Nagako Murase

The Role of Interneuron Networks in Driving Human Motor Cortical Plasticity

The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.

Cerebellar modulation of human associative plasticity.

Key point  •  Increases in the strength of synaptic connections in the motor cortex (long term potentiation) can be induced in humans by repetitively pairing peripheral nerve stimuli and motor cortex transcranial magnetic stimuli given 21–25 ms apart – paired associative stimulation (PAS). •  This ‘associative plasticity’ effect has been assumed to relate to synchronicity between sensory input and motor output, with a similar mechanism proposed to underlie effects at all interstimulus intervals. •  Here we show that modulation of cerebellar activity using transcranial direct current stimulation can abolish associative plasticity in the motor cortex, but only for sensory/motor stimuli paired at 25 ms, not at 21.5 ms. •  The results indicate that human associative plasticity can be affected by cerebellar activity and that at least two different mechanisms are involved in the effects previously reported in studies using PAS at different inter‐stimulus intervals.

Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia

Tardive dystonia is a disabling movement disorder as a consequence of exposure to neuroleptic drugs. We followed 6 patients with medically refractory tardive dystonia treated by bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for 21 ± 18 months. At last follow‐up, the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) motor score improved by 86% ± 14%, and the BFMDRS disability score improved by 80% ± 12%. Bilateral GPi‐DBS is a beneficial therapeutic option for the long‐term relief of tardive dystonia.

Functional reorganization of sensorimotor cortex in early Parkinson disease

Objective: Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. Methods: Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. Results: The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. Conclusions: Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD.

Pre-movement gating of short-latency somatosensory evoked potentials.

Somatosensory evoked potentials (SEPs) are reduced in amplitude during movement (gating). The mechanism involves central gating of afferent input and competition from other afferents activated by the movement. We distinguished these two by giving 11 normal subjects a warning sound followed 1 s later by an electric stimulus to the right median nerve at the wrist. The latter served both as a cue to start a finger movement and as stimulation to evoke SEPs. Gating effects were widespread in frontal (N30) and central (N60) areas, but were also seen, albeit to a lesser extent, in the recordings at P3 (P30). Since finger movement began after the stimulus, such gating must have been purely central in origin, presumably reflecting motor preparation.

Activity-dependent conduction block in multifocal motor neuropathy Magnetic fatigue test

Background: Multifocal motor neuropathy (MMN) is often misdiagnosed as motor neuron disease, especially when overt evidence of conduction block (CB) is lacking. Activity-dependent CB (ADCB), defined as transient CB induced by brief exercise, has been recently found in MMN but not in ALS. Methods: To test the diagnostic utility of ADCB for differentiating MMN from ALS, the authors recorded the compound muscle action potentials (CMAPs) from small hand muscles by magnetically stimulating nerve roots before and after 1 minute of maximal voluntary contraction (magnetic fatigue test). They examined nine patients with MMN with unequivocal clinical responses to IV immunoglobulins (IVIgs), yet lacked CB according to the conventional criteria. Results: Six MMN patients had postexercise CB/temporal dispersion maximum in the immediate postexercise period. ADCB in an MMN patient improved after IVIg. Further analysis revealed that prolongation of the duration from the onset to the positive peak of the CMAP was the most sensitive indicator for MMN, presumably because the phase cancellation obscures the abnormalities of the other parameters. Conclusion: The magnetic fatigue test is useful in detecting mild conduction block presumably located in a proximal nerve segment in patients with multifocal motor neuropathy who do not fulfill its conventional electrodiagnostic criteria.

Sensory function of basal ganglia.

