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

Neural Representations of the Voice Tremor Spectrum
Laura de Lima Xavier and Kristina Simonyan. 2020. “Neural Representations of the Voice Tremor Spectrum.” Mov Disord.Abstract
OBJECTIVES: Voice tremor is a common movement disorder that manifests as involuntary oscillations of laryngeal muscles, leading to rhythmic alterations in voice pitch and loudness. Differential diagnosis of essential tremor of voice (ETv) is often challenging and includes dystonic tremor of voice (DTv), which is characterized by irregular, isometric contractions of laryngeal muscles during dystonic activity. Although clinical characteristics of voice tremor are well described, the pathophysiology underlying its heterogeneous phenomenology remains limited. METHODS: We used a multimodal approach of functional magnetic resonance imaging for assessment of brain activity during symptomatic speech production, high-resolution magnetic resonance imaging for the examination of cortical thickness and gray matter volume, and diffusion-weighted imaging for evaluation of white matter integrity to identify disorder-specific neural alterations and their relationships with the symptomatology of ETv and DTv. RESULTS: We found a broad overlap between cortical alterations in ETv and DTv, involving sensorimotor regions responsible for the integration of multisensory information during speech production, such as primary sensorimotor, inferior/superior parietal, and inferior temporal cortices. In addition, ETv and DTv showed unique patterns of abnormalities in regions controlling speech motor preparation, which were localized in the cerebellum in ETv and the premotor cortex, insula, and superior temporal gyrus in DTv. Neural alterations in superior parietal and inferior temporal cortices were correlated with ETv severity, whereas changes in the left premotor cortex were associated with DTv severity. CONCLUSIONS: Our findings point to the pathophysiological spectrum underlying ETv and DTv and favor a more heterogeneous rather than dichotomous diagnostic classification of these voice tremor disorders. © 2020 International Parkinson and Movement Disorder Society.
Sexual Dimorphism Within Brain Regions Controlling Speech Production
Laura Lima de Xavier, Sandra Hanekamp, and Kristina Simonyan. 2019. “Sexual Dimorphism Within Brain Regions Controlling Speech Production.” Front Neurosci, 13, Pp. 795.Abstract
Neural processing of speech production has been traditionally attributed to the left hemisphere. However, it remains unclear if there are structural bases for speech functional lateralization and if these may be partially explained by sexual dimorphism of cortical morphology. We used a combination of high-resolution MRI and speech-production functional MRI to examine cortical thickness of brain regions involved in speech control in healthy males and females. We identified greater cortical thickness of the left Heschl’s gyrus in females compared to males. Additionally, rightward asymmetry of the supramarginal gyrus and leftward asymmetry of the precentral gyrus were found within both male and female groups. Sexual dimorphism of the Heschl’s gyrus may underlie known differences in auditory processing for speech production between males and females, whereas findings of asymmetries within cortical areas involved in speech motor execution and planning may contribute to the hemispheric localization of functional activity and connectivity of these regions within the speech production network. Our findings highlight the importance of consideration of sex as a biological variable in studies on neural correlates of speech control.
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.
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Latest News

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

Children's Choice Poster Award

June 12, 2019
Sandra
Sandra Hanekamp won the (PI's) Children's Choice Poster Award for her poster: "The structural connectome of isolated task-specific focal dystonia", which she presented at the annual meeting of the Ogranization for Human Brain Mapping, June 9-13, 2019 in Rome, Italy. 
Children's Poster Choice Award.pdf48.08 MB

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