Magnetic therapy utilizing static magnetic fields is nearly as old as civilization.  Today a pulsed electromagnetic field therapy PEMF utilizing minute, pulsed electromagnetic fields applied transcranially called repetitive transcranial magnetic stimulation (rTMS) has been found to safely treat epilepsy. 

Below, please find dozens of peer reviewed research studies which support a finding that magnetic therapy utilizing pulsed electromagnetic fields called repetitive transcranial magnetic stimulation  (rTMS/TMS) treatment for epilepsy reduces seizure activity and reduces symptoms of Parkinson’s disease, depression, MS, and migraine headache without side effects or expected/unexpected reactions. While modern research is nearly all done with very strong amplitude magnetic fields, Sandyk & Anninos showed that you can provide same or better effect with very-VERY minute fields in the Pico-Tesla range.

We are sure most pulsed electromagnetic therapies lead to enhanced cellular energy, however those in the 1-15 hz range result in cells producing more organically produced ATP; we call this  MoreATP; particularly from the TMS / rTMS done at frequencies between 1 and 20 Hz. Professor Photios Anninos discovered that brain waves of epileptic individuals have abnormality which correspond to a particular frequency range. He and his associates in Greece have developed a highly accurate method of measuring these abnormalities and then custom tuning their electromagnetic field therapy device for each individual on a case by case basis but generally at around 7 Hz. The magnetoencephalogram (MEG) is the magnetic activity emitted by the brain, which can be measured using a superconductive quantum interference device (SQUID). Total cost including brain mapping in your home country is in the US$5000 range. We can assist your participation in the next electromagnetic field therapy ‘excursion’ to Greece; just email us; the IABC contact we’ve got will be glad to send you out information which will probably convince you that a trip to Greece for electromagnetic field therapy is worth the time and expense. See IABC press release on Professor Anninos.

We’ve followed Professor Anninos’ research since summer 2000 and happened to meet 4 person’s who had been to see Professor Anninos in Greece for Parkinson’s therapy  We’ve talked at length and seen video tape of the electromagnetic field therapy process used upon dozens of his patients. If you’ve got Parkinson’s disease, MS, Epilepsy, migraine headache, cluster headache, ADD, ADHD, or suffer with depression and can afford the time and expense of travel, we HIGHLY recommend you see them for picoTesla electromagnetic field therapy to order one of his $5000 helmets. If not, you can achieve nearly the same or better effect at home for 600 usd.

EarthPulse™ has discovered that our patented geomagnetic field supplementation device and methods substantially enhance human (and animal) performance regardless of the etiology of disease by improving the efficiency of oxygen metabolism, subsequently increasing saturated blood oxygen and reducing oxidative stress. We’re the first and only device whose primary use frequency is 10 Hz. Read our treatise MoreATP for a rather simple explanation of it.

The Epilepsy rTMS bibliography is offered for your education only and studies contained are not intended as promotional material. This site is for informational purposes only. No therapeutic products can be sold in relation to the pulsed electromagnetic field therapy research bibliographies found here.

See also; Sandyk R, Anninos PA , Jacobson JI; three pioneers of electromagnetic field therapy to treat Parkinson’s, Alzheimer’s and epilepsy.


Pulsed Electromagnetic Therapy treatment for Epilepsy rTMS Bibliography

To read the original source, use Pubmed and search for Title of the citation

Neuroscience. 2014 Nov 7;280:181-92. doi: 10.1016/j.neuroscience.2014.09.022. Epub 2014 Sep 18.
Repeated transcranial magnetic stimulation prevents kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons.
Shojaei A1, Semnanian S1, Janahmadi M2, Moradi-Chameh H1, Firoozabadi SM3, Mirnajafi-Zadeh J4.

 
Brain Res. 2014 Sep 18;1581:103-16. doi: 10.1016/j.brainres.2014.06.006. Epub 2014 Jun 14. Frequency-dependent effects of contralateral repetitive transcranial magnetic stimulation on penicillin-induced seizures. Lin CY1, Li K2, Franic L3, Gonzalez-Martinez J3, Lin VW4, Najm I3, Lee YS2.

 
Epilepsy Res. 2014 Feb;108(2):190-201. doi: 10.1016/j.eplepsyres.2013.11.023. Epub 2013 Dec 5. Repetitive transcranial magnetic stimulation decreases the kindling induced synaptic potentiation: effects of frequency and coil shape. Yadollahpour A1, Firouzabadi SM1, Shahpari M2, Mirnajafi-Zadeh J3.

 
Seizure. 2013 Dec;22(10):893-6. doi: 10.1016/j.seizure.2013.06.014. Epub 2013 Jul 19. Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Liu A1, Pang T, Herman S, Pascual-Leone A, Rotenberg A.

 
Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Liu A, Pang T, Herman S, Pascual-Leone A, Rotenberg A.

 
Seizure. 2013 Jul 19. doi:pii: S1059-1311(13)00193-3. 10.1016/j.seizure.2013.06.014. [Epub ahead of print]
A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders.
Fuggetta G, Noh NA.

 
Exp Neurol. 2013 Jul;245:87-95. doi: 10.1016/j.expneurol.2012.10.010. Epub 2012 Oct 11. 
Possibly lifesaving, noninvasive, EEG-guided neuromodulation in anesthesia-refractory partial status epilepticus.
Thordstein M, Constantinescu R.

 
Epilepsy Behav. 2012 Nov;25(3):468-72. doi: 10.1016/j.yebeh.2012.07.026. Epub 2012 Sep 
A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders.
Fuggetta G, Noh NA.

 
Exp Neurol. 2012 Oct 11. doi:pii: S0014-4886(12)00393-7. 10.1016/j.expneurol.2012.10.010. [Epub ahead of print]
Repetitive transcranial magnetic stimulation (rTMS) noise: a relevance for tinnitus treatment?
Tringali S, Perrot X, Collet L, Moulin A.

 
Brain Stimul. 2012 Oct;5(4):655-6. doi: 10.1016/j.brs.2011.10.006. Epub 2012 Feb 22. No abstract available.
Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.
Sun W, Mao W, Meng X, Wang D, Qiao L, Tao W, Li L, Jia X, Han C, Fu M, Tong X, Wu X, Wang Y.

 
Epilepsia. 2012 Oct;53(10):1782-9. doi: 10.1111/j.1528-1167.2012.03626.x. Epub 2012 Sep 5.
Safety and tolerability of repetitive transcranial magnetic stimulation in patients with pathologic positive sensory phenomena: a review of literature.
Muller PA, Pascual-Leone A, Rotenberg A.

 
Brain Stimul. 2012 Jul;5(3):320-9.e27. doi: 10.1016/j.brs.2011.05.003. Epub 2011 Jun 14. Review.
Repetitive transcranial magnetic stimulation safely administered after seizure.
Bagati D, Mittal S, Praharaj SK, Sarcar M, Kakra M, Kumar P.

 
J ECT. 2012 Mar;28(1):60-1. doi: 10.1097/YCT.0b013e318221f9b1.
A neuronal network model for simulating the effects of repetitive transcranial magnetic stimulation on local field potential power spectra.
Bey A, Leue S, Wienbruch C.

 
PLoS One. 2012;7(11):e49097. doi: 10.1371/journal.pone.0049097. Epub 2012 Nov 7.
French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications].
Lefaucheur JP, André-Obadia N, Poulet E, Devanne H, Haffen E, Londero A, Cretin B, Leroi AM, Radtchenko A, Saba G, Thai-Van H, Litré CF, Vercueil L, Bouhassira D, Ayache SS, Farhat WH, Zouari HG, Mylius V, Nicolier M, Garcia-Larrea L.

 
Neurophysiol Clin. 2011 Dec;41(5-6):221-95. doi: 10.1016/j.neucli.2011.10.062. Epub 2011 Nov 10. French.
Repetitive transcranial magnetic stimulation in psychiatry. Mishra BR, Sarkar S, Praharaj SK, Mehta VS, Diwedi S, Nizamie SH.

 
Epilepsy Res. 2011 Oct;96(3):231-40. Epub 2011 Jun 29.
Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: A meta-analysis.
Hsu WY, Cheng CH, Lin MW, Shih YH, Liao KK, Lin YY.
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan; Integrated Brain Research Laboratory, Taipei Veterans General Hospital

 
Epilepsy Behav. 2011 Feb;20(2):355-9. Epub 2011 Jan 7.
An estimate of placebo effect of repetitive transcranial magnetic stimulation in epilepsy.
Bae EH, Theodore WH, Fregni F, Cantello R, Pascual-Leone A, Rotenberg A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

 
Clin EEG Neurosci. 2011 Jan;42(1):40-4.
Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy.
Sun W, Fu W, Mao W, Wang D, Wang Y.
Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, PR China.

 
Eur Neurol. 2010;63(4):205-10. Epub 2010 Feb 11. 
Transcranial magnetic stimulation for drug-resistant epilepsies: rationale and clinical experience.
Kimiskidis VK.
Department of Neurology III, Aristotle University of Thessaloniki, Thessaloniki, Greece.

 
Epilepsy Behav. 2009 Oct;16(2):353-5. Epub 2009 Sep 10.
In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy.
Rotenberg A, Bae EH, Muller PA, Riviello JJ Jr, Bourgeois BF, Blum AS, Pascual-Leone A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA

 
Epilepsy Behav. 2009 Jan;14(1):253-7. Epub 2008 Oct 30.
Repetitive transcranial magnetic stimulation in the treatment of epilepsia partialis continua.
Rotenberg A, Bae EH, Takeoka M, Tormos JM, Schachter SC, Pascual-Leone A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

 
Seizure. 2008 Dec;17(8):677-83. Epub 2008 May 20.
Repetitive transcranial magnetic stimulation decreases the number of seizures in patients with focal neocortical epilepsy.
Santiago-Rodríguez E, Cárdenas-Morales L, Harmony T, Fernández-Bouzas A, Porras-Kattz E, Hernández A.
Unidad de Investigación en Neurodesarrollo “Dr. Augusto Fernández Guardiola”, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico.

 
Epilepsy Behav. 2008 Jul;13(1):260-2. Epub 2008 Mar 4
Transient suppression of seizures by repetitive transcranial magnetic stimulation in a case of Rasmussen’s encephalitis.
Rotenberg A, Depositario-Cabacar DBae EHHarini CPascual-Leone ATakeoka M.
Division of Epilepsy and Clinical Neurophysiology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA. alexander.rotenberg@childrens.harvard.edu
Repetitive transcranial magnetic stimulation (rTMS) has been applied with variable success to terminate the seizures of epilepsia partialis continua. The rationale for using this technique to suppress ongoing seizures is the capacity of rTMS to interrupt ongoing neuronal activity, and to produce a lasting decrease in cortical excitability with low-frequency (1 Hz) stimulation. We report a case of epilepsia partialis continua in a child with Rasmussen’s encephalitis, in whom seizures were transiently suppressed by 1-Hz rTMS delivered in nine daily 30-minute sessions. In this case, total ictal time was significantly reduced during stimulation, but the daily baseline seizure rate remained unchanged. Notably, the detection and quantification of this short-lived improvement were enabled by recording EEG continuously during the rTMS session. Thus, we present this case to illustrate a potential utility of combined continuous EEG recording and rTMS in seizure treatment.

Seizure. 2008 May 19. [Epub ahead of print]
Repetitive transcranial magnetic stimulation decreases the number of seizures in patients with focal neocortical epilepsy.
Santiago-Rodríguez E, Cárdenas-Morales LHarmony TFernández-Bouzas APorras-Kattz EHernández A.
Unidad de Investigación en Neurodesarrollo “Dr. Augusto Fernández Guardiola”, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico. 
PURPOSE: To evaluate the number of seizures and interictal epileptiform discharges (IEDs) in patients with focal neocortical epilepsy before, during and after rTMS.
METHODS: Twelve patients (seven men and five women, mean age 29.3+/-15.8 years) were studied. An open-label study with baseline (4 weeks), intervention (2 weeks) and follow-up (8 weeks) periods was carried out. Repetitive transcranial magnetic stimulation (rTMS) with 900 pulses, intensity of 120% motor resting threshold and 0.5Hz frequency was used. A 120 channel EEG was recorded; an electrical source analysis of IEDs with Variable Resolution Electromagnetic Tomography (VARETA) was performed. The number of seizures per week and IEDs per minute were measured and compared in the three periods.
RESULTS: During the basal period the mean seizure frequency was 2.25 per week; in the intervention period it decreased to 0.66 per week (F=2.825; p=0.0036) which corresponds to a 71% reduction. In the follow-up period the mean frequency was 1.14 seizures per week, that is, a 50% reduction in the number of seizures. In the visual EEG analysis, the baseline IED frequency was 11.9+/-8.3events/min; it decreased to 9.3+/-7.9 during 2 weeks of rTMS with a further reduction to 8.2+/-6.6 in the follow-up period. These differences however were not significant (p=0.190).
CONCLUSION: We conclude that 2 weeks of rTMS at 0.5Hz with a figure-of-eight coil placed over the epileptic focus, determined with VARETA, decreases the number of seizures in patients with focal epilepsy, without reduction in IEDs.

 
Clin Neurophysiol. 2008 Mar;119(3):504-32. Epub 2007 Dec 11.
The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.
Chen R, Cros DCurra ADi Lazzaro VLefaucheur JPMagistris MRMills KRösler KMTriggs WJUgawa YZiemann U.
Division of Neurology, Toronto Western Research Institute, University of Toronto, 7MC411, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ont., Canada M5T 2S8. robert.chen@uhn.on.ca
The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer’s disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Epilepsia. 2008 Mar;49(3):470-80. Epub 2007 Nov 19.
Late EEG responses triggered by transcranial magnetic stimulation (TMS) in the evaluation of focal epilepsy.
Valentin A, Arunachalam RMesquita-Rodrigues AGarcia Seoane JJRichardson MPMills KRAlarcon G.
Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London, United Kingdom.
PURPOSE: To evaluate the use of EEG responses to transcranial magnetic stimulation (TMS-EEG responses) as a noninvasive tool for the diagnosis of focal epilepsy. METHODS: Fifteen patients and 15 healthy subjects were studied. TMS at an intensity set at resting corticomotor threshold were delivered at the standard EEG electrode positions. For each position, EEG responses to TMS were evaluated before and after averaging EEG recordings synchronized with the TMS pulse. RESULTS: Two types of TMS-EEG responses were seen: (A) early responses: consisting of a single slow wave seen after the TMS pulse; and (B) late TMS-EEG responses, which were subclassified into (b.1) delayed responses: waveforms resembling interictal epileptiform discharges induced by TMS; or (b.2) repetitive responses: onset of a new rhythym induced by TMS. Early responses were observed in patients and healthy subjects when stimulating at various sites and were considered normal responses to TMS. Late TMS-EEG responses were not seen in healthy subjects, whereas they were seen in 11 of the 15 epileptic patients. Late TMS-EEG responses occurred when stimulating the epileptogenic side in eight out of the nine patients who had lateralized late TMS-EEG responses. The combined use of late TMS-EEG responses and interictal scalp EEG would have suggested the diagnosis of focal epilepsy in all patients, despite the absence of late TMS-EEG responses in four patients and the presence of normal interictal scalp EEG in three. CONCLUSIONS: TMS-EEG responses can identify epileptogenic cortex and may substantially improve the diagnosis of focal epilepsy, particularly, if combined with standard EEG studies.

 
Neurorehabil Neural Repair. 2008 Mar-Apr;22(2):185-92. Epub 2007 Sep 17.
Safety of 6-Hz primed low-frequency rTMS in stroke.
Carey JR, Evans CDAnderson DCBhatt ENagpal AKimberley TJPascual-Leone A.
Program in Physical Therapy, University of Minnesota, Minneapolis 55455, USA. 
BACKGROUND: Suppression of activity in the contralesional motor cortex may promote recovery of function after stroke. Furthermore, the known depressant effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) can be increased and prolonged by preceding it with 6-Hz priming stimulation. OBJECTIVE: The authors explored the safety of 6-Hz primed low-frequency rTMS in 10 patients with ischemic stroke. METHODS: Priming consisted of 10 minutes of 6-Hz rTMS applied to the contralesional hemisphere at 90% of resting motor threshold delivered in 2 trains/min with 5 s/train and 25-second intervals between trains. Low-frequency rTMS consisted of an additional 10 minutes of 1-Hz rTMS at 90% of resting motor threshold without interruption. Possible adverse effects were assessed with the National Institutes of Health Stroke Scale (NIHSS), the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Hopkins Verbal Learning Test-Revised (HVLT-R), the Beck Depression Inventory-Second Edition (BDI-II), a finger movement tracking test, and individual self-assessments. Pretest, treatment, and posttest occurred on the first day with follow-up tests on the next 5 weekdays. RESULTS: There were no seizures and no impairment of NIHSS, WAIS-III, or BDI-II scores. Transient impairment occurred on the HVLT-R. Transient tiredness was common. Occasional reports of headache, neck pain, increased sleep, reduced sleep, nausea, and anxiety occurred. CONCLUSION: Because there were no major adverse effects, the authors concluded that the treatment was safe for the individuals in this study and that further investigation is now warranted to examine efficacy and safety of serial treatments of 6-Hz primed low-frequency rTMS.

 
Int J Neuropsychopharmacol. 2008 Feb;11(1):131-47. Epub 2007 Sep 20.
A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression.
Loo CK, McFarquhar TFMitchell PB.
School of Psychiatry, University of New South Wales, Sydney, Australia. 
 
There is growing interest worldwide in rTMS as a clinical treatment for depression. Apart from efficacy, its safety as a clinical treatment must be considered before its widespread use can be advocated. All published, sham-controlled rTMS depression trials were reviewed for reported side-effects and outcomes of formal neuropsychological testing. In addition, all reports of seizures occurring with rTMS were reviewed. Other safety concerns (effects on hearing; headache, pain, induced currents in electrical circuits, histotoxicity, electromagnetic field exposure, psychiatric complications, safety in pregnancy) are discussed. Common side-effects were of a minor nature, e.g. headache. There was a low incidence of accidental seizures and induced hypomania, both of which were associated with identified risk factors for which subjects should be screened. Long-term effects of repeated rTMS sessions are as yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment.

 
Exp Brain Res. 2008 Jan;184(3):439-43. Epub 2007 Nov 24.
Cortical silent period following TMS in a patient with supplementary sensorimotor area seizures.
Nardone R, Venturi AAusserer HLadurner GTezzon F.
Department of Neurology, Franz.Tappeiner Hospital, Via Rossini, 5, 39012, Merano, Italy. 
The cortical silent period (CSP) following transcranial magnetic stimulation (TMS) was evaluated in a patient with a dysembrioplastic neuroepithelial tumor (DNET) in the lateral portion of the right superior frontal gyrus (SFG) who suffered from supplementary sensorimotor area (SSMA) seizures. CSP duration was shortened on the affected side. Ipsilateral alterations of motor cortex excitability with TMS in epileptogenic DNET located outside the PMA argue in favour of cortico-cortical connections to primary motor cortex from SSMA. This functional connectivity should be taken into consideration to better understand the pathophysiology of ictal motor manifestations.

 
Med Hypotheses. 2008;71(2):279-82. Epub 2008 Apr 22.
Can the ‘yin and yang’ BDNF hypothesis be used to predict the effects of rTMS treatment in neuropsychiatry?
Brunoni AR, Boggio PSFregni F.
Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 430, Boston, MA 02215, USA; Institute of Psychiatry, University of São Paulo, Brazil.
Repetitive transcranial magnetic stimulation (rTMS) is a novel technique of non-invasive brain stimulation which has been used to treat several neuropsychiatric disorders such as major depressive disorder, chronic pain and epilepsy. Recent studies have shown that the therapeutic effects of rTMS are associated with plastic changes in local and distant neural networks. In fact, it has been suggested that rTMS induces long-term potentiation (LTP) and long-term depression (LTD) – like effects. Besides the initial positive clinical results; the effects of rTMS are still mixed. Therefore new tools to assess the effects of plasticity non-invasively might be useful to predict its therapeutic effects and design novel therapeutic approaches using rTMS. In this paper we propose that brain-derived neurotrophic factor (BDNF) might be such a tool. Brain-derived neurotrophic factor is a neurotrophin that plays a key role in neuronal survival and synaptic strength, which has also been studied in several neuropsychiatric disorders. There is robust evidence associating BDNF with the LTP/LTD processes, and indeed it has been proposed that BNDF might index an increase or decrease of brain activity – the ‘yin and yang’ BDNF hypothesis. In this article, we review the initial studies combining measurements of BDNF in rTMS clinical trials and discuss the results and potential usefulness of this instrument in the field of rTMS.

