Circadian influence on fear extinction resulting from prolonged exposure therapy for PTSD

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Fear extinction learning and memory are the neurocognitive bases of exposure therapies for anxiety- and trauma-related disorders, including prolonged exposure therapy (PE) for posttraumatic stress disorder (PTSD). Proposed research will examine time-of-day effects on extinction produced during PE for PTSD. Using an experimental paradigm in healthy individuals, we reported that extinction is better learned and generalized in the morning than evening. Our team also showed that exposure therapy for panic disorder is more efficacious when provided in the morning, and that higher endogenous cortisol levels mediate this effect. Thus a possible mechanism underlying this morning advantage is enhanced extinction learning by the morning circadian acrophase of endogenous cortisol. This Exploratory/Developmental mechanistic randomized clinical trial (RCT) will apply these findings to test the hypothesis that PE for PTSD delivered in the morning will show greater effects on fear memory extinction (target mechanism) and PTSD symptoms (clinical outcome), compared to PE delivered in the late afternoon. PE is an established, efficacious, manualized 10-session treatment. This RCT will compare 20 individuals treated with PE beginning within 2 hours of awakening (i.e., between 07:00- 10:00) to 20 treated at 16:00 or later. Participants will complete at-home exposures at the same time of day as PE sessions. Fear memory extinction, the primary mechanistic outcome, will be measured using a validated composite index for psychophysiological reactivity to trauma recall during script-driven imagery (SDI-PR). SDI- PR combines skin conductance, heart rate, and facial electromyography measures. The primary clinical outcome will be PTSD severity on the Clinician-Administered PTSD Scale (CAPS-5). SDI and CAPS-5 will occur at pre-, mid-, and post-treatment. Secondary mechanistic (peak subjective units of distress; SUDS) and clinical (PTSD Checklist for DSM-5) measures will be obtained at each PE session. Extinction learning will be operationalized as decreased SDI-PR across the 3 assessment time points and decreased SUDS across the 8 PE sessions that include imaginal exposure. Endogenous salivary cortisol levels, obtained immediately before each PE session and normalized using diurnal cortisol profiles, will be tested as a mechanism contributing to time of day effects on mechanistic and clinical outcome measures. Sleep quality will be assessed using wrist actigraphy and daily sleep diaries throughout treatment. We hypothesize that: (1) Morning, compared to late- afternoon, PE sessions will produce greater declines in mechanistic and clinical outcomes. (2) Higher cortisol levels measured at the previous PE session will be associated with greater session-to-session change in secondary mechanistic and clinical outcomes. (3) Better sleep quality will be associated with greater declines in mechanistic and clinical outcomes. Confirmation of hypotheses would suggest adopting strategic scheduling of PE to maximize clinical outcome, an easily implemented and inexpensive health care strategy.