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Understanding Disorder-specific Neural Pathophysiology in Laryngeal Dystonia and Voice Tremor

Primary Purpose

Laryngeal Dystonia, Spasmodic Dysphonia, Tremor

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Brain imaging
Laryngeal sensory block with topical bupivacaine
Sponsored by
Massachusetts Eye and Ear Infirmary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Laryngeal Dystonia

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria:

  1. Males and females of diverse racial and ethnic background;
  2. Age 18-80 years;
  3. Native English speakers;
  4. Right-handed;
  5. Normal cognitive status;
  6. Patients will have laryngeal dystonia or voice tremor;
  7. Healthy controls will be healthy individuals without neurological, psychiatric or otolaryngological problems.

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. All women of childbearing potential will have a urine pregnancy test performed before MRI, which must be negative for participation in the imaging studies;
  3. Subjects with a past or present medical history of (a) neurological problems, such as stroke, movement disorders (other than specified LD and VT in the patient groups), brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases; (b) psychiatric problems, such as schizophrenia, bipolar depression, obsessive-compulsive disorder, alcoholism, drug dependence; (c) laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis;
  4. Patients with any other form of dystonia;
  5. Patients who have dystonia symptoms at rest or have a presence of mirror dystonia;
  6. Patients who are not symptomatic due to treatment with botulinum toxin injections into the affected muscles. The duration of positive effects of botulinum toxin varies from patient to patient but lasts, on average, for 3-4 months. All patients will be evaluated to ensure that they are fully symptomatic and are at least 3 months post-injection before participation;
  7. To avoid the confounding effect of centrally acting drugs, all study participants will be questioned about any prescribed or over-the-counter medications as part of their initial screening. Those patients who receive medication(s) affecting the central nervous system will be excluded;
  8. Patients will be asked whether they have undergone any head or neck surgery, which resulted in changes in regional anatomy or innervation. Because brain or laryngeal surgery may potentially lead to brain structure and function re-organization, all patients with such a history will be excluded;
  9. Subjects who have certain tattoos and ferromagnetic objects in their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial heart valve) that cannot be removed for MRI studies.

Sites / Locations

  • Massachusetts Eye and Ear and University of California San FranciscoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Experimental

Other

Arm Label

Spatial and temporal CNS pathophysiology of laryngeal dystonia and voice tremor

Sensorimotor modulations on CNS pathophysiology of laryngeal dystonia and voice tremor

Motor learning and CNS pathophysiology of laryngeal dystonia and voice tremor

Arm Description

Simultaneous fMRI with EEG and MEG imaging will be used to examine neural dynamics during phonation.

Topical laryngeal block will be used to modulate somatosensory feedback from the laryngeal mucosa during speech production and examine associated changes in brain activity. The role of auditory feedback processing on task-induced speech sensorimotor activity will be examined using MEG imaging during perturbing pitch or formants of auditory feedback, unpredictably during speech production, and examining the behavioral and neural correlates of the resulting within-trial compensation responses.

Implicit learning of the production of motor sequences will be examined during simultaneous fMRI/EEG and MEG imaging. Sensorimotor adaptation of speech production during MEG imaging will be examined during perturbing pitch or formants of auditory feedback consistently during speech production and examining the behavioral and neural correlates of the resulting across-trial adaptation responses.

Outcomes

Primary Outcome Measures

Functional MRI, MEG and EEG signal changes in laryngeal dystonia compared to voice tremor
Qualitative analysis of brain regions with disorder-specific increases and decreases of spatial (functional MRI) and temporal (MEG and EEG) signals will be determined in patients with laryngeal dystonia compared to patients with voice tremor
Effects of sensorimotor brain modulation on voice function in laryngeal dystonia
Quantitative measures of symptoms will be determined using Burk-Fahn-Marsden Dystonia Rating Scale where higher score means a worse outcome, following sensorimotor feedback modulation in patients with laryngeal dystonia
Effects of sensorimotor brain modulation on voice function in voice tremor
Quantitative measures of symptoms will be determined using Fahn-Tolosa-Marin Rating Scale where higher score means a worse outcome, following sensorimotor feedback modulation in patients with voice tremor