 
Zhonghua Wai Ke Za Zhi. 2007 Dec 15;45(24):1685-7.
[The effect of low frequency transcranial magnetic stimulation on neuropeptide-Y expression and apoptosis of hippocampus neurons in epilepsy rats induced by pilocarpine]
[Article in Chinese] Wang YL, Zhai YHuo XLZhang JN.
Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin 300052, China. wang19690924@sina.com
OBJECTIVE: To analyze the effect of low frequency transcranial magnetic stimulation (LF-TMS) on changing neuropeptide-Y (NPY) expression and apoptosis of hippocampus neurons in epilepsy rats induced by pilocarpine (PLO). METHODS: Thirty male Sprague Dawley rats (240 g +/- 20 g) were randomly divided into 2 groups. I group simply celiac injected pilocarpine. II group celiac injected PLO after LF-TMS. Pathological item included HE staining, NPY immunohistochemical staining and apoptosis staining. RESULTS: HE staining revealed neurons of hippocampus were obviously death and cell’s structure was destroyed in PLO group. The PLO + LF-TMS group was less injured and destroyed. Using One-Way ANOVA, NPY immunohistochemical staining shown the positive cell number was increased at all areas of hippocampus in PLO group contrasting with the low positive cell number in the PLO + LF-TMS group. In PLO group the number of apoptosis cell at hippocampus areas was significant higher than the PLO + LF-TMS group. CONCLUSIONS: Using the PLO evoked epilepsy model, LF-TMS alleviated neurons injury at hippocampus area, so LF-TMS might playing an important role in resisting the progressing of epilepsy. The positive cell number of NPY increased at all areas of hippocampus, which indicated the close relation between NPY and epilepsy. NPY might have some function on resisting epilepsy.

Brain Res Rev. 2007 Dec;56(2):346-61. Epub 2007 Aug 28.
The use of tDCS and CVS as methods of non-invasive brain stimulation.
 
Been G, Ngo TTMiller SMFitzgerald PB.
Alfred Psychiatry Research Centre, The Alfred Hospital and Monash University School of Psychology, Psychiatry and Psychological Medicine, Commercial Rd, Melbourne, VIC 3004, Australia.
Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson’s disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).
 

Neurosci Behav Physiol. 2007 Nov;37(9):849-52.
Evoked motor response thresholds during transcranial magnetic stimulation in patients with symptomatic partial epilepsy.
 
Kotova OV, Vorob’eva OV.
Department of Nervous Diseases, Postgraduate Professional Educational Faculty, I. M. Sechenov Moscow Medical Academy.
Transcranial magnetic stimulation (TMS) occupies a leading position among noninvasive neurophysiological methods used for evaluating the balance of processes of cortical inhibition and excitation. The aim of the present work was to assess motor cortical excitability in symptomatic partial epilepsy using TMS in relation to the effects of antiepileptic treatment. A total of 31 patients were studied. A decrease in the motor response threshold was seen in a group consisting of untreated patients, with changes in cortical excitability during seizures. Treated patients showed no difference as compared with healthy subjects. The shorter the interval between a seizure and TMS, the smaller the evoked motor response threshold. The low threshold seen in patients with symptomatic partial epilepsy showed a significant correlation with clinical signs of neuromuscular excitability. The data obtained here provide evidence of changes in the functional state of the cortex and, thus, the motor response threshold, in patients with epilepsy.

Clin Neurophysiol. 2007 Sep;118(9):2072-5. Epub 2007 Jul 24.
Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke.
 
Lomarev MP, Kim DYRichardson SPVoller BHallett M.
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, NIH Building 10, Room 5N240, 10 Center Dr MSC 1428, Bethesda, MD 20892-1428, USA. lomarevm@ninds.nih.gov
OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a potential therapeutic tool to rehabilitate chronic stroke patients. In this study, the safety of high-frequency rTMS in stroke was investigated (Phase I). METHODS: The safety of 20 and 25 Hz rTMS over the motor cortex (MC) of the affected hemisphere, with intensities of 110-130% of the motor threshold (MT), was evaluated using surface electromyography (EMG) of hand and arm muscles. RESULTS: Brief EMG bursts, possibly representing peripheral manifestations of after discharges, and spread of excitation to proximal muscles are considered to be associated with a high risk of seizure occurrence. These events were recorded after the rTMS trains. Neither increased MC excitability nor improved pinch force dynamometry was found after rTMS. CONCLUSIONS: Stimulation parameters for rTMS, which are safe for healthy volunteers, may lead to a higher risk for seizure occurrence in chronic stroke patients. SIGNIFICANCE: rTMS at rates of 20 and 25 Hz using above threshold stimulation potentially increases the risk of seizures in patients with chronic stroke.

Epilepsia. 2007 Sep;48(9):1756-63. Epub 2007 Jun 11.
Ketogenic diet: electrophysiological effects on the normal human cortex.
Cantello RVarrasi CTarletti RCecchin MD’Andrea FVeggiotti PBellomo GMonaco F.
Department of Clinical and Experimental Medicine, Section of Neurology, A. Avagadro University, Novara, Italy. cantello@med.unipmn.it
PURPOSE: To explore the cortical electrophysiology of the ketogenic diet (KD) in the normal human. KD is effective against refractory epilepsy, but its precise mechanism is obscure. At the transmitter level, an enhancement of GABA inhibition has often been proposed. METHODS: We studied eight healthy volunteers undergoing a “classic” KD for 2 weeks. We measured several biochemical variables at baseline (T0), after 1 week (T1) and 2 weeks (T2) of KD, then 3 months after the KD conclusion (T3). Ketosis was quantified as 24-h ketonuria. At the same time, we studied the motor cortical excitability by means of transcranial magnetic stimulation (TMS). We also quantitatively evaluated the EEG signal in search of frequency shifts over the rolandic areas. RESULTS: Significant (p < 0.05) neurophysiological changes appeared at T2. These consisted of a strengthening of short-latency cortical inhibition (SICI), a TMS index which is thought to reflect GABA-A inhibition in the cortex. Then, there was an enhancement of the beta EEG band over the perirolandic region, similar to that following administration of GABA-A agonists. All changes disappeared at T3. CONCLUSIONS: A standard, short-term KD affected the cortical physiology of the normal human. The main changes were an augmented SICI and an increased perirolandic beta EEG activity, which are compatible with a lower level of neural excitation within the cortex.

Epilepsia. 2007 Aug;48(8):1538-42. Epub 2007 Apr 13.
A hypothesis for how non-REM sleep might promote seizures in partial epilepsies: a transcranial magnetic stimulation study.
 
Salih F, Khatami RSteinheimer SKretz RSchmitz BGrosse P.
Neurologische Klinik und Poliklinik, and Interdisziplinäres Schlafmedizinisches Zentrum, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany. Farid.Salih@charite.de
PURPOSE: To investigate alterations of inhibitory and excitatory cortical circuits during non-rapid eye movement (NREM) sleep in drug-naive patients with partial epilepsies and sleep-bound seizures only. METHODS: A paired-pulse TMS paradigm was used to test intracortical inhibition (ICI) and facilitation (ICF) in the hemisphere of the epileptic focus in three untreated patients with nonlesional, nongenetic frontal lobe epilepsy in NREM2 (three patients), NREM3/4 (one patient), and wakefulness (three patients). RESULTS: All three patients exhibited a major decrease of ICI in NREM sleep as opposed to the physiological enhancement of ICI with the progression of NREM sleep. CONCLUSIONS: Decreased ICI might reflect a substrate for the association of epileptic processes with thalamocortical networks that propagate sleep. Thus our findings contribute to a hypothesis of how NREM sleep could promote seizures.

J Neurol Sci. 2007 Jul 15;258(1-2):144-7. Epub 2007 Mar 29.
Heightened seizure susceptibility associated with brain dermoid cyst and the administration of human chorionic gonadotropin (hCG).
 
Milani P, Rocchi RCerase ARossi AMazzocchio R.
Section of Clinical Neurophysiology, Department of Neurological and Behavioral Sciences, University of Siena, Italy.
It is known that the intramuscular injection of human chorionic gonadotropin (hCG) lowers the threshold for motor evoked responses (MEPs) in the first dorsal interosseous (FDI) muscle to transcranial magnetic stimulation (TMS) in humans. We describe the case of a patient with a clinically silent left-sided nasofrontal dermoid cyst who, while being treated with hCG/LH for hypogonadotropic hypogonadism, presented with simple partial seizures, ipsilateral to the cyst, with secondary generalization. Motor cortex excitability was studied by single and paired TMS and MEPs were recorded from FDI. Resting motor threshold (RMT), active motor threshold (AMT), MEP size, intracortical inhibition (ICI) and intracortical facilitation (ICF) were tested during and after suspension of hormonal therapy. RMT and AMT were lower, MEP size was larger, ICI was decreased while ICF was slightly diminished during treatment. Overall, this indicated a reduced intracortical inhibition during hormonal therapy. It is concluded that treatment with hCG/LH may favour seizure onset in the presence of potentially epileptogenic lesions such as an intracranial dermoid cyst.

Epilepsy Res. 2007 Jul;75(2-3):197-205.
Motor representation areas in epileptic patients with focal motor seizures: a TMS study.
 
Labyt E, Houdayer ECassim FBourriez JLDerambure PDevanne H.
Department of Clinical Neurophysiology, EA 2683, R. Salengro Hospital, Lille University Medical Centre, F-59037 Lille, France. etienne.labyt@wanadoo.fr
PURPOSE: This study used TMS mapping to investigate the motor representation of the abductor pollicis brevis (APB) muscles in a group of patients with focal epilepsy originating in central or pre-central region. METHODS: Eight epileptic patients and eight control subjects participated in the study. The coil was moved in 1.5-cm steps along a grid drawn on the subject’s skull over the motor cortex of both hemispheres. At each site, six APB motor responses (evoked by TMS at 1.2 times the resting motor threshold) were recorded and averaged. The peak-to-peak amplitude was measured and plotted against the mediolateral and anteroposterior coil positions. The area of each APB muscle representation was measured and the position of the optimal point was calculated. RESULTS: The resting motor threshold was increased bilaterally in epileptic patients. The maps were distorted in most patients (but not in control subjects), as evidenced by an off-centre optimal point. Interhemispheric differences in APB map areas were greater in patients than in control subjects. However, whether these increases in map area were on the epileptic side or on healthy side depended on the given subject. CONCLUSIONS: The changes in APB representation observed in epileptic patients demonstrate that reorganization occurs within the motor cortex. The heterogeneity of the present results is probably related to different locations of the epileptogenic and/or lesional areas and to a variety of compensatory phenomena that may occur, notably with respect to the disease duration.

Nat Clin Pract Neurol. 2007 Jul;3(7):383-93
Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS.
 
Fregni F, Pascual-Leone A.
Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a given organ; they also reflect the consequences of the nervous system’s attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques–repetitive transcranial magnetic stimulation and transcranial direct current stimulation–to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson’s disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.

Epilepsy Behav. 2007 Jun;10(4):521-8. Epub 2007 May 9.
Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature.
Bae EHSchrader LMMachii KAlonso-Alonso MRiviello JJ JrPascual-Leone ARotenberg A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Repetitive transcranial magnetic stimulation (rTMS) is emerging as a new therapeutic tool in epilepsy, where it can be used to suppress seizures or treat comorbid conditions such as mood disorder. However, as rTMS carries a risk of inducing seizures among other adverse events, its safety and tolerability in the population with epilepsy warrant distinct consideration, as this group is especially seizure-prone. Accordingly, we performed a review of the literature to estimate the risk of seizures and other adverse events associated with rTMS in patients with epilepsy. We performed an English-language literature search, and reviewed all studies published from January 1990 to February 2007 in which patients with epilepsy were treated with rTMS, and complemented the literature search with personal correspondence with authors when necessary. We identified 30 publications that described patients with epilepsy who underwent rTMS, and noted total number of relevant subjects, medication usage, incidence of adverse events, and rTMS parameters including stimulus frequency, number of stimuli, train duration, intertrain interval, coil type, and stimulation sites. The data were analyzed for adverse events related to rTMS. Crude per-subject risk, as well as per-subject mean risk weighted by sample size and risk per 1000 stimuli weighted by number of stimuli in each study, were computed for seizures and for other adverse events. Adverse events or lack thereof was reported in 26 studies (n=280 subjects). Adverse events attributed to rTMS were generally mild and occurred in 17.1% of subjects. Headache was most common, occurring in 9.6%. The most serious adverse event was seizure during treatment, which occurred in four patients (1.4% crude per-subject risk). All but one case were the patients’ typical seizures with respect to duration and semiology, and were associated with low-frequency rTMS. A single case of an atypical seizure appearing to arise from the region of stimulation during high-frequency rTMS is reported. No rTMS-related episodes of status epilepticus were reported. We cautiously conclude that the risk of seizure in patients with epilepsy undergoing rTMS is small, and the risk of other mild adverse events is comparable to that seen when rTMS is used to treat other diseases. Status epilepticus or life-threatening seizures have not been reported in patients undergoing rTMS treatment. rTMS thus appears to be nearly as safe in patients with epilepsy as in nonepileptic individuals, and warrants further investigation as a therapy in this population.

Brain. 2007 Mar;130(Pt 3):610-22. Epub 2006 Nov 29.
Stimulating language: insights from TMS.
Devlin JTWatkins KE.
FMRIB Centre, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. devlin@fmrib.ox.ac.uk
Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These ‘virtual lesion’ studies offer not only the ability to explore causal relations between brain regions and language functions absent in functional neuroimaging, but also spatial and temporal precision not typically available in patient studies. For instance, TMS has been used to demonstrate functionally distinct sub-regions of the left inferior frontal gyrus; to clarify the relationship between pre-morbid language organization and susceptibility to unilateral lesions and to investigate the contribution of both left and right hemisphere language areas in recovery from aphasia. When TMS is used as a measure of functional connectivity, it demonstrates a close link between action words and motor programmes; it suggests a potential evolutionary link between hand gestures and language and it suggests a role in speech perception for the motor system underlying speech production. In combination with functional neuroimaging, it can elucidate the circuits responsible for this involvement. Finally, TMS may even be useful for enhancing recovery in aphasic patients. In other words, TMS has already become an important tool for studying language at both the cognitive and neural levels, and it is clear that further developments in TMS methodology are likely to result in even greater opportunities for language research.

Clin Neurophysiol. 2007 Mar;118(3):702-8. Epub 2007 Jan 16.
Antiepileptic effects of low-frequency repetitive transcranial magnetic stimulation by different stimulation durations and locations.
Joo EY, Han SJChung SHCho JWSeo DWHong SB.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-gu, 135-710 Seoul, South Korea.
OBJECTIVE: To evaluate the antiepileptic effect of low-frequency rTMS (repetitive transcranial magnetic stimulation) in the patients with intractable epilepsy. METHODS: We enrolled 35 patients with localization-related epilepsy who had experienced at least one complex partial seizure or a secondarily generalized seizure per week on a constant antiepileptic drug regimen over an 8-week period. rTMS was administered using a Rapid(2) magnetic stimulator with an air-cooled coil at 0.5Hz for 5 consecutive days at 100% of rMT (resting motor threshold). Patients were divided into a focal stimulation group with a localized epileptic focus, or a non-focal stimulation group with a non-localized or multifocal epileptic focus. These two groups were then randomly subdivided into four subgroups depending on the total number of stimulations administered, i.e., 3000 pulse and 1500 pulse subgroups. Weekly seizure frequencies were determined for 8 weeks before and after rTMS. To compare the number of interictal spikes before and after rTMS, EEG was recorded twice before (1st day) and after rTMS (5th day). RESULTS: Mean weekly seizure frequency was non-significantly decreased after rTMS (8.4–>6.8/week, -13.9%). Longer stimulation subgroups (3000 pulses, -23.0%) tended to have fewer seizures than shorter stimulation subgroups (1500 pulses, -3.0%), without statistical significance. TMS stimulation site and structural brain lesions did not influence seizure outcome. However, interictal spikes significantly decreased (-54.9%, P=0.012) after rTMS and they totally disappeared in 6 patients (17.1%, 6/35). CONCLUSIONS: Low-frequency rTMS reduced interictal spikes, but its effect on seizure outcome was not significant. Focal stimulation for a longer duration tended to further reduce seizure frequency. SIGNIFICANCE: These findings may help clinicians to further investigate the therapeutic potential of the rTMS for patients with intractable epilepsy.

Epilepsia. 2007 Feb;48(2):366-74.
Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial.
Cantello R, Rossi SVarrasi CUlivelli MCivardi CBartalini SVatti GCincotta MBorgheresi AZaccara GQuartarone ACrupi DLaganà AInghilleri MGiallonardo ATBerardelli APacifici LFerreri FTombini MGilio FQuarato PConte AManganotti PBongiovanni LGMonaco FFerrante DRossini PM.
Department of Clinical and Experimental Medicine, Section of Neurology, Amedeo Avogadro University, Novara, Italy. cantello@med.unipmn.it
PURPOSE: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy. METHODS: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex. RESULTS: “Active” rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability). CONCLUSIONS: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to “active” rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.

Epilepsia. 2007 Feb;48(2):359-65.
rTMS reveals premotor cortex dysfunction in frontal lobe epilepsy.
 
Löscher WN, Dobesberger J, Szubski C, Trinka E.
Department of Neurology, University Innsbruck, Innsbruck, Austria. wolfgang.loescher@i-med.ac.at
PURPOSE: Studies of motor cortex excitability provided evidence that focal epilepsies may alter the excitability of cortical areas distant from the epileptogenic zone. In order to explore this hypothesis we studied the functional connectivity between premotor and motor cortex in seven patients with frontal lobe epilepsy and seizure onset zone outside the premotor or motor cortex. METHODS: Low-frequency subthreshold repetitive transcranial magnetic stimulation was applied to the premotor cortex and its impact on motor cortex excitability was measured by the amplitude of motor-evoked potentials in response to direct suprathreshold stimulation of the motor cortex. RESULTS: Stimulation of the premotor cortex of the non-epileptogenic hemisphere resulted in a progressive and significant inhibition of the motor cortex as evidenced by a reduction of motor evoked potential amplitude. On the other hand, stimulation of the premotor cortex of the epileptogenic hemisphere failed to inhibit the motor cortex. The reduced inhibition of the motor cortex by remote areas was additionally supported by the significantly shorter cortical silent periods obtained after stimulation of the motor cortex of the epileptogenic hemisphere. CONCLUSION: These results show that the functional connectivity between premotor and motor cortex or motor cortex interneuronal excitability is impaired in the epileptogenic hemisphere in frontal lobe epilepsy while it is normal in the nonepileptogenic hemisphere.

Acta Neurochir Suppl. 2007;97(Pt 2):261-72. Brain stimulation for epilepsy.
Theodore WH, Fisher R.
Clinical Epilepsy Section, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. theodorw@ninds.nih.gov
Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients.

Neurosci Res. 2007 Jan;57(1):140-2. Epub 2006 Nov 7.
Effects of repetitive transcranial magnetic stimulation on spike-and-wave discharges.
 
Conte A, Gilio F, Iacovelli E, Bettolo CM, Di Bonaventura C, Frasca V, Carbone A, Prencipe M, Berardelli A, Inghilleri M.
Department of Neurological Sciences, University of Rome La Sapienza, Rome, Italy.
Aim of this study was to evaluate the effect of 5Hz-suprathreshold repetitive transcranial magnetic stimulation (rTMS) on the duration of the spike-and-wave discharges (SWDs) in a patient presenting idiopathic absence seizures. At the moment of the study the patient presented a mild blunting of consciousness due to the high frequency of absences and EEG recordings showed sub-continuous, generalized, symmetrical and synchronous 3c/s SWDs, petit mal status. Trains of 10 stimuli (120% resting motor threshold) were delivered at 5Hz frequency at the beginning of the SWDs. 5Hz-rTMS trains significantly changed the EEG activity by reducing the duration of SWDs without changing the intervals between two consecutive discharges. rTMS had not significant after-effects on the epileptic activity and patient’s clinical status. Despite the limitations of a single case report, our neurophysiological findings suggest that 5Hz-suprathreshold rTMS delivered in short trains induces a transitory interference of the ongoing epileptic activity.

Indian J Exp Biol. 2006 Dec;44(12):949-54.
Influence of transcranial magnetic stimulation on spike-wave discharges in a genetic model of absence epilepsy.
 
Godlevsky LS, Kobolev EV, van Luijtelaar EL, Coenen AM, Stepanenko KI, Smirnov IV.
Department of Biophysics, Informatics and Medical Devices, Medical University, Odessa, Valehovsky Lane 2, Ukraine. godlevsky@odmu.od.ua
Transcranial magnetic stimulation (TMS) impulses, (0.5 Hz, 3 impulses) were presented at threshold intensity to male WAG/Rij rats. One group received stimuli, which involved motor responses of hindlimbs, rats of the second group received sham stimulation. Electrocorticograms (ECoG) were recorded before and up to 2 hr from the moment of transcranial magnetic stimulation. It was established that such stimulation engendered a reduction of spike-wave discharge (SWD) bursts duration. This effect was most pronounced in 30 min from the moment of cessation of stimulation, when a decrease of 31.4% was noted in comparison with sham-stimulated control group. The number of bursts of spike-wave discharges was reduced, but did not reach significant difference when compared both with pre-stimulative base-line level and with sham-stimulated control rats. Bursts of spike-wave discharges restored up to pre-stimulative level in 90-150 minutes from the moment of cessation of transcranial stimulation. It can be concluded that transcranical magnetic stimulation possessed an ability to engender short-time suppression of bursts of spike-wave discharges in WAG/Rij rats.


Seizure. 2006 Dec;15(8):653-7. Epub 2006 Aug 21.
Erratum in:Seizure. 2007 Mar;16(2):194.
Cyclical excitability of the motor cortex in patients with catamenial epilepsy: a transcranial magnetic stimulation study.
 
