Pathophysiology of Dystonia

Dystonia is a movement disorder of yet unknown causes and pathophysiology. It is characterized by sustained or intermittent muscle contractions causing abnormal, 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 groups (e.g., cervical dystonia, focal hand dystonia, spasmodic dysphonia, blepharospasm). The treatment of this disorder is currently 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 pathophysiology of focal dystonia and to develop new strategies for enhanced clinical management of this disorder, including its accurate diagnosis, prediction in persons 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, including functional MRI (fMRI) for mapping of brain functional activity and networks, pharmacological fMRI (ph-fMRI) for the assessment of 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

starsFunctional architecture of neural networks in patients with familial and sporadic forms of laryngeal dystonia (i.e., spasmodic dysphonia). Left panel: spatial topology of functional communities in the group-averaged networks. Right panel: distribution of bivariate provincial (yellow) and connector (red) hubs and their connectivity profiles with high-influence nodes (purple) in familial and sporadic laryngeal dystonia (Fuertinger S and Simonyan K, J Neurosci, 2017).

Spasmodic dysphonia (SD) is an isolated focal laryngeal dystonia characterized by selective impairment of voluntary voice control during speech production. Despite well-characterized clinical features of SD, its causes and pathophysiology remain unclear. Consequently, the absence of objective biomarkers of SD leads to diagnostic inaccuracies, while the lack of understanding of the neural and molecular targets of SD pathophysiology hinders the development of novel therapeutic opportunities for patients. Funded by the National Institute on Deafness and other Communication Disorders, National Institutes of Health (NIDCD/NIH R01DC011805), our research program is set to identify imaging and genetic biomarkers of SD development and manifestation. We use a comprehensive approach of multi-modal neuroimaging, machine learning algorithms, and next-generation DNA sequencing as a tool for the discovery of the mediating neural mechanisms that bridge the gap between the DNA sequence and SD pathophysiology. Knowledge obtained from these studies is expected to have a direct clinical impact by establishing enhanced criteria for accurate differential diagnosis, screening of potential persons at-risk, and evaluation of mechanism-based novel pharmacological and/or surgical therapies for these patients.

Central Mechanisms of Sodium Oxybate in Spasmodic Dysphonia and Voice Tremor


The effect of sodium oxybate (Xyrem ®) in a patient with spasmodic dysphonia and voice tremor before (A) and after (B) drug intake (Simonyan K and Frucht SJ, Tremor Other Hyperkin Dis, 2013)

Spasmodic dysphonia (SD), or laryngeal dystonia, is a chronic debilitating condition that selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD 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 (VT), which is present in about 1/3 of patients with SD 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; however, this treatment is not effective in all patients and even less so in combined SD and VT cases. There is, therefore, a critical need to identify other therapeutic options that are specifically targeting the pathophysiology of these disorders. 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 patients with spasmodic dysphonia and voice tremor. This study will use a double-blinded, placebo-controlled randomized experimental design that focuses on the 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 a broad translational impact on improving the clinical management of these patients, also opening new therapeutic horizons for the treatment of similar disorders.

Brain Networks in Dystonia


Large-scale neural community architecture during the resting state in healthy subjects and its pathophysiological disorganization in patients with task-specific dystonia (spasmodic dysphonia and writer's cramp) and patients with nontask-specific dystonia (cervical dystonia and blepharospasm) (Battistella G et al. Cerebral Cortex, 2017). 

Task-specific focal dystonias are characterized by selective activation of dystonic movements during the performance of highly learned motor tasks, such as writing or speaking. To date, we have only limited knowledge about the distinct neural abnormalities that lead to the development of task-specificity in 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.

Dopaminergic and GABAergic Function in Focal Dystonia

dopamineTopological distribution of striatal dopaminergic function in healthy subjects and patients with writer’s cramp and laryngeal dystonia (Simonyan K et al., Brain 2017). 

Despite the recent progress in elucidating functional brain 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 GABAA, D1- and D2-family 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.