Fetal and Placental Development

Vopr Kurortol Fizioter Lech Fiz Kult. 2004 May-Jun;(3):28-32.

[Corrective action of the microwave electromagnetic field on progeny development in rats with impared uteroplacental circulation]

[Article in Russian]
Lysaia TN, Sheveleva GA, Strugatskii VM.
The experiment on 71 non-inbred white pregnant rats, 316 fetuses and placentas, 323 first progeny in experimental chronic impairment of uteroplacental circulation in females with pregnancy in the ploid period has found that decimetric waves (DW) in a weak heat dose (40 mW/cm2) prevents hypotrophy and disorders of fetal and placental development. Also, DW accelerate formation of motorsensory reflexes in the progeny in an early neonatal period and normalize their behavioral reactions at a mature age. The findings may serve experimental-theoretical grounds for application of weak heat DW radiation in obstetric practice in various general and regional hemocirculation.

Facial Paralysis – Bell’s Palsy – Nerve Regeneration

Lik Sprava. 2002 Jul-Sep;(5-6):49-53. Aspects of diagnosis and treatment of the facial nerve neuropathy [Article in Ukrainian] Mironenko TV, Korotnev VN. As many as 86 patients with neuropathy of the facial nerve complicated by development of postneuritic muscular contractures were examined. Based on the clinical-and-neurophysiological investigation, findings from rheoencephalography, electroencephalography, echoencephaloscopy, electrodiagnosis of the facial nerve, clinical variants of the facial nerve function return to normal were defined together with causes of development of muscular contractures. Efficiency is shown of use of acupuncture and magnetotherapy combined in treatment of the above trouble. Zh Nevropatol Psikhiatr Im S S Korsakova. 1997;97(3):32-5. Magnetic and electromagnetic stimulation in the combined treament of patients with paralysis of the mimetic musculature. [Article in Russian] Korotkikh NG, Korzh GM. The original method of treatment of patients with postoperative paresis of mimic muscles wis offered. The method included the use of two therapeutic factors: magnetotherapy and electromagnetostimulation of peripheral branches of facial nerve. The principles of combined influence of both components were described in detail. Data on functional control of treatment results confirm the reparation of peripheral branches of facial nerve. Nippon Jibiinkoka Gakkai Kaiho. 1995 Sep;98(9):1416-25.

Clinical investigation of transcranial magnetic stimulation of the facial nerve–an early prognostic diagnosis of patients with peripheral facial palsy and the facial nerve magnetic stimulation site.

[Article in Japanese]

Kohsyu H.

Department of Otolaryngology, Yamagata University School of Medicine.

To obtain an early prognostic diagnosis of patients with peripheral facial palsy, a magnetic stimulator (Dantec Mag 2) was used to directly stimulate the intracranial portion of the facial nerve in 15 normal subjects and 108 patients with peripheral facial palsy. In normal subjects and patients with facial palsy, compound muscle action potentials (CMAPs) of the orbicularis oris muscle elicited by transcranial magnetic stimulation were compared with CMAPs elicited by electrical stimulation at a peripheral site of the stylomastoid foramen. This technique is similar to electroneurography (ENoG) and is regularly used in our department. In normal subjects, the latency of magnetically evoked CMAPs was longer (1.0ms, SD 0.39ms) than that of CMAPs evoked by electrical stimulation. There were two categories of patients; the first group consisted of patients who visited our hospital within 2 weeks after palsy onset with a record of electrically evoked CMAPs (ENoG) and magnetically evoked CMAPs, the second group consisted of all others. The first group was then divided into four subgroups based on minimal ENoG values obtained within 2 weeks after the onset of palsy. In patients, ENoG values declined until the seventh day after palsy onset, and then plateaued. However, the amplitude ratio of magnetically evoked CMAPs between the affected side and normal side showed no tendency to deline until the seventh day after palsy onset. Thus, whether magnetically evoked CMAPs could be recorded must be discussed in relation to the prognosis of facial palsy. The patients in whom magnetically evoked CMAPs could be recorded within the seven days after the onset of palsy were classified into a group in which the minimal ENoG value was greater than 20%. These patients recovered almost 2 months after the onset of palsy, and were significantly better than the recovery rates of those patients in whom magnetically evoked CMAPs could not be recorded. The site at which the facial nerve is magnetically stimulated remains controversial. In patients with peripheral facial palsy, recovery of the stapedial reflex, blink reflex and magnetically evoked CMAPs were examined to investigate the site of magnetic stimulation. From the clinical perspective, the facial nerve is thought to be magnetically stimulated near the meatal foramen that Fisch reported the site of damage in Bell’s palsy. This stimulation site was almost the same point as that calculated from the mean latency difference between magnetically evoked CMAPs and ENoG in normal controls.

Eur Arch Otorhinolaryngol. 1995;252(6):344-7.

A comparison of transcranial magnetic stimulation with electroneuronography as a predictive test in patients with Bell’s palsy.

Laranne J, Rimpilainen I, Karma P, Eskola H, Hakkinen V, Laippala P.

Department of Otorhinolaryngology, School of Medicine, University of Tampere, Finland.

The aim of this study was to examine the neuronographic findings of electrical and transcranial magnetic stimulation of the facial nerve and to compare their ability to predict clinical recovery from idiopathic facial nerve palsy (Bell’s palsy). Eighty-six patients were examined clinically and neurophysiologically immediately on presentation to Tampere University Hospital. Electroneuronography (ENoG) and transcranial magnetic stimulation (TMS) were performed 1-6 times for each patient. The time interval between each examination varied from 2 to 7 days. Seventy-eight patients were followed for a median period of 13 months after the onset of palsy. Facial nerve function was graded according to the House-Brackmann grading system. Relative amplitude differences of ENoG and TMS during the acute phase were then correlated with clinical outcome. Statistical analysis of the results showed that a TMS response elicitable during the first 5 days of the palsy was correlatable with a good prognosis. ENoG results correlated with clinical outcome at a later time from onset of symptoms. TMS was well tolerated and no adverse effects were seen. These results indicate that TMS is a useful method for the early prediction of outcome in patients with Bell’s palsy.

HNO. 1994 Sep;42(9):559-64.

Does transcranial magnetic stimulation provide improved assessment of “idiopathic” facial paralysis?  Initial results.

[Article in German]

Wolf SR, Schneider W.

Klinik und Poliklinik fur Hals-Nasen- und Ohrenkranke, Universitat Erlangen-Nurnberg.

To evaluate transcranial magnetic stimulation (TMS) in patients suffering from idiopathic facial palsy, results from 31 patients were reviewed. TMS was applied to the facial nerve by parieto-occipital, ipsilateral coil placement. At the time of the first examination (2-25 days after the onset of palsy), 11 of 31 nerves on the affected side were excitably by TMS. Patients were classified according to whether magnetic excitability of the facial nerve was possible (group I) or not possible (group II). In general, the percentage of patients with complete or nearly complete recovery of facial function was 97% following either a standard infusion therapy (corticosteroids, hydroxyethylstarch and pentoxifyllin) or orally administered corticoids (equal percentages in each group, respectively). In the first group of patients, 11 had facial nerves that were excitable with TMS and showed complete recovery of motor function within a median period of 7 weeks. In those patients with successful TMS only one experienced “crocodile tears” syndrome one year after Bell’s palsy but without any further motor deficit of facial function. In patients with unresponsive nerve function following TMS 17 recovered without sequelae (median, 11 weeks), whereas 3 of 20 (15%) developed deficits of motor function. Two of these latter cases suffered from synkinesias (one that was slight after surgical decompression of the facial nerve and one severe) while one had facial contractures but without motor deficits.(ABSTRACT

Electroencephalogr Clin Neurophysiol. 1994 Apr;93(2):113-20.

Magnetic transcranial and electrical stylomastoidal stimulation of the facial motor pathways in Bell’s palsy: time course and relevance of electrophysiological parameters.

Glocker FX, Magistris MR, Rosler KM, Hess CW.

Department of Neurology, University of Berne, Switzerland.

Facial nerve motor neurography was performed at various times after the onset of Bell’s palsy in 97 patients. Stimulation of the facial nerve was performed (1) electrically in the fossa stylomastoidea (ElStim), and (2) magnetically in the labryinthine segment of the facial canal (MagStim), evaluating different coil positions over the skull. Additionally, the face-associated motor cortex was stimulated magnetically in 47 patients (CxStim). A marked reduction of the amplitudes of the compound muscle action potentials (CMAP) evoked by MagStim on either m. nasalis or mentalis, or both, was observed which was clearly more pronounced than the amplitude reduction to ElStim. This discrepancy occurred very early during the disease, the mean amplitude (expressed in percent of the amplitude on the unaffected side) being 82% (S.D. 9.1) for ElStim and 1% (2.7) for MagStim at days 0-4. It persisted for several months, often when facial nerve function had recovered to normal, as assessed by clinical observation, ElStim, and CxStim. This amplitude decrease to MagStim, which appears to be related to a locally enhanced stimulation threshold of the facial nerve, is a very sensitive and reproducible finding in Bell’s palsy. It may prove specific of the disorder, of diagnostic value, and of interest in the follow-up of patients during treatment trials.

Otolaryngol Pol. 1994;48(1):33-6.

Magnetic stimulation of the facial nerve: a new testing method

[Article in Polish]

Pietruski J.


Magnetic stimulation (MST) is the new method electrodiagnostic testing. The motor nerves are contrally stimulated proximally to the pathology. This technique enables to evaluate the function of the facial nerve immediately after onset. It can also be used to evaluate the function of the facial nerve in Bell’s palsy. The technique is absolutely painless. The results suggest that MST provides a sensitive data of evaluation of facial palsy and will be a very valuable prognostical test.

Nippon Jibiinkoka Gakkai Kaiho. 1993 Sep;96(9):1410-6.

Magnetic stimulation of the facial nerve.

[Article in Japanese]

Yamakawa T, Yoshikawa H, Sakurai A, Ichikawa G.

Department of Otorhinolaryngology, Juntendo University, School of Medicine, Tokyo.

Intracranial activation of the facial nerve and the face-associated motor cortex are now possible with noninvasive magnetic stimulation techniques. Compound muscle action potentials (CMAPs) and the Blink reflex, in response to magnetic stimulation, were investigated. Subjects were 10 normal controls and 2 Bell’s palsy patients. CMAPs were elicited in the orbicularis oris muscle by magnetic stimulation at the parieto-occipital skull and stylomastoid foramen. Furthermore, CMAPs were evoked by a magnetic coil oriented over the cortex. CMAP recording was possible with magnetic stimulation and the latencies of CMAPs at the parieto-occipital skull were slightly greater than those at the stylomastoid foramen. In 10 normal subjects, the mean onset latency following transcranial magnetic stimulation of the facial nerve at the parieto-occipital skull was 5.07 msec (SD = 0.40), while transcutaneous latency at the stylomastoid foramen was 2.77msec (SD = 0.539). In the blink reflex, R1 latency was 10.99 msec (SD = 1.27), ipsilateral-R2 latency was 37.46 msec (SD = 2.57), and contralateral-R2 latency was 38.925 msec (SD = 3.20). The blink reflex thus had a configuration similar to that evoked by conventional electrical stimulation. In the patients with Bell’s palsy, CMAPs elicited by magnetic stimulation were of low amplitude with normal latency. However, in the blink reflex, only a contralateral R2 response could be recorded, and R1 and ipsilateral-R2 showed no response to stimulation at the affected side. Investigation of patients with Bell’s palsy using this technique may therefore prove useful in the evaluation of peripheral facial nerve disorders.

Acta Otolaryngol. 1992;112(2):311-6.

Magnetic facial nerve stimulation in Bell’s palsy.

Rimpiläinen I, Karma P, Laranne J, Eskola H, Häkkinen V.

Department of Clinical Neurophysiology, Tampere University Central Hospital, Finland.


The transcranial magnetic stimulation (TMS) technique makes it possible to stimulate the intracranial part of the facial nerve. In a total of 51 patients with acute Bell’s palsy, TMS was performed, and the responses were compared with those elicited by conventional extracranial electric stimulation (EES). Clinical recovery was evaluated at 258-539, mean 410, days from the beginning of the palsy. With both techniques the motor evoked potentials (MEPs) could always be elicited on the healthy side, the mean latency being 4.7 ms with TMS and 3.7 ms with EES. In the acute phase, TMS elicited MEPs on the paralyzed side in 47% of the patients, and EES in 98%. The patients with TMS elicitable MEPs during the first 4 days of the palsy had significantly better recovery than those without response (p less than 0.05). The difference in recovery between patients with or without elicitable TMS responses on days 5-8 and 9-14 was not significant. In EES, the amplitude difference between the two sides within the first 4 days was not significantly (p greater than 0.05) different. On days 9-14 the patients with a less than 80% difference between the two sides recovered significantly (p less than 0.05) better than those with a difference of greater than or equal to 80%, So, TMS may be of help in the early prognosis of Bell’s palsy.

J Neurol. 1989 Feb;236(2):102-7.

Investigation of unilateral facial weakness: magnetic stimulation of the proximal facial nerve and of the face-associated motor cortex.

Meyer BU, Britton TC, Benecke R.

Neurologische Klinik, Universität Düsseldorf, Federal Republic of Germany.


Twenty-four patients with unilateral facial weakness of various aetiologies were investigated using a magnetic stimulator to stimulate the proximal segment of the facial nerve directly (short latency response) and also to activate the facial motoneurons bilaterally via corticonuclear pathways by placing the stimulating coil over the motor cortex (long latency responses). Electromyographic recordings were taken from both mentalis muscles using concentric needle electrodes. Seventeen patients were investigated at various times after onset of idiopathic facial palsy (Bell’s palsy). In the acute stage (less than 5 days after onset) short and long latency responses on the paretic side were abnormal, being absent in all but one patient, in whom the short latency response was delayed. These abnormal responses were the earliest neurographic correlate for nerve conduction block. In 4 out of 9 patients seen up to 30 days after onset of palsy, trans-synaptically evoked long latency responses were absent. In patients examined more than 2 months after onset, long latency responses could always be obtained and, in 5 of 8 patients, short latency responses could also be elicited, indicating a return of the direct excitability of the nerve. Five patients with cerebral hemisphere lesions causing mild unilateral facial weakness had absent long latency responses when stimulating over the affected hemisphere, but normal bilateral long latency responses following stimulation over the unaffected cerebral hemisphere; short latency responses were normal. Magnetic stimulation of the brain and of the facial nerve can differentiate between central and peripheral causes of unilateral facial weakness and may prove useful in the early assessment of the degree of conduction block in Bell’s palsy.

Ann Otolaryngol Chir Cervicofac. 1988;105(5):397-402.

On the contribution of magnets in sequelae of facial paralysis.  Preliminary clinical study.

[Article in French]

Fombeur JP, Koubbi G, Chevalier AM, Mousset C.

Service d’Oto-Rhino-Laryngologie, Hopital Saint-Michel, Paris.

This trial was designed to evaluate the efficacy of EPOREC 1 500 magnets as an adjuvant to rehabilitation following peripheral facial paralysis. Magnetotherapy is used in many other specialties, and in particular in rheumatology. The properties of repulsion between identical poles were used to decrease the effect of sequelae in the form of contractures on the facial muscles. There were two groups of 20 patients: one group with physiotherapy only and the other with standard rehabilitation together with the use of magnets. These 40 patients had facial paralysis of various origins (trauma, excision of acoustic neuroma, Bell’s palsy etc). Obviously all patients had an intact nerve. It was at the time of the development of contractures that magnets could be used in terms of evaluation of their efficacy of action on syncinesiae, contractures and spasticity. Magnets were worn at night for a mean period of six months and results were assessed in terms of disappearance of eye-mouth syncinesiae, and in terms of normality of facial tone. Improvement and total recovery without sequelae were obtained far more frequently in the group which wore magnets, encouraging us to continue along these lines.

Arch Ophtalmol (Paris). 1976 Aug-Sep;36(8-9):549-54.

Eyelid magnets for facial paralysis.

[Article in French]

Marchac D.

The author presents his experience in the use of lid magnets. The positioning is delicate but tolerance is good and the aesthetic and functional result satisfactory. The essential indication is the development of corneal problems overnight from defective occlusion.

Klin Monatsbl Augenheilkd. 1976 Oct;169(4):529-33.

A simple method of restoring lidfunction in facial nerve paralysis with permanent magnets (author’s transl).

[Article in German]

Momma WG, Biermann B.

This is a report on 8 cases of lagophthalmos due to paralysis of the facial nerve. The in-ability to close the eyelid may bring about severe diseases of the eyes. By implantation of permanent magnets in the rims of the eyelids the dynamic lidfunction can be restored. We developed a very easy method implanting the magnets. The operation can now be done on out-patients. The results after 2 1/2 years’ follow-up are presented

Clin Neurophysiol. 2005 Sep;116(9):2051-7.

Diagnostic relevance of transcranial magnetic and electric stimulation of the facial nerve in the management of facial palsy.

Nowak DA, Linder S, Topka H.

Department of Psychiatry III, University of Ulm, Germany.dr.dennis.nowak@gmx.de


OBJECTIVE: Earlier investigations have suggested that isolated conduction block of the facial nerve to transcranial magnetic stimulation early in the disorder represents a very sensitive and potentially specific finding in Bell’s palsy differentiating the disease from other etiologies.

METHODS: Stimulation of the facial nerve was performed electrically at the stylomastoid foramen and magnetically at the labyrinthine segment of the Fallopian channel within 3 days from symptom onset in 65 patients with Bell’s palsy, five patients with Zoster oticus, one patient with neuroborreliosis and one patient with nuclear facial nerve palsy due to multiple sclerosis.

RESULTS: Absence or decreased amplitudes of muscle responses to early transcranial magnetic stimulation was not specific for Bell’s palsy, but also evident in all cases of Zoster oticus and in the case of neuroborreliosis. Amplitudes of electrically evoked muscle responses were more markedly reduced in Zoster oticus as compared to Bell’s palsy, most likely due to a more severe degree of axonal degeneration. The degree of amplitude reduction of the muscle response to electrical stimulation reliably correlated with the severity of facial palsy.

CONCLUSIONS: Transcranial magnetic stimulation in the early diagnosis of Bell’s palsy is less specific than previously thought. While not specific with respect to the etiology of facial palsy, transcranial magnetic stimulation seems capable of localizing the site of lesion within the Fallopian channel.

SIGNIFICANCE: Combined with transcranial magnetic stimulation, early electrical stimulation of the facial nerve at the stylomastoid foramen may help to establish correct diagnosis and prognosis.

Laryngoscope. 1999 Mar;109(3):492-7.

A clinical study on the magnetic stimulation of the facial nerve.

Yamakawa T, Yoshikawa H, Arai A, Miyazaki T, Ichikawa G.

Department of Otorhinolaryngology, Juntendo University, School of Medicine,


OBJECTIVES: A clinical study on the usefulness of magnetic stimulation of the Tokyo, Japan.facial nerve, with special attention paid to the selection of the coil shape and stimulation procedures.

STUDY DESIGN: The subjects consisted of 55 patients with Bell’s palsy, 1 patient with a cerebellopontine angle (CPA) tumor, 1 patient with multiple sclerosis (MS), and 30 normal subjects. Three types of coils were used in this study; a 90-mm large single coil, a 40-mm small single coil, and a 20-mm small double coil.