Hattemer K, Knake S, Reis J, Oertel WH, Rosenow F, Hamer HM.
Interdisciplinary Epilepsy Center, Department of Neurology, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany. hattemer@med.uni-marburg.de
PURPOSE: The pathophysiology of catamenial epilepsy is still unclear. Therefore, we investigated the cortical excitability of women with catamenial epilepsy during different phases of the menstrual cycle. METHODS: Using transcranial magnetic stimulation, six patients suffering from catamenial epilepsy were investigated during ovulatory cycles. On days 8, -14, -7 and 2 of the cycle (day 1 being the first day of menstrual bleeding), resting motor threshold (RMT), cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF) were investigated. The non-parametric Friedman-test for multiple comparisons and Wilcoxon signed rank test were used for statistical analysis. RESULTS: Five patients suffered from focal epilepsy (three right hemispheric, one bitemporal, one unknown origin) and one patient had idiopathic generalized epilepsy. All patients experienced perimenstrual seizure clustering and two also showed an increased seizure frequency during the luteal phase. In the right hemispheres there was a significant change of CSP duration in the course of the menstrual cycle (chi(2)=8.3, P=0.041), due to a shorter CSP during the luteal phase (Z=-2.0, P=0.043) and menstruation (Z=-2.2, P=0.028) as compared to the follicular phase. There was no significant variation of CSP in the left hemispheres. RMT, ICI and ICF showed no significant changes in the course of the menstrual cycle. CONCLUSIONS: The CSP changes suggest a decreased inhibition involving GABA-ergic neurotransmission during the luteal phase and menstruation. These TMS alterations correlated with the clinical course of the epilepsies and were found in the hemispheres containing the majority of the epileptogenic zones.

Sleep. 2006 Dec 1;29(12):1595-8.
Increasing cortical excitability: a possible explanation for the proconvulsant role of sleep deprivation.
Scalise A, Desiato MT, Gigli GL, Romigi A, Tombini M, Marciani MG, Izzi F, Placidi F.
Department of Neurosciences, S. Maria della Misericordia Hospital, Udine, Italy. annascalise@libero.it
STUDY OBJECTIVE: Sleep deprivation (SD) is known to facilitate both seizures and interictal epileptiform abnormalities. For this reason, it is often used in the routine diagnostic workup of epileptic patients as an activating procedure for eliciting epileptiform and/or seizure patterns in their EEGs. In order to evaluate the effects of SD on cortical excitability, we studied the effects of sleep loss on healthy subjects by transcranial magnetic stimulation (TMS). DESIGN AND PARTICIPANTS: Seven normal subjects underwent TMS examination in baseline condition and after total sleep deprivation. The TMS investigation included two protocols: a) the evaluation of motor evoked potential and silent period parameters recorded in response to single-pulse magnetic stimulation; and b) the evaluation of the time course of intracortical motor activity tested with paired-pulse TMS applied at inter-stimulus intervals of 1-6 ms. SETTING: Clinical neurophysiology laboratory in a general hospital. INTERVENTIONS: None. RESULTS: After SD, the principal finding observed using single-pulse TMS was a decrease of the silent period duration, whereas a reduction of the intracortical inhibition, in particular at inter-stimulus intervals 1 and 2 ms, was found, using the paired-pulse TMS. CONCLUSION: Our findings suggest that SD may modify cortical excitability, seen as the balance between inhibitory and excitatory cortical phenomena, which could reduce the epileptic threshold.

Ann Neurol. 2006 Oct;60(4):447-55.
A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy.
 
Fregni F, Otachi PT, Do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Valente KD.
Center for Non-invasive Brain Stimulation, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: To study the antiepileptic effects of rTMS in patients with refractory epilepsy and malformations of cortical development in a randomized, double-blind, sham-controlled trial. METHODS: Twenty-one patients with malformations of cortical development and refractory epilepsy underwent five consecutive sessions of low-frequency rTMS, either sham or active (1Hz, 1,200 pulses), focally targeting the malformations of cortical development. The number of epileptiform discharges in the electroencephalogram and the number of clinical seizures were measured before (baseline), immediately after, as well as 30 and 60 days after rTMS treatment. RESULTS: rTMS significantly decreased the number of seizures in the active compared with sham rTMS group (p < 0.0001), and this effect lasted for at least 2 months. Furthermore, there was a significant decrease in the number of epileptiform discharges immediately after (p = 0.01) and at week 4 (p = 0.03) in the active rTMS group only. There were few mild adverse effects equally distributed in both groups. The preliminary cognitive evaluation suggests improvement in some aspects of cognition in the active rTMS group only. INTERPRETATION: Noninvasive brain stimulation for epilepsy may be an alternative treatment for pharmaco-resistant patients with clearly identifiable seizure foci in the cortical convexity and who are not eligible for surgical treatment.

Neuroimage. 2006 Oct 1;32(4):1499-509. Epub 2006 Jun 27.
Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus 
Shepherd TM, Ozarslan E, King MA, Mareci TH, Blackband SJ.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. tms@mbi.ufl.edu
The hippocampus is a critical structure for learning and memory formation injured by diverse neuropathologies such as epilepsy or Alzheimer’s disease. Recently, clinical investigations have attempted to use diffusion tensor MRI as a more specific surrogate marker for hippocampal damage. To first better understand the tissue architecture of healthy hippocampal regions, this study characterized 10 rat hippocampi with diffusion tensor imaging (DTI) at 50-microm in-plane image resolution using a 14.1-T magnet. Chemical fixation of the dissected and straightened rat hippocampus provided a simple, effective way to reduce partial volume effects when segmenting hippocampal regions and improved mean signal-to-noise per unit time (e.g. 50.6+/-4.4 at b=1250 s/mm2 in 27 min). Contrary to previous reports that water diffusion is homogeneous throughout the nervous system, statistically different mean diffusivities were observed (e.g. 0.238+/-0.054 and 0.318+/-0.084 microm2/ms for the molecular and granule cell layers respectively) (ANOVA, P<0.05). Different hippocampal subregions had lower fractional anisotropy than uniformly fibrous structures like corpus callosum because of their complex architecture. DTI-derived color fiber orientation maps and tractography demonstrated most components of the trisynaptic intrahippocampal pathway (e.g. orientations in stratum lacunosum-moleculare were dominated by perforant and Schaffer fibers) and also permitted some assessment of connectivity in the rat hippocampus.
PMID: 16806988 [PubMed – indexed for MEDLINE]

41: Neurology. 2006 Sep 26;67(6):1018-22. Related Articles
Comment in: Neurology. 2007 Jul 17;69(3):318; author reply 318-9.
Sleep deprivation increases cortical excitability in epilepsy: syndrome-specific effects.
Badawy RA, Curatolo JM, Newton M, Berkovic SF, Macdonell RA.
Department of Neurology, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia.
OBJECTIVE: To use transcranial magnetic stimulation (TMS) to investigate the hypothesis that sleep deprivation increases cortical excitability in people with epilepsy. METHODS: We performed paired pulse TMS stimulation, using a number of interstimulus intervals (ISIs) on each hemisphere of 30 patients with untreated newly diagnosed epilepsy (15 idiopathic generalized epilepsy [IGE] and 15 focal epilepsy) and on the dominant hemisphere of 13 healthy control subjects, before and after sleep deprivation. RESULTS: Both hemispheres in patients with IGE and the hemisphere ipsilateral to the EEG seizure focus in those with focal epilepsy showed an increase in cortical excitability following sleep deprivation at a number of ISIs. This change in excitability was most prominent in the patients with IGE. Although there were minor changes after sleep deprivation in control subjects and the contralateral hemisphere in the focal epilepsy group seen at the 250-millisecond ISI, it was less than in the other groups. CONCLUSIONS: Sleep deprivation increases cortical excitability in epilepsy; the pattern of change is syndrome dependent.
Publication Types:
PMID: 17000971 [PubMed – indexed for MEDLINE]

42: J Physiol. 2006 Sep 15;575(Pt 3):721-6. Epub 2006 Jun 29. 
GABAA receptor subtype specific enhancement of inhibition in human motor cortex.
Di Lazzaro V, Pilato F, Dileone M, Ranieri F, Ricci V, Profice P, Bria P, Tonali PA, Ziemann U.
Istituto di Neurologia, Università Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy. vdilazzaro@rm.unicatt.it
Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and gamma-aminobutyric acid A receptor (GABA(A)R) subtypes. Here we employed paired-pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABA(A)R-mediated inhibition in human motor cortex, to address the question of which GABA(A)R subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non-selective affinity profile at different alpha-subunit-bearing subtypes of the GABA(A)R while zolpidem has a 10-fold greater affinity to the alpha1-subunit-bearing GABA(A)R compared with those bearing the alpha2- or alpha3-subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an alpha1-subunit GABA(A)R-mediated effect. The findings strongly suggest that SICI is not mediated by the alpha1-subunit-bearing subtype of the GABA(A)R but by those bearing either the alpha2- or alpha3-subunit. This study represents an attempt by means of TMS to identify GABA(A)R subtype-specific action at the systems level of human cortex, a highly relevant issue because the different alpha-subunit-bearing subtypes of the GABA(A)R are differently involved in benzodiazepine-mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.
PMID: 16809358 [PubMed – indexed for MEDLINE] PMCID: PMC1995685

43: Arq Neuropsiquiatr. 2006 Sep;64(3A):639-44. 
[Morphological characteristics from the insula’s lobe in patients with medial temporal lobe epilepsy]
Chaddad Neto F, de Oliveira E, Paschoal E, Cendes F, Santana Filho M.
Instituto de Ciências Neurológicas, São Paulo, Brazil.
The temporal medial sclerosis (TMS) is characterized by hippocampal sclerosis in temporal and by distinguished grades of injury near to other neurological structures such as: amygdaloid nucleus, parahippocampal girus and entorhinal region. The study analyzed 40 patients with TMS and 40 people from the control cluster. All the cases were appreciated by one method for measurement of insula’s cortex (E-Film) and another method to calculate the insula’s volume (Neuroline). There is no variation statistical between the insula’s volume and insula’s measurement for the two clusters. This paper didn’t show the insula’s morphological variation when these two groups were compared.
Publication Types:
PMID: 17119810 [PubMed – indexed for MEDLINE]

Neurophysiol Clin. 2006 Sep-Dec;36(5-6):293-7. Epub 2007 Jan 17.
Myoclonus and transcranial magnetic stimulation.
Lefaucheur JP.
Service de physiologie, explorations fonctionnelles, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris, 51, avenue du Marechal-Lattre-de-Tassigny, 94010 Créteil, France. jean-pascal.lefaucheur@hmn.aphp.fr
The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.

Clin Neurophysiol. 2006 Jun;117(6):1217-27. Epub 2006 Apr 27.
Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1Hz rTMS in patients with juvenile myoclonic epilepsy. 
Fregni F, Boggio PS, Valle AC, Otachi P, Thut G, Rigonatti SP, Marcolin MA, Fecteau S, Pascual-Leone A, Fiore L, Valente K.
Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., KS 452, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. METHODS: Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. RESULTS: In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. CONCLUSIONS: Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. SIGNIFICANCE: The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.

Neurosci Lett. 2006 Apr 24;397(3):229-33. Epub 2006 Jan 19.
Hemispheric cerebellar rTMS to treat drug-resistant epilepsy: case reports.
Brighina F, Daniele O, Piazza A, Giglia G, Fierro B.
Neurophysiological Unit, University of Palermo, Institute of Neuropsychiatry, Via G. La Loggia, 1, 90129 Palermo, Italy.
Electrical stimulation of the cerebellar cortex by implanted electrodes has been shown to ameliorate refractory epilepsy. We investigated the potential therapeutic role of high-frequency cerebellar rTMS in patients affected by refractory epilepsy due to single or multiple foci. Six patients, three with single and three with multiple epileptic foci, underwent 20 rTMS sessions. Each session was given daily, excluding weekends, and consisted of two trains of 50 stimuli (5 Hz frequency and 90% motor threshold intensity), separated by 50s interval. rTMS was delivered through a focal coil (2 cm below and lateral to the inion) bilaterally in patients with multiple foci (two trains for hemisphere: 100 stimuli each side) and contralaterally to the epileptic focus in the others. Seizure frequency was monitored four weeks before stimulation (pre-rTMS), during the four-week treatment (rTMS) and four weeks after the treatment (post-rTMS). The rTMS over the cerebellar cortex was associated with a significant decrease of rTMS versus pre-rTMS seizure frequency both in patients with single and multiple epileptic foci. However, during the post-rTMS period seizure frequency was back to the pre-rTMS frequency. Although the results are still preliminary, they encourage further studies on larger series of patients. In particular, this rTMS approach, as compared with others, might be more useful in patients with multiple epileptic foci.

J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):56-60.
Effects of sleep deprivation on cortical excitability in patients affected by juvenile myoclonic epilepsy: a combined transcranial magnetic stimulation and EEG study.
Manganotti P, Bongiovanni LG, Fuggetta G, Zanette G, Fiaschi A.
Dipartimento di Scienze Neurologiche e della Visione, Sezione di Neurologia Riabilitativa, Policlinico Borgo Roma, Via delle Menegone, 37134 Verona, Italy. paolo.manganotti@univr.it
OBJECTIVE: To investigate the effect of sleep deprivation on corticospinal excitability in patients affected by juvenile myoclonic epilepsy (JME) using different transcranial magnetic stimulation (TMS) parameters. METHODS: Ten patients with JME and 10 normal subjects underwent partial sleep deprivation. Motor threshold (MT), motor evoked potential amplitude (MEP), and silent period (SP) were recorded from the thenar eminence (TE) muscles. Short latency intracortical inhibition (SICI) and short latency intracortical facilitation (SICF) were studied using paired magnetic stimulation. TMS was performed before and after sleep deprivation; EEG and TMS were performed simultaneously. RESULTS: In patients with JME, sleep deprivation induced a significant decrease in SICI and an increase in SICF, which was associated with increased paroxysmal activity. A significant decrease in the MT was observed. No significant changes in any TMS parameters were noted in normal subjects after sleep deprivation. The F wave was unchanged by sleep deprivation in both control subjects and in patients with JME. CONCLUSIONS: In patients with JME, sleep deprivation produces increases in corticospinal excitability in motor areas as measured by different TMS parameters.

J Clin Neurophysiol. 2005 Dec;22(6):418-21.
Crossed inhibition of sensory cortex by 0.3 Hz transcranial magnetic stimulation of motor cortex.
Seyal M, Shatzel AJ, Richardson SP.
Department of Neurology, University of California-Davis Medical Center, 2315 Stockton Boulevard, Rm. 5308, Sacramento, CA 95817, U.S.A. mseyal@ucdavis.edu
Low-frequency repetitive transcranial magnetic stimulation (rTMS) of motor cortex causes persistent inhibitory effects in the targeted area. rTMS of motor cortex impairs sensory perception and results in a persistent change in cortical function at remote sites. The ability of rTMS to induce sustained changes in cortical function has led to studies testing its therapeutic efficacy in neurologic disorders, including epilepsy. Studies on the effect of low-frequency rTMS of motor cortex on the contralateral motor cortex have provided evidence for both inhibitory and excitatory changes. This study was designed to determine the effect of low-frequency rTMS of the right motor cortex on the contralateral sensory cortex. Before and after 0.3-Hz rTMS of right motor cortex, perception of ipsilateral threshold of cutaneous stimuli was assessed and somatosensory evoked potentials (SEPs) recorded after stimulation of the right thumb in eight normal subjects. In a control group of six subjects, sensory responses were assessed after rTMS anterior to the right motor cortex. After rTMS of motor cortex, detection of threshold sensory stimuli decreased by more than 50% compared with pre-rTMS (P < 0.05). The change in sensory perception lasted at least 30 minutes. No change was detected in the control group. Amplitude of the N20-P25 waveform of the SEP decreased from a mean of 0.84 muV before rTMS to 0.54 muV immediately after rTMS of motor cortex (P < 0.05). 0.3 Hz rTMS of motor cortex inhibits the contralateral sensory cortex.

Rev Neurol (Paris). 2005 Nov;161(11):1121-30.
[Transcranial magnetic stimulation: applications in neurology]
[Article in French] Lefaucheur JP.
Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil. jean-pascal.lefaucheur@hmn.ap-hop-paris.fr
INTRODUCTION: Transcranial magnetic stimulation (TMS) was first applied to assess conduction time along the corticospinal tract, namely by recording motor evoked potentials. STATE OF ART: At present, TMS techniques include cortical excitability and mapping studies using single or paired-pulse paradigms on the one hand, and repetitive TMS to induce cortical plasticity and to modify brain function on the other hand. TMS is a valuable, non-invasive tool in the diagnosis and the pathophysiological assessment of cortical dysfunction involved in various neurological diseases (multiple sclerosis, myelopathy, amyotrophic lateral sclerosis, movement disorders, epilepsy, stroke). PERSPECTIVES AND CONCLUSION: In the near future, repetitive TMS could have therapeutic applications in neurology (epilepsy, stroke rehabilitation program) as is already the case in some psychiatric diseases. However, most of the new indications for treatment with cortical stimulation will be based on surgically-implanted neuromodulation procedures.

Rinsho Shinkeigaku. 2005 Nov;45(11):831-3.
[Clinical applications of transcranial magnetic stimulation for the treatment of various neurological diseases]
[Article in Japanese] Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine.
Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential therapeutic tool in various neurological and psychiatric diseases including depression, Parkinson disease, spinocerebellar degeneration, epilepsy, urinary incontinence, movement disorders, chronic pain, migraine and chronic tinnitus, etc. Several reports showed the therapeutic effects of rTMS as a treatment of depression and Parkinson disease (PD), whereas others found no significant effects. It is by now not yet fully understood whether rTMS has a therapeutic effect on those diseases. The controversy arises from the differences of the stimulation parameters and evaluation methods of the effects in those studies. The Japanese multi-center, double blinded, sham stimulation controlled trial in 85 patients with PD showed an efficacy in both the rTMS-treated and sham stimulated patients. This result does not prove the efficacy of the rTMS in PD; on the other hand, it does not rule out the efficacy. Possible mechanism of favorable effects of rTMS is related to increasing the release of dopamine in the mesolimbic and mesostriatal system. The other Japanese multi-center, double blinded, sham stimulation controlled trial in 99 patients with spinocerebellar degeneration revealed significant therapeutic effects of rTMS in 51 patients with SCA6. We studied the effects of rTMS on seizure susceptibility in rats which prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. This finding suggests the possibility of therapeutic use of rTMS in epilepsy. Further studies should be performed aiming to reveal the optimal stimulation parameters, and are necessary to reveal the therapeutic role of the rTMS in neurological and psychiatric diseases.

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.

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.

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 SCPascual-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 ABegum TYamamoto JHitomi TShibasaki 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 magnetic 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.

Neuron. 2005 Jan 20;45(2):181-3.
Neuron. 2005 Jan 20;45(2):201-6. Toward establishing a therapeutic window for rTMS by theta burst stimulation.
Paulus W.
Department of Clinical Neurophysiology, University of Goettingen, D-37075 Goettingen, Germany.
In this issue of Neuron, Huang et al. show that a version of the classic theta burst stimulation protocol used to induce LTP/LTD in brain slices can be adapted to a transcranial magnetic stimulation (TMS) protocol to rapidly produce long lasting (up to an hour), reversible effects on motor cortex physiology and behavior. These results may have important implications for the development of clinical applications of rTMS in the treatment of depression, epilepsy, Parkinson’s, and other diseases.

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.

Stereotact Funct Neurosurg. 2005;83(2-3):57-62. Epub 2005 Jun 30.
Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: an EEG and clinical study.
Fregni F, Thome-Souza S, Bermpohl F, Marcolin MA, Herzog A, Pascual-Leone A, Valente KD.
Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: To study the effects of repetitive transcranial magnetic stimulation (rTMS) on epileptic EEG discharges in patients with refractory epilepsy and malformations of cortical development (MCDs). METHODS: Eight patients with MCD and refractory epilepsy underwent 1 session of low-frequency rTMS (0.5 Hz, 600 pulses) focally targeting the MCD. The number of epileptiform discharges (EDs) in the EEG and seizures were measured before (baseline), immediately after as well as 15 and 30 days after rTMS treatment. RESULTS: Stimulation significantly decreased the number of EDs 15 and 30 days after rTMS treatment (mean reduction of 46.4%, 95% CI 12.7-80.2%, and mean reduction of 42.1%, 95% CI 8.2-75.7%, respectively). This was associated with a significant reduction in the number of seizures reported as compared with the 4-week period preceding rTMS (mean reduction of 57.3%, 95% CI 33.1-80.3%, and mean reduction of 51.2%, 95% CI 27.9-74.9%, respectively). CONCLUSION: This open study shows a significant antiepileptic effect of rTMS based on clinical and electrophysiological criteria and supports the therapeutic utility of rTMS for patients with well-localized epileptogenic cortical malformations. Copyright 2005 S. Karger AG, Basel.

69: 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, Università 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.
PMID: 15596749 [PubMed – indexed for MEDLINE]

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.

Laeknabladid. 2004 Nov;90(11):755-758.
[Transcranial magnetic stimulation.]
[Article in Icelandic]
Mœller AL, Stefánsson SB.
Department of Neurology, Landspitali University Hospital, Fossvogi, 108 Reykjavík, Iceland. annaltho@landspitali.is.
Transcranial Magnetic Stimulation (TMS) is a new non-invasive method to investigate the central nervous system. Initially it was used to assess the functional integrity of the pyramidal pathways but more recently various other aspects of brain function have been studied including cortical excitability. By localised interference with brain function, it is possible to use TMS to assess the relationship between various brain regions and cognitive functions. The therapeutic effect of TMS has been explored in the treatment of neurological diseases and psychiatric disorders such as epilepsy, cerebellar ataxia and depressive illness.

