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KEY POINTS Synaptic plasticity is involved in daily activities but abnormal plasticity may be deleterious. In this study, we found that motor plasticity could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Such changes in motor plasticity were associated with reduced learning of a simple motor task. We postulate that the premotor cortex adjusts the amount of motor plasticity to modulate motor learning through heterosynaptic metaplasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network, a concept that could be employed to intervene in diseases with abnormal plasticity. ABSTRACT Primary motor cortex (M1) plasticity is known to be influenced by the excitability and prior activation history of M1 itself. However, little is known about how its plasticity is influenced by other areas of the brain. In the present study on humans of either sex who were known to respond to theta burst stimulation from previous studies, we found plasticity of M1 could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Motor plasticity was distorted and disappeared 30 min and 120 min, respectively, after premotor excitability was suppressed. Further evaluation revealed that such changes in motor plasticity were associated with impaired learning of a simple motor task. We postulate that the premotor cortex modulates the amount of plasticity within M1 through heterosynaptic metaplasticity, and that this may impact on learning of a simple motor task previously shown to be directly affected by M1 plasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network. Furthermore, such concepts could be translated into therapeutic approaches for diseases with aberrant plasticity.

Background and purpose Investigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking. Methods The index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non-PD controls. Full-length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria-depleted rho-zero cells and donor mitochondria, were used for a rotenone-induced PD simulation study. Results Multivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33–0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone. Conclusions Our studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.

Essential tremor (ET) is the most common movement disorder among adults. Cerebellar dysfunction is thought to be involved in the pathogenesis of ET; however, imaging, electrophysiological studies, and clinical observations have suggested that the cerebral cortex also may participate. We sought to investigate the possible motor cortical contribution to ET by assessing response to continuous theta-burst stimulation (cTBS), a recognized tool that can produce transient plastic changes, in the primary motor and premotor cortex of patients with ET. We compared parameters, including motor-evoked potential amplitude, cortical silent period, and short-interval intracortical inhibition, before and after applying cTBS in healthy controls and patients with ET. We found that, although cTBS applied to either the motor or premotor cortex was capable of producing a suppressive effect on motor cortical excitability in ET patients, the effects lasted for a significantly shorter time compared with the effect produced in healthy individuals. The change seen in measures of intracortical inhibition after motor cortical or premotor cTBS in healthy controls was reduced or absent in the ET patients. Tremor amplitude was decreased significantly after applying cTBS over either the motor or premotor cortex, but the tremor frequency remained unchanged. These findings suggest that inhibitory circuits within the motor cortex are aberrant and less modifiable in ET patients. The reduced plasticity in response to motor and premotor TBS supports the theory of abnormal gamma-aminobutyric acid (GABA) modulation in ET.

Background The objective of this study was to clarify the excitability profiles of the somatosensory cortices in patients with paroxysmal kinesigenic dyskinesia. Methods Whole-head magnetoencephalography was used to record the somatosensory evoked fields elicited by paired-pulse electric stimulation of the median nerve in 15 patients with paroxysmal kinesigenic dyskinesia and in a control group of 18 age-matched, healthy volunteers. Twelve of the patients were studied in both the drug-off and drug-on state. Results The paired-pulse inhibition ratios of the primary somatosensory cortical P35m responses and the secondary somatosensory cortical responses were significantly greater in drug-off patients with paroxysmal kinesigenic dyskinesia compared with either the drug-on patients or the control group. No significant difference in paired-pulse inhibition ratio was observed between the drug-on patients with paroxysmal kinesigenic dyskinesia and the control group. Conclusions In patients with paroxysmal kinesigenic dyskinesia, intracortical inhibition of the primary and secondary somatosensory cortical areas is impaired, and the associated hyperexcitable phenomenon is modulatable by antiepileptic drugs. © 2013 International Parkinson and Movement Disorder Society

Background The involvement of motor cortex and sensorimotor integration in patients with writer's cramp (WC) has been well documented. However, the exact neurophysiological profile within the somatosensory system, including primary somatosensory cortex (SI), contralateral (SIIc), and ipsilateral (SIIi) secondary somatosensory areas remains less understood. Methods This study investigated the neuromagnetic cortical activities of median nerve stimulation in 10 patients with WC and 10 healthy controls (HC). To comprehensively explore all the aspects of somatosensory functioning, we analyzed our data with the minimum norm estimate (MNE), the time-frequency approach with evoked and induced activities, and functional connectivity between SI and SIIc (SI–SIIc), SI and SIIi (SI–SIIi), and SIIc and SIIi (SIIc–SIIi) from theta to gamma oscillations. Results No significant between-group differences were found in the MNE cortical amplitudes of SI, SIIc, and SIIi. Power strengths of evoked gamma oscillation and induced beta synchronization were also equivalent between WC and HC groups. However, we found significantly reduced theta coherence of SI–SIIi, alpha coherence of SI–SIIi and SIIc–SIIi, as well as beta coherence of SIIc–SIIi in patients with WC. Conclusion Our results suggest the involvement of somatosensory abnormalities, primarily with the form of functional connectivity, in patients with WC.

