Front Hum Neurosci. 2015 Jun 16;9:303. doi: 10.3389/fnhum.2015.00303. eCollection 2015. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation. Chervyakov AV1, Chernyavsky AY2, Sinitsyn DO3, Piradov MA1. Author information 1Research Center of Neurology , Moscow , Russia. 2Moscow Institute of Physics and Technology, Russian Academy of Sciences , Moscow , Russia ; Faculty of Computational Mathematics and Cybernetics, Moscow State University , Moscow , Russia. 3Research Center of Neurology , Moscow , Russia ; Semenov Institute of Chemical Physics, Russian Academy of Sciences , Moscow , Russia. Abstract Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson’s disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols. Brain.  2012 Oct 5. [Epub ahead of print] Magnetic flimmers: ‘light in the electromagnetic darkness’ Martens JW, Koehler PJ, Vijselaar J. Source 1 Department of Humanities, Utrecht University, Utrecht, The Netherlands. Abstract Transcranial magnetic stimulation has become an important field for both research in neuroscience and for therapy since Barker in 1985 showed that it was possible to stimulate the human motor cortex with an electromagnet. Today for instance, transcranial magnetic stimulation can be used to measure nerve conduction velocities and to create virtual lesions in the brain. The latter option creates the possibility to inactivate parts of the brain temporarily without permanent damage. In 2008, the American Food and Drugs Administration approved repetitive transcranial magnetic stimulation as a therapy for major depression under strict conditions. Repetitive transcranial magnetic stimulation has not yet been cleared for treatment of other diseases, including schizophrenia, anxiety disorders, obesity and Parkinson’s disease, but results seem promising. Transcranial magnetic stimulation, however, was not invented at the end of the 20th century. The discovery of electromagnetism, the enthusiasm for electricity and electrotherapy, and the interest in Beard’s concept of neurasthenia already resulted in the first electromagnetic treatments in the late 19th and early 20th century. In this article, we provide a history of electromagnetic stimulation circa 1900. From the data, we conclude that Mesmer’s late 18th century ideas of ‘animal magnetism’ and the 19th century absence of physiological proof had a negative influence on the acceptance of this therapy during the first decades of the 20th century. Electromagnetism disappeared from neurological textbooks in the early 20th century to recur at the end of that century. Stroke. 2005 Oct 27; [Epub ahead of print]

Repetitive Transcranial Magnetic Stimulation of Contralesional Primary Motor Cortex Improves Hand Function After Stroke.

Takeuchi N, Chuma T, Matsuo Y, Watanabe I, Ikoma K.

From the Department of Rehabilitation Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-0814, Japan.

BACKGROUND AND PURPOSE: A recent report has demonstrated that the contralesional primary motor cortex (M1) inhibited the ipsilesional M1 via an abnormal transcallosal inhibition (TCI) in stroke patients. We studied whether a decreased excitability of the contralesional M1 induced by 1 Hz repetitive transcranial magnetic stimulation (rTMS) caused an improved motor performance of the affected hand in stroke patients by releasing the TCI.

METHODS: We conducted a double-blind study of real versus sham rTMS in stroke patients. After patients had well- performed motor training to minimize the possibility of motor training during the motor measurement, they were randomly assigned to receive a subthreshold rTMS at the contralesional M1 (1 Hz, 25 minutes) or sham stimulation.

RESULTS: When compared with sham stimulation, rTMS reduced the amplitude of motor-evoked potentials in contralesional M1 and the TCI duration, and rTMS immediately induced an improvement in pinch acceleration of the affected hand, although a plateau in motor performance had been reached by the previous motor training. This improvement in motor function after rTMS was significantly correlated with a reduced TCI duration.

CONCLUSIONS: We have demonstrated that a disruption of the TCI by the contralesional M1 virtual lesion caused a paradoxical functional facilitation of the affected hand in stroke patients; this suggests a new neurorehabilitative strategy for stroke patients.

Schizophr Bull. 2005 Oct 27; [Epub ahead of print]

Therapeutic Effects of Individualized Alpha Frequency Transcranial Magnetic Stimulation ({alpha} TMS) on the Negative on the Negative Symptoms of Schizophrenia.

Jin Y, Potkin SG, Kemp AS, Huerta ST, Alva G, Thai TM, Carreon D, Bunney WE Jr.