Acta Neurol Scand. 2004 Apr;109(4):290-6.
rTMS reduces focal brain hyperperfusion in two patients with EPC.
Graff-Guerrero A, Gonzáles-Olvera J, Ruiz-García M, Avila-Ordoñez U, Vaugier V, García-Reyna JC.
Instituto Nacional de Psiquiatría Ramón de la Fuente, División de Neurociencias, Laboratorio de Neurofisiología, México 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.

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.

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 Araújo DP, Teixeira WA, Araújo VP, Boechat-Barros R.
Laboratório de Neurociências e Comportamento, Departamento de Ciências Fisiológicas, Instituto de Biologia, Universidade de Brasília, 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.

Neuroreport. 2004 Feb 9;15(2):293-6.
Reduction of cortical myoclonus-related epileptic activity following slow-frequency rTMS.
Rossi S, Ulivelli M, Bartalini S, Galli R, Passero S, Battistini N, Vatti G.
Dipartimento di Neuroscienze, Sezione Neurologia, Università di Siena, Policlinico Le Scotte, Viale Bracci I-53100, Italy. Rossimo@unisi.it
In a drug-resistant epilepsy patient with continuous forearm/hand positive myoclonia due to a focal cortical dysplasia of the right motor cortex, cortical jerk-related and electromyographic activity were recorded for 15 min before and after 1 Hz rTMS (15 min, 10% below the resting excitability threshold) of the right motor cortex. A stable negative cortical spike, time-locked with contralateral muscle jerks (60 > 100 microV), was detected only at perirolandic electrodes (maximal amplitudes: block 1 = 21.3 microV, block 2 = 22 microV, block 3 = 25.9 microV). After rTMS, only 20 muscle jerks accomplished the criterion of > 100 microV; blind back-averaging of these disclosed a topographically similar cortical spike, but with amplitude reduced by at least 50% (11.2 microV). This represents in vivo evidence of the possibility to selectively modulate the activity of an epileptic focus by intervening with local low-frequency rTMS.

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, Théoret 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.

 

86: 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.
Publication Types:PMID: 14692911 [PubMed – indexed for MEDLINE]

87: 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, Gnezditskiĭ 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.
Publication Types:
PMID: 15071841 [PubMed – indexed for MEDLINE]

J Neurosci. 2003 Nov 26;23(34):10867-72.
Priming stimulation enhances the depressant effect of low-frequency repetitive transcranial 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.

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.

Nervenarzt. 2003 Aug;74(8):664-76.
[Electric brain stimulation for epilepsy therapy]
[Article in German] Kellinghaus C, Loddenkemper T, Möddel G, Tergau F, Lüders J, Lüdemann P, Nair DR, Lüders 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”).

Clin Neurophysiol. 2003 May;114(5):777-98.
Transcranial magnetic stimulation and epilepsy.
Tassinari CA, Cincotta M, Zaccara G, Michelucci R.
Department of Neurosciences, Division of Neurology, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy. carloalberto.tassinari@ausl.bo.it
Epileptic conditions are characterized by an altered balance between excitatory and inhibitory influences at the cortical level. Transcranial magnetic stimulation (TMS) provides a noninvasive evaluation of separate excitatory and inhibitory functions of the cerebral cortex. In addition, repetitive TMS (rTMS) can modulate the excitability of cortical networks. We review the different ways that TMS has been used to investigate pathophysiological mechanisms and effects of antiepileptic drugs in patients with epilepsy and epileptic myoclonus. The safety of different TMS techniques is discussed too. Finally, we discuss the therapeutic prospects of rTMS in this field.

97: Magn Reson Med. 2003 May;49(5):856-63.
Water diffusion measurements in perfused human hippocampal slices undergoing tonicity changes.
Shepherd TM, Wirth ED 3rd, Thelwall PE, Chen HX, Roper SN, Blackband SJ.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. tms@ufbi.ufl.edu
Diffusion MRI has the potential to probe the compartmental origins of MR signals acquired from human nervous tissue. However, current experiments in human subjects require long diffusion times, which may confound data interpretation due to the effects of compartmental exchange. To investigate human nervous tissue at shorter diffusion times, and to determine the relevance of previous diffusion studies in rat hippocampal slices, water diffusion in 20 perfused human hippocampal slices was measured using a wide-bore 17.6-T magnet equipped with 1000-mT/m gradients. These slices were procured from five patients undergoing temporal lobectomy for epilepsy. Tissue viability was confirmed with electrophysiological measurements. Diffusion-weighted water signal attenuation in the slices was well-described by a biexponential function (R(2) > 0.99). The mean diffusion parameters for slices before osmotic perturbation were 0.686 +/- 0.082 for the fraction of fast diffusing water (F(fast)), 1.22 +/- 0.22 x 10(-3) mm(2)/s for the fast apparent diffusion coefficient (ADC), and 0.06 +/- 0.02 x 10(-3) mm(2)/s for the slow ADC. Slice perturbations with 20% hypotonic and 20% hypertonic artificial cerebrospinal fluid led to changes in F(fast) of -8.2% and +10.1%, respectively (ANOVA, P < 0.001). These data agree with previous diffusion studies of rat brain slices and human brain in vivo, and should aid the development of working models of water diffusion in nervous tissue, and thus increase the clinical utility of diffusion MRI. Copyright 2003 Wiley-Liss, Inc.
Publication Types:PMID: 12704768 [PubMed – indexed for MEDLINE]

Arq Neuropsiquiatr. 2003 Mar;61(1):146-52. Epub 2003 Apr 16.
Comment in:
[Transcranial magnetic stimulation]
[Article in Portuguese]
Conforto AB, Marie SK, Cohen LG, Scaff M.
Divisão de Clínica Neurológica, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil. abcong@yahoo.com
Transcranial magnetic stimulation (TMS) allows non-invasive study and modulation of cortical excitability in humans. Changes in cortical excitability in physiological and pathological conditions can be tracked by measurements such as motor threshold, motor evoked potentials, recruitment curves, intracortical facilitation and inhibition. The central motor conduction time can estimate neural transmission in central motor pathways. Changes in areas of representation in sensorimotor cortex can be studied with cortical mapping. Modulation of cortical processing can be used to evaluate different brain functions. Therapeutic use in depression, Parkinson’s disease and epilepsy has raised great interest over the past decade. Non-invasive cortical mapping may be achieved by combining TMS to other neurophysiological/ neuroimaging techniques. TMS has great potential both as an investigational and as a therapeutical tool in Neurology and Psychiatry.

Brain Res. 2002 Dec 6;957(1):37-41.
The long-term high-frequency repetitive transcranial magnetic stimulation does not induce mRNA expression of inflammatory mediators in the rat central nervous system.
 
Okada K, Matsunaga K, Yuhi T, Kuroda E, Yamashita U, Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. gion@med.uoeh-u.ac.jp
Repetitive transcranial magnetic stimulation (rTMS) has been applied for treatment of several diseases such as depression. However, the safety and biological effects of rTMS have not been fully elucidated. In this study, the effects of rTMS on the levels of inflammatory mediators in the central nervous system (CNS), which may be involved in neurodegenerative disorders, were investigated in comparison with the electric convulsive model. Long-term rTMS (1500 pulses at 30 Hz/day for series of 7 days) stimulation, which did not elicit convulsion, was given to rats (rTMS rats). Single high-frequency electrical stimulation (100 Hz, 0.5-ms pulse width, 1 s duration, 50 mA), which induced convulsion, was given to rats (ES rats). mRNA levels of interleukin (IL)-1beta, IL-6, cyclooxygenase (COX)-2 and inducible nitric oxide synthetase (iNOS) in the brain were evaluated by reverse transcription-polymerase chain reaction before and after these stimulations. mRNA of IL-1beta, IL-6 and COX-2 was induced in the brains of ES rats but not in the brains of long-term rTMS rats. mRNA of iNOS was not induced in the brain of long-term rTMS rats. These results suggest that long-term rTMS may safe and modulate neural function without up-regulation of inflammatory mediators, which may be involved in neurodegenerative disorders.

Am J Psychiatry. 2002 Jul;159(7):1093-102.
Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders.
 
Hoffman RE, Cavus I.
Yale-New Haven Psychiatric Hospital, Yale University School of Medicine, LV 108, 20 York Street, New Haven, CT 06504, USA. ralph.hoffman@yale.edu
OBJECTIVE: Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity. METHOD: Studies assessing effects of “slow” rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue. RESULTS: Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects. CONCLUSIONS: Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.

J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):772-6.
Reduced excitability of the motor cortex in untreated patients with de novo idiopathic “grand mal” seizures.
 
Delvaux V, Alagona G, Gérard P, De Pasqua V, Delwaide PJ, Maertens de Noordhout A.
University Department of Neurology, Hôpital de la Citadelle, B-4000 Liège, Belgium.
OBJECTIVES: Transcranial magnetic stimulation (TMS) was used to investigate motor cortex excitability, intracortical excitatory, and inhibitory pathways in 18 patients having experienced a first “grand mal” seizure within 48 hours of the electrophysiological test. All had normal brain MRI, and were free of any treatment, drug, or alcohol misuse. Results were compared with those of 35 age matched normal volunteers. METHODS: The following parameters of responses to TMS were measured: motor thresholds at rest and with voluntary contraction, amplitudes of responses, cortical silent periods, and responses to paired pulse stimulation with interstimulus intervals of 1 to 20 ms. RESULTS: In patients, there were significantly increased motor thresholds with normal amplitudes of motor evoked potentials (MEPs), suggesting decreased cortical excitability. Cortical silent periods were not significantly different from those of normal subjects. Paired TMS with short interstimulus intervals (1-5 ms) induced normal inhibition of test MEPs, suggesting preserved function of GABAergic intracortical inhibitory interneurons. On the contrary, the subsequent period of MEP facilitation found in normal subjects (ISIs of 6-20 ms) was markedly reduced in patients. This suggests the existence of abnormally prolonged intracortical inhibition or deficient intracortical excitation. In nine patients retested 2 to 4 weeks after the initial seizure, these abnormalities persisted, although to a lesser extent. CONCLUSION: The present findings together with abnormally high motor thresholds could represent protective mechanisms against the spread or recurrence of seizures.

Rinsho Shinkeigaku. 2001 Dec;41(12):1097-9.
[Treatment of status epilepticus]
[Article in Japanese]
 
Tsuji S, Akamatsu N.
Status epilepticus (SE) is a condition requiring emergency care. There are convulsive SE, non-convulsive SE including complex partial status and absence status, non-convulsive electric SE and pseudostatus epilepticus, although convulsive SE is the most common. Diagnosis of status epilepticus of complex partial seizures (CPS) and absence seizures was significantly delayed because delays in seeking medical attention were common. The seizures were generalized convulsive SE in 84% and CPS status in 16%, and the overall mortality rate was 15% in 41 SE patients of our study. EEG monitoring is important to make or exclude the diagnosis of SE. Diazepam is the first choice medication and effective in the management of SE, and lately, lorazepam, midazolam, propofol and pentobarbital etc as emergency therapy. Phenytoin is also considered first-line agent in the emergency management of SE. Repetitive transcranial magnetic stimulation (rTMS) led to a prolonged latency for seizure induction after an intraperitoneal injection of pentylenetetrazol (PTZ) and effectively prevented the development of status epilepticus of PTZ-induced convulsions in the rats. Our data suggest that rTMS has suppressive effects on the neuronal excitability in rats. These effects are anticonvulsive and suggest the possibility of therapeutic use of rTMS in the patients with refractory seizures.

Neurology. 2001 Nov 27;57(10):1793-9.
Hyperexcitable cortical responses in progressive myoclonic epilepsy: a TMS study.
 
Manganotti P, Tamburin S, Zanette G, Fiaschi A.
Department of Neurological Sciences and Vision, Section of Neurological Rehabilitation, University of Verona, Italy. paolomanganotti@yahoo.com
OBJECTIVE: Transcranial magnetic stimulation (TMS) has allowed investigators to study intracortical inhibition and facilitation and sensorimotor integration in motor disorders and epilepsy. The authors used TMS to elucidate the pathophysiology of reflex myoclonus with giant somatosensory evoked potentials (SEP). METHODS: The authors studied four patients with progressive myoclonic epilepsy. All patients had giant SEP elicited by mixed and digital nerve stimulation. They studied the response to paired-pulse TMS at interstimulus intervals (ISI) ranging from 1 to 15 ms and the conditioning effect of digital electrical stimulation at ISI ranging from 10 to 100 ms on the motor evoked potential amplitude to TMS. RESULTS: Digital stimulation markedly facilitated conditioned motor evoked potentials at ISI ranging from 25 to 40 ms in all patients. This pattern was significantly different from the inhibition observed in controls (n = 12) at the same ISI. In the patients, paired-pulse TMS showed a decrease in intracortical inhibition in the motor cortex in comparison with controls. CONCLUSIONS: These findings suggest cortical and subcortical components of abnormal sensorimotor integration in addition to hyperexcitability of the sensory and motor cortex in our myoclonic patients.

Can J Psychiatry. 2001 Oct;46(8):720-7.
Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy.
 
Hasey G.
Regional Mood Disorders Program, Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
OBJECTIVE: To review repetitive transcranial magnetic stimulation (rTMS) as a mode of therapy for depression. METHOD: The following aspects of rTMS were reviewed and compared with electroconvulsive therapy (ECT): history, basic principles, technical considerations, possible mode of action, safety, adverse effects, and effects on mood in both healthy individuals and those suffering from bipolar disorder (BD) or depression. RESULTS: rTMS may selectively increase or decrease neuronal activity over discrete brain regions. As a result of this focused intervention with TMS, the potential for unwanted side effects is substantially reduced, compared with ECT. In open trials, rTMS and ECT are reported to be equally efficacious for patients having depression without psychosis, but the therapeutic benefits reported in double-blind sham-rTMS controlled trials are more modest. CONCLUSION: The antidepressant and antimanic effects of rTMS depend on technical considerations such as stimulus frequency, intensity, and magnetic coil placement, which may not yet be optimized. Biological heterogeneity among the patients treated with rTMS may also contribute to differing efficacy across clinical trials. rTMS may possess tremendous potential as a treatment for mood disorder, but this has not yet been realized. rTMS must still be regarded as an experimental intervention requiring further refinement.

Neurosci Lett. 2001 Sep 14;310(2-3):153-6.
Decreased susceptibility to pentylenetetrazol-induced seizures after low-frequency transcranial magnetic stimulation in rats.
Akamatsu N, Fueta Y, Endo Y, Matsunaga K, Uozumi T, Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. akamatn@med.uoeh-u.ac.jp
We studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure susceptibility in rats. rTMS of 1000 pulses at 0.5 Hz led to a prolonged latency for seizure development after an intraperitoneal injection of pentylenetetrazol. The rTMS effectively prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. These findings indicate that low-frequency rTMS affects the neural excitability, in the direction of anticonvulsive, and therefore, suggest the possibility of therapeutic use of rTMS in epilepsy.

Neurology. 2001 Aug 28;57(4):706-8.
Prolonged cortical silent period after transcranial magnetic stimulation in generalized epilepsy.
 
Macdonell RA, King MA, Newton MR, Curatolo JM, Reutens DC, Berkovic SF.
Department of Neurology, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia. rmac@austin.unimelb.edu.au
Transcranial magnetic stimulation (TMS) produces a cortical silent period (CSP) during a voluntary contraction. The duration of the CSP was used to assess the level of intracortical inhibition in patients with untreated idiopathic generalized epilepsy (IGE). Mean CSP duration was assessed at three TMS stimuli in 21 patients with IGE compared with 19 normal control subjects. Mean CSP duration was increased at all stimulus intensities, indicating that intracortical inhibition is increased in patients with IGE.

Epilepsia. 2000 Feb;41(2):240-2.
 
Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia.
 
Menkes DL, Gruenthal M.
Department of Neurology, University of Louisville School of Medicine, Kentucky 40292, USA.
PURPOSE: To evaluate the effect of slow-frequency repetitive transcranial magnetic stimulation (SF-rTMS) on interictal epileptiform activity and seizure frequency in a patient with medically refractory partial seizures due to focal cortical dysplasia. METHODS: A 9-cm circular coil was positioned over the area of cortical dysplasia. One hundred stimuli given at 0.5 Hz at 5% below motor threshold were given biweekly for four consecutive weeks. The EEG was recorded for 30 min before and after the first 100 stimuli. The number of seizures during the month of stimulation was compared with that of the month before stimulation. RESULTS: Stimulation was associated with a 70% reduction in the frequency of seizures and a 77% reduction in the frequency of interictal spikes. No seizures occurred during stimulation. CONCLUSIONS: SF-rTMS was safe and well tolerated in this patient. The reduction in seizures and interictal spikes associated with SF-rTMS supports the concept of SF-rTMS-induced cortical inhibition.

Neurosci Lett. 1999 Oct 8;273(3):155-8.
Altered seizure susceptibility after high-frequency transcranial magnetic stimulation in rats.
 
Ebert U, Ziemann U.
Institute of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany. uebert@pharma.tiho-hannover.de
The long-term effect of repetitive transcranial magnetic stimulation (rTMS) on the susceptibility of amygdala kindling was studied. Two weeks after a single high-frequency rTMS train (120 A/micros, 20 Hz for 3 s), the rats had a 55% higher threshold for induction of epileptic afterdischarges compared with sham-treated or control rats. However, subsequent kindling revealed no difference between rTMS-treated and control rats. Our data suggest that a single rTMS train has long-term effects on the neuronal excitability. These effects may be anticonvulsant and therefore support the safety of rTMS in clinical use.

Biol Psychiatry. 1999 Mar 15;45(6):759-63.
Chronic treatment with repetitive transcranial magnetic stimulation inhibits seizure induction by electroconvulsive shock in rats.
 
Fleischmann A, Hirschmann S, Dolberg OT, Dannon PN, Grunhaus L.
Psychiatry Division, Sheba Medical Center, Ramat Gan, Israel.
BACKGROUND: Studies in laboratory animals suggest that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) increase seizure inhibition acutely. This study was designed to explore whether chronic rTMS would also have seizure inhibition properties. METHODS: To this purpose we administered rTMS (Magstim Rapid) and sham rTMS twice daily (2.5 T, 4-sec train duration, 20 Hz) to two groups of 10 rats for 16 days. The rTMS coil was a 50-mm figure-8 coil held directly over the rat’s head. Raters were blind to experimental groups. On days 11, 17, and 21 (5 days after the last rTMS) ECS was administered with a Siemens convulsator using three electrical charge levels. Variables examined were the presence or absence of seizures and seizure length (measured from the initiation of the tonic contraction until the end of the limb movement). RESULTS: At day 11 rTMS had no effect on seizures, and both rTMS and sham rTMS animals convulsed equally. At day 17, however, rTMS-treated animals convulsed significantly less (both at presence/absence of seizures, and at seizure length) than sham rTMS animals. At day 21 the effects of rTMS had disappeared. CONCLUSIONS: These findings suggest that rTMS administered chronically leads to changes in seizure threshold similar to those reported for ECS and ECT; however, these effects were short-lived.

Neuropsychologia. 1999 Feb;37(2):159-67.
Transcranial magnetic stimulation can measure and modulate learning and memory.
 
Grafman J, Wassermann E.
Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1440, USA. jgr@box-j.nih.gov
The potential uses for Transcranial Magnetic Stimulation (TMS) in the study of learning and memory range from a method to map the topography and intensity of motor output maps during visuomotor learning to inducing reversible lesions that allow for the precise temporal and spatial dissection of the brain processes underlying learning and remembering. Single-pulse TMS appears to be adequate to examine motor output maps but repetitive TMS (rTMS) appears necessary to affect most cognitive processes in measurable ways. The results we have reviewed in this article indicate that rTMS may have a potential clinical application in patients with epilepsy in whom it is important to identify the lateralization of verbal memory. Single-pulse TMS can help identify changes in motor output maps during training, that may indicate improved or diminished learning and memory processes following a stroke or other neurological insult. Other evidence indicates that rTMS may even have the capability of facilitating various aspects of memory performance. From a research perspective. rTMS has demonstrated site- and time-specific effects primarily in interfering with explicit retrieval of episodic information from long-term memory. rTMS may also be able to modulate retrieval from semantic memory as evidenced by response-time and accuracy changes after rTMS. All these findings suggest that the use of transcranial magnetic stimulation in the study of learning and memory will increase in the future and that it is already a valuable tool in the cognitive neuroscientists’ belt.

Neuropsychobiology 1998 Oct;38(3):152-66.
A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.
 
Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A.
Biological Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892-1272, USA.
Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.

Epilepsy Res. 1998 Mar;30(1):11-30.
Transcranial magnetic stimulation: its current role in epilepsy research.
 
Ziemann U, Steinhoff BJ, Tergau F, Paulus W.
Department of Clinical Neurophysiology, University of Gottingen, Germany.
This paper reviews the current role of transcranial magnetic stimulation (TMS) in epilepsy research. After a brief introduction to the technical principles, the physiology and the safety aspects of TMS, emphasis is put on how human cortex excitability can be assessed by TMS and how this may improve our understanding of pathophysiological mechanisms in epilepsy and the mode of action of antiepileptic drugs (AEDs). Also, potential therapeutical applications of TMS are reviewed. For all aspects of this paper, a clear distinction was made between single-/paired-pulse TMS and repetitive TMS, since these two techniques have fundamentally different scopes and applications.

this concludes our epilepsy repetitive transcranial magnetic stimulati

Magnetic therapy utilizing static magnetic fields is nearly as old as civilization.  Today a pulsed electromagnetic field therapy PEMF utilizing minute, pulsed electromagnetic fields applied transcranially called repetitive transcranial magnetic stimulation (rTMS) has been found to safely treat epilepsy. 

