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

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.
Central voice production and pathophysiology of spasmodic dysphonia
Niv Mor, Kristina Simonyan, and Andrew Blitzer. 2018. “Central voice production and pathophysiology of spasmodic dysphonia.” Laryngoscope, 128, 1, Pp. 177-183.Abstract
OBJECTIVE: Our ability to speak is complex, and the role of the central nervous system in controlling speech production is often overlooked in the field of otolaryngology. In this brief review, we present an integrated overview of speech production with a focus on the role of central nervous system. The role of central control of voice production is then further discussed in relation to the potential pathophysiology of spasmodic dysphonia (SD). DATA SOURCES: Peer-review articles on central laryngeal control and SD were identified from PUBMED search. Selected articles were augmented with designated relevant publications. REVIEW METHODS: Publications that discussed central and peripheral nervous system control of voice production and the central pathophysiology of laryngeal dystonia were chosen. RESULTS: Our ability to speak is regulated by specialized complex mechanisms coordinated by high-level cortical signaling, brainstem reflexes, peripheral nerves, muscles, and mucosal actions. Recent studies suggest that SD results from a primary central disturbance associated with dysfunction at our highest levels of central voice control. The efficacy of botulinum toxin in treating SD may not be limited solely to its local effect on laryngeal muscles and also may modulate the disorder at the level of the central nervous system. CONCLUSION: Future therapeutic options that target the central nervous system may help modulate the underlying disorder in SD and allow clinicians to better understand the principal pathophysiology. LEVEL OF EVIDENCE: NA.Laryngoscope, 128:177-183, 2018.

Latest News

Humans of HBI - Arman Simonyan

August 19, 2019

The neuroscience community at Harvard is brimming with talented and interesting individuals, each with their own unique stories on how they got here, what motivates them, what passions and dreams they have, who inspires them and what they do for fun.

Read here about Arman Simonyan, who visited and worked in the lab this Summer. 

Boston Speech Motor Control Symposium Award

June 21, 2019
Laura
Laura de Lima Xavier, MD, won the Best Poster Design Award at the Boston Speech Motor Contorl Symposium for her poster: "Sex differences and asymmetries in cortical thickness within the speech production network" on June 21, 2019, Boston, MA.
BSMCS Poster.pdf12.51 MB

Organization for Human Brain Mapping Award

June 13, 2019
dv
Davide Valeriani, PhD, won the People’s Choice Abstract Award for the poster: “Automatic Diagnosis of Spasmodic Dysphonia with Structural MRI and Machine Learning” presented at the annual meeting of the Organization for Human Brain Mapping (OHBM) on June 9-13, 2019, in Rome, Italy. 
OHBM Poster.pdf5.33 MB
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