Last updated on January 2019

Imaging Genetics of Spasmodic Dysphonia


Brief description of study

The contribution of genetic risk factors to the development of focal dystonias is evident. However, understanding of how variations in the causative gene expression lead to variations in brain abnormalities in different phenotypes of dystonia (e.g., familial, sporadic) remains limited. The research program of the investigators is set to determine the relationship between brain changes and genetic risk factors in spasmodic dysphonia (or laryngeal dystonia). The researchers use a novel approach of combined imaging genetics, next-generation DNA sequencing, and clinico-behavioral testing. The use of a cross-disciplinary approach as a tool for discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to pathophysiology of dystonia holds a promise for the understanding of the mechanistic aspects of brain function affected by risk gene variants, which can be used reliably for discovery of associated genes and neural integrity markers for this disorder. The expected outcome of this study may lead to better clinical management of this disorder, including its improved detection, accurate diagnosis, and assessment of the risk to develop spasmodic dysphonia in family members.

Detailed Study Description

Spasmodic dysphonia (SD) is an 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. The objective of this application is to identify imaging and genetic biomarkers of SD development and manifestation. The 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. 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, the 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 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.

Clinical Study Identifier: NCT03042975

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