Identifying the Optimal Neural Target for Misophonia Interventions

Misophonia, the inability to tolerate certain repetitive aversive sounds that are common, is gaining recognition as a debilitating condition. It is not a well-understood condition and there are no known treatments. Up to one in five people report moderate or higher misophonia symptoms; nevertheless, resources aimed at understanding and treating this problem are scarce. In order to align misophonia research with the priorities of large funding agencies such as the National Institute of Mental Health, the investigators propose a novel study aimed at separating misophonic distress from other types of emotional distress. The investigators plan to examine changes in brain activation during presentation and regulation of misophonic versus distressing sounds. Emergent neural networks that may be involved in misophonia will then be tested in the lab with the use of noninvasive neurostimulation, a novel tool that can enhance or inhibit activation in a targeted brain region. The investigators plan to modulate activation in key areas of the misophonia brain circuitry with the aim to identify the optimal neural target for misophonia interventions. Our multidisciplinary team at the Duke Center for Misophonia and Emotion Regulation brings together experts in misophonia, neuroscience, neuromodulation, neurology, and biostatistics who share the long-term goal of developing and refining an intervention for this condition in an environment that is optimal to conduct the proposed research.

The investigators propose to recruit adults who self-report significant misophonia symptoms and adults who meet criteria for a current psychiatric disorder and who self-report difficulties calming down when upset. All participants will undergo a brain imaging session during which misophonic cues; distressing, non-misophonic cues; or neutral cues will be presented. Participants will then be asked to experience, or attempt to downregulate emotions associated with these cues. Based on the imaging results, two personalized neurostimulation targets will be identified: (1) the region in the frontal cortex with the most activity during the downregulation of misophonic versus neutral sounds and (2) the prefrontal region with the strongest functional connectivity to the anterior insular cortex. Participants will receive real or sham neurostimulation over the prefrontal cortex and insula in a random order, while engaging in listening to versus downregulating misophonic, aversive, or neutral cues. The investigators plan to assess emotional dysregulation, psychopathology, and misophonia with a multi-method battery of measures during all three study appointments. Feasibility and acceptability will be examined qualitatively. If successful, our study can be the first step in a series of investigations that establish the unique targets for neural intervention for misophonia.

Study Overview

• Status: Completed
• Conditions: Misophonia; Emotion Dysregulation
• Intervention / Treatment: Behavioral: Cognitive Restructuring; Device: neurostimulation

Detailed Description

Consistent with NIMH strategic priorities, neural targets that account for individual differences are needed for the next generation of mental health interventions. Misophonia, the inability to tolerate certain aversive repetitive and common sounds, is gaining rapid recognition as a debilitating condition that is not currently well understood and for which interventions do not yet exist. In order to align research efforts to understand and treat misophonia with NIMH priorities, the investigators propose to conduct an experimental study that differentiates the neural circuitry of misophonia-induced distress from other types of emotional distress, and that begins to identify the optimal neural target for possible interventions. Noninvasive neurostimulation (i.e., the purposeful modulation of neural circuitry), such as repetitive transcranial magnetic stimulation (rTMS), is a powerful tool which can modulate neuronal activation and can be used to examine the responsiveness of neural circuits to intervention. Therefore, for this project, the investigators bring together a multidisciplinary team of researchers with expertise in misophonia, neuroscience, neuromodulation, biostatistics, and neurology with the aims to: (1) differentiate the brain circuitry dysfunction in misophonia compared to non-misophonia emotional distress and (2) identify the optimal intervention target for changing misophonic distress using rTMS. The investigators propose to recruit adults who self-report significant misophonia symptoms and a comparison group of adults who meet criteria for a current psychiatric disorder and who self-report high emotional dysregulation. Those who have contra-indications for MRI or rTMS will be excluded. All participants will undergo an MRI session during which misophonic cues; aversive, non-misophonic cues; or neutral cues will be presented. Participants will be asked to listen only or listen and attempt to downregulate emotions associated with these cues. Functional MRI (fMRI) analysis will then be performed to define two personalized neurostimulation targets defined as the region in the frontal cortex that is the most (1) activated during emotion regulation and (2) connected to the anterior insular cortex (AIC) during emotional experiencing. Participants will be assigned to receive active or sham neurostimulation over target 1 and target 2 in a random order, while engaged in listening to versus downregulating misophonic, aversive, or neutral cues. The investigators plan to employ excitatory neuromodulation to examine the effects of enhancing prefrontal cortex activation during emotion regulation. The investigators also plan to employ inhibitory neuromodulation to examine the effects of inhibiting AIC activation during listening only without efforts to regulate emotional distress. The investigators plan to assess emotional dysregulation, psychopathology, and misophonia with a multi-method battery of measures during all three study appointments. Feasibility and acceptability will be examined qualitatively. The investigators will use results from this study to design larger trials and to seek federal funding with the ultimate goal of designing an effective misophonia intervention. If successful, our study can be the first step in a series of investigations that establish the unique targets for neural intervention for misophonia.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center-Civitan Bldg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Interested participants will be excluded if:

