Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial.

INTRODUCTION: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall. METHODS: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect. RESULTS: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: -0.623 to -0.005; BDNF 95% CI: -0.941 to -0.005). CONCLUSIONS: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.

Aerobic exercise and consolidation of fear extinction learning among women with posttraumatic stress disorder.

This study tested whether aerobic exercise delivered during the consolidation window following fear extinction learning reduces the return of fear among women with posttraumatic stress disorder (PTSD). Participants (n=35) completed an initial clinical assessment followed by a 3-day fear acquisition, extinction, and recall protocol. On day 1, participants completed a fear acquisition training task in which one geometric shape (conditioning stimulus; CS+) was paired (with 50% probability) with a mild electric shock (unconditioned stimulus; US), while a different shape (CS-) was never paired with the US. On day 2 (24 h later), participants completed a fear extinction training task in which the CS+ no longer predicted administration of the US. Shortly following extinction, participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity exercise control (CON) condition. On day 3 (24 h later), participants completed fear recall tests assessing the return of fear (spontaneous recovery, renewal, and reinstatement). Fear responding was assessed via threat expectancy ratings and skin conductance responses (SCR). In the threat expectancy ratings, there were no significant differences between groups in spontaneous recovery; however, EX significantly (p=.02) reduced threat expectancy ratings following reinstatement relative to CON. In SCR measures, there were no significant differences between groups in spontaneous recovery, renewal, or reinstatement. These results support a role for moderate-intensity aerobic exercise during the consolidation window in reducing threat expectations following reinstatement in women with PTSD. Research should continue to examine exercise as a potential method for improving the efficacy of exposure-based therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04113798.