Using Neurostimulation to Accelerate Change in Misophonia: a Pilot Study

NCT06333925 | Active Not Recruiting FDA Device

• 1 other identifier: Pro00114183
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Misophonia, the inability to tolerate certain repetitive distressing sounds that are common, is gaining, recognition as an impairing condition. It is not a well-understood condition and there are no known treatments. The purpose of this study is to test a new misophonia intervention that uses emotion regulation strategies and different types of brain stimulation on misophonic distress. This study will examine changes in brain activity during presentation and regulation of misophonic versus distressing sounds. The study team plans to alter activity in a key area of the brain responsible for emotion regulation circuitry over 4 sessions with the goal to test if this intervention helps misophonic distress. Sixty adult participants with moderate to severe misophonia will be recruited and taught an emotion regulation skill and randomly assigned to receive one of two types of repetitive transcranial magnetic stimulation (rTMS). The study includes 9-10 visits: the remote screening visit(s), the initial MRI, the four neurostimulation sessions, the follow-up MRI, and two additional remote 1- and 3-month follow-up visits.

Conditions

Sound Sensitivity; Misophonia; Emotion Dysregulation; Sensory Processing Disorder; Anxiety Disorder; Auditory Over Responsivity

Keywords

Neurostimulation; Cognitive Restructuring; Sound Sensitivity; Neuroscience; Neuroimaging; Neuromodulation; Misophonia; Emotion Dysregulation; Emotion Regulation Skills; Repetitive Transmagnetic Stimulation; TMS; Emotion Regulation

Outcome Measures

Primary Outcomes (7)

• Number of clusters across the whole brain with significant BOLD changes between conditions contrasting follow up with intake, and exposure to misophonic versus aversive sounds

  Blood Oxygenation Level Dependent (BOLD) imaging is a technique that is commonly used for estimating brain activity using functional magnetic resonance imaging (fMRI). Change in the fMRI BOLD signal notes changes in brain blood flow and blood oxygenation, which are associated with neuronal activity. For each participant,the difference in BOLD activation between follow up and intake was computed. The BOLD signal contrast between engaging with misophonic sounds and engaging with aversive sounds were compared between conditions across the whole brain on a voxel-wise basis. Voxel-wise significant results (i.e., z \> 2.3) were clustered to statistically correct for multiple comparisons. The number of significant clusters that emerged from this analysis in each condition are presented as outcome.

  during the neuroimaging session, within 2 months of the intake assessment

• Number of clusters across the whole brain with significant BOLD changes between conditions contrasting follow up with intake, and downregulation of versus exposure to misophonic sounds

  Blood Oxygenation Level Dependent (BOLD) imaging is a technique that is commonly used for estimating brain activity using functional magnetic resonance imaging (fMRI). Change in the fMRI BOLD signal notes changes in brain blood flow and blood oxygenation, which are associated with neuronal activity. For each participant, the difference in BOLD activation between follow up and intake was computed. The BOLD signal contrast between downregulating and engaging with misophonic sounds were compared between conditions across the whole brain on a voxel-wise basis. Voxel-wise significant results (i.e., z \> 2.3) were clustered to statistically correct for multiple comparisons. The number of significant clusters that emerged from this analysis in each condition are presented as outcome.

  during the neuroimaging session, within 2 months of the intake assessment

• Differential change in BOLD signal within the Anterior Insular Cortex (AIC) activation when being presented with misophonic versus non-misophonic but aversive sounds

  Blood Oxygenation Level Dependent (BOLD) imaging is a technique that is commonly used for estimating brain activity using functional magnetic resonance imaging (fMRI). Change in the fMRI BOLD signal notes changes in brain blood flow and blood oxygenation, which are associated with neuronal activity. For each participant, change in activation during the presentation of misophonic versus aversive sounds from baseline to follow up will be computed. An anterior insular cortex (AIC) mask will be employed to find the maximum value of the \[hear misophonic sounds \> hear aversive sounds\] contrast in this region. Once the voxel containing this maximum will beidentified, a sphere ROI will be created around this spot (restricted to the AIC mask) and the average contrast value within this sphere will be used as the outcome variable. A larger score indicates more activity when hearing misophonic versus aversive sounds.

  during the neuroimaging session, within 2 months of the intake assessment

• Differential change in BOLD signal connectivity between the left Anterior Insular Cortex (AIC) and the right dorsolateral prefrontal cortex (dlPFC) when downregulating versus experiencing distress related to misophonic trigger sounds

