DYT1 Genotype- and Phenotype-Specific Brain Circuits in Dystonia - Project Summary/ Abstract DYT1 dystonia is a devastating movement disorder characterized by uncontrolled muscle contractions that result in abnormal, involuntary postures. The phenotype of dystonia is present in about 30% of DYT1 carriers, but it is unknown why 70% of carriers do not manifest the disorder. Unveiling the genetic underpinnings of the brain network dysfunction in dystonia is critical to fully understand the disorder. There is emerging evidence implicating cerebellar-striatal-cortical circuit dysfunction in the regulation of motor cortical output in dystonia. But previous neuroimaging studies were limited in resolution. We have an unprecedented opportunity to close this gap by determining the genotype-associated functional brain network, independent of the confound of clinical symptoms by studying the non-manifesting, gene-positive carriers compared with the DYT1 symptomatic carriers. Our central hypothesis is that there are maladaptive interactions in cognitive and motor networks, including the functional cerebellar-striatal-cortical network required for proper synchronization of movement in carriers with DYT1 compared to controls (i.e., the connectivity dysfunction is gene-specific), but varies according to clinical phenotype (i.e., DYT1 manifesting carriers with dystonia symptoms vs DYT1 non-manifesting carriers) which will help reveal the brain state associated with phenotype. While existing neuroimaging studies have provided important insights into the global neural circuitry underlying dystonia, brain region organization is variable across individuals, and standard group analyses may obscure biologically important signals. We propose a novel imaging paradigm to reliably measure the subject-specific, task-evoked functional activation (Aim 1) as well as subject-specific resting-state functional connectivity (Aim 2) for the first time in this disease. To reveal the gene-brain-behavior links in dystonia, we will study a unique group of patients and their families, using high resolution fMRI and advanced computational analyses of brain connectivity to determine the overall contribution of gene and clinical status to brain circuity. The outcome of this R21 proposal will be a clear understanding of the brain network dysfunction associated with the DYT1 gene, to elucidate why some people develop the dystonia phenotype (manifesting) and others do not. These findings will provide critical underpinnings for future work. We will be well-positioned to 1) test the resultant brain-based biomarker as a potential signal for which people with the DYT1 gene (carriers) will develop dystonia (manifest) or to explicate the physiologic effects of new treatments as they develop, and 2) develop neuromodulation protocols to address specific neural dysfunction as a treatment in dystonia, given its ability to modify brain connectivity. Finally, 3) the advanced neuroimaging methodology assures enhanced resolution in understanding the complex network abnormality that may be applicable in other types of dystonia.
