Shingo Okabe

0.2‐Hz repetitive transcranial magnetic stimulation has no add‐on effects as compared to a realistic sham stimulation in Parkinson's disease

To study the efficacy of 0.2‐Hz repetitive transcranial magnetic stimulation (rTMS) on Parkinsons disease (PD), 85 patients with PD were enrolled into three groups: 1) motor cortical, 2) occipital, and 3) sham stimulation. A round coil was centered over the vertex in motor cortical stimulation, and over the inion in occipital stimulation. In one session, 100 stimuli of 0.2‐Hz rTMS at an intensity of 1.1 times active motor threshold (AMT) were given. In sham stimulation, electric currents were given with electrodes fixed on the head to mimic the sensation in real stimulation. Each session was carried out once a week for the first 8 weeks. The Unified Parkinson Disease Rating Scale (UPDRS), Hamilton Rating Scale for Depression (HRSD) and subjective score (visual analogue scale) were assessed. There were no significant differences in clinical features among the three groups. Total and motor score of UPDRS were improved to the same extent by rTMS over Cz, inion, and sham stimulation. HRSD was improved by rTMS over Cz and sham stimulation in the same manner. Subjective score was not significantly improved by any methods of stimulation. 0.2‐Hz rTMS at an intensity of 1.1 × AMT has only a placebo effect on PD. Our realistic sham stimulation maneuver must produce powerful placebo effects as a real stimulation.

Effects of 1-Hz repetitive transcranial magnetic stimulation on acute pain induced by capsaicin.

&NA; The aim of this study is to investigate the efficacy of 1‐Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on acute pain induced by intradermal capsaicin injection and to elucidate its mechanisms by single‐photon emission computed tomography (SPECT). We compared time courses of a subjective scale of pain induced by intradermal capsaicin injection in seven normal subjects under three different conditions: rTMS over M1, sham stimulation, and control condition (natural course of acute pain without any stimulation). In ten normal subjects, using SPECT, we also studied differences in regional cerebral blood flow (rCBF) after capsaicin injection between two conditions: rTMS over M1 and the control condition. rTMS over M1 induced earlier recovery from acute pain compared with the sham or control conditions. Under rTMS over the right M1 condition compared with the control condition, the SPECT study demonstrated a significant relative rCBF decrease in the right medial prefrontal cortex (MPFC) corresponding to Brodmann area (BA) 9, and a significant increase in the caudal part of the right anterior cingulate cortex (ACC) corresponding to BA24 and the left premotor area (BA6). A region‐of‐interest analysis showed significant correlation between pain reduction and rCBF changes in both BA9 and BA24. We conclude that rTMS over M1 should have beneficial effects on acute pain, and its effects must be caused by functional changes of MPFC and caudal ACC.

Comparison between short train, monophasic and biphasic repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex.

OBJECTIVE To compare motor evoked potentials (MEPs) elicited by short train, monophasic, repetitive transcranial magnetic stimulations (rTMS) with those by short train, biphasic rTMS. METHODS Subjects were 13 healthy volunteers. Surface electromyographic (EMG) responses were recorded from the right first dorsal interosseous muscle (FDI) in several different stimulation conditions. We gave both monophasic and biphasic rTMS over the motor cortex at a frequency of 0.5, 1, 2 or 3Hz. To study excitability changes of the spinal cord, we also performed 3Hz rTMS at the foramen magnum level [Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation of corticospinal pathways at the foramen magnum level in humans. Ann Neurol 1994;36:618-24]. We measured the size and latency of each of 20 MEPs recorded in the different stimulation conditions. RESULTS 2 or 3Hz stimulation with either monophasic or biphasic pulses evoked MEPs that gradually increased in amplitude with the later MEPs being significantly larger than the earlier ones. Monophasic rTMS showed much more facilitation than biphasic stimulation, particularly at 3Hz. Stimulation at the foramen magnum level at 3Hz elicited fairly constant MEPs. CONCLUSIONS The enhancement of cortical MEPs with no changes of responses to foramen magnum level stimulation suggests that the facilitation occurred at the motor cortex. We hypothesize that monophasic TMS has a stronger short-term effect during repetitive stimulation than biphasic TMS because monophasic pulses preferentially activate one population of neurons oriented in the same direction so that their effects readily summate. Biphasic pulses in contrast may activate several different populations of neurons (both facilitatory and inhibitory) so that summation of the effects is not so clear as with monophasic pulses. When single stimuli are applied, however, biphasic TMS is thought to be more powerful than monophasic TMS because the peak-to-peak amplitude of stimulus pulse is higher and its duration is longer when the same intensity of stimulation (the same amount of current is stored by the stimulator) is used. SIGNIFICANCE This means that when using rTMS as a therapeutic tool or in research fields, the difference in waveforms of magnetic pulses (monophasic or biphasic) may affect the results.

