Imaging Genetics of Spasmodic Dysphonia

Spasmodic dysphonia (SD) is an isolated focal laryngeal dystonia characterized by selective
impairment of voluntary voice control during speech production. Despite well-characterized
clinical features of SD, its causes and pathophysiology remain unclear. Consequently, the
absence of objective biomarkers of SD leads to diagnostic inaccuracies, while the lack of
understanding of neural and molecular targets of SD pathophysiology hinders the development
of novel therapeutic opportunities for SD patients. The objective of this application is to
identify imaging and genetic biomarkers of SD development and manifestation. The central
hypothesis is that functional and structural brain abnormalities, shaped, in part, by
underlying causative genetic factors, exhibit disorder-characteristic features, which can be
used as diagnostic and predictive SD biomarkers. The rationale for the proposed studies is
that identification of SD neural and genetic biomarkers would have direct clinical impact by
establishing enhanced criteria for accurate differential diagnosis, screening of potential
persons at-risk, and evaluation of mechanism-based novel pharmacological and/or surgical
therapies for these patients. Using a comprehensive approach of multi-modal neuroimaging,
machine learning algorithms, and next-generation DNA sequencing, the central hypothesis will
be tested by pursuing three specific aims: (1) Identify and validate SD phenotype- and
genotype-specific neural markers; (2) Establish endophenotypic markers of SD development; and
(3) Identify SD gene(s) and their association with neural markers of SD susceptibility. This
research is innovative, because it uses a cross-disciplinary approach as a tool for discovery
of the mediating neural mechanisms that bridge the gap between the DNA sequence and SD
pathophysiology. The proposed research is significant because it is expected to advance and
expand the understanding of the mechanistic aspects of brain alterations, identify neural
markers and discover SD gene mutations. Ultimately, the results of these studies are expected
to establish new knowledge, which will be critical for enhancement of SD clinical management
and identification of novel approaches to new treatment options in these patients.

Inclusion Criteria:

- SD patients with clinically documented adductor or abductor form with and without
familial history of SD and/or other forms of isolated dystonia

- Unaffected relatives with a negative history of laryngeal, neurological, or
psychiatric problems who are first-degree relatives of patients with sporadic or
familial SD

- Healthy controls with a negative history of laryngeal, neurological, or psychiatric
problems and a negative family history of dystonia and any other movement disorders

- Age from 21 to 80 years.

- Native English speakers.

- Right-handedness.

Exclusion Criteria:

- Subjects who are incapable of giving an informed consent.

- Pregnant or breastfeeding women until a time when the women are no longer pregnant or
breastfeeding. All women of childbearing potential will have a pregnancy test
performed, which must be negative for participation in the imaging studies.

- Subjects with past or present medical history of (a) neurological problems, such as
stroke, movement disorders (other than SD in the patient groups), brain tumors,
traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia
gravis, demyelinating diseases, alcoholism, drug dependence; (b) psychiatric problems,
such as schizophrenia, bipolar depression, obsessive-compulsive disorder; (c)
laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and
polyps, carcinoma, chronic laryngitis.

- Patients who are not symptomatic at present due to treatment with botulinum toxin
injections into the laryngeal muscles. The duration of positive effects of botulinum
toxin vary from patient to patient but last on average for 3-4 months. Prior to
entering the study, all patients will be evaluated to ensure that they are fully
symptomatic and are at least 3 months post last injection.

- To avoid the possibility of confounding effects of drugs acting upon the central
nervous system, all study participants will be questioned about any prescribed or
over-the-counter medications as part of their initial intake screening. Those patients
who receive medication(s) affecting the central nervous system will be excluded from
the study.

- The patients will be asked whether they have undergone any head and neck surgeries,
particularly any brain surgery and laryngeal surgeries, such as thyroplasty, laryngeal
denervation, and selective laryngeal adductor denervation-reinnervation. Because both
brain and laryngeal surgery may potentially lead to the brain structure and function
re-organization, patients with history of brain and/or laryngeal surgery might be
excluded from the study.

- Subjects who have extensive tattoos on their head and neck, ferromagnetic objects in
their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial
heart valve, etc.) that cannot be removed for the purpose of imaging study
participation.