AmuIti-disciplinary approach to the genesis and therapy for dystonia

肌张力障碍是一种肌肉异常收缩的综合征，经常引起扭转或重复运动。据估计，日本的肌张力障碍患者超过2万人。其病因和病理表现尚不清楚。我们运用多学科方法，包括分子遗传学、组织化学、神经生理学方法，对肌张力障碍的病理机制和治疗方法进行了研究。我们首次发现了导致遗传性肌张力障碍的基因DYT3，并结合我们之前可能解释肌张力障碍的病理发现（Goto et al Ann Neurol 2005），我们提出了肌张力障碍发生的假设：肌张力障碍是一种运动程序（或子程序）的紊乱，它定义了在半自动任务（如转头、眨眼睛、写作、演奏乐器等）中的感觉输入与运动输出。这种整合很可能涉及到在多巴胺存在的情况下使用LTP的壳核皮质纹状体交感。如果对多巴胺释放的控制因纹状体功能障碍而受损，则可能存在ltp样神经可塑性异常，去增强功能受损，从而导致基质中直接途径多巴胺释放相对于间接途径增加。后者可能导致ltp样神经可塑性异常，导致肌张力障碍的感觉运动联系异常。我们还开发了B型肉毒杆菌毒素注射，深部脑刺激和重复经颅磁刺激的治疗方法。

Dystonia is defined as a syndrome of abnormal muscle contraction frequently causing twisting or repetitive meovements. The number of dystonia patients in Japan has been estimated to be more than 20,000. Its cause and pathological findings were unknown. We conducted a research claryfing the pathomechanism and developing therapeutic means for dystonia using a multi-disciplinary approach including molecular genetics, histochemical, neurophysiological methods. We for the first time discovered the gene causing a hereditary dystonia, DYT3, and together with our previous pathological findings possibly explaining dystonia (Goto et al Ann Neurol 2005), we put forward a hypothesis on the genesis of dystonia: dystonia is a disorder of motor program (or subroutine) that defines sensory input versus motor output in semi-automatic tasks such as head turning, blinking, writing, playing musical instruments and others. This integration most likely involves cortico-striatal symapse at the putamen using LTP in the presence of dopamine. If the control of dopamine release is impaired by the dysfunction of striosome, there may be abnormal LTP-like neuroplasticity with impaired depotentiation, which leads to relative increase of dopamine release in the direct comp oared to indirect pathway in the matrix. The latter may cause abnormal LTP-like neuroplasticity leading to abnormal sensorimotor link in dystonia.We also developed therapies using type B botulinum toxin injection, deep brain stimulation and repetitive transcranial magnetic stimulation.