Y. Terao

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

B-19. What does eye tracking tell us about neurological patients?

Performances of experimental oculomotor (saccade) paradigms have provided insights into the pathophysiology of neurological patients. However, to investigate the behavioral correlates and the physiological significance of these saccade abnormalities in daily life, we need to look into the difficulty patients actually experience in a more ecological setting. We review studies in which the eye tracking methodology was applied to normal subjects, e.g., when they viewed line drawings presented on a monitor screen to memorize them for later recall. In addition, simultaneous recording of hand (finger) movements with gaze movements allows us to evaluate how the eye and hand coordinates in performing daily actions. For example, eye-hand coordination was studied whey subjects wrote letters on a touch panel, and during a trail making test or in a task simulating finger-nose test. Even eye-voice coordination can be studied by recording the voice of subjects as they read aloud a text. Investigations in neurological patients such as Parkinson’s disease and cerebellar ataxia holds promise for giving insights into how saccade abnormalities observed in oculomotor tasks contribute to their clinical symptoms. They can also be used to quantitatively evaluate motor symptoms of neurological patients from a new perspective.

What do eye movements tell us about patients with neurological disorders? — An introduction to saccade recording in the clinical setting —

Non-invasive and readily implemented in the clinical setting, eye movement studies have been conducted extensively not only in healthy human subjects but also in patients with neurological disorders. The purpose of saccade studies is to “read out” the pathophysiology underlying neurological disorders from the saccade records, referring to known primate physiology. In the current review, we provide an overview of studies in which we attempted to elucidate the patterns of saccade abnormalities in over 250 patients with neurological disorders, including cerebellar ataxia and brainstem pathology due to neurodegenerative disorders, and what they tell about the pathophysiology of patients with neurological disorders. We also discuss how interventions, such as deep brain stimulation, affect saccade performance and provide further insights into the workings of the oculomotor system in humans. Finally, we argue that it is important to understand the functional significance and behavioral correlate of saccade abnormalities in daily life, which could require eye tracking methodologies to be performed in settings similar to daily life.

P224: Cauda equina conduction time in GBS, CIDP, and MMN

Introduction: To investigate the conductions of proximal and distal parts of peripheral nerves in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN), we measured cauda equina conduction time (CECT) and motor conduction velocity (MCV). Methods: Patients were 12 GBS (8 axonal and 4 demyelinating types), 14 CIDP, and 5 MMN patients. Compound muscle action potentials (CMAPs) were recorded from the abductor hallucis muscle. To measure MCV, electrical stimulation was conducted. To obtain CECT, magnetic stimulation was performed using a MATS coil (magnetic augmented translumbosacral stimulation coil). Results: CECT was normal in all axonal GBS patients but prolonged in all demyelinating GBS patients, whereas MCV was normal in all GBS patients. CECT was prolonged in 12 CIDP patients (85.7%), whereas MCV was delayed in 5 CIDP patients (35.7%). Both CECT and MCV were normal in all MMN patients. Conclusions: CECT is frequently prolonged in demyelinating GBS and CIDP, whereas it is usually normal in axonal GBS and MMN. MATS coil stimulation method can detect the conduction delay of cauda equina in some types of demyelinating polyneuropathy.

PTMS52 Normal SICI in Parkinson's disease: SICI using anterior posterior directed induced currents in the brain

phosphocholine [PCho] + glycerophosphocholine [GPC]) were measured bilaterally in primary sensorimotor cortex, lentiform nucleus, and the occipital region before and after 5 Hz TMS over the dominant motor cortex. Sixteen patients with upper limb primary dystonia were studied and compared to healthy volunteers. Results: At baseline, in patients with writer’s cramp, there was a higher GABA concentration bilaterally in the motor cortex as compared with controls. In controls but not patients, 5 Hz TMS over the left motor cortex induced an in situ-change in metabolite concentrations that depended on baseline concentration levels; i.e., increase for lower baseline levels and decrease for higher. Effects in basal ganglia were less consistent. Greater concentration decreases in NAA, mIns, and tCho were observed in the motor cortex of the patients after TMS. Conclusion: Together with previous results, our study points to a dysfunction of the GABAergic inhibitory system in dystonia. TMS-induced changes of NAA, mIns and tCho are interpreted in view of the maladaptive plasticity and abnormal membrane-related protein previously suggested in dystonia.

PTMS15 Abnormal motor cortex inhibitory circuits in mild cognitive impairment

experiment SICI and LICI recruitment curves (with varying conditioning stimulus intensities) were obtained before and 30 minutes after induction of INB. Results: MEP amplitude in the flexor increased rapidly following the induction of INB however there was no systematic change in the excitability of either SICI or LICI circuits during INB. Conclusions: Neither SICI nor LICI underlie the rapid reorganization of forearm flexor representations in M1 evident during INB. The rapid reorganization of M1 observed during INB might arise instead from changes in sensory-based inhibitory processes acting on motor cortex, such as shortand long-interval afferent inhibition.

