. Copyright © Vadalà et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abstract
Electromagnetic therapy is a non-invasive and safe approach for the management of several pathological conditions including neurodegenerative diseases. Parkinson’s disease is a neurodegenerative pathology caused by abnormal degeneration of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain resulting in damage to the basal ganglia. Electromagnetic therapy has been extensively used in the clinical setting in the form of transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, high-frequency transcranial magnetic stimulation and pulsed electromagnetic field therapy which can also be used in the domestic setting. In this review, we discuss the mechanisms and therapeutic applications of electromagnetic therapy to alleviate motor and non-motor deficits that characterize Parkinson’s disease.Keywords: Parkinson’s disease, Electromagnetic therapy, Transcranial magnetic stimulation, Repetitive transcranial magnetic stimulation, High-frequency transcranial magnetic stimulation, Pulsed electromagnetic field therapyBackground
Parkinson’s disease

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide, second only to Alzheimer’s disease (AD) [1]. PD is accompanied by the impairment of the cortico-subcortical excitation and inhibition systems, hence belonging to the involuntary movement diseases [2]. PD is caused by progressive loss of structure and function of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain with subsequent damage to the basal ganglia (BG) [3]. Cumulative evidence supports the hypothesis that PD is the result of complex interactions among genetic abnormalities, environmental toxins and mitochondrial dysfunction [4–6]. The mechanisms of neuronal degeneration characterizing PD have been studied extensively and include a complex interplay among multiple pathogenic processes including oxidative stress, protein aggregation, excitotoxicity and impaired axonal transport [7]. The increasing number of genes and proteins critical in PD is unraveling a complex network of molecular pathways involved in its etiology, suggesting that common mechanisms underlie familial and sporadic PD, the two forms of this pathology. While the sporadic form is the most common (90–95% of PD cases), only 5–10% of PD cases are familial [8, 9]. At least ten distinct loci are responsible for rare Mendelian forms of PD and mutations in five genes have been linked to familial PD [10]. PD is characterized by motor and non-motor symptoms. The main motor symptoms include bradykinesia, tremor at rest (tremor affecting the body part that is relaxed or supported against gravity and not involved in purposeful activities [11]), rigidity and postural instability [12–17]. However, motor symptoms are now considered as the “tip of the iceberg” of PD clinical manifestations. PD non-motor symptoms include cognitive decline, decrease in sleep efficiency, increased wake after sleep onset, sleep fragmentation, and vivid dreams as well as neuropsychiatric symptoms such as depression and psychosis, [18–23]. Pain syndrome and autonomic dysfunctions have also been observed in PD patients [24–26].

Neuroimaging and genes: towards a personalized medicine for Parkinson’s disease

Several research groups have begun to perform genome-wide association studies (GWAS) on data or index measures derived from brain images, with the final goal of finding new genetic variants that might account for abnormal variations in brain structure and function that increase the risk of a given disease. Numerous genes have been identified using GWAS and have been associated with PD. They include alpha-synuclein, vacuolar protein sorting-associated protein 35, human leukocyte antigen family, leucine-rich repeat kinase 2 and acid ?-glucosidase [27–29]. Neuroimaging associates individual differences in the human genome to structural and functional variations into the brain. Van der Vegt and colleagues reported structural and functional brain mapping studies that have been performed in individuals carrying a mutation in specific PD genes including PARK1, PARK2, PARK6, PARK7, PARK8, and discussed how this “neurogenetics-neuroimaging approach” provides unique means to study key PD pathophysiological aspects [30]. In addition, neuroimaging of presymptomatic (non-manifesting) mutation carriers has emerged as a valuable tool to identify mechanisms of adaptive motor reorganization at the preclinical stage that may prevent or delay PD clinical manifestation [30]. Neuroimaging may be useful to study the effectiveness of electromagnetic therapy in PD patients.

Available therapies for Parkinson’s disease

PD treatment includes the use of pharmacological agents such as the dopaminergic agent l-3,4-dihy-droxy-phenylalanine (Levodopa or l-dopa) and stereotactic brain surgery which are associated with numerous side effects [31]. For example, the on-and-off phenomenon includes profound diurnal fluctuations in the psychomotor state of PD patients treated with l-dopa [32]. Furthermore, l-dopa loses effectiveness over time and can induce motor fluctuations such as the “wearing off” effect and dyskinesia [33]. While l-dopa metabolites are neurotoxic [33], the search for alternate, non-dopaminergic therapies to overcome the l-dopa-induced side effects has positioned adenosine A2A receptor (A2AR) antagonists as a promising therapeutic option for PD treatment [34]. Despite the favorable features of A2AR antagonists, their pharmacological properties, such as poor oral bioavailability and the lack of blood–brain barrier permeability, constitute a major problem to their clinical application [35]. Furthermore, regular physiotherapy and instrumental rehabilitation that have been employed to manage PD symptoms, such as tremor, slowness and difficulty in walking, are only moderately helpful [36]. Electromagnetic therapy has also been extensively used for PD treatment and may represent a promising therapeutic option for this condition since it promotes a lasting improvement in motor and non-motor symptoms [37–41].

Electromagnetic therapy background

Electromagnetic therapy includes the use of six groups of electromagnetic fields as previously described [42, 43] and summarized below:

Static/permanent magnetic fields can be created by various permanent magnets as well as by passing direct current through a coil.
Transcranial magnetic stimulation (TMS) utilizes frequencies in the range 1–200 Hz.
Low-frequency electromagnetic fields mostly utilize 60 Hz (in the US and Canada) and 50 Hz (in Europe and Asia) frequencies in distribution lines.
Pulsed radiofrequency fields utilize frequencies in the range 12–42 MHz.
Millimeter waves refer to very high-frequency in the range 30–100 GHz.
Pulsed electromagnetic fields (PEMFs) utilize frequencies in the range 5–300 Hz with very specific shapes and amplitudes.
Electromagnetic therapy is defined as the use of time-varying electromagnetic fields of low-frequency values (3 Hz–3 kHz) that can induce a sufficiently strong current to stimulate living tissue [44]. Electromagnetic fields can penetrate all tissues including the epidermis, dermis, and subcutaneous tissue, as well as tendons, muscles and bones [45]. The amount of electromagnetic energy used and its effect on the target organ depends on the size, strength and duration of treatment [44]. Electromagnetic fields can be divided into two categories: static and time-varying. Electromagnetic therapy falls into two categories: (1) hospital use which includes TMS, repetitive transcranial magnetic stimulation (rTMS) and high-frequency TMS and (2) home use including PEMF therapy.

Aim and searching criteria

We searched Pubmed/Medline using the keywords “Parkinson’s Disease” combined with “electromagnetic therapy”, “TMS”, “rTMS”, “high-frequency TMS” or “PEMF” and we included articles published between 1971 and 2015. This article aims to review the state of the art of electromagnetic therapy for treatment of PD.

Transcranial magnetic stimulation
TMS is a safe and non-invasive method of electrical stimulation of neurons in the human cerebral cortex, modifying neuronal activity locally and at distant sites when delivered in series of pulses [46]. TMS is also a useful tool to investigate various aspects of human neurophysiology, particularly corticospinal function, in health and disease [47]. An electromagnetic field generator sends a current with a peak amplitude of about 8,000 A that lasts about 1 ms, through an induction coil placed on the scalp [48]. TMS is based on the principle of electromagnetic induction, as discovered by Faraday in 1838. The current flowing briefly in the iron coil placed over a patient’s head generates an electromagnetic field that penetrates the scalp and skull reaching the brain where it induces a secondary ionic current. The site of stimulation of the brain is the point along its length at which sufficient current passes through its membrane to cause depolarization [49]. TMS can be used to determine several parameters associated to different aspects of cortical excitability: (1) the resting motor threshold or active motor threshold which reflects membrane properties; (2) the silent period, which is a quiescent phase in the electromyogram (EMG), is partially of cortical origin and is related to the function of gamma-aminobutyric acid receptors; (3) the short intracortical inhibition and facilitation which occur when a subthreshold stimulus precedes a suprathreshold stimulus by less than 5 ms or 8–30 ms, respectively. The peak of electromagnetic field strength is related to the magnitude of the current and the number of turns of wire in the coil [50]. The electrical current is rapidly turned on and off in the coil through the discharge of electronic components called the capacitors.

Transcranial magnetic stimulation in Parkinson’s disease

TMS clinical applications were first reported by Barker and colleagues who stimulated the brain, spinal cord and peripheral nerves using TMS with low or no pain [51]. Following this work, several TMS protocols that evidenced the correlation of TMS with peripheral EMG and monitored the modulation of TMS-induced motor evoked potentials (MEPs), were described [52–54]. For example, Cantello and coworkers studied the EMG potentials evoked in the bilateral first dorsal interosseus muscle by electromagnetic stimulation of the corticomotoneuronal descending system in 10 idiopathic PD patients without tremor but with rigidity with asymmetric body involvement and 10 healthy controls [55]. The threshold to cortical stimulation measured on the rigid side of PD patients was lower than on the contralateral side or than normal values. PD patients’ MEPs on the rigid side were larger compared to controls when the cortical stimulus was at rest or during slight tonic contraction of the target muscle [55]. Several clinical trials have pointed out the therapeutic efficacy of TMS in PD patients [3, 31, 56, 57]. For example, biomagnetic measurements performed using magnetoencephalography (MEG) in 30 patients affected by idiopathic PD exposed to TMS evidenced that 60% of patients did not exhibit tremor, muscular ache or dyskinesias for at least 1 year after TMS therapy [58]. The patients’ responses to TMS included a feeling of relaxation, partial or complete disappearance of muscular ache and l-dopa-induced dyskinesias as well as rapid reversal of visuospatial impairment [58]. Additional MEG measurements in PD patients also showed abnormal brain functions including slowing of background activity (increased theta and decreased beta waves) and increased alpha band connectivity [59]. These changes may reflect abnormalities in specific networks and neurotransmitter systems, and could be useful for differential diagnosis and treatment monitoring.