METHODS: The compound muscle action potentials (CMAPs) and long latency response were evoked by transcranial magnetic stimulation (TMS) with a 90-mm large single coil. The 40-mm small single coil was used to test blink reflex by aiming it at the supraorbital nerve as the target site. The subcutaneous activation of the infra-auricular facial nerve was performed with the 20-mm double coil.

RESULTS: The reproducible CMAP and long latency responses were obtained from normal subjects with TMS. However, responses were observed only in patients with relatively mild Bell’s palsy. The magnetic stimulation-evoked responses reflected the brainstem function in the patients with a CPA tumor and MS.

CONCLUSION: Although magnetic stimulation remains inferior to conventional electric stimulation in some sense and requires further study, this method is potentially useful because it can stimulate the facial nerve continuously from the cortex to the periphery and can effectively evoke responses reflecting the brainstem function.

Neurosci Behav Physiol. 1998 Sep-Oct;28(5):594-7.

Magnetic and electrical stimulation in the rehabilitative treatment of patients with organic lesions of the nervous system.

Tyshkevich TG, Nikitina VV.

A. L. Polenov Russian Science Research Neurosurgical Institute, St. Petersburg.


Studies were performed on 89 patients with organic lesions of the nervous system in which the leading clinical symptoms consisted of paralysis and pareses. Patients received complex treatment, including pulsed magnetic fields and an electrical stimulation regime producing multilevel stimulation. A control group of 49 patients with similar conditions was included, and these patients received only sinusoidal currents. Combined treatment with magnetic and electrical stimulation was more effective, as indicated by radiographic and electromyographic investigations.

Arch Otolaryngol Head Neck Surg. 1998 Apr;124(4):383-9.

Effect of pulsed electromagnetic stimulation on facial nerve regeneration.

Byers JM, Clark KF, Thompson GC.

Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.

OBJECTIVE: To determine if exposure to electromagnetic fields influences regeneration of the transected facial nerve in the rat.

DESIGN AND METHODS: The left facial nerve was transected in the tympanic section of the fallopian canal in 24 rats randomly assigned to 2 groups. The cut ends of the facial nerve were reapproximated without sutures within the fallopian canal to maximize the potential for regeneration. Rats in the experimental group (n= 12) were then exposed to pulsed electromagnetic stimulation (0.4 millitesla at 120 Hz) for 4 hours per day, 5 days per week, for 8 weeks. Rats in the control group (n=12) were handled in an identical manner without pulsed electromagnetic stimulation. Four other rats were given sham operations in which all surgical procedures were carried out except for the actual nerve transection. Two of these rats were placed in each group. Nerve regeneration was evaluated using electroneurography (compound action potentials), force of whisker and eyelid movements, and voluntary facial movements before and at 2-week intervals after transection. Histological evaluation was performed at 10 weeks after transection. Each dependent variable was analyzed using a 2-way analysis of variance with 1 between variable (groups) and 1 within repeated measures variable (days after transection).

RESULTS: Statistical analysis indicated that N1 (the negative deflection of depolarization phase of the muscle and/or nerve fibers) area, N1 amplitude, and N1 duration, as well as absolute amplitude of the compound action potentials, were all significantly greater 2 weeks after transection in the experimental than in the control group of rats. The force of eye and whisker movements after electrical stimulation was statistically greater in the experimental group of rats 4 weeks after transection. Voluntary eye movements in the experimental group were significantly better at 5 and 10 weeks, while whisker movements were better at 3 and 10 weeks. There was no statistical difference between the 2 groups for any histological variable.

CONCLUSION: Results of this study indicate that pulsed electromagnetic stimulation enhances early regeneration of the transected facial nerve in rats.

Nippon Jibiinkoka Gakkai Kaiho. 1995 Sep;98(9):1416-25.

Clinical investigation of transcranial magnetic stimulation of the facial nerve–an early prognostic diagnosis of patients with peripheral facial palsy and the facial nerve magnetic stimulation site.

[Article in Japanese]

Kohsyu H.

Department of Otolaryngology, Yamagata University School of Medicine.

To obtain an early prognostic diagnosis of patients with peripheral facial palsy, a magnetic stimulator (Dantec Mag 2) was used to directly stimulate the intracranial portion of the facial nerve in 15 normal subjects and 108 patients with peripheral facial palsy. In normal subjects and patients with facial palsy, compound muscle action potentials (CMAPs) of the orbicularis oris muscle elicited by transcranial magnetic stimulation were compared with CMAPs elicited by electrical stimulation at a peripheral site of the stylomastoid foramen. This technique is similar to electroneurography (ENoG) and is regularly used in our department. In normal subjects, the latency of magnetically evoked CMAPs was longer (1.0ms, SD 0.39ms) than that of CMAPs evoked by electrical stimulation. There were two categories of patients; the first group consisted of patients who visited our hospital within 2 weeks after palsy onset with a record of electrically evoked CMAPs (ENoG) and magnetically evoked CMAPs, the second group consisted of all others. The first group was then divided into four subgroups based on minimal ENoG values obtained within 2 weeks after the onset of palsy. In patients, ENoG values declined until the seventh day after palsy onset, and then plateaued. However, the amplitude ratio of magnetically evoked CMAPs between the affected side and normal side showed no tendency to deline until the seventh day after palsy onset. Thus, whether magnetically evoked CMAPs could be recorded must be discussed in relation to the prognosis of facial palsy. The patients in whom magnetically evoked CMAPs could be recorded within the seven days after the onset of palsy were classified into a group in which the minimal ENoG value was greater than 20%. These patients recovered almost 2 months after the onset of palsy, and were significantly better than the recovery rates of those patients in whom magnetically evoked CMAPs could not be recorded. The site at which the facial nerve is magnetically stimulated remains controversial. In patients with peripheral facial palsy, recovery of the stapedial reflex, blink reflex and magnetically evoked CMAPs were examined to investigate the site of magnetic stimulation. From the clinical perspective, the facial nerve is thought to be magnetically stimulated near the meatal foramen that Fisch reported the site of damage in Bell’s palsy. This stimulation site was almost the same point as that calculated from the mean latency difference between magnetically evoked CMAPs and ENoG in normal controls.

Electroencephalogr Clin Neurophysiol. 1994 Apr;93(2):113-20.

Magnetic transcranial and electrical stylomastoidal stimulation of the facial motor pathways in Bell’s palsy: time course and relevance of electrophysiological parameters.

Glocker FX, Magistris MR, Rosler KM, Hess CW.

Department of Neurology, University of Berne, Switzerland.

Facial nerve motor neurography was performed at various times after the onset of Bell’s palsy in 97 patients. Stimulation of the facial nerve was performed (1) electrically in the fossa stylomastoidea (ElStim), and (2) magnetically in the labryinthine segment of the facial canal (MagStim), evaluating different coil positions over the skull. Additionally, the face-associated motor cortex was stimulated magnetically in 47 patients (CxStim). A marked reduction of the amplitudes of the compound muscle action potentials (CMAP) evoked by MagStim on either m. nasalis or mentalis, or both, was observed which was clearly more pronounced than the amplitude reduction to ElStim. This discrepancy occurred very early during the disease, the mean amplitude (expressed in percent of the amplitude on the unaffected side) being 82% (S.D. 9.1) for ElStim and 1% (2.7) for MagStim at days 0-4. It persisted for several months, often when facial nerve function had recovered to normal, as assessed by clinical observation, ElStim, and CxStim. This amplitude decrease to MagStim, which appears to be related to a locally enhanced stimulation threshold of the facial nerve, is a very sensitive and reproducible finding in Bell’s palsy. It may prove specific of the disorder, of diagnostic value, and of interest in the follow-up of patients during treatment trials.

Facial Pain

Med Hypotheses. 2010 Mar;74(3):505-7. Epub 2009 Nov 8.

Bioresonance hypothesis: a new mechanism on the pathogenesis of trigeminal neuralgia.

Jia DZ, Li G.

Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan 250012, China.


Trigeminal neuralgia (TN) is an uncommon disorder characterized by recurrent attacks of lancinating pain in the trigeminal nerve distribution. To date, the precise mechanism for TN remains unclear. Among a variety of causes of TN, the microvascular compression (MVC) hypothesis is the most popular one, but controversies still focus on the origin and pathogenesis of the disorder. A number of clinical phenomena still cannot be well explained. We propose a new hypothesis on the pathogenesis of TN – bioresonance. The bioresonance hypothesis states that when the vibration frequency of a structure surrounding the trigeminal nerve becomes close to its natural frequency, the resonance of the trigeminal nerve occurs. The bioresonance can damage trigeminal nerve fibers and lead to the abnormal transmission of the impulse, which may finally result in facial pain. Under the guidance of the bioresonance hypothesis, we hope to explore more non-invasive methods to treat or even cure TN.

Vopr Kurortol Fizioter Lech Fiz Kult. 2000 Nov-Dec;(6):29-32.

Physiopuncture therapy of trigeminal neuralgia

[Article in Russian]

Samosiuk IZ, Kozhanova AK, Samosiuk NI.


137 patients with typical trifacial neuralgia (TN) were divided into four groups. 30 patients of group 1 received EHF therapy, 30 patients of group 2 were exposed to laser, 67 patients of group 3 were treated with combination of laser with EHF-puncture, 10 patients of group 4 were controls on conventional physiotherapy. Patients of all the groups were given drug of choice–carbamazepin. The highest response was registered in group 3, 21(31.3%) patients of which could stop carbamazepin, while 40(59.7%) patients reduced carbamazepin dose by 50-70%. Positive results were due to restoration of self-regulation in pain and antipain systems which are disturbed in TN patients

Anesth Pain Control Dent. 1992 Spring;1(2):85-9.

The management of craniofacial pain in a pain relief unit.

Hillman L, Burns MT, Chander A, Tai YM.

Russells Hall Hospital, Dudley, United Kingdom.

This paper reports the results of 34 craniofacial pain sufferers who were treated at the Dudley Pain Relief Unit over a 1-year period. Most of the patients were referred by their general medical practitioners. They were adults representing all age groups, with a female-male ratio of 4:1. The average history of pain was 5.5 years. Neuralgic pain (as distinct from temporomandibular joint dysfunction syndrome, migrainous disorders, and pain of iatrogenic origin) was most frequently seen. Oral drug therapy, local injection of corticosteroids and analgesics, peripheral neurolysis, magnetotherapy, hypnotherapy, and acupuncture were the lines of management available. By the end of this study period, pain had been relieved or eliminated in 30 of the patients (88%).

Curr Rev Pain. 1999;3(5):342-347.

Sphenopalatine Ganglion Analgesia.

Day M.

Texas Tech University Health Sciences Center, Department of Anesthesiology, 3601 4th Street, Room 1C282, Lubbock, TX 79430, USA.

The sphenopalatine ganglion and its involvement in the pathogenesis of pain has been the subject of debate for the last 90 years. The ganglion is a complex neural center composed of sensory, motor, and autonomic nerves, which makes it difficult to determine its pathophysiology. Current indications for blockade of the sphenopalatine ganglion include sphenopalatine and trigeminal neuralgia, migraine and cluster headaches, and atypical facial pain. Methods of blockade use local anesthetics, steroids, phenol, and conventional radiofrequency and electromagnetic field- pulsed radiofrequency lesioning. The techniques for blockade range from superficial to highly invasive. Efficacy studies, though few and small, show promise in patients who have failed pharmacologic or surgical therapies.

Eye Disorders

Vopr Kurortol Fizioter Lech Fiz Kult. 2009 May-Jun;(3):25-8.

Transcranial magnetotherapy for the correction of initial manifestations of diabetic retinopathy in children.

[Article in Russian]

Nikolaeva NV, Bolotova NV, Kamenskikh TG, Ra?gorodski? IuM, Kolbenev IO, Luk’ianov VF.


This study included 45 children at the age from 5 to 17 years with type I diabetes mellitus complicated by diabetic retinopathy. All the patients showed retinal thickening at the macula and reduced amplitude of local electroretinogram suggesting compromised capillary circulation. The capillary blood flow was corrected by transcranial magnetotherapy with the use of an AMO-ATOS Ogolovie unit. The results of the treatment were evaluated from characteristics of laser Doppler flometry. A course of transcranial magnetotherapy comprising 10 daily seances resulted in a significant increase of microcirculation index, respiratory rhythm, and myogenic tone (by 1.64, 1.35, and 1.16 times respectively). In addition, morphometric and electrophysiological properties of the retina underwent positive changes. Transcranial exposure to the traveling magnetic field is recommended for the correction of intraocular microcirculation and prevention of diabetic macular oedema.

Electromagn Biol Med. 2007;26(4):293-8.

Effects of endogenous cyclotronic ionic resonance (ICR) on macular diabetic edema: preliminary results.

D’Andrea P, Maurizio L.

D’Andrea Clinic, Pescara, Italy. crs767fr@yahoo.com


The intent in this research was to verify the effects of the application of low frequency magnetic fields to cases of macular diabetic edema. We treated six patients afflicted by non-proliferating diabetic retinopathy with macular oedema. Quantitative clinical appraisals of the retinal thickness were obtained for the Optical Coherence Tomography (OCT I). None of the cases affected by non-cystoid macular oedema (non-CMO), or with a relevant ischemic component, evidenced by retinal fluorangiography, had further worsening in their clinical course during the treatment. Only one of the patients, who underwent a long treatment period with ICR demonstrated a significant reduction of the macular edema, with no need of other invasive therapeutic procedures (intravitreous injection of triamcinolone and/or laser therapy).

Vestn Oftalmol. 2005 Jan-Feb;121(1):35-7.

Quantum therapy and the composition of the eye anterior chamber (an experimental study).

[Article in Russian]

Pavliuk EIu, Sherkhoeva DTs, Pavliuk AIu, Khristoforov VN.

We examined 12 rabbits, 6 of whom (12 eyes) were exposed to magneto-infrared laser radiation (MILR) and another 6 (12 eyes) were controls. The parameters of pulse and continuous infrared LED radiation were as follows: wavelength–860 nm, pulse capacity–2 W, mean radiation capacity–10 mW, magnetic field strength–up to 17 mTl. A study of the moister of the anterior chamber showed a MILR-induced activated metabolism, i.e. a better acid-base balance (ABB), more intense oxygenation in the ocular tissues and decreased acidosis. Higher concentrations of buffer bases (ABEe and SBEc) cause shifts in ABB towards metabolic alkalosis. A lower concentration of glucose denotes intensified processes related with its utilization. A lack of changes in the quantity of salts in the moister of the anterior chamber rules out the possibility of that the content of glucose would go down due to its dissolution with a big volume of newly produced moister. A lack of an increase in the concentration of whole protein, as observed after MILR, can be regarded as indirect evidence to absence of any adverse effect on the vascular wall.

Ophthalmologica. 2003 Mar-Apr;217(2):143-7.

Evaluation of treatment by pulsed electromagnetic fields in a rabbit hyphema model.

Wollensak G, Muchamedjarow F, Funk R.

Department of Ophthalmology, Universitätsklinikum CGC, Dresden, Germany. gwollens@hotmail.com


PURPOSE: Previous clinical studies have suggested a positive effect of low-frequency pulsed electromagnetic fields (PEMF) on wound healing and inflammation in the eye. We tried to test the value of PEMF treatment in a hyphema animal model with well-defined conditions.

METHODS: After injection of citrated autologous blood for the production of hyphema, 16 rabbit eyes were treated with 10 or 20 mT for 60 min on 4 days within the postoperative week. Two control groups with hyphema alone (n = 8) and PEMF irradiation without hyphema (n = 4) were also included. The rate of resorption was recorded daily. Histopathologic evaluation was performed.

RESULTS: The incidence of endothelial cell damage and fibrotic clots was markedly reduced in the 10-mT group while the resorption time of 8 days was identical with the control group. In the 20-mT group, the complication rate and the resorption time was increased versus the control group.

CONCLUSIONS: The use of PEMF treatment is of some, however, limited value as it did not reduce the resorption time of hyphema but displayed a dose-dependent, beneficial influence on some serious side effects. Future clinical studies with low-dose PEMF irradiation are justified and should determine the optimal dosage and suitable indications of PEMFs as an adjunctive treatment in ocular inflammation or trauma.

Vestn Oftalmol. 2000 Jul-Aug;116(4):3-5.

Differentiated approaches to the treatment of nonstabilized primary open-angle glaucoma with normalized intraocular pressure considering its pathogenic features.

[Article in Russian]

Egorov VV, Sorokin EL, Smoliakova GP.

Clinical efficiency of dedystrophic treatments for nonstabilized primary open-angle glaucoma (POAG) in the presence of normalized intraocular pressure is compared in 168 patients (246 eyes). In one group of patients ischemic angiopathy and hyperreactivity of optic vessel adrenoreceptors associated with hypokinetic central hemodynamics and constitutional metabolic status of the organism was corrected by cinnarisin and riboxin. Patients with predominating congestive angiopathy symptoms, hyper- or eukinetic circulation and “slow” acetylation were treated by pantothenic acid, endotelon, and hyperbaric oxygenation. In both groups epithalamine, eiconol, and magnetic laser therapy were used, if indicated. This helped stabilize the process in 91% patients with initial POAG, in 87.5% with well-developed condition vs. 66.1% and 38.2% patients treated by traditional therapy (period of observation 3 years).

Vestn Oftalmol. 2002 May-Jun;118(3):15-7.

Laser magnetotherapy after cataract extraction with implantation of intraocular lens.

[Article in Russian]

Maksimov VIu, Zakharova NV, Maksimova IS, Golushkov GA, Evseev SIu.

Effects of low-intensive laser and alternating magnetic field on the course of the postoperative period were studied in patients with exudative reaction after extracapsular cataract extraction with implantation of intraocular lens (IOL). The results are analyzed for 148 eyes with early exudative reaction after IOL implantation (136 patients aged 42-75 years). The patients were observed for up to 6 months. The treatment efficiency was evaluated by the clinical picture of inflammatory reaction, visual acuity, and results of biochemical analysis of the lacrimal fluid (the ratio of lipid peroxidation products to antioxidants in cell membrane). The course of the postoperative period was more benign and recovery sooner in patients of the main group in comparison with the control.

Eur J Ophthalmol. 1998 Oct-Dec;8(4):253-7.

The effect of pulsed electromagnetic field on patients with endocrine ophthalmopathy.

Jankauskiene J, Paunksnis A, Bluziene A, Saulgozis J.

Department of Ophthalmology, Kaunas Medical Academy, Lithuania.

PURPOSE: To evaluate eye signs, proptosis and ocular movements in patients with endocrine ophthalmopathy under the influence of pulsed electromagnetic field therapy.

METHODS: We examined 14 patients (9 women, 5 men) with endocrine ophthalmopathy and evaluated eye signs, proptosis and ocular movements before and after the course of pulsed electromagnetic field therapy, and 12 controls. Their age ranged from 29 to 57 years. Visual sensitivity was investigated with a static automatic perimeter (Allergan Humphrey Field Analyzer). The score was calculated by rating the severity of involvement of soft tissue, proptosis, extraocular movements, corneal state and optic nerve function on a scale from 0 to 3. The pulsed electromagnetic field procedures were carried out with the help of electromagnetic spectacles.

RESULTS: Pulsed electromagnetic field therapy reduced the score for soft tissue and proptosis in patients who suffered from endocrine ophthalmopathy. There was fall in the mean score for ocular movements, corneal and optic nerve function but it did not reach significance after treatment. Electromagnetic field therapy has no useful effect on visual signs and eye movements in two patients who had had the illness more than two years.

