Transcranial Direct Current Stimulation and Fear Extinction
Condition: Anxiety Disorders
MeSH terms: Anxiety Disorders
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): tDCS
Intervention type(s): Device
Intervention description(s): Subjects will receive 20 minutes of multifocal transcranial direct current stimulation. The anode will be placed over the frontal pole (Fpz, 10-20 EEG) and will be surrounded by 5 return electrodes (cathodes). Current will be set at 1.5mA and will be ramped in/out at the begging and end of the 20-minutes of stimulation over the course of 30 seconds.
Other intervention name(s): transcranial direct current stimulation; transcranial electrical stimulation; Starstim®
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be randomly assigned to receive Active (real) or Sham (placebo) transcranial direct current stimulation.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science