Below, please find dozens of peer reviewed research studies which support a finding that magnetic therapy utilizing pulsed electromagnetic fields called repetitive transcranial magnetic stimulation  (rTMS/TMS) treatment for epilepsy reduces seizure activity and reduces symptoms of Parkinson’s disease, depression, MS, and migraine headache without side effects or expected/unexpected reactions. While modern research is nearly all done with very strong amplitude magnetic fields, Sandyk & Anninos showed that you can provide same or better effect with very-VERY minute fields in the Pico-Tesla range.

We are sure most pulsed electromagnetic therapies lead to enhanced cellular energy, however those in the 1-15 hz range result in cells producing more organically produced ATP; we call this  MoreATP; particularly from the TMS / rTMS done at frequencies between 1 and 20 Hz. Professor Photios Anninos discovered that brain waves of epileptic individuals have abnormality which correspond to a particular frequency range. He and his associates in Greece have developed a highly accurate method of measuring these abnormalities and then custom tuning their electromagnetic field therapy device for each individual on a case by case basis but generally at around 7 Hz. The magnetoencephalogram (MEG) is the magnetic activity emitted by the brain, which can be measured using a superconductive quantum interference device (SQUID). Total cost including brain mapping in your home country is in the US$5000 range. We can assist your participation in the next electromagnetic field therapy ‘excursion’ to Greece; just email us; the IABC contact we’ve got will be glad to send you out information which will probably convince you that a trip to Greece for electromagnetic field therapy is worth the time and expense. See IABC press release on Professor Anninos.

We’ve followed Professor Anninos’ research since summer 2000 and happened to meet 4 person’s who had been to see Professor Anninos in Greece for Parkinson’s therapy  We’ve talked at length and seen video tape of the electromagnetic field therapy process used upon dozens of his patients. If you’ve got Parkinson’s disease, MS, Epilepsy, migraine headache, cluster headache, ADD, ADHD, or suffer with depression and can afford the time and expense of travel, we HIGHLY recommend you see them for picoTesla electromagnetic field therapy to order one of his $5000 helmets. If not, you can achieve nearly the same or better effect at home for 600 usd.

EarthPulse™ has discovered that our patented geomagnetic field supplementation device and methods substantially enhance human (and animal) performance regardless of the etiology of disease by improving the efficiency of oxygen metabolism, subsequently increasing saturated blood oxygen and reducing oxidative stress. We’re the first and only device whose primary use frequency is 10 Hz. Read our treatise MoreATP for a rather simple explanation of it.

The Epilepsy rTMS bibliography is offered for your education only and studies contained are not intended as promotional material. This site is for informational purposes only. No therapeutic products can be sold in relation to the pulsed electromagnetic field therapy research bibliographies found here.

See also; Sandyk R, Anninos PA , Jacobson JI; three pioneers of electromagnetic field therapy to treat Parkinson’s, Alzheimer’s and epilepsy.


Pulsed Electromagnetic Therapy treatment for Epilepsy rTMS Bibliography

To read the original source, use Pubmed and search for Title of the citation

Neuroscience. 2014 Nov 7;280:181-92. doi: 10.1016/j.neuroscience.2014.09.022. Epub 2014 Sep 18.
Repeated transcranial magnetic stimulation prevents kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons.
Shojaei A1, Semnanian S1, Janahmadi M2, Moradi-Chameh H1, Firoozabadi SM3, Mirnajafi-Zadeh J4.

Brain Res. 2014 Sep 18;1581:103-16. doi: 10.1016/j.brainres.2014.06.006. Epub 2014 Jun 14. Frequency-dependent effects of contralateral repetitive transcranial magnetic stimulation on penicillin-induced seizures. Lin CY1, Li K2, Franic L3, Gonzalez-Martinez J3, Lin VW4, Najm I3, Lee YS2.

Epilepsy Res. 2014 Feb;108(2):190-201. doi: 10.1016/j.eplepsyres.2013.11.023. Epub 2013 Dec 5. Repetitive transcranial magnetic stimulation decreases the kindling induced synaptic potentiation: effects of frequency and coil shape. Yadollahpour A1, Firouzabadi SM1, Shahpari M2, Mirnajafi-Zadeh J3.

Seizure. 2013 Dec;22(10):893-6. doi: 10.1016/j.seizure.2013.06.014. Epub 2013 Jul 19. Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Liu A1, Pang T, Herman S, Pascual-Leone A, Rotenberg A.

Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Liu A, Pang T, Herman S, Pascual-Leone A, Rotenberg A.

Seizure. 2013 Jul 19. doi:pii: S1059-1311(13)00193-3. 10.1016/j.seizure.2013.06.014. [Epub ahead of print]
A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders.
Fuggetta G, Noh NA.

Exp Neurol. 2013 Jul;245:87-95. doi: 10.1016/j.expneurol.2012.10.010. Epub 2012 Oct 11. 
Possibly lifesaving, noninvasive, EEG-guided neuromodulation in anesthesia-refractory partial status epilepticus.
Thordstein M, Constantinescu R.

Epilepsy Behav. 2012 Nov;25(3):468-72. doi: 10.1016/j.yebeh.2012.07.026. Epub 2012 Sep 
A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders.
Fuggetta G, Noh NA.

Exp Neurol. 2012 Oct 11. doi:pii: S0014-4886(12)00393-7. 10.1016/j.expneurol.2012.10.010. [Epub ahead of print]
Repetitive transcranial magnetic stimulation (rTMS) noise: a relevance for tinnitus treatment?
Tringali S, Perrot X, Collet L, Moulin A.

Brain Stimul. 2012 Oct;5(4):655-6. doi: 10.1016/j.brs.2011.10.006. Epub 2012 Feb 22. No abstract available.
Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.
Sun W, Mao W, Meng X, Wang D, Qiao L, Tao W, Li L, Jia X, Han C, Fu M, Tong X, Wu X, Wang Y.

Epilepsia. 2012 Oct;53(10):1782-9. doi: 10.1111/j.1528-1167.2012.03626.x. Epub 2012 Sep 5.
Safety and tolerability of repetitive transcranial magnetic stimulation in patients with pathologic positive sensory phenomena: a review of literature.
Muller PA, Pascual-Leone A, Rotenberg A.

Brain Stimul. 2012 Jul;5(3):320-9.e27. doi: 10.1016/j.brs.2011.05.003. Epub 2011 Jun 14. Review.
Repetitive transcranial magnetic stimulation safely administered after seizure.
Bagati D, Mittal S, Praharaj SK, Sarcar M, Kakra M, Kumar P.

J ECT. 2012 Mar;28(1):60-1. doi: 10.1097/YCT.0b013e318221f9b1.
A neuronal network model for simulating the effects of repetitive transcranial magnetic stimulation on local field potential power spectra.
Bey A, Leue S, Wienbruch C.

PLoS One. 2012;7(11):e49097. doi: 10.1371/journal.pone.0049097. Epub 2012 Nov 7.
French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications].
Lefaucheur JP, André-Obadia N, Poulet E, Devanne H, Haffen E, Londero A, Cretin B, Leroi AM, Radtchenko A, Saba G, Thai-Van H, Litré CF, Vercueil L, Bouhassira D, Ayache SS, Farhat WH, Zouari HG, Mylius V, Nicolier M, Garcia-Larrea L.

Neurophysiol Clin. 2011 Dec;41(5-6):221-95. doi: 10.1016/j.neucli.2011.10.062. Epub 2011 Nov 10. French.
Repetitive transcranial magnetic stimulation in psychiatry. Mishra BR, Sarkar S, Praharaj SK, Mehta VS, Diwedi S, Nizamie SH.

Epilepsy Res. 2011 Oct;96(3):231-40. Epub 2011 Jun 29.
Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: A meta-analysis.
Hsu WY, Cheng CH, Lin MW, Shih YH, Liao KK, Lin YY.
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan; Integrated Brain Research Laboratory, Taipei Veterans General Hospital

Epilepsy Behav. 2011 Feb;20(2):355-9. Epub 2011 Jan 7.
An estimate of placebo effect of repetitive transcranial magnetic stimulation in epilepsy.
Bae EH, Theodore WH, Fregni F, Cantello R, Pascual-Leone A, Rotenberg A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

Clin EEG Neurosci. 2011 Jan;42(1):40-4.
Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy.
Sun W, Fu W, Mao W, Wang D, Wang Y.
Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, PR China.

Eur Neurol. 2010;63(4):205-10. Epub 2010 Feb 11. 
Transcranial magnetic stimulation for drug-resistant epilepsies: rationale and clinical experience.
Kimiskidis VK.
Department of Neurology III, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Epilepsy Behav. 2009 Oct;16(2):353-5. Epub 2009 Sep 10.
In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy.
Rotenberg A, Bae EH, Muller PA, Riviello JJ Jr, Bourgeois BF, Blum AS, Pascual-Leone A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA

Epilepsy Behav. 2009 Jan;14(1):253-7. Epub 2008 Oct 30.
Repetitive transcranial magnetic stimulation in the treatment of epilepsia partialis continua.
Rotenberg A, Bae EH, Takeoka M, Tormos JM, Schachter SC, Pascual-Leone A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

Seizure. 2008 Dec;17(8):677-83. Epub 2008 May 20.
Repetitive transcranial magnetic stimulation decreases the number of seizures in patients with focal neocortical epilepsy.
Santiago-Rodríguez E, Cárdenas-Morales L, Harmony T, Fernández-Bouzas A, Porras-Kattz E, Hernández A.
Unidad de Investigación en Neurodesarrollo “Dr. Augusto Fernández Guardiola”, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico.

Epilepsy Behav. 2008 Jul;13(1):260-2. Epub 2008 Mar 4
Transient suppression of seizures by repetitive transcranial magnetic stimulation in a case of Rasmussen’s encephalitis.
Rotenberg A, Depositario-Cabacar DBae EHHarini CPascual-Leone ATakeoka M.
Division of Epilepsy and Clinical Neurophysiology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA. alexander.rotenberg@childrens.harvard.edu
Repetitive transcranial magnetic stimulation (rTMS) has been applied with variable success to terminate the seizures of epilepsia partialis continua. The rationale for using this technique to suppress ongoing seizures is the capacity of rTMS to interrupt ongoing neuronal activity, and to produce a lasting decrease in cortical excitability with low-frequency (1 Hz) stimulation. We report a case of epilepsia partialis continua in a child with Rasmussen’s encephalitis, in whom seizures were transiently suppressed by 1-Hz rTMS delivered in nine daily 30-minute sessions. In this case, total ictal time was significantly reduced during stimulation, but the daily baseline seizure rate remained unchanged. Notably, the detection and quantification of this short-lived improvement were enabled by recording EEG continuously during the rTMS session. Thus, we present this case to illustrate a potential utility of combined continuous EEG recording and rTMS in seizure treatment.

Seizure. 2008 May 19. [Epub ahead of print]
Repetitive transcranial magnetic stimulation decreases the number of seizures in patients with focal neocortical epilepsy.
Santiago-Rodríguez E, Cárdenas-Morales LHarmony TFernández-Bouzas APorras-Kattz EHernández A.
Unidad de Investigación en Neurodesarrollo “Dr. Augusto Fernández Guardiola”, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico. 
PURPOSE: To evaluate the number of seizures and interictal epileptiform discharges (IEDs) in patients with focal neocortical epilepsy before, during and after rTMS.
METHODS: Twelve patients (seven men and five women, mean age 29.3+/-15.8 years) were studied. An open-label study with baseline (4 weeks), intervention (2 weeks) and follow-up (8 weeks) periods was carried out. Repetitive transcranial magnetic stimulation (rTMS) with 900 pulses, intensity of 120% motor resting threshold and 0.5Hz frequency was used. A 120 channel EEG was recorded; an electrical source analysis of IEDs with Variable Resolution Electromagnetic Tomography (VARETA) was performed. The number of seizures per week and IEDs per minute were measured and compared in the three periods.
RESULTS: During the basal period the mean seizure frequency was 2.25 per week; in the intervention period it decreased to 0.66 per week (F=2.825; p=0.0036) which corresponds to a 71% reduction. In the follow-up period the mean frequency was 1.14 seizures per week, that is, a 50% reduction in the number of seizures. In the visual EEG analysis, the baseline IED frequency was 11.9+/-8.3events/min; it decreased to 9.3+/-7.9 during 2 weeks of rTMS with a further reduction to 8.2+/-6.6 in the follow-up period. These differences however were not significant (p=0.190).
CONCLUSION: We conclude that 2 weeks of rTMS at 0.5Hz with a figure-of-eight coil placed over the epileptic focus, determined with VARETA, decreases the number of seizures in patients with focal epilepsy, without reduction in IEDs.

Clin Neurophysiol. 2008 Mar;119(3):504-32. Epub 2007 Dec 11.
The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.
Chen R, Cros DCurra ADi Lazzaro VLefaucheur JPMagistris MRMills KRösler KMTriggs WJUgawa YZiemann U.
Division of Neurology, Toronto Western Research Institute, University of Toronto, 7MC411, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ont., Canada M5T 2S8. robert.chen@uhn.on.ca
The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer’s disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Epilepsia. 2008 Mar;49(3):470-80. Epub 2007 Nov 19.
Late EEG responses triggered by transcranial magnetic stimulation (TMS) in the evaluation of focal epilepsy.
Valentin A, Arunachalam RMesquita-Rodrigues AGarcia Seoane JJRichardson MPMills KRAlarcon G.
Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London, United Kingdom.
PURPOSE: To evaluate the use of EEG responses to transcranial magnetic stimulation (TMS-EEG responses) as a noninvasive tool for the diagnosis of focal epilepsy. METHODS: Fifteen patients and 15 healthy subjects were studied. TMS at an intensity set at resting corticomotor threshold were delivered at the standard EEG electrode positions. For each position, EEG responses to TMS were evaluated before and after averaging EEG recordings synchronized with the TMS pulse. RESULTS: Two types of TMS-EEG responses were seen: (A) early responses: consisting of a single slow wave seen after the TMS pulse; and (B) late TMS-EEG responses, which were subclassified into (b.1) delayed responses: waveforms resembling interictal epileptiform discharges induced by TMS; or (b.2) repetitive responses: onset of a new rhythym induced by TMS. Early responses were observed in patients and healthy subjects when stimulating at various sites and were considered normal responses to TMS. Late TMS-EEG responses were not seen in healthy subjects, whereas they were seen in 11 of the 15 epileptic patients. Late TMS-EEG responses occurred when stimulating the epileptogenic side in eight out of the nine patients who had lateralized late TMS-EEG responses. The combined use of late TMS-EEG responses and interictal scalp EEG would have suggested the diagnosis of focal epilepsy in all patients, despite the absence of late TMS-EEG responses in four patients and the presence of normal interictal scalp EEG in three. CONCLUSIONS: TMS-EEG responses can identify epileptogenic cortex and may substantially improve the diagnosis of focal epilepsy, particularly, if combined with standard EEG studies.

Neurorehabil Neural Repair. 2008 Mar-Apr;22(2):185-92. Epub 2007 Sep 17.
Safety of 6-Hz primed low-frequency rTMS in stroke.
Carey JR, Evans CDAnderson DCBhatt ENagpal AKimberley TJPascual-Leone A.
Program in Physical Therapy, University of Minnesota, Minneapolis 55455, USA. 
BACKGROUND: Suppression of activity in the contralesional motor cortex may promote recovery of function after stroke. Furthermore, the known depressant effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) can be increased and prolonged by preceding it with 6-Hz priming stimulation. OBJECTIVE: The authors explored the safety of 6-Hz primed low-frequency rTMS in 10 patients with ischemic stroke. METHODS: Priming consisted of 10 minutes of 6-Hz rTMS applied to the contralesional hemisphere at 90% of resting motor threshold delivered in 2 trains/min with 5 s/train and 25-second intervals between trains. Low-frequency rTMS consisted of an additional 10 minutes of 1-Hz rTMS at 90% of resting motor threshold without interruption. Possible adverse effects were assessed with the National Institutes of Health Stroke Scale (NIHSS), the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Hopkins Verbal Learning Test-Revised (HVLT-R), the Beck Depression Inventory-Second Edition (BDI-II), a finger movement tracking test, and individual self-assessments. Pretest, treatment, and posttest occurred on the first day with follow-up tests on the next 5 weekdays. RESULTS: There were no seizures and no impairment of NIHSS, WAIS-III, or BDI-II scores. Transient impairment occurred on the HVLT-R. Transient tiredness was common. Occasional reports of headache, neck pain, increased sleep, reduced sleep, nausea, and anxiety occurred. CONCLUSION: Because there were no major adverse effects, the authors concluded that the treatment was safe for the individuals in this study and that further investigation is now warranted to examine efficacy and safety of serial treatments of 6-Hz primed low-frequency rTMS.

Int J Neuropsychopharmacol. 2008 Feb;11(1):131-47. Epub 2007 Sep 20.
A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression.
Loo CK, McFarquhar TFMitchell PB.
School of Psychiatry, University of New South Wales, Sydney, Australia. 
 
There is growing interest worldwide in rTMS as a clinical treatment for depression. Apart from efficacy, its safety as a clinical treatment must be considered before its widespread use can be advocated. All published, sham-controlled rTMS depression trials were reviewed for reported side-effects and outcomes of formal neuropsychological testing. In addition, all reports of seizures occurring with rTMS were reviewed. Other safety concerns (effects on hearing; headache, pain, induced currents in electrical circuits, histotoxicity, electromagnetic field exposure, psychiatric complications, safety in pregnancy) are discussed. Common side-effects were of a minor nature, e.g. headache. There was a low incidence of accidental seizures and induced hypomania, both of which were associated with identified risk factors for which subjects should be screened. Long-term effects of repeated rTMS sessions are as yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment.

Exp Brain Res. 2008 Jan;184(3):439-43. Epub 2007 Nov 24.
Cortical silent period following TMS in a patient with supplementary sensorimotor area seizures.
Nardone R, Venturi AAusserer HLadurner GTezzon F.
Department of Neurology, Franz.Tappeiner Hospital, Via Rossini, 5, 39012, Merano, Italy. 
The cortical silent period (CSP) following transcranial magnetic stimulation (TMS) was evaluated in a patient with a dysembrioplastic neuroepithelial tumor (DNET) in the lateral portion of the right superior frontal gyrus (SFG) who suffered from supplementary sensorimotor area (SSMA) seizures. CSP duration was shortened on the affected side. Ipsilateral alterations of motor cortex excitability with TMS in epileptogenic DNET located outside the PMA argue in favour of cortico-cortical connections to primary motor cortex from SSMA. This functional connectivity should be taken into consideration to better understand the pathophysiology of ictal motor manifestations.

Med Hypotheses. 2008;71(2):279-82. Epub 2008 Apr 22.
Can the ‘yin and yang’ BDNF hypothesis be used to predict the effects of rTMS treatment in neuropsychiatry?
Brunoni AR, Boggio PSFregni F.
Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 430, Boston, MA 02215, USA; Institute of Psychiatry, University of São Paulo, Brazil.
Repetitive transcranial magnetic stimulation (rTMS) is a novel technique of non-invasive brain stimulation which has been used to treat several neuropsychiatric disorders such as major depressive disorder, chronic pain and epilepsy. Recent studies have shown that the therapeutic effects of rTMS are associated with plastic changes in local and distant neural networks. In fact, it has been suggested that rTMS induces long-term potentiation (LTP) and long-term depression (LTD) – like effects. Besides the initial positive clinical results; the effects of rTMS are still mixed. Therefore new tools to assess the effects of plasticity non-invasively might be useful to predict its therapeutic effects and design novel therapeutic approaches using rTMS. In this paper we propose that brain-derived neurotrophic factor (BDNF) might be such a tool. Brain-derived neurotrophic factor is a neurotrophin that plays a key role in neuronal survival and synaptic strength, which has also been studied in several neuropsychiatric disorders. There is robust evidence associating BDNF with the LTP/LTD processes, and indeed it has been proposed that BNDF might index an increase or decrease of brain activity – the ‘yin and yang’ BDNF hypothesis. In this article, we review the initial studies combining measurements of BDNF in rTMS clinical trials and discuss the results and potential usefulness of this instrument in the field of rTMS.

Zhonghua Wai Ke Za Zhi. 2007 Dec 15;45(24):1685-7.
[The effect of low frequency transcranial magnetic stimulation on neuropeptide-Y expression and apoptosis of hippocampus neurons in epilepsy rats induced by pilocarpine]
[Article in Chinese] Wang YL, Zhai YHuo XLZhang JN.
Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin 300052, China. wang19690924@sina.com
OBJECTIVE: To analyze the effect of low frequency transcranial magnetic stimulation (LF-TMS) on changing neuropeptide-Y (NPY) expression and apoptosis of hippocampus neurons in epilepsy rats induced by pilocarpine (PLO). METHODS: Thirty male Sprague Dawley rats (240 g +/- 20 g) were randomly divided into 2 groups. I group simply celiac injected pilocarpine. II group celiac injected PLO after LF-TMS. Pathological item included HE staining, NPY immunohistochemical staining and apoptosis staining. RESULTS: HE staining revealed neurons of hippocampus were obviously death and cell’s structure was destroyed in PLO group. The PLO + LF-TMS group was less injured and destroyed. Using One-Way ANOVA, NPY immunohistochemical staining shown the positive cell number was increased at all areas of hippocampus in PLO group contrasting with the low positive cell number in the PLO + LF-TMS group. In PLO group the number of apoptosis cell at hippocampus areas was significant higher than the PLO + LF-TMS group. CONCLUSIONS: Using the PLO evoked epilepsy model, LF-TMS alleviated neurons injury at hippocampus area, so LF-TMS might playing an important role in resisting the progressing of epilepsy. The positive cell number of NPY increased at all areas of hippocampus, which indicated the close relation between NPY and epilepsy. NPY might have some function on resisting epilepsy.

