Psychiatric disorders characterized by pathological fear and anxiety are common and often disabling. Despite their limitations, exposure therapies are among the most efficacious treatments for these disorders. Extinction learning is thought to be a core mechanism of therapeutic exposure. Extinction learning is mediated by a well-defined circuit encompassing the medial prefrontal cortex (mPFC), amygdala, and hippocampus. This raises the exciting possibility that direct engagement of this circuitry might enhance the response to therapeutic exposure. Transcranial direct current stimulation (tDCS) is a neuromodulation technology that can augment brain plasticity, learning, and memory. The proposed study will evaluate whether tDCS can engage extinction circuitry, and improve extinction learning and memory.

This study will enroll psychiatrically healthy volunteers to test whether tDCS applied to the mPFC can augment spontaneous mPFC activity, engagement of extinction circuitry during extinction learning and recall, and classically-conditioned extinction learning and memory. Healthy volunteers will complete a standardized, three-day fear conditioning and extinction learning and memory task. On day 1, participants will complete a fear conditioning task. On day 2, participants will receive sham (placebo) or active tDCS prior to completing a fear extinction learning task. On day 3, participants will complete an extinction recall task. Electrodermal activity and heart rate will be continuously monitored during the conditioning and extinction procedures to assess autonomic arousal. All procedures will be completed in a magnetic resonance imaging (MRI) scanner; imaging data will be collected before and after tDCS and during all conditioning and extinction procedures.

Most effective behavioral treatments of disordered anxiety involve repeated exposure to feared stimuli, which often results in systematic reductions in fearful responding to said stimuli. It is believed that this process results from successful fear extinction, a well-characterized learning process that is mediated by fear extinction brain circuitry. Namely, fear extinction is an inhibitory learning process that requires activation and plasticity within a variety of brain regions, including the medial prefrontal cortex (mPFC), which can exert inhibitory control over fearful responding and parts of the brain that drive said responding. Behavioral treatments of disordered anxiety, while effective, have serious limitations; many patients fail to respond at all or only partially respond to exposure-based treatments. One candidate reason for this is deficits in fear extinction learning or memory processes. The proposed study aims to examine the effects of non-invasive neuromodulation - namely, multifocal transcranial direct current stimulation (tDCS) targeting the mPFC - on spontaneous mPFC activity (Aim 1), functional activation of fear extinction circuitry (Aim 2), and fear extinction learning and memory (Aim 3).

This study will randomize 64 psychiatrically healthy volunteers at the Yale (proposed n = 32) and the University of Kentucky (proposed n = 32) for Aims 1-3. Following the completion of proper diagnostic and safety screening and Institutional Review Board (IRB) approved informed consent, healthy volunteers will complete a 3-day experimental procedure. Subjects will be conditioned to fear a previously neutral stimulus on Day 1. Subjects will be randomized (1:1, double-blind) to receive Active or Sham tDCS prior to fear extinction training on Day 2. Allocation will be done by independent research staff at Yale, who is experienced with such allocation, using block randomization (blocks of 8), stratified by sex. Subjects and investigators will be blind to allocation. Lastly, the strength of extinction recall will be tested on Day 3. Functional magnetic resonance imaging (fMRI) and psychophysiological measures (electrodermal activity and heart rate) will be acquired during all fear conditioning, extinction, and recall procedures and prior to and after tDCS.

tDCS will be delivered using an 8-channel Starstim transcranial electric stimulator from Neuroelectrics. To target the mPFC, the anodal electrode will be placed over the frontal pole (Fpz, 10-20 EEG landmarks) and will be surrounded by five return (cathodal) electrodes in a circumferential array (AF7, AF8, F3, Fz, and F4). Subjects in the Active tDCS condition will receive 20 minutes of direct current stimulation for 20 minutes; current will be ramped in and out for 30 seconds at the beginning and end of the 20-minute period. Subjects in the Sham tDCS condition will receive the same electrode placement and ramping procedures, but no current will be delivered between ramping.

All healthy volunteers will complete state-of-the-art Human Connectome Project Style (HCP-Style) accelerated multiband acquisition sequences. Scan sequences will be identical across sites. Scans will include a mixture of structural, resting state, and functional fMRI sequences. All scans will be completed on Siemens Prisma 3T scanners using 64-channel head coils. Psychophysiological measures will include electrodermal activity (EDA) and heart rate. All psychophysiological data will be collected with MRI-compatible Biopac systems.

Study 1 is well-powered for both planned and exploratory analyses; proposed methods help to improve signal-to-noise-ratio (SCR) and our proposed sample size of 64 will adequately power all a priori analyses, planned contrasts, and exploratory analyses. Power analysis suggested a sample of 42 would be adequate for the proposed primary hypothesis tests. We propose to recruit 70 participants to allow for approximately 10% attrition or data failures (e.g., head movement or null skin conductance response [SCR]). Our statistical approach and statistical power were developed in collaboration with statistical consultants of the PI and the primary mentor.

The proposed study will provide important preliminary data to examine the potential for medial prefrontal tDCS to augment and enhance fear extinction processes across multiple levels of analyses: the effects of tDCS on extinction circuitry and classically-conditioned extinction learning and memory.

Inclusion Criteria:

• Ability to provide informed consent (as established by clinical interview), and voluntary, signed informed consent prior to the performance of any study-specific procedures;
• Ability and willingness to perform study-relevant clinical assessments;
• Ability and willingness to receive transcranial direct current stimulation (tDCS);
• Ability and willingness to complete magnetic resonance imaging (MRI) scans;
• Free of current psychiatric diagnosis;
• Psychiatrically healthy;
• 18-55 years of age;
• Medication free or stable (> 4 weeks) medication(s).

Exclusion Criteria:

• Any unstable medical, psychiatric, or neurological condition (including active or otherwise problematic suicidality) that may necessitate urgent treatment;
• Any substance dependence or severe substance abuse within the past 6 months;
• Daily use of psychotropic medications that substantially lower seizure threshold (e.g., clozapine);
• Daily use of psychotropic drugs that may interfere with extinction learning (e.g., anxiolytics);
• Any history of a psychotic disorder or of mania;
• Current active suicidal ideation or any suicidal intent;
• Any major neurological disease or history of major head trauma, including concussion with extended loss of consciousness, or of psychosurgery;
• Any history of epilepsy;
• Pregnancy;
• Any metal in the body or other contraindication to MRI scanning or tDCS;
• Any history of adverse effects to brain stimulation;
• A current Diagnostic and Statistical Manual diagnosis in the past 6 months, as determined by clinical interview;
• History of a severe psychiatric disorder, either documented or by clinician judgment;
• Use of drugs that are known to influence hemodynamic properties, except for drugs that are used to treat hypertension;
• Severe claustrophobia, back pain, or other condition that may make an extended magnetic resonance scan difficult or lead to excessive movement during the scan.

Raw imaging and psychophysiological data will be freely available upon study publication. Data will be stored on a yet to be determined data sharing repository supported by the National Institutes of Health.

Data will be made available following study publication.

Randomization will be administrated by independent research staff. Double-blind software will be used to ensure that the experimenter and subject remain blind during task administration.