SD is a chronic debilitating condition, characterized by selective loss of voluntary voice control during speech production due to uncontrolled spasms in the laryngeal muscles. SD becomes even more incapacitating when it is associated with action-induced voice tremor (VT) due to its poor response to gold standard treatment with botulinum toxin. There is, therefore, a critical need to identify new treatment opportunities for SD/VT patients who receive limited, if any, benefits from botulinum toxin injections. The design and use of novel therapeutic approaches for these patients will, however, be largely unattainable if the central mechanisms of SD and VT development remain unknown. Our long-term goal is to determine the pathophysiology of SD and related disorders, such as VT, for the development of new diagnostic and treatment options for these patients. The objective of this application is to identify brain abnormalities in SD and SD/VT patients as the basis for characterization of central mechanisms underlying symptom improvement following the use of sodium oxybate, a novel pharmacological agent for treatment of ethanol-responsive dystonia. Our central hypothesis is that, compared to SD patients, SD/VT patients will have additional brain abnormalities within the sensorimotor brain circuits controlling voice production, which are being modulated to a greater extent with sodium oxybate treatment. We further postulate that clinical efficacy of sodium oxybate treatment will correlate with its central modulatory effects. The rationale for the proposed research is that identification of distinct brain mechanisms underlying SD and SD/VT clinical manifestations would provide the necessary insights into the pathophysiology of these disorders, while understanding the neural correlates of sodium oxybate action would allow establishment of a scientific rationale for the use of a novel treatment in these disorders. Using a comprehensive approach of multi-modal neuroimaging and clinico-behavioral testing, our central hypothesis will be tested by pursuing two specific aims: (1) determine disorder-specific brain abnormalities in SD and SD/VT patients, and (2) characterize the central effects of sodium oxybate treatment in ethanol-responsive SD and SD/VT patients. This research is innovative because it focuses not only on identification of distinct pathophysiological factors contributing to SD and VT development, but also on discovery of mechanisms of central effects of a novel oral medication, sodium oxybate, which holds promise for treatment of refractory symptoms in SD and SD/VT. The proposed research is significant because it will advance our understanding of the pathophysiology of dystonia in general and SD in particular as well as will have direct impact on improvement of clinical management of SD and SD/VT patients.

Public Health Relevance

The proposed research aims to determine brain abnormalities in SD and SD/VT patients as the basis for characterization of central mechanisms underlying symptom improvement following the use of sodium oxybate, a novel oral medication for the treatment of ethanol-responsive dystonia. The proposed research is relevant to public health because the elucidation of disorder-specific mechanistic aspects of brain organization in SD vs. SD/VT is ultimately expected to lead to establishment of enhanced criteria for clinical management of these disorders, including differential 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 to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
4R01DC012545-05
Application #
9094539
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2012-07-17
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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
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
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

Showing the most recent 10 out of 15 publications