Repetitive transcranial magnetic stimulation
rTMS is a non-invasive technique of brain stimulation based on electromagnetic induction [60]. rTMS has the potential to alter cortical excitability depending on the duration and mode of stimulation [61]. The electromagnetic pulse easily passes through the skull, and causes small electrical currents that stimulate nerve cells in the targeted brain region [62]. Since this type of pulse generally does not reach further than two inches into the brain, it is possible to selectively target specific brain areas [62]. Generally, the patient feels a slight knocking or tapping on the head as the pulses are administered. rTMS frequencies of around 1 Hz induce an inhibitory effect on cortical excitability [63] and stimulus rates of more than 5 Hz generate a short-term increase in cortical excitability [64]. rTMS induces a MEP of the muscles of the lower extremities by stimulating the motor and supplementary motor area (SMA) of the cerebral cortex [31].

Repetitive transcranial magnetic stimulation in Parkinson’s disease

Several studies have reported the efficacy of rTMS on PD motor symptoms [65–69]. These effects are primarily directed at surface cortical regions, since the dopaminergic deficiency in PD is localized to the subcortical BG. The BG comprises a group of interconnected deep brain nuclei, i.e. the caudate and putamen, globus pallidus, substantia nigra and the subthalamic nucleus (STN) that, through their connections with the thalamus and the cortex, primarily influence the involuntary components of movement and muscle tone [70]. Several studies have documented the long-term effects of rTMS applied to PD patients for several days, rather than single sessions [71–73]. For instance, Shimamoto and coworkers applied rTMS on a broad area including the left and right motor, premotor and SMAs in nine PD patients for a period of 2 months, and observed improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS), a rating scale used to follow PD progression [74]. A further trial in PD patients reported a shortened interruption of voluntary muscle contraction, defined cortical silent period, suggesting a disturbed inhibitory mechanism in the motor cortex [57]. PD patients show altered activation patterns in the SMA and overall less cortico-cortical excitability [75–81] that play a key role in motor selection in sequentially structured tasks, including handwriting. In a randomized controlled trial with a crossover design in PD patients, rTMS applied over the SMA influenced several key aspects of handwriting, e.g. vertical size and axial pressure, at least in the short term [82]. Ten PD patients treated with rTMS, evidenced short-term changes in functional fine motor task performance. rTMS over the SMA compensated for cortico-striatal imbalance and enhanced cortico-cortical connections. This treatment improved PD patients deficits such as reduction in speed during the writing task and decrease in letter size (micrographia).

Two mechanisms have been proposed to explain how cortically directed rTMS may improve PD symptoms: (1) rTMS induces brain network changes and positively affects the BG function; (2) rTMS directed to cortical sites compensates for PD-associated abnormal changes in cortical function [60]. Indeed, in support of the former mechanism, rTMS might modulate cortical areas, such as the prefrontal cortex and primary motor cortex, which are substantially connected to both the striatum and STN via glutamatergic projection, and thus indirectly modulate the release of dopamine in the BG [83]. Several TMS/functional imaging studies have demonstrated the effects of rTMS on BG and an increase in dopamine in the BG after rTMS applied to the frontal lobe [84].

rTMS can also transiently disrupt the function of a cortical target creating a temporary “virtual brain lesion” [85–87]. Mottaghy and coworkers have studied the ability of rTMS to produce temporary functional lesions in the BG, an area involved in working memory, and correlated these behavioral effects with changes in regional cerebral blood flow in the involved neuronal network [88]. Functional imaging and TMS studies in PD subjects have shown altered cortical physiology in areas associated to the BG such as the SMA, dorsolateral prefrontal cortex and primary motor cortex [57, 89], characterized by excessive corticospinal output at rest, concomitant to, or resulting from a reduced intracortical inhibition [60]. These altered changes in cortical function in PD patients might avoid the suppression of competing motor areas and therefore decrease the motor system performance, resulting in symptoms such as tonic contractions and rigidity [89].

rTMS has not only been applied to a motor area of the brain but has also been used to target PD non-motor deficits. For example, in a study involving six PD patients with mild cognitive impairment, a cognitive dysfunction defined by deficits in memory, rTMS was delivered over the frontal region at 1.2 times the motor threshold (minimum stimulation intensity) of the right abductor pollicis brevis muscle [3]. Over a period of 3 months, rTMS was performed for a total of 1200 stimulations. Improvement in neuropsychological tests (the trail-making test part B and the Wisconsin card-sorting test) was observed in all patients. In addition, an improvement in subjective symptoms and objective findings were also observed by the subjects, their families, and the therapists. The changes observed in PD subjects included “faster reactions”, “better body movement and smoother standing-up and movement”, “more active”, “more cheerful”, and “more expressive”. An increase in the amount of conversation, an increase in the neural mechanisms of mutual understanding within daily living and an improvement in responses to visitors were also noted, if compared to baseline. Additionally, changes such as better hand usage while eating and better sleep were also observed.

Cognitive dysfunction is often seen in PD patients with major depression and its neural basis could be the functional failure of the frontostriatal circuit [3, 90]. Ten days of rTMS in the frontal cortex can effectively alleviate PD-associated depression as shown by an open trial reporting a significant decrease in the Hamilton Depression Rating Scale (HDRS) scores [91]. A further double blind, sham stimulation-controlled, randomized study, involving 42 idiopathic PD patients affected by major or minor depression undergoing rTMS for 10 days, evidenced a mean decrease in HDRS and Beck depression inventory after therapy [92].

In opposition to the above mentioned positive reports concerning the efficacy of rTMS in PD patients, a lack of effectiveness of rTMS on objective or subjective symptoms has also been described. For example, in a study involving 85 idiopathic PD patients, no significant differences in clinical features were observed between patients receiving rTMS and sham stimulation [65]. Moreover, total and motor score of UPDRS were improved by rTMS and sham stimulation in the same manner. Despite this improvement, PD patients treated with rTMS revealed signs of depression, reporting no subjective benefits. In another randomized crossover study, 10 patients affected by idiopathic PD received rTMS to the SMA which resulted in subclinical worsening of complex and preparatory movement [93]. The rTMS protocol was not tolerated by 2 out of 10 patients. Furthermore, this study showed that, following rTMS, subtle regional disruption can persist for over 30 min, raising safety concerns. A further randomized crossover study involving 11 patients with idiopathic PD, treated with rTMS over the motor cortex, did not show any therapeutic effect on concurrent fine movement in PD [94].

In summary, conflicting findings regarding the efficacy of rTMS in PD have been reported and they can be explained by differences in stimulation parameters, including intensity, frequency, total number of pulses, stimulation site and total number of sessions. Therefore, further studies comparing different parameters are required.High-frequency transcranial magnetic stimulation
High-frequency TMS consists of continuous high-frequency stimulation of specific brain regions, including the motor cortex, cerebellum and BG, through implanted large four-contact electrodes connected to a pulse generator and positioned into the center of the target region [70]. Such stimulation induces an electrical field that spreads and depolarizes neighboring membranes of cell bodies, afferent and efferent axons, depending on neuronal element orientation and position in the field and on stimulation parameters [95]. Optimal clinical results are obtained by using pulses of 60–200 ms duration and 1–5 V amplitude, delivered in the STN at 120–180 Hz [96]. For example, high-frequency TMS produces a transient blockade of spontaneous STN activity, defined HFS-induced silence. During HFS-induced silence, the persistent Na+ current is totally blocked and the Ca2+-mediated responses are strongly reduced, suggesting that T- and L-type Ca2+ currents are transiently depressed by high-frequency TMS [97].Indeed, recent evidence suggests that the stimulation of the motor cortex, the cerebellum and the BG not only produces inhibitory and excitatory effects on local neurons, but also influences afferent and efferent pathways. Therefore, the mechanism of action of high-frequency TMS depends on changes in neural activity generated in the stimulated, afferent and efferent nuclei of the BG and motor cortex [98].High-frequency transcranial magnetic stimulation in Parkinson’s diseaseIn the first PD patients treated with high-frequency TMS in 1993, motor symptoms, tremor, rigidity and akinesia improved significantly allowing to decrease the administration of l-dopa by a mean of 55% [99]. Since then, several thousands of patients worldwide have been fitted with high-frequency TMS implants achieving marked improvements in their symptoms, making this method the reference procedure for advanced PD [100]. The time course of improvement following high-frequency TMS treatment differs for different cardinal symptoms of PD [101]. For instance, rigidity and resting tremor decrease immediately, within a few seconds after high-frequency TMS [102]. Different clinical effects are observed in PD patients depending on the site of stimulation [103]. For example, stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve PD-associated tremor [104]. Similarly, stimulation of the STN or globus pallidus interna (GPi) can substantially reduce rigidity, tremor, and gait difficulties in patients affected by idiopathic PD [105]. Stimulation of the GPi also reduces all of the major PD motor manifestations, including the reduction of l-dopa-induced dyskinesias and involuntary movements produced by individual doses of dopaminergic medications that can limit treatment efficacy [106]. Thalamic stimulation in the region of the ventral intermediate nucleus reduces limb tremor but it has little effect on other manifestations of the disease [107]. In order to explain the beneficial effects of high-frequency TMS, two fundamental mechanisms have been proposed by Garcia and coworkers: silencing and excitation of STN neurons [95]. They reported that high-frequency TMS using stimulus parameters that yield therapeutic effects has a dual effect, i.e. it suppresses spontaneous activity and drives STN neuronal activity. High-frequency TMS switches off a pathological disrupted activity in the STN (i.e. silencing of STN neurons mechanism) and imposes a new type of discharge in the upper gamma-band frequency (60–80 Hz range) that is endowed with beneficial effects (i.e. excitation of STN neurons mechanism) [95]. This improvement generated by high-frequency TMS is due to parallel non-exclusive actions, i.e. silencing of ongoing activity and generation of an activity pattern in the gamma range [108]. There is an important advantage in silencing spontaneous activity and generating a pattern: the signal to noise ratio and the functional significance of the new signal are enhanced [109].

