Tetsuo Touge

Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses?

OBJECTIVES To investigate the mechanisms responsible for suppressing the amplitude of electromyogram (EMG) responses to a standard transcranial magnetic stimulus (TMS) after prior conditioning of the motor cortex with repetitive subthreshold TMS (rTMS) at a frequency of 1 Hz. METHODS EMG responses from the first dorsal interosseous, abductor pollicis brevis and flexor carpi radialis (FCR) muscles were recorded after suprathreshold TMS of the motor cortex. In some experiments, H-reflexes were also obtained in the FCR. The amplitude of these responses was compared before and after applying from 150 to 1500 rTMS pulses to motor cortex at an intensity of 95% resting motor threshold through the same figure-of-8 coil. RESULTS When tested with subjects relaxed, rTMS conditioning reduced the amplitude of motor evoked potentials (MEPs) to approximately 60% of pre-conditioning values for 2-10 min after the end of the conditioning train, depending on the number of pulses in the train. There was more suppression with 1500 rTMS pulses than with 150 pulses. There was no effect on H-reflexes. There was no effect on MEPs if the test stimuli were given during active contraction of the target muscle. CONCLUSIONS The findings confirm previous observations that low-frequency, low-intensity rTMS to motor cortex can produce transient depression of MEP excitability. Since there was no effect on spinal H-reflexes, this is consistent with the idea that some of the suppression occurs because of an effect on the motor cortex itself. The lack of any conditioning effect on MEPs evoked in actively contracting muscle is not readily consistent with the idea that rTMS depresses transmission in synaptic connections to pyramidal cells activated by the test TMS pulse. An alternative explanation is that rTMS reduces the excitability of cortical neurones in relaxed subjects, so that responses to a given input are smaller than before conditioning. Voluntary contraction normalises excitability levels so that the effect is no longer seen.

Reduced excitability of the cortico-spinal system during the warning period of a reaction time task

Seven subjects made a wrist flexion movement as rapidly as possible in response to a cutaneous shock on the opposite hand. In some trials, an auditory warning signal was given 0.5 s beforehand. In random trials, transcranial magnetic stimulation (TMS) was used to elicit EMG responses (MEPs) in forearm flexor and extensor muscles 0-500 ms before the cutaneous shock. H-reflexes were elicited in flexor muscles at the same intervals. The warning stimulus reduced reaction time from about 400 ms to 200 ms. MEPs in the flexor muscles were significantly suppressed from 125 ms after the warning stimulus until the time of the cutaneous shock whilst MEPs in the extensors, and H-reflexes in the flexor were either unaffected, or reduced by a smaller amount at a later time. Responses in relaxed contralateral muscles were unchanged. If the task was changed to a choice reaction, in which the imperative stimulus (but not the warning signal) indicated whether to flex or extend the wrist, then there was no change in the MEPs or H-reflex in the warning period. A similar effect was seen if the duration of the warning period was extended from 0.5 to 2 s in a simple reaction (flexion) task. We conclude that increased excitability of the corticospinal output is not required to speed up reaction times. The time taken to discharge cortical output elements is relatively unimportant compared with the time needed to process the sensory input and link it to the motor output.

Effects of successive repetitive transcranial magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinson's disease

We studied the effects of 0.2 Hz repetitive transcranial magnetic stimulation (rTMS) successively performed 6 times for 2 weeks in 12 patients with idiopathic Parkinsons disease (PD). Ten patients received rTMS to the bilateral frontal cortex (frontal rTMS) and six patients received rTMS to the bilateral occipital cortex (occipital rTMS). Before and after rTMS, we evaluated regional cerebral blood flow (rCBF) using 99m-Tc-ECD single photon emission computed tomography (SPECT) and clinical tests. In an analysis with statistic parametric mapping, both frontal and occipital rTMS reduced rCBF in the cortical areas around the stimulated site. The activities of daily living (ADL) and motor scores of Unified Parkinsons Disease Rating Scale (UPDRS), pronation-supination movements, and buttoning up significantly improved after frontal rTMS than before it, while occipital rTMS had no significant effects in clinical tests.The findings of the present study suggest that successive 0.2 Hz rTMS has outlasting inhibitory effects on neuronal activity around the stimulated cortical areas. Because there were no significant relations between improved clinical tests and reduced rCBF, we speculate that the indirect effects of 0.2 Hz rTMS on subcortical structures are related to improved parkinsonian symptoms. Further studies recruiting large numbers of subjects are required to confirm the efficacy of 0.2 Hz rTMS on PD.

Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan

Objective: To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan. Methods: We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed. Results: Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family. Conclusion: SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.