CONCLUSIONS: Localised pulsed electromagnetic field procedures can be recommended, together with other methods of conservative treatment of endocrine ophthalmopathy.

Int J Neurosci. 1998 Apr;93(3-4):239-50.

Treatment with AC pulsed electromagnetic fields normalizes the latency of the visual evoked response in a multiple sclerosis patient with optic atrophy.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Visual evoked response (VER) studies have been utilized as supportive information for the diagnosis of multiple sclerosis (MS) and may be useful in objectively monitoring the effects of various therapeutic modalities. Delayed latency of the VER, which reflects slowed impulse transmission in the optic pathways, is the most characteristic abnormality associated with the disease. Brief transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density are efficacious in the symptomatic treatment of MS and may also reestablish impulse transmission in the optic pathways. A 36 year old man developed an attack of right sided optic neuritis at the age of 30. On presentation he had blurring of vision with reduced acuity on the right and fundoscopic examination revealed pallor of the optic disc. A checkerboard pattern reversal VER showed a delayed latency to right eye stimulation (P100 = 132 ms; normal range: 95-115 ms). After he received two successive applications of AC pulsed EMFs of 7.5 picotesla flux density each of 20 minutes duration administered transcranially, there was a dramatic improvement in vision and the VER latency reverted to normal (P100= 107 ms). The rapid improvement in vision coupled with the normalization of the VER latency despite the presence of optic atrophy, which reflects chronic demyelination of the optic nerve, cannot be explained on the basis of partial or full reformation of myelin. It is proposed that in MS synaptic neurotransmitter deficiency is associated with the visual impairment and delayed VER latency following optic neuritis and that the recovery of the VER latency by treatment with pulsed EMFs is related to enhancement of synaptic neurotransmitter functions in the retina and central optic pathways. Recovery of the VER latency in MS patients may have important implications with respect to the treatment of visual impairment and prevention of visual loss. Specifically, repeated pulsed applications of EMFs may maintain impulse transmission in the optic nerve and thus potentially sustain its viability.

Vestn Oftalmol. 1996 Jan-Mar;112(1):6-8.

Possibilities of magnetotherapy in stabilization of visual function in patients with glaucoma.

[Article in Russian]

Bisvas Shutanto Kumar, Listopadova NA.

Courses of magnetotherapy (MT) using ATOS device with 33 mT magnetic field induction were administered to 31 patients (43 eyes) with primary open-angle glaucoma with compensated intraocular pressure. The operation mode was intermittent, with 1.0 to 1.5 Hz field rotation frequency by 6 radii. The procedure is administered to a patient in a sitting posture with magnetic inductor held before the eye. The duration of a session is 10 min, a course consists of 10 sessions. Untreated eyes (n = 15) of the same patients were examined for control. The patients were examined before and 4 to 5 months after MT course. Vision acuity improved by 0.16 diopters, on an average, in 29 eyes (96.7%) out of 30 with vision acuity below 1.0 before treatment. Visocontrastometry was carried out using Visokontrastometer-DT device with spatial frequency range from 0.4 to 19 cycle/degree (12 frequencies) and 125 x 125 monitor. The orientation of lattices was horizontal and vertical. The contrasts ranged from 0.03 to 0.9 (12 levels). MT brought about an improvement of spatial contrast sensitivity by at least 7 values of 12 levels in 22 (84.6%) out of 26 eyes and was unchanged in 4 eyes. Visual field was examined using Humphry automated analyzer. A 120-point threshold test was used. After a course of MT, visual field deficit decreased by at least 10% in 31 (72%) out of 43 eyes, increased in 3, and was unchanged in 9 eyes; on an average, visual field deficit decreased by 22.4% vs. the initial value. After 4 to 5 months the changes in the vision acuity and visual field deficit were negligible. In controls these parameters did not appreciably change over the entire follow-up period.

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.

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.

Vestn Oftalmol. 1993 Jul-Sep;109(4):16-8.

A new method for treating chronic blepharitis using magnetic compounds and an alternating magnetic field.

[Article in Russian]

Machekhin VA, Sheludchenko VM, Iablokova NV, Zvegintseva GB, Kapranova NE.

Discusses a new method of clinical use of alternating magnetic field from 0.1 to 0.25 T and of a magnetic ointment composition with reduced iron powder in patients with chronic blepharitis. Such treatment was found fairly effective, reducing the rehabilitation periods 2-3-fold and giving a good clinical effect (41-87%).

Vestn Oftalmol. 1990 Sep-Oct;106(5):54-7.

Effectiveness of magnetotherapy in optic nerve atrophy. A preliminary study.

[Article in Russian]

Zobina LV, Orlovskaia LS, Sokov SL, Sabaeva GF, Konde LA, Iakovlev AA.

Magnetotherapy effects on visual functions (vision acuity and field), on retinal bioelectric activity, on conductive vision system, and on intraocular circulation were studied in 88 patients (160 eyes) with optic nerve atrophy. A Soviet Polyus-1 low-frequency magnetotherapy apparatus was employed with magnetic induction of about 10 mT, exposure 7-10 min, 10-15 sessions per course. Vision acuity of patients with its low (below 0.04 diopters) values improved in 50 percent of cases. The number of patients with vision acuity of 0.2 diopters has increased from 46 before treatment to 75. Magnetotherapy improved ocular hemodynamics in patients with optic nerve atrophy, it reduced the time of stimulation conduction along the vision routes and stimulated the retinal ganglia cells. The maximal effect was achieved after 10 magnetotherapy sessions. A repeated course carried out in 6-8 months promoted a stabilization of the process.

Oftalmol Zh. 1990;(3):154-7.

The effect of a pulsed electromagnetic field on the hemodynamics of eyes with glaucoma.

[Article in Russian]

Tsisel’skii IuV, Kashintseva LT, Skrinnik AV.

The influence of pulse electromagnetic field (PEMF) on hemodynamics of the eye in open-angle glaucoma has been studied by means of a method and a device proposed at the Filatov Institute. The PEMF characteristics are: impulse frequency–50 Hz, exposition–0,02 sec., impulse shape–square, rate of impulse rise–4.10(4) c rate of magnetic induction rise–2.10(4) mT/c, amplitude value of magnetic induction at the impulse height–9.0–8.5 mT, duration of the procedure–7 min., a course–10 sessions. Observations over 150 patients (283 eyes) with latent, initial and advanced glaucoma have shown a positive influence of PEMF on hemodynamics of a glaucomatous eye: a rise of rheographic coefficient and relative volume pulse in 87,99 and 81,63%, respectively. The degree of the rise and restoration frequency of rheographic values of the glaucomatous eye under the influence of PEMF to the age norm was more expressed at initial stages of the glaucomatous process (latent and initial glaucoma).

Antibiotiki. 1982 Oct;27(10):774-5.

Action of gentamycin against a background of magnetotherapy of the anterior chamber in a traumatic infected erosion of the cornea.

[Article in Russian]

Verzin AA.

Fifteen patients with surface infections of the cornea due to a foreign body in one eye were treated with magnetophoresis and gentamicin before and after removal of the foreign bodies. The lower eyelid was turned back and a cotton tampon impregnated with 1 ml of a 0.3 per cent aqueous solution of gentamicin was applied. After that the tube of the alternating magneto was placed before the eyelids. The magnetic field (50 oersted, 50 Hz) was applied for 9 minutes. Such a treatment promoted suppression of the eye inflammatory reaction and accelerated corneal epithelization.

Erectile Dysfunction – Impotence

Urologiia. 2009 Nov-Dec;(6):17-21.

Nonpharmacological treatment of erectile dysfunction in obese patients.

[Article in Russian]

glybochko PV, Shaplygin LV, Ra?gorodski? IuM, Spirin PV, Alise?ko SV, Tverdokhleb SA.


An original combined treatment of obese patients with erectile dysfunction including transcranial magnetotherapy and transabdominal electrostimulation in the region of fat deposit for 6 months reduces body weight by up to 17% and elevates testosterone by up to 29%. Erectile function improved to normal in 31.8% patients. This method is pathogenetically sound in minimal use of medicines and low risk of cardiovascular disorders.

Adv Ther. 2002 Jan-Feb;19(1):53-60

Impulse magnetic-field therapy for erectile dysfunction: a double-blind, placebo-controlled trial.

Pelka R. Et.al. Universitat der Bundeswehr Munchen, Neubiberg/Munich, Germany.

This double-blind, placebo-controlled study assessed the efficacy of 3 weeks of pulsing magnetic-field therapy for erectile dysfunction (ED). In the active-treatment group, all efficacy endpoints were significantly improved at study end (P < or = .01), with 80% reporting increases in intensity and duration of erection, frequency of genital warmth, and general well-being. Only 30% of the placebo group noted some improvement in their sexual activity; 70% had no change. No side effects were reported.

Vopr Kurortol Fizioter Lech Fiz Kult. 1999 Mar-Apr;(2):25-7.

Physical factors in the treatment and rehabilitation of patients with chronic prostatitis complicated by impotence.

[Article in Russian]

Karpukhin IV, Bogomol’nyi VA.

103 patients with chronic prostatitis complicated by erectile impotence were given combined treatment including shock-wave massage, mud applications, local vacuum magnetotherapy. This combination was found to stimulate copulative function, urodynamics of the lower urinary tracts, to produce an antiinflammatory effect. These benefits allow to recommend the above physical factors for management of chronic prostatitis patients with copulative dysfunction.

Vopr Kurortol Fizioter Lech Fiz Kult. 1997 Jul-Aug;(4):24-5.

The sequential use of local vacuum magnetotherapy and papaverine electrophoresis with sinusoidal modulated currents in impotence.

[Article in Russian]

Karpukhin IV, Bogomol’nyi VA.

105 patients with chronic nonspecific prostatitis were examined and treated with papaverin electrophoresis using sinusoidal modulated currents (SMC) and local vacuum magnetotherapy (LVMT). Papaverin SMC electrophoresis and LVMT stimulated cavernous circulation. The highest stimulation was achieved at successive use of LVMT and the electrophoresis. LVMT followed by the electrophoresis maintained good cavernous circulation for 5-6 hours after the procedure in the course of which several spontaneous erections were observed.

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.

Lik Sprava. 1995 Mar-Apr;(3-4):95-7.

The use of magnetic devices in treating sexual disorders in men.

[Article in Russian]

Gorpinchenko II.

An effect was studied of appliances for magnetotherapy, such as <<Biopotenzor>>, <<Eros>>, <<Bioskan-1>>, on sexual function of 105 men presenting with sexual problems. A total of 96 sexological patients were examined according to a general programme, to study placebo-effect. The magnetic field beneficial effect was recordable in 70-80 % of the patients, that of placebo in 33 % men. It is suggested that augmentation of sexual activity is associated with an increase in cavernous bloodflow.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2001 Dec;18(4):658-60.

The development of clinical application of the rejuvenator and a study of its mechanism for the treatment of functional erectile dysfunction.

[Article in Chinese]

Meng Z, Zou Y, Luo E, Zou L.

Andrology Laboratory, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038.

In this paper, we describe the development and clinical application of the Rejuvenator and report the result of our study on its mechanism for the treatment of functional erectile dysfunction (FED). The Rejuvenator, which can be used both at home and in hospitals to treat patients with FED, was developed on the basis of our clinical practice in the light of the modern theory of traditional Chinese medicine and by integrating multiple techniques of engineering science. It works by means of the paraoral use of the special herbal medicine, electro-magnetic effects, thermal moxibustion and drug-ingression. 2250 patients with FED received the treatment. Using combined electro-neurophysiological techniques, pulsed ultrasound Doppler and microcomputer image-scanning, we further studied the mechanism of the Rejuvenator for the treatment of FED. The total effective rate was 92%. The clinical data and result of study indicate that the Rejuvenator for the patients with functional erectile dysfunction is a safe, effective and scientific new method.


Rev Med Suisse. 2005 Sep 21;1(33):2162-4, 2166.

Novel brain stimulation techniques: therapeutic perspectives in psychiatry.

[Article in French]
Berney A, Vingerhoets F.

Service de psychiatrie de liaison, CHUV, 1011 Lausanne. Alexandre.Berney@chuv.ch

Recent advances have allowed the development of new physical techniques in neurology and psychiatry, such as Transcranial Magnetic Stimulation (TMS), Vagus Nerve Stimulation (VNS), and Deep Brain Stimulation (DBS). These techniques are already recognized as therapeutic approaches in several late stage refractory neurological disorders (Parkinson’s disease, tremor, epilepsy), and currently investigated in psychiatric conditions, refractory to medical treatment (obsessive-compulsive disorder, resistant major depression). In Paralell, these new techniques offer a new window to understand the neurobiology of human behavior.

Curr Psychiatry Rep. 2005 Oct;7(5):381-90.

Transcranial magnetic stimulation for the treatment of depression in neurologic disorders.

Fregni F, Pascual-Leone A.

Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 452, Boston, MA 02215, USA.ffregni@bidmc.harvard.edu

Depression is commonly associated with neurologic disorders. Although depression in neurologic conditions often is associated with a negative impact on quality of life, it frequently is poorly managed. Some factors, such as a multidrug regimen, lack of efficacy, and side effects of antidepressants may explain why depression is not adequately treated in patients with neurologic disorders. Therefore, this population needs new approaches for depression treatment, and repetitive transcranial magnetic stimulation (rTMS) may be one of them because it has been shown to be effective for the treatment of depression alone and depression in certain neurologic diseases such as Parkinson’s disease and stroke. rTMS is a noninvasive, focal, and painless treatment associated with few, mild side effects. It may be effective in the treatment of neurologic diseases such as Parkinson’s disease, stroke, and epilepsy. In this paper, we discuss the potential risks and benefits of rTMS treatment for depression in Parkinson’s disease, epilepsy, stroke, multiple sclerosis, and Alzheimer’s disease. Lastly, a framework that includes the parameters of stimulation (intensity, frequency, number of pulses, and site of stimulation) for the treatment of depression in neurologic diseases is proposed.

Seizure. 2005 Sep;14(6):387-92.

Low-frequency repetitive transcranial magnetic stimulation for seizure suppression in patients with extratemporal lobe epilepsy-a pilot study.

Kinoshita M, Ikeda A, Begum T, Yamamoto J, Hitomi T, Shibasaki H.

Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.

We evaluated the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure frequency in adult patients with medically intractable extratemporal lobe epilepsy (ETLE). Seven patients with medically intractable ETLE received low-frequency rTMS at 0.9 Hz, basically two sets of 15 min stimulation per day for five days in a week, with the stimulus intensity of 90% of resting motor threshold (RMT). The number of seizures during two weeks before and after the stimulation of one week was compared. Furthermore, RMT and active motor threshold (AMT) were measured before and after rTMS for each daily session. After low-frequency rTMS of one week, the frequency of all seizure types, complex partial seizures (CPSs) and simple partial seizures was reduced by 19.1, 35.9 and 7.4%, respectively. The patients with smaller difference between RMT and AMT before rTMS had higher reduction rate of CPSs. A favorable tendency of seizure reduction, though not statistically significant, during two weeks after low-frequency rTMS was demonstrated in medically intractable ETLE patients. As far as CPSs are concerned, smaller decrease of motor threshold by voluntary muscle contraction was associated with better response to rTMS.

Epilepsy Behav. 2005 Sep;7(2):182-9.

Transcranial magnetic stimulation treatment for epilepsy: can it also improve depression and vice versa?

Fregni F, Schachter SC, Pascual-Leone A.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. ffregni@bidmc.harvard.edu

Comorbidity with depression is an important determinant of the quality of life for patients with epilepsy. Antidepressant medications can effectively treat depression in epileptic patients, but drug-drug interactions and epileptogenic effects of these drugs pose therapeutic challenges. The mood-stabilizing effects of antiepileptic medications may not be sufficient to treat depression. Therefore, treatments that alleviate the burden of depression without increasing seizure risk or, better yet, with the possibility of improving seizure control are worth exploring. Neuroimaging techniques, such as functional magnetic resonance imaging, are providing novel insights into the pathophysiology of depression in epilepsy. For example, there appears to be prominent brain prefrontal hypoactivity, which may be sustained by the hyperactivity of the seizure focus. If so, neuromodulatory approaches that suppress epileptic focus hyperactivity and concurrently enhance prefrontal activity may be ideally suited. Indeed, vagus nerve stimulation has been shown to yield simultaneous antiseizure and mood effects. Another neuromodulatory technique, transcranial magnetic stimulation (TMS), can also modulate brain activity, but in a noninvasive, painless, and focal manner. Depending on the stimulation parameters, it is possible to enhance or reduce activity in the targeted brain region. Furthermore, TMS has been shown to be effective in treating depression, and preliminary data suggest that this treatment may also be effective for epilepsy treatment. This article reviews these data and explores further the question of whether depression and epilepsy can be simultaneously treated with TMS for optimal therapeutic impact.

Seizure. 2005 Sep;14(6):387-92.

Low-frequency repetitive transcranial magnetic stimulation for seizure suppression in patients with extratemporal lobe epilepsy-a pilot study.

Kinoshita M, Ikeda A, Begum T, Yamamoto J, Hitomi T, Shibasaki H.

Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.

We evaluated the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure frequency in adult patients with medically intractable extratemporal lobe epilepsy (ETLE). Seven patients with medically intractable ETLE received low-frequency rTMS at 0.9 Hz, basically two sets of 15 min stimulation per day for five days in a week, with the stimulus intensity of 90% of resting motor threshold (RMT). The number of seizures during two weeks before and after the stimulation of one week was compared. Furthermore, RMT and active motor threshold (AMT) were measured before and after rTMS for each daily session. After low-frequency rTMS of one week, the frequency of all seizure types, complex partial seizures (CPSs) and simple partial seizures was reduced by 19.1, 35.9 and 7.4%, respectively. The patients with smaller difference between RMT and AMT before rTMS had higher reduction rate of CPSs. A favorable tendency of seizure reduction, though not statistically significant, during two weeks after low-frequency rTMS was demonstrated in medically intractable ETLE patients. As far as CPSs are concerned, smaller decrease of motor threshold by voluntary muscle contraction was associated with better response to rTMS.

J Neurol Sci. 2005 Jul 15;234(1-2):37-9.

Low-frequency transcranial stimulation for epilepsia partialis continua due to cortical dysplasia.

Misawa S, Kuwabara S, Shibuya K, Mamada K, Hattori T.

Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. sonoko.m@mb.infoweb.ne.jp

The potential therapeutic role of repetitive transcranial magnetic stimulation (rTMS) in epilepsy has been increasingly recognized. We investigated the effects of low-frequency rTMS in a patient with epilepsia partialis continua (EPC) due to cortical dysplasia. A 31-year-old female patient experienced EPC in the right upper and lower extremities, which had lasted for 15 years without generalized seizures. MRI showed focal megaencephaly around the motor cortex suggestive of cortical dysplasia. A figure of eight magnetic coil was placed over the hand motor area, and 100 stimuli with an intensity at 90% of motor threshold were given at 0.5 Hz. Immediately after rTMS, EPC was nearly abolished. The effects had continued approximately for 2 months, and the second trial resulted in the similar effects and time-course. Low-frequency rTMS was safe and well tolerated in this patient. These findings support the concept that rTMS decreases cortical excitability, and may be an effective treatment for focal partial seizures.

J ECT. 2005 Jun;21(2):88-95.