Secondary Outcome Measures

Full Information

First Posted
November 27, 2021
Last Updated
October 24, 2023
Sponsor
Massachusetts Eye and Ear Infirmary
Collaborators
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT05216770
Brief Title
Understanding Disorder-specific Neural Pathophysiology in Laryngeal Dystonia and Voice Tremor
Official Title
Understanding Disorder-specific Neural Pathophysiology in Laryngeal Dystonia and Voice Tremor
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 24, 2022 (Actual)
Primary Completion Date
August 31, 2026 (Anticipated)
Study Completion Date
August 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts Eye and Ear Infirmary
Collaborators
University of California, San Francisco

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The researchers will examine functional neural correlates that differentiate between laryngeal dystonia and voice tremor and contribute to disorder-specific pathophysiology using a cross-disciplinary approach of multimodal brain imaging.
Detailed Description
Laryngeal dysphonia (LD) and Voice Tremor (VT) are neurological voice disorders that impair speech production. The characteristic feature of LD (i.e., occurring during speaking but not laughing or crying) and the lack of physical laryngeal abnormalities suggests that LD is likely a disorder affecting the task-specific control of phonation by the central nervous system (CNS). Similarly, VT is often observed without any clear peripheral laryngeal etiology, also suggesting a central origin but distinct from that affected in LD. The overall goal of this project is to characterize the common and distinct features of CNS pathophysiology in the neurological voice disorders, LD and VT. The act of speech is a dynamic process, including initial glottal movement, voice onset, and compensatory responses to sensory feedback fluctuations during sustained phonation. Identifying specific functional impairments in LD and VT requires a clear understanding of when in the process of phonation, as well as where in the CNS, aberrant activity occurs. Due to their poor temporal resolution, prior neuroimaging studies have not been able to address the question of when abnormal CNS activation occurs relative to specific phonation events. As a result, critical clues about the underlying etiologies in these disorders have likely been missed. A multimodal brain imaging will asses CNS abnormalities associated with LD and VT, specifically 1) Spatial and temporal CNS pathophysiology during speech and other vocal tasks; 2) Sensorimotor modulations on CNS pathophysiology; and 3) Motor learning and CNS pathophysiology. Future treatments for LD and VT can be developed by targeting CNS pathophysiological mechanisms identified in this project.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Laryngeal Dystonia, Spasmodic Dysphonia, Tremor

