Spasmodic dysphonia, or laryngeal dystonia, is a chronic debilitating condition that selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD often extends beyond vocal communication impairment and causes significant occupational disability and life-long social isolation. SD becomes even more incapacitating when it is associated with dystonic voice tremor (VT), which is present in about 1/3 of SD patients and is characterized by the inability to sustain a vowel for more than a few seconds. Current treatment of these disorders is limited to the temporary management of voice symptoms with repeated injections of botulinum toxin into the laryngeal muscles, which, however, are not effective in all SD patients and even less so in combined SD/VT cases. There is, therefore, a critical need to identify alternative therapeutic options that are specifically targeting the pathophysiology of SD and VT. On the other hand, the design and use of such novel therapeutic approaches will be largely unattainable if their central mechanisms of action remain unknown. Our long-term goal is to determine the pathophysiology of SD and related disorders, such as VT, and develop new diagnostic and treatment options for these patients. The objective of this application is to elucidate the primary determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem), in alcohol-responsive SD and SD/VT patients. Our central hypothesis is that clinical benefits of sodium oxybate are contingent upon selective modulation of neural alterations associated with genetics susceptibility factors that underlie symptom responsiveness to alcohol in SD and VT. Using a comprehensive approach of clinico- behavioral testing, neuroimaging and pharmacogenetics, our central hypothesis will be tested by pursuing two specific aims, which will: (1) determine the clinical response of SD and VT symptoms to sodium oxybate, and (2) identify primary markers of clinical benefits of sodium oxybate in these disorders. This research is innovative because it will use a controlled experimental design that focuses on detailed characterization of primary effects of a novel oral medication, sodium oxybate, for treatment of SD and VT symptoms. The proposed research is significant because it is expected to have broad translational impact on improving the clinical management of patients with SD and VT, opening new therapeutic horizons for treatment of these and similar disorders.

Public Health Relevance

The proposed research aims to determine the central mechanisms and functional markers that underlie the clinical response to a novel pharmacological agent, sodium oxybate (Xyrem), in spasmodic dysphonia with and without voice tremor. The proposed research is relevant to public health because the establishment of the central mechanisms of drug's action that are specifically linked to the disorder pathophysiology is expected to have a rigorous scientific premise for the future design of large clinical trials and the ultimate translation of this novel treatment into clinical practice. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help significantly 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 #
5R01DC012545-07
Application #
9539510
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2012-07-17
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
7
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
Blitzer, Andrew; Brin, Mitchell F; Simonyan, Kristina et al. (2018) Phenomenology, genetics, and CNS network abnormalities in laryngeal dystonia: A 30-year experience. Laryngoscope 128 Suppl 1:S1-S9
Mor, Niv; Simonyan, Kristina; Blitzer, Andrew (2018) Central voice production and pathophysiology of spasmodic dysphonia. Laryngoscope 128:177-183
Simonyan, Kristina (2018) Neuroimaging Applications in Dystonia. Int Rev Neurobiol 143:1-30
Battistella, Giovanni; Kumar, Veena; Simonyan, Kristina (2018) Connectivity profiles of the insular network for speech control in healthy individuals and patients with spasmodic dysphonia. Brain Struct Funct 223:2489-2498
Rumbach, Anna F; Blitzer, Andrew; Frucht, Steven J et al. (2017) An open-label study of sodium oxybate in Spasmodic dysphonia. Laryngoscope 127:1402-1407
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 :
Kirke, Diana N; Battistella, Giovanni; Kumar, Veena et al. (2017) Neural correlates of dystonic tremor: a multimodal study of voice tremor in spasmodic dysphonia. Brain Imaging Behav 11:166-175
Simonyan, Kristina; Cho, Hyun; Hamzehei Sichani, Azadeh et al. (2017) The direct basal ganglia pathway is hyperfunctional in focal dystonia. Brain 140:3179-3190
Simonyan, Kristina; Ackermann, Hermann; Chang, Edward F et al. (2016) New Developments in Understanding the Complexity of Human Speech Production. J Neurosci 36:11440-11448
Simonyan, Kristina; Fuertinger, Stefan (2015) Speech networks at rest and in action: interactions between functional brain networks controlling speech production. J Neurophysiol 113:2967-78

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