This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 0062 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. Investigators will perform an in-depth characterization of functional/anatomical connectivity in subjects expressing genes for primary dystonia. The goal of this work will be to compare learning and related brain function in clinically manifesting and non-manifesting carriers of the major 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 positron emission tomography (PET) imaging. Complementary examinations will be conducted in the same subjects using diffusion tensor imaging (DTI)an magnetic resonance imaging (MRI) 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.
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