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 the 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

Connectivity profiles of the insular network for speech control in healthy individuals and patients with spasmodic dysphonia
Giovanni Battistella, Veena Kumar, and Kristina Simonyan. 2018. “Connectivity profiles of the insular network for speech control in healthy individuals and patients with spasmodic dysphonia.” Brain Struct Funct, 223, 5, Pp. 2489-2498.Abstract
The importance of insula in speech control is acknowledged but poorly understood, partly due to a variety of clinical symptoms resulting from insults to this structure. To clarify its structural organization within the speech network in healthy subjects, we used probabilistic diffusion tractography to examine insular connectivity with three cortical regions responsible for sound processing [Brodmann area (BA) 22], motor preparation (BA 44) and motor execution (laryngeal/orofacial primary motor cortex, BA 4). To assess insular reorganization in a speech disorder, we examined its structural connectivity in patients with spasmodic dysphonia (SD), a neurological condition that selectively affects speech production. We demonstrated structural segregation of insula into three non-overlapping regions, which receive distinct connections from BA 44 (anterior insula), BA 4 (mid-insula) and BA 22 (dorsal and posterior insula). There were no significant differences either in the number of streamlines connecting each insular subdivision to the cortical target or hemispheric lateralization of insular clusters and their projections between healthy subjects and SD patients. However, spatial distribution of the insular subdivisions connected to BA 4 and BA 44 was distinctly organized in healthy controls and SD patients, extending ventro-posteriorly in the former group and anterio-dorsally in the latter group. Our findings point to structural segregation of the insular sub-regions, which may be associated with the different aspects of sensorimotor and cognitive control of speech production. We suggest that distinct insular involvement may lead to different clinical manifestations when one or the other insular region and/or its connections undergo spatial reorganization.
Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity
Gregory Garbès Putzel, Giovanni Battistella, Anna F Rumbach, Laurie J Ozelius, Mert R Sabuncu, and Kristina Simonyan. 2018. “Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity.” Cereb Cortex, 28, 1, Pp. 158-166.Abstract
Spasmodic dysphonia (SD), or laryngeal dystonia, is an isolated task-specific dystonia of unknown causes and pathophysiology that selectively affects speech production. Using next-generation whole-exome sequencing in SD patients, we computed polygenic risk score from 1804 genetic markers based on a genome-wide association study in another form of similar task-specific focal dystonia, musician's dystonia. We further examined the associations between the polygenic risk score, resting-state functional connectivity abnormalities within the sensorimotor network, and SD clinical characteristics. We found that the polygenic risk of dystonia was significantly associated with decreased functional connectivity in the left premotor/primary sensorimotor and inferior parietal cortices in SD patients. Reduced connectivity of the inferior parietal cortex was correlated with the age of SD onset. The polygenic risk score contained a significant number of genetic variants lying near genes related to synaptic transmission and neural development. Our study identified a polygenic contribution to the overall genetic risk of dystonia in the cohort of SD patients. Associations between the polygenic risk and reduced functional connectivity of the sensorimotor and inferior parietal cortices likely represent an endophenotypic imaging marker of SD, while genes involved in synaptic transmission and neuron development may be linked to the molecular pathophysiology of this disorder.
Phenomenology, genetics, and CNS network abnormalities in laryngeal dystonia: A 30-year experience
Andrew Blitzer, Mitchell F Brin, Kristina Simonyan, Laurie J Ozelius, and Steven J Frucht. 2018. “Phenomenology, genetics, and CNS network abnormalities in laryngeal dystonia: A 30-year experience.” Laryngoscope, 128 Suppl 1, Pp. S1-S9.Abstract
OBJECTIVE: Laryngeal dystonia (LD) is a functionally specific disorder of the afferent-efferent motor coordination system producing action-induced muscle contraction with a varied phenomenology. This report of long-term studies aims to review and better define the phenomenology and central nervous system abnormalities of this disorder and improve diagnosis and treatment. METHODS: Our studies categorized over 1,400 patients diagnosed with LD over the past 33 years, including demographic and medical history records and their phenomenological presentations. Patients were grouped on clinical phenotype (adductor or abductor) and genotype (sporadic and familial) and with DNA analysis and functional magnetic resonance imaging (fMRI) to investigate brain organization differences and characterize neural markers for genotype/phenotype categorization. A number of patients with alcohol-sensitive dystonia were also studied. RESULTS: A spectrum of LD phenomena evolved: adductor, abductor, mixed, singer's, dystonic tremor, and adductor respiratory dystonia. Patients were genetically screened for DYT (dystonia) 1, DYT4, DYT6, and DYT25 (GNAL)-and several were positive. The functional MRI studies showed distinct alterations within the sensorimotor network, and the LD patients with a family history had distinct cortical and cerebellar abnormalities. A linear discriminant analysis of fMRI findings showed a 71% accuracy in characterizing LD from normal and in characterizing adductor from abductor forms. CONCLUSION: Continuous studies of LD patients over 30 years has led to an improved understanding of the phenomenological characteristics of this neurological disorder. Genetic and fMRI studies have better characterized the disorder and raise the possibility of making objective rather than subjective diagnoses, potentially leading to new therapeutic approaches. Laryngoscope, 128:S1-S9, 2018.
Screening study of TUBB4A in isolated dystonia
Franca Vulinovic, Susen Schaake, Aloysius Domingo, Kishore Raj Kumar, Giovanni Defazio, Pablo Mir, Kristina Simonyan, Laurie J Ozelius, Norbert Brüggemann, Sun Ju Chung, Aleksandar Rakovic, Katja Lohmann, and Christine Klein. 2017. “Screening study of TUBB4A in isolated dystonia.” Parkinsonism Relat Disord, 41, Pp. 118-120.Abstract
Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum ranging from hereditary generalized dystonia with whispering dysphonia (DYT4) to the leukodystrophy hypomyelination syndrome with atrophy of the basal ganglia and cerebellum (H-ABC). To test for the contribution of TUBB4A mutations in different ethnicities (Spanish, Italian, Korean, Japanese), we screened 492 isolated dystonia cases for mutations in this gene and for the first time determined TUBB4A copy number variations in 336 dystonia patients. A potentially pathogenic rare 3bp-in-frame deletion was found in a patient with cervical dystonia but no copy number variations were detected in this study, suggesting that TUBB4A mutations exceedingly rarely contribute to the etiology of isolated dystonia.

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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