Spasmodic dysphonia (SD) is isolated focal laryngeal dystonia characterized by selective impairment of voluntary voice control during speech production. Despite well-characterized clinical features of SD, its causes and pathophysiology remain unclear. Consequently, the absence of objective biomarkers of SD leads to diagnostic inaccuracies, while the lack of understanding of neural and molecular targets of SD pathophysiology hinders the development of novel therapeutic opportunities for SD patients. Our long-term goal is to determine the causes and pathophysiology of SD and to develop new diagnostic and treatment options for this disorder. The objective of this application is to identify imaging and genetic biomarkers of SD development and manifestation. Our central hypothesis is that functional and structural brain abnormalities, shaped, in part, by underlying causative genetic factors, exhibit disorder-characteristic features, which can be used as diagnostic and predictive SD biomarkers. Our central hypothesis has been formulated on the bases of our preliminary data. The rationale for the proposed studies is that identification of SD neural and genetic biomarkers would have direct clinical impact by establishing enhanced criteria for accurate differential diagnosis, screening of potential persons at-risk, and evaluation of mechanism-based novel pharmacological and/or surgical therapies for these patients. Using a comprehensive approach of multi-modal neuroimaging, machine learning algorithms, and next-generation DNA sequencing, our central hypothesis will be tested by pursuing three specific aims: (1) Identify and validate SD phenotype- and genotype-specific neural markers; (2) Establish endophenotypic markers of SD development; and (3) Identify SD gene(s) and their association with neural markers of SD susceptibility. This research is innovative, because it uses a cross-disciplinary approach as a tool for discovery of the mediating neural mechanisms that bridge the gap between the DNA sequence and SD pathophysiology. The proposed research is significant because it is expected to vertically advance and expand the understanding of the mechanistic aspects of brain alterations, identify neural markers and discover SD gene mutations. Ultimately, the results of these studies are expected to establish new knowledge, which will be critical for enhancement of SD clinical management and identification of novel approaches to new treatment options in these patients.