Transcranial Direct Current Stimulation and Fear Extinction

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.