Kristina Simonyan

Harvard Medical School, Massachusetts Eye and Ear, Boston, United States

Background and objective: Laryngeal dystonia (LD) is focal task-specific dystonia, predominantly affecting speech but not whispering or emotional vocalizations. Prior neuroimaging studies identified brain regions forming a dystonic neural network and contributing to LD pathophysiology. However, the underlying temporal dynamics of these alterations...

Background: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatme...

Isolated dystonia is a neurological disorder of diverse etiology, multifactorial pathophysiology, and wide spectrum of clinical presentations. We review the recent neuroimaging advances that led to the conceptualization of dystonia as a neural network disorder and discuss how current knowledge is shaping the identification of biomarkers of dystonia...

Parkinson’s disease (PD) can affect speech as well as emotion processing. We employ whole-brain graph-theoretical network analysis to determine how the speech processing network (SPN) changes in PD, and assess its susceptibility to emotional distraction. Functional magnetic resonance images of 14 patients (aged 59.6 ± 10.1 years, 5 female) and 23 h...

Abnormal sensory discriminatory processing has been implicated as an endophenotypic marker of isolated dystonia. However, the extent of alterations across the different sensory domains and their commonality in different forms of dystonia are unclear. Based on the previous findings of abnormal temporal but not spatial discrimination in patients with...

Dystonia is a common movement disorder involving abnormal, often twisting postures and is a challenging condition to diagnose as we present here in a comprehensive overview. The pathophysiology of dystonia involves abnormalities in brain motor networks, sensorimotor integration, and maladaptive cortical plasticity in the context of genetic factors....

Objective: Isolated dystonia is characterized by abnormal, often painful, postures and repetitive movements due to sustained or intermittent involuntary muscle contractions. Botulinum toxin (BoTX) injections into the affected muscles are the first line of therapy. However, there are no objective predictive markers or standardized tests of BoTX eff...

Objective: Critical decisions are made by effective teams that are characterized by individuals who trust each other and know how to best integrate their opinions. Here, we introduce a multimodal BCI to help collaborative teams of humans and an artificial agent achieve more accurate decisions in assessing danger zones during a pandemic scenario....

Descriptions of tremor encompass ancient civilizations to the present day. This book covers the increasingly rich and diverse research arena in tremors, and how research connects with improved recognition and treatment of tremors. The initial book sections cover fundamental concepts in tremor nosology and classification, pathophysiology, and etiolo...

Task‐specificity in isolated focal dystonias is a powerful feature that may successfully be targeted with therapeutic brain–computer interfaces. While performing a symptomatic task, the patient actively modulates momentary brain activity (disorder signature) to match activity during an asymptomatic task (target signature), which is expected to tran...

Descriptions of tremor encompass ancient civilizations to the present day. This book covers the increasingly rich and diverse research arena in tremors, and how research connects with improved recognition and treatment of tremors. The initial book sections cover fundamental concepts in tremor nosology and classification, pathophysiology, and etiolo...

Background and objectives: Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We invest...

Speech production relies on the interplay of different brain regions. Healthy aging leads to complex changes in speech processing and production. Here, we investigated how the whole-brain functional connectivity of healthy elderly individuals differs from that of young individuals. In total, 23 young (aged 24.6 ± 2.2 years) and 23 elderly (aged 64....

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 abnorma...

Speech production relies on the orchestrated control of multiple brain regions. The specific, directional influences within these networks remain poorly understood. We used regression dynamic causal modelling to infer the whole-brain directed (effective) connectivity from functional magnetic resonance imaging data of 36 healthy individuals during t...

Objective To delineate research priorities for improving clinical management of laryngeal dystonia, the NIH convened a multi-disciplinary panel of experts for a one-day workshop to examine the current progress in understanding its etiopathophysiology and clinical care. Methods The participants reviewed the current terminology of disorder and discu...

Importance In recent years, there have been several meaningful advances in the understanding of the cognitive effects of chronic rhinosinusitis. However, an investigation exploring the potential link between the underlying inflammatory disease and higher-order neural processing has not yet been performed. Objective To describe the association of s...

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-questi...

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of larynge...

