シンポジウム（Symposium）

Symposium Insight about higher brain functions on the cerebro-cerebellar network from collaboration between basic science and clinical research シンポジウム基礎と臨床の融合型研究から見えてきた大脳小脳ネットワークによる高次脳機能

7月28日（日）10:55～11:15　第7会場（朱鷺メッセ　2F　201B） 4S07a-1 毛細血管拡張性運動失調症における神経症状～現状と課題 Setsuko Hasegawa（長谷川節子）東京医歯大医歯総合発生発達病態学 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms not only cerebellar ataxia but also abnormal eye movements, involuntary movements and peripheral neuropathy. These symptoms will be shown in a video. The neuropathological feature of A-T is diffuse atrophy of the cerebellar vermis and hemispheres involving gradual loss and aberrant location of Purkinje cells. Some of the neurologic abnormalities in A-T are explained with this pathophysiology except of involuntary movements. The mechanism of Purkinje cell death and neurological symptoms caused by ATM deficiency is still unknown. Curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. To evaluate the long-term benefits and adverse effects of betamethasone, we administrated oral betamethasone to 6 A-T patients for 2 years. After cessation of betamethasone, the patients were observed for 2 additional years. Neurological assessments and monitoring of adverse effects were performed throughout the 4-year study period. Scale for the assessment and rating of ataxia (SARA) and A-T Neuro Examination Scale Toolkit (AT-NEST) were used for neurological assessments. Transient improvement of neurological score was observed in five of the six patients, however after 2 years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, while one patient showed no change, and the neurological scores of the remaining four patients deteriorated. More over after the cessation of betamethasone treatment, neurological score worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. We conclude benefits and risks of long-term oral betamethasone therapy should be carefully considered. A new trial of steroids is currently being conducted overseas, and development of gene therapy is also expected. On the other hand, it is also desirable to develop more objective evaluation methods for cerebellar symptoms and involuntary movements.		7月28日（日）11:15～11:35　第7会場（朱鷺メッセ　2F　201B） 4S07a-2 小脳内部モデルを意識的に切り替える脳の理論 Takeru Honda（本多武尊）公益財団法人東京都医学総合研究所 When you reach for a cup in front of you, you can strategically control your hand movement by seeing both your hand and the cup at the same time. This is generally called online feedback control. Moreover, you can easily do this during being blindfolded after confirming a position of a target because you can control your movements according to information, known as an internal model, which is memorized in the brain. This is called feedforward control. There is a hypothesis that the cerebellum plays an important role for the internal model. The internal model represents present physical information for movements (e.g., a motion of your arm based on a prediction; forward model) or motor command information (e.g., how to move your arm; inverse model). However, there is ongoing debate as to which information is represented in the internal model. Our previous study have been designed to answer this question by researching what human being wearing the prism glasses learn during reaching by the feedforward control and have provided a theoretical system including tandem connection from the forward model toward the inverse model, which is called for the tandem internal models. Furthermore, we have found that healthy subjects wearing the prism googles drastically changed between touching a real target and touching a virtual image elicited by the psychophysical command. In this study, I simply formulated a system of the tandem internal models. The formulation represents the drastic change elicited by the psychophysical command and predicts that there is a switch function outside of the cerebellum, where may be the cerebral cortex. This suggests that the psychophysical command selects which use internal models, forward model or inverse model. It is also reveled that the psychophysical command intentionally blocks learning not the forward model but the inverse model in the cerebellum. Finally, this theory predicts that repetitive hand-reaching causes learning and depresses the neural activity in the cerebral cortex. These results suggest that the cerebral cortex determines appropriate movements by using information of the forward model in the cerebellum.