  Blood Oxygenation Level Dependent (BOLD) imaging is a technique that is commonly used for estimating brain activity using functional magnetic resonance imaging (fMRI). For each participant, change in activation during the \[downregulate vs. listen to misophonic sounds\] contrast from baseline to follow up will be computed. A left anterior insular cortex (AIC) mask will be employed to find the maximum value for the contrast of interest in this region. A psychophysiological interaction (PPI) analysis will be conducted, to identify the voxel within the right dlPFC with the highest positive correlation with the max activation AIC voxel. A sphere ROI will be created around this right dlPFC spot (restricted with a dlPFC mask) and the average contrast value within this sphere will be used as the outcome connectivity variable. A larger score indicates more connectivity when downregulating versus hearing misophonic sounds.

  during the neuroimaging session, within 2 months of the intake assessment

• Change in misophonia impairment and severity using a composite

  Change in misophonia impairment and severity will be investigated by using a composite score that will be created from the following scales and interview to examine changes in misophonia impairment and severity: the Duke Misophonia Questionnaire (DMQ), the Duke Misophonia Interview (DMI), the Duke-Vanderbilt Misophonia Screening Questionnaire (DVMSQ). A higher score on the DMQ impairment indicates more impairment (ranges 0-48). Similarly, higher scores on the DVMSQ and DMI indicate higher levels of impairment and distress. These measures are collected at all possible time points, depending on the range of time that they cover (e.g., DMI is not collected at 1 week follow up because it asks for impairment in the past month).

  Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up

• Skin conductance level (scl)

  Physiological arousal measured by SCL during each neurostimulation visit will be extracted using Acqknowledge software and BIOPAC hardware. Raw galvanic skin response will be continuously collected throughout the experiment. Raw data will then be examined for abrupt changes (skin conductance responses), which will be removed. The processed data will then be averaged for each experimental block. Higher SCL means higher arousal.

  Baseline, and two minute blocks during the 4 neurostimulation sessions (when participants downregulate emotions associated with misophonic triggers)

• Change in Subjective Unites of Distress (SUDS)

  Self reported distress after each sound presentation will also be examined for differences when accounting for baseline distress (during the neurostimulation sessions). SUDS will be measured using a 0-9 sale, where 0 indicates no distress, and 9 indicates extreme distress. The outcome measure represents SUDS after misophonic sound presentations minus SUDS after baseline. Higher SUDS represents higher distress.

  Baseline, during the experimental blocks of the neurostimulation sessions (which will occur over 4 days within a month of the initial assessment)

Secondary Outcomes (3)

• Changes in self-reported psychopathology

  Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up

• Changes in clinician-assessed psychopathology

  Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up

• Emotional dysregulation as measured by the Difficulties in Emotion Regulation Scale (DERS)

  Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up

Other Outcomes (8)

• Changes in self-reported cognitive flexibility

  Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up

• Baseline emotional dysregulation

  Baseline

• Baseline hyperacusis

  Baseline

Study Arms (2)

Cognitive Restructuring + High Frequency Repetitive Transcranial Magnetic Stimulation (rTMS)

EXPERIMENTAL

30 eligible participants will receive training in Cognitive Restructuring (CR). These participants will use CR while being exposed to misophonic trigger sounds and also receiving high frequency rTMS over their personalized right dorsal lateral prefrontal cortex (dlPFC) target. These participants will partake in short term and long term follow-up testing.

Device: High Frequency Repetitive Transcranial Magnetic Stimulation (HF rTMS); Behavioral: Cognitive Restructuring

Cognitive Restructuring + Shame Repetitive Transcranial Magnetic Stimulation (rTMS)

ACTIVE COMPARATOR

30 eligible participants will receive training in Cognitive Restructuring (CR). These participants will use CR while being exposed to misophonic trigger sounds and also receiving placebo rTMS over their personalized right dorsal lateral prefrontal cortex (dlPFC) target. These participants will partake in short term and long term follow-up testing.

