Task-specific primary focal dystonias (tsPFDs) are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing, playing a musical instrument, speaking, or singing. Despite the recent advances in describing the clinical features of dystonia, there is a fundamental gap in understanding the neural abnormalities underlying the development of tsPFDs, which affect the same muscles but result in different clinical manifestations as in writer's cramp vs. pianist's dystonia or spasmodic dysphonia vs. singer's dystonia. Continued existence of this gap is an important problem because it renders us unable to differentiate between primary and secondary brain changes contributing to the tsPFD pathophysiology and to develop novel treatment options targeting disorder-specific brain alterations. Our long-term goal is to determine the causes and pathophysiology of primary focal dystonia for its improved clinical management. The objective of this application is to identify the brain mechanisms underlying the phenomenon of task specificity in two representative groups of patients with writer's cramp vs. musician's hand dystonia and spasmodic dysphonia vs. singer's laryngeal dystonia using a novel approach of combined clinico-behavioral examination, brain network analysis and quantitative neuropathology of postmortem brain tissue. Our central hypothesis is that each tsPFD is characterized by distinct brain abnormalities, which selectively affect the focal segments of brain networks responsible for the performance of the respective motor task. The rationale for the proposed research is that identification of tsPFD-specific brain changes and associated neuropathology will clarify the neural mechanisms (primary vs. secondary) contributing to the clinical manifestation of these disorders and thus explain the phenomenon of task-specificity in PFDs. The obtained results are expected to provide strong scientific bases for the next series of studies directed towards identification and validation of novel pharmacological and/or surgical therapies for these patients. We will pursue the following two specific aims: (1) determine distinct features of brain functional network abnormalities underlying task-specificity in different tsPFDs, and (2) establish structural correlates of functional neuroimaging abnormalities in tsPFDs. This research is innovative because it will be among the first detailed investigations designed specifically to focus on defining tsPFD neural markers. The proposed research is significant because it is expected to establish scientific evidence that tsPFD is a network disorder with abnormalities following distinct patterns in different tsPFDs and certain abnormalities showing structure-function correlations are associated with underlying neuropathology. By converging the results from multimodal cross-disciplinary studies to a coherent and pathophysiologically meaningful picture, we will be well positioned to identify primary vs. secondary changes in tsPFDs and establish a scientific framework for the development of diagnostic biomarkers and novel treatment options for these disorders.
The proposed research aims to determine the pathophysiological mechanisms underlying the phenomenon of task specificity in dystonia using a novel approach of combined brain network analysis, clinico-behavioral testing, and neuropathological examination of postmortem brain tissue. The proposed research is relevant to public health because identification of distinct neural abnormalities between different forms of tsPFDs is ultimately expected to lead to establishment of enhanced criteria for clinical management of tsPFDs, including their detection, 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.
| Simonyan, Kristina (2018) Neuroimaging Applications in Dystonia. Int Rev Neurobiol 143:1-30 |
| 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 |
| Fuertinger, Stefan; Simonyan, Kristina (2018) Task-specificity in focal dystonia is shaped by aberrant diversity of a functional network kernel. Mov Disord 33:1918-1927 |
| Fuertinger, Stefan; Simonyan, Kristina (2017) Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. J Neurosci 37:7438-7449 |
| 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 |
| 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 : |
| 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 |
| 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 |
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