1. current or past history of mania or psychosis,
2. verbal IQ < 70,
3. not medically cleared for TMS or fMRI (for example taking medications known to reduce the seizure threshold such as Lamictal, Lithium, Clozaril, stimulants including the ADHD medications (e.g. Ritalin, Adderall), Wellbutrin/Buproprion, Provigil (Modafinil), Aminophylline, and Theophylline, implants, TBI, stroke, etc),
4. going to jail in the next 2 months,
5. pregnant,
6. high risk for suicide
7. moderate/severe current alcohol or substance dependence,
8. cannot come to Duke for the three study visits.

Inclusion criteria are:

1. stable psychotherapy and medication for at least 4 weeks
2. self reports high emotional dysregulation OR misophonia

Participants will be matched on gender and age between the two groups

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Misophonia Group; Participants who endorse Misophonia will undergo a neuroimaging session to identify different neurostimulation targets. Then Misophonic participants will be exposed to aversive and neutral sounds while receiving real or sham neurostimulation over different pre-established neural targets.	Behavioral: Cognitive Restructuring; All participants will learn how to change their thinking in order to be less upset when confronted with stressors; Device: neurostimulation; all participants will receive inhibitory, excitatory, and sham transcranial magnetic stimulation over different neural targets during the experimental session. The purpose of the neurostimulation is not treatment, but causal interference/enhancing of brain circuitry to identify candidate neural regions for future interventions; Other Names: transcranial magnetic stimulation
Active Comparator: Emotional Dysregulation Clinical Group; Participants who self report high emotional dysregulation and who meet diagnostic criteria for a DSM disorder will undergo a neuroimaging session to identify different neurostimulation targets. Then these participants will be exposed to aversive and neutral sounds while receiving real or sham neurostimulation over different pre-established neural targets.	Behavioral: Cognitive Restructuring; All participants will learn how to change their thinking in order to be less upset when confronted with stressors; Device: neurostimulation; all participants will receive inhibitory, excitatory, and sham transcranial magnetic stimulation over different neural targets during the experimental session. The purpose of the neurostimulation is not treatment, but causal interference/enhancing of brain circuitry to identify candidate neural regions for future interventions; Other Names: transcranial magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiological Outcome: High Frequency Heart Rate Variability (HF-HRV) Recorded During Experimental Blocks	HF-HRV was extracted from 2 minute blocks during which participants engage in a behavioral strategy (listen or downregulate emotions using cognitive restructuring), while listening to neutral, aversive, and misophonic sounds and receive active or sham neurostimulation. The results represent the average HF-HRV during experimental blocks. The raw values were transformed using a logarithmic function to preserve the normality assumption.	Two minute blocks during the neurostimulation experimental session during which participants listened to or downregulated emotions associated with experimental sounds (45 minutes total).
Skin Conductance Level (SCL)	Physiological arousal measured by SCL during each experimental block was extracted using Acqknowledge software and BIOPAC hardware (during the neurostimulation session). Raw galvanic skin response was continuously collected throughout the experiment. Raw data was then examined for abrupt changes (skin conductance responses), which were removed. The processed data was then averaged for each two minute experimental block. Higher SCL means higher arousal.	Two minute blocks during the neurostimulation experimental session (when participants listened to or downregulated emotions associated with experimental sounds)
Behavioral Outcome: Acceptability of Procedures	The investigators will record how many participants completed the neurostimulation session as a marker of acceptability.	At the end of the neurostimulation session (session 3 in the experiment), which occured within a month of the initial assessment
Neuroimaging Outcome: Differential Change in BOLD Signal Between Groups Within the Dorsolateral Prefrontal Cortex (dlPFC), That is Greater During Regulation of Misophonic Versus Non-misophonic Distress	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. Higher values indicate higher activity changes within a contrast of interes. A dlPFC mask was employed to find the maximum value of the [downregulate misophonic sounds > downregulate aversive sounds] contrast in this region. Once the voxel containing this maximum was identified, a 6 mm sphere ROI was created around this spot (restricted to the dlPFC mask) and the average contrast value within this sphere was used as the outcome variable.	during the neuroimaging session, within a month of the intake assessment
Neuroimaging Outcome: Differential Change in BOLD Signal Within the Ventromedial Prefrontal Cortex (vmPFC) When Engaging in the Regulation of Emotional Versus Misophonic Distress	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. A vmPFC mask was employed to find the maximum value of the [downregulate misophonic sounds > downregulate aversive sounds] contrast in this region. Once the voxel containing this maximum was identified, a 6 mm sphere ROI was created around this spot (restricted to the vmPFC mask) and the average contrast value within this sphere will be used as the outcome variable. Higher scores indicate more activity when downregulating misophonic versus aversive sounds.	during the neuroimaging session, within a month of the intake assessment
