Frustrative non-reward: A cross-species probe to study brain mechanisms of irritability.

Irritability is common and often impairing, especially in youth, and evidence-based, effective treatments are lacking. Frustration is the emotional and behavioral response to the omission, decrease, or delay of an expected reward. Frustration responses, including increased activity and aggression, are evolutionarily conserved. Evidence suggests that maladaptive frustration responses may be a central mechanism in irritability e.g., the developmentally inappropriate temper outbursts that are the most prominent symptom of irritability can represent an exaggeration of the normatively increased activity seen in response to frustration. Thus, cross-species studies of frustration provide a translational approach to research on irritability that could elucidate pathophysiological mechanisms and provide novel treatment targets. We review animal and human studies on frustration, highlighting major findings and opportunities for cross-species work. Currently, animal studies of frustration provide detailed behavioral data but relatively limited data on neurobiology or individual differences. Animal studies determined the behavioral effects of frustrative non-reward (FNR), emphasizing increased activity, built a conceptual framework to explain them, and started the investigation of the underling neural mechanisms. The relatively small body of literature on animal neurobiology underlying FNR, compared to behavioral evidence, highlights opportunities for more future research in this area. Validating animal work, human studies show that FNR increases invigorated behaviors and resistance to extinction. Human neuroimaging implicates dopaminergic, emotion, and pain-processing circuits in behavioral and emotional responses. Emerging evidence links irritability to altered neural activation and connectivity associated with FNR while highlighting the need for more translational research on behavioral and physiological FNR indicators. Future collaborations should focus on designing cross-species paradigms and circuitry-based studies.