Projects and Grants
The contribution of genetic risk factors to the development of primary focal dystonias is evident. However, our understanding of how variations in the causative gene expression lead to variations in brain abnormalities in different phenotypes of dystonia (e.g., familial, sporadic) remains limited. Our research program, in collaboration with Dr. Laurie Ozelius, is set to identify phenotype-specific brain abnormalities associated with genetic risk factors in spasmodic dysphonia using 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 SD 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.
Spasmodic dysphonia, as other forms of primary dystonia, is a chronic debilitating condition, which becomes even more incapacitating when it is associated with voice tremor due to poor response of the latter to currently available treatment options. In collaboration with Dr. Steven Frucht and Dr. Andrew Blitzer, this study aims to identify shared and distinct brain abnormalities in spasmodic dysphonia and vocal tremor as the basis for characterization of central mechanisms underlying symptom improvement following the use of sodium oxybate, a novel pharmacological agent for treatment of ethanol-responsive dystonia.
Despite the recent progress in elucidating brain functional abnormalities within the basal ganglia-thalamo-cortical circuitry in primary focal dystonias, there is a fundamental gap in understanding the neurochemical correlates underpinning the functional alterations in these disorders. We aim to determine the role played by the major basal ganglia neurotransmitters in pathophysiology of dystonia by identifying their contribution to altered brain activity during symptomatic and asymptomatic task production in two forms of focal dystonia, spasmodic dysphonia and writer’s cramp. This study is among the first detailed investigations designed to determine dopaminergic and GABAergic contributions to the pathophysiology of primary focal dystonia.
Neuroimaging, neuropathological and genetic correlates of task-specific primary focal dystonias
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-specific primary focal dystonias affecting similar muscle groups but resulting in different clinical manifestations, such as writer’s cramp vs. pianist’s dystonia and embouchure dystonia vs. oromandibular dystonia. Our goal is to dissect the pathophysiological mechanisms underlying the phenomenon of task specificity in primary focal dystonias using a combined approach of brain network analysis and neuropathological examination. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.
Parkinson's disease is a progressive movement disorder that impairs the ability to speak clearly. Deep brain stimulation (DBS) improves many of the motor symptoms of Parkinson’s disease, but does not help and sometimes harms the ability to speak. The nature and extent of speech changes following DBS in Parkinson’s disease remain open questions. In collaboration with Dr. John Sidtis, we aim to characterize the morphology of the subthalamic nucleus, the target brain structure for DBS, and examine the relationship between the position of the DBS stimulating electrode and adjacent white matter tracts in patients with Parkinson’s disease using high-resolution MRI and DTI. We seek to understand the effects of DBS on speech in Parkinson’s disease with the long-term goals of modifying DBS to preserve or improve speech in these patients.
Laryngeal motor cortex and control of speech in humans
Speech production is one of the most complex and rapid motor behaviors that are uniquely human. The development of human ability to speak relies on the abilities to listen to speech, comprehend and process the meaning of the heard words, and precisely coordinate the function of more than 100 laryngeal, orofacial and respiratory muscles in order to utter speech sounds. Neural correlates of speech production have been explored for over a century. Yet, we lack a complete understanding of laryngeal motor cortical control during production of speech and other voluntary laryngeal behaviors. In recent years, a number of studies have confirmed the laryngeal motor cortical representation in humans and have provided some information about its interactions with other cortical and subcortical regions that are principally involved in vocal motor control of speech production. We proposed earlier that the location of the laryngeal motor cortex in the primary motor cortex and its direct connections with the brain stem laryngeal motoneurons in humans, as opposed to its location in the premotor cortex with only indirect connections to the laryngeal motoneurons in nonhuman primates, may represent one of the major evolutionary developments in humans toward the ability to speak and vocalize voluntarily. Our current research is directed to further elucidation of the organization of central laryngeal control based on neuroimaging studies in humans and non-human primates.
Bachmann-Strauss Dystonia and Parkinson Foundation
Structural biomarkers of primary focal dystonias
PI: Kristina Simonyan
01/01/2010 – 12/31/2011