Background: There are few large-scale clinical analyses of essential tremor (ET) in Asia. We studied the detailed clinical profile with emphasizing the age of onset, tremor location, specific tremor patterns, and rate of progression (ROP) to delineate the characteristics of Taiwanese ET patients and found the difference between the Taiwanese and the Caucasians ET patients. Methods: All ET patients fulfilled the Movement Disorders Society diagnosis criteria were investigated with a standardized assessment protocol, which including clinical evaluation, uniform severity scoring, self-reported questionnaires, accelerometry, surface electromyography, and videotaped tremor examination. Results: Of 219 patients recruited from July 2008 to October 2009, 153 completed the study protocol. Their mean age was 58.9 years and 47% were women, and 33.3% had family history (FH). There was bimodal distribution in age of tremor onset in patients without but not in those with FH. Head tremor (HT) was present in 48 of 153 (31%) patients. Patients with HT showed slower tremor frequency and less ROP than those without HT. Sixty-seven (44%) patients presented with intention tremor (IT). Male gender and voice tremor were predictive factors of IT occurrence. Conclusions: Comparing with the Caucasians, Taiwanese ET patients have different patterns of onset-age distribution and lack of female predominance in ET with HT. However, patients with IT and without HT also progressed more rapid as found in the Caucasian.

Background and purpose: The association between glucocerebrosidase (GBA) mutations and Parkinson’s disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. Methods: We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon–intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. Results: In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 RecNciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 RecNciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation (P

A number of experiments in animals have shown that successful induction of plasticity can be abolished if an individually ineffective intervention is given shortly afterwards. Such effects are termed depotentiation/de-depression. These effects contrast with metaplasticity/homeostatic plasticity in which pretreatment of the system with one protocol modulates the response to a second plasticity-inducing protocol. Homeostatic plasticity maintains the balance of plasticity in the nervous system at a stable level whereas depotentiation/de-depression abolishes synaptic plasticity that has just occurred in order to prevent ongoing learning. In the present study, we developed novel protocols to explore the reversal of LTP- and LTD-like effects in healthy conscious humans based on the recently developed theta burst form of repetitive transcranial magnetic stimulation (TBS). The potentiation effect induced by intermittent TBS (iTBS) was completely erased by a short form of continuous TBS (cTBS150) given 1 min after iTBS, whereas the depressive effect of continuous TBS (cTBS) was successfully abolished by a short form of iTBS (iTBS150). The reversal was specific to the nature of the second protocol and was time dependent since it was less effective when the intervention was given 10 min after induction of plasticity. All these features are compatible with those of depotentiation and de-depression demonstrated in animal studies. The development of the present protocols would be helpful to study the physiology of the reversal of plasticity and learning and to probe the abnormal depotentiation/de-depression shown in animal models of neurological diseases (e.g. Parkinson's disease with dyskinesia, dystonia and Huntingon's disease).

Purpose: To determine whether progressive supranuclear palsy (PSP) is associated with specific diffusion tensor imaging (DTI) patterns of diffusivity, anisotropy, and coherence in functionally relevant brain areas. Materials and Methods: In all, 17 PSP patients and 17 controls were scanned using a 3 T magnetic resonance imaging (MRI) scanner. Patients were assessed in the off-medication condition using the Hoehn and Yahr staging and the United Parkinson's Disease Rating Scale, motor subscale (UPDRS-III). Diffusion information were analyzed in relation to disease severity and subtypes. Results: Numerous changes in diffusion properties were identified in the subcortical areas. In the midbrain, fractional anisotropy (FA) decreased and MD (mean diffusivity) increased with disease progression. UPDRS-III scores correlated positively with both FA in the caudate and MD in the pons. DTI analysis of disease subtypes demonstrated significant differences between PSP-Parkinsonism and Steele-Richardson-Olszewski syndrome in axial diffusivity values in the putamen and globus pallidus, as well as in intervoxel diffusion coherence values in the middle cerebellar peduncle. Conclusion: Our findings, cautiously interpreted, demonstrate the advantage of using a functional imaging technique to aid in the specificity of defining more precisely the pathological processes taking place in white and gray matter regions in PSP. J. Magn. Reson. Imaging 2010;32:69–75. © 2010 Wiley-Liss, Inc.