Techniques and preparations employed to study the mechanisms of high-frequency TMS include electrophysiological techniques, measurement of neurotransmitter release in vivo, post-mortem immunohistochemistry of a metabolic marker such as cytochrome oxidase and imaging studies in vivo [95]. Such results consistently show a post-stimulus period of reduced neuronal firing followed by the slow recovery of spontaneous activity. High-frequency TMS, at frequencies >50 Hz, applied to the STN of PD patients undergoing functional stereotactic procedures [110–112], to the STN of rats in vivo [113, 114] and rat STN slices in vitro [97, 115, 116], produces a period of neuronal silence of hundreds of milliseconds to tens of seconds. During brief high-frequency TMS in PD patients off medication and in the murine model of parkinsonism obtained by acute injections of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for 5 consecutive days, a reduced STN activity, as response to stimulation, is observed at 5–14 Hz and this response is frequency-dependent [114]. High-frequency TMS has two main advantages: (a) it reduces the time a patient spends in the “off” state because the individual dose of these profound diurnal fluctuations leaves a person slow, shaky, stiff, and unable to rise from a chair; (b) it allows the reduction of medications and their consequent side effects [117].

Pulsed electromagnetic field therapy
PEMF therapy is a non-static energy delivery system, characterized by electromagnetic fields inducing microcurrents in the target body tissues [118]. These microcurrents elicit specific biological responses depending on field parameters such as intensity, frequency and waveform [119]. The benefits of PEMF therapy have been observed in several clinical studies for treatment of several medical conditions including knee osteoarthritis [120], shoulder impingement syndrome [121], lower back pain [122, 123], multiple sclerosis [124, 125], cancer [121, 123, 125, 126], PD [127], AD [128] and reflex sympathetic dystrophy syndrome [129]. A large number of PEMF therapy devices contains user-friendly software packages with pre-recorded programs with the ability to modify programs depending on the patient’s needs [43, 130–132]. Examples of PEMF devices are the Curatron® (Amjo Corp, West Chester, PA, USA), Seqex® system (S.I.S.T.E.M.I. Srl, Trento, Italy), MRS 2000®, iMRS®, QRS® (all produced by Swiss Bionic Solutions Schweiz GmbH, Dulliken, Switzerland) and TESLA Stym (Iskra Medical, Ljubljana, Slovenia).

Pulsed electromagnetic field therapy in Parkinson’s disease

In October 2008 the Food and Drug Administration approved the use of PEMF therapy for treatment of major depressive disorder in PD patients who failed to achieve satisfactory improvement from very high dosages of antidepressant medications [133, 134]. Several studies reported PEMF therapy improved cognitive functions and motor symptoms. For example, an investigation involving three elderly PD patients with cognitive impairment assessed the effect of PEMF therapy on macrosomatognosia, a disorder of the body image in which the patient perceives a part or parts of his body as disproportionately large [135]. After receiving PEMF therapy, PD patients’ drawings showed reversal of macrosomatognosia (assessed by Draw-a-Person test) with reduction of the right parietal lobe dysfunction. Furthermore, PEMF therapy applied to a 49-year-old male PD patient with stage 3 disease, as assessed by Hoehn and Yahr scale, resulted in a marked improvement in motor and non-motor symptoms such as mood swings, sleeplessness, pain and sexual and cognitive dysfunctions, suggesting that PEMF therapy should be tested in large cohorts of PD patients as monotherapy and should also be considered as a treatment modality for de novo diagnosed PD patients [136]. PEMF therapy was also effective in improving visuospatial deficits in four PD patients, as assessed by the clock-drawing test [137]. Moreover, PEMF therapy improved PD-associated freezing (a symptom manifesting as a sudden attack of immobility usually experienced during walking) in 3 PD patients through the facilitation of serotonin neurotransmission at both junctional and non-junctional neuronal target sites [127].

Discussion
Although many studies on electromagnetic therapy included only a small number of participants, several investigations suggest that this therapy is effective in treating PD patients’ motor and non-motor symptoms. In the development of electromagnetic therapies, it is important to clarify the pathophysiological mechanisms underlying the symptoms to treat in order to determine the appropriate brain region to target. Thus, in the future, electromagnetic therapy must tend towards a more personalized approach, tailored to the specific PD patient’s symptoms. All the types of electromagnetic therapy described in this review can be used in combination with pharmacological and non-pharmacological therapies but this approach is understudied in PD patients. Therefore, specific protocols should be designed and tested in combination with other therapies in future controlled trials in patients affected by PD.

Transcranial magnetic stimulation

TMS increases the release of dopamine in the striatum and frontal cortex, which in turn improves PD symptoms including motor performance [138]. Furthermore, TMS applied in the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus as observed by positron emission tomography in healthy human subjects [89]. TMS application results in partial or complete disappearance of muscular pain and l-dopa-induced dyskinesia as well as regression of visuospatial impairment. This clinical improvement is followed by MEG improvement and normalization recorded after TMS, suggesting that TMS has an immediate and beneficial effect on corticostriatal interactions that play an important role in the pathophysiology of PD [58]. Cerasa and coworkers observed that repetitive TMS applied over the inferior frontal cortex reduced the amount of dyskinesia induced by a supramaximal single dose of levodopa in PD patients, suggesting that this area may play a key role in controlling the development of dyskinesia [139]. The mechanism underlying TMS effectiveness in PD remains an unanswered question due to the complexity of behavioral and neuroendocrine effects exerted by the TMS when applied to biological systems and their potential impact on neurotransmitter functions [140]. The effect of TMS differs depending on the stage of the disease, the age of disease onset, the amount of cerebral atrophy and genetic factors [37]. TMS has a low cost and is simple to operate and portable, opening the possibility for patients to perform at home stimulation which could be of high relevance in the elderly and in patients who are severely disabled. As far as side effects are concerned, the muscles of the scalp, jaw or face may contract or tingle during the procedure and mild headache or brief lightheadedness may occur [141, 142]. A recent large-scale study on the safety of TMS found that most side effects, such as headaches or scalp discomfort, were mild or moderate, and no seizures occurred [143]. Although evidence shows that TMS exerts complex cellular, systemic and neuroendocrine effects on biological systems impacting neurotransmitter functions [58], future controlled studies in larger cohorts of patients and with a long term follow-up are needed to further clarify the mechanisms underlying TMS efficacy in PD patients.

Repetitive transcranial magnetic stimulation

rTMS can be defined as a safe and non-invasive technique of brain stimulation which allows to specifically treat PD with low-frequency electromagnetic pulses [60]. As opposed to high-frequency TMS, which can induce convulsions in healthy subjects, rTMS does not affect the electroencephalogram pattern [71, 144]. Slow waves have been induced by rTMS over the right prefrontal area, a brain area involved in executive dysfunction that is observed in early stages of PD and is characterized by deficits in internal control of attention, set shifting, planning, inhibitory control, dual task performance, decision-making and social cognition tasks [3, 145]. rTMS applied to PD patients, enhances not only executive function, but also motor function, subjective symptoms and objective findings [3]. rTMS also increases cognitive function and other symptoms associated to the prefrontal area in PD patients [146]. In PD patients, therapeutic efficacy and long-term benefits of rTMS are obtained following multiple regular sessions rather than single sessions, but side effects associated to this therapy still warrant investigation in large controlled trials.

High-frequency magnetic stimulation

The observations that STN activity is disorganized in PD patients and that a lesion or chemical inactivation of STN neurons ameliorate motor symptoms led to the hypothesis that high-frequency TMS silences STN neurons and, by eliminating a pathological pattern, alleviates PD symptoms [147–151]. Garcia and colleagues proposed another hypothesis suggesting that high-frequency TMS suppresses not only the pathological STN activity but also imposes a new activity on STN neurons [95]. They proposed that high-frequency TMS excites the stimulated structure and evokes a regular pattern time-locked to the stimulation, overriding the pathological STN activity. As a consequence, high-frequency TMS removes the STN spontaneous activity and introduces a new and regular pattern that improves the dopamine-deficient network [95]. Elahi and coworkers found that high-frequency TMS modulates the excitability of the targeted brain regions and produces clinically significant motor improvement in PD patients [66]. This improvement is due to parallel non-exclusive actions, i.e. silencing of ongoing activity and generation of an activity pattern in the high gamma range [152]. Several clinical studies reported positive clinical results following high-frequency TMS in l-dopa-responsive forms of PD, including patients with selective brain dopaminergic lesions [153]. It remains unclear whether the mechanisms of action of high-frequency TMS and l-dopa are similar or they could be even synergic. However, high-frequency TMS improves the l-dopa-sensitive cardinal motor symptoms of PD patients with benefits similar to those given by l-dopa, though with reduced motor complications [154, 155]. The interactions with the dopaminergic system seem to be a key factor explaining the efficacy of both treatments [156]. High-frequency TMS changes dopamine lesion-induced functional alterations in the BG of PD animal models and gives an insight into the mechanisms underlying its antiparkinsonian effects [114, 157, 158]. The intrinsic capacity of the BG to generate oscillations and change rapidly from a physiological to a pathogenic pattern is crucial; the next step will be to identify how high-frequency TMS is propagated inside the BG. Disadvantages of this therapy are the high cost and limited availability of the devices to specialized medical centers, limited knowledge of potential long-term side effects and the necessity to employ highly trained personnel.

