Cerebellar-neocortical motor network alterations in dystonia – myoclonus-dystonia as a model disease

肌张力障碍是一种运动障碍，其特征是持续或间歇性肌肉收缩，导致不自主的异常运动或姿势。虽然肌张力障碍早在1911年就被描述为一种可能由遗传决定的器质性疾病，但其独特的病理生理学仍不清楚，这使得任何因果治疗的发展都很困难。近年来，越来越多的证据表明肌张力障碍是一种网络疾病，涉及多个节点，并对某些形式产生特殊的小脑影响。为了进一步澄清，具有确定的小脑缺陷的模型疾病将是优选的。在这方面，肌阵挛-肌张力障碍（M-D）由于突变的β-肌聚糖基因（SGCE）似乎非常适合。SGCE在浦肯野细胞中高度表达，并在突触膜组分中富集。我们自己和其他神经生理学和影像学研究表明，小脑发电机潜在的运动症状的M-D，使M-D一个理想的体内模型疾病研究小脑功能障碍。在此背景下，我们提出了一种多模式的方法，包括临床，行为，影像学和神经生理学测量M-D患者更详细地定义小脑缺陷及其对新皮质运动网络的影响，在各种形式，可以相互关联。此外，通过使用非侵入性脑刺激，包括小脑的经颅直流电刺激（tDCS），我们希望阐明小脑可塑性的诱导是否可以补偿浦肯野细胞的缺陷，以及如何通过小脑兴奋性输出的变化来修改临床，行为，成像和神经生理学特征。这将使我们能够建立因果关系和基因型-表型-神经生理学的相关性，可以应用于小脑功能障碍的特发性疾病形式。它还将进一步了解小脑非侵入性脑刺激技术（如tDCS）的作用方式，并可能为新的治疗方法打开窗口。

Dystonia is a movement disorder characterized by sustained or intermittent muscle contraction resulting in involuntary, abnormal movements or postures. Although dystonia was already described as an organic presumably genetically determined disorder in 1911, its distinct pathophysiology is still unclear, making any causal therapeutic development difficult. Recently, increasing evidence has accumulated pointing towards the concept of dystonia as a network disorder with multiple nodes being involved and special cerebellar impact on some forms. For further clarification a model disease with defined cerebellar deficit would be preferable. In this respect, myoclonus-dystonia (M-D) due to mutations in the epsilon sarcoglycan gene (SGCE) appears very well suited. SGCE has shown to be highly expressed in Purkinje cells and enriched in synaptic membrane fractions. Our own and other neurophysiological and imaging studies suggested a cerebellar generator underlying motor symptoms in M-D, making M-D an ideal in vivo model disease to study cerebellar dysfunction. Against this background, we propose a multimodal approach in M-D patients including clinical, behavioral, imaging and neurophysiological measurements to define in closer detail the cerebellar deficit and its influences on neocortical motor networks in various modalities that can be correlated with each other. In addition, by using non-invasive brain stimulation including transcranial direct current stimulation (tDCS) of the cerebellum we want to elucidate if the induction of cerebellar plasticity can compensate the Purkinje cell deficit and how clinical, behavioral, imaging and neurophysiological characteristics are modified through the change in cerebellar excitability output. This will enable us to create cause-consequence and genotype-phenotype-neurophysiological correlations that could be applied to idiopathic disease forms of cerebellar dysfunction. It will also further the understanding of the mode of action of cerebellar non-invasive brain stimulation techniques like tDCS and may open windows for new treatment approaches.