A meta-analysis of conditioned fear generalization in anxiety-related disorders

Abstract

Generalization of conditioned fear is adaptive in some situations but maladaptive when fear excessively generalizes to innocuous stimuli with incidental resemblance to a genuine threat cue. Recently, empirical interest in fear generalization as a transdiagnostic explanatory mechanism underlying anxiety-related disorders has accelerated. As there are now several studies of fear generalization across multiple types of anxiety-related disorders, the authors conducted a meta-analysis of studies reporting behavioral measures (subjective ratings and psychophysiological indices) of fear generalization in anxiety-related disorder vs. comparison groups. We conducted systematic searches of electronic databases (conducted from January-October 2020) for fear generalization studies involving anxiety-related disorder groups or subclinical analog groups. A total of 300 records were full-text screened and two unpublished datasets were obtained, yielding 16 studies reporting behavioral fear generalization measures. Random-effects meta-analytic models and meta-regressions were applied to the identified data. Fear generalization was significantly heightened in anxiety-related disorder participants (N = 439) relative to comparison participants (N = 428). We did not identify any significant clinical, sample, or methodological moderators. Heightened fear generalization is quantitatively supported as distinguishing anxiety-related disorder groups from comparison groups. Evidence suggests this effect is transdiagnostic, relatively robust to experimental or sample parameters, and that generalization paradigms are a well-supported framework for neurobehavioral investigations of learning and emotion in anxiety-related disorders. We discuss these findings in the context of prior fear conditioning meta-analyses, past neuroimaging investigations of fear generalization in anxiety-related disorders, and future directions and challenges for the field.

Fig. 1. Example illustrations of differential fear acquisition, extinction, and generalization tests and response patterns related to anxiety-related disorders.

A Successful discrimination between CS+ and CS− vs. poorer discrimination, meta-analytically observed in anxiety-related disorders (Duits et al. [26]). B Successful extinction, in which conditioned responses diminish, vs. poorer extinction, in which CS+ remains elevated, meta-analytically observed in anxiety-related disorders. C Generalization test, in which generalization stimuli (GSs, white points) that parametrically differ in similarity from the CS+ (red points) are presented with hypothetical response slopes. Conditioned responses typically diminish as a function of similarity to the CS+ in a curvilinear (i.e., quadratic) fashion—proposed to be characteristic of psychiatrically normative/non-anxiety groups (bottommost slope). Heightened generalization (also referred to as overgeneralization, middle slope) involves relatively increased responding to GSs—proposed to be linked to anxiety-related disorders. Monotonic responding (topmost slope) represents a failure to discriminate between stimuli—not considered a form of stimulus generalization. Abbreviations: CS+ conditioned threat cue, CS− conditioned safety cue, GS generalization stimuli, US unconditioned stimulus.

Fig. 2. PRISMA flow diagram and overall quality of included studies.

PRISMA flow diagram (A) shows the process of identification, screening, eligibility determination, and inclusion that lead to the final N = 16 studies that were meta-analyzed. B shows results from QA of included studies, which were evaluated by independent reviewers and assigned a rating of “low risk of bias”, “some concerns”, “high risk of bias”, or “no information” for each criterion. Bars represent proportion of studies that obtained each rating on each criterion, with a greater proportion of “low risk of bias” (pale yellow) indicative of higher overall study quality. Unpublished studies were not included in QA. Abbreviations: PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, QA quality assessment.

Fig. 3. Meta-analytic results by anxiety-related disorder diagnosis.

Plotted points represent effect sizes and 95% confidence intervals derived from random-effects meta-analytic models. Pooled effects are the average effect size for each disorder; summary pooled effect represents average effect size across all disorders. GAD generalized anxiety disorder, OCD obsessive-compulsive disorder, PD panic disorder, PTSD posttraumatic stress disorder, SAD social anxiety disorder, SP specific phobia.