Significance This research identified a microstructural neural network biomarker for objective and accurate diagnosis of isolated dystonia based on the disorder pathophysiology using an advanced deep learning algorithm, DystoniaNet, and raw structural brain images of large cohorts of patients with isolated focal dystonia and healthy controls. Dysto...

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, isometr...

The vagus nerve is the 10th of the 12 pairs of cranial nerves and is a part of the parasympathetic nervous system. It originates in the medulla oblongata and is comprised of sensory and motor neurons that innervate the peripheral nervous system. The vagus nerve exits the central nervous system at the vagal ganglia and spreads to the rest of the bod...

The emerging view of dystonia is that of a large‐scale functional network disorder, in which the communication is disrupted between sensorimotor cortical areas, basal ganglia, thalamus, and cerebellum. The structural underpinnings of functional alterations in dystonia are, however, poorly understood. Notably, it is unclear whether structural change...

Epilepsy affects more than 50 million people of all ages and ethnicities worldwide. About one-third of patients develop medication-resistant seizures, for which surgical resection of the brain region causing seizures remains the best treatment option.

Objective Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities. Methods The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natur...

Objectives: Alterations in sensory discrimination are a prominent nonmotor feature of dystonia. Abnormal temporal discrimination in focal dystonia is considered to represent its mediational endophenotype, albeit unclear pathophysiological correlates. We examined the associations between the visual temporal discrimination threshold (TDT) and brain...

A unique overview of the human language faculty at all levels of organization. Language is not only one of the most complex cognitive functions that we command, it is also the aspect of the mind that makes us uniquely human. Research suggests that the human brain exhibits a language readiness not found in the brains of other species. This volume br...

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 functi...

Introduction: Spasmodic dysphonia (SD) is an isolated focal dystonia characterized by laryngeal spasms during voluntary voice production. Environmental factors have been assumed to play a role in SD pathophysiology; however, the exact extrinsic risk factors and their association with neural alterations remain unknown. Methods: A total of 186 SD...

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. Indepe...

Background Task‐specific focal dystonias selectively affect movements during the production of highly learned and complex motor behaviors. Manifestation of some task‐specific focal dystonias, such as musician's dystonia, has been associated with excessive practice and overuse, whereas the etiology of others remains largely unknown. Objectives In t...

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 sough...

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 ga...

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 alt...

Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigatio...

Objectives: Task‐specific focal dystonia selectively affects the motor control during skilled and highly learned behaviors. Recent data suggest the role of neural network abnormalities in the development of the pathophysiological dystonic cascade. Methods: We used resting‐state functional MRI and analytic techniques rooted in network science and gr...

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...

The importance of insula in speech control is acknowledged but poorly understood, partly due to a variety of clinical symptoms resulting from insults to this structure. To clarify its structural organization within the speech network in healthy subjects, we used probabilistic diffusion tractography to examine insular connectivity with three cortica...

Dystonia is a neurological disorder characterized by involuntary, repetitive movements. Although the precise mechanisms of dystonia development remain unknown, the diversity of its clinical phenotypes is thought to be associated with multifactorial pathophysiology, which is linked not only to alterations of brain organization, but also environmenta...

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 multi...

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...

See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research to...

Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline...

Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum ranging from hereditary generalized dystonia with whispering dysphonia (DYT4) to the leukodystrophy hypomyelination syndrome with atrophy of the basal ganglia and cerebellum (H-ABC). To test for the contribution of TUBB4A mutations in different ethnicities (Spanish, Italia...

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...

Tremor, affecting a dystonic body part, is a frequent feature of adult-onset dystonia. However, our understanding of dystonic tremor pathophysiology remains ambiguous as its interplay with the main co-occurring disorder, dystonia, is largely unknown. We used a combination of functional MRI, voxel-based morphometry and diffusion-weighted imaging to...

Background: Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder...

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Su...

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 s...

Speech is one of the most unique features of human communication. Our ability to articulate our thoughts by means of speech production depends critically on the integrity of the motor cortex. Long thought to be a low-order brain region, exciting work in the past years is overturning this notion. Here, we highlight some of major experimental advance...

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...

