The 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.

## Recent Publications

Jana Schill, Kirsten E. Zeuner, Arne Knutzen, Inken Tödt, Kristina Simonyan, and Karsten Witt. 2021. “Functional Neural Networks in Writer's Cramp as Determined by Graph-Theoretical Analysis.” Frontiers in Neurology, 12, Pp. 2106.Abstract
Dystonia, a debilitating neurological movement disorder, is characterized by involuntary muscle contractions and develops from a complex pathophysiology. Graph theoretical analysis approaches have been employed to investigate functional network changes in patients with different forms of dystonia. In this study, we aimed to characterize the abnormal brain connectivity underlying writer's cramp, a focal hand dystonia. To this end, we examined functional magnetic resonance scans of 20 writer's cramp patients (11 females/nine males) and 26 healthy controls (10 females/16 males) performing a sequential finger tapping task with their non-dominant (and for patients non-dystonic) hand. Functional connectivity matrices were used to determine group averaged brain networks. Our data suggest that in their neuronal network writer's cramp patients recruited fewer regions that were functionally more segregated. However, this did not impair the network's efficiency for information transfer. A hub analysis revealed alterations in communication patterns of the primary motor cortex, the thalamus and the cerebellum. As we did not observe any differences in motor outcome between groups, we assume that these network changes constitute compensatory rerouting within the patient network. In a secondary analysis, we compared patients with simple writer's cramp (only affecting the hand while writing) and those with complex writer's cramp (affecting the hand also during other fine motor tasks). We found abnormal cerebellar connectivity in the simple writer's cramp group, which was less prominent in complex writer's cramp. Our preliminary findings suggest that longitudinal research concerning cerebellar connectivity during WC progression could provide insight on early compensatory mechanisms in WC.
Kristina Simonyan, Julie Barkmeier-Kraemer, Andrew Blitzer, Mark Hallett, John F Houde, Teresa Jacobson Kimberley, Laurie J Ozelius, Michael J Pitman, Robert Mark Richardson, Nutan Sharma, and Kristine Tanner. 2021. “Laryngeal Dystonia: Multidisciplinary Update on Terminology, Pathophysiology, and Research Priorities.” Neurology, 96, 21, Pp. 989-1001.Abstract
OBJECTIVE: To delineate research priorities for improving clinical management of laryngeal dystonia, the NIH convened a multidisciplinary panel of experts for a 1-day workshop to examine the current progress in understanding its etiopathophysiology and clinical care. METHODS: The participants reviewed the current terminology of disorder and discussed advances in understanding its pathophysiology since a similar workshop was held in 2005. Clinical and research gaps were identified, and recommendations for future directions were delineated. RESULTS: The panel unanimously agreed to adopt the term "laryngeal dystonia" instead of "spasmodic dysphonia" to reflect the current progress in characterizations of this disorder. Laryngeal dystonia was recognized as a multifactorial, phenotypically heterogeneous form of isolated dystonia. Its etiology remains unknown, whereas the pathophysiology likely involves large-scale functional and structural brain network disorganization. Current challenges include the lack of clinically validated diagnostic markers and outcome measures and the paucity of therapies that address the disorder pathophysiology. CONCLUSION: Research priorities should be guided by challenges in clinical management of laryngeal dystonia. Identification of disorder-specific biomarkers would allow the development of novel diagnostic tools and unified measures of treatment outcome. Elucidation of the critical nodes within neural networks that cause or modulate symptoms would allow the development of targeted therapies that address the underlying pathophysiology. Given the rarity of laryngeal dystonia, future rapid research progress may be facilitated by multicenter, national and international collaborations.
Alexis Worthley and Kristina Simonyan. 2021. “Suicidal Ideations and Attempts in Patients with Isolated Dystonia.” Neurology, 96, 11, Pp. e1551-e1560.Abstract
OBJECTIVE: To evaluate the hypothesis that individuals with isolated dystonia are at an increased risk for suicidal behavior, we administered an anonymous electronic survey to patients with dystonia, asking them about their history of suicidal ideations and suicide attempt. METHODS: A total of 542 patients with dystonia completed an online 97-question survey, which captured the demographics of suicidal behavior and major psychiatric disorders in these patients. Statistical analyses examined the prevalence of suicidal behavior in patients with dystonia compared to the prevalence of suicidal ideations and attempt in the general global population and assessed the significance of risk associations between suicidality and psychiatric history in these patients. RESULTS: Overall, 32.3% of patients with isolated dystonia reported a lifetime history of suicidal behavior, which was significantly different from the reported rates of suicidal ideation (9.2%) and attempt (2.7%) in the general global population. The prevalence of suicidality was higher in patients with multifocal/segmental and generalized forms of dystonia (range of 46%-50%) compared to patients with focal dystonias (range of 26.1%-33.3%). The highest suicidal ideation-to-attempt ratio of 4:1 was found in patients with generalized dystonia. Suicidality in patients with focal dystonia was significantly associated with their history of depression and anxiety disorders. CONCLUSION: Patients with isolated dystonia have an increased, albeit unrecognized, prevalence of suicidal behavior compared to the general global population. The screening for suicidal risk should be incorporated as part of the clinical evaluation of patients with dystonia to prevent their suicide-induced injury and death.
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.
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# Harvard Otolaryngology Fall 2021 issue

