PROJECT SUMMARY The objective of this application is to use the novel approach of neuro-reinforcement based on decoded fMRI information to reduce fear responses to fearful stimuli (e.g., spiders, heights) in individuals with phobias, directly and unconsciously in the brain, without repeatedly exposing participants to their feared stimuli. The Specific Aims of the R61 Phase are to: (1) confirm that our method engages the neurobiological target (amygdala reactivity to images of a feared object) in a population of individuals with specific phobia; and (2) to determine dosage-response optimization. The Specific Aims of the R33 Phase are to: (1) quantify how changes in amygdala reactivity with neuro-reinforcement covary with changes in behavioral, subjective, and physiological outcomes in the same context as the treatment; and (2) determine how engagement of the neurobiological target and related effects in subjective fear ratings and physiological outcomes generalize to new contexts and clinically relevant outcomes. Pilot Data demonstrate that the proposed method can effectively reduce amygdala reactivity to feared stimuli (target engagement). The R61 Phase will confirm engagement of the neurobiological target (amygdala reactivity to fearful stimuli) by our intervention method in patients suffering from phobia of everyday objects and animals (e.g., spiders). Varying the number of neuro- reinforcement sessions across different subject groups (3 groups of 10 subjects each) and measuring reductions in the amygdala reactivity will demonstrate the robustness and mechanisms of target engagement. This will also enable assessment of the optimal dosage required to balance between maximal target engagement and imaging costs, in order to inform the studies in the R33 Phase. The R33 Phase will utilize the optimal dosage determined in the R61 Phase to test mediation of clinically relevant outcomes (clinical diagnostic interviews, subjective fear ratings, and skin conductance) by engagement of the neurobiological target, both immediately after treatment and after a 4-month period. The R33 Phase will further assess whether the effects generalize to a clinically relevant measure of phobic individuals' readiness to approach the feared objects in a virtual environment (Behavioral Approach Test).

PROJECT NARRATIVE Specific phobias and other anxiety disorders, such as post-traumatic stress disorder (PTSD), represent a major mental health problem, and present a significant challenge to researchers because effective treatment usually involves repeated exposure to feared stimuli, and the high levels of associated distress can lead to termination of treatment. Recent advances in computational functional magnetic resonance imaging (fMRI) provide a method by which individuals may be unconsciously exposed to fearful stimuli, leading to effective fear extinction while eliminating a primary cause of attrition. Because such treatment happens directly in the brain, we further hypothesize that the behavior outcomes may generalize particularly well to different contexts beyond the treatment period, and this approach, if successful, may be extended to treatments for post- traumatic stress disorder (PTSD) and other mental disorders.