Testing three models of cognitive stress effects: A psychopharmacological randomized controlled trial of acute stress and stress hormones across visual perception, response inhibition and cognitive flexibility

Acute stress alters cognitive performance, yet competing models make divergent predictions regarding the mechanisms, scope, and temporal dynamics of these effects. This large-scale randomized controlled trial tested predications from three influential stress-effect models using a broad cognitive task battery embedded within a psychopharmacological stress paradigm. Across 606 testing sessions, 303 healthy male participants completed both the Maastricht Acute Stress Test (MAST) and its non-stress control condition. To independently manipulate acute stress and stress hormone availability, participants were additionally randomized to receive atomoxetine (40 mg; to prolong norepinephrine availability), hydrocortisone (10 mg; to increase cortisol availability), or placebo. Cognitive performance was assessed over 80-minutes (post-stress) using tasks targeting visual perception (rapid serial visual presentation), response inhibition (stop-signal), and cognitive flexibility (dual and switch tasks). MAST exposure selectively impaired response inhibition, reflected in shorter stop-signal delays, lower probabilities of successful stopping and prolonged stop-signal reaction times, particularly during later testing phases (40-80 minutes post-stress). MAST exposure did not affect visual perception or task-switching performance but buffered time-related declines in processing efficiency at the expense of task prioritization in the dual task. Pharmacological manipulation of norepinephrine or cortisol availability was effective but did not moderate cognitive stress effects. Overall, this pattern of task-specific impairment alongside stabilized processing efficiency cannot be fully explained by any tested model, highlighting the need to refine existing models and adopt more integrative approaches to advance our mechanistic understanding of cognitive stress-effects in laboratory and real-world contexts.