Brain Res Rev. 2007 Dec;56(2):346-61. Epub 2007 Aug 28.
The use of tDCS and CVS as methods of non-invasive brain stimulation.
Been G, Ngo TTMiller SMFitzgerald PB.
Alfred Psychiatry Research Centre, The Alfred Hospital and Monash University School of Psychology, Psychiatry and Psychological Medicine, Commercial Rd, Melbourne, VIC 3004, Australia.
Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson’s disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).

Neurosci Behav Physiol. 2007 Nov;37(9):849-52.
Evoked motor response thresholds during transcranial magnetic stimulation in patients with symptomatic partial epilepsy.
Kotova OV, Vorob’eva OV.
Department of Nervous Diseases, Postgraduate Professional Educational Faculty, I. M. Sechenov Moscow Medical Academy.
Transcranial magnetic stimulation (TMS) occupies a leading position among noninvasive neurophysiological methods used for evaluating the balance of processes of cortical inhibition and excitation. The aim of the present work was to assess motor cortical excitability in symptomatic partial epilepsy using TMS in relation to the effects of antiepileptic treatment. A total of 31 patients were studied. A decrease in the motor response threshold was seen in a group consisting of untreated patients, with changes in cortical excitability during seizures. Treated patients showed no difference as compared with healthy subjects. The shorter the interval between a seizure and TMS, the smaller the evoked motor response threshold. The low threshold seen in patients with symptomatic partial epilepsy showed a significant correlation with clinical signs of neuromuscular excitability. The data obtained here provide evidence of changes in the functional state of the cortex and, thus, the motor response threshold, in patients with epilepsy.

Clin Neurophysiol. 2007 Sep;118(9):2072-5. Epub 2007 Jul 24.
Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke.
Lomarev MP, Kim DYRichardson SPVoller BHallett M.
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, NIH Building 10, Room 5N240, 10 Center Dr MSC 1428, Bethesda, MD 20892-1428, USA. lomarevm@ninds.nih.gov
OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a potential therapeutic tool to rehabilitate chronic stroke patients. In this study, the safety of high-frequency rTMS in stroke was investigated (Phase I). METHODS: The safety of 20 and 25 Hz rTMS over the motor cortex (MC) of the affected hemisphere, with intensities of 110-130% of the motor threshold (MT), was evaluated using surface electromyography (EMG) of hand and arm muscles. RESULTS: Brief EMG bursts, possibly representing peripheral manifestations of after discharges, and spread of excitation to proximal muscles are considered to be associated with a high risk of seizure occurrence. These events were recorded after the rTMS trains. Neither increased MC excitability nor improved pinch force dynamometry was found after rTMS. CONCLUSIONS: Stimulation parameters for rTMS, which are safe for healthy volunteers, may lead to a higher risk for seizure occurrence in chronic stroke patients. SIGNIFICANCE: rTMS at rates of 20 and 25 Hz using above threshold stimulation potentially increases the risk of seizures in patients with chronic stroke.

Epilepsia. 2007 Sep;48(9):1756-63. Epub 2007 Jun 11.
Ketogenic diet: electrophysiological effects on the normal human cortex.
Cantello RVarrasi CTarletti RCecchin MD’Andrea FVeggiotti PBellomo GMonaco F.
Department of Clinical and Experimental Medicine, Section of Neurology, A. Avagadro University, Novara, Italy. cantello@med.unipmn.it
PURPOSE: To explore the cortical electrophysiology of the ketogenic diet (KD) in the normal human. KD is effective against refractory epilepsy, but its precise mechanism is obscure. At the transmitter level, an enhancement of GABA inhibition has often been proposed. METHODS: We studied eight healthy volunteers undergoing a “classic” KD for 2 weeks. We measured several biochemical variables at baseline (T0), after 1 week (T1) and 2 weeks (T2) of KD, then 3 months after the KD conclusion (T3). Ketosis was quantified as 24-h ketonuria. At the same time, we studied the motor cortical excitability by means of transcranial magnetic stimulation (TMS). We also quantitatively evaluated the EEG signal in search of frequency shifts over the rolandic areas. RESULTS: Significant (p < 0.05) neurophysiological changes appeared at T2. These consisted of a strengthening of short-latency cortical inhibition (SICI), a TMS index which is thought to reflect GABA-A inhibition in the cortex. Then, there was an enhancement of the beta EEG band over the perirolandic region, similar to that following administration of GABA-A agonists. All changes disappeared at T3. CONCLUSIONS: A standard, short-term KD affected the cortical physiology of the normal human. The main changes were an augmented SICI and an increased perirolandic beta EEG activity, which are compatible with a lower level of neural excitation within the cortex.

Epilepsia. 2007 Aug;48(8):1538-42. Epub 2007 Apr 13.
A hypothesis for how non-REM sleep might promote seizures in partial epilepsies: a transcranial magnetic stimulation study.
Salih F, Khatami RSteinheimer SKretz RSchmitz BGrosse P.
Neurologische Klinik und Poliklinik, and Interdisziplinäres Schlafmedizinisches Zentrum, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany. Farid.Salih@charite.de
PURPOSE: To investigate alterations of inhibitory and excitatory cortical circuits during non-rapid eye movement (NREM) sleep in drug-naive patients with partial epilepsies and sleep-bound seizures only. METHODS: A paired-pulse TMS paradigm was used to test intracortical inhibition (ICI) and facilitation (ICF) in the hemisphere of the epileptic focus in three untreated patients with nonlesional, nongenetic frontal lobe epilepsy in NREM2 (three patients), NREM3/4 (one patient), and wakefulness (three patients). RESULTS: All three patients exhibited a major decrease of ICI in NREM sleep as opposed to the physiological enhancement of ICI with the progression of NREM sleep. CONCLUSIONS: Decreased ICI might reflect a substrate for the association of epileptic processes with thalamocortical networks that propagate sleep. Thus our findings contribute to a hypothesis of how NREM sleep could promote seizures.

J Neurol Sci. 2007 Jul 15;258(1-2):144-7. Epub 2007 Mar 29.
Heightened seizure susceptibility associated with brain dermoid cyst and the administration of human chorionic gonadotropin (hCG).
Milani P, Rocchi RCerase ARossi AMazzocchio R.
Section of Clinical Neurophysiology, Department of Neurological and Behavioral Sciences, University of Siena, Italy.
It is known that the intramuscular injection of human chorionic gonadotropin (hCG) lowers the threshold for motor evoked responses (MEPs) in the first dorsal interosseous (FDI) muscle to transcranial magnetic stimulation (TMS) in humans. We describe the case of a patient with a clinically silent left-sided nasofrontal dermoid cyst who, while being treated with hCG/LH for hypogonadotropic hypogonadism, presented with simple partial seizures, ipsilateral to the cyst, with secondary generalization. Motor cortex excitability was studied by single and paired TMS and MEPs were recorded from FDI. Resting motor threshold (RMT), active motor threshold (AMT), MEP size, intracortical inhibition (ICI) and intracortical facilitation (ICF) were tested during and after suspension of hormonal therapy. RMT and AMT were lower, MEP size was larger, ICI was decreased while ICF was slightly diminished during treatment. Overall, this indicated a reduced intracortical inhibition during hormonal therapy. It is concluded that treatment with hCG/LH may favour seizure onset in the presence of potentially epileptogenic lesions such as an intracranial dermoid cyst.

Epilepsy Res. 2007 Jul;75(2-3):197-205.
Motor representation areas in epileptic patients with focal motor seizures: a TMS study.
Labyt E, Houdayer ECassim FBourriez JLDerambure PDevanne H.
Department of Clinical Neurophysiology, EA 2683, R. Salengro Hospital, Lille University Medical Centre, F-59037 Lille, France. etienne.labyt@wanadoo.fr
PURPOSE: This study used TMS mapping to investigate the motor representation of the abductor pollicis brevis (APB) muscles in a group of patients with focal epilepsy originating in central or pre-central region. METHODS: Eight epileptic patients and eight control subjects participated in the study. The coil was moved in 1.5-cm steps along a grid drawn on the subject’s skull over the motor cortex of both hemispheres. At each site, six APB motor responses (evoked by TMS at 1.2 times the resting motor threshold) were recorded and averaged. The peak-to-peak amplitude was measured and plotted against the mediolateral and anteroposterior coil positions. The area of each APB muscle representation was measured and the position of the optimal point was calculated. RESULTS: The resting motor threshold was increased bilaterally in epileptic patients. The maps were distorted in most patients (but not in control subjects), as evidenced by an off-centre optimal point. Interhemispheric differences in APB map areas were greater in patients than in control subjects. However, whether these increases in map area were on the epileptic side or on healthy side depended on the given subject. CONCLUSIONS: The changes in APB representation observed in epileptic patients demonstrate that reorganization occurs within the motor cortex. The heterogeneity of the present results is probably related to different locations of the epileptogenic and/or lesional areas and to a variety of compensatory phenomena that may occur, notably with respect to the disease duration.

Nat Clin Pract Neurol. 2007 Jul;3(7):383-93
Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS.
Fregni F, Pascual-Leone A.
Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a given organ; they also reflect the consequences of the nervous system’s attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques–repetitive transcranial magnetic stimulation and transcranial direct current stimulation–to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson’s disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.

Epilepsy Behav. 2007 Jun;10(4):521-8. Epub 2007 May 9.
Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature.
Bae EHSchrader LMMachii KAlonso-Alonso MRiviello JJ JrPascual-Leone ARotenberg A.
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Repetitive transcranial magnetic stimulation (rTMS) is emerging as a new therapeutic tool in epilepsy, where it can be used to suppress seizures or treat comorbid conditions such as mood disorder. However, as rTMS carries a risk of inducing seizures among other adverse events, its safety and tolerability in the population with epilepsy warrant distinct consideration, as this group is especially seizure-prone. Accordingly, we performed a review of the literature to estimate the risk of seizures and other adverse events associated with rTMS in patients with epilepsy. We performed an English-language literature search, and reviewed all studies published from January 1990 to February 2007 in which patients with epilepsy were treated with rTMS, and complemented the literature search with personal correspondence with authors when necessary. We identified 30 publications that described patients with epilepsy who underwent rTMS, and noted total number of relevant subjects, medication usage, incidence of adverse events, and rTMS parameters including stimulus frequency, number of stimuli, train duration, intertrain interval, coil type, and stimulation sites. The data were analyzed for adverse events related to rTMS. Crude per-subject risk, as well as per-subject mean risk weighted by sample size and risk per 1000 stimuli weighted by number of stimuli in each study, were computed for seizures and for other adverse events. Adverse events or lack thereof was reported in 26 studies (n=280 subjects). Adverse events attributed to rTMS were generally mild and occurred in 17.1% of subjects. Headache was most common, occurring in 9.6%. The most serious adverse event was seizure during treatment, which occurred in four patients (1.4% crude per-subject risk). All but one case were the patients’ typical seizures with respect to duration and semiology, and were associated with low-frequency rTMS. A single case of an atypical seizure appearing to arise from the region of stimulation during high-frequency rTMS is reported. No rTMS-related episodes of status epilepticus were reported. We cautiously conclude that the risk of seizure in patients with epilepsy undergoing rTMS is small, and the risk of other mild adverse events is comparable to that seen when rTMS is used to treat other diseases. Status epilepticus or life-threatening seizures have not been reported in patients undergoing rTMS treatment. rTMS thus appears to be nearly as safe in patients with epilepsy as in nonepileptic individuals, and warrants further investigation as a therapy in this population.

Brain. 2007 Mar;130(Pt 3):610-22. Epub 2006 Nov 29.
Stimulating language: insights from TMS.
Devlin JTWatkins KE.
FMRIB Centre, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. devlin@fmrib.ox.ac.uk
Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These ‘virtual lesion’ studies offer not only the ability to explore causal relations between brain regions and language functions absent in functional neuroimaging, but also spatial and temporal precision not typically available in patient studies. For instance, TMS has been used to demonstrate functionally distinct sub-regions of the left inferior frontal gyrus; to clarify the relationship between pre-morbid language organization and susceptibility to unilateral lesions and to investigate the contribution of both left and right hemisphere language areas in recovery from aphasia. When TMS is used as a measure of functional connectivity, it demonstrates a close link between action words and motor programmes; it suggests a potential evolutionary link between hand gestures and language and it suggests a role in speech perception for the motor system underlying speech production. In combination with functional neuroimaging, it can elucidate the circuits responsible for this involvement. Finally, TMS may even be useful for enhancing recovery in aphasic patients. In other words, TMS has already become an important tool for studying language at both the cognitive and neural levels, and it is clear that further developments in TMS methodology are likely to result in even greater opportunities for language research.

Clin Neurophysiol. 2007 Mar;118(3):702-8. Epub 2007 Jan 16.
Antiepileptic effects of low-frequency repetitive transcranial magnetic stimulation by different stimulation durations and locations.
Joo EY, Han SJChung SHCho JWSeo DWHong SB.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-gu, 135-710 Seoul, South Korea.
OBJECTIVE: To evaluate the antiepileptic effect of low-frequency rTMS (repetitive transcranial magnetic stimulation) in the patients with intractable epilepsy. METHODS: We enrolled 35 patients with localization-related epilepsy who had experienced at least one complex partial seizure or a secondarily generalized seizure per week on a constant antiepileptic drug regimen over an 8-week period. rTMS was administered using a Rapid(2) magnetic stimulator with an air-cooled coil at 0.5Hz for 5 consecutive days at 100% of rMT (resting motor threshold). Patients were divided into a focal stimulation group with a localized epileptic focus, or a non-focal stimulation group with a non-localized or multifocal epileptic focus. These two groups were then randomly subdivided into four subgroups depending on the total number of stimulations administered, i.e., 3000 pulse and 1500 pulse subgroups. Weekly seizure frequencies were determined for 8 weeks before and after rTMS. To compare the number of interictal spikes before and after rTMS, EEG was recorded twice before (1st day) and after rTMS (5th day). RESULTS: Mean weekly seizure frequency was non-significantly decreased after rTMS (8.4–>6.8/week, -13.9%). Longer stimulation subgroups (3000 pulses, -23.0%) tended to have fewer seizures than shorter stimulation subgroups (1500 pulses, -3.0%), without statistical significance. TMS stimulation site and structural brain lesions did not influence seizure outcome. However, interictal spikes significantly decreased (-54.9%, P=0.012) after rTMS and they totally disappeared in 6 patients (17.1%, 6/35). CONCLUSIONS: Low-frequency rTMS reduced interictal spikes, but its effect on seizure outcome was not significant. Focal stimulation for a longer duration tended to further reduce seizure frequency. SIGNIFICANCE: These findings may help clinicians to further investigate the therapeutic potential of the rTMS for patients with intractable epilepsy.

Epilepsia. 2007 Feb;48(2):366-74.
Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial.
Cantello R, Rossi SVarrasi CUlivelli MCivardi CBartalini SVatti GCincotta MBorgheresi AZaccara GQuartarone ACrupi DLaganà AInghilleri MGiallonardo ATBerardelli APacifici LFerreri FTombini MGilio FQuarato PConte AManganotti PBongiovanni LGMonaco FFerrante DRossini PM.
Department of Clinical and Experimental Medicine, Section of Neurology, Amedeo Avogadro University, Novara, Italy. cantello@med.unipmn.it
PURPOSE: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy. METHODS: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex. RESULTS: “Active” rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability). CONCLUSIONS: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to “active” rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.

Epilepsia. 2007 Feb;48(2):359-65.
rTMS reveals premotor cortex dysfunction in frontal lobe epilepsy.
Löscher WN, Dobesberger J, Szubski C, Trinka E.
Department of Neurology, University Innsbruck, Innsbruck, Austria. wolfgang.loescher@i-med.ac.at
PURPOSE: Studies of motor cortex excitability provided evidence that focal epilepsies may alter the excitability of cortical areas distant from the epileptogenic zone. In order to explore this hypothesis we studied the functional connectivity between premotor and motor cortex in seven patients with frontal lobe epilepsy and seizure onset zone outside the premotor or motor cortex. METHODS: Low-frequency subthreshold repetitive transcranial magnetic stimulation was applied to the premotor cortex and its impact on motor cortex excitability was measured by the amplitude of motor-evoked potentials in response to direct suprathreshold stimulation of the motor cortex. RESULTS: Stimulation of the premotor cortex of the non-epileptogenic hemisphere resulted in a progressive and significant inhibition of the motor cortex as evidenced by a reduction of motor evoked potential amplitude. On the other hand, stimulation of the premotor cortex of the epileptogenic hemisphere failed to inhibit the motor cortex. The reduced inhibition of the motor cortex by remote areas was additionally supported by the significantly shorter cortical silent periods obtained after stimulation of the motor cortex of the epileptogenic hemisphere. CONCLUSION: These results show that the functional connectivity between premotor and motor cortex or motor cortex interneuronal excitability is impaired in the epileptogenic hemisphere in frontal lobe epilepsy while it is normal in the nonepileptogenic hemisphere.

Acta Neurochir Suppl. 2007;97(Pt 2):261-72. Brain stimulation for epilepsy.
Theodore WH, Fisher R.
Clinical Epilepsy Section, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. theodorw@ninds.nih.gov
Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients.

Neurosci Res. 2007 Jan;57(1):140-2. Epub 2006 Nov 7.
Effects of repetitive transcranial magnetic stimulation on spike-and-wave discharges.
Conte A, Gilio F, Iacovelli E, Bettolo CM, Di Bonaventura C, Frasca V, Carbone A, Prencipe M, Berardelli A, Inghilleri M.
Department of Neurological Sciences, University of Rome La Sapienza, Rome, Italy.
Aim of this study was to evaluate the effect of 5Hz-suprathreshold repetitive transcranial magnetic stimulation (rTMS) on the duration of the spike-and-wave discharges (SWDs) in a patient presenting idiopathic absence seizures. At the moment of the study the patient presented a mild blunting of consciousness due to the high frequency of absences and EEG recordings showed sub-continuous, generalized, symmetrical and synchronous 3c/s SWDs, petit mal status. Trains of 10 stimuli (120% resting motor threshold) were delivered at 5Hz frequency at the beginning of the SWDs. 5Hz-rTMS trains significantly changed the EEG activity by reducing the duration of SWDs without changing the intervals between two consecutive discharges. rTMS had not significant after-effects on the epileptic activity and patient’s clinical status. Despite the limitations of a single case report, our neurophysiological findings suggest that 5Hz-suprathreshold rTMS delivered in short trains induces a transitory interference of the ongoing epileptic activity.

Indian J Exp Biol. 2006 Dec;44(12):949-54.
Influence of transcranial magnetic stimulation on spike-wave discharges in a genetic model of absence epilepsy.
Godlevsky LS, Kobolev EV, van Luijtelaar EL, Coenen AM, Stepanenko KI, Smirnov IV.
Department of Biophysics, Informatics and Medical Devices, Medical University, Odessa, Valehovsky Lane 2, Ukraine. godlevsky@odmu.od.ua
Transcranial magnetic stimulation (TMS) impulses, (0.5 Hz, 3 impulses) were presented at threshold intensity to male WAG/Rij rats. One group received stimuli, which involved motor responses of hindlimbs, rats of the second group received sham stimulation. Electrocorticograms (ECoG) were recorded before and up to 2 hr from the moment of transcranial magnetic stimulation. It was established that such stimulation engendered a reduction of spike-wave discharge (SWD) bursts duration. This effect was most pronounced in 30 min from the moment of cessation of stimulation, when a decrease of 31.4% was noted in comparison with sham-stimulated control group. The number of bursts of spike-wave discharges was reduced, but did not reach significant difference when compared both with pre-stimulative base-line level and with sham-stimulated control rats. Bursts of spike-wave discharges restored up to pre-stimulative level in 90-150 minutes from the moment of cessation of transcranial stimulation. It can be concluded that transcranical magnetic stimulation possessed an ability to engender short-time suppression of bursts of spike-wave discharges in WAG/Rij rats.


