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Developmental Differences in Neural Responding to Threat and Safety: Implications for Treating Youths With Anxiety.

Anxiety disorders are the most prevalent mental health disorders, affecting approximately one in three individuals, and they often onset during development (1). Cognitivebehavioral therapy and selective serotonin reuptake inhibitors can be highly effective for treating anxiety. However, up to 50% of both youths and adultswith anxiety do not respond sufficiently to these evidence-based treatments (2), highlighting the critical need to optimize interventions to more effectively reduce the immense burden of anxiety on individuals and society. Given the dynamic course of anxiety across the lifespan (1), as well as marked developmental changes in frontolimbic circuitry implicated in anxiety (3, 4), tailoring interventions based on developmental stage represents a promising approach to maximize efficacy (5). Difficulty discriminating between cues that predict threat and safety is a core featureof anxietydisorders, leading to fear even in situations and environments that are safe (6). Delineating normative developmental trajectories of threat and safety learningandhowsuch trajectoriesdiffer inyouthswith anxiety may provide critical insight into ways in which mechanisms underlying anxiety vary by age. The ability to distinguish between threat and safety cues improves with age among youths without anxiety disorders (7); however, adolescentswithoutanxietydisorders showdiminishedextinction (8) and retention of learned safety (9) comparedwith children andadultswithout anxietydisorders.Althoughdevelopmental changes have been less explored in children and adolescents with anxiety disorders, cross-sectional evidence suggests that youths with anxiety exhibit altered neural responses when processing cues that no longer predict threat, compared with both youthswithout anxiety and adultswith anxiety (6, 10). At the same time,findingshavebeenmixed,with someevidenceof similar processing in pediatric and adult anxiety disorders (10). Reconciling inconsistent findings and identifying the conditions under which youths and adults with anxiety may respond similarly versus differently to threat and safety are essential to advance knowledge of the basic mechanisms underlying the development of anxiety and to inform interventions. In this issue of the Journal, Gold and colleagues (11) examine neural responses to ambiguous threat and safety cues among youths and adults with and without anxiety disorders, with the goal of testing for age-related similarities anddifferences.Threat conditioningandextinctionwerefirst assessed via psychophysiological and self-report measures. Three weeks later, participants completed a functional MRI (fMRI) paradigm of extinction recall, during which they rated their own fear (i.e., threat appraisal) and explicit memory of stimuli with varying levels of similarity to the threat cues that had previously been extinguished. Importantly, diagnosticdifferences inage-relatedpatterns emerged for both neural activation and functional connectivity. For activation, age-related diagnostic differences varied by task condition, as well as by brain region. When participants attended to their own fear, activation in the ventromedial prefrontal cortex (vmPFC) and inferior temporal cortex (ITC) differed between adults with and without anxiety, such that nonanxious adults exhibited less vmPFC deactivation and greater ITC activation compared with anxious adults. Notably, these differences in vmPFC and ITC activation during threat appraisal did not emerge between youths with and without anxiety. By contrast, when participants rated memory for morphed stimuli, ITC activation was higher in youths with anxiety compared with youths without anxiety, but there were no differences in adults. For functional connectivity, as the degree of safety in morphed stimuli increased, diagnostic differences in amygdala-vmPFC functional connectivity depended on age.Whereas adultswithout anxiety exhibited stronger positive amygdala-vmPFC functional connectivity than adults with anxiety, youths with anxiety exhibited stronger connectivity than youths without anxiety. Findings from Gold and colleagues of anxiety-related neural alterations during extinction recall may be consistent with evidence that individuals with anxiety disorders have difficulty recognizing safety during laboratory paradigms and in daily life (6, 12). Moreover, the developmental nature of thefindings in this study is consistentwith previous Tailoring interventions based on developmental stage represents apromising approach to maximize efficacy.