Pulsed electromagnetic fields

PEMF therapy improves PD symptoms including tremor, slowness of movement and difficulty in walking [159]. It is non-invasive, safe and improves PD patients’ quality of life [124, 160]. PEMF therapy, employed for PD treatment, supports the body’s own healing process for 4–6 h after therapy session [161–163]. It can be used at home and applied to the entire body or locally to target a specific body area and, if compared with dopaminergic systemic therapy, e.g. l-dopa, it can offer an alternative treatment avoiding systemic side effects such as hepatotoxicity and nephrotoxicity.

Conclusions
Electromagnetic therapy opens a new avenue for PD treatment. Each electromagnetic therapy technique described in this review can be applied according to a single protocol or as a combination of different protocols specifically tailored to the PD patient’s needs. Beyond the necessity to choose coil or electrode size and placement, there is a variety of parameters that have to be taken into account when designing electromagnetic therapy approaches and they include stimulation intensity, duration, frequency, pattern, electrode polarity and size. Furthermore, electromagnetic therapy can also be combined with pharmacological or non-pharmacological treatments, e.g. physical therapy and cognitive tasks, to produce additive or potentiated clinical effects. In conclusion, electromagnetic therapy represents a non-invasive, safe and promising approach that can be used alone or combined with conventional therapies for the challenging treatment of PD motor and non-motor symptoms.

Authors’ contributions
MV, AV, LP, BP, JCMM, and TI contributed equally to this review. All authors read and approved the final manuscript.

Acknowledgements

JCMM thanks CONACyT, México for membership. The authors thank Iskra Medical (Stegne 23, 1000 Ljubljana, Slovenia) for supporting the open access publication of this article.

Compliance with ethical guidelines

Competing interests The authors declare that they have no competing interests.

Contributor Information
Maria Vadalà, Email: moc.liamg@aladav.yram.

Annamaria Vallelunga, Email: moc.liamg@airamannaagnulellav.

Lucia Palmieri, Email: moc.liamg@ireimlap.aicul.

Beniamino Palmieri, Email: ti.erominu@ireimlap.

Julio Cesar Morales-Medina, Email: xm.vatsevnic@mselaromj.

Tommaso Iannitti, Email: moc.liamg@ittinnai.osammot.

