Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia
Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia
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.
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.