Aim: Few studies have examined the prevalence of restless legs syndrome (RLS) in Asian populations, with existing data suggesting substantially lower rates of RLS in Asian populations compared with Caucasians. However, varying definitions of RLS as well as problematic methodology make conclusions about RLS prevalence in Asian populations difficult to interpret. The current study therefore examines the prevalence of RLS in Taiwanese adults. Methods: Subjects were 4011 Taiwanese residents over the age of 15 years. Data was collected using a computer-assisted telephone interviewing (CATI) system between 25 October 2006 and 6 November 2006. Results: The prevalence of RLS in Taiwanese adults was found to be 1.57%. In addition, individuals with RLS had a higher body mass index (BMI) and incidence of chronic conditions and comorbidities including insomnia, hypertension, cardiovascular disease, respiratory disease, arthritis, backache and mental illness. Women with RLS also had a higher incidence of post-menopausal syndrome. Conclusion: Findings from the current study suggest that the prevalence of RLS in Taiwan is 1.57% by telephone interview. Individuals with RLS had a higher incidence of chronic insomnia and many other chronic disorders. The association and long-term consequences of RLS with these chronic disorders warrants further longitudinal observation and study.

To clarify the rationale for using rTMS of dorsal premotor cortex (PMd) to treat dystonia, we examined how the motor system reacts to an inhibitory form of rTMS applied to the PMd in healthy subjects and in a group of patients with focal hand dystonia and DYT1 gene carriers. Continuous theta burst transcranial magnetic stimulation (cTBS) with 300 and 600 pulses (cTBS300 and cTBS600) was applied to PMd, and its after-effects were quantified by measuring the amplitude of MEPs evoked by single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), short interval intracortical inhibition/facilitation (SICI/ICF) within M1, the third phase of spinal reciprocal inhibition (RI), and writing tests. In addition, in DYT1 gene carriers, the effects of cTBS300 over M1 and PMd on MEPs were studied in separate experiments. In healthy subjects, cTBS300 and cTBS600 over PMd suppressed MEPs for 30 min or more and cTBS600 decreased SICI and RI. In contrast, neither form of cTBS over PMd had any significant effect on MEPs, while cTBS600 increased effectiveness of SICI and RI and improved writing in patients with writer's cramp. NMDYT1 had a normal response to cTBS300 over left PMd. We suggest that the reduced PMd to M1 interaction in dystonic patients is likely to be due to reduced excitability of PMd-M1 connections. The possible therapeutic effects of premotor rTMS may therefore involve indirect effects of PMd on SICI and RI, which this study has shown can be normalised by cTBS.

Surgical lesions in the medial pallidum have been shown to ameliorate motor deficits in patients with Parkinson's disease (PD). It is believed that interruption of the pallidothalamocortical projections to the motor cortex is required for the satisfactory results. In this report, we adopt cortico-cortical inhibition as the tool to assess the pallidotomy effect on cortical excitability in PD. Interstimulus interval between 1 and 15 msec were investigated. The average peak-to-peak amplitude was measured and calculated at each delay. A total of 8 patients (M:F = 4:4) 54.9 years of age (SD = 9.6) and 10 controls were recruited for the study. In the controls, the inhibitory phenomenon was observed from the 1-msec to the 4-msec delay points and the maximal inhibition was at the 3-msec delay point (33.69% ± 6.50% of the control response). Mild facilitation was noticed since the 5-msec delay point and thereafter. In patients before operation, a similar trend of inhibition was also observed in the initial 4 msec with the maximal inhibition also at the 3-msec delay point (64.66 ± 6.77% of the control response). In the postoperative group, the short interstimulus interval inhibition can no longer be observed and the conditioned response was 95.06 ± 23.68% of the control at the 3-msec delay point. The suppression was gone at and after the 7-msec delay point. Results of repeated-measures analysis of variance show a significant difference among the controls and PD patients before and 3 months after pallidotomy (F = 3.40, P = 0.05). Post hoc examination revealed a significant difference between the controls and PD patients 3 months after pallidotomy at the 3-msec delay point (P = 0.004). However, no correlation was observed between the 3-msec inhibition and the Unified Parkinson's Disease Rating Scale Motor score or the dyskinesia score. The results suggest that pallidotomy can modulate the cortical inhibitory circuitry in patients with PD. © 2004 Movement Disorder Society

