ClinicalTrials.gov
ClinicalTrials.gov Menu

Imaging Genetics of Spasmodic Dysphonia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03042975
Recruitment Status : Recruiting
First Posted : February 3, 2017
Last Update Posted : January 4, 2018
Sponsor:
Collaborator:
National Institute on Deafness and Other Communication Disorders (NIDCD)
Information provided by (Responsible Party):
Kristina Simonyan, Massachusetts Eye and Ear Infirmary

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 spasmodic dysphonia (or laryngeal dystonia). The researchers use a novel approach of combined imaging genetics, next-generation DNA sequencing, and clinico-behavioral testing. The use of a cross-disciplinary approach as a tool for discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to 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 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 to develop spasmodic dysphonia in family members.

Condition or disease Intervention/treatment
Spasmodic Dysphonia Other: MRI Procedure: Blood draw

Detailed Description:
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.

Study Type : Observational
Estimated Enrollment : 298 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Imaging Genetics of Spasmodic Dysphonia
Actual Study Start Date : January 23, 2017
Estimated Primary Completion Date : February 28, 2022
Estimated Study Completion Date : February 28, 2022

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Spasmodic dysphonia
Patients with spasmodic dysphonia will undergo MRI of the brain and blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

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

Unaffected relatives
Unaffected relatives of patients with spasmodic dysphonia will undergo MRI of the brain and blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

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

Healthy volunteers
Healthy subjects without any neurological, psychiatric or otolaryngological problems will undergo MRI of the brain and blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

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




Primary Outcome Measures :
  1. Brain structural changes [ Time Frame: 5 years ]
    Identify imaging biomarker of SD


Secondary Outcome Measures :
  1. Genes responsible for SD [ Time Frame: 5 years ]
    Identify genetic biomarker of SD. Identify causative genes of spasmodic


Biospecimen Retention:   Samples With DNA
Blood samples will be collected, the DNA will be extracted and banked for genetic studies


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   21 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients with spasmodic dysphonia, their unaffected family members, and healthy volunteers
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03042975


Contacts
Contact: Kristina Simonyan, MD, PhD 617-573-6016 Simonyan_Lab@MEEI.HARVARD.EDU
Contact: Samantha Guiry 617-573-6016 Simonyan_Lab@MEEI.HARVARD.EDU

Locations
United States, Massachusetts
Massachusetts Eye and Ear Infirmary Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kristina Simonyan, MD, PhD    617-573-6016    Simonyan_Lab@MEEI.HARVARD.EDU   
Principal Investigator: Kristina Simonyan, MD, PhD         
Sponsors and Collaborators
Kristina Simonyan
National Institute on Deafness and Other Communication Disorders (NIDCD)
Investigators
Principal Investigator: Kristina Simonyan, MD, PhD Massachusetts Eye and Ear Infirmary

Publications of Results:

Responsible Party: Kristina Simonyan, Director of Laryngology Research, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier: NCT03042975     History of Changes
Other Study ID Numbers: 17-068H
R01DC011805 ( U.S. NIH Grant/Contract )
First Posted: February 3, 2017    Key Record Dates
Last Update Posted: January 4, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kristina Simonyan, Massachusetts Eye and Ear Infirmary:
spasmodic dysphonia
dystonia
laryngeal dystonia
imaging
genetics

Additional relevant MeSH terms:
Dysphonia
Hoarseness
Voice Disorders
Laryngeal Diseases
Respiratory Tract Diseases
Otorhinolaryngologic Diseases
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Respiration Disorders
Signs and Symptoms, Respiratory