Department of Psychiatry and Human Behavior, University of California, Irvine, School of Medicine.

Previous research in clinical electroencephalography (EEG) has demonstrated that reduction of alpha frequency (8-13 Hz) EEG activity may have particular relevance to the negative symptoms of schizophrenia. Repetitive Transcranial Magnetic Stimulation (rTMS) was utilized to investigate this relationship by assessing the therapeutic effects of stimulation set individually at each subject’s peak alpha frequency (alphaTMS). Twenty-seven subjects, with predominantly negative symptom schizophrenia, received 2 weeks of daily treatment with either alphaTMS, 3 Hz, 20 Hz, or sham stimulation bilaterally over the dorsolateral prefrontal cortex. Individualized alphaTMS demonstrated a significantly larger (F 3,33 = 4.7, p = .007) therapeutic effect (29.6% reduction in negative symptoms) than the other 3 conditions (< 9%). Furthermore, these clinical improvements were found to be highly correlated (r = 0.86, p = .001) with increases (34%) in frontal alpha amplitude following alphaTMS. These results affirm that the resonant features of alpha frequency EEG play an important role in the pathophysiology of schizophrenia and merit further investigation as a particularly efficacious frequency for rTMS treatments.

Neuroreport. 2005 Nov 7;16(16):1839-42.

Effects of repetitive transcranial magnetic stimulation in depression: a magnetoencephalographic study.

Maihofner C, Ropohl A, Reulbach U, Hiller M, Elstner S, Kornhuber J, Sperling W.

Departments of aNeurology bPsychiatry and Psychotherapy cInstitute for Experimental Physiology and Pathophysiology, University of Erlangen – Nuremberg, Erlangen, Germany.

Recently, repetitive transcranial magnetic stimulation has evolved as a potential therapeutic tool to interfere with brain changes associated with neurological and psychiatric diseases. Little is known about its mode of action, however. Here, we investigated effects of repetitive transcranial magnetic stimulation on spontaneous magnetoencephalographic activity in patients with major depression. Before treatment, depressed patients showed a significant increase in slow magnetoencephalographic activity (2-6 Hz) over the left prefrontal cortex, compared with healthy controls. This activity significantly decreased during 10 days of repetitive transcranial magnetic stimulation, paralleled by clinical improvement. We conclude that therapeutic repetitive transcranial magnetic stimulation effects can be mirrored by changes of spontaneous magnetoencephalographic activity.

Psychiatry Res. 2005 Nov 15;137(1-2):1-10. Epub 2005 Oct 12.

Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial.

Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E.

Department of Psychiatry, School of Medicine, Vita-Salute University, San Raffaele Hospital, via Stamira d’Ancona 20, Milan 20127, Italy.

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Neuroreport. 2005 Nov 7;16(16):1849-1852.

Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex affects strategic decision-making.

Wout MV, Kahn RS, Sanfey AG, Aleman A.

aDepartment of Psychonomics, Helmholtz Research Institute, University of Utrecht bDepartment of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht cBCN NeuroImaging Center, Groningen, The Netherlands dDepartment of Psychology, University of Arizona, Tucson, Arizona, USA.

Although decision-making is typically seen as a rational process, emotions play a role in tasks that include unfairness. Recently, activation in the right dorsolateral prefrontal cortex during offers experienced as unfair in the Ultimatum Game was suggested to subserve goal maintenance in this task. This is restricted to correlational evidence, however, and it remains unclear whether the dorsolateral prefrontal cortex is crucial for strategic decision-making. The present study used repetitive transcranial magnetic stimulation in order to investigate the causal role of the dorsolateral prefrontal cortex in strategic decision-making in the Ultimatum Game. The results showed that repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex resulted in an altered decision-making strategy compared with sham stimulation. We conclude that the dorsolateral prefrontal cortex is causally implicated in strategic decision-making in healthy human study participants.

Psychiatry Res. 2005 Nov 15;137(1-2):113-21. Epub 2005 Oct 11.

Chronic repetitive transcranial magnetic stimulation is antidepressant but not anxiolytic in rat models of anxiety and depression.

Hargreaves GA, McGregor IS, Sachdev PS.

