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.

Public Health Relevance

The proposed research aims to identify the neural markers and causative genetic factors of spasmodic dysphonia (SD), which is a form of isolated focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The proposed research is relevant to public health because the elucidation of the mechanistic aspects of abnormal brain organization and underlying genetic factors is ultimately expected to have a positive translational impact on establishing the enhanced criteria for improved clinical management of SD, including its detection, accurate diagnosis and treatment. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burden of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC011805-08
Application #
9411095
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2012-03-19
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Killian, Owen; McGovern, Eavan M; Beck, Rebecca et al. (2017) Practice does not make perfect: Temporal discrimination in musicians with and without dystonia. Mov Disord 32:1791-1792
Simonyan, Kristina; Cho, Hyun; Hamzehei Sichani, Azadeh et al. (2017) The direct basal ganglia pathway is hyperfunctional in focal dystonia. Brain 140:3179-3190
Fuertinger, Stefan; Simonyan, Kristina (2017) Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. J Neurosci 37:7438-7449
Vancea, Roxana; Simonyan, Kristina; Petracca, Maria et al. (2017) Cognitive performance in mid-stage Parkinson's disease: functional connectivity under chronic antiparkinson treatment. Brain Imaging Behav :
Fuertinger, Stefan; Zinn, Joel C; Sharan, Ashwini D et al. (2017) Dopamine drives left-hemispheric lateralization of neural networks during human speech. J Comp Neurol :
Vulinovic, Franca; Schaake, Susen; Domingo, Aloysius et al. (2017) Screening study of TUBB4A in isolated dystonia. Parkinsonism Relat Disord 41:118-120
Bianchi, Serena; Battistella, Giovanni; Huddleston, Hailey et al. (2017) Phenotype- and genotype-specific structural alterations in spasmodic dysphonia. Mov Disord 32:560-568
Battistella, Giovanni; Termsarasab, Pichet; Ramdhani, Ritesh A et al. (2017) Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks. Cereb Cortex 27:1203-1215
Putzel, Gregory G; Fuchs, Tania; Battistella, Giovanni et al. (2016) GNAL mutation in isolated laryngeal dystonia. Mov Disord 31:750-5
Rittiner, Joseph E; Caffall, Zachary F; Hernández-Martinez, Ricardo et al. (2016) Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2? Signaling as a Generalizable Mechanism for Dystonia. Neuron 92:1238-1251

Showing the most recent 10 out of 27 publications