Transcranial magnetic stimulation in persons younger than the age of 18.

Quintana H.

Department of Psychiatry, Division of Child and Adolescent Psychiatry, Louisiana State University Health Science Center, School of Medicine, New Orleans, Louisiana 70112-2822, USA. Hquint@lsuhsc.edu

OBJECTIVES: To review the use of transcranial magnetic stimulation (single-pulse TMS, paired TMS, and repetitive TMS [rTMS]) in persons younger than the age of 18 years. I discuss the technical differences, as well as the diagnostic, therapeutic, and psychiatric uses of TMS/rTMS in this age group.

METHODS: I evaluated English-language studies from 1993 to August 2004 on nonconvulsive single-pulse, paired, and rTMS that supported a possible role for the use of TMS in persons younger than 18. Articles reviewed were retrieved from the MEDLINE database and Clinical Scientific index.

RESULTS: The 48 studies reviewed involved a total of 1034 children ages 2 weeks to 18 years; 35 of the studies used single-pulse TMS (980 children), 3 studies used paired TMS (20 children), and 7 studies used rTMS (34 children). Three studies used both single and rTMS. However, the number of subjects involved was not reported.

CONCLUSIONS: Single-pulse TMS, paired TMS, and rTMS in persons younger than 18 has been used to examine the maturation/activity of the neurons of various central nervous system tracts, plasticity of neurons in epilepsy, other aspects of epilepsy, multiple sclerosis, myoclonus, transcallosal inhibition, and motor cortex functioning with no reported seizure risk. rTMS has been applied to psychiatric disorders such as ADHD, ADHD with Tourette’s, and depression. Adult studies support an antidepressant effect from repetitive TMS, but there is only one study that has been reported on 7 patients that used rTMS to the left dorsal prefrontal cortex on children/adolescents with depression (5 of the 7 subjects treated responded). Although there are limited studies using rTMS (in 34 children), these studies did not report significant adverse effects or seizures. Repetitive TMS safety, ethical, and neurotoxicity concerns also are discussed.

Neurobiol Dis. 2005 Jun-Jul;19(1-2):119-28.

Repetitive low-frequency stimulation reduces epileptiform synchronization in limbic neuronal networks.

D’Arcangelo G, Panuccio G, Tancredi V, Avoli M.

Dipartimento di Neuroscienze, Universita degli Studi di Roma Tor Vergata, 00173, Roma, Italy.

Deep-brain electrical or transcranial magnetic stimulation may represent a therapeutic tool for controlling seizures in patients presenting with epileptic disorders resistant to antiepileptic drugs. In keeping with this clinical evidence, we have reported that repetitive electrical stimuli delivered at approximately 1 Hz in mouse hippocampus-entorhinal cortex (EC) slices depress the EC ability to generate ictal activity induced by the application of 4-aminopyridine (4AP) or Mg(2+)-free medium (Barbarosie, M., Avoli, M., 1997. CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J. Neurosci. 17, 9308-9314.). Here, we confirmed a similar control mechanism in rat brain slices analyzed with field potential recordings during 4AP (50 microM) treatment. In addition, we used intrinsic optical signal (IOS) recordings to quantify the intensity and spatial characteristics of this inhibitory influence. IOSs reflect the changes in light transmittance throughout the entire extent of the slice, and are thus reliable markers of limbic network epileptiform synchronization. First, we found that in the presence of 4AP, the IOS increases, induced by a train of electrical stimuli (10 Hz for 1 s) or by recurrent, single-shock stimulation delivered at 0.05 Hz in the deep EC layers, are reduced in intensity and area size by low-frequency (1 Hz), repetitive stimulation of the subiculum; these effects were observed in all limbic areas contained in the slice. Second, by testing the effects induced by repetitive subicular stimulation at 0.2-10 Hz, we identified maximal efficacy when repetitive stimuli are delivered at 1 Hz. Finally, we discovered that similar, but slightly less pronounced, inhibitory effects occur when repetitive stimuli at 1 Hz are delivered in the EC, suggesting that the reduction of IOSs seen during repetitive stimulation is pathway dependent as well as activity dependent. Thus, the activation of limbic networks at low frequency reduces the intensity and spatial extent of the IOS changes that accompany ictal synchronization in an in vitro slice preparation. This conclusion supports the view that repetitive stimulation may represent a potential therapeutic tool for controlling seizures in patients with pharmaco-resistant epileptic disorders.

Neuron. 2005 Jan 20;45(2):181-3.

Towar 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.

Neurology. 2004 Dec 14;63(11):2051-5.

Cortical excitability in drug-naive patients with partial epilepsy: a cross-sectional study.

Varrasi C, Civardi C, Boccagni C, Cecchin M, Vicentini R, Monaco F, Cantello R.

Department of Medical Sciences, Section of Neurology, Universita del Piemonte Orientale A. Avogadro, Novara, Italy.

OBJECTIVE: To use paired-pulse transcranial magnetic stimulation (TMS) to investigate cortical excitability in drug-naive patients with partial epilepsy.

METHODS: Twenty-one drug-naive patients with partial epilepsy and 15 control subjects were studied. The relaxed threshold to TMS, the central silent period, and the intracortical inhibition/facilitation were measured. Statistics implied cluster analysis methods. Also assessed were the patient interictal EEG epileptiform abnormalities (EAs) on a semiquantitative basis. Then the TMS was contrasted to the clinical and EEG findings, using chi2 or Fisher exact tests.

RESULTS: One-third of the patients made up a “pathologic” cluster with a disrupted intracortical inhibition (p < 0.01). Two-thirds had a normal inhibition. Interictal EAs predominated in the pathologic cluster, for frequency (p < 0.04), duration (p < 0.04), and focality (p < 0.02).

CONCLUSIONS: Intracortical inhibition, which was impaired in one-third of the patients, reflects gamma-aminobutyric acid (GABA) activity within cortical area 4. Defective GABA inhibition is a typical pathogenic factor in partial epilepsy. Transcranial magnetic stimulation proved able to detect it. The weaker cortical inhibition had a direct relation to the severity of interictal epileptiform abnormalities.

Child Adolesc Psychiatr Clin N Am. 2005 Jan;14(1):193-210, viii-ix.

Electoconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua.

Morales OG, Henry ME, Nobler MS, Wassermann EM, Lisanby SH.

Magnetic Brain Stimulation Laboratory, Department of Biological Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, Box 126, New York, NY 10032-2695, USA. om2102@columbia.edu

Brain stimulation for the treatment of psychiatric disorders has received increasing attention over the past decade. The introduction of experimental means to stimulate the brain noninvasively with magnetic fields not only has raised interest in these novel means of modulating brain activity but also has refocused attention on a mainstay in the treatment of severe major depression and other disorders (electroconvulsive therapy). This article reviews the current state of knowledge concerning the use electroconvulsive therapy, repetitive transcranial magnetic stimulation, and magnetic seizure therapy in children and adolescents. Two cases of medically intractable epilepsia partialis continua are presented to add to the limited literature on the use of repetitive transcranial magnetic stimulation in children and adolescents and illustrate the concept of using functional neuroimaging results to target the application of a focal intervention in an attempt to dampen hyperactive regions of the cortex.

Zh Vyssh Nerv Deiat Im I P Pavlova. 2005 Mar-Apr;55(2):202-6.

Transcranial magnetic stimulation in research of emotion in the healthy and patients with epilepsy.

[Article in Russian]

Gimranov RF, Kurdiukova EN.

The main aim of this work was by using transcranial magnetic stimulation to investigate mechanisms of interhemispheric organization the emotion in the healthy and patients with epilepsy. The research was carried out on three groups: the first and second groups of healthy and third group of the patients with idiopatical epilepsy. The first and third groups received transcranial magnetic stimulation on right and left frontalis area. The second group was control (sham transcranial magnetic stimulation). Is shown, that transcranial magnetic stimulation of right frontalis area increases the examining time on negative photos and decreases on positive photos. Transcranial magnetic stimulation of left frontalis area in the healthy and patients with epilepsy increases the examining time on positive photos and decreases on negative photos. The right hemisphere at the healthy and patients with epilepsy in the greater degree is connected to negative marks of emotions, and left hemisphere with positive marks of emotions.

Child Adolesc Psychiatr Clin N Am. 2005 Jan;14(1):1-19, v.

Emerging brain-based interventions for children and adolescents: overview and clinical perspective.

Hirshberg LM, Chiu S, Frazier JA.

The NeuroDevelopment Center, 260 West Exchange Street, Suite 302, Providence, RI 02903, USA. lhirshberg@neruodevelopmentcenter.com

Electroencephalogram biofeedback (EBF), repetitive transcranial magnetic stimulation (rTMS), and vagal nerve stimulation (VNS) are emerging interventions that attempt to directly impact brain function through neurostimulation and neurofeedback mechanisms. This article provides a brief overview of each of these techniques, summarizes the relevant research findings, and examines the implications of this research for practice standards based on the guidelines for recommending evidence based treatments as developed by the American Academy of Child and Adolescent Psychiatry for attention deficit hyperactivity disorder (ADHD). EBF meets the “Clinical Guidelines” standard for ADHD, seizure disorders, anxiety, depression, and traumatic brain injury. VNS meets this same standard for treatment of refractory epilepsy and meets the lower “Options” standard for several other disorders. rTMS meets the standard for “Clinical Guidelines” for bipolar disorder, unipolar disorder, and schizophrenia. Several conditions are discussed regarding the use of evidence based thinking related to these emerging interventions and future directions.

Clin Neurophysiol. 2004 Dec;115(12):2728-37.

Seizure incidence during single- and paired-pulse transcranial magnetic stimulation (TMS) in individuals with epilepsy.

Schrader LM, Stern JM, Koski L, Nuwer MR, Engel J Jr.

Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Room 1-194 RNRC, Los Angeles, CA 90095, USA. ischrader@mednet.ucla.edu

OBJECTIVE: We reviewed published data and our own data to determine a quantitative incidence of seizure in subjects with epilepsy undergoing single- and paired-pulse transcranial magnetic stimulation (spTMS and ppTMS) and to explore conditions that may increase this risk.

METHODS: A PubMed literature search was performed, and articles from this search were reviewed. Subjects from our institution also were included.

RESULTS: The crude risk of a TMS-associated seizure ranges from 0.0 to 2.8% for spTMS and 0.0-3.6% for ppTMS. Medically intractable epilepsy and lowering antiepileptic drugs were associated with increased incidence. There was significant center-to-center variability that could not be explained by differences in patient population or by differences in reported stimulation parameters. In all cases, seizures were similar to each subject’s typical seizure and without long-term adverse outcome. In most cases, doubt was expressed in the original reports as to whether the seizures were induced by TMS or merely coincidental.

CONCLUSIONS: The incidence of seizure in a subject with epilepsy during spTMS and ppTMS appears to be small and not associated with long-term adverse outcome. The incidence is higher under the specific conditions mentioned above.

SIGNIFICANCE: These findings may enable researchers to more accurately inform subjects of seizure risk during TMS.

Rev Bras Psiquiatr. 2004 Jun;26(2):131-4. Epub 2004 Oct 27.

Transcranial magnetic stimulation: review of accidental seizures.

[Article in Portuguese]

Rosa MA, Odebrecht M, Rigonatti SP, Marcolin MA.

Instituto e Departamento de Psiquiatria, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, SP, Brazil. moarosa@yahoo.com

Transcranial magnetic stimulation (TMS) is a new technique that has been used for the treatment of neuropsychiatric disorders, specially depression. It uses a magnetic stimulator that generates a magnetic field that is applied over the patient’s skull with a coil. Possible seizures may be induced accidentally by TMS. TMS is usually used with sub threshold stimuli and seizures may occur by chance, especially when over the safety parameters. This article reviews the eight cases of undesirable seizures occurred with rTMS The possible mechanisms of seizure induction and the patients profile with a higher risk of convulsion are also described.

J Neurol Sci. 2004 Oct 15;225(1-2):157-60.

Epilepsia partialis continua as an isolated manifestation of motor cortical dysplasia.

Misawa S, Kuwabara S, Hirano S, Shibuya K, Arai K, Hattori T.

Department of Neurology, Chiba University School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan. sonoko.m@mb.infoweb.ne.jp

Cortical dysplasia has been increasingly recognized as a cause of epilepsy. We describe herein a 31-year-old female patient with epilepsia partialis continua (EPC) in the right extremities, which had lasted for 15 years without generalized seizures and other neurological deteriorations. MRI showed a focal thickening around the left motor area, indicative of cortical dysplasia, with adjacent subcortical abnormal T2 high intensity, suggestive of dysmyelination. Transcranial magnetic stimulation revealed low motor thresholds and markedly prolonged latencies of motor-evoked potentials (MEP) of the affected side, consistent with hyperexcitability of the cortical motoneurons accompanied by dysmyelination. This case demonstrates that motor cortex dysplasia can result in a mild and non-progressive form of epilepsia partialis continua, associated with the characteristic MRI and MEP abnormalities.

Mult Scler. 2004 Aug;10(4):475-6.

Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis.

Haupts MR, Daum S, Ahle G, Holinka B, Gehlen W.

Department of Neurology, Ruhr University/Knappschaftskrankenhaus, In der Schornau 23-25, D-44892 Bochum, Germany. Michael.Haupts@ruhr-uni-bochum.de

Epileptic seizures may be of a provoked origin in acute phases of multiple sclerosis (MS), while chronic epilepsy typically occurs in advanced stages of the disease. A case of seizure provocation during diagnostic transcranial magnetic stimulation (TMS) is described here with a corresponding central nervous system (CNS) lesion in cranial magnetic resonance imaging. A subsequent chronic epileptogenesis originating from the opposite cerebral hemisphere was observed without further TMS influence after several years. The case in its clinical rarity demonstrates that standard single pulse TMS may trigger epileptic seizures only under limited conditions. Single pulse TMS is still regarded a safe procedure in MS.

Rinsho Shinkeigaku. 2003 Nov;43(11):799-801.

Current diagnosis and treatment of status epilepticus.

[Article in Japanese]

Akamatsu N, Tsuji S.

We reviewed the current diagnosis and treatment of status epilepticus (SE). The SE is defined as the condition in which a seizure persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur. Until recently, the most popular duration of seizures qualifying as SE has been 30 min. Nonetheless some clinicians suggest that the duration of the seizures that qualifies the SE should be shorter. In clinical settings the diagnosis of SE could be difficult without EEGs in patients who have complex partial SE or subtle SE, as their manifestation is coma without apparent motor sings. Pseudo-SE (psychogenic seizures) should be included in the differential diagnosis. Antiepileptic treatment should be administered immediately according to the protocol once the diagnosis of SE is made. In patients with refractory SE, general anesthesia with propofol or midazolam is recommended. Repetitive transcranial magnetic stimulation to the brain is effective for the treatment of SE in experimental animals, however further studies are necessary for clinical use.

Arq Neuropsiquiatr. 2004 Mar;62(1):21-5. Epub 2004 Apr 28.

Experimental therapy of epilepsy with transcranial magnetic stimulation: lack of additional benefit with prolonged treatment.

Brasil-Neto JP, de Araujo DP, Teixeira WA, Araujo VP, Boechat-Barros R.

Laboratorio de Neurociencias e Comportamento, Departamento de Ciencias Fisiologicas, Instituto de Biologia, Universidade de Brasilia, Brasilia, DF, Brasil. jbrasil@unb.br

OBJECTIVE: To investigate the effect of three months of low-frequency repetitive transcranial magnetic stimulation (rTMS) treatment in intractable epilepsy.

METHODS: Five patients (four males, one female; ages 6 to 50 years), were enrolled in the study; their epilepsy could not be controlled by medical treatment and surgery was not indicated. rTMS was performed twice a week for three months; patients kept records of seizure frequency for an equal period of time before, during, and after rTMS sessions. rTMS was delivered to the vertex with a round coil, at an intensity 5% below motor threshold. During rTMS sessions, 100 stimuli (five series of 20 stimuli, with one-minute intervals between series) were delivered at a frequency of 0.3 Hz.

RESULTS: Mean daily number of seizures (MDNS) decreased in three patients and increased in two during rTMS–one of these was treated for only one month; the best result was achieved in a patient with focal cortical dysplasia (reduction of 43.09% in MDNS). In the whole patient group, there was a significant (p<0.01) decrease in MDNS of 22.8%.

CONCLUSION: Although prolonged rTMS treatment is safe and moderately decreases MDNS in a group of patients with intractable epilepsy, individual patient responses were mostly subtle and clinical relevance of this method is probably low. Our data suggest, however, that patients with focal cortical lesions may indeed benefit from this novel treatment. Further studies should concentrate on that patient subgroup.

Clin EEG Neurosci. 2004 Jan;35(1):4-13.

Current status of the utilization of antiepileptic treatments in mood, anxiety and aggression: drugs and devices.

Barry JJ, Lembke A, Bullock KD.

Department of Psychiatry, Stanford University Medical Center, 401 Quarry Road MC 5723, Stanford, CA 94305, USA.jbarry@leland.stanford.edu

Interventions that have been utilized to control seizures in people with epilepsy have been employed by the psychiatric community to treat a variety of disorders. The purpose of this review will be to give an overview of the most prominent uses of antiepileptic drugs (AEDs) and devices like the Vagus Nerve Stimulator (VNS) and Transcranial Magnetic Stimulation (TMS) in the treatment of psychiatric disease states. By far, the most prevalent use of these interventions is in the treatment of mood disorders. AEDs have become a mainstay in the effective treatment of Bipolar Affective Disorder (BAD). The U.S. Food and Drug Administration has approved the use of valproic acid for acute mania, and lamotrigine for BAD maintenance therapy. AEDs are also effectively employed in the treatment of anxiety and aggressive disorders. Finally, VNS and TMS are emerging as possibly useful tools in the treatment of more refractory depressive illness.

Zh Nevrol Psikhiatr Im S S Korsakova. 2004;104(3):25-31.

Clinical and neurophysiological aspects of epilepsy with photosensitivity.

[Article in Russian]

Karlov VA, Dondov B, Gnezditskii VV, Savitskaia NV, Andreeva OV.

Using mapping EEG with dipole source location, transcranial magnetic stimulation (TMS), and visual evoked potential (VEP), clinico-neurophysiological analysis of photosensitivity was carried out in 7 patients with different types of epilepsy. In all the patients, an increase of visual response amplitude in VEP assessment and location of photogenic and eye-closing spike activity was observed in parietal and occipital areas that suggested a significant role of the striate and para striate cortex, along with primary projection cortex, in photosensitivity. Although motor cortex excitability by TMS causes hypersynchronization of the background activity and increase of slow wave discharge on the EEG after TMS. TMS is supposed to cause an activation of antiepileptic system.

Acta Neurol Scand. 2004 Apr;109(4):290-6.

rTMS reduces focal brain hyperperfusion in two patients with EPC.

Graff-Guerrero A, Gonzales-Olvera J, Ruiz-Garcia M, Avila-Ordonez U, Vaugier V, Garcia-Reyna JC.

Instituto Nacional de Psiquiatria Ramon de la Fuente, Division de Neurociencias, Laboratorio de Neurofisiologia, Mexico DF. agraff@imp.edu.mx

OBJECTIVE: This study was performed to evaluate the acute effect of a single repetitive transcranial magnetic stimulation (rTMS) session in a focal hyperperfusion epileptogenic region to induce a transitory decrease of epileptiform activity.