School of Psychiatry, University of New South Wales, Sydney, 2052, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031, Australia.

Transcranial magnetic stimulation (TMS) has been proposed as a treatment for depression and anxiety disorders. While the antidepressant effect has been modelled in animals, there have been few attempts to examine a possible anxiolytic effect of repetitive TMS (rTMS) in animal models. We administered 18 days of rTMS to male Sprague-Dawley rats. On days 10 through 18, rats were tested in several anxiety models (social interaction, emergence, elevated plus-maze, and predator odor avoidance) and in the forced swim test. No group differences were apparent on any of the anxiety models, while TMS produced an antidepressant effect in the forced swim test. Interestingly, on day 1 of the forced swim test, the home cage control group displayed increased swimming behaviour compared with sham-treated animals, suggesting an observable level of stress may have accompanied sham treatment. The results from the forced swim test suggested that TMS had modest antidepressant properties, but it did not show anxiolytic properties in the models examined. The study also suggested that stress associated with handling should be taken into account in the interpretation of TMS studies in animals.

PLoS Biol. 2005 Oct 18;3(11):e362 [Epub ahead of print]

Improvement of Tactile Discrimination Performance and Enlargement of Cortical Somatosensory Maps after 5 Hz rTMS.

Tegenthoff M, Ragert P, Pleger B, Schwenkreis P, Forster AF, Nicolas V, Dinse HR.

Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Bochum, Germany.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to investigate mechanisms of brain functions and plasticity, but also as a promising new therapeutic tool. The effects of rTMS depend on the intensity and frequency of stimulation and consist of changes of cortical excitability, which often persists several minutes after termination of rTMS. While these findings imply that cortical processing can be altered by applying current pulses from outside the brain, little is known about how rTMS persistently affects learning and perception. Here we demonstrate in humans, through a combination of psychophysical assessment of two-point discrimination thresholds and functional magnetic resonance imaging (fMRI), that brief periods of 5 Hz rTMS evoke lasting perceptual and cortical changes. rTMS was applied over the cortical representation of the right index finger of primary somatosensory cortex, resulting in a lowering of discrimination thresholds of the right index finger. fMRI revealed an enlargement of the right index finger representation in primary somatosensory cortex that was linearly correlated with the individual rTMS-induced perceptual improvement indicative of a close link between cortical and perceptual changes. The results demonstrate that repetitive, unattended stimulation from outside the brain, combined with a lack of behavioral information, are effective in driving persistent improvement of the perception of touch. The underlying properties and processes that allow cortical networks, after being modified through TMS pulses, to reach new organized stable states that mediate better performance remain to be clarified.

Exp Neurol. 2005 Sep 26; [Epub ahead of print]

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex excitability in patients with major depressive disorder.

Bajbouj M, Brakemeier EL, Schubert F, Lang UE, Neu P, Schindowski C, Danker-Hopfe H.

Department of Psychiatry, Charite-University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.

Prog Brain Res. 2005;150:527-35.

Neural plasticity and recovery of function.

Ward NS.

Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College London, 12 Queen Square, London WC1N 3BG, UK.

Recovery of the function after stroke is a consequence of many factors including resolution of oedema and survival of the ischaemic penumbra. In addition there is a growing interest in the role of central nervous system (CNS) reorganization. Much of the evidence supporting this comes from animal models of focal brain injury, but non-invasive techniques such as functional magnetic resonance imaging, transcranial magnetic stimulation, electroencephalography and magnetoencephalography now allow the study of the working human brain. Using these techniques it is apparent that the motor system of the brain adapts to damage in a way that attempts to preserve motor function. This has been demonstrated after stroke, as part of the ageing process, and even after disruption of normal motor cortex with repetitive transcranial magnetic stimulation. The result of this reorganization is a new functional architecture, one which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and lastly the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new functional architecture. Thus it is crucial that the study of novel therapeutic strategies for treating motor impairment after stroke take account of this. This review maps out the attempts to describe functionally relevant adaptive changes in the human brain following focal damage. A greater understanding of how these changes are related to the recovery process will allow not only the development of novel therapeutic techniques that are based on neurobiological principles and designed to minimize impairment in patients suffering from stroke, but also to target these therapies at the appropriate patients.

