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

• Applicant: Dr. Anne Weißbach
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Human Cognitive and Systems Neuroscience
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419234264

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.

• DFG Programme: Research Grants