Spasmodic Dysphonia and Other Focal Dystonias

Dystonia is a movement disorder of yet unknown causes and pathophysiology. It is characterized by sustained or intermittent muscle contractions causing abnormal, and often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and is associated with overflow muscle activation. 

Focal dystonias are the most common forms of dystonia and can affect different muscle group (e.g., cervical dystonia, focal hand dystonia, spasmodic dysphonia, blepharospasm). Treatment of this disorder is limited to symptom management, typically with botulinum toxin injections into the affected muscles. 

Our long-term goal is to identify the neural mechanisms underlying the causative pathophysiology of focal dystonia and to develop new strategies for enhanced clinical management of this disorder, including its accurate diagnosis, prediction in those at risk, and discovery of novel therapeutic approaches. As a research tool for elucidation of brain organization in dystonia, we use a variety of neuroimaging methodologies, such as functional MRI (fMRI) for mapping brain functional activity and networks, pharmacological fMRI (ph-fMRI) for assessment of the drug effects on brain function, high-resolution structural MRI and diffusion weighted imaging (DWI) with tractography for evaluation of brain structural organization, and positron emission tomography (PET) with radiolabeled ligands for neuroreceptor mapping.

Imaging genetics of spasmodic dysphonia

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Large-scale brain networks (left) and the relationship between sensorimotor cortex, basal ganglia and cerebellum (right) in healthy subjects and patients with two different forms of spasmodic dysphonia, the adductor, and abductor types (Simonyan and Ludlow, Cerebral Cortex, 2010).

The contribution of genetic risk factors to the development of focal dystonias is evident. However, our understanding of how variations in the causative gene expression lead to variations in brain abnormalities in different forms of dystonia (e.g., familial, sporadic) remains limited. Funded by the National Institute on Deafness and other Communication Disorders, National Institutes of Health (NIDCD/NIH) R01DC011805, our research program is set to determine the relationship between brain changes and genetic risk factors in spasmodic dysphonia (or laryngeal dystonia). We use a novel approach of combined imaging genetics, next-generation DNA sequencing, and clinico-behavioral neurotesting. The use of a cross-disciplinary approach as a tool for discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to pathophysiology of dystonia holds a promise for the understanding of the mechanistic aspects of brain function affected by risk gene variants, which can be used reliably for discovery of associated genes and neural integrity markers for this disorder. The expected outcome of this study may lead to better clinical management of this disorder, including its improved detection, accurate and objective diagnosis, and assessment of the risk to develop spasmodic dysphonia in family members.

Central mechanisms and treatment response of sodium oxybate in spasmodic dysphonia and voice tremor

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The effect of sodium oxybate (Xyrem) on brain activation in a patient with spasmodic dysphonia (Simonyan and Frucht, Tremor and Other Hyperkinetic Disorders 2013).

Spasmodic dysphonia, or laryngeal dystonia, is a chronic debilitating condition that selectively affects speech production due to involuntary spasms in the laryngeal muscles. Spasmodic dysphonia often extends beyond vocal communication impairment and causes significant occupational disability and life-long social isolation. It becomes even more incapacitating when it is associated with dystonic voice tremor, which is present in about 1/3 of patients with spasmodic dysphonia and is characterized by the inability to sustain a vowel for more than a few seconds. Current treatment of these disorders is limited to the temporary management of voice symptoms with repeated injections of botulinum toxin into the laryngeal muscles, which, however, are not effective in all patients. There is, therefore, a critical need to identify other therapeutic options that are specifically targeting the pathophysiology of these disorder. On the other hand, the design and use of such novel therapeutic approaches will be largely unattainable if their central mechanisms of action remain unknown. Funded by the National Institute on Deafness and other Communication Disorders, National Institutes of Health (NIDCD/NIH) R01DC012545, we aim to identify the primary determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem®), in alcohol-responsive patients with spasmodic dysphonia and voice tremor. This study will use a controlled experimental design that focuses on detailed characterization of primary effects of a novel oral medication, sodium oxybate, for treatment of spasmodic dysphonia and voice tremor. It is expected to have broad translational impact on improving the clinical management of these patients, also opening new therapeutic horizons for treatment of similar disorders.

Brain networks in dystonia

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Gray matter volumetric differences between task-specific dystonia (TSD: spasmodic dysphonia and writer’s cramp) and non-task-specific dystonia (NTSD: cervical dystonia and blepharospasm) (Ramdhani et al., Movement Disorders, 2014). 

Task-specific primary focal dystonias are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing or playing a musical instrument. To date, we have only limited knowledge about the distinct neural abnormalities that lead to the development of task-specificity in primary focal dystonias, which affect similar muscle groups but result in different clinical manifestations, such as writer’s cramp vs. pianist’s dystonia or spasmodic dysphonia vs. singer's dystonia. Funded by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH) R01NS088160, our goal is to dissect the pathophysiological mechanisms underlying the phenomenon of task specificity in isolated focal dystonias using multi-level brain network analysis in conjunction with neuropathological examination of postmortem brain tissue from patients with dystonia. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.

The role of dopaminergic and GABAergic function in primary focal dystonia

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The organization of the basal ganglia circuitry involved in speech control (left) and decreased striatal dopamine D2/D3 receptor availability in patients with spasmodic dysphonia (right) (Simonyan et al., Brain and Language, 2012; Simonyan et al., Journal of Neuroscience, 2013).

Despite the recent progress in elucidating brain functional abnormalities within the basal ganglia-thalamo-cortical circuitry in focal dystonias, there is a fundamental gap in understanding the neurochemical correlates underpinning the functional alterations in these disorders. In collaboration with Mark Hallett, MD, at NINDS/NIH, our goal is to provide detailed knowledge about the neurotransmission via GABA-A, D1- and D2-familiy receptors in patients with different forms of focal dystonia (i.e., spasmodic dysphonia and writer’s cramp). This information will help determine the contribution of GABAergic and dopaminergic neurotransmission to the pathophysiology of dystonia as well as identify potential new pharmacological targets for novel treatment options.