Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia

Focal Dystonia Clinical Trial

Official title: Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia and Other Focal Dystonias

Status Completed

Clinical Trial Summary

This study will examine how the brain controls speech in patients with spasmodic dysphonia, a voice disorder that involves involuntary spasms of muscles in the larynx (voice box), causing breaks in speech. Although the causes of spasmodic dysphonia are unknown, recent studies found changes in brain function in patients with the disorder that may play a role in its development.

People between 21 and 80 years of age with adductor spasmodic dysphonia may be eligible for this study. Candidates are screened with the following procedures:

Medical history and physical examination.

Nasolaryngoscopy to examine the larynx. For this test, the inside of the subject s nose is sprayed with a decongestant and a small, flexible tube called a nasolaryngoscope is passed through the nose to the back of the throat to allow examination of the larynx. The subject may be asked to talk, sing, whistle and say prolonged vowels during the procedure. The nasolaryngoscope is connected to a camera that records the movement of the vocal cords during these tasks.

Voice and speech recording to measure the type and severity of voice disorder. Subjects are asked questions about their voice disorder and their voice is recorded while they repeat sentences and sounds.

Participants undergo positron emission tomography (PET) and magnetic resonance imaging (MRI) of the brain, as follows:

PET: A catheter is placed in a vein in the subject s arm to inject a radioactive substance called a tracer that is detected by the PET scanner and provides information on brain function. [11C]flumazenil is used in one scanning session and [11C]raclopride is used in another. For the scan, the subject lies on a bed that slides in and out of the doughnut-shaped scanner, wearing a custom-molded mask to support the head and prevent it from moving during the scan. For the first scan the subject lies quietly for 60 minutes. For the second scan, the subject lies quietly for 50 minutes and is then asked to say sentences during another 50 minutes. The amount of radiation received in this study equals to a uniform whole-body exposure of 0.9 rem, which is within the dose guideline established by the NIH Radiation Safety Committee for research subjects. The guideline is an effective dose of 5 rem received per year.

MRI: This procedure uses a strong magnetic field and radio waves instead of X-rays to obtain images of the brain. The subject lies on a table that slides into the scanner, a narrow metal cylinder, wearing ear plugs to muffle loud knocking sounds that occur during the scan. Images of the brain structure are obtained while the subject lies still in the machine for 10 minutes. This is followed by functional MRI (fMRI) for 60 minutes, in which pictures are taken while the subject speaks, showing changes in brain regions that are involved in speech production.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Dysphonia
• Dystonia
• Dystonic Disorders
• Focal Dystonia
• Hoarseness
• Spasmodic Dysphonia

• NCT number: NCT00713414
• Study type: Observational
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Start date: July 9, 2008
• Completion date: September 21, 2016