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.
 

We have new studies and we are recruiting particpants! Come join us to move the research forward! More info here

 

Join our Team - Open Positions! More info here

Recent Publications

Functional and structural neural bases of task specificity in isolated focal dystonia
Serena Bianchi, Stefan Fuertinger, Hailey Huddleston, Steven J Frucht, and Kristina Simonyan. 2019. “Functional and structural neural bases of task specificity in isolated focal dystonia.” Mov Disord.Abstract
BACKGROUND: Task-specific focal dystonias selectively affect movements during the production of highly learned and complex motor behaviors. Manifestation of some task-specific focal dystonias, such as musician's dystonia, has been associated with excessive practice and overuse, whereas the etiology of others remains largely unknown. OBJECTIVES: In this study, we aimed to examine the neural correlates of task-specific dystonias in order to determine their disorder-specific pathophysiological traits. METHODS: Using multimodal neuroimaging analyses of resting-state functional connectivity, voxel-based morphometry and tract-based spatial statistics, we examined functional and structural abnormalities that are both common to and distinct between four different forms of task-specific focal dystonias. RESULTS: Compared to the normal state, all task-specific focal dystonias were characterized by abnormal recruitment of parietal and premotor cortices that are necessary for both modality-specific and heteromodal control of the sensorimotor network. Contrasting the laryngeal and hand forms of focal dystonia revealed distinct patterns of sensorimotor integration and planning, again involving parietal cortex in addition to inferior frontal gyrus and anterior insula. On the other hand, musician's dystonia compared to nonmusician's dystonia was shaped by alterations in primary and secondary sensorimotor cortices together with middle frontal gyrus, pointing to impairments of sensorimotor guidance and executive control. CONCLUSION: Collectively, this study outlines a specialized footprint of functional and structural alterations in different forms of task-specific focal dystonia, all of which also share a common pathophysiological framework involving premotor-parietal aberrations. © 2019 International Parkinson and Movement Disorder Society.
Recent advances in understanding the role of the basal ganglia
Kristina Simonyan. 2019. “Recent advances in understanding the role of the basal ganglia.” F1000Res, 8.Abstract
The basal ganglia are a complex subcortical structure that is principally involved in the selection and implementation of purposeful actions in response to external and internal cues. The basal ganglia set the pattern for facilitation of voluntary movements and simultaneous inhibition of competing or interfering movements. In addition, the basal ganglia are involved in the control of a wide variety of non-motor behaviors, spanning emotions, language, decision making, procedural learning, and working memory. This review presents a comparative overview of classic and contemporary models of basal ganglia organization and functional importance, including their increased integration with cortical and cerebellar structures.
Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling
Ikuo Masuho, Sreenivas Chavali, Brian S Muntean, Nickolas K Skamangas, Kristina Simonyan, Dipak N Patil, Grant M Kramer, Laurie Ozelius, Madan M Babu, and Kirill A Martemyanov. 2018. “Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling.” Cell Rep, 24, 3, Pp. 557-568.e5.Abstract
Despite the wealth of genetic information available, mechanisms underlying pathological effects of disease-associated mutations in components of G protein-coupled receptor (GPCR) signaling cascades remain elusive. In this study, we developed a scalable approach for the functional analysis of clinical variants in GPCR pathways along with a complete analytical framework. We applied the strategy to evaluate an extensive set of dystonia-causing mutations in G protein Gαolf. Our quantitative analysis revealed diverse mechanisms by which pathogenic variants disrupt GPCR signaling, leading to a mechanism-based classification of dystonia. In light of significant clinical heterogeneity, the mechanistic analysis of individual disease-associated variants permits tailoring personalized intervention strategies, which makes it superior to the current phenotype-based approach. We propose that the platform developed in this study can be universally applied to evaluate disease mechanisms for conditions associated with genetic variation in all components of GPCR signaling.
Dopamine drives left-hemispheric lateralization of neural networks during human speech
Stefan Fuertinger, Joel C Zinn, Ashwini D Sharan, Farid Hamzei-Sichani, and Kristina Simonyan. 2018. “Dopamine drives left-hemispheric lateralization of neural networks during human speech.” J Comp Neurol, 526, 5, Pp. 920-931.Abstract
Although the concept of left-hemispheric lateralization of neural processes during speech production has been known since the times of Broca, its physiological underpinnings still remain elusive. We sought to assess the modulatory influences of a major neurotransmitter, dopamine, on hemispheric lateralization during real-life speaking using a multimodal analysis of functional MRI, intracranial EEG recordings, and large-scale neural population simulations based on diffusion-weighted MRI. We demonstrate that speech-induced phasic dopamine release into the dorsal striatum and speech motor cortex exerts direct modulation of neuronal activity in these regions and drives left-hemispheric lateralization of speech production network. Dopamine-induced lateralization of functional activity and networks during speaking is not dependent on lateralization of structural nigro-striatal and nigro-motocortical pathways. Our findings provide the first mechanistic explanation for left-hemispheric lateralization of human speech that is due to left-lateralized dopaminergic modulation of brain activity and functional networks.

Latest News

Dr. Simonyan has been named an Associate Editor of the Journal of Clinical Movement Disorders

February 12, 2019
Journal of Clinical Movement Disorders focuses on scientific investigations into the diagnosis, evaluation and management of patients with involuntary movement disorders. The journal reviews, illustrates and emphasizes clinical phenomenology as an indispensable tool for diagnosis and application of translational medicine to movement disorders. Topics covered in the journal include Parkinson's disease, tremor, dystonia, chorea, myoclonus, Huntington's disease, tics, deep brain stimulation, botulinum toxin, and pediatric movement disorders. Journal of Clinical Movement Disorders is particularly interested in receiving submissions on international perspectives and clinical observations in movement disorders, and welcomes investigations in both hypokinetic and hyperkinetic movement disorders. Video demonstrations of patients are also strongly encouraged.

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.
 
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