brainThe 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

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.
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

Presentations at the annual meeting of the Organization for Human Brain Mapping 2018, Singapore

June 17, 2018
Laura de Lima Xavier, MD, presented her latest study on environmental factors for developing spasmodic dysphonia, which showed that stressors influencing the sensory feedback from the larynx and upper respiratory tract represent major risk factors and are associated with abnormal cortical sensorimotor integration.
 
Daniel Moyer from USC presented our collaborative study with Greg Ver Steeg, PhD, and Aram Galstyan, PhD, on the use of a novel CorEx approach for analysis of high-dimensional fMRI networks.
 
Click here for the posters
 
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