CASE REPORT: Two epilepsia partialis continua (EPC)-diagnosed patients, received one session with 15 trains of rTMS (20 Hz; 2 s train, inter-train of 58 s). Before rTMS session, a brain ictal single photon emission computed tomography (SPECT) was performed to localize the focal frontal hyperperfusion region to establish the stimulation site. Immediately after the rTMS session another ictal SPECT was performed. Both patients showed a decrease of perfusion in the stimulated regions. For patient 1 epileptic seizures became intermittent until they stopped in the following 24 h. Patient 2 showed only a minimal improvement with a frequency decrease of epileptic spikes.

CONCLUSIONS: Our findings suggest that a single rTMS session reduces focal epileptogenic activity and could be an alternative approach for epileptic-resistant patients, but efficacy should be confirmed in a larger series.

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

Transcranial magnetic stimulation.  Applications in cognitive neuroscience.

[Article in Spanish]

Calvo-Merino B, Haggard P.

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

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

DEVELOPMENT: Among the many methods now available for studying activity of the human brain, magnetic stimulation is the only technique that allows us to interfere actively with human brain function. At the same time it provides a high degree of spatial and temporal resolution. Standard TMS applications (central motor conduction time, threshold and amplitude of motor evoked potentials) allow the evaluation of the motor conduction in the central nervous system and more complex TMS applications (paired pulse stimulation, silent period) permit study the mechanisms of diseases causing changes in the excitability of cortical areas. These techniques also allow investigation into motor disorder, epilepsy, cognitive function and psychiatric disorders.

CONCLUSIONS: Transcranial magnetic stimulation applications have an important place among the investigative tools to study cognitive functions and neurological and psychiatric disorders. Even so, despite the many published research and clinical studies, a systematic study about the possible diagnostic value and role in neurocognitive rehabilitation of TMS testing need to be realized to offer new possibilities of future applications.

Lancet Neurol. 2004 Feb;3(2):111-8.

Brain stimulation for epilepsy.

Theodore WH, Fisher RS.

Clinical Epilepsy Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. theodorw@ninds.nih.gov

Neural stimulation is a promising new technology for the treatment of medically-intractable seizures. Vagus-nerve stimulation (VNS) is licensed in several countries as an adjunctive therapy. VNS is as effective as antiepileptic drug therapy, and serious complications are rare. Transcranial magnetic stimulation is simple, non-invasive, and widely used in neurophysiology. Therapeutic results in a few studies are equivocal at best. Deep brain stimulation, although experimental, has been applied to the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus, and neocortical seizure foci. Preliminary results are encouraging, but not conclusive. Electrode implantation in the brain for indications other than seizures has been associated with a 5% risk for intracranial haemorrhage and 5% for infection. A controlled study of anterior thalamic stimulation in patients with intractable partial and secondarily generalised seizures has been started. Future investigations are likely to study extrathalamic sites of stimulation, and effects of stimulation contingent upon detection of or prediction of EEG patterns of epileptiform activity.

J Pharmacol Exp Ther. 2004 Apr;309(1):1-7. Epub 2004 Jan 16.

Brain stimulation for neurological and psychiatric disorders, current status and future direction.

Chang JY.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA. jchang@wfubmc.edu

Interest in brain stimulation therapies has been rejuvenated over the last decade and brain stimulation therapy has become an alternative treatment for many neurological and psychiatric disorders, including Parkinson’s disease (PD), dystonia, pain, epilepsy, depression, and schizophrenia. The effects of brain stimulation on PD are well described, and this treatment has been widely used for such conditions worldwide. Treatments for other conditions are still in experimental stages and large-scale, well controlled studies are needed to refine the treatment procedures. In the treatment of intractable brain disorders, brain stimulation, especially transcranial magnetic stimulation (TMS), is an attractive alternative to surgical lesioning as it is relatively safe, reversible, and flexible. Brain stimulation, delivered either via deeply implanted electrodes or from a surface-mounted transcranial magnetic device, can alter abnormal neural circuits underlying brain disorders. The neural mechanisms mediating the beneficial effects of brain stimulation, however, are poorly understood. Conflicting theories and experimental data have been presented. It seems that the action of stimulation on brain circuitry is not limited to simple excitation or inhibition. Alterations of neural firing patterns and long-term effects on neurotransmitter and receptor systems may also play important roles in the therapeutic effects of brain stimulation. Future research on both the basic and clinical fronts will deepen our understanding of how brain stimulation works. Real-time computation of neural activity allows for integration of brain stimulation signals into ongoing neural processing. In this way abnormal circuit activity can be adjusted by optimal therapeutic brain stimulation paradigms.

Neurosci Lett. 2004 Jan 9;354(2):91-4.

Intracranial measurement of current densities induced by transcranial magnetic stimulation in the human brain.

Wagner T, Gangitano M, Romero R, Theoret H, Kobayashi M, Anschel D, Ives J, Cuffin N, Schomer D, Pascual-Leone A.

Laboratory for Magnetic Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave KS-454, Boston, MA 02215, USA.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that uses the principle of electromagnetic induction to generate currents in the brain via pulsed magnetic fields. The magnitude of such induced currents is unknown. In this study we measured the TMS induced current densities in a patient with implanted depth electrodes for epilepsy monitoring. A maximum current density of 12 microA/cm2 was recorded at a depth of 1 cm from scalp surface with the optimum stimulation orientation used in the experiment and an intensity of 7% of the maximal stimulator output. During TMS we recorded relative current variations under different stimulating coil orientations and at different points in the subject’s brain. The results were in accordance with current theoretical models. The induced currents decayed with distance form the coil and varied with alterations in coil orientations. These results provide novel insight into the physical and neurophysiological processes of TMS.

Epilepsia. 2004 Jan;45(1):77-80.

Motor responses to afferent stimulation in juvenile myoclonic epilepsy.

Manganotti P, Tamburin S, Bongiovanni LG, Zanette G, Fiaschi A.

Department of Neurological Sciences and Vision, Section of Neurological Rehabilitation Clinical Neurology, University of Verona, Verona, Italy.

PURPOSE: To document whether the mechanisms responsible for myoclonic jerks in juvenile myoclonic epilepsy (JME) are similar to those causing other forms of myoclonus.

METHODS: We studied somatosensory evoked potentials, the conditioning effect of cutaneous afferents on motor potentials evoked by transcranial magnetic stimulation (TMS), and intracortical inhibition and facilitation in response to paired TMS in a group of nine patients with JME and 20 normal controls.

RESULTS: Intracortical inhibition was abnormal, whereas cortical somatosensory evoked potentials and TMS conditioned by cutaneous afferents were unaltered in JME patients.

CONCLUSIONS: Abnormal processing of cutaneous afferents would not appear to contribute to myoclonus in JME.

J Neurosci. 2003 Nov 26;23(34):10867-72.

Priming stimulation enhances the depressant effect of low-frequency repetitive trnscranial magnetic stimulation.

Iyer MB, Schleper N, Wassermann EM.

Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1430, USA.

Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) can depress the excitability of the cortex locally and has been proposed for the treatment of disorders such as schizophrenia and epilepsy. Some have speculated that the depressant effect is related to long-term depression (LTD) of cortical synapses. Because in vitro LTD can be enhanced by pretreatment of synapses with higher-frequency stimulation, we hypothesized that if rTMS depression had mechanisms in common with LTD, higher-frequency priming would increase it also. In 25 healthy volunteers in two experiments, we measured motor-evoked potentials (MEPs) from TMS of the motor cortex to define the baseline response. Subthreshold rTMS (6 Hz, fixed rate or frequency modulated) was used to prime the motor cortex, followed by suprathreshold 1 Hz stimulation for 10 min at just above the MEP threshold. Over the next 60 min, we recorded MEPs every 10 sec and found significant increases in the amount of cortical depression with both types of 6 Hz priming rTMS relative to sham. The MEP depression from 6 Hz-primed 1 Hz rTMS showed no evidence of decay after 60 min. Pretreatment with 6 Hz primes both 1 Hz rTMS depression and LTD. Although not conclusive evidence, this strengthens the case for overlapping mechanisms and suggests a potent new technique for enhancing low-frequency rTMS depression that may have experimental and clinical applications.

Epilepsy Behav. 2003 Oct;4 Suppl 3:S46-54.

Treatment of depression in patients with epilepsy: problems, pitfalls, and some solutions.

Krishnamoorthy ES.

T.S. Srinivasan Institute of Neurological Sciences and Research, Public Health Centre, Chennai, India. E.S.Krishnamoorthy@ion.ucl.ac.uk

Many people with epilepsy suffer from comorbid depression. Despite this, there have been few studies addressing the treatment of depression in this population, and the literature on psychiatric management techniques in patients with epilepsy is composed largely of opinions rather than evidence from randomized, controlled trials or other systematic investigations. Antidepressant drugs, including tricyclics and selective serotonin reuptake inhibitors, can be used to treat patients with epilepsy and comorbid depression. Nonpharmacological treatment options include vagus nerve stimulation, transcranial magnetic stimulation, and psychological therapies including cognitive-behavioral therapy, individual or group psychotherapy, patient support groups, family therapy, and counseling. Another important area that remains largely uninvestigated is psychiatric research in patients with epilepsy in non-Western cultures (with the exception of Japan). Factors such as problems with access to and acceptability of therapies in many developing nations have further implications for the treatment of psychiatric disorders in epilepsy.

Neurosci Lett. 2003 Nov 6;351(1):9-12.

Anti-kindling effect of slow repetitive transcranial magnetic stimulation in rats.

Anschel DJ, Pascual-Leone A, Holmes GL.

Laboratory for Magnetic Brain Stimulation, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. danschel@stanford.edu

The cerebrospinal fluid (CSF) of animals exposed to electroconvulsive shock (ECS) has anticonvulsant properties when injected into naive animals. The present study investigated whether the CSF of humans exposed to 1 or 10 Hz repetitive transcranial magnetic stimulation (rTMS) has similar properties. Using a 4 day rat flurothyl kindling seizure model we found that the kindling rate was significantly decreased by intraventricular injection of CSF from depressed patients exposed to 1 Hz rTMS. The CSF from patients that underwent 10 Hz rTMS showed a trend toward an increased kindling rate. These results support the similarity of ECS and rTMS and suggest that 1 Hz and 10 Hz rTMS produce distinct physiologic changes.

Clin Neurophysiol. 2003 Oct;114(10):1827-33.

Suprathreshold 0.3 Hz repetitive TMS prolongs the cortical silent period: potential implications for therapeutic trials in epilepsy.

Cincotta M, Borgheresi A, Gambetti C, Balestrieri F, Rossi L, Zaccara G, Ulivelli M, Rossi S, Civardi C, Cantello R.

Unita’ Operativa di Neurologia, Azienda Sanitaria di Firenze, Ospedale S. Maria Nuova, Piazza S. Maria Nuova, 1 50122, Florence, Italy. cincotta@unifi.it

OBJECTIVE: To investigate the after-effects of 0.3 Hz repetitive transcranial magnetic stimulation (rTMS) on excitatory and inhibitory mechanisms at the primary motor cortex level, as tested by single-pulse TMS variables.

METHODS: In 9 healthy subjects, we studied a wide set of neurophysiological and behavioral variables from the first dorsal interosseous before (Baseline), immediately after (Post 1), and 90 min after (Post 2) the end of a 30 min long train of 0.3 Hz rTMS delivered at an intensity of 115% resting motor threshold (RMT). Variables under investigation were: maximal M wave, F wave, and peripheral silent period after ulnar nerve stimulation; RMT, amplitude and stimulus-response curve of the motor evoked potential (MEP), and cortical silent period (CSP) following TMS; finger-tapping speed.

RESULTS: The CSP was consistently lengthened at both Post 1 and Post 2 compared with Baseline. The other variables did not change significantly.

CONCLUSIONS: These findings suggest that suprathreshold 0.3 Hz rTMS produces a relatively long-lasting enhancement of the inhibitory mechanisms responsible for the CSP. These effects differ from those, previously reported, of 0.9-1 Hz rTMS, which reduces the excitability of the circuits underlying the MEP and does not affect the CSP. This provides rationale for sham-controlled trials aiming to assess the therapeutic potential of 0.3 Hz rTMS in epilepsy.

Seizure. 2003 Sep;12(6):373-8.

Usefulness of magnetic motor evoke potentials in the surgical treatment of hemiplegic patients with intractable epilepsy.

Kamida T, Baba H, Ono K, Yonekura M, Fujiki M, Kobayashi H.

Department of Neurosurgery, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita 879-55, Japan.

Five hemiplegic patients with intractable epilepsy were studied with transcranial magnetic stimulation (TMS) before and after various surgical treatments. These patients had unilateral widespread cerebral lesions acquired at various times, including congenital, infantile and childhood injury. Motor evoked potentials (MEPs) of the abductor pollicis brevis (APB) muscles were simultaneously recorded on both sides following TMS of the motor cortex in the respective hemisphere using a figure-8 or circular coil. In all patients with congenital disease, the abolition of motor function in the affected hemisphere was estimated by magnetic MEPs, and the hemiplegia did not deteriorate after functional hemispherectomy (HS) was performed in two of them. In two patients with acquired disease, HS was not performed because it was shown by magnetic maps that the motor function in the affected hemisphere remained. Furthermore, it was shown by electric MEPs using subdural electrodes that a patient who had had encephalitis in early childhood had a reorganised motor area in the parietal cortex of the affected hemisphere. The present findings indicate that magnetic MEPs are a very useful non-invasive method of assessing whether the motor area in the affected hemisphere can be resected in hemiplegic patients with intractable epilepsy.

Nervenarzt. 2003 Aug;74(8):664-76.

Electric brain stimulation for epilepsy therapy.

[Article in German]

Kellinghaus C, Loddenkemper T, Moddel G, Tergau F, Luders J, Ludemann P, Nair DR, Luders HO.

Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. kelling@uni-muenster.de

Attempts to control epileptic seizures by electrical brain stimulation have been performed for 50 years. Many different stimulation targets and methods have been investigated. Vagal nerve stimulation (VNS) is now approved for the treatment of refractory epilepsies by several governmental authorities in Europe and North America. However, it is mainly used as a palliative method when patients do not respond to medical treatment and epilepsy surgery is not possible. Numerous studies of the effect of deep brain stimulation (DBS) on epileptic seizures have been performed and almost invariably report remarkable success. However, a limited number of controlled studies failed to show a significant effect. Repetitive transcranial magnetic stimulation (rTMS) also was effective in open studies, and controlled studies are now being carried out. In addition, several uncontrolled reports describe successful treatment of refractory status epilepticus with electroconvulsive therapy (ECT). In summary, with the targets and stimulation parameters investigated so far, the effects of electrical brain stimulation on seizure frequency have been moderate at best. In the animal laboratory, we are now testing high-intensity, low-frequency stimulation of white matter tracts directly connected to the epileptogenic zone (e.g., fornix, corpus callosum) as a new methodology to increase the efficacy of DBS (“overdrive method”).

Int J Neurosci, 66(1-2):75-85 1992 Sep

Attenuation of epilepsy with application of external magnetic fields: a case report.

Sandyk R; Anninos PA , Democrition University of Thrace, Department of Medical Physics, Alexandroupolis, Greece.

We have previously demonstrated that magnetoencephalographic (MEG) brain measurements in patients with seizure disorders show significant MEG activity often in the absence of conventional EEG abnormalities. We localized foci of seizure activity using the mapping technique characterized by the ISO-Spectral Amplitude (ISO-SA) on the scalp distribution of specified spectral components or frequency bands of the emitted MEG Fourier power spectrum. In addition, using an electronic device, we utilized the above recorded activity to emit back the same intensity and frequency of magnetic field to the presumed epileptic foci. Using this method we were able, over the past two and one-half years, successfully to attenuate seizure activity in a cohort of over 150 patients with various forms of epilepsy. We present a patient with severe epilepsy and behavioral disturbances in whom application of an external artificial magnetic field of low intensity produced a substantial attenuation of seizure frequency which coincided with an improvement in the patient’s behavior. This case demonstrates that artificial magnetic treatment may be a valuable adjunctive procedure in the management of epilepsy.


Clin Rheumatol. 2006 Apr 22; [Epub ahead of print]

Effectiveness of pulsed electromagnetic field therapy in lateral epicondylitis.

Uzunca K, Birtane M, Tastekin N.

Trakya University Medical Faculty Physical Medicine and Rehabilitation Department, Edirne, Turkey, druzunca@yahoo.com

We aimed to investigate the efficacy of pulsed electromagnetic field (PEMF) in lateral epicondylitis comparing the modality with sham PEMF and local steroid injection. Sixty patients with lateral epicondylitis were randomly and equally distributed into three groups as follows: Group I received PEMF, Group II sham PEMF, and Group III a corticosteroid + anesthetic agent injection. Pain levels during rest, activity, nighttime, resisted wrist dorsiflexion, and forearm supination were investigated with visual analog scale (VAS). Pain threshold on elbow was determined with algometer. All patients were evaluated before treatment at the third week and the third month. VAS values during activity and pain levels during resisted wrist dorsiflexion were significantly lower in Group III than Group I at the third week. Group I patients had lower pain during rest, activity and nighttime than Group III at third month. PEMF seems to reduce lateral epicondylitis pain better than sham PEMF. Corticosteroid and anesthetic agent injections can be used in patients for rapid return to activities.

J Hand Ther. 2004 Apr-Jun;17(2):243-66.

Rehabilitation for patients with lateral epicondylitis: a systematic review.

Trudel D, Duley J, Zastrow I, Kerr EW, Davidson R, MacDermid JC.

Canadian Forces Base Kingston, Ontario, Canada.

The purpose of this systematic review was to determine the effectiveness of conservative treatments for lateral epicondylitis and to provide recommendations based on this evidence. Five reviewers searched computerized bibliographic databases for articles on the conservative treatment of lateral epicondylitis from the years 1983 to 2003. A total of 209 studies were located; however, only 31 of these met the study inclusion criteria. Each of the articles was randomly allocated to reviewers and critically appraised using a structured critical appraisal tool with 23 items. Treatment recommendations were based on this rating and Sackett’s Level of Evidence. This review has determined, with at least level 2b evidence, that a number of treatments, including acupuncture, exercise therapy, manipulations and mobilizations, ultrasound, phonophoresis, Rebox, and ionization with diclofenac all show positive effects in the reduction of pain or improvement in function for patients with lateral epicondylitis. There is also at least level 2b evidence showing laser therapy and pulsed electromagnetic field therapy to be ineffective in the management of this condition. Practitioners should use the treatment techniques that have strongest evidence and ensure that studies findings are generalized to patients who are similar to those reported in primary research studies in terms of patient demographics and injury presentation

Ortop Travmatol Protez. 1990 Jul;(7):33-5.

Use of electromagnetic feedback in the rehabilitation of children with injuries of the elbow joint.

[Article in Russian]

Iakovlev NM, Solov’ev OA, Chuzhov AL, Smetankin AA.


The paper is devoted to the non-drug functional treatment of children with elbow joint damages by the use of portable self-contained device, based on the principle of electromagnetic feedback. It is demonstrated that sending of artificial feedback signals (light, sound) at the moment of arbitrary contraction of the muscles being trained during 8-10 treatment procedures ensures restoration of muscular-articular sense, strength, endurance of weakened muscle groups, normalizes volume of motion in the elbow joint.

Clin Exp Rheumatol. 1985 Oct-Dec;3(4):333-6.