Evaluation of corticospinal tracts in ALS with diffusion tensor MRI and brainstem stimulation.

Objective: To assess corticospinal tract involvement in patients with amyotrophic lateral sclerosis (ALS) by correlating diffusion tensor imaging (DTI) measures with intra- and extracranial central motor conduction time (CMCT) and clinical features of the patients. Methods: We investigated 31 patients with ALS and 31 normal volunteers by DTI and measured fractional anisotropy (FA) within the corticospinal tracts and in the extramotor white matter. We measured CMCT for the first dorsal interosseous muscle and segmented it into cortical-brainstem (CTX-BS CT) and brainstem-cervical root (BS-CV CT) conduction times by magnetic brainstem stimulation at the foramen magnum level. Clinical status of each patient was evaluated with the ALS Functional Rating Scale–Revised (ALSFRS-R) and upper motor neuron (UMN) score devised for this study. Results: We found a significant decrease of mean FA in all regions of the corticospinal tracts in patients with ALS as compared with controls. We found that FA along the corticospinal tract decreased significantly with higher UMN scores. There was no significant correlation between FA and ALSFRS-R, to which both upper and lower motoneuron involvements contribute. FA showed a significant correlation with the intracranial part of the central motor conduction (CTX-BS CT) but not with the extracranial conduction time. Conclusions: Fractional anisotropy reflects functional abnormality of intracranial corticospinal tracts and can be used for objective evaluation of upper motor neuron impairment in amyotrophic lateral sclerosis. GLOSSARY: ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale–Revised; BS-CV CT = brainstem-cervical root conduction time; CMCT = central motor conduction time; CTX-BS CT = cortical-brainstem conduction time; FA = fractional anisotropy; FDI = first dorsal interosseous; LMN = lower motor neuron; ROI = region of interest; UMN = upper motor neuron.

Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinsons disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. METHODS We used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. RESULTS rTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. CONCLUSIONS Our results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.

Primary motor cortical metaplasticity induced by priming over the supplementary motor area

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS‐induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor‐related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico‐cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS‐induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor‐evoked potential sizes on its own but specifically modulated the excitatory I‐wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.

Differences in after-effect between monophasic and biphasic high-frequency rTMS of the human motor cortex

OBJECTIVE To study differences in the long-term after-effect between high-frequency, monophasic and biphasic repetitive transcranial magnetic stimulation (rTMS). METHODS Ten hertz rTMS was delivered over the left primary motor cortex and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle. To probe motor cortex excitability we recorded MEPs at several timings before, during and after several types of conditioning rTMSs. We also recorded F-waves to probe spinal excitability changes. Thousand pulses were given in total, with a train of 10 Hz, 100 pulses delivered every minute (ten trains for 10min). The intensity was fixed at 90% active motor threshold (AMT) or 90% resting motor threshold (RMT) for both monophasic and biphasic rTMS. In addition, we performed a monophasic rTMS experiment using a fixed intensity of 90% RMT for biphasic pulses. RESULTS At 90% AMT, MEPs were enhanced for a few minutes after both monophasic and biphasic rTMS. On the other hand, at 90% RMT, a larger and longer enhancement of MEPs was evoked after monophasic rTMS than after biphasic rTMS. Monophasic rTMS at an intensity adjusted to biphasic 90% RMT elicited a great enhancement similar to that after monophasic rTMS at monophasic 90% RMT. Neither F-wave amplitude nor its occurrence rate was significantly altered by 90% RMT monophasic rTMS. CONCLUSIONS These results suggest that enhancement after rTMS occurs at the motor cortex. Monophasic rTMS has a stronger after-effect on motor cortical excitability than biphasic rTMS. This is probably because monophasic pulses preferentially activate a relatively uniform population of neurons oriented in the same direction and their effects summate more readily than biphasic rTMS activating differently oriented neurons at slight different timings altogether. SIGNIFICANCE The present results suggest that when using rTMS as a therapeutic tool or in research fields, the waveforms of magnetic pulses may affect the results profoundly.