Prog Neuropsychopharmacol Biol Psychiatry. 2005 Oct 19; [Epub ahead of print]

A double-blind sham controlled study of right prefrontal repetitive transcranial magnetic stimulation (rTMS): Therapeutic and cognitive effect in medication free unipolar depression during 4 weeks.

Januel D, Dumortier G, Verdon CM, Stamatiadis L, Saba G, Cabaret W, Benadhira R, Rocamora JF, Braha S, Kalalou K, Vicaut PE, Fermanian J.

Unite de recherche clinique, EPS de Ville Evrard a Saint Denis, G03, 5 Rue du Dr Delafontaine 93200 Saint-Denis, France.

BACKGROUND: Transcranial magnetic stimulation (TMS) has become a therapeutic tool in psychiatric diseases.

METHODOLOGY: The objective was to evaluate the efficacy of TMS in unipolar depression: the percentage of responders (>50% HDRS reduction) and remission (HDRS score </=8, after four weeks of active TMS treatment in depressed patients free of any antidepressive agent versus placebo-TMS.

RESULTS: 27 patients were randomized in two groups: rTMS (N=11) versus sham TMS (N=16). Statistical differences were detected between sham and TMS treated groups on remission (0/16 versus 4/11 p=0.032, 1/16 versus 6/11 0.028 and 1/16 versus 7/11 p=0.011 at day 14, day 21 and day 28, respectively) and on response (2/16 versus 5/11 at day 14 (NS), 2/16 versus 7/11 p=0.0115 at day 21 and 1/16 versus 7/11 (p=0.025) day 28, respectively, using the exact Fisher test). Significant differences were observed between day 1 versus day 8 (p<0.01), day 15, day 21 and day 28 (p<0.001) in TMS group and only versus day 21 (p<0.01) and day 28 (p<0.05) for the sham group. ANOVA comparison between TMS and sham groups was significant at day 14 and day 28 (p<0.05).

LIMITATIONS: The few number of patients.

CONCLUSION: Our study has shown an efficacy of right rTMS in free medication unipolar depression over a month. Nevertheless, number of patients included is limited and multicentric studies will be necessary to specify the antidepressive action of TMS.

Ann Neurol. 2005 Oct 20; [Epub ahead of print]

Altered plasticity of the human motor cortex in Parkinson’s disease.

Ueki Y, Mima T, Ali Kotb M, Sawada H, Saiki H, Ikeda A, Begum T, Reza F, Nagamine T, Fukuyama H.

Human Brain Research Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Interventional paired associative stimulation (IPAS) to the contralateral peripheral nerve and cerebral cortex can enhance the primary motor cortex (M1) excitability with two synchronously arriving inputs. This study investigated whether dopamine contributed to the associative long-term potentiation-like effect in the M1 in Parkinson’s disease (PD) patients. Eighteen right-handed PD patients and 11 right-handed age-matched healthy volunteers were studied. All patients were studied after 12 hours off medication with levodopa replacement (PD-off). Ten patients were also evaluated after medication (PD-on). The IPAS comprised a single electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 milliseconds (240 paired stimuli every 5 seconds for 20 minutes). The motor-evoked potential amplitude in the right abductor pollicis brevis muscle was increased by IPAS in healthy volunteers, but not in PD patients. IPAS did not affect the motor-evoked potential amplitude in the left abductor pollicis brevis. The ratio of the motor-evoked potential amplitude before and after IPAS in PD-off patients increased after dopamine replacement. Thus, dopamine might modulate cortical plasticity in the human M1, which could be related to higher order motor control, including motor learning. Ann Neurol 2006.

HNO. 2005 Sep 17; [Epub ahead of print]

Treatment of chronic tinnitus with neuronavigated repetitive Transcranial Magnetic Stimulation (rTMS).

[Article in German]

Kleinjung T, Steffens T, Langguth B, Eichhammer P, Marienhagen J, Hajak G, Strutz J.

Klinik fur HNO-Heilkunde der Universitat Regensburg, .

BACKGROUND AND OBJECTIVE: Idiopathic tinnitus is a frequent and debilitating disorder of largely unknown pathophysiology. Focal brain activation in the auditory cortex has recently been demonstrated in chronic tinnitus. Low-frequency rTMS can reduce cortical hyperexcitability.

