This application responds to RFA-MH-15-300 (Exploratory Clinical Trials of Novel Interventions for Mental Disorders [R21/R33]) by proposing to translate neuroscience findings into a novel non-pharmacologic treatment for Acute Fear, a Research Domain Criteria (RDoC) construct common to many DSM defined anxiety disorders. The neuroscience findings which serve as the basis for this effort are an extensive pre- clinical literature documenting that the region of the brainstem known as the locus coeruleus (LC) plays a key role in mediating symptoms of Acute Fear. We capitalize on evidence that LC activity can be non-invasively measured with pupillometry and our pilot data indicating that we can modulate LC activity with transcranial direct current stimulation (tDCS) applied via electrodes attached to the skin/scalp. Our approach is to develop tDCS as a means of inhibiting LC activity and then determine if this diminishes symptoms of Acute Fear. Our translational effort will consist of two stages, a 2 year R21 phase where we establish feasibility, tolerability, safety, and proof-of-concept (POC) in terms of capacity to engage the neural target, followed by a 3 year R33 parallel-group, double-blind, controlled trial. In the R21 phase we will employ an iterative approach where we use electric field modeling with a realistic head model to identify promising treatment electrode placements which we will test across a series of electrical doses in 3 cohorts of healthy controls to attempt to identify a tDCS treatment electrode configuration with which we can identify a dosage in each subject that is: (1) tolerable (5-point Likert ratings of nomore than mild discomfort); and (2) engages the target neural circuitry by transiently inhibiting LC activity as reflected in prevention of the pupil dilation response to rare stimuli in the auditoy oddball task (AOT), which reliably activates LC. If successful we will proceed to a 3 year R33 parallel- group trial where 60 healthy volunteers are randomized to electrical dose-personalized active tDCS vs an active control therapy (tDCS that delivers the same skin current density as the active but does not affect LC) where clinical symptoms Acute Fear, the primary outcome, are elicited by inhalation of 7.5% CO2. Future development viability will be assumed if there is preliminary evidence that engaging the target (inhibiting LC) safely diminishes clinical Acute Fear symptoms. Our broad scientific goal is to evaluate if engagement of the target brain circuitry, inhibition of LC, is a viable target for treating Acute Fear. This is of high public heath importance as Acute Fear is extremely widespread and debilitating problem and current treatment options are quite limited.

Public Health Relevance

Many individuals suffer from Acute Fear; however; available treatments are quite limited. If successful; thisstudy will identify a promising target neural circuit in the brain which could serve as the basis for developingbetter therapies for Acute Fear that could improve the lives of those suffering from Acute Fear relateddifficulties.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1-ERB-D (01))
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Mcmullen, David
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Tremblay, S├ębastien; Sharika, K M; Platt, Michael L (2017) Social Decision-Making and the Brain: A Comparative Perspective. Trends Cogn Sci 21:265-276