Thirty minutes mobile phone use has no short-term adverse effects on central auditory pathways

OBJECTIVE To investigate whether pulsed high-frequency electromagnetic field (pulsed EM field) emitted by a mobile phone for 30 min has short-term adverse effects on the human central auditory system. METHODS We studied the auditory brainstem response (ABR), the ABR recovery function and middle latency response (MLR) before and after using a mobile phone for 30 min in 15 normal hearing volunteers. RESULTS None of the 3 measures were affected by exposure to pulsed EM field emitted by a mobile phone for 30 min. CONCLUSIONS Based on the ABR and MLR methods utilized in the study, we conclude that 30 min mobile phone use has no short-term adverse effects on the human auditory system.

Functional connectivity revealed by single-photon emission computed tomography (SPECT) during repetitive transcranial magnetic stimulation (rTMS) of the motor cortex

OBJECTIVE In the present study, we studied effects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the left primary motor cortex (M1) on regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT). METHODS SPECT measurements were carried out under two experimental conditions: real and sham stimulation. In sham stimulation, to exclude other components besides currents in the brain in rTMS, we applied sound and electrical stimulation to the skin of the head. 99mTc-ethyl cysteinate dimer was injected during the real or sham stimulation. Images were analyzed with the statistical parametric mapping software (SPM99). Relative differences in adjusted rCBF between two conditions were determined by a voxel-by-voxel paired t test. RESULTS 1 Hz rTMS at an intensity of 1.1 x active motor threshold evoked increase of rCBF in the contralateral (right) cerebellar hemisphere. Reduction of rCBF was observed in the contralateral M1, superior parietal lobule (most probably corresponding to PE area in the monkey) (Rizzolatti G, Luppino G, Matelli M. Electroenceph clin Neurophysiol 1998;106:283-296), inferior parietal lobule (PF area in the monkey (Rizzolatti et al., 1998)), dorsal and ventral premotor areas (dPM, vPM) and supplementary motor area (SMA). CONCLUSIONS Increase of rCBF in the contralateral cerebellum must reflect facilitatory connection between the motor cortex and contralateral cerebellum. Reduced rCBF in the contralateral M1 may be produced by transcallosal inhibitory effect of the left motor cortical activation. CBF decrease in the right PM, SMA and parietal cortex may reflect some secondary effects. Low frequency rTMS at an intensity of around threshold for active muscles can evoke rCBF changes. SIGNIFICANCE We demonstrated that rCBF changes could be elicited even by low frequency rTMS at such a low intensity as the threshold for an active muscle. Combination of rTMS and SPECT is one of powerful tools to study interareal connection within the human brain.

Long-term effect of motor cortical repetitive transcranial magnetic stimulation induces

Repetitive transcranial magnetic stimulation (rTMS) recently has been assessed as a noninvasive treatment modality for movement and psychiatric disorders, whereas the mechanism underlying the therapeutic effects is not fully understood. Studies in rodents showed lasting functional changes in some selected regions, such as limbic‐associated structures, but unfocused brain stimulation did not clarify the regional effects. To address the topographical and temporal profiles of the effects on glucose metabolism in primate brain, we performed rTMS and repeated 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) before, during, and up to 16 days after rTMS in anesthetized cynomologous monkeys. We delivered a total of 2,000 pulses of 5Hz‐rTMS over the right precentral gyrus using a small‐sized eight‐figured coil that induced a localized electrical field. Voxel‐based analysis in a standard space of the macaque brain showed statistically robust changes in FDG uptake: a decrease in the motor/premotor cortices and an increase in the limbic‐associated areas involving the anterior/posterior cingulate, and orbitofrontal cortices. Interestingly, these uptake changes continued for at least 8 days and the magnitude of the lasting effects in the limbic‐related areas was negatively correlated across subjects with those in the motor/premotor cortices. The results demonstrate that motor rTMS has a long‐term lasting effect on motor‐related regions and distant limbic‐related areas via functional connections.