The structural underpinnings of disinhibition in dystonia

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PROJECT SUMMARY / ABSTRACT Dystonia is a brain-based disorder that leads affected muscles to twist and spasm, contorting the sufferer into painful and disabling positions. Dystonia afflicts 1 in 1000 people (the third-most common movement disorder). It can occur in isolation or be a symptom of many other neurological disorders (eg, stroke, cerebral palsy, Parkinson disease). Chronic pain, disability, and withdrawal from school or work are common, and in severe cases, dystonia can be fatal. A shared electrophysiologic abnormality links many types of dystonia: local and long-range disinhibition. This led to the hypothesis that impaired inhibition, and a related finding, poorly-refined sensory feedback, leads to abnormal co-contraction of agonist and antagonist muscles, producing the contorting movements of dystonia. However, impaired inhibition is only one step in a mechanistic cascade that leads to dystonia – the underlying structural abnormalities that produce disinhibition are unknown. Structural abnormalities in neurological disorders point the way to improved therapies. This proposal will use MRI to investigate brain regions that are potential anatomical substrates for impaired inhibition, with a larger goal of identifying new targets for dystonia treatment and prevention. We will address two key gaps in current dystonia knowledge: 1) the role of interhemispheric projections in regulating cortical motor activity (long-range disinhibition); 2) the role of the striatal compartments, striosome and matrix, in inhibiting unwanted movements. The study will employ novel structural, diffusion, and functional MRI techniques in two dystonia patient cohorts: we will carry out our imaging assessments in the most common forms in adults, cervical dystonia, and children, limb dystonia. These clinically-distinct populations will help determine which abnormalities are shared (mechanisms generalizable to other dystonias) and which are specific to certain types of dystonia. The mission of this Mentored Career Development Award is to seek fundamental knowledge about the brain’s inhibitory control of movement, and to use that knowledge to reduce the burden of dystonia. This goal parallels that of the National Institute of Neurological Disorders and Stroke: to investigate the neural mechanisms of sensory and motor circuits that can be compromised by disease. The proposal is tailored to my educational and training needs, ensuring that I will be prepared to succeed as an independent investigator utilizing the tools of systems neuroscience. With this award, I will gain essential training in: 1) biostatistics and network assessment tools such as principal component analysis, graph theoretical analysis, and causal inference modeling; 2) the experimental design and implementation of functional MRI (fMRI), including both task-based and resting state methods; 3) knowledge of the structure and connectivity of the striatum, pallidum, and thalamus. I will benefit from an environment enriched in neuroimaging, movement disorders, and neurodevelopmental expertise, where I can build a substantial foundation for a successful independent research career devoted to improving the therapies available for treating dystonia.