Obsessive-compulsive disorder (OCD) is associated with substantial impairments in quality of life and is among the most disabling psychiatric disorders. Exposure therapy is among the first-line of treatments for obsessive-compulsive disorder (OCD) . Extinction learning is thought to be a core mechanism of therapeutic exposure. Fear and safety signal learning are traditionally associated with activity and connectivity within the canonical corticolimbic "fear circuit", which includes the amygdala, medial prefrontal cortex (mPFC), and hippocampus. Transcranial direct current stimulation (tDCS) is a neuromodulation technology that can augment brain plasticity, learning, and memory. The proposed study will test if obsessive-compulsive disorder (OCD) is associated with inhibitory safety learning deficits and if transcranial direct current stimulation (tDCS) normalizes functional connectivity and safety signal processing to recover extinction deficits in obsessive-compulsive disorder (OCD).

The proposed study aims to test if obsessive-compulsive disorder (OCD) is associated with dyconnectivity between the default mode network (DMN) and salience network (SN) (Aim 1), if obsessive-compulsive disorder (OCD) is associated with extinction learning deficits (Aim 2), and if front-polar transcranial direct current stimulation (tDCS) normalizes dysconnectivity and extinction learning in obsessive-compulsive disorder (OCD) (Aim 3).

This study will randomize 180 adults with obsessive-compulsive disorder (OCD) (n=120) and matched non-clinical controls (n=60) for aims 1-3. After providing informed consent, baseline screening, and clinical characterization, participants would complete a three-day experiment. On day 1, all participants would complete structural and resting functional magnetic resonance imaging (fMRI) scans followed by standardized fear conditioning procedures with functional magnetic resonance imaging (fMRI) and measures of fearful responding (i.e., skin conductance response [SCR] and threat expectancy ratings). Participants would be conditioned to two different conditioned stimuli (CS+; CS+A and CS+B) by pairing each CS+ with an aversive shock (unconditioned stimulus [US]) at a 50% schedule of reinforcement. A third, neutral stimulus (CS-), would never be paired with the US. On day 2, participants would complete extinction training for the CS+A, then participants with obsessive-compulsive disorder (OCD) would be randomized (1:1, stratified, double-blind) to receive active or sham multifocal frontopolar transcranial direct current stimulation (tDCS) with resting functional magnetic resonance imaging (fMRI) before, during, and after transcranial direct current stimulation (tDCS). Blocked randomization, stratified by sex, age, and current psychiatric medication usage, would be implemented by an individual who would have no direct contact with the participants and no knowledge of the assignment to the group labels. Participants and assessors will be blind to allocation. All non-clinical controls would not receive any transcranial direct current stimulation (tDCS). Next, extinction training for the CS+B would be completed. On day 3, return of fear testing (spontaneous recovery, context renewal, and reinstatement) would be completed.

Transcranial direct current stimulation (tDCS) would be administered using a battery-driven, Soterix© transcranial electric stimulator. A single anode would be placed over the frontal pole and five return electrodes would be arranged in a circumferential array. Positively charged e-fields produced by this montage would concentrate over the medial frontal pole. Participants in the active-transcranial direct current stimulation (tDCS) condition would receive 20-minutes of offline (while resting with eyes open) frontopolar transcranial direct current stimulation (tDCS) (30-seconds ramp in/out). Participants in the sham-transcranial direct current stimulation (tDCS) condition would receive 30-seconds ramp in/out followed by 20-minutes of no stimulation.

Brain imaging would be performed with a Siemens MAGNETOM Prisma 3T scanner using a 64-channel phased array padded head coil. A vitamin E capsule would be secured to the outer center of the transcranial direct current stimulation (tDCS) anode to create a precise contrast in structural magnetic resonance imaging (MRI). After localization, all participants would undergo anatomical imaging for registration and normalization purposes. 6-min of rs-functional magnetic resonance imaging (fMRI) data would be collected immediately before and after frontopolar transcranial direct current stimulation (tDCS) and four ~5-min blocks rs-functional magnetic resonance imaging (fMRI) sequences would be collected during the 20-min of active- or sham-transcranial direct current stimulation (tDCS) to characterize temporal elements of dosage (e.g., linear change in rs-FC over the time course of transcranial direct current stimulation [tDCS] administration) in exploratory analyses.

Inclusion Criteria:

• All Participant Inclusion Criteria would include:

  1. 18 years of age or older
  2. speak English fluently, and
  3. able to provide written and verbal informed consent.

• Obsessive-compulsive disorder (OCD) Inclusion Criteria would include:

  1. meet criteria for OCD as determined by structured clinical interview
  2. exhibit significant current symptoms of OCD
  3. report duration of OCD symptoms of at least 1-year
  4. OCD symptoms are primary or co-primary relative to other psychiatric diagnoses
  5. stable psychiatric treatment (≥8-weeks) or no active treatment.
  6. exhibit significant current symptoms of OCD as determined by the Dimensional Obsessive-Compulsive Scale (DOCS) (≥18).

Exclusion Criteria:

• All Participant Exclusion Criteria would include:

  1. active severe substance use disorder(s)
  2. acute suicidality
  3. history of bipolar or psychotic disorder(s)
  4. significant developmental disabilities
  5. loss of consciousness > 10 minutes
  6. history of traumatic brain injury
  7. major neurological disease
  8. a positive pregnancy test
  9. other brain stimulation or magnetic resonance imaging contraindications
  10. new psychological treatment within the past 8 weeks
  11. daily anxiolytic medication use (e.g., benzodiazepine).

• Non-Clinical Control Exclusion Criteria would include:

  1. meet current criteria for a psychiatric disorder as determined by structured clinical interview
  2. active-psychotropic medications.

Raw de-identified data will be shared using the National Data Archive.

IPD will be shared within one year of study completion.

Access to IPD will be public per NDA guidelines.