PATIENTS AND METHODS: In 12 patients with chronic tinnitus, fusion of [(18)F]deoxyglucose-PET and structural MRI (T1, MPRAGE) scans allowed the area of increased metabolic activity in the auditory cortex to be exactly identified; this area was selected as the target for rTMS. A neuronavigational system adapted for TMS positioning enabled the relative positions of the figure-8 coil and the target area to be monitored. Repetitive TMS (110% motor threshold; 1 Hz; 2000 stimuli per day over 5 days) was performed using a placebo-controlled crossover design. A sham coil system was used for the placebo stimulation. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller).

RESULTS: In all 12 patients an asymmetrically increased metabolic activation of the gyrus of Heschl was detected. The tinnitus score was significantly improved after 5 days of active rTMS, an effect not seen after placebo stimulation.

CONCLUSION: These preliminary results show that neuronavigated rTMS may improve our understanding and treatment of chronic tinnitus.

Clin Neurophysiol. 2005 Oct 24; [Epub ahead of print]

Transcranial magnetic and electrical stimulation compared: Does TES activate intracortical neuronal circuits?

Brocke J, Irlbacher K, Hauptmann B, Voss M, Brandt SA.

Department of Neurology, Berlin NeuroImaging Center, Charite, 10117 Berlin, Germany.

OBJECTIVE: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings.

METHODS: Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse).

RESULTS: TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3ms) and facilitation at longer ISIs (maximum: 10ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5ms).

CONCLUSIONS: Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. SIGNIFICANCE: TES is a suitable tool to induce intracortical inhibition and excitation.

Neurosci Behav Physiol. 2005 Mar;35(3):313-7.

The effects of L-DOPA and transcranial magnetic stimulation on behavioral reactions in kindled rats.

Godlevskii LS, Kobolev EV.

Odessa State Medical University, 2 Valikhovskii Lane, 65026 Odessa, Ukraine.

Acute experiments were performed on rats to produce a model of chronic epileptic activity–pharmacological kindling by repeated doses of picrotoxin (1.0-1.2 mg/kg, i.p.). During the early period following kindling (24 h from the last dose of epileptogen), animals showed decreases in measures of investigative behavior as measured in an open field test, along with reductions in sexual and feeding behavior. The severity of these impairments had decreased by two weeks from the last picrotoxin dose. Both treatment with L-DOPA (100 mg/kg, i.p.) and transcranial magnetic stimulation (20 impulses with induction, peak 1.5 T) were accompanied by increases in measures of investigative, sexual, and feeding behavior in the animals, suggesting that mechanism of action of transcranial magnetic stimulation in relation to kindling-induced behavioral abnormalities is mediated by activation of the dopaminergic system of the brain.

Eur J Neurosci. 2005 Nov;22(9):2392-6.

High-frequency repetitive transcranial magnetic stimulation over the hand area of the primary motor cortex disturbs predictive grip force scaling.

Nowak DA, Voss M, Huang YZ, Wolpert DM, Rothwell JC.

Sobell Department of Motor Neuroscience and Movements Disorders, Institute of Neurology, University College London, London, UK.

When we repetitively lift an object, our grip force is influenced by the mechanical object properties of the preceding lift, irrespective of whether the subsequent lift is performed with the same hand or the hand opposite to the preceding lift. This study investigates if repetitive high-frequency transcranial magnetic stimulation (rTMS) over the dominant primary motor cortex affects this relationship. After completion of 10 lifts of an object using the dominant hand, rTMS was applied over the dominant primary motor cortex for 20 s. On the first lift following rTMS, the peak grip force was significantly higher than on the lift preceding rTMS. Moreover, this measure remained elevated throughout the following set of lifts after rTMS. rTMS did not change the peak lift force generated by more proximal arm muscles. The same effect was observed when the lifts following rTMS over the dominant motor cortex were performed with the ipsilateral hand. These effects were not observed when subjects rested both hands on their lap or when a sham stimulation was applied for the same period of time. These preliminary data suggest that rTMS over the sensorimotor cortex disturbs predictive grip force planning.

J Psychiatr Res. 2005 Oct 28; [Epub ahead of print]

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: Preliminary results of a dynamic [(123)I] IBZM SPECT study.

