Sensory Block + Brain Imaging for Spasmodic Dysphonia

Overseen By Kristina Simonyan, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Massachusetts Eye and Ear Infirmary

Must not be taking: CNS drugs

Disqualifiers: Neurological, Psychiatric, Laryngeal, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 years

165 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to understand the brain activity differences between laryngeal dystonia (a voice disorder) and voice tremor. Participants will undergo brain imaging while receiving either a sensory block with bupivacaine (a local anesthetic), a placebo, or auditory feedback testing to explore how these treatments affect speech-related brain activity. The trial seeks individuals with either laryngeal dystonia or voice tremor who are right-handed native English speakers. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a unique opportunity to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

If you are taking medications that affect the central nervous system, you will not be able to participate in the trial. The protocol does not specify other medication restrictions, but you will be asked about all medications during the initial screening.

What prior data suggests that brain imaging and topical bupivacaine are safe for this study?

Research shows that bupivacaine, a local numbing medicine, is generally safe for use on the skin. It often numbs areas for surgeries and medical procedures, indicating it has been well-studied and is usually well-tolerated by adults. Despite its long history of use, some side effects may occur, such as temporary numbness or tingling at the application site.

In studies examining its use for conditions like laryngeal dystonia, researchers are testing bupivacaine to see how it affects brain activity during speech. These studies remain in the early stages, but the FDA's approval of bupivacaine for other uses supports its safety. However, like any medication, it is important to be aware of possible side effects and discuss them with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it's exploring innovative ways to understand and potentially treat spasmodic dysphonia and voice tremor. Unlike current treatments like botulinum toxin injections, which target muscle activity, this trial examines how modulating sensory feedback from the larynx with bupivacaine or placebo affects brain activity during speech. Additionally, researchers are using advanced imaging techniques like MEG, fMRI, and EEG to study how the brain processes auditory and motor signals during speech. This could lead to new insights into the neural mechanisms underlying these conditions and pave the way for novel therapeutic strategies.

What evidence suggests that this trial's treatments could be effective for spasmodic dysphonia?

In this trial, participants will receive either a topical laryngeal block with bupivacaine or a saline placebo to modulate somatosensory feedback from the laryngeal mucosa during speech production. A previous study showed that a cream containing bupivacaine improved conditions during medical procedures compared to lidocaine. Bupivacaine numbs the area, potentially reducing symptoms of throat muscle spasms and voice tremors. Although direct evidence for these specific conditions is still being gathered, bupivacaine's ability to alter sensory perception offers potential benefits. The treatment aims to change how the brain processes signals from the throat, possibly leading to relief from symptoms of spasmodic dysphonia. While more research is needed, early signs suggest bupivacaine could effectively manage these voice disorders. ^{3 4 6 7 8}

Who Is on the Research Team?

Kristina Simonyan, MD, PhD

Principal Investigator

Professor of Otolaryngology - Head and Neck Surgery

Are You a Good Fit for This Trial?

This trial is for native English-speaking, right-handed adults aged 18-80 who are healthy or have laryngeal dystonia or voice tremor. Excluded are those with other neurological issues, psychiatric disorders, certain laryngeal conditions, history of brain/laryngeal surgery affecting anatomy/function, tattoos/objects unsafe for MRI, and use of central nervous system drugs.

Inclusion Criteria

I belong to a diverse racial or ethnic background.

You primarily use your right hand.

I am a native English speaker.

Exclusion Criteria

I am not taking any medications that affect the brain.

I experience muscle contractions without moving or have mirror dystonia.

You have tattoos or metal objects inside your body that can't be taken out for MRI scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo sensorimotor modulations and auditory feedback processing using bupivacaine, placebo, and MEG imaging to assess CNS pathophysiology

5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Brain Imaging
• Topical Bupivacaine

Trial Overview

The study aims to understand the differences in brain function between laryngeal dystonia and voice tremor using a sensory block with bupivacaine and advanced brain imaging techniques to identify disorder-specific neural activity patterns.

How Is the Trial Designed?

Group I: Spatial and temporal CNS pathophysiology of laryngeal dystonia and voice tremor Experimental Treatment 1 Intervention

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

Group II: Motor learning and CNS pathophysiology of laryngeal dystonia and voice tremor Experimental Treatment 1 Intervention

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.

Group III: Auditory feedback processing in laryngeal dystonia and voice tremor Experimental Treatment 1 Intervention

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.

Group IV: Sensorimotor modulations of laryngeal dystonia and voice tremor with bupivacaine Active Control 1 Intervention

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.

Group V: Placebo effects in laryngeal dystonia and voice tremor Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Massachusetts Eye and Ear Infirmary

Lead Sponsor

Trials

115

Recruited

15,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

Surgical treatment (lateralization thyroplasty) for spasmodic dysphonia significantly reduced or eliminated voice symptoms in all three patients studied, demonstrating its efficacy.

Post-operative brain imaging revealed a normalization of brain activity patterns, indicating that successful treatment not only alleviates vocal symptoms but also reverses abnormal central nervous system activity associated with the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Type II thyroplasty changes cortical activation in patients with spasmodic dysphonia. Tateya, I., Omori, K., Kojima, H., et al.[2016]

In a study of 19 patients with spasmodic dysphonia, MRI revealed abnormal findings in 6 patients, including brain infarcts and demyelinating lesions, suggesting potential underlying neurological issues.

There was a weak correlation between abnormal MRI results and auditory brain stem response tests, indicating that while MRI can show associated lesions, it may not directly identify the causes of spasmodic dysphonia, highlighting the complexity of this voice disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging findings and correlations in spasmodic dysphonia patients. Schaefer, S., Freeman, F., Finitzo, T., et al.[2017]

The study involved 14 patients with adductor-type spasmodic dysphonia (ADSD) and 15 control subjects, using functional MRI to assess central tactile processing and resting-state connectivity before and during the effects of botulinum neurotoxin type A (BoNT-A).