Seizure. 2006 Dec;15(8):653-7. Epub 2006 Aug 21.
Erratum in:Seizure. 2007 Mar;16(2):194.
Cyclical excitability of the motor cortex in patients with catamenial epilepsy: a transcranial magnetic stimulation study.
Hattemer K, Knake S, Reis J, Oertel WH, Rosenow F, Hamer HM.
Interdisciplinary Epilepsy Center, Department of Neurology, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany. hattemer@med.uni-marburg.de
PURPOSE: The pathophysiology of catamenial epilepsy is still unclear. Therefore, we investigated the cortical excitability of women with catamenial epilepsy during different phases of the menstrual cycle. METHODS: Using transcranial magnetic stimulation, six patients suffering from catamenial epilepsy were investigated during ovulatory cycles. On days 8, -14, -7 and 2 of the cycle (day 1 being the first day of menstrual bleeding), resting motor threshold (RMT), cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF) were investigated. The non-parametric Friedman-test for multiple comparisons and Wilcoxon signed rank test were used for statistical analysis. RESULTS: Five patients suffered from focal epilepsy (three right hemispheric, one bitemporal, one unknown origin) and one patient had idiopathic generalized epilepsy. All patients experienced perimenstrual seizure clustering and two also showed an increased seizure frequency during the luteal phase. In the right hemispheres there was a significant change of CSP duration in the course of the menstrual cycle (chi(2)=8.3, P=0.041), due to a shorter CSP during the luteal phase (Z=-2.0, P=0.043) and menstruation (Z=-2.2, P=0.028) as compared to the follicular phase. There was no significant variation of CSP in the left hemispheres. RMT, ICI and ICF showed no significant changes in the course of the menstrual cycle. CONCLUSIONS: The CSP changes suggest a decreased inhibition involving GABA-ergic neurotransmission during the luteal phase and menstruation. These TMS alterations correlated with the clinical course of the epilepsies and were found in the hemispheres containing the majority of the epileptogenic zones.

Sleep. 2006 Dec 1;29(12):1595-8.
Increasing cortical excitability: a possible explanation for the proconvulsant role of sleep deprivation.
Scalise A, Desiato MT, Gigli GL, Romigi A, Tombini M, Marciani MG, Izzi F, Placidi F.
Department of Neurosciences, S. Maria della Misericordia Hospital, Udine, Italy. annascalise@libero.it
STUDY OBJECTIVE: Sleep deprivation (SD) is known to facilitate both seizures and interictal epileptiform abnormalities. For this reason, it is often used in the routine diagnostic workup of epileptic patients as an activating procedure for eliciting epileptiform and/or seizure patterns in their EEGs. In order to evaluate the effects of SD on cortical excitability, we studied the effects of sleep loss on healthy subjects by transcranial magnetic stimulation (TMS). DESIGN AND PARTICIPANTS: Seven normal subjects underwent TMS examination in baseline condition and after total sleep deprivation. The TMS investigation included two protocols: a) the evaluation of motor evoked potential and silent period parameters recorded in response to single-pulse magnetic stimulation; and b) the evaluation of the time course of intracortical motor activity tested with paired-pulse TMS applied at inter-stimulus intervals of 1-6 ms. SETTING: Clinical neurophysiology laboratory in a general hospital. INTERVENTIONS: None. RESULTS: After SD, the principal finding observed using single-pulse TMS was a decrease of the silent period duration, whereas a reduction of the intracortical inhibition, in particular at inter-stimulus intervals 1 and 2 ms, was found, using the paired-pulse TMS. CONCLUSION: Our findings suggest that SD may modify cortical excitability, seen as the balance between inhibitory and excitatory cortical phenomena, which could reduce the epileptic threshold.

Ann Neurol. 2006 Oct;60(4):447-55.
A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy.
Fregni F, Otachi PT, Do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Valente KD.
Center for Non-invasive Brain Stimulation, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: To study the antiepileptic effects of rTMS in patients with refractory epilepsy and malformations of cortical development in a randomized, double-blind, sham-controlled trial. METHODS: Twenty-one patients with malformations of cortical development and refractory epilepsy underwent five consecutive sessions of low-frequency rTMS, either sham or active (1Hz, 1,200 pulses), focally targeting the malformations of cortical development. The number of epileptiform discharges in the electroencephalogram and the number of clinical seizures were measured before (baseline), immediately after, as well as 30 and 60 days after rTMS treatment. RESULTS: rTMS significantly decreased the number of seizures in the active compared with sham rTMS group (p < 0.0001), and this effect lasted for at least 2 months. Furthermore, there was a significant decrease in the number of epileptiform discharges immediately after (p = 0.01) and at week 4 (p = 0.03) in the active rTMS group only. There were few mild adverse effects equally distributed in both groups. The preliminary cognitive evaluation suggests improvement in some aspects of cognition in the active rTMS group only. INTERPRETATION: Noninvasive brain stimulation for epilepsy may be an alternative treatment for pharmaco-resistant patients with clearly identifiable seizure foci in the cortical convexity and who are not eligible for surgical treatment.

Neuroimage. 2006 Oct 1;32(4):1499-509. Epub 2006 Jun 27.
Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus 
Shepherd TM, Ozarslan E, King MA, Mareci TH, Blackband SJ.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. tms@mbi.ufl.edu
The hippocampus is a critical structure for learning and memory formation injured by diverse neuropathologies such as epilepsy or Alzheimer’s disease. Recently, clinical investigations have attempted to use diffusion tensor MRI as a more specific surrogate marker for hippocampal damage. To first better understand the tissue architecture of healthy hippocampal regions, this study characterized 10 rat hippocampi with diffusion tensor imaging (DTI) at 50-microm in-plane image resolution using a 14.1-T magnet. Chemical fixation of the dissected and straightened rat hippocampus provided a simple, effective way to reduce partial volume effects when segmenting hippocampal regions and improved mean signal-to-noise per unit time (e.g. 50.6+/-4.4 at b=1250 s/mm2 in 27 min). Contrary to previous reports that water diffusion is homogeneous throughout the nervous system, statistically different mean diffusivities were observed (e.g. 0.238+/-0.054 and 0.318+/-0.084 microm2/ms for the molecular and granule cell layers respectively) (ANOVA, P<0.05). Different hippocampal subregions had lower fractional anisotropy than uniformly fibrous structures like corpus callosum because of their complex architecture. DTI-derived color fiber orientation maps and tractography demonstrated most components of the trisynaptic intrahippocampal pathway (e.g. orientations in stratum lacunosum-moleculare were dominated by perforant and Schaffer fibers) and also permitted some assessment of connectivity in the rat hippocampus.
PMID: 16806988 [PubMed – indexed for MEDLINE]

41: Neurology. 2006 Sep 26;67(6):1018-22. Related Articles
Comment in: Neurology. 2007 Jul 17;69(3):318; author reply 318-9.
Sleep deprivation increases cortical excitability in epilepsy: syndrome-specific effects.
Badawy RA, Curatolo JM, Newton M, Berkovic SF, Macdonell RA.
Department of Neurology, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia.
OBJECTIVE: To use transcranial magnetic stimulation (TMS) to investigate the hypothesis that sleep deprivation increases cortical excitability in people with epilepsy. METHODS: We performed paired pulse TMS stimulation, using a number of interstimulus intervals (ISIs) on each hemisphere of 30 patients with untreated newly diagnosed epilepsy (15 idiopathic generalized epilepsy [IGE] and 15 focal epilepsy) and on the dominant hemisphere of 13 healthy control subjects, before and after sleep deprivation. RESULTS: Both hemispheres in patients with IGE and the hemisphere ipsilateral to the EEG seizure focus in those with focal epilepsy showed an increase in cortical excitability following sleep deprivation at a number of ISIs. This change in excitability was most prominent in the patients with IGE. Although there were minor changes after sleep deprivation in control subjects and the contralateral hemisphere in the focal epilepsy group seen at the 250-millisecond ISI, it was less than in the other groups. CONCLUSIONS: Sleep deprivation increases cortical excitability in epilepsy; the pattern of change is syndrome dependent.
Publication Types:
PMID: 17000971 [PubMed – indexed for MEDLINE]

42: J Physiol. 2006 Sep 15;575(Pt 3):721-6. Epub 2006 Jun 29. 
GABAA receptor subtype specific enhancement of inhibition in human motor cortex.
Di Lazzaro V, Pilato F, Dileone M, Ranieri F, Ricci V, Profice P, Bria P, Tonali PA, Ziemann U.
Istituto di Neurologia, Università Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy. vdilazzaro@rm.unicatt.it
Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and gamma-aminobutyric acid A receptor (GABA(A)R) subtypes. Here we employed paired-pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABA(A)R-mediated inhibition in human motor cortex, to address the question of which GABA(A)R subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non-selective affinity profile at different alpha-subunit-bearing subtypes of the GABA(A)R while zolpidem has a 10-fold greater affinity to the alpha1-subunit-bearing GABA(A)R compared with those bearing the alpha2- or alpha3-subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an alpha1-subunit GABA(A)R-mediated effect. The findings strongly suggest that SICI is not mediated by the alpha1-subunit-bearing subtype of the GABA(A)R but by those bearing either the alpha2- or alpha3-subunit. This study represents an attempt by means of TMS to identify GABA(A)R subtype-specific action at the systems level of human cortex, a highly relevant issue because the different alpha-subunit-bearing subtypes of the GABA(A)R are differently involved in benzodiazepine-mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.
PMID: 16809358 [PubMed – indexed for MEDLINE] PMCID: PMC1995685

43: Arq Neuropsiquiatr. 2006 Sep;64(3A):639-44. 
[Morphological characteristics from the insula’s lobe in patients with medial temporal lobe epilepsy]
Chaddad Neto F, de Oliveira E, Paschoal E, Cendes F, Santana Filho M.
Instituto de Ciências Neurológicas, São Paulo, Brazil.
The temporal medial sclerosis (TMS) is characterized by hippocampal sclerosis in temporal and by distinguished grades of injury near to other neurological structures such as: amygdaloid nucleus, parahippocampal girus and entorhinal region. The study analyzed 40 patients with TMS and 40 people from the control cluster. All the cases were appreciated by one method for measurement of insula’s cortex (E-Film) and another method to calculate the insula’s volume (Neuroline). There is no variation statistical between the insula’s volume and insula’s measurement for the two clusters. This paper didn’t show the insula’s morphological variation when these two groups were compared.
Publication Types:
PMID: 17119810 [PubMed – indexed for MEDLINE]

Neurophysiol Clin. 2006 Sep-Dec;36(5-6):293-7. Epub 2007 Jan 17.
Myoclonus and transcranial magnetic stimulation.
Lefaucheur JP.
Service de physiologie, explorations fonctionnelles, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris, 51, avenue du Marechal-Lattre-de-Tassigny, 94010 Créteil, France. jean-pascal.lefaucheur@hmn.aphp.fr
The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.

Clin Neurophysiol. 2006 Jun;117(6):1217-27. Epub 2006 Apr 27.
Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1Hz rTMS in patients with juvenile myoclonic epilepsy. 
Fregni F, Boggio PS, Valle AC, Otachi P, Thut G, Rigonatti SP, Marcolin MA, Fecteau S, Pascual-Leone A, Fiore L, Valente K.
Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., KS 452, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. METHODS: Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. RESULTS: In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. CONCLUSIONS: Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. SIGNIFICANCE: The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.

Neurosci Lett. 2006 Apr 24;397(3):229-33. Epub 2006 Jan 19.
Hemispheric cerebellar rTMS to treat drug-resistant epilepsy: case reports.
Brighina F, Daniele O, Piazza A, Giglia G, Fierro B.
Neurophysiological Unit, University of Palermo, Institute of Neuropsychiatry, Via G. La Loggia, 1, 90129 Palermo, Italy.
Electrical stimulation of the cerebellar cortex by implanted electrodes has been shown to ameliorate refractory epilepsy. We investigated the potential therapeutic role of high-frequency cerebellar rTMS in patients affected by refractory epilepsy due to single or multiple foci. Six patients, three with single and three with multiple epileptic foci, underwent 20 rTMS sessions. Each session was given daily, excluding weekends, and consisted of two trains of 50 stimuli (5 Hz frequency and 90% motor threshold intensity), separated by 50s interval. rTMS was delivered through a focal coil (2 cm below and lateral to the inion) bilaterally in patients with multiple foci (two trains for hemisphere: 100 stimuli each side) and contralaterally to the epileptic focus in the others. Seizure frequency was monitored four weeks before stimulation (pre-rTMS), during the four-week treatment (rTMS) and four weeks after the treatment (post-rTMS). The rTMS over the cerebellar cortex was associated with a significant decrease of rTMS versus pre-rTMS seizure frequency both in patients with single and multiple epileptic foci. However, during the post-rTMS period seizure frequency was back to the pre-rTMS frequency. Although the results are still preliminary, they encourage further studies on larger series of patients. In particular, this rTMS approach, as compared with others, might be more useful in patients with multiple epileptic foci.

J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):56-60.
Effects of sleep deprivation on cortical excitability in patients affected by juvenile myoclonic epilepsy: a combined transcranial magnetic stimulation and EEG study.
Manganotti P, Bongiovanni LG, Fuggetta G, Zanette G, Fiaschi A.
Dipartimento di Scienze Neurologiche e della Visione, Sezione di Neurologia Riabilitativa, Policlinico Borgo Roma, Via delle Menegone, 37134 Verona, Italy. paolo.manganotti@univr.it
OBJECTIVE: To investigate the effect of sleep deprivation on corticospinal excitability in patients affected by juvenile myoclonic epilepsy (JME) using different transcranial magnetic stimulation (TMS) parameters. METHODS: Ten patients with JME and 10 normal subjects underwent partial sleep deprivation. Motor threshold (MT), motor evoked potential amplitude (MEP), and silent period (SP) were recorded from the thenar eminence (TE) muscles. Short latency intracortical inhibition (SICI) and short latency intracortical facilitation (SICF) were studied using paired magnetic stimulation. TMS was performed before and after sleep deprivation; EEG and TMS were performed simultaneously. RESULTS: In patients with JME, sleep deprivation induced a significant decrease in SICI and an increase in SICF, which was associated with increased paroxysmal activity. A significant decrease in the MT was observed. No significant changes in any TMS parameters were noted in normal subjects after sleep deprivation. The F wave was unchanged by sleep deprivation in both control subjects and in patients with JME. CONCLUSIONS: In patients with JME, sleep deprivation produces increases in corticospinal excitability in motor areas as measured by different TMS parameters.

J Clin Neurophysiol. 2005 Dec;22(6):418-21.
Crossed inhibition of sensory cortex by 0.3 Hz transcranial magnetic stimulation of motor cortex.
Seyal M, Shatzel AJ, Richardson SP.
Department of Neurology, University of California-Davis Medical Center, 2315 Stockton Boulevard, Rm. 5308, Sacramento, CA 95817, U.S.A. mseyal@ucdavis.edu
Low-frequency repetitive transcranial magnetic stimulation (rTMS) of motor cortex causes persistent inhibitory effects in the targeted area. rTMS of motor cortex impairs sensory perception and results in a persistent change in cortical function at remote sites. The ability of rTMS to induce sustained changes in cortical function has led to studies testing its therapeutic efficacy in neurologic disorders, including epilepsy. Studies on the effect of low-frequency rTMS of motor cortex on the contralateral motor cortex have provided evidence for both inhibitory and excitatory changes. This study was designed to determine the effect of low-frequency rTMS of the right motor cortex on the contralateral sensory cortex. Before and after 0.3-Hz rTMS of right motor cortex, perception of ipsilateral threshold of cutaneous stimuli was assessed and somatosensory evoked potentials (SEPs) recorded after stimulation of the right thumb in eight normal subjects. In a control group of six subjects, sensory responses were assessed after rTMS anterior to the right motor cortex. After rTMS of motor cortex, detection of threshold sensory stimuli decreased by more than 50% compared with pre-rTMS (P < 0.05). The change in sensory perception lasted at least 30 minutes. No change was detected in the control group. Amplitude of the N20-P25 waveform of the SEP decreased from a mean of 0.84 muV before rTMS to 0.54 muV immediately after rTMS of motor cortex (P < 0.05). 0.3 Hz rTMS of motor cortex inhibits the contralateral sensory cortex.

Rev Neurol (Paris). 2005 Nov;161(11):1121-30.
[Transcranial magnetic stimulation: applications in neurology]
[Article in French] Lefaucheur JP.
Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil. jean-pascal.lefaucheur@hmn.ap-hop-paris.fr
INTRODUCTION: Transcranial magnetic stimulation (TMS) was first applied to assess conduction time along the corticospinal tract, namely by recording motor evoked potentials. STATE OF ART: At present, TMS techniques include cortical excitability and mapping studies using single or paired-pulse paradigms on the one hand, and repetitive TMS to induce cortical plasticity and to modify brain function on the other hand. TMS is a valuable, non-invasive tool in the diagnosis and the pathophysiological assessment of cortical dysfunction involved in various neurological diseases (multiple sclerosis, myelopathy, amyotrophic lateral sclerosis, movement disorders, epilepsy, stroke). PERSPECTIVES AND CONCLUSION: In the near future, repetitive TMS could have therapeutic applications in neurology (epilepsy, stroke rehabilitation program) as is already the case in some psychiatric diseases. However, most of the new indications for treatment with cortical stimulation will be based on surgically-implanted neuromodulation procedures.

Rinsho Shinkeigaku. 2005 Nov;45(11):831-3.
[Clinical applications of transcranial magnetic stimulation for the treatment of various neurological diseases]
[Article in Japanese] Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine.
Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential therapeutic tool in various neurological and psychiatric diseases including depression, Parkinson disease, spinocerebellar degeneration, epilepsy, urinary incontinence, movement disorders, chronic pain, migraine and chronic tinnitus, etc. Several reports showed the therapeutic effects of rTMS as a treatment of depression and Parkinson disease (PD), whereas others found no significant effects. It is by now not yet fully understood whether rTMS has a therapeutic effect on those diseases. The controversy arises from the differences of the stimulation parameters and evaluation methods of the effects in those studies. The Japanese multi-center, double blinded, sham stimulation controlled trial in 85 patients with PD showed an efficacy in both the rTMS-treated and sham stimulated patients. This result does not prove the efficacy of the rTMS in PD; on the other hand, it does not rule out the efficacy. Possible mechanism of favorable effects of rTMS is related to increasing the release of dopamine in the mesolimbic and mesostriatal system. The other Japanese multi-center, double blinded, sham stimulation controlled trial in 99 patients with spinocerebellar degeneration revealed significant therapeutic effects of rTMS in 51 patients with SCA6. We studied the effects of rTMS on seizure susceptibility in rats which prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. This finding suggests the possibility of therapeutic use of rTMS in epilepsy. Further studies should be performed aiming to reveal the optimal stimulation parameters, and are necessary to reveal the therapeutic role of the rTMS in neurological and psychiatric diseases.

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.

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.

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 SCPascual-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 ABegum TYamamoto JHitomi TShibasaki 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 magnetic 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.

Neuron. 2005 Jan 20;45(2):181-3.
Neuron. 2005 Jan 20;45(2):201-6. Toward establishing a therapeutic window for rTMS by theta burst stimulation.
Paulus W.
Department of Clinical Neurophysiology, University of Goettingen, D-37075 Goettingen, Germany.
In this issue of Neuron, Huang et al. show that a version of the classic theta burst stimulation protocol used to induce LTP/LTD in brain slices can be adapted to a transcranial magnetic stimulation (TMS) protocol to rapidly produce long lasting (up to an hour), reversible effects on motor cortex physiology and behavior. These results may have important implications for the development of clinical applications of rTMS in the treatment of depression, epilepsy, Parkinson’s, and other diseases.

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.

Stereotact Funct Neurosurg. 2005;83(2-3):57-62. Epub 2005 Jun 30.
Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: an EEG and clinical study.
Fregni F, Thome-Souza S, Bermpohl F, Marcolin MA, Herzog A, Pascual-Leone A, Valente KD.
Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: To study the effects of repetitive transcranial magnetic stimulation (rTMS) on epileptic EEG discharges in patients with refractory epilepsy and malformations of cortical development (MCDs). METHODS: Eight patients with MCD and refractory epilepsy underwent 1 session of low-frequency rTMS (0.5 Hz, 600 pulses) focally targeting the MCD. The number of epileptiform discharges (EDs) in the EEG and seizures were measured before (baseline), immediately after as well as 15 and 30 days after rTMS treatment. RESULTS: Stimulation significantly decreased the number of EDs 15 and 30 days after rTMS treatment (mean reduction of 46.4%, 95% CI 12.7-80.2%, and mean reduction of 42.1%, 95% CI 8.2-75.7%, respectively). This was associated with a significant reduction in the number of seizures reported as compared with the 4-week period preceding rTMS (mean reduction of 57.3%, 95% CI 33.1-80.3%, and mean reduction of 51.2%, 95% CI 27.9-74.9%, respectively). CONCLUSION: This open study shows a significant antiepileptic effect of rTMS based on clinical and electrophysiological criteria and supports the therapeutic utility of rTMS for patients with well-localized epileptogenic cortical malformations. Copyright 2005 S. Karger AG, Basel.

69: 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, Università 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.
PMID: 15596749 [PubMed – indexed for MEDLINE]

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.

Laeknabladid. 2004 Nov;90(11):755-758.
[Transcranial magnetic stimulation.]
[Article in Icelandic]
Mœller AL, Stefánsson SB.
Department of Neurology, Landspitali University Hospital, Fossvogi, 108 Reykjavík, Iceland. annaltho@landspitali.is.
Transcranial Magnetic Stimulation (TMS) is a new non-invasive method to investigate the central nervous system. Initially it was used to assess the functional integrity of the pyramidal pathways but more recently various other aspects of brain function have been studied including cortical excitability. By localised interference with brain function, it is possible to use TMS to assess the relationship between various brain regions and cognitive functions. The therapeutic effect of TMS has been explored in the treatment of neurological diseases and psychiatric disorders such as epilepsy, cerebellar ataxia and depressive illness.

