Projects and Grants

Projects

Role of neurotransmission and functional CNS networks in spasmodic dysphonia and writer’s cramp

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. The outcome of this study is expected to lay scientific foundation for identifying the mechanisms for neuropharmacological interventions in patients with primary focal dystonias.

Imaging genetics of spasmodic dysphonia

Although the contribution of genetic risk factors to the development of primary focal dystonias is evident, 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. Continued existence of this gap represents an important problem because, until it is filled, full characterization of dystonia phenotypes, assessment of risk in families, and the design of novel therapeutic approaches for these patients will remain largely unattainable. 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 rationale for this study is that identification of phenotype-specific brain abnormalities and the associated genetic susceptibility risk factors will establish a strong scientific framework for characterization and development of diagnostic biomarkers for detection and evaluation of patients with spasmodic dysphonia as well as for screening of persons at-risk. 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.

Voice tremor in spasmodic dysphonia: Central mechanisms and treatment response

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. There is, therefore, a critical need to identify new treatment opportunities for patients with spasmodic dysphonia with co-occurring vocal tremor who receive limited, if any, benefits from the current gold standard treatment of dystonia with botulinum toxin injections. The design and use of novel therapeutic approaches for these patients will, however, be largely impossible if the central mechanisms of these disorders remain unknown. In collaboration with Drs. Steven Frucht and 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. This research study focuses not only on identification of distinct pathophysiological factors contributing to the development of spasmodic dysphonia and vocal tremor, but also on discovery of mechanisms of central effects of sodium oxybate, which holds promise for treatment of refractory symptoms in these disorders.

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. We expect that identification of distinct neural abnormalities between different forms of task-specific primary focal dystonias would establish a scientific framework for the development of diagnostic biomarkers and novel treatment approaches for these disorders. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.

Cortico-subcortical interactions in Parkinson’s disease

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. The rationale for this study is that identification of the relationship between the placement of DBS-induced micro-lesions and speech changes would allow for characterization of specific contributions of basal ganglia function to speech production and help better estimation of how often DBS procedure may lead to greater speech impairment, and when it occurs, how it can be characterized. Collectively, 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 healthy humans and through knowledge gained from patients with neurological voice and speech disorders, such as spasmodic dysphonia, vocal tremor and Parkinson’s disease.

Grants

NIH/NIDCD R00DC009629 
Role of neurotransmission and functional CNS networks in spasmodic dysphonia
PI: Kristina Simonyan
09/25/2009 – 08/31/2013

NIH/NIDCD R01DC011805
Imaging genetics of spasmodic dysphonia
PI: Kristina Simonyan
03/19/2012 – 02/28/2017

NIH/NIDCD R01DC012545
Voice tremor in spasmodic dysphonia: Central mechanisms and treatment response
PI: Kristina Simonyan
07/17/2012 – 06/30/2017 

NIH/NIDCD R01DC007658
Cortical-subcortical interaction in Parkinson's disease and normal speech
PI: John Sidtis and Diana Sidtis
Subcontract PI: Kristina Simonyan
04/01/2012 – 03/31/2017 

Bachmann-Strauss Dystonia and Parkinson Foundation
Structural biomarkers of primary focal dystonias
PI: Kristina Simonyan
01/01/2010 – 12/31/2011