References
1. Granado N, Ares-Santos S, Moratalla R. Methamphetamine and Parkinson’s disease. Parkinsons Dis. 2013;1:1–10.
2. Popa LCA, Constantinescu A, Popescu CD. Differences of cortical excitability between Parkinson’s disease patients and healthy subjects. A comparative TMS study. Romanian J Neurol. 2012;11:1.
3. Furukawa T, Izumi S, Toyokura M, Masakado Y. Effects of low-frequency repetitive transcranial magnetic stimulation in Parkinson’s disease. Tokai J Exp Clin Med. 2009;34(3):63–71. [PubMed]
4. Desplats P, Patel P, Kosberg K, Mante M, Patrick C, Rockenstein E, et al. Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson’s disease. Mol Neurodegener. 2012;7:49. doi: 10.1186/1750-1326-7-49. [PMC free article] [PubMed] [Cross Ref]
5. Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106–107:17–32. doi: 10.1016/j.pneurobio.2013.04.004. [PMC free article] [PubMed] [Cross Ref]
6. Vallelunga A, Ragusa M, Di Mauro S, Iannitti T, Pilleri M, Biundo R, et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and Multiple System Atrophy. Front Cell Neurosci. 2014;8:156. doi: 10.3389/fncel.2014.00156. [PMC free article] [PubMed] [Cross Ref]
7. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol. 2009;7(1):65–74. doi: 10.2174/157015909787602823. [PMC free article] [PubMed] [Cross Ref]
8. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39(6):889–909. doi: 10.1016/S0896-6273(03)00568-3. [PubMed] [Cross Ref]
9. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol. 2004;56:336–341. doi: 10.1002/ana.20256. [PubMed] [Cross Ref]
10. Polymeropoulos MHLC, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [PubMed] [Cross Ref]
11. Chou KL. Diagnosis and management of the patient with tremor. Med Health R I. 2004;87(5):135–138. [PubMed]
12. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39(6):889–909. doi: 10.1016/S0896-6273(03)00568-3. [PubMed] [Cross Ref]
13. McGeer PL, McGeer EG. Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord. 2004;10(1):S3–S7. doi: 10.1016/j.parkreldis.2004.01.005. [PubMed] [Cross Ref]
14. Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, et al. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med. 2008;14(5):507–509. doi: 10.1038/nm1752. [PMC free article] [PubMed] [Cross Ref]
15. Richardson PJ, Kase H, Jenner PG. Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson’s disease. Trends Pharmacol Sci. 1997;18(9):338–344. doi: 10.1016/S0165-6147(97)01096-1. [PubMed] [Cross Ref]
16. Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov. 2006;5(10):845–854. doi: 10.1038/nrd2087. [PubMed] [Cross Ref]
17. Bezard E, Gerlach I, Moratalla R, Gross CE, Jork R. 5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson’s disease. Neurobiol Dis. 2006;23(1):77–86. doi: 10.1016/j.nbd.2006.02.003. [PubMed] [Cross Ref]
18. Poryazova RG, Zachariev ZI. REM sleep behavior disorder in patients with Parkinson’s disease. Folia Med (Plovdiv) 2005;47(1):5–10. [PubMed]
19. Eisensehr I, v Lindeiner H, Jäger M, Noachtar S. REM sleep behavior disorder in sleep-disordered patients with versus without Parkinson’s disease: is there a need for polysomnography? J Neurol Sci. 2001;186(1–2):7–11. doi: 10.1016/S0022-510X(01)00480-4. [PubMed] [Cross Ref]
20. Kales A, Ansel RD, Markham CH, Scharf MB, Tan TL. Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration. Clin Pharmacol Ther. 1971;12(2):397–406. [PubMed]
21. Factor SA, McAlarney T, Sanchez-Ramos JR, Weiner WJ. Sleep disorders and sleep effect in Parkinson’s disease. Mov Disord Off J Mov Disord Soc. 1990;5(4):280–285. doi: 10.1002/mds.870050404. [PubMed] [Cross Ref]
22. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol. 1988;11(6):512–519. doi: 10.1097/00002826-198812000-00004. [PubMed] [Cross Ref]
23. Comella CL, Nardine TM, Diederich NJ, Stebbins GT. Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology. 1998;51(2):526–529. doi: 10.1212/WNL.51.2.526. [PubMed] [Cross Ref]
24. Chaudhuri KR, Healy DG, Schapira AH, FmedSci Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235–245. doi: 10.1016/S1474-4422(06)70373-8. [PubMed] [Cross Ref]
25. Lieberman A. Depression in Parkinson’s disease—a review. Acta Neurol Scand. 2006;113(1):1–8. doi: 10.1111/j.1600-0404.2006.00536.x. [PubMed] [Cross Ref]
26. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(1):14–20. doi: 10.1111/j.1468-1331.2008.02056.x. [PubMed] [Cross Ref]
27. Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol. 2013;9(8):445–454. doi: 10.1038/nrneurol.2013.132. [PubMed] [Cross Ref]
28. Lubbe S, Morris HR. Recent advances in Parkinson’s disease genetics. J Neurol. 2014;261(2):259–266. doi: 10.1007/s00415-013-7003-2. [PubMed] [Cross Ref]
29. Taymans JM, Baekelandt V. Phosphatases of alpha-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism. Front Genet. 2014;5:382. doi: 10.3389/fgene.2014.00382. [PMC free article] [PubMed] [Cross Ref]
30. van der Vegt JP, van Nuenen BF, Bloem BR, Klein C, Siebner HR. Imaging the impact of genes on Parkinson’s disease. Neuroscience. 2009;164(1):191–204. doi: 10.1016/j.neuroscience.2009.01.055. [PubMed] [Cross Ref]
31. Kimura H, Kurimura M, Kurokawa K, Nagaoka U, Arawaka S, Wada M, et al. A comprehensive study of repetitive transcranial magnetic stimulation in Parkinson’s disease. ISRN Neurol. 2011;2011:845453. doi: 10.5402/2011/845453. [PMC free article] [PubMed] [Cross Ref]
32. Lees AJ. The on-off phenomenon. J Neurol Neurosurg Psychiatry. 1989;52(1):29–37. doi: 10.1136/jnnp.52.Suppl.29. [PMC free article] [PubMed] [Cross Ref]
33. Hattoria N, Wanga M, Taka H, Fujimura T, Yoritaka A, Kubo S, et al. Toxic effects of dopamine metabolism in Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(1):S35–S38. doi: 10.1016/S1353-8020(09)70010-0. [PubMed] [Cross Ref]
34. Belcastro V, Tozzi A, Tantucci M, Costa C, Di Filippo M, Autuori A, et al. A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity. Exp Neurol. 2009;217(1):231–234. doi: 10.1016/j.expneurol.2009.01.010. [PubMed] [Cross Ref]
35. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol. 2009;8(1):67–81. doi: 10.1016/S1474-4422(08)70291-6. [PubMed] [Cross Ref]
36. Wang Z, Che PL, Du J, Ha B, Yarema KJ. Static magnetic field exposure reproduces cellular effects of the Parkinson’s disease drug candidate ZM241385. PLoS One. 2010;5(11):e13883. doi: 10.1371/journal.pone.0013883. [PMC free article] [PubMed] [Cross Ref]
37. Anderkova L, Rektorova I. Cognitive effects of repetitive transcranial magnetic stimulation in patients with neurodegenerative diseases—clinician’s perspective. J Neurol Sci. 2014;339(1–2):15–25. doi: 10.1016/j.jns.2014.01.037. [PubMed] [Cross Ref]
38. Caspar S. Invasive and non-invasive stimulation in Parkinson’s disease. Germany: Department of Clinical Neurophysiol; 2011.
39. Sandyk R. Weak magnetic fields as a novel therapeutic modality in Parkinson’s disease. Int J Neurosci. 1992;66(1–2):1–15. [PubMed]
40. Sandyk R. Treatment with weak electromagnetic fields restores dream recall in a parkinsonian patient. Int J Neurosci. 1997;90(1–2):75–86. doi: 10.3109/00207459709000627. [PubMed] [Cross Ref]
41. Vonloh M, Chen R, Kluger B. Safety of transcranial magnetic stimulation in Parkinson’s disease: a review of the literature. Parkinsonism Relat Disord. 2013;19(6):573–585. doi: 10.1016/j.parkreldis.2013.01.007. [PMC free article] [PubMed] [Cross Ref]
42. Wade B. A review of pulsed electromagnetic field (PEMF) mechanisms at a cellular level: a rationale for clinical use. Am J Health Res. 2013;1(3):51–55. doi: 10.11648/j.ajhr.20130103.13. [Cross Ref]
43. Markov MS. Expanding use of pulsed electromagnetic field therapies. Electromagn Biol Med. 2007;26(3):257–274. doi: 10.1080/15368370701580806. [PubMed] [Cross Ref]
44. Weintraub MI. Magnetotherapy: historical background with a stimulating future. Phys Rehabil Med. 2004;16(2):95–108.
45. De Loecker W, Cheng N, Delport PH. Emerging electromagnetic medicine. New York: Springer; 1990. Effects of pulsed electromagnetic fields on membrane transport; pp. 45–57.
46. Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2001;112(8):1367–1377. doi: 10.1016/S1388-2457(01)00585-5. [PubMed] [Cross Ref]
47. Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, et al. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol. 1996;101(5):412–417. doi: 10.1016/0924-980X(96)96004-X. [PubMed] [Cross Ref]
48. Edwards MJ, Talelli P, Rothwell JC. Clinical applications of transcranial magnetic stimulation in patients with movement disorders. Lancet Neurol. 2008;7(9):827–840. doi: 10.1016/S1474-4422(08)70190-X. [PubMed] [Cross Ref]
49. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2:145–156. doi: 10.1016/S1474-4422(03)00321-1. [PubMed] [Cross Ref]
50. Rudiak D, Marg E. Finding the depth of magnetic brain stimulation: a re-evaluation. Electroencephalogr Clin Neurophysiol. 1994;93(5):358–371. doi: 10.1016/0168-5597(94)90124-4. [PubMed] [Cross Ref]
51. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985;1(8437):1106–1107. doi: 10.1016/S0140-6736(85)92413-4. [PubMed] [Cross Ref]
52. Fuhr P, Agostino R, Hallett M. Spinal motor neuron excitability during the silent period after cortical stimulation. Electroencephalogr Clin Neurophysiol. 1991;81(4):257–262. doi: 10.1016/0168-5597(91)90011-L. [PubMed] [Cross Ref]
53. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol. 1993;466:521–534. [PMC free article] [PubMed]
54. Farzan F, Barr MS, Hoppenbrouwers SS, Fitzgerald PB, Chen R, Pascual-Leone A, et al. The EEG correlates of the TMS-induced EMG silent period in humans. Neuroimage. 2013;83:120–134. doi: 10.1016/j.neuroimage.2013.06.059. [PMC free article] [PubMed] [Cross Ref]
55. Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis MS, Mutani R. Parkinson’s disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology. 1991;41(9):1449–1456. doi: 10.1212/WNL.41.9.1449. [PubMed] [Cross Ref]
56. Khedr EM, Farweez HM, Islam H. Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson’s disease patients. Eur J Neurol. 2003;10(5):567–572. doi: 10.1046/j.1468-1331.2003.00649.x. [PubMed] [Cross Ref]
57. Lefaucheur JP. Motor cortex dysfunction revealed by cortical excitability studies in Parkinson’s disease: influence of antiparkinsonian treatment and cortical stimulation. Clin Neurophysiol. 2005;116(2):244–253. doi: 10.1016/j.clinph.2004.11.017. [PubMed] [Cross Ref]
58. Anninos P, Adamopoulos A, Kotini A, Tsagas N, Tamiolakis D, Prassopoulos P. MEG evaluation of Parkinson’s diseased patients after external magnetic stimulation. Acta Neurol Belg. 2007;107(1):5–10. [PubMed]
59. Stam CJ. Use of magnetoencephalography (MEG) to study functional brain networks in neurodegenerative disorders. J Neurol Sci. 2010;289(1–2):128–134. doi: 10.1016/j.jns.2009.08.028. [PubMed] [Cross Ref]
