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.

- INCLUSION CRITERIA:

Healthy research volunteers and adult patients with ADSD and WC will be eligible for the
study.

1. Adult patients with ADSD will have clinically documented ADSD established by voice and
speech testing and fiberoptic nasolaryngoscopy.

Patients will be required to have:

- Intermittent uncontrolled voice breaks in vowels, liquids (r & l), semivowels (w
& y) during speech in ADSD (at least 3 voice breaks), or

- Less prominent symptoms during whisper, singing, falsetto, or shout;

- Normal voice and vocal fold movement during protective laryngeal functions and
emotional phonation, such as cough, laughter, cry.

2. Adult patients with WC will have clinically documented WC established by history and
neurological examination.

3. Controls will be healthy subjects with a negative history of laryngeal, neurological,
or psychiatric problems.

4. All participants will be from 21 to 80 years old and right hand dominant.

5. All participants should be able to perform a sequential finger-tapping task for 40
seconds consecutively

EXCLUSION CRITERIA:

1. Subjects who are incapable of giving an informed consent.

2. Pregnant or breastfeeding women until a time when they are no longer pregnant or
breastfeeding.

3. Subjects with past or present medical history of (a) neurological problems, such as
stroke, movement disorders (other than SD and WC in the patient group), brain tumors,
traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia
gravis, demyelinating diseases, alcoholism, drug dependence; (b) psychiatric problems,
such as schizophrenia, major and/or bipolar depression, obsessive-compulsive disorder;
(c) laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and
polyps, carcinoma, chronic laryngitis. (d) ventricular arrhythmias, renal and hepatic
insufficiency, vascular headache, or carcinoid syndrome.

4. Patients who are currently taking medications known to affect GABA and dopamine
receptor binding. Occasionally, patients report receiving such medication, although
dopaminergic and GABA agonist/antagonists are not typically prescribed in these
patients.

5. Patients who received treatment with botulinum toxin injections into the laryngeal
muscles within the past 3 months.

6. Patients with vocal and hand tremor or muscle tension dysphonia.

7. Subjects who have tattoos with contraindications to MRI, ferromagnetic objects in
their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial
heart valve, etc.) that cannot be removed for the purpose of study participation.

8. Subjects who received previous radiation exposure greater than 5.0 rem per year.

9. WC patients who experience focal hand dystonia at rest.

10. WC patients who have focal hand dystonia associated with trauma or a known
neuroanatomic lesion or disease.