Chronic lateral humeral epicondylitis–a double-blind controlled assessment of pulsed electromagnetic field therapy.

Devereaux MD, Hazleman BL, Thomas PP.


Pulsed electromagnetic fields (PEMF) have been shown to be beneficial in the treatment of rotator cuff tendinitis. As lateral humeral epicondylitis (tennis elbow) is a similar chronic tendon lesion, 30 patients with both clinical and thermographic evidence of tennis elbow were randomly allocated to receive either active or inactive PEMF therapy. Treatment was continued for a minimum period of eight weeks. At this time there was no statistical difference between the two groups.

Endothelial Effects and Angiogenesis

Bioelectromagnetics. 2010 May;31(4):296-301.

Effects of weak static magnetic fields on endothelial cells.

Martino CF, Perea H, Hopfner U, Ferguson VL, Wintermantel E.

Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, Colorado, USA. martino@colorado.edu


Pulsed electromagnetic fields (PEMFs) have been used extensively in bone fracture repairs and wound healing. It is accepted that the induced electric field is the dose metric. The mechanisms of interaction between weak magnetic fields and biological systems present more ambiguity than that of PEMFs since weak electric currents induced by PEMFs are believed to mediate the healing process, which are absent in magnetic fields. The present study examines the response of human umbilical vein endothelial cells to weak static magnetic fields. We investigated proliferation, viability, and the expression of functional parameters such as eNOS, NO, and also gene expression of VEGF under the influence of different doses of weak magnetic fields. Applications of weak magnetic fields in tissue engineering are also discussed. Static magnetic fields may open new venues of research in the field of vascular therapies by promoting endothelial cell growth and by enhancing the healing response of the endothelium.

Br J Dermatol. 2010 Feb 1;162(2):258-66. Epub 2009 Oct 3.

Extremely low frequency electromagnetic fields modulate expression of inducible nitric oxide synthase, endothelial nitric oxide synthase and cyclooxygenase-2 in the human keratinocyte cell line HaCat: potential therapeutic effects in wound healing.

Patruno A, Amerio P, Pesce M, Viazio S, Tulli A, Franceschelli S, Grilli A, Muraro R, Reale M.nale G, Di Lu

Department of Drug Sciences, University ‘G. d’Annunzio’ of Chieti-Pescara, Via dei Vestini, 66100 Chieti, Italy.


BACKGROUND: Extremely low frequency (ELF) electromagnetic fields (EMF) are known to produce a variety of biological effects. Clinical studies are ongoing using EMF in healing of bone fractures and skin wounds. However, little is known about the mechanisms of action of ELF-EMF. Several studies have demonstrated that expression and regulation of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) are vital for wound healing; however, no reports have demonstrated a direct action of ELF-EMF in the modulation of these inflammatory molecules in human keratinocytes.

OBJECTIVES: The present study analysed the effect of ELF-EMF on the human keratinocyte cell line HaCaT in order to assess the mechanisms of action of ELF-EMF and to provide further support for their therapeutic use in wound healing.

METHODS: Exposed HaCaT cells were compared with unexposed control cells. At different exposure times, expression of inducible NOS (iNOS), endothelial NOS (eNOS) and COX-2 was evaluated by Western blot analysis. Modulation of iNOS and eNOS was monitored by evaluation of NOS activities, production of nitric oxide (NO) and O(2)(-) and expression of activator protein 1 (AP-1). In addition, catalase activity and prostaglandin (PG) E(2) production were determined. Effects of ELF-EMF on cell growth and viability were monitored.

RESULTS: The exposure of HaCaT cells to ELF-EMF increased iNOS and eNOS expression levels. These ELF-EMF-dependent increased expression levels were paralled by increased NOS activities, and increased NO production. In addition, higher levels of AP-1 expression as well as a higher cell proliferation rate were associated with ELF-EMF exposure. In contrast, ELF-EMF decreased COX-2 expression, PGE(2) production, catalase activity and O(2)(-) production.

CONCLUSIONS: Mediators of inflammation, such as reactive nitrogen and PGE(2), and keratinocyte proliferation are critical for the tissue regenerative processes. The ability of ELF-EMF to upmodulate NOS activities, thus nitrogen intermediates, as well as cell proliferation, and to downregulate COX-2 expression and the downstream intermediate PGE(2), highlights the potential therapeutic role of ELF-EMF in wound healing processes.

Bioelectromagnetics. 2009 Apr;30(3):189-97.

Osteoblasts stimulated with pulsed electromagnetic fields increase HUVEC proliferation via a VEGF-A independent mechanism.

Hopper RA, VerHalen JP, Tepper O, Mehrara BJ, Detch R, Chang EI, Baharestani S, Simon BJ, Gurtner GC.

Department of Surgery, University of Washington, Seattle, WA 98105, USA. richard.hopper@seattlechildrens.org


The clinically beneficial effect of low frequency pulsed electromagnetic fields (ELF-PEMF) on bone healing has been described, but the exact mechanism of action remains unclear. A recent study suggests that there is a direct autocrine mitogenic effect of ELF-PEMF on angiogenesis. The hypothesis of this study is that ELF-PEMF also has an indirect effect on angiogenesis by manipulation of vascular endothelial growth factor (VEGF)-A-based paracrine intercellular communication with neighboring osteoblasts. Conditioned media experiments measured fetal rat calvarial cell (FRC) and human umbilical vein endothelial cell (HUVEC) proliferation using tritiated thymidine uptake. We demonstrate that ELF-PEMF (15 Hz, 1.8 mT, for 8 h) has an indirect effect on the proliferation rate of both endothelial cells and osteoblasts in vitro by altering paracrine mediators. Conditioned media from osteoblast cells stimulated with ELF-PEMF increased endothelial proliferation 54-fold, whereas media from endothelial cells stimulated with ELF-PEMF did not affect osteoblast proliferation. We examined the role of the pro-angiogenic mediator VEGF-A in the mitogenic effect of ELF-PEMF-stimulated osteoblast media on endothelial cells. The production of VEGF-A by FRC as measured by ELISA was not changed by exposure to PEMF, and blocking experiments demonstrated that the ELF-PEMF-induced osteoblast-derived endothelial mitogen observed in these studies was not VEGF-A, but some other soluble angiogenic mediator.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2008 Jun;25(3):694-8.

The influence of the pulsed electrical stimulation on the morphology and the functions of the endothelial cells.

[Article in Chinese]

Yue A, Yang G, Wu J, Lai Y, Huang H, Chen H.

Institute of Biomedical Engineering, West China Medical Center, Sichuan University, Chengdu 610041, China.


The aim of this study is to explore the effects of the pulsed electrical stimulation (PES) on the morphology, the proliferation and the values of NO and ET-1 of the endothelial cells (ECs). We chose the different frequency PES (1, 5, 10, 20, 50, 100 Hz) with 25 mV to stimulate the ECs for 6 hours. We observed the cell’s morphous by the scanning electron microscope (SEM) and detected the values of MTT, NO and ET-1. The proliferation of the ECs was obviously rose up under the PES from 10 to 100 Hz. But the PES inhibited the proliferation with the frequency lower than 10 Hz. After stimulated with PES (20 – 100 Hz), the NO expression of ECs were increased obviously, and the peak value was appeared at 50 Hz. The peak value of ET-1 was appeared at 100 Hz. The PES has significant effects on the ECs’ morphology, proliferation and expression of NO and ET-1. Particularly, the 50 Hz PES plays a positive role to enhance the ECs’ function and to maintain the vascular biology.

Plast Reconstr Surg. 2008 Jan;121(1):130-41.

Pulsed electromagnetic fields accelerate normal and diabetic wound healing by increasing endogenous FGF-2 release.

Callaghan MJ, Chang EI, Seiser N, Aarabi S, Ghali S, Kinnucan ER, Simon BJ, Gurtner GC.

Stanford University Medical Center, Palo Alto, Calif, USA.


BACKGROUND: Chronic wounds, particularly in diabetics, result in significant morbidity and mortality and have a profound economic impact. The authors demonstrate that pulsed electromagnetic fields significantly improve both diabetic and normal wound healing in 66 mice through up-regulation of fibroblast growth factor (FGF)-2 and are able to prevent tissue necrosis in diabetic tissue after an ischemic insult.

METHODS: Db/db and C57BL6 mice were wounded and exposed to pulsed electromagnetic fields. Gross closure, cell proliferation, and vascularity were assessed. Cultured medium from human umbilical vein endothelial cells exposed to pulsed electromagnetic fields was analyzed for FGF-2 and applied topically to wounds. Skin flaps were created on streptozocin-induced diabetic mice and exposed to pulsed electromagnetic fields. Percentage necrosis, oxygen tension, and vascularity were determined.

RESULTS: Pulsed electromagnetic fields accelerated wound closure in diabetic and normal mice. Cell proliferation and CD31 density were significantly increased in pulsed electromagnetic field-treated groups. Cultured medium from human umbilical vein endothelial cells in pulsed electromagnetic fields exhibited a three-fold increase in FGF-2, which facilitated healing when applied to wounds. Skin on diabetic mice exposed to pulsed electromagnetic fields did not exhibit tissue necrosis and demonstrated oxygen tensions and vascularity comparable to those in normal animals.

CONCLUSIONS: This study demonstrates that pulsed electromagnetic fields are able to accelerate wound healing under diabetic and normal conditions by up-regulation of FGF-2-mediated angiogenesis. They also prevented tissue necrosis in response to a standardized ischemic insult, suggesting that noninvasive angiogenic stimulation by pulsed electromagnetic fields may be useful to prevent ulcer formation, necrosis, and amputation in diabetic patients.

FASEB J. 2004 Aug;18(11):1231-3. Epub 2004 Jun 18.

Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2.

Tepper OM, Callaghan MJ, Chang EI, Galiano RD, Bhatt KA, Baharestani S, Gan J, Simon B, Hopper RA, Levine JP, Gurtner GC.

New York University Medical Center, Institute of Reconstructive Plastic Surgery, New York, New York 10016, USA .


Pulsed electromagnetic fields (PEMF) have been shown to be clinically beneficial, but their mechanism of action remains unclear. The present study examined the impact of PEMF on angiogenesis, a process critical for successful healing of various tissues. PEMF increased the degree of endothelial cell tubulization (sevenfold) and proliferation (threefold) in vitro. Media from PEMF cultures had a similar stimulatory effect, but heat denaturation ablated this activity. In addition, conditioned media was able to induce proliferative and chemotactic changes in both human umbilical vein endothelial cells and fibroblasts, but had no effect on osteoblasts. Angiogenic protein screening demonstrated a fivefold increase in fibroblast growth factor beta-2 (FGF-2), as well as smaller increases in other angiogenic growth factors (angiopoietin-2, thrombopoietin, and epidermal growth factor). Northern blot analysis demonstrated an increase in FGF-2 transcription, and FGF-2 neutralizing antibody inhibited the effects of PEMF. In vivo, PEMF exposure increased angiogenesis more than twofold. We conclude that PEMF augments angiogenesis primarily by stimulating endothelial release of FGF-2, inducing paracrine and autocrine changes in the surrounding tissue. These findings suggest a potential role for PEMF in therapeutic angiogenesis.

Vestn Khir Im I I Grek. 1996;155(5):37-9.

The potentials of laser and electromagnetic-laser therapy in the treatment of patients with arteriosclerosis obliterans of the vessels of the lower extremities.

[Article in Russian]

Galimzianov FV.

A comparative analysis of the laser and electromagnetic laser therapy was performed in the complex treatment of patients with obliterating atherosclerosis of the lower extremity vessels. Laser treatment exerts a therapeutic effect related with its influence upon microcirculation. The effectiveness of complex treatment becomes higher when using a combination of laser therapy with the impulse electromagnetic therapy of complex modulation at the expense of improvement of the regional blood circulation in all links of the vasculature.

Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):22-5.

The use of magnetics and laser therapy in treating obliterating vascular disease of the extremities.

[Article in Russian]

Kirillov IuB, Shval’b PG, Lastushkin AV, Sigaev AA, Kachinskii AE, Shashkova SN.

The paper presents the results of treatment received by 60 patients suffering from lower limb vascular obliteration stage IIA-III. The treatment involved combined use of magnetic field and laser irradiation. Peripheral circulation and central hemodynamics were evaluated rheographically and using ultrasound Doppler sphygmomanometry. Combined application of the above two modalities produced a greater effect on central hemodynamics compared to them introduced alone.

J Cell Physiol. 1988 Jan;134(1):37-46.

Endothelial cell response to pulsed electromagnetic fields: stimulation of growth rate and angiogenesis in vitro.

Yen-Patton GP, Patton WF, Beer DM, Jacobson BS.

Department of Biochemistry, University of Massachusetts, Amherst 01003.


The effects of pulsed electromagnetic fields on the repopulation rate of denuded regions of endothelial cell monolayers and on endothelial cell reorganization into complex vessellike structures was monitored in vitro by using human umbilical vein and bovine aortic endothelial cells. A small (20-40%) but statistically significant enhancement in growth rate of partially denuded endothelial cell monolayers as determined by tritiated thymidine incorporation was observed in the presence of pulsed electromagnetic fields. Morphologically, endothelial cells entering the denuded regions were observed to be elongated, often connecting end to end to form a mycelial or “sprouting” pattern when exposed to pulsed electromagnetic fields. This was in contrast to cells outside of the field which had a more cuboidal morphology. Complete disruption of the endothelial cell monolayer by passaging the cells with EDTA-trypsin resulted in reorganization of some of the cells into three-dimensional vessellike structures after as little as 5-8 hours in the presence of the pulsed electromagnetic field. This reorganization occurred in the presence of heparin, endothelial cell growth factor, and a competent fibronectin matrix. Vascularization for comparable cultures outside of the field did not occur during the time-course of the experiments. Discrete stages of neovascularization were observed in the presence of the field that were qualitatively similar to stages of angiogenesis observed in vivo.

Endometritis – Endometriosis

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.


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.

Vopr Kurortol Fizioter Lech Fiz Kult. 1996 Nov-Dec;(6):21-4.

A permanent magnetic field in the combined treatment of acute endometritis after an artificial abortion.

[Article in Russian]

Strugatskii VM, Strizhakov AN, Kovalenko MV, Istratov VG, Iakubovich DV.

117 patients with acute endometritis after induced abortion were examined using markers of wound process phases and treated according to the original method. This consists in combination of constant magnetic field with other modalities. Application of the constant magnetic field produced a significant clinical response and reduced the hospital stay through positive effect on healing of the endometrial wound.

Eur J Surg Suppl. 1994;(574):83-6.

Electrochemical therapy of pelvic pain: effects of pulsed electromagnetic fields (PEMF) on tissue trauma.

Jorgensen WA, Frome BM, Wallach C.

International Pain Research Institute, Los Angeles, California.

Unusually effective and long-lasting relief of pelvic pain of gynaecological origin has been obtained consistently by short exposures of affected areas to the application of a magnetic induction device producing short, sharp, magnetic-field pulses of a minimal amplitude to initiate the electrochemical phenomenon of electroporation within a 25 cm2 focal area. Treatments are short, fasting-acting, economical and in many instances have obviated surgery. This report describes typical cases such as dysmenorrhoea, endometriosis, ruptured ovarian cyst, acute lower urinary tract infection, post-operative haematoma, and persistent dyspareunia in which pulsed magnetic field treatment has not, in most cases, been supplemented by analgesic medication. Of 17 female patients presenting with a total of 20 episodes of pelvic pain, of which 11 episodes were acute, seven chronic and two acute as well as chronic, 16 patients representing 18 episodes (90%) experienced marked, even dramatic relief, while two patients representing two episodes reported less than complete pain relief.


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

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

Traitcheva N, Berg H.

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


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

Pol Merkur Lekarski. 2010 Jun;28(168):501-4.

Electroporation and its application.

[Article in Polish]

Sko?ucka N, Saczko J, Kotulska M, Kulbacka J, Choroma?ska A.

Akademia Medyczna we Wroclawiu, Katedra i Zak?ad Biochemii Lekarskiej. nina.skolucka@gmail.com


Electroporation (EP) is a modern and versatile method that allows the penetration of macromolecules from the intercellular space into cells by forming the channels, under the influence of electromagnetic field. In addition to natural channels and pumps, building cell membranes, resulting electropores an additional way for the transport of macromolecules. The use of this phenomenon has brought good results as a complement to traditional therapeutic methods of treatment during application of cytostatics. EP combination with chemotherapy has reduced the need for surgical intervention (rescue authority). Electroporation is particularly useful for cancer with multidrug resistance, where the dose that enters the interior of cancer cells is limited. Electroporation was also used in transfection of nucleic acids, in photodynamic therapy, cosmetology, as well as the consolidation of the food.

EEE Trans Biomed Eng. 2009 May;56(5):1491-501. Epub 2009 Feb 6.

A time-dependent numerical model of transmembrane voltage inducement and electroporation of irregularly shaped cells.

Pucihar G, Miklavcic D, Kotnik T.

Faculty of Electrical Engineering, University of Ljubljana, Ljubljana SI-1000, Slovenia. gorazd.pucihar@fe.uni-lj.si


We describe a finite-element model of a realistic irregularly shaped biological cell in an external electric field that allows the calculation of time-dependent changes of the induced transmembrane voltage (Delta Psi) and simulation of cell membrane electroporation. The model was first tested by comparing its results to the time-dependent analytical solution for Delta Psi on a nonporated spherical cell, and a good agreement was obtained. To simulate electroporation, the model was extended by introducing a variable membrane conductivity. In the regions exposed to a sufficiently high Delta Psi, the membrane conductivity rapidly increased with time, leading to a modified spatial distribution of Delta Psi. We show that steady-state models are insufficient for accurate description of Delta Psi, as well as determination of electroporated regions of the membrane, and time-dependent models should be used instead. Our modeling approach also allows direct comparison of calculations and experiments. As an example, we show that calculated regions of electroporation correspond to the regions of molecular transport observed experimentally on the same cell from which the model was constructed. Both the time-dependent model of Delta Psi and the model of electroporation can be exploited further to study the behavior of more complicated cell systems, including those with cell-to-cell interactions.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2008 Oct;25(5):1206-9.

Research progress of nanosecond pulsed electric field applied to intracellular electromanipulation.

[Article in Chinese]

Yao C, Mo D, Sun C, Chen X, Xiong Z.

Key Lab of High Voltage Engineering and Electrical New Technology, Ministry of Education, Chongqing University, Chongqing 400044, China. yaochenguo@cqu.edu.cn


In recent years, many experts have done some researches on experiment and mechanism of intracellular electromanipulation (IEM) under nanosecond pulsed electric field (nsPEF). The experiment results have shown that nsPEF could not induce electroporation of cell membrane, but could induce intracellular effects such as apoptosis, calcium release, enhancement of gene expression, and fragmentation of DNA and chromosome. In order to account for the phenomenon, researchers believe that when the pulse width of the pulsed electric field is larger than the charging time of plasma membrane, the pulsed electric field mainly targets on the outer membrane of cell; and that the effect of the pulsed electric field on nucleus and nuclear membrane increases with the decrease of the pulse width. It is also believed that the effect of electroporation changes from the outer membrane to intracellular electromanipulation when the pulse width decreases to a value being smaller than the charging time of plasma membrane.

Biomech Model Mechanobiol. 2008 Oct;7(5):379-86. Epub 2007 Jul 27.

Finite element analysis of microelectrotension of cell membranes.

