Fear and Safety Learning in Anxiety-Related Psychopathology: A Transdiagnostic and Multi-Method Investigation

Abstract

Fear and safety learning processes are essential for survival, but excessive fear in anxiety-related psychopathology – covering symptoms, traits, and states beyond traditional diagnostic categories – causes suffering and impairment. Thus, fear and safety learning has been increasingly studied to understand its role in the development, maintenance, and treatment of anxiety- and stress-related disorders, including anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder. Differential fear conditioning is a well-established approach, offering translational potential for bridging experimental and clinical studies. For instance, pathological fear and anxiety are assumed to arise through associative learning and overgeneralization, while deficits in extinction and inhibitory learning form the dominant theoretical framework of exposure therapy. Individuals with anxiety- and stress-related disorders often show deficits in differentiating threat (CS+) from safety cues (CS-), impaired extinction learning, and fear overgeneralization, although empirical evidence remains partly inconsistent and contradictory. The present dissertation aimed to advance a transdiagnostic understanding of fear and safety learning in anxiety-related psychopathology, examining how these processes contribute to the development, maintenance, and treatment of anxiety- and stress-related disorders. To this end, differential fear conditioning was assessed across multiple phases (acquisition, generalization, extinction, extinction recall, and return of fear (RoF)) and outcome measures (US expectancy, affect ratings, fear-potentiated startle, skin conductance response, and late positive potential) using both meta-analytic and cross-sectional approaches. Categorical group comparisons, symptom-specific dimensional effects, and the influence of comorbid depression were considered. The meta-analysis of study I (n = 77 studies) extends previous findings by demonstrating heightened responses to the CS- during fear acquisition and persistence after extinction, alongside increased affect ratings to the CS+ across phases in individuals with anxiety- and stress-related disorders compared to healthy controls. Effect sizes were small to medium, with heterogeneity limiting synthesis across studies. Study II (n = 156) investigated fear conditioning in social anxiety disorder (SAD), specific phobia, and OCD using a cross-sectional design, finding higher shock expectancy for the CS- during fear acquisition in SAD and impaired extinction learning in comorbid depression. Anxious arousal was associated with altered fear acquisition and overgeneralization. Study III (n = 201) focused on fear conditioning in OCD and individuals with genetic and environmental risk for anxiety-related psychopathology. Individuals with OCD exhibited elevated stimulus-unspecific shock expectancy and fear ratings across most phases, but no evidence emerged for altered fear and safety learning as a vulnerability factor. Obsessive-compulsive symptoms were associated with elevated shock expectancy and fear ratings across most phases, while depressive symptoms particularly influenced responses during RoF. In conclusion, individuals with anxiety- and stress-related disorders compared to controls show altered fear and safety learning, primarily reflected in subjective ratings rather than physiological or neural measures, suggesting cognitive biases and impaired inhibitory learning. The impact of comorbid depression and symptom severity underscores the importance of personalized treatment approaches. At the same time, inconsistencies across studies, disorders, phases, and outcome measures highlight the complexity and heterogeneity of these processes across different anxiety- and stress-related disorders. Future research should prioritize longitudinal and methodologically harmonized designs to clarify the translational relevance of fear and safety learning mechanisms for the development, maintenance, and treatment of anxiety- and stress-related disorders.