Brain Networks in Dystonia

Task-specific primary focal dystonias (tsPFDs) are characterized by selective activation of
dystonic movements during performance of highly learned motor tasks, such as writing, playing
a musical instrument, speaking, or singing. Despite the recent advances in describing the
clinical features of dystonia, there is a fundamental gap in understanding the neural
abnormalities underlying the development of tsPFDs, which affect the same muscles but result
in different clinical manifestations as in writer's cramp vs. pianist's dystonia or spasmodic
dysphonia vs. singer's dystonia. Continued existence of this gap is an important problem
because it renders us unable to differentiate between primary and secondary brain changes
contributing to the tsPFD pathophysiology and to develop novel treatment options targeting
disorder-specific brain alterations. The objective of this application is to identify the
brain mechanisms underlying the phenomenon of task specificity in two representative groups
of patients with writer's cramp vs. musician's hand dystonia and spasmodic dysphonia vs.
singer's laryngeal dystonia using a novel approach of combined clinico-behavioral
examination, brain network analysis and quantitative neuropathology of postmortem brain
tissue. Our central hypothesis is that each tsPFD is characterized by distinct brain
abnormalities, which selectively affect the focal segments of brain networks responsible for
the performance of the respective motor task. The rationale for the proposed research is that
identification of tsPFD-specific brain changes and associated neuropathology will clarify the
neural mechanisms (primary vs. secondary) contributing to the clinical manifestation of these
disorders and thus explain the phenomenon of tsPFDs. The obtained results are expected to
provide strong scientific bases for the next series of studies directed towards
identification and validation of novel pharmacological and/or surgical therapies for these
patients. The researchers will pursue the following two specific aims: (1) determine distinct
features of brain functional network abnormalities underlying task-specificity in different
tsPFDs, and (2) establish structural correlates of functional neuroimaging abnormalities in
tsPFDs. The proposed research is significant because it is expected to establish scientific
evidence that tsPFD is a network disorder with abnormalities following distinct patterns in
different tsPFDs and certain abnormalities showing structure-function correlations are
associated with underlying neuropathology. By converging the results from multimodal
cross-disciplinary studies to a coherent and pathophysiologically meaningful picture, the
researchers will be well positioned to identify primary vs. secondary changes in tsPFDs and
establish a scientific framework for the development of diagnostic biomarkers and novel
treatment options for these disorders.

Inclusion Criteria:

- Patients will have clinically documented focal dystonia (including spasmodic
dysphonia, singer's dystonia, writer's cramp, musician's focal hand dystonia)

- Healthy controls will be healthy volunteers with a negative history of neurological,
laryngeal or psychiatric problems

- Age from 21 to 80 years.

- Native English speakers.

- Right-handedness (based on Edinburgh Handedness Inventory).

Exclusion Criteria:

- Subjects who are incapable of giving an informed consent.

- Pregnant or breastfeeding women until a time when they are no longer pregnant or
breastfeeding. All women of childbearing potential will have a urine 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 dystonia in the patient groups), brain tumors,
traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia
gravis, demyelinating diseases, alcoholism, drug depend-ence; (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.

- Patients who are not symptomatic 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 lasts on average for 3-4 months. All patients will be evaluated
to ensure that they are fully symptomatic prior to entering the study.

- Patients with other forms of dystonia.

- Patients with hereditary forms of dystonia (e.g., DYT1, DYT6, GNAL). If ARSG gene is
identified in musician's dystonia patients, it will be used as a nuisance covariate in
imaging analysis.

- Patients who have dystonia symptoms at rest in order to avoid the potential confound
of dystonic spasms occurring during the scanning.

- 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, neck, or hand
surgeries, which resulted in changes in regional anatomy or innervation. Because
brain, hand and laryngeal surgery may potentially lead to the brain structure and
function re-organization, all patients with history of brain, hand and/or laryngeal
surgery will be excluded from the study.

- Subjects who have tattoos, 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.