Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia

Spasmodic dysphonia (SD) and writer s cramp (WC) are primary focal dystonias with selective impairment of voluntary control of speaking and writing, respectively. Although the pathophysiology of SD and WC is unknown, dystonia is considered to be a disorder of basal ganglia that leads to secondary cortical and subcortical sensorimotor dysfunction. Results of recent neuroimaging studies have established microstructural abnormalities, as well as alterations of functional activity and neurotransmission within the basal ganglia-thalamo-cortical circuitry during symptom production in these patients. Abnormal functional relationships between these brain regions may play an important role in the pathophysiology of dystonia. However, the organization of functional networks and the neurochemical correlates underpinning their abnormalities have not, to date, been fully investigated. A few pharmacological reports of patients have provided indirect evidence of the contributing role of the major basal ganglia neurotransmitters, >=-aminobutyric acid (GABA) and dopamine, to the pathophysiology of this disorder. We identified decreased D2/D3 receptor binding at rest and abnormal dopamine release during both symptomatic and asymptomatic tasks in SD and WC compared to controls. We also identified altered GABAergic transmission, especially involving the laryngeal and hand sensorimotor cortex. These changes in neurotransmission may, in turn, be coupled with abnormalities of network functional activity in these patients and thus contribute to the pathophysiology of this disorder. There is, therefore, a critical need to further investigate the contribution of dopaminergic transmission via D1-family receptors as well as dopaminergic function of substantia nigra, pars compacta (SNc), in order to fully characterize abnormalities of dopaminergic neurotransmission in this disorder. Filling this knowledge gap is essential for development of effective neuropharmacological treatments for patients with SD and WC, which are limited, to date, to only short-term benefits from injections of botulinum toxin into the affected muscles every 3-4 months for a lifetime.

Objective

The objective of this application is to determine the role played by major basal ganglia neurotransmitters in the pathophysiology of primary focal dystonia. The central hypothesis is that dopaminergic transmission is selectively altered within the nigro-striatal and direct basal ganglia pathways and is correlated with abnormal dopaminergic function within the indirect basal ganglia circuitry in SD and WC patients.

Study Population:

We plan to examine patients with adductor SD (ADSD) compared to two other groups of subjects: (1) patients with another form of task-specific focal dystonia (writer s cramp, WC) and (2) healthy volunteers without history of neurological, psychiatric, or head and neck disorders. The research volunteers may be spouses of persons with SD and WC without a familial relationship.

Design:

This is a natural history study. Using neuroimaging techniques (positron emission tomography (PET), the central hypothesis will be tested by pursuing two specific aims: (1) to map the D1-like dopaminergic receptor binding in SD and WC patients as measured with PET using [11C]NNC-112; (2) to map the nigro-strital dopaminergic function in SD and WC patients as measured with PET using [18F]FDOPA.

Outcome Measures:

These studies will determine neurotransmitter function in patients with ADSD and WC compared to healthy subjects. The proposed research is expected to advance our understanding of the pathophysiology of voluntary motor control of voice and hand movements in diseased individuals as an important step in identifying possible mechanisms for potential neuropharmacological interventions in these patients.