Imaging Genetics of Laryngeal Dystonia

NCT ID: NCT03042975

Last Updated: 2025-12-02

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 410 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-01-23
• Study Completion Date: 2028-07-31

Brief Summary

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.

Detailed Description

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.

Conditions

Laryngeal Dystonia; Unaffected Relatives of Laryngeal Dystonia Patients; Voice Tremor; Muscle Tension Dysphonia

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Laryngeal Dystonia

Patients with laryngeal dystonia will undergo an MRI of the brain and a blood draw.

MRI

Intervention Type: OTHER

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Blood draw

Intervention Type: PROCEDURE

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Unaffected relatives of laryngeal dystonia patients

Unaffected relatives of patients with laryngeal dystonia will undergo an MRI of the brain and a blood draw.

MRI

Intervention Type: OTHER

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Blood draw

Intervention Type: PROCEDURE

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Voice tremor

Patients with voice tremor will undergo an MRI of the brain and a blood draw.

MRI

Intervention Type: OTHER

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Blood draw

Intervention Type: PROCEDURE

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Muscle tension dysphonia

Patients with muscle tension dysphonia will undergo an MRI of the brain and a blood draw.

MRI

Intervention Type: OTHER

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Blood draw

Intervention Type: PROCEDURE

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Interventions

MRI

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Intervention Type: OTHER

Blood draw

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Intervention Type: PROCEDURE

Eligibility Criteria

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.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Deafness and Other Communication Disorders (NIDCD)

NIH

Sponsor Role: collaborator

Kristina Simonyan

OTHER

Sponsor Role: lead

Responsible Party

Kristina Simonyan

Professor of Otolaryngology - Head & Neck Surgery

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Kristina Simonyan, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts Eye and Ear Infirmary

Locations

Massachusetts Eye and Ear Infirmary

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kristina Simonyan, MD, PhD

Role: CONTACT

Simonyan_Lab@MEEI.HARVARD.EDU

617-573-6016

Facility Contacts

Kristina Simonyan, MD, PhD

Role: primary

Simonyan_Lab@MEEI.HARVARD.EDU

617-573-6016

References

Battistella G, Termsarasab P, Ramdhani RA, Fuertinger S, Simonyan K. Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks. Cereb Cortex. 2017 Feb 1;27(2):1203-1215. doi: 10.1093/cercor/bhv313.

Reference Type: RESULT

PMID: 26679193 (View on PubMed)

Vulinovic F, Schaake S, Domingo A, Kumar KR, Defazio G, Mir P, Simonyan K, Ozelius LJ, Bruggemann N, Chung SJ, Rakovic A, Lohmann K, Klein C. Screening study of TUBB4A in isolated dystonia. Parkinsonism Relat Disord. 2017 Aug;41:118-120. doi: 10.1016/j.parkreldis.2017.06.001. Epub 2017 Jun 10.

Reference Type: RESULT

PMID: 28655586 (View on PubMed)

Termsarasab P, Ramdhani RA, Battistella G, Rubien-Thomas E, Choy M, Farwell IM, Velickovic M, Blitzer A, Frucht SJ, Reilly RB, Hutchinson M, Ozelius LJ, Simonyan K. Neural correlates of abnormal sensory discrimination in laryngeal dystonia. Neuroimage Clin. 2015 Oct 30;10:18-26. doi: 10.1016/j.nicl.2015.10.016. eCollection 2016.

Reference Type: RESULT

PMID: 26693398 (View on PubMed)

Fuertinger S, Horwitz B, Simonyan K. The Functional Connectome of Speech Control. PLoS Biol. 2015 Jul 23;13(7):e1002209. doi: 10.1371/journal.pbio.1002209. eCollection 2015 Jul.

Reference Type: RESULT

PMID: 26204475 (View on PubMed)

Simonyan K, Fuertinger S. Speech networks at rest and in action: interactions between functional brain networks controlling speech production. J Neurophysiol. 2015 Apr 1;113(7):2967-78. doi: 10.1152/jn.00964.2014. Epub 2015 Feb 11.

Reference Type: RESULT

PMID: 25673742 (View on PubMed)

Battistella G, Fuertinger S, Fleysher L, Ozelius LJ, Simonyan K. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia. Eur J Neurol. 2016 Oct;23(10):1517-27. doi: 10.1111/ene.13067. Epub 2016 Jun 27.

Reference Type: RESULT

PMID: 27346568 (View on PubMed)

Putzel GG, Fuchs T, Battistella G, Rubien-Thomas E, Frucht SJ, Blitzer A, Ozelius LJ, Simonyan K. GNAL mutation in isolated laryngeal dystonia. Mov Disord. 2016 May;31(5):750-5. doi: 10.1002/mds.26502. Epub 2016 Feb 1.

Reference Type: RESULT

PMID: 27093447 (View on PubMed)

Rittiner JE, Caffall ZF, Hernandez-Martinez R, Sanderson SM, Pearson JL, Tsukayama KK, Liu AY, Xiao C, Tracy S, Shipman MK, Hickey P, Johnson J, Scott B, Stacy M, Saunders-Pullman R, Bressman S, Simonyan K, Sharma N, Ozelius LJ, Cirulli ET, Calakos N. Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2alpha Signaling as a Generalizable Mechanism for Dystonia. Neuron. 2016 Dec 21;92(6):1238-1251. doi: 10.1016/j.neuron.2016.11.012. Epub 2016 Dec 8.

Reference Type: RESULT

PMID: 27939583 (View on PubMed)

Bianchi S, Battistella G, Huddleston H, Scharf R, Fleysher L, Rumbach AF, Frucht SJ, Blitzer A, Ozelius LJ, Simonyan K. Phenotype- and genotype-specific structural alterations in spasmodic dysphonia. Mov Disord. 2017 Apr;32(4):560-568. doi: 10.1002/mds.26920. Epub 2017 Feb 10.

Reference Type: RESULT

PMID: 28186656 (View on PubMed)

Fuertinger S, Simonyan K. Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. J Neurosci. 2017 Aug 2;37(31):7438-7449. doi: 10.1523/JNEUROSCI.0384-17.2017. Epub 2017 Jul 3.

Reference Type: RESULT

PMID: 28674168 (View on PubMed)

de Lima Xavier L, Simonyan K. The extrinsic risk and its association with neural alterations in spasmodic dysphonia. Parkinsonism Relat Disord. 2019 Aug;65:117-123. doi: 10.1016/j.parkreldis.2019.05.034. Epub 2019 May 24.

Reference Type: DERIVED

PMID: 31153765 (View on PubMed)

Other Identifiers

R01DC011805

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2019P001576

Identifier Type: -

Identifier Source: org_study_id