Associative learning deficits increase symptoms of anxiety in humans

Background: Unpredictability has been postulated to be fundamental to anxiety and mood disorders. The origin of this unpredictability remains obscure. Because classical conditioning promotes predictability, this study investigated whether failure to learn conditioned stimulus (CS)-unconditioned stimulus (US) relationship during fear conditioning increased anxiety and avoidance. Methods: Healthy subjects participated in two similar differential fear conditioning sessions separated by 1 week (n = 72) or a month (n = 61) in which one of two conditioned stimuli was associated with a shock/US. Following initial acquisition, subjects’ awareness of CS-US relationship was assessed. Conditioned responses (CR) to the CS and to the experimental context were examined using the startle reflex and the skin conductance. Avoidance was operationally defined as failure to return for the second session. Results: Only aware subjects showed differential CR. In the unaware subjects, the deficit in differential conditioning was associated with increased signs of anxiety during the first and second sessions. In addition, there was greater avoidance in the unaware subjects. Conclusions: Deficits in explicit cue fear conditioning can enhance anxiety. These findings are consistent with theories that associate anxiety and mood disorders with perceived unpredictability. Contextual conditioning models may be relevant to study chronic forms of anxiety.