PTMS25 Long-term effects induced by quadripulse stimulation in Huntington's disease

excitability was evaluated before and after navigation-guided 5 Hz-rTMS of the primary motor cortex corresponding to the painful hand. Resting motor threshold, amplitude of motor evoked potential, duration of cortical silent period, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were measured as parameters of cortical excitability with singleor paired-pulse TMS methods. Pain reduction of rTMS was assessed with a visual analogue scale (VAS). Results: Eight of 20 patients showed 30% pain reduction in their VAS after rTMS (good responders). SICI in all patients and ICF in good responders were significantly lower than those in the controls at baseline (0.34±0.40 vs. 0.55±0.17, p = 0.045 and 1.10±0.35 vs. 1.71±0.79, p = 0.034, respectively) which were in line with previous reports. The rate of ICF increase in good responders after rTMS was significantly larger than that in the other patients (1.60±0.67 vs. 1.04±0.41, p = 0.042). There were no significant differences or changes in the other parameters. Conclusions: Our findings suggested that restoration of abnormal cortical excitability might be one of the mechanisms underlying pain relief as a result of rTMS in CPSP.

P20-23 Bidirectional human sensory cortical excitability modulation by quadripulse magnetic stimulation (QPS) of various cortical areas

Objective: Brief interruption of voluntary EMG in hand muscles by focal transcranial magnetic stimulation (TMS) of the ipsilateral primary motor cortex (M1), the so-called ipsilateral silent period (ISP), is a measure of interhemispheric motor inhibition. However, little is known about how volitional motor activity would modulate the ISP. Here we tested in 30 healthy adults to what extent and under what conditions voluntary activation of the stimulated right M1 by moving the left hand strengthens interhemispheric inhibition as indexed by an enhancement of the ISP area in the maximally contracting right first dorsal interosseous (FDI). Methods and Results: Left index finger abduction significantly enhanced the ISP compared to left hand at rest. Even imagination of left index finger movement enhanced the ISP compared to rest or mental calculation. This enhancement occurred in absence of motor-evoked potential amplitude modulation in the left FDI, excluding a non-specific contribution from increased right M1 corticospinal excitability. Contraction of the left extensor indicis, but not contraction of more proximal left upper limb or lower limb muscles also enhanced the ISP. A reaction time experiment showed that the ISP enhancement developed at a late stage of movement preparation. Interhemispheric inhibition of the motor-evoked potential as tested by a bifocal paired-pulse TMS protocol and thought to be mediated via a neuronal circuit different to the ISP was not enhanced when tested under identical motor task conditions. Finally, ISP enhancement by contraction of the left FDI correlated inversely with EMG mirror activity in the right FDI during phasic abductions of the left index finger. Conclusions: Findings strongly suggest that voluntary M1 activation by real or imagined movement of the contralateral hand increases interhemispheric inhibition of the opposite M1. This phenomenon shows substantial topographical, temporal and neuronal circuit specificity, and likely plays a pivotal role in suppressing mirror activity.

P20-7 The effective coil position for magnetic brainstem stimulation

Methods: Twenty healthy adults participated in this study after giving their informed consents. Each subject was asked to simultaneously gait on a treadmill and perform fingertip precision grip following a visual tracking task (precision task). The precision task was performed in thumb and index finger, this task force output was in the setting of 5% maximum voluntary contraction. We examined the responses of motor evoked potentials (MEPs) elicited from FDI, Thenar, FCR and ECR muscles by TMS. The gait condition was employed from 80%, 50% and 30% of maximum gait speed (gait 80%, gait 50%, gait 30%), i.e., gait 50% condition was almost adapted to be optimal gait speed. Additional studies, each subjects was asked to the optimal gait synchronized with precision task along with optimal gait rhythm (2 Hz Dual motor Task condition) and to the optimal gait desynchronized with precision task (0.7 Hz Dual motor Task condition). Results & Conclusions: The excitability changes of motor cortex by Dual motor Task was strongly dependent on gait speeds. MEP of FDI at the gait 50% condition was significantly the smallest at the gait 30% and gait 80% conditions. Moreover, in the 2 Hz Dual motor Task, MEP of FDI was significantly reduced compared with 0.7 Hz Dual motor Task. Present results suggest that excitability changes in M1 during Dual motor Task was dependent on task properties. That is, the precision task was regulated and affected with alterations in gait speed and rhythmic synchronization.