Device: Sham Repetitive Transcranial Magnetic Stimulation (sham- rTMS); Behavioral: Cognitive Restructuring

Interventions

High Frequency Repetitive Transcranial Magnetic Stimulation (HF rTMS) DEVICE

10 Hz rTMS over the right dorsal lateral prefrontal cortex (dlPFC)

Cognitive Restructuring + High Frequency Repetitive Transcranial Magnetic Stimulation (rTMS)

Sham Repetitive Transcranial Magnetic Stimulation (sham- rTMS) DEVICE

inactive rTMS over the right dorsolateral prefrontal cortex (dlPFC)

Cognitive Restructuring + Shame Repetitive Transcranial Magnetic Stimulation (rTMS)

Cognitive Restructuring BEHAVIORAL

Cognitive restructuring is a cognitive behavioral intervention through which participants learn how to think differently about misophonic sound triggers in order to feel less emotional arousal.

Also known as: CR

Cognitive Restructuring + High Frequency Repetitive Transcranial Magnetic Stimulation (rTMS); Cognitive Restructuring + Shame Repetitive Transcranial Magnetic Stimulation (rTMS)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• DMQ Impairment score \>= 14

You may not qualify if:

• current or past history of mania or psychosis; current hypomania
• verbal IQ\< 90 as per the NART
• not medically cleared for TMS or fMRI (such as taking medications known to reduce the seizure threshold such as Lithium, Clozaril, stimulants including the ADHD medications (e.g. Ritalin, Adderall), Wellbutrin/Buproprion, Provigil (Modafinil), Aminophylline, and Theophylline)
• DMQ Impairment score \< 14
• younger than 18 and older than 55
• pregnant
• high risk for suicide (defined as having attempted suicide in past 6 months; suicide attempt within the past 10 years with current ideation with plan or preferred method available)
• moderate/severe current alcohol or substance use disorder, or past severe alcohol use disorder
• unable to read, blind, or deaf, or unwilling to give consent
• cannot come to Duke for the in-person study visits
• current uncontrolled anorexia or other condition requiring hospitalization
• conditions associated with increased intracranial pressure, space occupying brain lesion, transient ischemic attack, cerebral aneurysm, dementia, Parkinson's or Huntington's disease, multiple sclerosis
• use of investigational drug or devices within 4 weeks of screening
• started/changed psychotropic medications or started psychotherapy in the prior 4 weeks, or plans to change medication or stop psychotherapy during the study

Sponsors & Collaborators

• Duke University: lead
• Misophonia Research Fund: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (16)

• Brout JJ, Edelstein M, Erfanian M, Mannino M, Miller LJ, Rouw R, Kumar S, Rosenthal MZ. Investigating Misophonia: A Review of the Empirical Literature, Clinical Implications, and a Research Agenda. Front Neurosci. 2018 Feb 7;12:36. doi: 10.3389/fnins.2018.00036. eCollection 2018.

  PMID: 29467604 BACKGROUND

• Kumar S, Tansley-Hancock O, Sedley W, Winston JS, Callaghan MF, Allen M, Cope TE, Gander PE, Bamiou DE, Griffiths TD. The Brain Basis for Misophonia. Curr Biol. 2017 Feb 20;27(4):527-533. doi: 10.1016/j.cub.2016.12.048. Epub 2017 Feb 2.

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• Neacsiu AD, Szymkiewicz V, Galla JT, Li B, Kulkarni Y, Spector CW. The neurobiology of misophonia and implications for novel, neuroscience-driven interventions. Front Neurosci. 2022 Jul 25;16:893903. doi: 10.3389/fnins.2022.893903. eCollection 2022.

  PMID: 35958984 BACKGROUND

• Schroder A, van Wingen G, Eijsker N, San Giorgi R, Vulink NC, Turbyne C, Denys D. Misophonia is associated with altered brain activity in the auditory cortex and salience network. Sci Rep. 2019 May 17;9(1):7542. doi: 10.1038/s41598-019-44084-8.

  PMID: 31101901 BACKGROUND

• Eijsker N, Schroder A, Smit DJA, van Wingen G, Denys D. Neural Basis of Response Bias on the Stop Signal Task in Misophonia. Front Psychiatry. 2019 Oct 23;10:765. doi: 10.3389/fpsyt.2019.00765. eCollection 2019.

  PMID: 31708818 BACKGROUND

• Kumar S, Dheerendra P, Erfanian M, Benzaquen E, Sedley W, Gander PE, Lad M, Bamiou DE, Griffiths TD. The Motor Basis for Misophonia. J Neurosci. 2021 Jun 30;41(26):5762-5770. doi: 10.1523/JNEUROSCI.0261-21.2021. Epub 2021 May 21.

