circosThe research focus of the Simonyan Laboratory is two-fold: identification of the central mechanisms responsible for speech production and elucidation of the pathophysiology of neurological voice and speech disorders. 
Our earlier contributions involved identification of the extensive projection system of the laryngeal motor cortex in the rhesus monkey using neuroanatomical tract tracing. Using multimodal neuroimaging, our laboratory later played a central role in i) identification of the laryngeal motocortical representation in humans; ii) defining the functional connectome of speech production, and iii) elucidation of the mechanisms of dopaminergic neurotransmission during speaking, as well as those underlying left-hemispheric lateralization of speech networks. We are currently focused on examining temporal characteristics of laryngeal motocortical activity and the modulatory role of different neurotransmitters on neural networks controlling speech production. To this end, we are developing multi-compartmental neural population models to test specific hypotheses about speech motor control, which have remained extremely challenging to address due to either invasiveness of the applied methods or technical limitations.
Our contributions to the understanding of the pathophysiology of neurological speech disorders include a comprehensive mapping of brain functional, structural and dopaminergic alterations as well as identification of neuropathological changes in spasmodic dysphonia (laryngeal dystonia) and voice tremor. We demonstrated that focal dystonia is a disorder of large-scale functional neural networks, where abnormal regional interactions may contribute to network-wide alterations. We also established that abnormal sensory discrimination thresholds in patients with focal dystonias represent a common endophenotypic trait of this disorder. We further showed that clinically and genetically distinct forms of spasmodic dysphonia can be accurately classified based on cortical sensorimotor abnormalities, the latter serving as potential objective diagnostic markers for this disorder. Our laboratory described the first spasmodic dysphonia patient with a causative DYT25 (GNAL) mutation and determined the polygenic risk of focal dystonia. Most recently, we delineated the first effective use of a novel oral medication, sodium oxybate (Xyrem®), in patients with spasmodic dysphonia and voice tremor.
The Simonyan laboratory currently uses multi-modal neuroimaging, machine learning and neural population modeling to determine and validate phenotype- and genotype-specific neural markers of dystonia as well as the endophenotypic markers of its development. We are also working on identification of the primary neural determinants of clinical response to sodium oxybate in patients with dystonia and tremor as a potential new therapeutic option. Another goal is to delineate abnormal neurotransmission in dystonia, which would ultimately help identify other novel pharmacological targets. We are applying several genetic strategies, including next-generation sequencing in dystonia families and singleton cases as well as genome-wide association studies in isolated populations, in order to identify new genes and risk factors of spasmodic dysphonia.

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Recent Publications

Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia
Giovanni Battistella and Kristina Simonyan. 2019. “Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia.” Neurology.Abstract
OBJECTIVES: To determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia. METHODS: A total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder. RESULTS: ICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice. CONCLUSIONS: Abnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.
A separation of innate and learned vocal behaviors defines the symptomatology of spasmodic dysphonia
Samantha Guiry, Alexis Worthley, and Kristina Simonyan. 2018. “A separation of innate and learned vocal behaviors defines the symptomatology of spasmodic dysphonia.” Laryngoscope.Abstract
OBJECTIVE: Spasmodic dysphonia (SD) is a neurological disorder characterized by involuntary spasms in the laryngeal muscles. It is thought to selectively affect speaking; other vocal behaviors remain intact. However, the patients' own perspective on their symptoms is largely missing, leading to partial understanding of the full spectrum of voice alterations in SD. METHODS: A cohort of 178 SD patients rated their symptoms on the visual analog scale based on the level of effort required for speaking, singing, shouting, whispering, crying, laughing, and yawning. Statistical differences between the effort for speaking and the effort for other vocal behaviors were assessed using nonparametric Wilcoxon rank-sum tests within the overall SD cohort as well as within different subgroups of SD. RESULTS: Speech production was found to be the most impaired behavior, ranking as the most effortful type of voice production in all SD patients. In addition, singing required nearly similar effort as speaking, ranking as the second most altered vocal behavior. Shouting showed a range of variability in its alterations, being especially difficult to produce for patients with adductor form, co-occurring voice tremor, late onset of disorder, and familial history of dystonia. Other vocal behaviors, such as crying, laughing, whispering, and yawning, were within the normal ranges across all SD patients. CONCLUSION: Our findings widen the symptomatology of SD, which has predominantly been focused on selective speech impairments. We suggest that a separation of SD symptoms is rooted in selective aberrations of the neural circuitry controlling learned but not innate vocal behaviors. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018.
Neuroimaging Applications in Dystonia
Kristina Simonyan. 2018. “Neuroimaging Applications in Dystonia.” Int Rev Neurobiol, 143, Pp. 1-30.Abstract
Dystonia is a neurological disorder characterized by involuntary, repetitive movements. Although the precise mechanisms of dystonia development remain unknown, the diversity of its clinical phenotypes is thought to be associated with multifactorial pathophysiology, which is linked not only to alterations of brain organization, but also environmental stressors and gene mutations. This chapter will present an overview of the pathophysiology of isolated dystonia through the lens of applications of major neuroimaging methodologies, with links to genetics and environmental factors that play a prominent role in symptom manifestation.
A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity
Kristina Simonyan, Steven J Frucht, Andrew Blitzer, Azadeh Hamzehei Sichani, and Anna F Rumbach. 2018. “A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity.” Sci Rep, 8, 1, Pp. 16111.Abstract
Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.
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Latest News

A new grant award from the Department of Defense

September 25, 2018
BARI: Bilateral Academic Research Initiative
International partnerships for high-impact science
BARI is a pilot program that supports high-risk basic research as a bilateral academic collaboration. BARI’s inaugural year focuses on artificial intelligence and collaborative decision-making and sought proposals that build new frameworks for artificial intelligence agents to more truly team with human counterparts.  BARI also aims to support academic teams from the U.S. and U.K. to combine unique skillsets and approaches and provide rapid advances in scientific areas of mutual potential interest to the U.S. DoD and U.K. MOD.
Project Overview
This project aims to develop a novel architecture for complex group decision making that integrates, in an unprecedented way, the strengths of human and AI team members while compensating for their respective weaknesses. To address the challenges posed by the project, the proposers have assembled a multidisciplinary team with expertise in AI, machine learning, neural engineering, computer science, neuroscience and cognitive psychology. The team approach builds on many years of highly interdisciplinary research on group decision making assisted by Brain-Computer Interfaces (BCIs) in human and human-machine teams, as well as state of the art machine-learning technology, neuroscience, human-factors and psychophysiologic knowledge on decision making in humans and human teams.

Harvard Otolaryngology Spring 2018 issue

June 22, 2018
New Findings in Dystonia - Dr. Simonyan's research is highlighted in the Spring 2018 issue of Harvard Otolaryngology. 
“Continuation of [dystonia] research is vital in determining the exact causes and mechanisms of this disorder. This knowledge will be crucial for the future development of novel diagnostic procedures and advanced treatments, which will offer hope to so many people worldwide.”
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