The basal ganglia lie between the cerebral cortex and the thalamus, with which they have dense fibre connections which form four to five distinct circuits to allow parallel processing of information. 1 The most studied is the motor loop, which has direct and indirect pathways. The direct pathway disinhibits the powerful inhibition of the internal segment of the globus pallidus/substantia nigra pars reticulata upon thalamic ventrolateral nuclei with a net facilitation on the motor cortex. By contrast, the indirect pathway exerts an inhibitory effect. This dual system provides a center(excitatory)-surround(inhibitory) mechanism to focus its effect on selected cortical neurons. Despite considerable knowledge of the chemical messengers in these projections, the functional role of the loop in motor control is not precisely understood. Parkinson’s disease primarily affects nigrostriatal dopaminergic neurons and is characterised by bradykinesia (slowness of movement), rigidity of muscles, disturbed postural reflex, and tremor. Hallett and Khoshbin 2 studied the physiological mechanism of bradykinesia using surface electromyographs (EMGs) in a ballistic elbow flexion movement. They found a fractionated pattern of agonist-antagonist muscle bursts, which were repetitions of the normal triphasic (agonist-antagonist-agonist) muscle activation. The basic abnormality was a smaller than normal scaling of movement excursion at each burst, which was compensated for by repeating the normal triphasic pattern. An intriguing feature of Parkinson’s disease is the benefit of external sensory cues for initiating and performing movements ( kinesie paradoxale ). Auditory or visual input can correct the small excursion of movement, implying that abnormal scaling of movement is secondary to disturbed utilisation of proprioceptive sensory input. In support of this idea, Walshe 3 demonstrated that blockade of muscle afferents with local anaesthetic corrected the small excursion of elbow movement in a boy with postencephalitic Parkinsonism. Dystonia is a sustained involuntary muscle contraction frequently causing twisting or repetitive movements or abnormal postures. It is regarded as a basal ganglia sign, because focal lesions in the motor loop cause dystonia in the limbs contralateral to the lesion ( hemidystonia ), and because trihexyphenidyl, an anticholinergic agent frequently used for Parkinson’s disease, may be effective in treating the condition. A distinctive feature of dystonia is the sensory trick,in which a tactile or proprioceptive sensory input to the nearby body part improves abnormal posture or movement. In the case of blepharospasm, avoiding bright light with sunglasses is effective in reducing contractions in orbicularis oculi muscles. Thus, the sensory trick suggests a sensory-motor mismatch in motor control. Another important characteristic is that dystonia may affect a specific task ( task specificity ). Writer’s cramp usually begins as a task-specific disorder, but may later spread to involve other dexterous tasks. Other taskspecific dystonias include musician’s cramp, typist’s and sportsman’s cramp, all of which affect activities of frequently or repetitiously used motor acts. Electromyographic analyses showed simultaneous contraction of agonist and antagonist muscles ( cocontraction) or contraction of surrounding muscles ( overflow). These findings suggest that dystonia is a disorder of a frequently used motor program or subroutine,in which motor output is matched to a fixed sensory input. 4 Probably this motor subroutine is stored as connectivities in the motor loop. If the center-surround inhibitory mechanism in the motor loop is disrupted, the lack of inhibition of antagonist or surrounding muscles causes cocontraction or overflow phenomena. *Correspondence to: Ryuji Kaji MD, PhD, Department of Neurology, Tokushima University Hospital, Kuramotocho 2-5-1, Tokushima City, Tokushima 770-8503 Japan. E-mail: kajkyoto@mbox.kyotoinet.or.jp Published online 11 July 2001; DOI 10.1002/mds.1137 Movement Disorders Vol. 16, No. 4, 2001, pp. 593–594

DYT1 mutation in Japanese patients with primary torsion dystonia.

A GAG deletion at position 946 in the DYT1 gene has been identified as one of the gene mutations responsible for autosomal dominant primary torsion dystonia. We examined 178 Japanese patients with various forms of dystonia, and found the mutation in six patients (3.4%) from three families. Five of them had early clinical onset (before age 12) with initial involvement of a limb. To our knowledge, this is the first report of the frequency and the clinical features of DYT1 mutation in oriental patients, and the clinical presentation of the mutation in these patients was similar to that of Jewish or non-Jewish Caucasian patients.

Comparison of monophasic versus biphasic stimulation in rTMS over premotor cortex: SEP and SPECT studies

OBJECTIVE To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. METHODS In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. RESULTS Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. CONCLUSIONS Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. SIGNIFICANCE Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.

Abnormal sensory gating in basal ganglia disorders

Basal ganglia encompass four to five distinct loops to allow parallel processing of information. Among them, the most intensively studied is the motor loop, which includes two distinct direct and indirect pathways. The direct pathway exerts facilitatory influence upon the motor cortex, whereas the indirect pathway exerts an inhibitory effect. Overall, this dual system provides a center(excitatory)-surround-(inhibitory) mechanism to focus its effect on selected cortical neurons, and several lines of evidence suggest that this center-surround mechanism is used to focus the output on a specific group of muscles required for performing a specific task. This operation is made possible through opening the sensory channel for the expected sensory feed-back afferents during movement. Thus, one of the important functions of basal ganglia seems to be the gating of sensory input for motor control. Dystonia may be caused by a mismatch between sensory input versus motor output, and parkinsonism may be viewed as a disorder of gain control of this sensorimotor integration.