Neuroimaging Outcome: Differential Change in BOLD Signal Within the Anterior Insular Cortex (AIC) Activation When Being Presented With Cues for Emotional Versus Misophonic Distress	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. An AIC mask was employed to find the maximum value of the [hear misophonic sounds > hear aversive sounds] contrast in this region. Once the voxel containing this maximum was identified, a 6 mm sphere ROI was 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 a month of the intake assessment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Subjective Units of Distress (SUDS)	Self reported distress after experimental blocks will also be examined for differences when accounting for baseline distress (during the neurostimulation session). 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 negative sound presentations (misophonic and aversive) minus SUDS after baseline. Higher SUDS represents higher distress.	Baseline, during the experimental blocks during the neurostimulation session (which will occur within a month of the initial assessment)
Emotional Dysregulation as Measured by the Difficulties in Emotion Regulation Scale (DERS)	A self report assessing difficulties regulating emotions will be examined before and after the experiment (i.e., at the end of the neurostimulation session). The DERS ranges from 36 to 180, with higher scores indicating more dysregulation.	From baseline to the end of neurostimulation session, an average of 4 weeks.
Self-reported Health Status as Measured by the Patient Reported Outcome Measurement Information System (PROMIS)-43 Adult Profile	The PROMIS-43 is a 43-item questionnaire assessing health status in seven domains: physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, and participation in social roles. Lower scores indicate less impairment in functioning when compared to higher scores. Each item has five response options ranging in value from 1 to 5, except for the 1 Pain Intensity item which has eleven response options ranging in value from 0 to 10. A raw score is created from each domain that makes up the Profile. Each domain raw score ranging from 6-30 corresponds to a T-Score in the PROMIS scoring manual.	At baseline
Number of Clusters Across the Whole Brain With Significant BOLD Changes Between Groups When Contrasting the Exposure to Aversive Versus Neutral 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. The BOLD signal contrast between engaging with aversive sounds and engaging with neutral sounds were compared between groups 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 group are presented as outcome.	During the neuroimaging session, within a month of the intake assessment
Number of Clusters Across the Whole Brain With Significant BOLD Changes Between Groups When Contrasting the Exposure to Misophonic Versus Aversive Sounds.	Blood Oxygenation Level Dependent (BOLD) imaging is a technique that is commonly used for measuring brain activity using functional magnetic resonance imaging (fMRI). Change in a BOLD signal detected in fMRI, notes changes in brain blood flow and blood oxygenation. Neural activation across the brain when engaging with misophonic sounds versus aversive sounds during the neuroimaging day. The BOLD signal contrast between engaging with misophonic sounds and engaging with aversive sounds were compared between groups 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 group are presented as outcome.	during the neuroimaging session, within a month of the intake assessment
Number of Clusters Across the Whole Brain With Significant BOLD Changes Between Groups When Contrasting the Downregulation of Distress Associated With Misophonic Sounds to 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. The BOLD signal contrast between regulating versus engaging with misophonic sounds across the entire brain was compared between participant groups on a voxel-wise basis. Voxel-wise results were clustered to statistically correct for multiple comparisons. The number of significant clusters within each group are presented as outcome (more cluster indicates more differences during regulation in that group versus the control group).	during the neuroimaging session, within a month of the intake assessment
Number of Clusters Across the Whole Brain With Significant BOLD Changes Between Groups When Contrasting the Downregulation of Distress Associated With Aversive Sounds to Exposure to AversiveSounds	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. The BOLD signal contrast between regulating and engaging with aversive sounds was compared between participant groups on a voxel-wise basis. Voxel-wise results were clustered to statistically correct for multiple comparisons. The number of significant clusters within each group are reported as the outcome measure.	during the neuroimaging session, within a month of the intake assessment

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Misophonia Research Fund
• Investigators: Principal Investigator: Andrada D Neacsiu, PhD, Duke Health

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2020
• Primary Completion (Actual): May 27, 2022
• Study Completion (Actual): May 28, 2022

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 13, 2020
• First Posted (Actual): April 16, 2020

Study Record Updates

• Last Update Posted (Actual): August 25, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: neurostimulation; neuroscience; misophonia; emotion dysregulation; insula
• Other Study ID Numbers: Pro00103863

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Participant data from the study was shared to the Duke Research Data Repository (RDR).

Neacsiu, A., LaBar, K., Rosenthal, M. Z., Bukhari-Parlakturk, N., Kelley, L. (2022). Identifying the optimal neural target for misophonia interventions. Duke Research Data Repository. https://doi.org/10.7924/r4ww7jg4k

• IPD Sharing Time Frame: Data in SPSS and .csv format along with the data dictionary was submitted and accepted on 10/27/2022. It is available currently at the Duke Research Data Repository (RDR). The Duke RDR provides access to and preservation of the data for a minimum period of 25 years.
• IPD Sharing Access Criteria: Open to any researcher to view and access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No