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Only one of three arms includes Intervention. The other two arms are Observational. The Interventional arm has a parallel study model where patients with laryngeal dystonia and voice tremor will be assigned to laryngeal sensory block in parallel. Allocation will be non-randomized.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
165 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Spatial and temporal CNS pathophysiology of laryngeal dystonia and voice tremor
Arm Type
Other
Arm Description
Simultaneous fMRI with EEG and MEG imaging will be used to examine neural dynamics during phonation.
Arm Title
Sensorimotor modulations on CNS pathophysiology of laryngeal dystonia and voice tremor
Arm Type
Experimental
Arm Description
Topical laryngeal block will be used to modulate somatosensory feedback from the laryngeal mucosa during speech production and examine associated changes in brain activity. The role of auditory feedback processing on task-induced speech sensorimotor activity will be examined using MEG imaging during perturbing pitch or formants of auditory feedback, unpredictably during speech production, and examining the behavioral and neural correlates of the resulting within-trial compensation responses.
Arm Title
Motor learning and CNS pathophysiology of laryngeal dystonia and voice tremor
Arm Type
Other
Arm Description
Implicit learning of the production of motor sequences will be examined during simultaneous fMRI/EEG and MEG imaging. Sensorimotor adaptation of speech production during MEG imaging will be examined during perturbing pitch or formants of auditory feedback consistently during speech production and examining the behavioral and neural correlates of the resulting across-trial adaptation responses.
Intervention Type
Other
Intervention Name(s)
Brain imaging
Intervention Description
Brain images will be conducted with function MRI, magnetoencephalography (MEG), and electroencephalography (EEG) to identify disorder-specific neural markers
Intervention Type
Drug
Intervention Name(s)
Laryngeal sensory block with topical bupivacaine
Intervention Description
Laryngeal sensory block with bupivacaine will be used to modulate sensory feedback from vocal fold mucosa and examine the impact of sensory feedback on abnormal neural activity in LD and VT
Primary Outcome Measure Information:
Title
Functional MRI, MEG and EEG signal changes in laryngeal dystonia compared to voice tremor
Description
Qualitative analysis of brain regions with disorder-specific increases and decreases of spatial (functional MRI) and temporal (MEG and EEG) signals will be determined in patients with laryngeal dystonia compared to patients with voice tremor
Time Frame
5 years
Title
Effects of sensorimotor brain modulation on voice function in laryngeal dystonia
Description
Quantitative measures of symptoms will be determined using Burk-Fahn-Marsden Dystonia Rating Scale where higher score means a worse outcome, following sensorimotor feedback modulation in patients with laryngeal dystonia
Time Frame
5 years
Title
Effects of sensorimotor brain modulation on voice function in voice tremor
Description
Quantitative measures of symptoms will be determined using Fahn-Tolosa-Marin Rating Scale where higher score means a worse outcome, following sensorimotor feedback modulation in patients with voice tremor
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria: Males and females of diverse racial and ethnic background; Age 18-80 years; Native English speakers; Right-handed; Normal cognitive status; Patients will have laryngeal dystonia or voice tremor; Healthy controls will be healthy individuals without neurological, psychiatric or otolaryngological problems. Exclusion criteria: Subjects who are incapable of giving 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 before MRI, which must be negative for participation in the imaging studies; Subjects with a past or present medical history of (a) neurological problems, such as stroke, movement disorders (other than specified LD and VT in the patient groups), brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases; (b) psychiatric problems, such as schizophrenia, bipolar depression, obsessive-compulsive disorder, alcoholism, drug dependence; (c) laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis; Patients with any other form of dystonia; Patients who have dystonia symptoms at rest or have a presence of mirror dystonia; Patients who are not symptomatic due to treatment with botulinum toxin injections into the affected muscles. The duration of positive effects of botulinum toxin varies from patient to patient but lasts, on average, for 3-4 months. All patients will be evaluated to ensure that they are fully symptomatic and are at least 3 months post-injection before participation; To avoid the confounding effect of centrally acting drugs, all study participants will be questioned about any prescribed or over-the-counter medications as part of their initial screening. Those patients who receive medication(s) affecting the central nervous system will be excluded; Patients will be asked whether they have undergone any head or neck surgery, which resulted in changes in regional anatomy or innervation. Because brain or laryngeal surgery may potentially lead to brain structure and function re-organization, all patients with such a history will be excluded; Subjects who have certain tattoos and ferromagnetic objects in their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial heart valve) that cannot be removed for MRI studies.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kristina Simonyan, MD, PhD
Phone
617-573-6016
Email
simonyan_lab@meei.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kristina Simonyan, MD, PhD
Organizational Affiliation
Professor of Otolaryngology - Head and Neck Surgery
Official's Role
Study Director
Facility Information:
Facility Name
Massachusetts Eye and Ear and University of California San Francisco
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristina Simonyan, MD, PhD
Phone
617-573-6016
Email
Simonyan_Lab@MEEI.HARVARD.EDU
First Name & Middle Initial & Last Name & Degree
Kristina Simonyan, MD, PhD
First Name & Middle Initial & Last Name & Degree
Srikantan Nagarajan, PhD
First Name & Middle Initial & Last Name & Degree
John Houde, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Understanding Disorder-specific Neural Pathophysiology in Laryngeal Dystonia and Voice Tremor

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