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 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 we 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 be used to examine the responsiveness of neural circuits to intervention. Therefore for this project we 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. We 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. We plan to employ excitatory neuromodulation to examine the effects of enhancing prefrontal cortex activation during emotion regulation. We also plan to employ inhibitory neuromodulation to examine the effects of inhibiting AIC activation during listening only without efforts to regulate emotional distress. We 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. We 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.
