Neural patterns of threat response in adolescents predict vulnerability for and resilience against internalizing symptoms during COVID-19 waves.

Defensive stress reactions, such as freezing and active fight-or-flight, are relevant for coping with threat. Action-preparatory activity supporting these reactions, including the amygdala, has been posited as a potential marker for stress-resilience. We considered the successive COVID-19 lockdowns as two pervasive stressors, to prospectively investigate the predictive value of neural threat-responses towards symptom development. Five years prior to the COVID-19 pandemic, 17-year-old adolescents (n = 64, Baseline-17) performed the fMRI-adapted Go/Nogo Under Threat (GUNT) task, where threat-anticipatory freezing reactions and transition to action are evoked to avoid a shock. A majority (n = 44) made themselves available for follow-up assessments before COVID (Baseline-20, age 20), during the first COVID-19 lockdown in the Netherlands (LD1, age 22.5), and during a second lockdown (LD2, age 23). The GUNT task quantified neural (thalamic, subcortical, amygdala) and physiological (bradycardia) markers of threat-anticipatory freezing and transition to action (mediated by anterior cingulate cortex). Threat-anticipatory amygdala responses (Baseline-17) were linked to stressor resilience, as quantified by self-reported anxiety symptoms between LD1 and LD2. However, stronger amygdala responses to low threat cues (Baseline-17) were associated with stronger anxiety symptoms. These effects occurred over and above early-life stress, COVID-19 stress burden, and overall symptom changes between age 17 and 20. These findings suggest that amygdala responses to acute threat provide a marker for resilience against real-life stressors, with adequate threat discrimination signaling resilience and stronger amygdala responses to low threat predicting vulnerability. The findings support the notion that neural responses to threat are instrumental for adaptive coping with pervasive stress.