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• Enzler F, Loriot C, Fournier P, Norena AJ. A psychoacoustic test for misophonia assessment. Sci Rep. 2021 May 26;11(1):11044. doi: 10.1038/s41598-021-90355-8.

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• Erfanian M, Kartsonaki C, Keshavarz A. Misophonia and comorbid psychiatric symptoms: a preliminary study of clinical findings. Nord J Psychiatry. 2019 May-Jul;73(4-5):219-228. doi: 10.1080/08039488.2019.1609086. Epub 2019 May 8.

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• Neacsiu AD, Beynel L, Graner JL, Szabo ST, Appelbaum LG, Smoski MJ, LaBar KS. Enhancing cognitive restructuring with concurrent fMRI-guided neurostimulation for emotional dysregulation-A randomized controlled trial. J Affect Disord. 2022 Mar 15;301:378-389. doi: 10.1016/j.jad.2022.01.053. Epub 2022 Jan 14.

  PMID: 35038479 BACKGROUND

• Neacsiu AD, Beynel L, Powers JP, Szabo ST, Appelbaum LG, Lisanby SH, LaBar KS. Enhancing Cognitive Restructuring with Concurrent Repetitive Transcranial Magnetic Stimulation: A Transdiagnostic Randomized Controlled Trial. Psychother Psychosom. 2022;91(2):94-106. doi: 10.1159/000518957. Epub 2021 Sep 22.

  PMID: 34551415 BACKGROUND

• Mai S, Braun J, Probst V, Kammer T, Pollatos O. Changes in emotional processing following interoceptive network stimulation with rTMS. Neuroscience. 2019 May 15;406:405-419. doi: 10.1016/j.neuroscience.2019.03.014. Epub 2019 Mar 14.

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• Abdelrahman AA, Noaman M, Fawzy M, Moheb A, Karim AA, Khedr EM. A double-blind randomized clinical trial of high frequency rTMS over the DLPFC on nicotine dependence, anxiety and depression. Sci Rep. 2021 Jan 15;11(1):1640. doi: 10.1038/s41598-020-80927-5.

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• Kleinjung T, Eichhammer P, Langguth B, Jacob P, Marienhagen J, Hajak G, Wolf SR, Strutz J. Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus. Otolaryngol Head Neck Surg. 2005 Apr;132(4):566-9. doi: 10.1016/j.otohns.2004.09.134.

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MeSH Terms

Conditions

misophonia; Anxiety Disorders; Hyperacusis; Emotional Regulation

Interventions

Cognitive Restructuring

Condition Hierarchy (Ancestors)

Mental Disorders; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Self-Control; Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Cognitive Behavioral Therapy; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities

Study Officials

• Andrada D Neacsiu, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: All participants will engage in a behavioral training session (Cognitive Restructuring). The study team member who will conduct the behavioral session will be kept blind to the type of neurostimulation the participant will receive. Participants will also be kept blinded to what neurostimulation they receive and their perception of what they received will be assessed at follow-up. The intervention provider will also be kept blind to the treatment condition to ensure non-biased administration of the intervention. Participants will only be told about the type of neurostimulation at the end of the study to protect against different expectations
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: In regards to the neurostimulation used in the study, there will be two conditions, receiving either active or sham neurostimulation. Both conditions will receive behavioral training in cognitive restructuring (CR; a type of emotion regulation skill). Randomization procedures will match participants on age, gender at birth, and misophonia impairment severity.

Study Record Dates

• First Submitted: February 12, 2024
• First Posted: March 27, 2024
• Study Start: May 14, 2024
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): November 30, 2026
• Last Updated: March 31, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: either at the manuscript publication or within 1 year of study data collection completion. Per Duke Data Research repository website, the Duke Research Data Repository (RDR) is included under the Libraries' general digital Preservation Policy. While they currently do not have a formal retention schedule for data published in the RDR, they anticipate keeping datasets for at least 25 years. After which, the deposited content may be assessed (number of downloads, page visits) to determine whether they should remain in the repository.
• Access Criteria: Acceptable Use Policy What users of files agree to: * You will not attempt to identify any individuals included in the data or otherwise infringe the privacy or confidentiality rights of individuals discovered inadvertently or intentionally in the data If you should identify anyone unintentionally, you will contact the RDR at https://library.duke.edu/data/data-management * You will abide by the Creative Commons license conditions applied to the data (if any). * You will properly cite the data by including a data citation in any publication or presentation resulting from use of the data.

Locations

US (1)