AmuIti-disciplinary approach to the genesis and therapy for dystonia

肌张力障碍被定义为一种肌肉异常收缩的综合征，经常导致扭转或重复运动。据估计，日本的肌张力障碍患者人数超过2万人。其病因和病理结果尚不清楚。本研究综合运用分子遗传学、组织化学、神经生理学等多学科方法，对肌张力障碍的发病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，并与我们之前可能解释肌张力障碍的病理发现(Goto Et Al Ann Neurol 2005)一起，提出了肌张力障碍的起源假说：肌张力障碍是一种运动程序(或子程序)的障碍，它定义了半自动任务中的感觉输入与运动输出，如转头、眨眼、写作、演奏乐器等。这种整合很可能涉及壳核的皮质-纹状体交感，在多巴胺存在的情况下使用LTP。如果纹状体功能障碍损害了多巴胺释放的控制，可能存在LTP样神经可塑性异常并伴有去增强作用，从而导致基质中直接途径或间接途径中多巴胺释放的相对增加。后者可能导致LTP样神经可塑性异常，导致肌张力障碍时感觉运动环节异常。我们还开发了B型肉毒毒素注射、脑深部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.