60. Fregni F, Simon DK, Wu A, Pascual-Leone A. Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. J Neurol Neurosurg Psychiatry. 2005;76(12):1614–1623. doi: 10.1136/jnnp.2005.069849. [PMC free article] [PubMed] [Cross Ref]
61. Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55(2):187–199. doi: 10.1016/j.neuron.2007.06.026. [PubMed] [Cross Ref]
62. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2006;31(11):2384–2393. doi: 10.1038/sj.npp.1301165. [PubMed] [Cross Ref]
63. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997;48(5):1398–1403. doi: 10.1212/WNL.48.5.1398. [PubMed] [Cross Ref]
64. Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain J Neurol. 1994;117(Pt 4):847–858. doi: 10.1093/brain/117.4.847. [PubMed] [Cross Ref]
65. Okabe S, Ugawa Y, Kanazawa I. 0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson’s disease. Mov Disord. 2003;18(4):382–388. doi: 10.1002/mds.10370. [PubMed] [Cross Ref]
66. Elahi B, Chen R. Effect of transcranial magnetic stimulation on Parkinson motor function—systematic review of controlled clinical trials. Mov Disord. 2009;24(3):357–363. doi: 10.1002/mds.22364. [PubMed] [Cross Ref]
67. Wang M, Ping GU, Xiao-wei MA, Yan-min LI. Effects of low frequency repetitive transcranial magnetic stimulation on motor function and affective disorder in patients with Parkinson’s disease. Chin J Geriatr. 2009;28:729–732.
68. Niu X, G Y. Observation of repetitively transcranial magnetic stimulation in the treatment of depression induced by Parkinson’s disease. Chin J Pract Nerv Dis. 2012;15:11–13.
69. Shirota Y, Ohtsu H, Hamada M, Enomoto H, Ugawa Y. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. 2013;80(15):1400–1405. doi: 10.1212/WNL.0b013e31828c2f66. [PubMed] [Cross Ref]
70. Pizzolato G, Mandat T. Deep brain stimulation for movement disorders. Mini Rev Art Front Integr Neurosci. 2012;6(2):1–5.
71. Boutros NN, Berman RM, Hoffman R, Miano AP, Campbell D, Ilmoniemi R. Electroencephalogram and repetitive transcranial magnetic stimulation. Depress Anxiety. 2000;12(3):166–169. doi: 10.1002/1520-6394(2000)12:3<166::AID-DA8>3.0.CO;2-M. [PubMed] [Cross Ref]
72. Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006;37(8):2115–2122. doi: 10.1161/01.STR.0000231390.58967.6b. [PubMed] [Cross Ref]
73. Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013;66:151–160. doi: 10.1016/j.neuroimage.2012.10.082. [PMC free article] [PubMed] [Cross Ref]
74. Shimamoto H, Takasaki K, Shigemori M, Imaizumi T, Ayabe M, Shoji H. Therapeutic effect and mechanism of repetitive transcranial magnetic stimulation in Parkinson’s disease. J Neurol. 2001;248(3):III48–III52. doi: 10.1007/PL00007826. [PubMed] [Cross Ref]
75. Eckert T, Peschel T, Heinze HJ, Rotte M. Increased pre-SMA activation in early PD patients during simple self-initiated hand movements. J Neurol. 2006;253(2):199–207. doi: 10.1007/s00415-005-0956-z. [PubMed] [Cross Ref]
76. Buhmann C, Glauche V, Stürenburg HJ, Oechsner M, Weiller C, Büchel C. Pharmacologically modulated fMRI–cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients. Brain. 2003;126(Pt 2):451–461. doi: 10.1093/brain/awg033. [PubMed] [Cross Ref]
77. Ceballos-Baumann AO, Boecker H, Bartenstein P, von Falkenhayn I, Riescher H, Conrad B, et al. A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity. Arch Neurol. 1999;56(8):997–1003. doi: 10.1001/archneur.56.8.997. [PubMed] [Cross Ref]
78. Jahanshahi M, Jenkins IN, Brown RG, Marsden CD, Passingham RE, Brooks DJ. Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson’s disease subjects. Brain. J Neurol. 1995;118(Pt 4):913–933. [PubMed]
79. Jenkins IH, Fernandez W, Playford ED, Lees AJ, Frackowiak RS, Passingham RE, et al. Impaired activation of the supplementary motor area in Parkinson’s disease is reversed when akinesia is treated with apomorphine. Ann Neurol. 1992;32(6):749–757. doi: 10.1002/ana.410320608. [PubMed] [Cross Ref]
80. Playford ED, Jenkins IH, Passingham RE, Nutt J, Frackowiak RSJ, Brooks DJ. Impaired mesial frontal and putamen activation in Parkinson’s disease: a positron emission tomography study. Ann Neurol. 1992;32(2):151–161. doi: 10.1002/ana.410320206. [PubMed] [Cross Ref]
81. Rascol O, Sabatini U, Chollet F, Fabre N, Senard JM, Montastruc JL, et al. Normal activation of the supplementary motor area in patients with Parkinson’s disease undergoing long-term treatment with levodopa. J Neurol Neurosurg Psychiatry. 1994;57(5):567–571. doi: 10.1136/jnnp.57.5.567. [PMC free article] [PubMed] [Cross Ref]
82. Randhawa BK, Farley BG, Boyd LA. Repetitive transcranial magnetic stimulation improves handwriting in Parkinson’s disease. Parkinsons Dis. 2013;2013:751925. [PMC free article] [PubMed]
83. Morari M, Marti M, Sbrenna S, Fuxe K, Bianchi C, Beani L. Reciprocal dopamine-glutamate modulation of release in the basal ganglia. Neurochem Int. 1998;33(5):383–397. doi: 10.1016/S0197-0186(98)00052-7. [PubMed] [Cross Ref]
84. Keck ME, Welt T, Müller MB, Erhardt A, Ohl F, Toschi N, et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology. 2002;43(1):101–109. doi: 10.1016/S0028-3908(02)00069-2. [PubMed] [Cross Ref]
85. Grafman J, Pascual-Leone A, Alway D, Nichelli P, Gomez-Tortosa E, Hallett M. Induction of a recall deficit by rapid-rate transcranial magnetic stimulation. Neuroreport. 1994;5(9):1157–1160. doi: 10.1097/00001756-199405000-00034. [PubMed] [Cross Ref]
86. Jahanshahi M, Profice P, Brown RG, Ridding MC, Dirnberger G, Rothwell JC. The effects of transcranial magnetic stimulation over the dorsolateral prefrontal cortex on suppression of habitual counting during random number generation. Brain. 1998;121(Pt 8):1533–1544. doi: 10.1093/brain/121.8.1533. [PubMed] [Cross Ref]
87. Pascual-Leone A, Bartres-Faz D, Keenan JP. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’ Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1229–1238. doi: 10.1098/rstb.1999.0476. [PMC free article] [PubMed] [Cross Ref]
88. Mottaghy FM, Krause BJ, Kemna LJ, Töpper R, Tellmann L, Beu M, et al. Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation. Neurosci Lett. 2000;280(3):167–170. doi: 10.1016/S0304-3940(00)00798-9. [PubMed] [Cross Ref]
89. Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci. 2001;21(15):RC157. [PubMed]
90. Gessler M, Bruns GA. A physical map around the WAGR complex on the short arm of chromosome 11. Genomics. 1989;5(1):43–55. doi: 10.1016/0888-7543(89)90084-0. [PubMed] [Cross Ref]
91. Dragasevic N, Potrebic A, Damjanovi? A, Stefanova E, Kosti? VS. Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson’s disease: an open study. Mov Disord Off J Mov Disord Soc. 2002;17(3):528–532. doi: 10.1002/mds.10109. [PubMed] [Cross Ref]
92. Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, et al. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75(8):1171–1174. doi: 10.1136/jnnp.2003.027060. [PMC free article] [PubMed] [Cross Ref]
93. Boylan LS, Pullman SL, Lisanby SH, Spicknall KE, Sackeim HA. Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson’s disease. Clin Neurophysiol. 2001;112(2):259–264. doi: 10.1016/S1388-2457(00)00519-8. [PubMed] [Cross Ref]
94. Ghabra MB, Hallett M, Wassermann EM. Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology. 1999;52(4):768–770. doi: 10.1212/WNL.52.4.768. [PubMed] [Cross Ref]
95. Garcia L, D’Alessandro G, Bioulac B, Hammond C. High-frequency stimulation in Parkinson’s disease: more or less? Trends Neurosci. 2005;28(4):209–216. doi: 10.1016/j.tins.2005.02.005. [PubMed] [Cross Ref]
96. Moro E, Esselink RJA, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology. 2002;59(5):706–713. doi: 10.1212/WNL.59.5.706. [PubMed] [Cross Ref]
97. Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol. 2001;85(4):1351–1356. [PubMed]
98. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol. 2004;21(1):40–50. doi: 10.1097/00004691-200401000-00006. [PubMed] [Cross Ref]
99. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925–1934. doi: 10.1056/NEJMoa035275. [PubMed] [Cross Ref]
100. Maltete D, Jodoin N, Karachi C, Houeto JL, Navarro S, Cornu P, et al. Subthalamic stimulation and neuronal activity in the substantia nigra in Parkinson’s disease. J Neurophysiol. 2007;97(6):4017–4022. doi: 10.1152/jn.01104.2006. [PubMed] [Cross Ref]
101. Kita H, Tachibana Y, Nambu A, Chiken S. Balance of monosynaptic excitatory and disynaptic inhibitory responses of the globus pallidus induced after stimulation of the subthalamic nucleus in the monkey. J Neurosci Off J Soc Neurosci. 2005;25(38):8611–8619. doi: 10.1523/JNEUROSCI.1719-05.2005. [PubMed] [Cross Ref]
102. Zhao XD, Cao YQ, Liu HH, Li FQ, You BM, Zhou XP. Long term high frequency stimulation of STN increases dopamine in the corpus striatum of hemiparkinsonian rhesus monkey. Brain Res. 2009;1286:230–238. doi: 10.1016/j.brainres.2009.06.069. [PubMed] [Cross Ref]
103. Putzke JD, Wharen RE, Wszolek ZK, Turk MF, Strongosky AJ, Uitti RJ. Thalamic deep brain stimulation for tremor-predominant Parkinson’s disease. Parkinsonism Relat Disord. 2003;10(2):81–88. doi: 10.1016/j.parkreldis.2003.09.002. [PubMed] [Cross Ref]
104. Dipti P, Yogesh B, Kain AK, Pauline T, Anju B, Sairam M, et al. Lead induced oxidative stress: beneficial effects of Kombucha tea. Biomed Environ Sci. 2003;16(3):276–282. [PubMed]
105. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol. 2005;62(4):554–560. doi: 10.1001/archneur.62.4.554. [PubMed] [Cross Ref]
106. Peppe A, Pierantozzi M, Altibrandi MG, Giacomini P, Stefani A, Bassi A, et al. Bilateral GPi DBS is useful to reduce abnormal involuntary movements in advanced Parkinson’s disease patients, but its action is related to modality and site of stimulation. Eur J Neurol Off J Eur Fed Neurol Soc. 2001;8(6):579–586. [PubMed]
107. Benabid AL, Pollak P, Gao D, Hofmann D, Limousin P, Gay E, et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg. 1996;84(2):203–214. doi: 10.3171/jns.1996.84.2.0203. [PubMed] [Cross Ref]
108. Brown P, Mazzone P, Oliviero A, Altibrandi MG, Pilato F, Tonali PA, et al. Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson’s disease. Exp Neurol. 2004;188(2):480–490. doi: 10.1016/j.expneurol.2004.05.009. [PubMed] [Cross Ref]
109. Hassani OK, Fèger J. Effects of intrasubthalamic injection of dopamine receptor agonists on subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an electrophysiological and c-Fos study. Neuroscience. 1999;92(2):533–543. doi: 10.1016/S0306-4522(98)00765-9. [PubMed] [Cross Ref]
110. Filali M, Hutchison WD, Palter VN, Lozano AM, Dostrovsky JO. Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus. Exp Brain Res. 2004;156(3):274–281. doi: 10.1007/s00221-003-1784-y. [PubMed] [Cross Ref]
