The contribution of genetic risk factors to the development of focal dystonias is evident. However, understanding of how variations in the causative gene expression lead to variations in brain abnormalities in different phenotypes of dystonia (e.g., familial, sporadic) remains limited. The research program of the investigators is set to determine the relationship between brain changes and genetic risk factors in laryngeal dystonia (or spasmodic dysphonia). The researchers use a novel approach of combined imaging genetics, next-generation DNA sequencing, and clinical-behavioral testing. The use of a cross-disciplinary approach as a tool for the discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to the pathophysiology of dystonia holds a promise for the understanding of the mechanistic aspects of brain function affected by risk gene variants, which can be used reliably for the discovery of associated genes and neural integrity markers for this disorder. The expected outcome of this study may lead to better clinical management of this disorder, including its improved detection, accurate diagnosis, and assessment of the risk of developing dystonia in family members.

Laryngeal dystonia (LD), or spasmodic dysphonia, is an isolated focal dystonia characterized by selective impairment of speech production due to involuntary spasms in the laryngeal muscles. Despite the well-characterized clinical features of LD, its clinical management remains challenging due, in part, to the absence of objective measures (biomarkers) for early detection and differential diagnosis. This results in diagnostic inaccuracies, which have a negative impact on the patient's quality of life and healthcare costs. Importantly, delayed diagnosis leads to deferred treatment. The objective of this application is to conduct a series of studies that combine advanced machine-learning with neuroimaging and genetics to (1) identify the neural markers that accurately differentiate LD between its clinical phenotypes (adductor vs. abductor), genotypes (sporadic vs. familial), and comorbid disorders (voice tremor and muscle tension dysphonia); (2) determine the early predictive neural markers of LD development in at-risk individuals, and (3) validate associated LD gene mutations. Supported by our preliminary data, our central hypothesis is that brain abnormalities are shaped, in part, by underlying genetic factors and exhibit LD form-characteristic features, which can be used as differential diagnostic and early predictive biomarkers of this disorder. This research is innovative both conceptually and methodologically because it uses a cross-disciplinary approach to focus on the neural pathophysiology and genetic susceptibility factors for LD diagnostic and predictive biomarker discovery. The proposed research is significant because it will directly contribute to closing the critically existing gap in the clinical management of LD. Identification of LD neural and genetic markers is expected to have a positive translational impact by establishing enhanced criteria for accurate differential diagnosis and screening of persons at risk. In short, the successful completion of these studies will open new horizons for the clinical management of LD patients.

Inclusion criteria:

1. Males and females of diverse racial and ethnic background, with age across the lifespan;

2. Laryngeal Dystonia patients

   • phenotype: adductor or abductor
   • genotype: familial or sporadic

3. Voice Tremor patients

   • essential or
   • dystonic

4. Muscle tension dysphonia patients

5. Unaffected relatives of laryngeal dystonia patients with

   • familial laryngeal dystonia
   • early-onset laryngeal dystonia (onset at ≤ 35 y.o.)
   • typical onset laryngeal dystonia (onset at ≥ 40 y.o.)

6. Native English speakers.

7. Right-handedness.

8. Normal cognitive status.

Exclusion criteria:

1. Subjects who are incapable of giving 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) major neurological problems, such as stroke, movement disorders (other than LD and VT 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) laryn¬geal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis.
4. Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles.
5. Subjects who receive medication(s) affecting the central nervous system.
6. Subjects with a history of major brain and/or laryngeal surgery.
7. Subjects who have tattoos, ferromagnetic objects in their bodies that cannot be removed for imaging study participation.

laryngeal dystonia unaffected relatives of laryngeal dystonia patients voice tremor muscle tension dysphonia