Kristina Simonyan
Job Description
We investigate neural mechanisms of isolated focal dystonia and tremor to determine the disorder-specific pathophysiology and develop novel diagnostic tools and therapeutic strategies for these patients. We use a variety of experimental approaches, including multimodal neuroimaging, advanced machine learning, clinical-behavioral testing, neuropathology, and genetics.
The Dystonia and Speech Motor Control Laboratory is supported by the National Institutes of Health – National Institute on Deafness and Other Communication Disorders (NIDCD) and National Institute of Neurological Disorders and Stroke (NINDS), Department of Defense, Amazon Web Services, Jazz Pharmaceuticals, Mass General Brigham Innovation.
The organziation of functional neural communities during the resting state, sequential finger tapping, syllable production, auditory discrimination of pure tones, and sentence production (left to right) (Fueritnger S, Horwitz B, Simonyan K et al., PLoS Biol 2015)
Speech production is one of the most complex and rapid motor behaviors that are uniquely human. The development of our ability to speak relies on the abilities to listen to the speech, comprehend and process the meaning of heard words, and precisely coordinate the function of more than 100 laryngeal, orofacial and respiratory muscles in order to utter speech sounds. Neural correlates of speech production have been explored for over a century. However, a number of questions still remain unanswered about their structure and function in both healthy humans and patients with neurological voice and speech disorders. Our research focuses on the organization of functional and structural brain networks during speech production, the temporal characteristics of the laryngeal motor cortical activity, and how different neurotransmitters (e.g., dopamine, GABA) influence and modulate the brain networks during speaking and other laryngeal behaviors.
(A) Empirical and simulated functional networks in the resting state and during speech production and (B) nodal strength for experimental (left column) and simulated (right column) functional networks in resting state (gray) and during speech production (red) (Fürtinger S, Zinn JC, Simonyan, PLoS Comp Biol, 2014)
Starting with the Hodgkin-Huxley model in the 1950s, the fundamental concept of computational neuroscience has always been to understand the theoretical mechanisms of information processing in the human brain. The exponential growth of computing power in recent years allowed detailed simulations of brain activity using large-scale neural models. We are developing multi-compartment neural population models based on detailed neurophysiological considerations using our experimental data. Through neural modeling, we are targeting the unanswered questions about the functional networks and neurotransmitter function in speech control, which are difficult to address experimentally due to either invasiveness of applied methods or technical challenges. One example of these studies is to determine the extent of dopaminergic and GABAergic influence on the well-known lateralization of functional and structural brain networks controlling speech production.
Functional architecture of neural networks in patients with familial and sporadic forms of laryngeal dystonia (i.e., spasmodic dysphonia). Left panel: spatial topology of functional communities in the group-averaged networks. Right panel: distribution of bivariate provincial (yellow) and connector (red) hubs and their connectivity profiles with high-influence nodes (purple) in familial and sporadic laryngeal dystonia (Fuertinger S and Simonyan K, J Neurosci, 2017).
Laryngeal dystonia is isolated focal dystonia characterized by selective impairment of voluntary voice control predominantly during speech production. Despite well-characterized clinical features of LD, its causes and pathophysiology remain unclear. Consequently, the absence of objective biomarkers of LD leads to diagnostic inaccuracies, while the lack of understanding of its neural and molecular targets hinders the development of novel therapeutic opportunities for these patients. Funded by the National Institute on Deafness and other Communication Disorders, National Institutes of Health (NIDCD/NIH R01DC011805), our research program is set to identify imaging and genetic biomarkers of LD development and manifestation. We use a comprehensive approach of multi-modal neuroimaging, machine learning, and next-generation DNA sequencing as tools for the discovery of the mediating neural mechanisms that bridge the gap between the DNA sequence and LD pathophysiology. Knowledge obtained from these studies is expected to have a direct clinical impact by establishing enhanced criteria for accurate and objective diagnosis, screening of persons at-risk, and evaluation of mechanism-based novel pharmacological and/or surgical therapies for these patients.
Large-scale neural community architecture during the resting state in healthy subjects and its pathophysiological disorganization in patients with task-specific dystonia (laryngeal dystonia and writer’s cramp) and patients with nontask-specific dystonia (cervical dystonia and blepharospasm) (Battistella G et al. Cerebral Cortex, 2017).
Task-specific focal dystonias are characterized by selective activation of dystonic movements during the performance of highly learned motor tasks, such as writing or speaking. To date, we have only limited knowledge about the distinct neural abnormalities that lead to the development of task-specificity in focal dystonias, which affect similar muscle groups but result in different clinical manifestations, such as writer’s cramp vs. pianist’s dystonia or spasmodic dysphonia vs. singer’s dystonia. Funded by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH R01NS088160), our goal is to dissect the pathophysiological mechanisms underlying the phenomenon of task specificity in isolated focal dystonias using multi-level brain network analysis in conjunction with neuropathological examination of postmortem brain tissue from patients with dystonia. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.
Topological distribution of striatal dopaminergic function in healthy subjects and patients with writer’s cramp and laryngeal dystonia (Simonyan K et al., Brain 2017).
Despite the recent progress in elucidating functional brain abnormalities within the basal ganglia-thalamo-cortical circuitry in focal dystonias, there is a fundamental gap in understanding the neurochemical correlates underpinning the functional alterations in these disorders. Our goal is to provide detailed knowledge about the neurotransmission via GABAA, D1– and D2-family receptors in patients with different forms of focal dystonia. This information will help determine the contribution of GABAergic and dopaminergic neurotransmission to the pathophysiology of dystonia, as well as identify potential new pharmacological targets for novel treatment options.