111. Lozano AM, Dostrovsky J, Chen R, Ashby P. Deep brain stimulation for Parkinson’s disease: disrupting the disruption. Lancet Neurol. 2002;1(4):225–231. doi: 10.1016/S1474-4422(02)00101-1. [PubMed] [Cross Ref]
112. Welter ML, Houeto JL, Bonnet AM, Bejjani PB, Mesnage V, Dormont D, et al. Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients. Arch Neurol. 2004;61(1):89–96. doi: 10.1001/archneur.61.1.89. [PubMed] [Cross Ref]
113. Burbaud P, Gross C, Bioulac B. Effect of subthalamic high frequency stimulation on substantia nigra pars reticulata and globus pallidus neurons in normal rats. J Physiol Paris. 1994;88(6):359–361. doi: 10.1016/0928-4257(94)90029-9. [PubMed] [Cross Ref]
114. Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A. Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J Off Publ Fed Am Soc Exp Biol. 2003;17(13):1820–1830. [PubMed]
115. Garcia L, Audin J, D’Alessandro G, Bioulac B, Hammond C. Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci Off J Soc Neurosci. 2003;23(25):8743–8751. [PubMed]
116. Lee KH, Chang SY, Roberts DW, Kim U. Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus. J Neurosurg. 2004;101(3):511–517. doi: 10.3171/jns.2004.101.3.0511. [PubMed] [Cross Ref]
117. Jaggi JL, Umemura A, Hurtig HI, Siderowf AD, Colcher A, Stern MB, et al. Bilateral stimulation of the subthalamic nucleus in Parkinson’s disease: surgical efficacy and prediction of outcome. Stereotact Funct Neurosurg. 2004;82(2–3):104–114. doi: 10.1159/000078145. [PubMed] [Cross Ref]
118. Holden KR (2012) Biological effects of pulsed electromagnetic field (PEMF) therapy. Med News
119. Siskin BF, Walker J. Therapeutic aspects of electromagnetic fields for soft-tissue healing. In: Blank M, editor. Electromagnetic fields: biological interactions and mechanisms. Washington, DC: American Chemical Society; 1995. pp. 277–285.
120. Iannitti T, Fistetto G, Esposito A, Rottigni V, Palmieri B. Pulsed electromagnetic field therapy for management of osteoarthritis-related pain, stiffness and physical function: clinical experience in the elderly. Clin Interv Aging. 2013;8:1289–1293. doi: 10.2147/CIA.S35926. [PMC free article] [PubMed] [Cross Ref]
121. Aktas I, Akgun K, Cakmak B. Therapeutic effect of pulsed electromagnetic field in conservative treatment of subacromial impingement syndrome. Clin Rheumatol. 2007;26(8):1234–1239. doi: 10.1007/s10067-006-0464-2. [PubMed] [Cross Ref]
122. Thomas AW, Graham K, Prato FS, McKay J, Forster PM, Moulin DE, et al. A randomized, double-blind, placebo-controlled clinical trial using a low-frequency magnetic field in the treatment of musculoskeletal chronic pain. Pain Res Manage J Can Pain Soc (journal de la societe canadienne pour le traitement de la douleur) 2007;12(4):249–258. [PMC free article] [PubMed]
123. Lee PB, Kim YC, Lim YJ, Lee CJ, Choi SS, Park SH, et al. Efficacy of pulsed electromagnetic therapy for chronic lower back pain: a randomized, double-blind, placebo-controlled study. J Int Med Res. 2006;34(2):160–167. doi: 10.1177/147323000603400205. [PubMed] [Cross Ref]
124. Lappin MS, Lawrie FW, Richards TL, Kramer ED. Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial. Altern Ther Health Med. 2003;9(4):38–48. [PubMed]
125. Richards TL, Lappin MS, Acosta-Urquidi J, Kraft GH, Heide AC, Lawrie FW, et al. Double-blind study of pulsing magnetic field effects on multiple sclerosis. J Altern Complement Med. 1997;3(1):21–29. doi: 10.1089/acm.1997.3.21. [PubMed] [Cross Ref]
126. Barbault A, Costa FP, Bottger B, Munden RF, Bomholt F, Kuster N, et al. Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach. J Exp Clin Cancer Res. 2009;28:51. doi: 10.1186/1756-9966-28-51. [PMC free article] [PubMed] [Cross Ref]
127. Sandyk R. Freezing of gait in Parkinson’s disease is improved by treatment with weak electromagnetic fields. Int J Neurosci. 1996;85(1–2):111–124. doi: 10.3109/00207459608986356. [PubMed] [Cross Ref]
128. Arendash GW, Sanchez-Ramos J, Mori T, Mamcarz M, Lin X, Runfeldt M, et al. Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer’s disease mice. J Alzheimers Dis. 2010;19(1):191–210. [PubMed]
129. Ericsson AD, Hazlewood CF, Markov M, Crawford F. Biological effects of EMF’s. Greece: KOS; 2004. Specific Biochemical changes in circulating lymphocytes following acute ablation of symptoms in Reflex Sympathetic Dystrophy (RSD): a pilot study; pp. 683–688.
130. Yost MG, Liburdy RP. Time-varying and static magnetic fields act in combination to alter calcium signal transduction in the lymphocyte. FEBS Lett. 1992;296(2):117–122. doi: 10.1016/0014-5793(92)80361-J. [PubMed] [Cross Ref]
131. Edmonds DT. Larmor precession as a mechanism for the detection of static and alternating magnetic fields. Bioelectrochem Bioenerg. 1993;30:3–12. doi: 10.1016/0302-4598(93)80057-2. [Cross Ref]
132. Liboff AR, Cherng S, Jenrow KA, Bull A. Calmodulin-dependent cyclic nucleotide phosphodiesterase activity is altered by 20 microT magnetostatic fields. Bioelectromagnetics. 2003;24(1):32–38. doi: 10.1002/bem.10063. [PubMed] [Cross Ref]
133. Demitrack MA, Thase ME. Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data. Psychopharmacol Bull. 2009;42(2):5–38. [PubMed]
134. Liboff AR (2004) Signal shapes in electromagnetic therapies: a primer. In: Rosch PJ, Markov MS (eds) Bioelectromagnetic medicine. Marcel Dekker, NY, pp 17–37
135. Sandyk R. Reversal of a body image disorder (macrosomatognosia) in Parkinson’s disease by treatment with AC pulsed electromagnetic fields. Int J Neurosci. 1998;93(1–2):43–54. doi: 10.3109/00207459808986411. [PubMed] [Cross Ref]
136. Sandyk R. A drug naive parkinsonian patient successfully treated with weak electromagnetic fields. Int J Neurosci. 1994;79(1–2):99–110. [PubMed]
137. Sandyk R. Reversal of visuospatial deficit on the Clock Drawing Test in Parkinson’s disease by treatment with weak electromagnetic fields. Int J Neurosci. 1995;82(3–4):255–268. doi: 10.3109/00207459508999805. [PubMed] [Cross Ref]
138. Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. TMS induces alterations in brain monoamines. J Neural Trans. 1997;104:191–197. doi: 10.1007/BF01273180. [PubMed] [Cross Ref]
139. Cerasa A, Koch G, Donzuso G, Mangone G, Morelli M, Brusa L, et al. A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias. Brain. 2015;138(2):414–427. doi: 10.1093/brain/awu329. [PubMed] [Cross Ref]
140. Keck ME, Welt T, Post A, Müller MB, Toschi N, Wigger A, et al. Neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological animal model are suggestive of antidepressant-like effects. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2001;24(4):337–349. doi: 10.1016/S0893-133X(00)00191-3. [PubMed] [Cross Ref]
141. Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2003;60(10):1002–1008. [PubMed]
142. Loo CK, Mitchell PB, Croker VM, Malhi GS, Wen W, Gandevia SC, et al. Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med. 2003;33(1):33–40. doi: 10.1017/S0033291702006839. [PubMed] [Cross Ref]
143. Janicak PG, O’Reardon RJ, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69(2):222–232. doi: 10.4088/JCP.v69n0208. [PubMed] [Cross Ref]
144. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108(1):1–16. doi: 10.1016/S0168-5597(97)00096-8. [PubMed] [Cross Ref]
145. Dirnberger G, Jahanshahi M. Executive dysfunction in Parkinson’s disease: a review. J Neuropsychol. 2013;7(2):193–224. doi: 10.1111/jnp.12028. [PubMed] [Cross Ref]
146. Narayanan NS, Rodnitzky RL, Uc EY. Prefrontal dopamine signaling and cognitive symptoms of Parkinson’s disease. Rev Neurosci. 2013;24(3):267–278. doi: 10.1515/revneuro-2013-0004. [PMC free article] [PubMed] [Cross Ref]
147. Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord Off J Mov Disord Soc. 1991;6(4):288–292. doi: 10.1002/mds.870060404. [PubMed] [Cross Ref]
148. Benazzouz A, Gross C, Féger J, Boraud T, Bioulac B. Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci. 1993;5(4):382–389. doi: 10.1111/j.1460-9568.1993.tb00505.x. [PubMed] [Cross Ref]
149. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249(4975):1436–1438. doi: 10.1126/science.2402638. [PubMed] [Cross Ref]
150. Lang AE. Surgery for Parkinson disease: a critical evaluation of the state of the art. Arch Neurol. 2000;57(8):1118–1125. doi: 10.1001/archneur.57.8.1118. [PubMed] [Cross Ref]
151. Levy R, Lang AE, Dostrovsky JO, Pahapill P, Romas J, Saint-Cyr J, et al. Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain J Neurol. 2001;124(Pt 10):2105–2118. doi: 10.1093/brain/124.10.2105. [PubMed] [Cross Ref]
152. Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci Off J Soc Neurosci. 2003;23(5):1916–1923. [PubMed]
153. Lacombe E, Carcenac C, Boulet S, Feuerstein C, Bertrand A, Poupard A, et al. High-frequency stimulation of the subthalamic nucleus prolongs the increase in striatal dopamine induced by acute l-3,4-dihydroxyphenylalanine in dopaminergic denervated rats. Eur J Neurosci. 2007;26(6):1670–1680. doi: 10.1111/j.1460-9568.2007.05747.x. [PMC free article] [PubMed] [Cross Ref]
154. Benabid AL, Krack PP, Benazzouz A, Limousin P, Koudsie A, Pollak P. Deep brain stimulation of the subthalamic nucleus for Parkinson’s disease: methodologic aspects and clinical criteria. Neurology. 2000;12(6):S40–S44. [PubMed]
155. Welter ML, Houeto J, Tezenas du Montcel S, Mesnage V, Bonnet AM, Pillon B, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain J Neurol. 2002;125(Pt 3):575–583. doi: 10.1093/brain/awf050. [PubMed] [Cross Ref]
156. Stoffers D, Bosboom JL, Wolters E, Stam CJ, Berendse HW. Dopaminergic modulation of cortico-cortical functional connectivity in Parkinson’s disease: an MEG study. Exp Neurol. 2008;213(1):191–195. doi: 10.1016/j.expneurol.2008.05.021. [PubMed] [Cross Ref]
157. Degos B, Deniau JM, Thierry AM, Glowinski J, Pezard L, Maurice N. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J Neurosci Off J Soc Neurosci. 2005;25(33):7687–7696. doi: 10.1523/JNEUROSCI.1056-05.2005. [PubMed] [Cross Ref]
158. Salin P, Manrique C, Forni C, Kerkerian-Le Goff L. High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat. J Neurosci. 2002;22(12):5137–5148. [PubMed]
159. Poulet E, Haesebaert F, Saoud M, Suaud-Chagny MF, Brunelin J. Treatment of schizophrenic patients and rTMS. Psychiatr Danub. 2010;22(1):S143–S146. [PubMed]
160. Markov MS (2007) History of Pulsed Electro Magnetic Field Therapy. PEMF Systems Inc
161. Sklar B (2014) Announcing the iMRS from swiss bionic solutions. Relax Restore Massage
162. Sklar B (2009) MRS 2000 + the revolutionary “sawtooth” wave impulse. Relax and Restore Massage Services
163. Andras V (1999) Proof of ion transport due to application of QRS System Salut-II. Quantron Medizin GmbH zHd Dr Fischer Nußloch Brain.  2012 Oct 5. [Epub ahead of print]