Findings revealed that ADSD patients exhibited abnormal tactile processing and increased connectivity in certain brain regions, but BoNT-A treatment did not significantly change these activation patterns, suggesting that central sensory processing abnormalities are a key feature of ADSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered sensory system activity and connectivity patterns in adductor spasmodic dysphonia. Mantel, T., Dresel, C., Welte, M., et al.[2021]

Patients with adductor and abductor spasmodic dysphonia (SD) show distinct brain activation patterns, with increased activity in the primary sensorimotor cortex and decreased activity in the basal ganglia, thalamus, and cerebellum during voice tasks, indicating potential neural mechanisms underlying the disorder.

The primary somatosensory cortex appears to play a significant role in the pathophysiology of SD, as its activation correlates with symptom severity, suggesting it could be a target for future therapeutic interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. Simonyan, K., Ludlow, CL.[2021]

A study involving 11 patients with spasmodic dysphonia (SD) and healthy participants revealed that the sensorimotor cortex and thalamus are key areas affected in SD, as they showed different neural activation patterns during a sound discrimination task.

The findings suggest that sensorimotor signals correlate with the severity of SD and could serve as a potential biomarker for diagnosing the condition, with a classification accuracy of 73% between patients and healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperactive sensorimotor cortex during voice perception in spasmodic dysphonia. Kanazawa, Y., Kishimoto, Y., Tateya, I., et al.[2021]

In a study involving 9 adults with adductor spasmodic dysphonia (ADSD), botulinum toxin (BTX) injections significantly improved speech-related brain activity, particularly in areas responsible for motor control, compared to 10 healthy volunteers.

The enhanced brain responses after BTX treatment correlated strongly with clinical improvements in speech, indicating that BTX may help the brain process sensory information more efficiently, leading to better control of laryngeal movements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study. Ali, SO., Thomassen, M., Schulz, GM., et al.[2019]

This study identified specific brain abnormalities in patients with spasmodic dysphonia using diffusion tensor imaging (DTI) and postmortem histopathology, revealing changes in the internal capsule and other brain regions associated with voice production.

The observed brain changes, including decreased axonal density and increased water diffusivity, correlate with the severity of clinical symptoms, suggesting that these abnormalities may disrupt the brain's control over voluntary voice production, contributing to the disorder's pathophysiology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study. Simonyan, K., Tovar-Moll, F., Ostuni, J., et al.[2021]

In a study of 14 patients with spasmodic dysphonia, no abnormalities were found in their auditory brainstem responses (ABR), suggesting that brainstem function may be intact in these individuals.

The SCAN-A test, which assesses central auditory processing, showed negligible positive findings, indicating that central auditory processing deficits may not be a significant feature in patients with spasmodic dysphonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central auditory evaluation of patients with spasmodic dysphonia. Middleton, ML., Wilson, KM., Keith, RW.[2010]

In a case report involving three patients with spasmodic dysphonia (SD) following head injury, multiple neurodiagnostic tests revealed significant neurological abnormalities, highlighting the potential link between head trauma and the onset of SD symptoms.

The study emphasizes the importance of considering prior head trauma in patients with SD and suggests that a single negative test for central nervous system function does not rule out the presence of neurological lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spasmodic dysphonia subsequent to head trauma. Finitzo, T., Pool, KD., Freeman, FJ., et al.[2019]

Citations

1.

go.drugbank.com

go.drugbank.com/drugs/DB00297/clinical_trials?conditions=DBCOND0068014%2CDBCOND0041038%2CDBCOND0003658&phase=1&purpose=basic_science&status=recruiting

Bupivacaine Recruiting Phase 1 Trials for Laryngeal ...

Bupivacaine Recruiting Phase 1 Trials for Laryngeal Dystonia / Spasmodic Dysphonia / Tremor Basic Science ; NCT05216770. Understanding Disorder-specific Neural ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11805872/

Laryngeal dystonia and vocal tremor response to ...

The main objective of this study was to compare laryngeal dystonia (LD) and vocal tremor's (VT) response to botulinum toxin injection.

3.

ejo.springeropen.com

ejo.springeropen.com/articles/10.1186/s43163-024-00678-2

Effectiveness of topical bupivacaine versus topical lidocaine ...

Topical application of bupivacaine was associated with better extubation conditions and parental satisfaction when compared to topical lidocaine ...

4.

malacards.org

malacards.org/card/spasmodic_dystonia

Spasmodic Dystonia

Integrated disease information for Spasmodic Dystonia including associated genes, mutations, phenotypes, pathways, drugs, and more - integrated from 78 data ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/24980226/

Comparison of topical anesthetic effects of lidocaine, ...

This study was designed to investigate the topical anesthetic efficacy of four different solutions including lidocaine spray, bupivacaine, ropivacaine, and ...

6.

go.drugbank.com

go.drugbank.com/drugs/DB00297

Bupivacaine: Uses, Interactions, Mechanism of Action

Bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia ...

7.

ncbi.nlm.nih.gov

ncbi.nlm.nih.gov/books/NBK532883/

Bupivacaine - StatPearls - NCBI Bookshelf - NIH

Bupivacaine is a potent local anesthetic with unique characteristics from the amide group of local anesthetics, first discovered in 1957.

8.

aetna.com

aetna.com/cpb/medical/data/100_199/0113.html

Botulinum Toxin - Medical Clinical Policy Bulletins

The most commonly observed adverse reactions in cervical dystonia (5% or more) include headache, injection site pain, injection site erythema, muscular weakness ...