Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements, ranging from action-induced dystonic symptoms to disabling, generalized dystonia. The most frequent genetic variant of PTD is an autosomal dominant mutation mapping to the DYT1 gene on chromosome 9q34 within the coding area for torsin A. However, the pathophysiological link between mutant torsin A and disease manifestation remains unknown. We have developed an integrated psychophysical and multimodal imaging approach to identify abnormal brain-behavior relationships in basal ganglia disease, and to assess their potential reversal with treatment. In the proposed studies, we plan to use this approach to perform an in-depth characterization of functional/anatomical connectivity in subjects expressing genes for primary dystonia. The overarching goal of this work will be to compare learning and related brain function in clinically manifesting and nonmanifesting carriers of the majopr genotypes associated with PTD, DYT1 and the DYT6 mutations in North American Mennonites. Our hypothesis, based on our preliminary data, is that PTD is associated with a functional/anatomical disorder of fronto-striatal pathways, and that this abnormality is more extensive in affecteds as compared with non-manifesting dystonia gene carriers. Group differences in the functional organization of the brain during sequence learning will be assessed using PET imaging. Complementary examinations of anatomical connectivity will be conducted in the same subjects using diffusion tensor imaging (DTI), a novel magnetic resonance technique for the assessment of the direction and integrity of fiber tracts. The role of striatal D2 receptor binding in the development of functional abnormalities in basal ganglia output pathways and in concomitant manifestations will be assessed in both PTD mutation carriers. Lastly, we will use our psychophysical/PET approach in conjunction with deep brain stimulation (DBS) to determine the degree to which motor and non-motor functioning can be reversed through treatment. Together, these studies will provide important information about the physiological mechanisms that underlie primary torsion dystonia, and the possible therapeutic effect of deep brain stimulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroscience and Disease Study Section (CND)
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Tagle, Danilo A
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Feinstein Institute for Medical Research
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