7月28日（日）11:35～11:55　第7会場（朱鷺メッセ　2F　201B） 4S07a-3 小脳出力系として中脳大細胞性赤核が担う運動協調機構 Tomomichi Oya（大屋知徹）¹，Tomohiko Takei（武井智彦）^2,3，Kazuhiko Seki（関和彦）¹ ¹国立精神・神経セ神経研モデル動物 ²京都大院医神経生物 ³京都大次世代研究者育成セ白眉プロジェクト The magnocellular red nucleus (Rmg), forming the descending rubrospinal tract, predominantly receives inputs from the cerebellar interpositus nucleus, a part of deep cerebellar nuclei. Its enlargement in volume paralleled with limbs and locomotive development alludes to a tight link to limb control, in particular an inter-joint coordination. However, it is unclear how the Rmg contributes the coordinated patterns of limb movement. To address this issue, we sought to identify functional muscle groups shaped by the population of the Rmg neurons, and relate the muscle activity with the Rmg population neuronal activity in the macaque monkey. A functional connectivity between Rmg and muscles was determined based upon spike triggered averaging technique (STA); we recorded the single-unit electrophysiological activities of Rmg neurons concurrently with EMG activities from the 26 forelimbs muscles while macaque monkeys were performing a sequence of whole-limb movements (reach-to-grasp-and-pull of a ball-shaped object, precision grip of pellets, and transportation of pellets to the mouth). The identified 90 premotoneuronal neurons of Rmg exhibit predominantly flexor organization spanning around multiple joints from the shoulder to the wrist; shoulder and elbow flexors are reciprocal, whereas wrist flexors are cofacilitated with either shoulder or elbow flexors, and the cells belonging to each module increase the discharge rate in a sequential manner, i.e., from shoulder to wrist flexor modules. This sequential activation pattern of synergistic flexor modules markedly corresponds to the muscle activation patterns in quadrupedal locomotion. By considering Rmg as a cerebellum-mediated motor pathway, the present study indicates that Rmg represents the common flexor module by which tetrapods may have achieved adaptive locomotion, that may be co-opted for coordination of reaching movements.		7月28日（日）11:55～12:15　第7会場（朱鷺メッセ　2F　201B） 4S07a-4 Non-invasive cerebellar stimulation to rearrange disrupted functional networks Kim van Dun（van Dun Kim）¹，Mario Manto（Manto Mario）^2,3 ¹University of Hasselt ²Unite d etude du Mouvement (UEM), FNRS, ULB-Erasme Brussels Belgium ³Service des Neurosciences, UMons Mons Belgium Non-invasive brain stimulation (NIBS) is a promising technique that has been proven to modify neural excitability using electric current (transcranial electric current, TES) or magnetic pulses (transcranial magnetic stimulation, TMS) (Janssen, Oostendorp, & Stegeman, 2015; Woods et al., 2016). Most research focused on stimulating the area directly beneath the electrodes or the coil to directly facilitate or inhibit the functioning of that area (e.g. motor cortex stimulation). Recently, a different strategy has been introduced in NIBS research, focusing on the cerebellum as a window upon functional connectivity networks (van Dun, Bodranghien, Manto, & Marien, 2017). Indeed, the cerebellum is strongly connected to the motor and associative regions of the cerebrum via closed loops running in parallel, allowing communication in both directions. In addition, the cerebellum has the highest density of neurons and has a dense cortical cellularity, making it very susceptible to NIBS (van Dun & Manto, 2018; van Dun, Overwalle, Manto, & Marien, 2018). EEG studies using cerebellar TMS have shown that cerebellar stimulation induces activity in the contralateral cerebral hemisphere that spreads towards the bilateral prefrontal cortices and to the ipsilateral cerebral hemisphere within 40ms (Arimatsu, Sato, Ge, Ueno, & Iramina, 2007; Iramina, Maeno, Kowatari, & Ueno, 2002; Iramina, Maeno, Nonaka, & Ueno, 2003; Iramina, Maeno, & Ueno, 2004; Iwahashi et al., 2009). In addition, studies using cerebellar TES showed altered excitatory and inhibitory cortico-cortical and cerebello-cortical networks (e.g. Chothia, Doeltgen, & Bradnam, 2016; Galea, Jayaram, Ajagbe, & Celnik, 2009). Modulating remote functional connectivity via the cerebellum is especially interesting for subcortical lesions. These lesions are not reachable by NIBS but can disturb networks involving several cortical regions. By targeting the cerebellum with NIBS, it might be possible to target the whole disrupted network and regain some connectivity between the affected regions (van Dun et al., 2018). We will present functional MRI (fMRI) and behavioral data of a patient with a left basal ganglia hemorrhagic stroke resulting in hypokinetic dysarthria. Cerebellar stimulation (anode over left, cathode over right cerebellar hemisphere) was applied during language therapy. fMRI was taken before and after an 8-week protocol.

7月28日（日）12:15～12:35　第7会場（朱鷺メッセ　2F　201B） 4S07a-5 熟練した認知機能に小脳が関与する可能性の検討 Hironori Nakatani（中谷裕教）^1,2 ¹東京大院総合文化研 ²理研CBS 認知行動連携 The cerebellum is well known to contribute to skilled motor control. The gist of cerebellar motor control is an internal model that is a neural representation of dynamics in body parts and external would. Through a learning process, the cerebellum acquires an internal model. The internal model in the cerebellum makes it possible to control quickly and precisely learned movements without any reference to feedback of sensory information. Masao Ito has proposed that the same principal is applicable to non-motor, cognitive function. According to Ito's hypothesis, structured knowledge for cognitive processing is first acquired in the temporo-parietal cortex though a learning. The cerebellum, then, acquires the structured knowledge as an internal model. If this is the case, the cerebellum might be involved in skilled cognitive capabilities in experts. We have tested this possibility with a board game named shogi (Japanese chess). We recruited expert shogi players from the University of Tokyo and Waseda university and 26 players have participated our experiment. We carried out thought experiment with Tsume-shogi (shogi problem) in a scanner of magnetic resonance imaging. Number of problem was 60. Participants were asked to solve each problem within 30 seconds and to answer the last move. We analyzed brain activity during thought based on answer time. We divided answer time into three categories, very quick (shorter than 10 seconds), relatively quick (10 to 30 seconds), and slow (could not solve within 30 seconds). We found that the lateral part of the cerebellum showed activity, when participants solved problems quickly. The result indicates a possible involvement of the cerebellum in intuitive thought in shogi experts.