Role of Neurotransmission and Functional CNS Networks in Spasmodic Dysphonia
Condition: Spasmodic Dysphonia; Focal Dystonia
MeSH terms: Dysphonia; Hoarseness; Dystonia; Dystonic Disorders
Study type: Observational

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.
    

Detailed 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.
    

Observational model: Cohort
Time perspective: Prospective
Keywords: Spasmodic Dysphonia; Dystonia; Basal Ganglia; PET Imaging; fMRI; Voice Disorder; Healthy Volunteer; HV