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.
Given the urgent need for interventions for misophonia, the primary purpose of this study is to establish short and long-term effects for an intervention that combines emotion regulation with neurostimulation. The secondary goal is to examine the best parameters needed for a successful intervention. It is important to highlight that the study findings would not only inform future behavioral and neurostimulation interventions but may also provide critical information for other intervention approaches that aim to alter neural circuitry involved in misophonia. Interested participants who pass the online and phone screen are scheduled for the first study visit that will be conducted remotely. Those who are interested and provide e-consent, will complete demographic questions and several interviews and measures aimed to examine misophonic and psychiatric distress, verbal IQ, treatment history, and MRI/neurostimulation safety. Participants will listen to a set of standardized aversive and misophonic sounds and rate how distressing they find them. They will also be invited to send recordings of their own misophonic sounds in different contexts and together with them and other standardized misophonic sounds, they will listen to the sounds and rate their distress. The goal in the study is to generate a personalized set of triggers that includes personalized misophonic, aversive and neutral sounds for each participant. The type of neuromodulation that is being tested in the study is repetitive transcranial magnetic stimulation (rTMS), a procedure which involves placement of an electromagnetic coil over the scalp that produces very small electric currents in the part of the brain that is closest to the coil. rTMS is a noninvasive procedure that is currently approved by the Food and Drug Administration (FDA) for the treatment for depression, obsessive compulsive disorder, and smoking. In this study, rTMS will be used differently than what has been approved for by the FDA but within safety guidelines. The goal of the study is to enroll sixty eligible adult participants with misophonia who will then be asked to come to Duke for the initial brain MRI visit. Following established procedures, participants will be briefly taught CR (cognitive restructuring), an emotion regulation strategy selected because it successfully adjusts the emotion regulation network. Participants will undergo a functional neuroimaging (MRI) task based on which a personalized neurostimulation target will be established. Participants will then be randomly assigned to active or sham rTMS intervention matching on age, gender at birth and misophonia impairment severity. Participants will then undergo four consecutive intervention sessions during which they will receive either type of rTMS over their personalized target on the right side of the brain while being exposed to personalized misophonic cues and instructed to engage in cognitive emotion regulation. At the initial TMS visit, all participants will be trained in CR in depth using a standardized training session. During each neurostimulation session, biophysiological data including heart rate and skin conductance will be collected. A week after the intervention, participants will undergo a follow up MRI brain scan and will complete some of the questionnaires from the first visit regarding misophonia, mood, anxiety, difficulties managing emotions, general health and distress. Two additional remote follow-up visits will be scheduled at the 1- and 3-month follow-up time points. Participants will complete the remote sound task similar to the first remote study visit. Measures of misophonia, mood, anxiety, difficulties managing emotions, general health and distress will again be assessed. At the final 3-month follow-up visit, participants will also complete an exit interview to give feedback on their study participation. As part of the exit interview, a member of the study team will inform the participant what type of neurostimulation they received during the study and referrals will be provided, if applicable.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
10 Hz rTMS over the right dorsal lateral prefrontal cortex (dlPFC)
inactive rTMS over the right dorsolateral prefrontal cortex (dlPFC)
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.
Duke University Medical Center
Durham, North Carolina, United States
RECRUITINGNumber 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline, during the experimental blocks of the neurostimulation sessions (which will occur over 4 days within a month of the initial assessment)
Changes in self-reported psychopathology
Change in self-reported psychopathology as measured by the OQ-45 will be examined one week, one month and three months after the intervention when compared to baseline. The Outcome Questionnaire-45 (OQ-45) is a 45-item self-report measure used to track severity of psychopathology throughout treatment. It consists of subscales that identify three types of problems that lead to general stress: psychological symptoms, interpersonal conflicts, and problems with social roles. Items are rated on a Likert scale ranging from 0 (never) to 4 (almost always). Scores range from 0 to 180. Higher scores indicate higher psychopathological distress than lower scores.
Time frame: Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up
Changes in clinician-assessed psychopathology
The Quick structural clinical interview for DSM-5 disorders (Quick-SCID) will be administered to examine changes in clinician-rated psychopathology. This clinician administered interview will be done at baseline and then again at the 1 and 3 month follow-up timepoints to assess for any change compared to baseline.
Time frame: 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)
DERS will examine changes in emotional dysregulation between conditions after the intervention. The DERS has Min-Max score ranges from 36-180 (with higher scores signifying more difficulties with emotion regulation).
Time frame: Baseline, 1 week follow-up after neurostimulation, 1- and 3-month follow-up
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