Abnormalities of rate-corrected QT intervals in Parkinson's disease—a comparison with multiple system atrophy and progressive supranuclear palsy

A number of patients with Parkinsons disease (PD) and multiple system atrophy (MSA), in whom sudden death does occur occasionally, have QT or rate-corrected QT (QTc) interval prolongation on electrocardiogram (ECG). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown. The aim of this study was to compare the degree of QTc interval prolongation among akinetic-rigid syndromes, namely PD and related disorders, and to evaluate the relationship between QTc prolongation and severity of autonomic dysfunction. Thirty-four patients with PD, 22 with MSA, 11 with progressive supranuclear palsy (PSP) and 30 healthy controls underwent standard autonomic function tests, and electrocardiography variables (RR, QT and QTc intervals) were measured by an ECG recorder with an automated analyzer. The relationship between QTc interval and cardiovascular reflex tests were also analyzed. Orthostatic hypotension and decreased heart rate in response to respiratory stimuli were prominent in MSA, while these were relatively mild in PD. Unlike the RR and QT intervals, the QTc interval significantly differed among all groups (p<0.01). The QTc interval was significantly prolonged in PD (409+/-17 ms; p<0.001) and MSA (404+/-14 ms; p<0.05) compared with healthy controls (394+/-19 ms). Neither autonomic dysfunction nor QTc interval prolongation was evident in PSP. QTc intervals and cardiovascular reflexes did not correlate, except for Valsalva ratio. The QTc interval was obviously prolonged in PD patients to an extent that could not be accounted for simply by autonomic dysfunction levels. MSA patients showed slightly prolonged QTc intervals in spite of marked cardiovascular autonomic dysfunction. Abnormalities of the QTc may reflect the degeneration of cardioselective sympathetic and parasympathetic neurons that cannot be fully captured by cardiovascular autonomic function tests.

Multisensory interactions elicited by audiovisual stimuli presented peripherally in a visual attention task: a behavioral and event-related potential study in humans.

We applied behavioral and event-related potential measurements to study human multisensory interactions induced by audiovisual (AV) stimuli presented peripherally in a visual attention task in which an irrelevant auditory stimulus occasionally accompanied the visual stimulus. A stream of visual, auditory, and AV stimuli was randomly presented to the left or right side of the subjects; subjects covertly attended to the visual stimuli on either the left or right side and promptly responded to visual targets on that side. Behavioral results showed that responses to AV stimuli were faster and more accurate than those to visual stimuli only. Three event-related potential components related to AV interactions were identified: (1) over the right temporal area, approximately 200 to 220 milliseconds; (2) over the centromedial area, approximately 290 to 310 milliseconds; and (3) over the left and right ventral temporal area, approximately 290 to 310 milliseconds. We found that these interaction effects occurred slightly later than those reported in previously published AV interaction studies in which AV stimuli were presented centrally. Our results suggest that the retinotopic location of stimuli affects AV interactions occurring at later stages of cognitive processing in response to a visual attention task.

Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy.

ObjectiveIt has been demonstrated that the increased blood pressure (BP) caused by a single dose of water alleviates orthostatic hypotension (OH) and postprandial hypotension (PPH) in patients with autonomic failure (AF). The aim of this study was to evaluate the practical effect of daily water drinking on OH and PPH in the morning when patients with AF are usually most affected.MethodsIn five patients with multiple system atrophy (MSA) characterized by intractable OH and PPH, we measured seated, standing and postprandial BP in the morning without and with ingestion of 350 ml tap water at 07.30 hours for seven successive days. The changes from the basal BP level at 07.30 hours (ΔBP) were assessed as an index of the effect of water drinking.ResultsWater drinking elicited a rapid pressor response in all patients. The ΔBP during sitting, standing and after a meal following water drinking (day 1 and day 7) was significantly higher than without water drinking (day 0). The effects of reducing OH and PPH on day 7 were equivalent to those on day 1. No adverse effects associated with daily water drinking were observed, except later diuresis, which occurred in one patient.ConclusionsDaily water drinking demonstrated constant pressor effects in the morning with no severe adverse effects in MSA patients. This finding suggests that water drinking should be tried as a practical measure to prevent or reduce OH and PPH.

Audiovisual interaction enhances auditory detection in late stage: an event-related potential study.

Although many behavioral studies have investigated auditory detection enhancement by crossmodal audiovisual interaction, the results are controversial. In addition, no neuroimaging studies that identify this phenomenon have been conducted. Therefore, we used event-related potential (ERP) measures to investigate this phenomenon by comparing the ERPs elicited by the audiovisual stimuli to the sum of the ERPs elicited by the visual and auditory stimuli, and identified two brain regions that showed significantly different responses: the centro-medial area at 280–300 ms after the presentation of the stimulus and the right fronto-temporal area at 300–320 ms after the presentation of the stimulus. The ERP results suggested that the behavioral enhancement of auditory detection results from late-stage cognitive processes rather than early-stage sensory processes.

An autopsy case of Creutzfeldt‐Jakob disease with a V180I mutation of the PrP gene and Alzheimer‐type pathology

We report an autopsy case of Creutzfeldt‐Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77‐year‐old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post‐mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic‐type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid β plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer‐type pathology of this case are remarkable. We suppose that amyloid β plaques might act as a facilitating factor for PrP deposition.

Painful legs and moving toes syndrome associated with herpes zoster myelitis

A 75-year-old woman developed painful legs and moving toes syndrome (PLMT) 16 months after the onset of herpes zoster (HZ) myelitis. Although the scattered extensive lesions due to HZ myelitis were observed to be eccentric near the posterior horn on MRI, these changes had disappeared upon the development of PLMT. Combined median and tibial nerve somatosensory evoked potentials demonstrated abnormal findings only in the tibial nerve stimuli, suggesting that a severe alteration occurred in the somatosensory fibers coming selectively from the lower legs. These findings suggest plasticity in the ascending somatosensory pathway including the posterior horn cells, probably involving the interneuron networks, for the lower legs may underlie the development of PLMT associated with HZ myelitis.