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

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.

Study Overview

• Status: Recruiting
• Conditions: Tremor; Spasmodic Dysphonia; Laryngeal Dystonia
• Intervention / Treatment: Other: Brain imaging; Drug: Laryngeal sensory block with topical bupivacaine

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.

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Kristina Simonyan, MD, PhD; Phone Number: 617-573-6016; Email: simonyan_lab@meei.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts Eye and Ear and University of California San Francisco
      • Contact: Kristina Simonyan, MD, PhD; Phone Number: 617-573-6016; Email: simonyan_lab@meei.harvard.edu
      • Principal Investigator: Kristina Simonyan, MD, PhD
      • Principal Investigator: Srikantan Nagarajan, PhD
      • Principal Investigator: John Houde, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Spatial and temporal CNS pathophysiology of laryngeal dystonia and voice tremor; Simultaneous fMRI with EEG and MEG imaging will be used to examine neural dynamics during phonation.	Other: Brain imaging; Brain images will be conducted with function MRI, magnetoencephalography (MEG), and electroencephalography (EEG) to identify disorder-specific neural markers
Other: Motor learning and CNS pathophysiology of laryngeal dystonia and voice tremor; 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.	Other: Brain imaging; Brain images will be conducted with function MRI, magnetoencephalography (MEG), and electroencephalography (EEG) to identify disorder-specific neural markers
Active Comparator: Sensorimotor modulations of laryngeal dystonia and voice tremor with bupivacaine; Topical laryngeal block (1 ml of 0.75% bupivacaine solution) will be used to modulate somatosensory feedback from the laryngeal mucosa during speech production and examine associated changes in brain activity.	Drug: Laryngeal sensory block with topical bupivacaine; 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
Placebo Comparator: Placebo effects in laryngeal dystonia and voice tremor; 1 ml of saline placebo matching to 1 ml of 0.75% bupivacaine solution will be used for a comparison with the topical laryngeal block to modulate somatosensory feedback from the laryngeal mucosa during speech production and examine associated changes in brain activity.	Drug: Laryngeal sensory block with topical bupivacaine; 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
Other: Auditory feedback processing in laryngeal dystonia and voice tremor; 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.	Other: Brain imaging; Brain images will be conducted with function MRI, magnetoencephalography (MEG), and electroencephalography (EEG) to identify disorder-specific neural markers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	5 years
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	5 years
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	5 years

Collaborators and Investigators

• Sponsor: Massachusetts Eye and Ear Infirmary
• Collaborators: University of California, San Francisco
• Investigators: Study Director: Kristina Simonyan, MD, PhD, Professor of Otolaryngology - Head and Neck Surgery

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2022
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: November 27, 2021
• First Submitted That Met QC Criteria: January 11, 2022
• First Posted (Actual): February 1, 2022

Study Record Updates

• Last Update Posted (Actual): December 2, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Dyskinesias; Laryngeal Diseases; Voice Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Tremor; Dysphonia; Organic Chemicals; Investigative Techniques; Diagnostic Techniques and Procedures; Diagnosis; Anilides; Amides; Aniline Compounds; Amines; Diagnostic Imaging; Diagnostic Techniques, Neurological; Bupivacaine; Neuroimaging
• Other Study ID Numbers: 2021P003142

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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