logoThe 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

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.
Cognitive performance in mid-stage Parkinson's disease: functional connectivity under chronic antiparkinson treatment
Roxana Vancea, Kristina Simonyan, Maria Petracca, Miroslaw Brys, Alessandro Di Rocco, Maria Felice Ghilardi, and Matilde Inglese. 2017. “Cognitive performance in mid-stage Parkinson's disease: functional connectivity under chronic antiparkinson treatment.” Brain Imaging Behav.Abstract
Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.
An open-label study of sodium oxybate in Spasmodic dysphonia
Anna F Rumbach, Andrew Blitzer, Steven J Frucht, and Kristina Simonyan. 2017. “An open-label study of sodium oxybate in Spasmodic dysphonia.” Laryngoscope, 127, 6, Pp. 1402-1407.Abstract
OBJECTIVES/HYPOTHESIS: Spasmodic dysphonia (SD) is a task-specific laryngeal dystonia that affects speech production. Co-occurring voice tremor (VT) often complicates the diagnosis and clinical management of SD. Treatment of SD and VT is largely limited to botulinum toxin injections into laryngeal musculature; other pharmacological options are not sufficiently developed. STUDY DESIGN: Open-label study. METHODS: We conducted an open-label study in 23 SD and 22 SD/VT patients to examine the effects of sodium oxybate (Xyrem), an oral agent with therapeutic effects similar to those of alcohol in these patients. Blinded randomized analysis of voice and speech samples assessed symptom improvement before and after drug administration. RESULTS: Sodium oxybate significantly improved voice symptoms (P = .001) primarily by reducing the number of SD-characteristic voice breaks and severity of VT. Sodium oxybate further showed a trend for improving VT symptoms (P = .03) in a subset of patients who received successful botulinum toxin injections for the management of their SD symptoms. The drug's effects were observed approximately 30 to 40 minutes after its intake and lasted about 3.5 to 4 hours. CONCLUSIONS: Our study demonstrated that sodium oxybate reduced voice symptoms in 82.2% of alcohol-responsive SD patients both with and without co-occurring VT. Our findings suggest that the therapeutic mechanism of sodium oxybate in SD and SD/VT may be linked to that of alcohol, and as such, sodium oxybate might be beneficial for alcohol-responsive SD and SD/VT patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:1402-1407, 2017.
Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks
Giovanni Battistella, Pichet Termsarasab, Ritesh A Ramdhani, Stefan Fuertinger, and Kristina Simonyan. 2017. “Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks.” Cereb Cortex, 27, 2, Pp. 1203-1215.Abstract
Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations.

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