Background: Up to 12% of patients with laryngeal dystonia report a familial history of dystonia, pointing to involvement of genetic factors. However, its genetic causes remain unknown. Method: Using Sanger sequencing, we screened 57 patients with isolated laryngeal dystonia for mutations in known dystonia genes TOR1A (DYT1), THAP1 (DYT6), TUBB4A...

The analysis of the community architecture in functional brain networks has revealed important relations between specific behavioral patterns and characteristic features of the associated functional organization. Numerous studies assessed changes in functional communities during different states of awareness, learning, information processing, and v...

Background and purpose: Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to expl...

Objective: Cortical high-frequency oscillations (HFOs; 100-500 Hz) play a critical role in the pathogenesis of epilepsy; however, whether they represent a true epileptogenic process remains largely unknown. HFOs have been recorded in the human cortex but their network dynamics during the transitional period from interictal to ictal phase remain la...

Unlabelled: The laryngeal motor cortex (LMC) is essential for the production of learned vocal behaviors because bilateral damage to this area renders humans unable to speak but has no apparent effect on innate vocalizations such as human laughing and crying or monkey calls. Several hypotheses have been put forward attempting to explain the evoluti...

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 feature...

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phe...

In the past few years, several studies have been directed to understanding the complexity of functional interactions between different brain regions during various human behaviors. Among these, neuroimaging research installed the notion that speech and language require an orchestration of brain regions for comprehension, planning, and integration o...

Laryngeal dystonia (LD) is a task-specific focal dystonia of unknown pathophysiology affecting speech production. We examined the demographics of anecdotally reported alcohol use and its effects on LD symptoms using an online survey based on Research Electronic Data Capture (REDCap™) and National Spasmodic Dysphonia Association's patient registry....

Speech production is one of the most complex human behaviors. While brain activation during speaking has been well investigated, our understanding of interactions between the brain regions and neural networks remains scarce. We combined seed-based inter-regional correlation analysis with graph theoretical analysis of functional MRI data during rest...

To present the first documented series of patients with negative dystonia (ND) of the palate, including clinical symptoms, functional MRI findings, and management options. Case series ascertained from clinical research centers that evaluated patients with both hyperkinetic and hypokinetic movement disorders. Between July 1983 and March 2013, data w...

Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear mul...

Background / Purpose: Human speech production is a complex multi-level process that recruits multiple brain networks. To assess the interactions between those networks, a graph theoretical approach was used to analyze functional MRI (fMRI) data during the resting state, and the production of meaningless vowels and grammatically correct sentences....

Numerous brain imaging studies have demonstrated structural changes in the basal ganglia, thalamus, sensorimotor cortex, and cerebellum across different forms of primary dystonia. However, our understanding of brain abnormalities contributing to the clinically well-described phenomenon of task specificity in dystonia remained limited. We used high-...

Our ability to learn and control the motor aspects of complex laryngeal behaviors, such as speech and song, is modulated by the laryngeal motor cortex (LMC), which is situated in the area 4 of the primary motor cortex and establishes both direct and indirect connections with laryngeal motoneurons. In contrast, the LMC in monkeys is located in the a...

Symptoms of spasmodic dysphonia (SD) are usually managed successfully with botulinum toxin injections. Vocal tremor (VT), which accompanies SD, has a poor response to this treatment. We report a case of a female with SD and VT who became symptom-free for 10 months after the intake of a single dose of sodium oxybate (Xyrem®). The long-term treatment...

Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously in...

Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormal...

Dystonia is a hyperkinetic movement disorder characterized by involuntary, repetitive twisting movements. The anatomical structures and pathways implicated in its pathogenesis and their relationships to the neurophysiological paradigms of abnormal surround inhibition, maladaptive plasticity, and impaired sensorimotor integration remain unclear. We...

Objective: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. Methods: Genome-wide linkage analysis was carried out in 14 family members followed by genome...

Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speec...

Somatosensory feedback from the larynx plays a critical role in regulation of normal upper airway functions, such as breathing, deglutition, and voice production, while altered laryngeal sensory feedback is known to elicit a variety of pathological reflex responses, including persistent coughing, dysphonia, and laryngospasm. Despite its clinical im...