November 12, 2021

Dr. Simonyan's research is highlighted in the Fall 2021 issue of Harvard Otolaryngology

Logging in to DystoniaNet: A new deep-learning platform has cracked the code to diagnosing dystonia.

“Dystonia has frustrated clinicians and researchers for decades. Without an objective measure of diagnosing the disorder, physicians often rely on a process of elimination to rule out dozens of similar conditions before arriving at a dystonia diagnosis."

# Dr. Simonyan is Awarded $11.9 Million NIH Grant to Lead New Multi-Institutional Center for Neurological Voice Disorders # New NIH R01 funding received September 1, 2021 We are exctied to receive a new NIH grant (NIDCD/NIH R01DC019353) to develop and test the first brain-computer interface (BCI) for rehabilitation of laryngeal dystonia. We will start inviting patients to participate in this study soon!... Read more about New NIH R01 funding received # Mass General Brigham 2020 Innovation Discovery Grant awarded to Dr. Kristina Simonyan and her team January 7, 2021 Five disruptive scientific advancements from Mass General Brigham have been awarded Innovation Discovery Grants (IDG) in the 2020 round of awards, as the highly competitive IDG program exceeds$3.5 million in grants since inception. Each of the five potential patient health and healthcare delivery break-throughs for 2020 will receive \$100,000 toward ongoing development and future commercialization, based on their potential to improve health outcomes, meet articulated...

Read more about Mass General Brigham 2020 Innovation Discovery Grant awarded to Dr. Kristina Simonyan and her team
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2019 Aug 12

# Voice and Speech Lecture Series - Anne J. Blood, Ph.D.

12:00pm to 1:00pm

2019 Apr 26

(All day)

2019 Apr 22

# Voice and Speech Lecture Series - Matthias Heyne, Ph.D.

12:10pm to 1:10pm

2019 Mar 11

# Voice and Speech Lecture Series - Benjamin Umans

12:00pm to 1:00pm

2019 Jan 14

# Voice and Speech Lecture Series - Einat Liebenthal, Ph.D.

12:00pm to 1:00pm

2018 Nov 12

# Voice and Speech Lecture Series - Teresa Jacobson Kimberley, PhD, PT

12:00pm to 1:00pm

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The Simonyan Laboratory is currently supported by the National Institute on Deafness and other Communication Disorders, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of DefenseAmazon Web ServicesJazz Pharmaceuticals, and Mass General Brigham Innovation.

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