Pogarell O, Koch W, Popperl G, Tatsch K, Jakob F, Zwanzger P, Mulert C, Rupprecht R, Moller HJ, Hegerl U, Padberg F.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany.

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [(123)I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [(123)I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D(2) receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6+/-6.2% in IBZM binding to striatal dopamine D(2) receptors after rTMS challenge compared to baseline (p=0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.

Vision Res. 2005 Oct 26; [Epub ahead of print]

Processing of global form and motion in migraineurs.

Ditchfield JA, McKendrick AM, Badcock DR.

School of Psychology, University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.

Previous studies have identified anomalies of cortical visual processing in migraineurs that appear to extend beyond V1. Migraineurs respond differently than controls to transcranial magnetic stimulation of V5, and can demonstrate impairments of global motion processing. This study was designed to assess the integrity of intermediate stages of both motion and form processing in people with migraine. We measured the ability to integrate local orientation information into a global form percept, and to integrate local motion information into a global motion percept. Control subjects performed significantly better than migraineurs on both tasks, suggesting a diffuse visual cortical processing anomaly in migraine.

J Clin Neurosci. 2005 Oct 25; [Epub ahead of print]

The use of transcranial magnetic stimulation in the clinical evaluation of suspected myelopathy.

Chan YC, Mills KR.

Department of Clinical Neurophysiology, King’s College Hospital, London SE5 9RS.

Central motor conduction time (CMCT) and motor evoked potential (MEP) latencies measured by using transcranial magnetic stimulation (TMS) are parameters used to evaluate electrophysiologic function of the corticospinal motor tract. We present 5 cases to illustrate how the use of TMS had contributed to clinical management. CMCT and MEP latency measurements were found to be useful in determining the significance of lesions seen on neuroimaging and helped clinical decisions in the presence of multiple lesions or multiple clinical conditions that cause similar clinical manifestations. TMS study is particularly useful in localizing levels of conduction defect.

Exp Brain Res. 2005 May;163(1):21-31. Epub 2005 Feb 3.

Silent period to transcranial magnetic

Kimiskidis VK, Papagiannopoulos S, Sotirakoglou K, Kazis DA, Kazis A, Mills KR.

Department of Neurology III, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, 57010 Thessaloniki, Greece. kimiskid@med.auth.gr

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus-response (S-R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900-1800 mg). The S-R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947-0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8+/-3.31 ms (x+/-SEM), -11.51+/-3.31 ms, 11.56+/-0.65%, and 49.82+/-0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69+/-0.72 vs 47.95+/-0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3+/-5.8% at baseline to 59.4+/-10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6+/-42.4 ms to 143.5+/-46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5+/-4.9% to 59.9+/-7.2% and from 29.1+/-6.4% to 34.6+/-6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S-R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Invest Radiol. 1998 Jun;33(6):336-40.

Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation.

Bohning DE, Shastri A, Nahas Z, Lorberbaum JP, Andersen SW, Dannels WR, Haxthausen EU, Vincent DJ, George MS.

Department of Radiology, Medical University of South Carolina, Charleston 29425, USA. bohninde@musc.edu

RATIONALE AND OBJECTIVES: The authors demonstrate the feasibility of combining transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) inside an MR scanner to noninvasively stimulate and image regional brain activity.

METHODS: Echoplanar blood oxygen level dependent (BOLD)-based fMRI studies of TMS response were performed on three human volunteers inside a standard 1.5 T MR scanner using independent computer control to interleave echoplanar image acquisition and stimulation of right thumb primary motor cortex with a nonferromagnetic TMS coil.

RESULTS: Significant (P< 0.001) response was observed in motor cortex under the TMS coil during stimulation compared to rest, as well in auditory cortex, the latter presumably due to the loud “snap” when the coil was pulsed.

CONCLUSIONS: Concurrent TMS stimulation and echoplanar BOLD fMRI imaging is possible. This method has potential for tracing neural circuits with brain imaging, as well as investigating the effects of TMS.

Int J Neurosci. 1998 May;94(1-2):41-54.

Transcranial AC pulsed applications of weak electromagnetic fields reduces freezing and falling in progressive supranuclear palsy: a case report.

Sandyk R.