Magnetic flimmers: ‘light in the electromagnetic darkness’

Martens JW, Koehler PJ, Vijselaar J.

Source

1 Department of Humanities, Utrecht University, Utrecht, The Netherlands.

Abstract

Transcranial magnetic stimulation has become an important field for both research in neuroscience and for therapy since Barker in 1985 showed that it was possible to stimulate the human motor cortex with an electromagnet. Today for instance, transcranial magnetic stimulation can be used to measure nerve conduction velocities and to create virtual lesions in the brain. The latter option creates the possibility to inactivate parts of the brain temporarily without permanent damage. In 2008, the American Food and Drugs Administration approved repetitive transcranial magnetic stimulation as a therapy for major depression under strict conditions. Repetitive transcranial magnetic stimulation has not yet been cleared for treatment of other diseases, including schizophrenia, anxiety disorders, obesity and Parkinson’s disease, but results seem promising. Transcranial magnetic stimulation, however, was not invented at the end of the 20th century. The discovery of electromagnetism, the enthusiasm for electricity and electrotherapy, and the interest in Beard’s concept of neurasthenia already resulted in the first electromagnetic treatments in the late 19th and early 20th century. In this article, we provide a history of electromagnetic stimulation circa 1900. From the data, we conclude that Mesmer’s late 18th century ideas of ‘animal magnetism’ and the 19th century absence of physiological proof had a negative influence on the acceptance of this therapy during the first decades of the 20th century. Electromagnetism disappeared from neurological textbooks in the early 20th century to recur at the end of that century.

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.

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.

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.

Rev Neurol (Paris). 2005 Jan;161(1):27-41.

Motor cortex stimulation for Parkinson’s disease and dystonia: lessons from transcranial magnetic stimulation? A review of the literature

[Article in French]

Lefaucheur JP.

Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil. jean-pascal.lefaucheur@hmn.ap-hop-paris.fr

Abstract

INTRODUCTION: Over the last few years, deep brain stimulation techniques, with targets such as the subthalamic nucleus or the pallidum, have bee found to be beneficial in the treatment of Parkinson’s disease and dystonia. Conversely, therapeutic strategies of cortical stimulation have not yet been validated in these diseases, although they are known to be associated with various cortical dysfunctions. Transcranial magnetic stimulation (TMS) is a valuable tool for non-invasive study of the role played by the motor cortex in the pathophysiology of movement disorders, in particular by assessing various cortical excitability determinants using single or paired pulse paradigms. In addition, repetitive TMS (rTMS) trains can be used to study the effects of transient activity changes of a targeted cortical area.

BACKGROUND: Studies with TMS revealed significant motor cortex excitability changes, particularly regarding intracortical inhibitory pathways, both in Parkinson’s disease and in dystonia, and these changes can be distinguished owing to the resting state or to the phases of movement preparation or execution. However, more specific correlation between electrophysiological features and clinical symptoms remains to be established. In addition, the stimulation of various cortical targets by rTMS protocols applied at low or high frequencies have induced some clear clinical effects.

PERSPECTIVES: The TMS effects are and will remain applied in movement disorders to better understand the role played by the motor cortex, to assess various types of treatment and appraise the therapeutic potential of cortical stimulation.

CONCLUSION: TMS provides evidence for motor cortex dysfunction in Parkinson’s disease or dystonia. Moreover, rTMS results have opened new perspectives for therapeutic strategies of implanted cortical stimulation. By these both aspects, TMS techniques show their usefulness in the assessment of movement disorders.

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.

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.

Abstract

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.

Abstract

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.

Abstract

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.

Int J Neurosci. 1999 Mar;97(1-2):139-45.

Yawning and stretching induced by transcranial application of AC pulsed electromagnetic fields 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.

Abstract

Yawning is considered a brainstem regulated behavior which is associated with changes in arousal and activity levels. Yawning and stretching are dopamine (DA) mediated behaviors and pharmacological studies indicate that these behaviors are associated with increased DA release coupled with stimulation of postsynaptic DA-D2 receptors. Despite their relation to the dopaminergic system, yawning and stretching are poorly documented in untreated or treated patients with Parkinson’s disease (PD). A 49 year old fully medicated female patient with juvenile onset PD is presented in whom recurrent episodes of yawning and stretching developed during transcranial administration of AC pulsed electromagnetic fields (EM Fs) of picotesla flux density. These episodes have not been observed previously in this or other patients during treatment with levodopa or DA receptor agonists or in unmedicated PD patients during treatment with AC pulsed EMFs. It is suggested that yawning and stretching behavior resulted in this patient from a synergistic interaction between EMFs and DA derived from levodopa supplementation with EMFs possibly facilitating the release of DA and simultaneously activating postsynaptic DA-D2 receptors in the nigrostriatal dopaminergic pathways. In addition, it is postulated that the release of ACTH/MSH peptides from peptidergic neurons in the brain upon stimulation of the DA-D2 receptors reinforced the yawning and stretching behavior.

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 reducing 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 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. 1995 Mar;81(1-2):47-65.

Weak electromagnetic fields reverse visuospatial hemi-inattention in Parkinson’s disease.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Abstract

Drawing tasks, both free and copied, have achieved a central position in neuropsychological testing of patients with unilateral cerebral dysfunction by virtue of their sensitivity to different kinds of organic brain disorders and their ability to provide information on lateralized brain damage. In the drawings of patients with right hemispheric damage, visuospatial neglect is revealed by the omission of details on the side of the drawing contralateral to the hemispheric lesion. Patients with unilateral cerebral damage, particularly those with left hemispheric damage, also demonstrate a tendency to place their drawings on the side of the page ipsilateral to the cerebral lesion, a phenomenon which has been termed visuospatial hemi-inattention. It has been reported previously that brief external application of alternating pulsed electromagnetic fields (EMFs) in the picotesla (pT) range intensity improved visuoperceptive and visuospatial functions and reversed neglect in Parkinsonian patients. The present communication concerns four fully medicated elderly nondemented Parkinsonian patients (mean age: 74.7 +/- 4.6 yrs; mean duration of illness: 7.7 +/- 5.2 yrs) in whom application of these EMFs produced reversal of visuospatial hemi-inattention related to left hemispheric dysfunction. These findings support prior observations demonstrating that pT EMFs may bring about reversal of certain cognitive deficits in Parkinsonian patients.

Rev Environ Health. 1994 Apr-Jun;10(2):127-34.

Pulsed magnetotherapy in Czechoslovakia–a review.

Jerabek J.

National Institute of Public Health, Praha, Czech Republic.

Abstract

Pulsed magnetotherapy has been used in Czechoslovakia for more than one decade. It has been proved that this type of physical therapy is very efficient mainly in rheumatic diseases, in paediatrics (sinusitis, enuresis), and in balneological care of patients suffering from ischaemic disorders of lower extremities. Promising results have also been obtained in neurological diseases (multiple sclerosis, spastic conditions) and in ophthalmology, in degenerative diseases of the retina.

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.

Pancreatitis

Vopr Kurortol Fizioter Lech Fiz Kult. 1994 May-Jun;(3):17-9.

The efficacy of the combined use of 5-fluorouracil electrophoresis and magnetotherapy in experimental pancreatitis.

[Article in Russian]

Kents VV, Tsympilova TA, Mavrodii VM, Godlevskii LS.

As shown on the experimental model of rat acute pancreatitis, an intensive 5-fluorouracil electrophoresis course in combination with magnetotherapy significantly reduces the activity of blood trypsin, amylase, lipase and corticosterone. The treatment is thought effective in experimental pancreatitis.