Bae C, Butler PJ.

Department of Bioengineering, The Pennsylvania State University, 205 Hallowell Building, University Park, PA 16802, USA. cub120@psu.edu


Electric fields can be focused by micropipette-based electrodes to induce stresses on cell membranes leading to tension and poration. To date, however, these membrane stress distributions have not been quantified. In this study, we determine membrane tension, stress, and strain distributions in the vicinity of a microelectrode using finite element analysis of a multiscale electro-mechanical model of pipette, media, membrane, actin cortex, and cytoplasm. Electric field forces are coupled to membranes using the Maxwell stress tensor and membrane electrocompression theory. Results suggest that micropipette electrodes provide a new non-contact method to deliver physiological stresses directly to membranes in a focused and controlled manner, thus providing the quantitative foundation for micreoelectrotension, a new technique for membrane mechanobiology.

Ann Biomed Eng. 2007 Jul;35(7):1264-75. Epub 2007 Mar 6.

Electric fields around and within single cells during electroporation-a model study.

Mossop BJ, Barr RC, Henshaw JW, Yuan F.

Department of Biomedical Engineering, Duke University, 136 Hudson Hall, Box 90281, Durham, NC 27708, USA.


One of the key issues in electric field-mediated molecular delivery into cells is how the intracellular field is altered by electroporation. Therefore, we simulated the electric field in both the extracellular and intracellular domains of spherical cells during electroporation. The electroporated membrane was modeled macroscopically by assuming that its electric resistivity was smaller than that of the intact membrane. The size of the electroporated region on the membrane varied from zero to the entire surface of the cell. We observed that for a range of values of model constants, the intracellular current could vary several orders of magnitude whereas the maximum variations in the extracellular and total currents were less than 8% and 4%, respectively. A similar difference in the variations was observed when comparing the electric fields near the center of the cell and across the permeabilized membrane, respectively. Electroporation also caused redirection of the extracellular field that was significant only within a small volume in the vicinity of the permeabilized regions, suggesting that the electric field can only facilitate passive cellular uptake of charged molecules near the pores. Within the cell, the field was directed radially from the permeabilized regions, which may be important for improving intracellular distribution of charged molecules.

Biophys J. 2008 Jun;94(12):5018-27. Epub 2008 Mar 13.

Quantification of electroporative uptake kinetics and electric field heterogeneity effects in cells.

Kennedy SM, Ji Z, Hedstrom JC, Booske JH, Hagness SC.

Department of Electrical and Computer Engineering, University of Wisconsin, Madison, Wisconsin 53706, USA. smkennedy@wisc.edu


We have conducted experiments quantitatively investigating electroporative uptake kinetics of a fluorescent plasma membrane integrity indicator, propidium iodide (PI), in HL60 human leukemia cells resulting from exposure to 40 mus pulsed electric fields (PEFs). These experiments were possible through the use of calibrated, real-time fluorescence microscopy and the development of a microcuvette: a specialized device designed for exposing cell cultures to intense PEFs while carrying out real-time microscopy. A finite-element electrostatic simulation was carried out to assess the degree of electric field heterogeneity between the microcuvette’s electrodes allowing us to correlate trends in electroporative response to electric field distribution. Analysis of experimental data identified two distinctive electroporative uptake signatures: one characterized by low-level, decelerating uptake beginning immediately after PEF exposure and the other by high-level, accelerating fluorescence that is manifested sometimes hundreds of seconds after PEF exposure. The qualitative nature of these fluorescence signatures was used to isolate the conditions required to induce exclusively transient electroporation and to discuss electropore stability and persistence. A range of electric field strengths resulting in transient electroporation was identified for HL60s under our experimental conditions existing between 1.6 and 2 kV/cm. Quantitative analysis was used to determine that HL60s experiencing transient electroporation internalized between 50 and 125 million nucleic acid-bound PI molecules per cell. Finally, we show that electric field heterogeneity may be used to elicit asymmetric electroporative PI uptake within cell cultures and within individual cells.

Bioelectrochemistry. 2007 May;70(2):275-82. Epub 2006 Oct 18.

High electrical field effects on cell membranes.

Pliquett U, Joshi RP, Sridhara V, Schoenbach KH.

Frank Reidy Research Center for Bioelectrics 830 Southampton Ave., Suite 5100, Norfolk, VA 23510, United States.


Electrical charging of lipid membranes causes electroporation with sharp membrane conductance increases. Several recent observations, especially at very high field strength, are not compatible with the simple electroporation picture. Here we present several relevant experiments on cell electrical responses to very high external voltages. We hypothesize that, not only are aqueous pores created within the lipid membranes, but that nanoscale membrane fragmentation occurs, possibly with micelle formation. This effect would produce conductivity increases beyond simple electroporation and display a relatively fast turn-off with external voltage. In addition, material loss can be expected at the anode side of cells, in agreement with published experimental reports at high fields. Our hypothesis is qualitatively supported by molecular dynamics simulations. Finally, such cellular responses might temporarily inactivate voltage-gated and ion-pump activity, while not necessarily causing cell death. This hypothesis also supports observations on electrofusion.

J Biomol Struct Dyn. 2007 Apr;24(5):495-503.

Self-electroporation as a model for fusion pore formation.

Luitel P, Schroeter DF, Powell JW.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.


The creation of a small opening called the fusion pore is a necessary prerequisite for neurotransmitter release from synaptic vesicles. It is known that high intensity electric fields can create pores in vesicles by a process called electroporation. Due to the presence of charged phosphatidylserine (PS) molecules on the inner leaflet of the cell membrane, an electric field that is strong enough to cause electroporation of a synaptic vesicle might be present. It was shown by K. Rosenheck [K. Rosenheck. Biophys J 75, 1237-1243 (1998)] that in a planar geometry, fields sufficient to cause electroporation can occur at intermembrane separations of less than approximately 3 nm. It is frequently found, however, that the cell membrane is not planar but caves inward at the locations where a vesicle is close to it. Indentation of the cell membrane in the fusion region was modelled as a hemisphere and a theoretical study of the electric field in the vicinity of the cell membrane taking into account the screening effect of dissolved ions in the cytoplasm was performed. It was discovered that fields crossing the electroporation threshold occurred at a distance of 2 nm or less, supporting the claim that electroporation could be a possible mechanism for fusion pore formation.

IEEE Trans Biomed Eng. 2007 Apr;54(4):611-20.

Hybrid finite element method for describing the electrical response of biological cells to applied fields.

Ying W, Henriquez CS.

Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA. ying@cel-mail.bme.duke.edu


A novel hybrid finite element method (FEM) for modeling the response of passive and active biological membranes to external stimuli is presented. The method is based on the differential equations that describe the conservation of electric flux and membrane currents. By introducing the electric flux through the cell membrane as an additional variable, the algorithm decouples the linear partial differential equation part from the nonlinear ordinary differential equation part that defines the membrane dynamics of interest. This conveniently results in two subproblems: a linear interface problem and a nonlinear initial value problem. The linear interface problem is solved with a hybrid FEM. The initial value problem is integrated by a standard ordinary differential equation solver such as the Euler and Runge-Kutta methods. During time integration, these two subproblems are solved alternatively. The algorithm can be used to model the interaction of stimuli with multiple cells of almost arbitrary geometries and complex ion-channel gating at the plasma membrane. Numerical experiments are presented demonstrating the uses of the method for modeling field stimulation and action potential propagation.

Electromagn Biol Med. 2007;26(3):239-50.

Modeling environment for numerical simulation of applied electric fields on biological cells.

Suzuki DO, Ramos A, Marques JL.

Department of Electrical Engineering, Institute of Biomedical Engineering, Federal University of Santa Catarina (UFSC), Santa Catarina, Brazil.


The application of electric pulses in cells increases membrane permeability. This phenomenon is called electroporation. Current electroporation models do not explain all experimental findings: part of this problem is due to the limitations of numerical methods. The Equivalent Circuit Method (ECM) was developed in an attempt to solve electromagnetic problems in inhomogeneous and anisotropic media. ECM is based on modeling of the electrical transport properties of the medium by lumped circuit elements as capacitance, conductance, and current sources, representing the displacement, drift, and diffusion current, respectively. The purpose of the present study was to implement a 2-D cell Model Development Environment (MDE) of ionic transport process, local anisotropy around cell membranes, biological interfaces, and the dispersive behaviour of tissues. We present simulations of a single cell, skeletal muscle, and polygonal cell arrangement. Simulation of polygonal form indicates that the potential distribution depends on the geometrical form of cell. The results demonstrate the importance of the potential distributions in biological cells to provide strong evidences for the understanding of electroporation.

Biophys J. 2007 Jan 15;92(2):404-17. Epub 2006 Oct 20.

Modeling electroporation in a single cell.

Krassowska W, Filev PD.

Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA. wanda.krassowska@duke.edu


Electroporation uses electric pulses to promote delivery of DNA and drugs into cells. This study presents a model of electroporation in a spherical cell exposed to an electric field. The model determines transmembrane potential, number of pores, and distribution of pore radii as functions of time and position on the cell surface. For a 1-ms, 40 kV/m pulse, electroporation consists of three stages: charging of the cell membrane (0-0.51 micros), creation of pores (0.51-1.43 micros), and evolution of pore radii (1.43 micros to 1 ms). This pulse creates approximately 341,000 pores, of which 97.8% are small ( approximately 1 nm radius) and 2.2% are large. The average radius of large pores is 22.8 +/- 18.7 nm, although some pores grow to 419 nm. The highest pore density occurs on the depolarized and hyperpolarized poles but the largest pores are on the border of the electroporated regions of the cell. Despite their much smaller number, large pores comprise 95.3% of the total pore area and contribute 66% to the increased cell conductance. For stronger pulses, pore area and cell conductance increase, but these increases are due to the creation of small pores; the number and size of large pores do not increase.

Phys Biol. 2006 Nov 2;3(4):233-47.

Nanopore-facilitated, voltage-driven phosphatidylserine translocation in lipid bilayers–in cells and in silico.

Vernier PT, Ziegler MJ, Sun Y, Gundersen MA, Tieleman DP.

Department of Electrical Engineering-Electrophysics, Viterbi School of Engineering, University of Southern California, Los Angeles CA, 90089-0271, USA. vernier@mosis.org


Nanosecond, megavolt-per-meter pulses–higher power but lower total energy than the electroporative pulses used to introduce normally excluded material into biological cells–produce large intracellular electric fields without destructively charging the plasma membrane. Nanoelectropulse perturbation of mammalian cells causes translocation of phosphatidylserine (PS) to the outer face of the cell, intracellular calcium release, and in some cell types a subsequent progression to apoptosis. Experimental observations and molecular dynamics (MD) simulations of membranes in pulsed electric fields presented here support the hypothesis that nanoelectropulse-induced PS externalization is driven by the electric potential that appears across the lipid bilayer during a pulse and is facilitated by the poration of the membrane that occurs even during pulses as brief as 3 ns. MD simulations of phospholipid bilayers in supraphysiological electric fields show a tight association between PS externalization and membrane pore formation on a nanosecond time scale that is consistent with experimental evidence for electropermeabilization and anode-directed PS translocation after nanosecond electric pulse exposure, suggesting a molecular mechanism for nanoelectroporation and nanosecond PS externalization: electrophoretic migration of the negatively charged PS head group along the surface of nanometer-diameter electropores initiated by field-driven alignment of water dipoles at the membrane interface.

BMC Cell Biol. 2006 Oct 19;7:37.

Nanoelectropulse-driven membrane perturbation and small molecule permeabilization.

Vernier PT, Sun Y, Gundersen MA.

Department of Electrical Engineering-Electrophysics, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089-0271, USA. vernier@mosis.org


BACKGROUND: Nanosecond, megavolt-per-meter pulsed electric fields scramble membrane phospholipids, release intracellular calcium, and induce apoptosis. Flow cytometric and fluorescence microscopy evidence has associated phospholipid rearrangement directly with nanoelectropulse exposure and supports the hypothesis that the potential that develops across the lipid bilayer during an electric pulse drives phosphatidylserine (PS) externalization.

RESULTS: In this work we extend observations of cells exposed to electric pulses with 30 ns and 7 ns durations to still narrower pulse widths, and we find that even 3 ns pulses are sufficient to produce responses similar to those reported previously. We show here that in contrast to unipolar pulses, which perturb membrane phospholipid order, tracked with FM1-43 fluorescence, only at the anode side of the cell, bipolar pulses redistribute phospholipids at both the anode and cathode poles, consistent with migration of the anionic PS head group in the transmembrane field. In addition, we demonstrate that, as predicted by the membrane charging hypothesis, a train of shorter pulses requires higher fields to produce phospholipid scrambling comparable to that produced by a time-equivalent train of longer pulses (for a given applied field, 30, 4 ns pulses produce a weaker response than 4, 30 ns pulses). Finally, we show that influx of YO-PRO-1, a fluorescent dye used to detect early apoptosis and activation of the purinergic P2X7 receptor channels, is observed after exposure of Jurkat T lymphoblasts to sufficiently large numbers of pulses, suggesting that membrane poration occurs even with nanosecond pulses when the electric field is high enough. Propidium iodide entry, a traditional indicator of electroporation, occurs with even higher pulse counts.

CONCLUSION: Megavolt-per-meter electric pulses as short as 3 ns alter the structure of the plasma membrane and permeabilize the cell to small molecules. The dose responses of cells to unipolar and bipolar pulses ranging from 3 ns to 30 ns duration support the hypothesis that a field-driven charging of the membrane dielectric causes the formation of pores on a nanosecond time scale, and that the anionic phospholipid PS migrates electrophoretically along the wall of these pores to the external face of the membrane.

IEEE Trans Nanobioscience. 2006 Sep;5(3):157-63.

Effect of pore size on the calculated pressure at biological cells pore wall.

El-Hag AH, Zheng Z, Boggs SA, Jayaram SH.

Electrical Engineering Department, American University of Sharjah, Sharjah, United Arab Emirate. ahalhaj@engmail.uwaterloo.ca


A transient nonlinear finite-element program has been used to calculate the electric field distribution as a function of time for a spherical cell with a pore in a conducting medium during application of a subnanosecond rise time “step” wave, including the effects of dipolar saturation in the water-based cytoplasm and cell medium. The time-dependent pressure on the pore wall has been computed as a function of time as the system polarizes from the change of the energy in the electric field to the left (inside the pore) and to the right (inside the membrane) of the pore wall. The computations suggest that dipolar saturation, while significant, has little effect on the time-dependent electric field distribution but a substantial effect on the field-induced pore wall pressure. Also, the effect of pore size on both the computed electric field and field-induced pressure was studied. As the pore size increases, a collapse in both the electric field and field-induced pressure has been noticed. This suggests that as the pore size increases, the driving force for further opening the pore is not electrical.

Phys Rev E Stat Nonlin Soft Matter Phys. 2006 Aug;74(2 Pt 1):021904. Epub 2006 Aug 3.

Membrane electroporation: The absolute rate equation and nanosecond time scale pore creation.

Vasilkoski Z, Esser AT, Gowrishankar TR, Weaver JC.

Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.


The recent applications of nanosecond, megavolt-per-meter electric field pulses to biological systems show striking cellular and subcellular electric field induced effects and revive the interest in the biophysical mechanism of electroporation. We first show that the absolute rate theory, with experimentally based parameter input, is consistent with membrane pore creation on a nanosecond time scale. Secondly we use a Smoluchowski equation-based model to formulate a self-consistent theoretical approach. The analysis is carried out for a planar cell membrane patch exposed to a 10 ns trapezoidal pulse with 1.5 ns rise and fall times. Results demonstrate reversible supraelectroporation behavior in terms of transmembrane voltage, pore density, membrane conductance, fractional aqueous area, pore distribution, and average pore radius. We further motivate and justify the use of Krassowska’s asymptotic electroporation model for analyzing nanosecond pulses, showing that pore creation dominates the electrical response and that pore expansion is a negligible effect on this time scale.

J Biomech Eng. 2006 Feb;128(1):76-84.

Numerical modeling of in vivo plate electroporation thermal dose assessment.

Becker SM, Kuznetsov AV.

Mechanical and Aerospace Engineering, North Carolina State University, Box 7910, Raleigh, NC 27695, USA. smbecker@unity.ncsu.edu


Electroporation is an approach used to enhance the transport of large molecules to the cell cytosol in which a targeted tissue region is exposed to a series of electric pulses. The cell membrane, which normally acts as a barrier to large molecule transport into the cell interior, is temporarily destabilized due to the development of pores in the cell membrane. Consequently, agents that are ordinarily unable enter the cell are able to pass through the cell membrane. Of possible concern when exposing biological tissue to an electric field is thermal tissue damage associated with joule heating. This paper explores the thermal effects of various geometric, biological, and electroporation pulse parameters including the blood vessel presence and size, plate electrode configuration, and pulse duration and frequency. A three-dimensional transient finite volume model of in vivo parallel plate electroporation of liver tissue is used to develop a better understanding of the underlying relationships between the physical parameters involved with tissue electroporation and resulting thermal damage potential.

Conf Proc IEEE Eng Med Biol Soc. 2006;1:2276-9.

Field stimulation of cells in suspension: use of a hybrid finite element method.

Ying W, Pourtaheri N, Henriquez CS.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. ying@cel-mail.bme.duke.edu


Electric fields are used in a range of applications, including gene transfection, electrochemotherapy of tumors and cardiac defibrillation. Despite the widespread use of electric fields, most of the theoretical and computational studies on discrete cellular tissue have focused on a single cell. In this work, we propose a hybrid finite element method to simulate the effects of external electric fields on clusters of excitable cells. The method can be used to model cells of arbitrary cell geometries and non-linear membrane dynamics. The results show that the response of multiple cell, like a single cell, is a two-stage process consisting of the initial polarization that proceeds with cellular time constant (less than one microsecond) and the actual excitation of the cell membrane that proceeds with the membrane time constant (on the order of milliseconds). The results also show that the stimulation of a given cell depends in part on the arrangement of cells within the field and not simply the location within the field, suggesting that classical approaches that ignores the effect of the cells on the field do not adequately predict the cellular response.

Phys Rev E Stat Nonlin Soft Matter Phys. 2005 Sep;72(3 Pt 1):031902. Epub 2005 Sep 8.

Simulations of nanopore formation and phosphatidylserine externalization in lipid membranes subjected to a high-intensity, ultrashort electric pulse.

Hu Q, Joshi RP, Schoenbach KH.

Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, Virginia 23529-0246, USA.


A combined MD simulator and time dependent Laplace solver are used to analyze the electrically driven phosphatidylserine externalization process in cells. Time dependent details of nanopore formation at cell membranes in response to a high-intensity (100 kV/cm), ultrashort (10 ns) electric pulse are also probed. Our results show that nanosized pores could typically be formed within about 5 ns. These predictions are in very good agreement with recent experimental data. It is also demonstrated that defect formation and PS externalization in membranes should begin on the anode side. Finally, the simulations confirm that PS externalization is a nanopore facilitated event, rather than the result of molecular translocation across the trans-membrane energy barrier.

Phys Rev E Stat Nonlin Soft Matter Phys. 2005 Mar;71(3 Pt 1):031914. Epub 2005 Mar 29.

Simulations of transient membrane behavior in cells subjected to a high-intensity ultrashort electric pulse.

Hu Q, Viswanadham S, Joshi RP, Schoenbach KH, Beebe SJ, Blackmore PF.

Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, Virginia 23529-0246, USA.


A molecular dynamics (MD) scheme is combined with a distributed circuit model for a self-consistent analysis of the transient membrane response for cells subjected to an ultrashort (nanosecond) high-intensity (approximately 0.01-V/nm spatially averaged field) voltage pulse. The dynamical, stochastic, many-body aspects are treated at the molecular level by resorting to a course-grained representation of the membrane lipid molecules. Coupling the Smoluchowski equation to the distributed electrical model for current flow provides the time-dependent transmembrane fields for the MD simulations. A good match between the simulation results and available experimental data is obtained. Predictions include pore formation times of about 5-6 ns. It is also shown that the pore formation process would tend to begin from the anodic side of an electrically stressed membrane. Furthermore, the present simulations demonstrate that ions could facilitate pore formation. This could be of practical importance and have direct relevance to the recent observations of calcium release from the endoplasmic reticulum in cells subjected to such ultrashort, high-intensity pulses.

Bioelectromagnetics. 2004 Dec;25(8):634-7.

Electroporation of a lipid bilayer as a chemical reaction.

Bier M, Gowrishankar TR, Chen W, Lee RC.

Department of Physics, East Carolina University, Greenville, North Carolina 27858, USA. bierm@mail.ecu.edu


When a cell’s transmembrane potential is increased from a physiological one to more than 370 mV, the transmembrane current increases more than hundredfold within a millisecond. This is due to the formation of conductive pores in the membrane. We construct a model in which we conceive of pore formation as a voltage sensitive chemical reaction. The model predicts the logarithm of the pore formation rate to increase proportionally to the square of the voltage. We measure currents through frog muscle cell membranes under 8 ms pulses of up to 440 mV. The experimental data appear consistent with the model.

IEEE Trans Nanobioscience. 2004 Sep;3(3):225-31.

Electric fields within cells as a function of membrane resistivity–a model study.

Mossop BJ, Barr RC, Zaharoff DA, Yuan F.

Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA.


Externally applied electric fields play an important role in many therapeutic modalities, but the fields they produce inside cells remain largely unknown. This study makes use of a three-dimensional model to determine the electric field that exists in the intracellular domain of a 10-microm spherical cell exposed to an applied field of 100 V/cm. The transmembrane potential resulting from the applied field was also determined and its change was compared to those of the intracellular field. The intracellular field increased as the membrane resistance decreased over a wide range of values. The results showed that the intracellular electric field was about 1.1 mV/cm for Rm of 10,000 omega x cm2, increasing to about 111 mV/cm as Rm decreased to 100 omega x cm2. Over this range of Rm the transmembrane potential was nearly constant. The transmembrane potential declined only as Rm decreased below 1 omega x cm2. The simulation results suggest that intracellular electric field depends on Rm in its physiologic range, and may not be negligible in understanding some mechanisms of electric field-mediated therapies.

FEBS Lett. 2004 Aug 13;572(1-3):103-8.

Nanosecond pulsed electric fields perturb membrane phospholipids in T lymphoblasts.

Vernier PT, Sun Y, Marcu L, Craft CM, Gundersen MA.

Department of Materials Science, School of Engineering, University of Southern California, Los Angeles, CA 90089-0271, USA. vernier@mosis.org


Nanosecond, megavolt-per-meter pulsed electric fields scramble the asymmetric arrangement of phospholipids in cell membranes without the permeabilization associated with longer, lower-field pulses. A single 30 ns, 2.5 MV/m pulse produces perturbations consistent with phosphatidylserine (PS) externalization in Jurkat T lymphoblasts within milliseconds, polarized in the direction of the applied field, indicating an immediate interaction between membrane components and the electric field. This disturbance occurs only at the anode pole of the cell, supporting the hypothesis that the pulsed field drives the negatively charged PS head group toward the positive electrode, directly providing the energy for crossing the membrane dielectric barrier.

Bioelectrochemistry. 2004 Jun;63(1-2):311-5.

The effect of resting transmembrane voltage on cell electropermeabilization: a numerical analysis.

Valic B, Pavlin M, Miklavcic D.

Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, SI-1000 Ljubljana, Slovenia.


The transmembrane voltage induced due to applied electric field superimposes to the resting transmembrane voltage of the cell. On the part of the cell membrane, where the transmembrane voltage exceeds the threshold transmembrane voltage, changes in the membrane occur, leading to increase in membrane permeability known as electropermeabilization. This part of the cell membrane represents the permeabilized area through which the transport of molecules occurs. In this paper we calculated numerically the permeabilized area for different electric field strength, resting transmembrane voltage, cell shape and cell orientation with respect to the applied electric field. Results show that when the transmembrane voltage is near the threshold transmembrane voltage, the permeabilized area of the cell is increased on the anodic side and decreased on the cathodic side due to the resting transmembrane voltage. In some cases, only anodic side of the cell is permeabilized. Therefore, by using bipolar pulses, the permeabilized area can be significantly increased and consequentially also the efficiency of electropermeabilization. However, when the induced transmembrane voltage is far above the threshold, the effect of the resting transmembrane voltage is negligible. These observations are valid for different cell shapes and orientations.

Biophys J. 2004 Jun;86(6):4040-8.

Nanoelectropulse-induced phosphatidylserine translocation.

Vernier PT, Sun Y, Marcu L, Craft CM, Gundersen MA.

Department of Electrical Engineering-Electrophysics, School of Engineering, MOSIS, University of Southern California, Los Angeles, California, USA. vernier@mosis.org


Nanosecond, megavolt-per-meter, pulsed electric fields induce phosphatidylserine (PS) externalization, intracellular calcium redistribution, and apoptosis in Jurkat T-lymphoblasts, without causing immediately apparent physical damage to the cells. Intracellular calcium mobilization occurs within milliseconds of pulse exposure, and membrane phospholipid translocation is observed within minutes. Pulsed cells maintain cytoplasmic membrane integrity, blocking propidium iodide and Trypan blue. Indicators of apoptosis-caspase activation and loss of mitochondrial membrane potential-appear in nanoelectropulsed cells at later times. Although a theoretical framework has been established, specific mechanisms through which external nanosecond pulsed electric fields trigger intracellular responses in actively growing cells have not yet been experimentally characterized. This report focuses on the membrane phospholipid rearrangement that appears after ultrashort pulse exposure. We present evidence that the minimum field strength required for PS externalization in actively metabolizing Jurkat cells with 7-ns pulses produces transmembrane potentials associated with increased membrane conductance when pulse widths are microseconds rather than nanoseconds. We also show that nanoelectropulse trains delivered at repetition rates from 2 to 2000 Hz have similar effects, that nanoelectropulse-induced PS externalization does not require calcium in the external medium, and that the pulse regimens used in these experiments do not cause significant intra- or extracellular Joule heating.

Phys Rev E Stat Nonlin Soft Matter Phys. 2004 Apr;69(4 Pt 1):041901. Epub 2004 Apr 14.

Fields and forces acting on a planar membrane with a conducting channel.

Bivas I, Danelon C.

Laboratory of Liquid Crystals, Institute of Solid State Physics, Bulgarian Academy of Sciences, 72 Tzarigradsko Chaussee Boulevard, Sofia 1784, Bulgaria. bivas@issp.bas.bg


Modeling electric fields and forces around a channel in a planar membrane is still an open problem. Until now, most of the existing theories have oversimplified the electric field distribution by placing the electrode directly at the entry of the channel. However, in any relevant experimental setup the electrodes are placed far away in the electrolyte solution. We demonstrate that long-range deformation of the electric field distribution appears around the membrane, spanning on distances of the order of the distance between the membrane and the electrode. The forces acting due to this distribution are in most of the cases negligible. They can be important for channels with radii of the order of the thickness of the layer of structured water at the oil-water interface.

Bioelectrochemistry. 2003 Oct;61(1-2):65-72.

Sub-microsecond, intense pulsed electric field applications to cells show specificity of effects.

Hair PS, Schoenbach KH, Buescher ES.

Center for Pediatric Research, Eastern Virginia Medical School, Norfolk, VA 23510, USA.


Application of sub-microsecond duration (60-300 ns), intense (15-60 kV/cm) pulsed electric fields (sm/i-PEF) to six types of human cells was examined for its effects on individual cell surface membrane permeability and membrane potential. With short (60 ns) pulses, increasing percentages of Jurkat cells showed propidium iodide (PI) uptake at progressively shorter post-pulse times as the pulse train increased from 1 to 10 sequential pulses, while human blood polymorphonuclear leukocytes (PMN) were unresponsive to these short pulses regardless of train size. With 300 ns pulses, a similar pattern (increasing percentages of cells taking up PI, and progressively shorter times of onset after pulse applications as pulse train size increased) was seen with both Jurkat cells and PMN, but the patterns for both effects were different. Jurkat cell size did not appear to influence the responsiveness of this cell type. Comparisons of sm/i-PEF-induced PI uptake by human monocyte-derived macrophages vs. aged human mononuclear cells, human trunk skin (HTS) cells vs. fresh human mononuclear cells and human macrophages vs. HTS cells showed similar overall effects, but with differences between the patterns for each cell type compared (except the macrophages vs. HTS cells comparison). Application of sm/i-PEFs also caused different patterns of membrane potential loss in Jurkat cells vs. PMN. Jurkat cells developed significant decreases in t heir membrane potential only following the highest intensity pulse applications examined, i.e., 300 ns, 60 kV/cm x5, while PMN showed this effect over the entire range of pulse intensities (300 ns, 15-60 kV/cm, x5) applied. These data indicate that sm/i-PEF applications can have “specificity” (i.e., achieve different levels of effect in different cell types), that cell size does not appear to be the major factor determining sm/i-PEF effects in either Jurkat cells or PMN, that heterogeneous sm/i-PEF effects on cells tend to become homogeneous with increasing pulse train size, and that specificity of sm/i-PEF applications effects can occur at either end of the sm/i-PEF intensity spectrum examined.

Eur Biophys J. 2003 Sep;32(6):519-28. Epub 2003 Apr 24.

Effect of electric field induced transmembrane potential on spheroidal cells: theory and experiment.

Valic B, Golzio M, Pavlin M, Schatz A, Faurie C, Gabriel B, Teissié J, Rols MP, Miklavcic D.

Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, 1000 Ljubljana, Slovenia.


The transmembrane potential on a cell exposed to an electric field is a critical parameter for successful cell permeabilization. In this study, the effect of cell shape and orientation on the induced transmembrane potential was analyzed. The transmembrane potential was calculated on prolate and oblate spheroidal cells for various orientations with respect to the electric field direction, both numerically and analytically. Changing the orientation of the cells decreases the induced transmembrane potential from its maximum value when the longest axis of the cell is parallel to the electric field, to its minimum value when the longest axis of the cell is perpendicular to the electric field. The dependency on orientation is more pronounced for elongated cells while it is negligible for spherical cells. The part of the cell membrane where a threshold transmembrane potential is exceeded represents the area of electropermeabilization, i.e. the membrane area through which the transport of molecules is established. Therefore the surface exposed to the transmembrane potential above the threshold value was calculated. The biological relevance of these theoretical results was confirmed with experimental results of the electropermeabilization of plated Chinese hamster ovary cells, which are elongated. Theoretical and experimental results show that permeabilization is not only a function of electric field intensity and cell size but also of cell shape and orientation.

Biophys J. 2003 Aug;85(2):719-29.

Effective conductivity of a suspension of permeabilized cells: a theoretical analysis.

Pavlin M, Miklavcic D.

University of Ljubljana, Faculty of Electrical Engineering, Ljubljana, Slovenia. mojca@svarun.fe.uni-lj.si


During the electroporation cell membrane undergoes structural changes, which increase the membrane conductivity and consequently lead to a change in effective conductivity of a cell suspension. To correlate microscopic membrane changes to macroscopic changes in conductivity of a suspension, we analyzed the effective conductivity theoretically, using two different approaches: numerically, using the finite elements method; and analytically, by using the equivalence principle. We derived the equation, which connects membrane conductivity with effective conductivity of the cell suspension. The changes in effective conductivity were analyzed for different parameters: cell volume fraction, membrane and medium conductivity, critical transmembrane potential, and cell orientation. In our analysis we used a tensor form of the effective conductivity, thus taking into account the anisotropic nature of the cell electropermeabilization and rotation of the cells. To determine the effect of cell rotation, as questioned by some authors, the difference between conductivity of a cell suspension with normally distributed orientations and parallel orientation was also calculated, and determined to be <10%. The presented theory provides a theoretical basis for the analysis of measurements of the effective conductivity during electroporation.

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

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

Heida T.

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


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

IEEE Trans Biomed Eng. 2002 Oct;49(10):1195-203.

Investigating membrane breakdown of neuronal cells exposed to nonuniform electric fields by finite-element modeling and experiments.

Heida T, Wagenaar JB, Rutten WL, Marani E.

Institute of BioMedical Technology, Department of Biomedical Engineering, Faculty of Electrical Engineering, University of Twente, Enschede, The Netherlands.



High electric field strengths may induce high cell membrane potentials. At a certain breakdown level the membrane potential becomes constant due to the transition from an insulating state into a high conductivity and high permeability state. Pores are thought to be created through which molecules may be transported into and out of the cell interior. Membrane rupture may follow due to the expansion of pores or the creation of many small pores across a certain part of the membrane surface. In nonuniform electric fields, it is difficult to predict the electroporated membrane area. Therefore, in this study the induced membrane potential and the membrane area where this potential exceeds the breakdown level is investigated by finite-element modeling. Results from experiments in which the collapse of neuronal cells was detected were combined with the computed field strengths in order to investigate membrane breakdown and membrane rupture. It was found that in nonuniform fields membrane rupture is position dependent, especially at higher breakdown levels. This indicates that the size of the membrane site that is affected by electroporation determines rupture.

Phys Med Biol. 2000 Jul;45(7):1965-88.

Nonlinear cell response to strong electric fields.

Bardos DC, Thompson CJ, Yang YS, Joyner KH.

Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria , Australia.


The response of living cells to externally applied electric fields is of widespread interest. In particular, the intensification of electric fields across cell membranes is believed to be responsible, through membrane rupture and reversible membrane breakdown processes, for certain types of tissue damage in electrical trauma cases which cannot be attributed to Joule heating. Large elongated cells such as skeletal muscle fibres are particularly vulnerable to such damage. Previous theoretical studies of field intensification across cell membranes in such cells have assumed the membrane current to be linear in the applied field (Ohmic membrane conductivity) and were limited to sinusoidal applied fields. In this paper, we investigate a simple model of a long cylindrical cell, corresponding to nerve or skeletal muscle cells. Employing the electroquasistatic approximation, a system of coupled first-order differential equations for the membrane electric field is derived which incorporates arbitrary time dependence in the external field and nonlinear membrane response (non-Ohmic conductivity). The behaviour of this model is investigated for a variety of applied fields in both the linear and highly nonlinear regimes. We find that peak membrane fields predicted by the nonlinear model are approximately twice as intense, for low-frequency electrical trauma conditions, as those of the linear theory.

IEEE Trans Biomed Eng. 2002 Jun;49(6):605-12.

Dependence of induced transmembrane potential on cell density, arrangement, and cell position inside a cell system.

Pavlin M, Pavselj N, Miklavcic D.

University of Ljubljana, Faculty of Electrical Engineering, Slovenia.


A nonuniform transmembrane potential (TMP) is induced on a cell membrane exposed to external electric field. If the induced TMP is above the threshold value, cell membrane becomes permeabilized in a reversible process called electropermeabilization. Studying electric potential distribution on the cell membrane gives us an insight into the effects of the electric field on cells and tissues. Since cells are always surrounded by other cells, we studied how their interactions influence the induced TMP. In the first part of our study, we studied dependence of potential distribution on cell arrangement and density in infinite cell suspensions where cells were organized into simple-cubic, body-centered cubic, and face-centered cubic lattice. In the second part of the study, we examined how induced TMP on a cell membrane is dependent on its position inside a three-dimensional cell cluster. Finally, the results for cells inside the cluster were compared to those in infinite lattice. We used numerical analysis for the study, specifically the finite-element method (FEM). The results for infinite cell suspensions show that the induced TMP depends on both: cell volume fraction and cell arrangement. We established from the results for finite volume cell clusters and layers, that there is no radial dependence of induced TMP for cells inside the cluster.

Laryngoscope. 2001 Jan;111(1):52-6.

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

Allegretti JP, Panje WR.

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


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

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

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

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

J Membr Biol. 1984;78(1):53-60.

Electric field-induced breakdown of lipid bilayers and cell membranes: a thin viscoelastic film model.

Dimitrov DS.


A simple viscoelastic film model is presented, which predicts a breakdown electric potential having a dependence on the electric pulse length which approximates the available experimental data for the electric breakdown of lipid bilayers and cell membranes (summarized in the reviews of U. Zimmermann and J. Vienken, 1982, J. Membrane Biol. 67:165 and U. Zimmermann, 1982, Biochim. Biophys. Acta 694:227). The basic result is a formula for the time tau of membrane breakdown (up to the formation of pores): tau = alpha (mu/G)/(epsilon 2m epsilon 2oU4/24 sigma Gh3 + T2/sigma Gh-1), where alpha is a proportionality coefficient approximately equal to ln(h/2 zeta o), h being the membrane thickness and zeta o the amplitude of the initial membrane surface shape fluctuation (alpha is usually of the order of unity), mu represents the membrane shear viscosity, G the membranes shear elasticity modules, epsilon m the membrane relative permittivity, epsilon o = 8.85 X 10(-12) F/m, U the electric potential across the membrane, sigma the membrane surface tension and T the membrane tension. This formula predicts a critical potential Uc; Uc = (24 sigma Gh3/epsilon 2m epsilon 2o)1/4 (for tau = infinity and T = 0). It is proposed that the time course of the electric field-induced membrane breakdown can be divided into three stages: (i) growth of the membrane surface fluctuations, (ii) molecular rearrangements leading to membrane discontinuities, and (iii) expansion of the pores, resulting in the mechanical breakdown of the membrane.

Biophys Chem. 1984 May;19(3):211-25.

Stochastic model for electric field-induced membrane pores. Electroporation.

Sugar IP, Neumann E.


Electric impulses (1-20 kV cm-1, 1-5 microseconds) cause transient structural changes in biological membranes and lipid bilayers, leading to apparently reversible pore formation ( electroporation ) with cross-membrane material flow and, if two membranes are in contact, to irreversible membrane fusion ( electrofusion ). The fundamental process operative in electroporation and electrofusion is treated in terms of a periodic lipid block model, a block being a nearest-neighbour pair of lipid molecules in either of two states: (i) the polar head group in the bilayer plane or (ii) facing the centre of a pore (or defect site). The number of blocks in the pore wall is the stochastic variable of the model describing pore size and stability. The Helmholtz free energy function characterizing the transition probabilities of the various pore states contains the surface energies of the pore wall and the planar bilayer and, if an electric field is present, also a dielectric polarization term (dominated by the polarization of the water layer adjacent to the pore wall). Assuming a Poisson process the average number of blocks in a pore wall is given by the solution of a non-linear differential equation. At subcritical electric fields the average pore size is stationary and very small. At supercritical field strengths the pore radius increases and, reaching a critical pore size, the membrane ruptures (dielectric breakdown). If, however, the electric field is switched off, before the critical pore radius is reached, the pore apparently completely reseals to the closed bilayer configuration (reversible electroporation ).