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

Freezing is a common and disabling symptom in patients with Parkinsonism. It affects most commonly the gait in the form of start hesitation and sudden immobility often resulting in falling. A higher incidence of freezing occurs in patients with progressive supranuclear palsy (PSP) which is characterized clinically by a constellation of symptoms including supranuclear ophthalmoplegia, postural instability, axial rigidity, dysarthria, Parkinsonism, and pseudobulbar palsy. Pharmacologic therapy of PSP is currently disappointing and the disease progresses relentlessly to a fatal outcome within the first decade after onset. This report concerns a 67 year old woman with a diagnosis of PSP in whom freezing and frequent falling were the most disabling symptoms of the disease at the time of presentation. Both symptoms, which were rated 4 on the Unified Parkinson Rating Scale (UPRS) which grades Parkinsonian symptoms and signs from 0 to 4, with 0 being normal and 4 being severe symptoms, were resistant to treatment with dopaminergic drugs such as levodopa, amantadine, selegiline and pergolide mesylate as well as with the potent and highly selective noradrenergic reuptake inhibitor nortriptyline. Weekly transcranial applications of AC pulsed electromagnetic fields (EMFs) of picotesla flux density was associated with approximately 50% reduction in the frequency of freezing and about 80-90% reduction in frequency of falling after a 6 months follow-up period. At this point freezing was rated 2 while falling received a score of 1 on the UPRS. In addition, this treatment was associated with an improvement in Parkinsonian and pseudobulbar symptoms with the difference between the pre-and post EMF treatment across 13 measures being highly significant (p < .005; Sign test). These results suggest that transcranial administration AC pulsed EMFs in the picotesla flux density is efficacious in the treatment of PSP.

Int J Neurosci. 1997 Nov;92(1-2):63-72.

Speech impairment in Parkinson’s disease is improved by transcranial application of electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 52 year old fully medicated physician with juvenile onset Parkinsonism experienced 4 years ago severe “on-off” fluctuations in motor disability and debilitating speech impairment with severe stuttering which occurred predominantly during “on-off” periods. His speech impairment improved 20%-30% when sertraline (75 mg/day), a serotonin reuptake inhibitor, was added to his dopaminergic medications which included levodopa, amantadine, selegiline and pergolide mesylate. A more dramatic and consistent improvement in his speech occurred over the past 4 years during which time the patient received, on a fairly regular basis, weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Recurrence of speech impairment was observed on several occasions when regular treatments with EMFs were temporarily discontinued. These findings demonstrate that AC pulsed applications of picotesla flux density EMFs may offer a nonpharmacologic approach to the management of speech disturbances in Parkinsonism. Furthermore, this case implicates cerebral serotonergic deficiency in the pathogenesis of Parkinsonian speech impairment which affects more than 50% of patients. It is believed that pulsed applications of EMFs improved this patient’s speech impairment through the facilitation of serotonergic transmission which may have occurred in part through a synergistic interaction with sertraline.

Int J Neurosci. 1997 Sep;91(1-2):57-68.

Reversal of cognitive in an elderly parkinsonian patient by transcranial application of picotesla electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 74 year old retired building inspector with a 15 year history of Parkinson’s disease (PD) presented with severe resting tremor in the right hand, generalized bradykinesia, difficulties with the initiation of gait with freezing, mental depression and generalized cognitive impairment despite being fully medicated. Testing of constructional abilities employing various drawing tasks demonstrated drawing impairment compatible with severe left hemispheric dysfunction. After receiving two successive transcranial applications, each of 20 minutes duration, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density and frequencies of 5Hz and 7Hz respectively, his tremor remitted and there was dramatic improvement in his drawing performance. Additional striking improvements in his drawing performance occurred over the following two days after he continued to receive daily treatments with EMFs. The patient’s drawings were subjected to a Reliability Test in which 10 raters reported 100% correct assessment of pre- and post drawings with all possible comparisons (mean 2 = 5.0; p < .05). This case demonstrates in PD rapid reversal of drawing impairment related to left hemispheric dysfunction by brief transcranial applications of AC pulsed picotesla flux density EMFs and suggests that cognitive deficits associated with Parkinsonism, which usually are progressive and unaffected by dopamine replacement therapy, may be partly reversed by administration of these EMFs. Treatment with picotesla EMFs reflects a “cutting edge” approach to the management of cognitive impairment in Parkinsonism.