Brain-based mediation of non-conscious reduction of phobic avoidance in young women during functional MRI: a randomised controlled experiment.

Background: Exposure therapy is the treatment of choice for anxiety disorders but requires people to confront feared situations and can be distressing. We tested the hypothesis that exposure without conscious awareness would reduce fear in participants with specific phobia by harnessing the neural circuitry supporting the automatic extinction of fear.

Methods: In this single-centre, randomised controlled experiment, we recruited women aged 18-29 years from an ethnically diverse, community-based population in northeastern USA, between Sept 1, 2013, and Aug 1, 2016. Eligible participants classified as having phobia met the DSM-5 criteria for specific phobia but not for any other disorder, had scores in the top 10% of respondents to the Fear of Spiders Questionnaire, and exhibited impairing avoidance of a live tarantula. Eligible controls met no criteria for any disorder, were in the bottom 30% of questionnaire respondents, and displayed no avoidance of the tarantula. The randomisation schedule was generated with the open source Research Randomizer Tool. A research assistant randomly assigned participants to the active intervention of very brief exposure (VBE)-the repeated presentation of masked phobic stimuli (ie, spiders)-or the control intervention which used masked flowers (VBF). VBE and VBF were given code numbers to prevent staff from knowing which intervention they were administering. During a 10 min functional MRI (fMRI) task, each participant was exposed to 16 blocks of ten masked target stimuli (spiders or flowers), alternating with 16 blocks of ten masked neutral stimuli. A few minutes after fMRI, participants with spider phobia approached the tarantula again so we could measure changes in phobic behaviour. The primary outcome was real-time changes in brain activity measured by fMRI. All analyses were done by intention to treat.

Results: We recruited 82 women, of whom 42 had spider phobia and 40 were controls. VBE generated stronger neural activity in participants with spider phobia than in controls, particularly in regions supporting emotion, emotion regulation, and attention systems, such as the inferior frontal cortex (Cohen's d 0·95, 95% CI 0·93-0·98, Bayesian posterior probability 99·5%) and the caudate nucleus (1·16, 1·14-1·18, 100·0%). In participants with phobia, VBE also generated stronger activity in these regions than did VBF (eg, dorsal anterior cingulate cortex Cohen's d 0·80, 95% CI 0·78-0·80, Bayesian posterior probability 98·5%; caudate nucleus 1·0, 0·98-1·02, 99·5%). VBE reduced avoidance of the live tarantula in participants with phobia. Regions supporting fear extinction (including ventral medial prefrontal cortex) and emotional salience processing mediated this effect. No adverse events occurred.

Interpretation: VBE reduced fear non-consciously in participants with spider phobia by recruiting brain regions supporting automatic fear extinction, emotion regulation, and top-down attentional processing. Future studies should explore the use of VBE in other fear-based disorders.

Funding: National Institutes of Mental Health and Brain & Behavior Research Foundation.