We conducted electrophysiological studies in two Asian patients with probable corticobasal degeneration (CBD). The duration of illness from onset was 16 and 20 months, respectively. The clinical manifestations were markedly asymmetric and characterized by cortical sensory loss, apraxia, action myoclonus, action tremor, and akinetic-rigid parkinsonism. Neither patient responded to levodopa therapy. Simple photon-emission computed tomography (SPECT) study showed significantly decreased regional cerebral blood flow in the frontoparietal areas and thalamus opposite to the predominantly affected limb. A series of electrophysiological studies failed to identify giant somatosensory evoked potentials (SEPs), enhanced long latency electromyography (EMG) reflex, and cortical spikes preceding myoclonic jerk. However, the earliest cortical component of the median nerve SEP was exclusively enlarged in one patient and preserved with depression of the subsequent components in the other patient. Significantly shorter postmotor-evoked potential (MEP) silent period was found after the transcranial magnetic stimulation of the motor cortex in both patients. CBD is a unique clinical entity characterized by action myoclonus probably the result of the pathologic hyperexcitability of the motor cortex, based on a loss of inhibitory input from the sensory cortex.

Asymmetrical manifestation of dystonia was investigated in 26 patients with Wilson's disease with modified dystonia rating scale and correlated with the asymmetricity of CT and/or MRI findings. Ten patients (eight men and two women) had dystonia. The age of disease onset ranged from 11 to 30 years with a mean of 18.6 ± 5.2 years. The duration of the illness was from 2 to 15 years (mean 7.0; S.D. 3.6). Six patients had subcortical white matter lesions in the frontal and/or parietal lobes, as well as lesions in the basal ganglia. Five patients, who had asymmetrical white matter lesions in the frontal lobes and symmetrical lesions in the basal ganglia and the thalamus, developed more severe contralateral dystonia. The other four patients with symmetric lesions in the basal ganglia and the thalamus had nearly-symmetrical dystonia. One patient with symmetrical lesions in the frontal lobes and the basal ganglia also had symmetrical manifestation of dystonia. We suggest that the interruption of the loop between the thalamus and premotor cortex by subcortical white matter lesions may enhance contralateral dystonia.

We report myoclonic epilepsy with ragged-red fibers (MERRF) syndrome in a Chinese family with confirmed mitochondrial DNA point mutation. Six members of the family including the grandmother, two siblings, and three grandchildren were affected. Among them, action myoclonus was seen in five; short stature, muscle weakness, and mental retardation in four; lactic acidosis, hearing impairment, and ataxia in two; and seizures in one. Muscle biopsy from two affected siblings revealed ragged-red fibers and abundant subsarcolemmal mitochondria with paracrystalline inclusions. Pedigree analysis suggests a maternal transmission. Analysis of mitochondrial DNA showed a point mutation from A to G at the 8344th nucleotide position located in the tRNA(Lys) gene. To our knowledge, this is the first report of MERRF syndrome with such genetic defect from a Chinese family. The present and previous reports support the notion that mitochondrial DNA point mutation at the 8344th nucleotide position is the most common cause of MERRF syndrome.

Large deletions in the GCH1 gene have been reported in a minority of cases of dopa-responsive dystonia (DRD). In this study, we performed an extensive clinical and genetic investigation of 22 affected members in eight families. Sequence analysis revealed five different mutations in five families (n = 10); Ser81Pro (novel), Ser76X, Gly203Arg, 249del A, and IVS5 + 3insT. Applying multiple ligation-dependent probe amplification analysis, we detected a large heterozygous deletion of exons 1-3 in the remaining three families (n = 12), which was verified by quantitative real-time PCR analysis. Therefore, the large deletion accounted for 37.5% of the total families and 55% of our DRD population. The deletion appeared to have high penetrance and was associated with multifocal dystonia and adult onset in males. Adult-onset patients were commonly presenting with resting tremor, rigidity, and bradykinesia, indistinguishable from those in Parkinson's disease. In conclusion, a high frequency of multiexonic deletion of GCH1 was identified in the Taiwanese DRD population. By dosage analysis, we were able to detect a mutation in all patients. Our study demonstrates that dosage analysis is necessary for molecular diagnostics in DRD patients of Han Chinese ethnicity.