Acta Neurol Scand. 2004 Apr;109(4):290-6.
rTMS reduces focal brain hyperperfusion in two patients with EPC.
Graff-Guerrero A, Gonzáles-Olvera J, Ruiz-García M, Avila-Ordoñez U, Vaugier V, García-Reyna JC.
Instituto Nacional de Psiquiatría Ramón de la Fuente, División de Neurociencias, Laboratorio de Neurofisiología, México 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.

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.

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 Araújo DP, Teixeira WA, Araújo VP, Boechat-Barros R.
Laboratório de Neurociências e Comportamento, Departamento de Ciências Fisiológicas, Instituto de Biologia, Universidade de Brasília, 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.

Neuroreport. 2004 Feb 9;15(2):293-6.
Reduction of cortical myoclonus-related epileptic activity following slow-frequency rTMS.
Rossi S, Ulivelli M, Bartalini S, Galli R, Passero S, Battistini N, Vatti G.
Dipartimento di Neuroscienze, Sezione Neurologia, Università di Siena, Policlinico Le Scotte, Viale Bracci I-53100, Italy. Rossimo@unisi.it
In a drug-resistant epilepsy patient with continuous forearm/hand positive myoclonia due to a focal cortical dysplasia of the right motor cortex, cortical jerk-related and electromyographic activity were recorded for 15 min before and after 1 Hz rTMS (15 min, 10% below the resting excitability threshold) of the right motor cortex. A stable negative cortical spike, time-locked with contralateral muscle jerks (60 > 100 microV), was detected only at perirolandic electrodes (maximal amplitudes: block 1 = 21.3 microV, block 2 = 22 microV, block 3 = 25.9 microV). After rTMS, only 20 muscle jerks accomplished the criterion of > 100 microV; blind back-averaging of these disclosed a topographically similar cortical spike, but with amplitude reduced by at least 50% (11.2 microV). This represents in vivo evidence of the possibility to selectively modulate the activity of an epileptic focus by intervening with local low-frequency rTMS.

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, Théoret 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.


86: 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.
Publication Types:PMID: 14692911 [PubMed – indexed for MEDLINE]

87: 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, Gnezditskiĭ 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.
Publication Types:
PMID: 15071841 [PubMed – indexed for MEDLINE]

J Neurosci. 2003 Nov 26;23(34):10867-72.
Priming stimulation enhances the depressant effect of low-frequency repetitive transcranial 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.

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.

Nervenarzt. 2003 Aug;74(8):664-76.
[Electric brain stimulation for epilepsy therapy]
[Article in German] Kellinghaus C, Loddenkemper T, Möddel G, Tergau F, Lüders J, Lüdemann P, Nair DR, Lüders 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”).

Clin Neurophysiol. 2003 May;114(5):777-98.
Transcranial magnetic stimulation and epilepsy.
Tassinari CA, Cincotta M, Zaccara G, Michelucci R.
Department of Neurosciences, Division of Neurology, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy. carloalberto.tassinari@ausl.bo.it
Epileptic conditions are characterized by an altered balance between excitatory and inhibitory influences at the cortical level. Transcranial magnetic stimulation (TMS) provides a noninvasive evaluation of separate excitatory and inhibitory functions of the cerebral cortex. In addition, repetitive TMS (rTMS) can modulate the excitability of cortical networks. We review the different ways that TMS has been used to investigate pathophysiological mechanisms and effects of antiepileptic drugs in patients with epilepsy and epileptic myoclonus. The safety of different TMS techniques is discussed too. Finally, we discuss the therapeutic prospects of rTMS in this field.

97: Magn Reson Med. 2003 May;49(5):856-63.
Water diffusion measurements in perfused human hippocampal slices undergoing tonicity changes.
Shepherd TM, Wirth ED 3rd, Thelwall PE, Chen HX, Roper SN, Blackband SJ.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. tms@ufbi.ufl.edu
Diffusion MRI has the potential to probe the compartmental origins of MR signals acquired from human nervous tissue. However, current experiments in human subjects require long diffusion times, which may confound data interpretation due to the effects of compartmental exchange. To investigate human nervous tissue at shorter diffusion times, and to determine the relevance of previous diffusion studies in rat hippocampal slices, water diffusion in 20 perfused human hippocampal slices was measured using a wide-bore 17.6-T magnet equipped with 1000-mT/m gradients. These slices were procured from five patients undergoing temporal lobectomy for epilepsy. Tissue viability was confirmed with electrophysiological measurements. Diffusion-weighted water signal attenuation in the slices was well-described by a biexponential function (R(2) > 0.99). The mean diffusion parameters for slices before osmotic perturbation were 0.686 +/- 0.082 for the fraction of fast diffusing water (F(fast)), 1.22 +/- 0.22 x 10(-3) mm(2)/s for the fast apparent diffusion coefficient (ADC), and 0.06 +/- 0.02 x 10(-3) mm(2)/s for the slow ADC. Slice perturbations with 20% hypotonic and 20% hypertonic artificial cerebrospinal fluid led to changes in F(fast) of -8.2% and +10.1%, respectively (ANOVA, P < 0.001). These data agree with previous diffusion studies of rat brain slices and human brain in vivo, and should aid the development of working models of water diffusion in nervous tissue, and thus increase the clinical utility of diffusion MRI. Copyright 2003 Wiley-Liss, Inc.
Publication Types:PMID: 12704768 [PubMed – indexed for MEDLINE]

Arq Neuropsiquiatr. 2003 Mar;61(1):146-52. Epub 2003 Apr 16.
Comment in:
[Transcranial magnetic stimulation]
[Article in Portuguese]
Conforto AB, Marie SK, Cohen LG, Scaff M.
Divisão de Clínica Neurológica, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil. abcong@yahoo.com
Transcranial magnetic stimulation (TMS) allows non-invasive study and modulation of cortical excitability in humans. Changes in cortical excitability in physiological and pathological conditions can be tracked by measurements such as motor threshold, motor evoked potentials, recruitment curves, intracortical facilitation and inhibition. The central motor conduction time can estimate neural transmission in central motor pathways. Changes in areas of representation in sensorimotor cortex can be studied with cortical mapping. Modulation of cortical processing can be used to evaluate different brain functions. Therapeutic use in depression, Parkinson’s disease and epilepsy has raised great interest over the past decade. Non-invasive cortical mapping may be achieved by combining TMS to other neurophysiological/ neuroimaging techniques. TMS has great potential both as an investigational and as a therapeutical tool in Neurology and Psychiatry.

Brain Res. 2002 Dec 6;957(1):37-41.
The long-term high-frequency repetitive transcranial magnetic stimulation does not induce mRNA expression of inflammatory mediators in the rat central nervous system.
Okada K, Matsunaga K, Yuhi T, Kuroda E, Yamashita U, Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. gion@med.uoeh-u.ac.jp
Repetitive transcranial magnetic stimulation (rTMS) has been applied for treatment of several diseases such as depression. However, the safety and biological effects of rTMS have not been fully elucidated. In this study, the effects of rTMS on the levels of inflammatory mediators in the central nervous system (CNS), which may be involved in neurodegenerative disorders, were investigated in comparison with the electric convulsive model. Long-term rTMS (1500 pulses at 30 Hz/day for series of 7 days) stimulation, which did not elicit convulsion, was given to rats (rTMS rats). Single high-frequency electrical stimulation (100 Hz, 0.5-ms pulse width, 1 s duration, 50 mA), which induced convulsion, was given to rats (ES rats). mRNA levels of interleukin (IL)-1beta, IL-6, cyclooxygenase (COX)-2 and inducible nitric oxide synthetase (iNOS) in the brain were evaluated by reverse transcription-polymerase chain reaction before and after these stimulations. mRNA of IL-1beta, IL-6 and COX-2 was induced in the brains of ES rats but not in the brains of long-term rTMS rats. mRNA of iNOS was not induced in the brain of long-term rTMS rats. These results suggest that long-term rTMS may safe and modulate neural function without up-regulation of inflammatory mediators, which may be involved in neurodegenerative disorders.

Am J Psychiatry. 2002 Jul;159(7):1093-102.
Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders.
Hoffman RE, Cavus I.
Yale-New Haven Psychiatric Hospital, Yale University School of Medicine, LV 108, 20 York Street, New Haven, CT 06504, USA. ralph.hoffman@yale.edu
OBJECTIVE: Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity. METHOD: Studies assessing effects of “slow” rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue. RESULTS: Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects. CONCLUSIONS: Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.

J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):772-6.
Reduced excitability of the motor cortex in untreated patients with de novo idiopathic “grand mal” seizures.
Delvaux V, Alagona G, Gérard P, De Pasqua V, Delwaide PJ, Maertens de Noordhout A.
University Department of Neurology, Hôpital de la Citadelle, B-4000 Liège, Belgium.
OBJECTIVES: Transcranial magnetic stimulation (TMS) was used to investigate motor cortex excitability, intracortical excitatory, and inhibitory pathways in 18 patients having experienced a first “grand mal” seizure within 48 hours of the electrophysiological test. All had normal brain MRI, and were free of any treatment, drug, or alcohol misuse. Results were compared with those of 35 age matched normal volunteers. METHODS: The following parameters of responses to TMS were measured: motor thresholds at rest and with voluntary contraction, amplitudes of responses, cortical silent periods, and responses to paired pulse stimulation with interstimulus intervals of 1 to 20 ms. RESULTS: In patients, there were significantly increased motor thresholds with normal amplitudes of motor evoked potentials (MEPs), suggesting decreased cortical excitability. Cortical silent periods were not significantly different from those of normal subjects. Paired TMS with short interstimulus intervals (1-5 ms) induced normal inhibition of test MEPs, suggesting preserved function of GABAergic intracortical inhibitory interneurons. On the contrary, the subsequent period of MEP facilitation found in normal subjects (ISIs of 6-20 ms) was markedly reduced in patients. This suggests the existence of abnormally prolonged intracortical inhibition or deficient intracortical excitation. In nine patients retested 2 to 4 weeks after the initial seizure, these abnormalities persisted, although to a lesser extent. CONCLUSION: The present findings together with abnormally high motor thresholds could represent protective mechanisms against the spread or recurrence of seizures.

Rinsho Shinkeigaku. 2001 Dec;41(12):1097-9.
[Treatment of status epilepticus]
[Article in Japanese]
Tsuji S, Akamatsu N.
Status epilepticus (SE) is a condition requiring emergency care. There are convulsive SE, non-convulsive SE including complex partial status and absence status, non-convulsive electric SE and pseudostatus epilepticus, although convulsive SE is the most common. Diagnosis of status epilepticus of complex partial seizures (CPS) and absence seizures was significantly delayed because delays in seeking medical attention were common. The seizures were generalized convulsive SE in 84% and CPS status in 16%, and the overall mortality rate was 15% in 41 SE patients of our study. EEG monitoring is important to make or exclude the diagnosis of SE. Diazepam is the first choice medication and effective in the management of SE, and lately, lorazepam, midazolam, propofol and pentobarbital etc as emergency therapy. Phenytoin is also considered first-line agent in the emergency management of SE. Repetitive transcranial magnetic stimulation (rTMS) led to a prolonged latency for seizure induction after an intraperitoneal injection of pentylenetetrazol (PTZ) and effectively prevented the development of status epilepticus of PTZ-induced convulsions in the rats. Our data suggest that rTMS has suppressive effects on the neuronal excitability in rats. These effects are anticonvulsive and suggest the possibility of therapeutic use of rTMS in the patients with refractory seizures.

Neurology. 2001 Nov 27;57(10):1793-9.
Hyperexcitable cortical responses in progressive myoclonic epilepsy: a TMS study.
Manganotti P, Tamburin S, Zanette G, Fiaschi A.
Department of Neurological Sciences and Vision, Section of Neurological Rehabilitation, University of Verona, Italy. paolomanganotti@yahoo.com
OBJECTIVE: Transcranial magnetic stimulation (TMS) has allowed investigators to study intracortical inhibition and facilitation and sensorimotor integration in motor disorders and epilepsy. The authors used TMS to elucidate the pathophysiology of reflex myoclonus with giant somatosensory evoked potentials (SEP). METHODS: The authors studied four patients with progressive myoclonic epilepsy. All patients had giant SEP elicited by mixed and digital nerve stimulation. They studied the response to paired-pulse TMS at interstimulus intervals (ISI) ranging from 1 to 15 ms and the conditioning effect of digital electrical stimulation at ISI ranging from 10 to 100 ms on the motor evoked potential amplitude to TMS. RESULTS: Digital stimulation markedly facilitated conditioned motor evoked potentials at ISI ranging from 25 to 40 ms in all patients. This pattern was significantly different from the inhibition observed in controls (n = 12) at the same ISI. In the patients, paired-pulse TMS showed a decrease in intracortical inhibition in the motor cortex in comparison with controls. CONCLUSIONS: These findings suggest cortical and subcortical components of abnormal sensorimotor integration in addition to hyperexcitability of the sensory and motor cortex in our myoclonic patients.

Can J Psychiatry. 2001 Oct;46(8):720-7.
Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy.
Hasey G.
Regional Mood Disorders Program, Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
OBJECTIVE: To review repetitive transcranial magnetic stimulation (rTMS) as a mode of therapy for depression. METHOD: The following aspects of rTMS were reviewed and compared with electroconvulsive therapy (ECT): history, basic principles, technical considerations, possible mode of action, safety, adverse effects, and effects on mood in both healthy individuals and those suffering from bipolar disorder (BD) or depression. RESULTS: rTMS may selectively increase or decrease neuronal activity over discrete brain regions. As a result of this focused intervention with TMS, the potential for unwanted side effects is substantially reduced, compared with ECT. In open trials, rTMS and ECT are reported to be equally efficacious for patients having depression without psychosis, but the therapeutic benefits reported in double-blind sham-rTMS controlled trials are more modest. CONCLUSION: The antidepressant and antimanic effects of rTMS depend on technical considerations such as stimulus frequency, intensity, and magnetic coil placement, which may not yet be optimized. Biological heterogeneity among the patients treated with rTMS may also contribute to differing efficacy across clinical trials. rTMS may possess tremendous potential as a treatment for mood disorder, but this has not yet been realized. rTMS must still be regarded as an experimental intervention requiring further refinement.

Neurosci Lett. 2001 Sep 14;310(2-3):153-6.
Decreased susceptibility to pentylenetetrazol-induced seizures after low-frequency transcranial magnetic stimulation in rats.
Akamatsu N, Fueta Y, Endo Y, Matsunaga K, Uozumi T, Tsuji S.
Department of Neurology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. akamatn@med.uoeh-u.ac.jp
We studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure susceptibility in rats. rTMS of 1000 pulses at 0.5 Hz led to a prolonged latency for seizure development after an intraperitoneal injection of pentylenetetrazol. The rTMS effectively prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. These findings indicate that low-frequency rTMS affects the neural excitability, in the direction of anticonvulsive, and therefore, suggest the possibility of therapeutic use of rTMS in epilepsy.

Neurology. 2001 Aug 28;57(4):706-8.
Prolonged cortical silent period after transcranial magnetic stimulation in generalized epilepsy.
Macdonell RA, King MA, Newton MR, Curatolo JM, Reutens DC, Berkovic SF.
Department of Neurology, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia. rmac@austin.unimelb.edu.au
Transcranial magnetic stimulation (TMS) produces a cortical silent period (CSP) during a voluntary contraction. The duration of the CSP was used to assess the level of intracortical inhibition in patients with untreated idiopathic generalized epilepsy (IGE). Mean CSP duration was assessed at three TMS stimuli in 21 patients with IGE compared with 19 normal control subjects. Mean CSP duration was increased at all stimulus intensities, indicating that intracortical inhibition is increased in patients with IGE.

Epilepsia. 2000 Feb;41(2):240-2.
 
Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia.
Menkes DL, Gruenthal M.
Department of Neurology, University of Louisville School of Medicine, Kentucky 40292, USA.
PURPOSE: To evaluate the effect of slow-frequency repetitive transcranial magnetic stimulation (SF-rTMS) on interictal epileptiform activity and seizure frequency in a patient with medically refractory partial seizures due to focal cortical dysplasia. METHODS: A 9-cm circular coil was positioned over the area of cortical dysplasia. One hundred stimuli given at 0.5 Hz at 5% below motor threshold were given biweekly for four consecutive weeks. The EEG was recorded for 30 min before and after the first 100 stimuli. The number of seizures during the month of stimulation was compared with that of the month before stimulation. RESULTS: Stimulation was associated with a 70% reduction in the frequency of seizures and a 77% reduction in the frequency of interictal spikes. No seizures occurred during stimulation. CONCLUSIONS: SF-rTMS was safe and well tolerated in this patient. The reduction in seizures and interictal spikes associated with SF-rTMS supports the concept of SF-rTMS-induced cortical inhibition.

Neurosci Lett. 1999 Oct 8;273(3):155-8.
Altered seizure susceptibility after high-frequency transcranial magnetic stimulation in rats.
Ebert U, Ziemann U.
Institute of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany. uebert@pharma.tiho-hannover.de
The long-term effect of repetitive transcranial magnetic stimulation (rTMS) on the susceptibility of amygdala kindling was studied. Two weeks after a single high-frequency rTMS train (120 A/micros, 20 Hz for 3 s), the rats had a 55% higher threshold for induction of epileptic afterdischarges compared with sham-treated or control rats. However, subsequent kindling revealed no difference between rTMS-treated and control rats. Our data suggest that a single rTMS train has long-term effects on the neuronal excitability. These effects may be anticonvulsant and therefore support the safety of rTMS in clinical use.

Biol Psychiatry. 1999 Mar 15;45(6):759-63.
Chronic treatment with repetitive transcranial magnetic stimulation inhibits seizure induction by electroconvulsive shock in rats.
Fleischmann A, Hirschmann S, Dolberg OT, Dannon PN, Grunhaus L.
Psychiatry Division, Sheba Medical Center, Ramat Gan, Israel.
BACKGROUND: Studies in laboratory animals suggest that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) increase seizure inhibition acutely. This study was designed to explore whether chronic rTMS would also have seizure inhibition properties. METHODS: To this purpose we administered rTMS (Magstim Rapid) and sham rTMS twice daily (2.5 T, 4-sec train duration, 20 Hz) to two groups of 10 rats for 16 days. The rTMS coil was a 50-mm figure-8 coil held directly over the rat’s head. Raters were blind to experimental groups. On days 11, 17, and 21 (5 days after the last rTMS) ECS was administered with a Siemens convulsator using three electrical charge levels. Variables examined were the presence or absence of seizures and seizure length (measured from the initiation of the tonic contraction until the end of the limb movement). RESULTS: At day 11 rTMS had no effect on seizures, and both rTMS and sham rTMS animals convulsed equally. At day 17, however, rTMS-treated animals convulsed significantly less (both at presence/absence of seizures, and at seizure length) than sham rTMS animals. At day 21 the effects of rTMS had disappeared. CONCLUSIONS: These findings suggest that rTMS administered chronically leads to changes in seizure threshold similar to those reported for ECS and ECT; however, these effects were short-lived.

Neuropsychologia. 1999 Feb;37(2):159-67.
Transcranial magnetic stimulation can measure and modulate learning and memory.
Grafman J, Wassermann E.
Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1440, USA. jgr@box-j.nih.gov
The potential uses for Transcranial Magnetic Stimulation (TMS) in the study of learning and memory range from a method to map the topography and intensity of motor output maps during visuomotor learning to inducing reversible lesions that allow for the precise temporal and spatial dissection of the brain processes underlying learning and remembering. Single-pulse TMS appears to be adequate to examine motor output maps but repetitive TMS (rTMS) appears necessary to affect most cognitive processes in measurable ways. The results we have reviewed in this article indicate that rTMS may have a potential clinical application in patients with epilepsy in whom it is important to identify the lateralization of verbal memory. Single-pulse TMS can help identify changes in motor output maps during training, that may indicate improved or diminished learning and memory processes following a stroke or other neurological insult. Other evidence indicates that rTMS may even have the capability of facilitating various aspects of memory performance. From a research perspective. rTMS has demonstrated site- and time-specific effects primarily in interfering with explicit retrieval of episodic information from long-term memory. rTMS may also be able to modulate retrieval from semantic memory as evidenced by response-time and accuracy changes after rTMS. All these findings suggest that the use of transcranial magnetic stimulation in the study of learning and memory will increase in the future and that it is already a valuable tool in the cognitive neuroscientists’ belt.

Neuropsychobiology 1998 Oct;38(3):152-66.
A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.
Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A.
Biological Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892-1272, USA.
Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.

Epilepsy Res. 1998 Mar;30(1):11-30.
Transcranial magnetic stimulation: its current role in epilepsy research.
Ziemann U, Steinhoff BJ, Tergau F, Paulus W.
Department of Clinical Neurophysiology, University of Gottingen, Germany.
This paper reviews the current role of transcranial magnetic stimulation (TMS) in epilepsy research. After a brief introduction to the technical principles, the physiology and the safety aspects of TMS, emphasis is put on how human cortex excitability can be assessed by TMS and how this may improve our understanding of pathophysiological mechanisms in epilepsy and the mode of action of antiepileptic drugs (AEDs). Also, potential therapeutical applications of TMS are reviewed. For all aspects of this paper, a clear distinction was made between single-/paired-pulse TMS and repetitive TMS, since these two techniques have fundamentally different scopes and applications.

this concludes our epilepsy repetitive transcranial magnetic stimulation rTMS research bibliography

on rTMS research bibliography

[pb_builder]