Multimodal Categorical and Dimensional Approaches to Understanding Threat Conditioning and Its Extinction in Individuals With Anxiety Disorders

Key PointsQuestionWhat can DSM-IV-based and Research Domain Criteria-based analytic approaches contribute to the understanding of threat and extinction learning in individuals with anxiety disorders? FindingsIn this cross-sectional study of 114 adults with and without anxiety disorders, the categorical DSM-IV-based approach indicated that all groups of individuals with an anxiety disorder, irrespective of DSM-IV diagnosis, exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall. The dimensional research domain criteria-based approach revealed that higher arousal to the unconditioned stimulus during threat learning was associated with higher threat responses during extinction recall. MeaningPersonalized medicine may be better served with the inclusion of both DSM-IV-based and research domain criteria-based approaches, as they provide distinct yet complementary information. ImportanceThe Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested. ObjectiveTo use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders. Design, Setting, and ParticipantsThis cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019. ExposuresA 2-day threat conditioning and extinction protocol. Main Outcomes and MeasuresSkin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning. ResultsThis cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (eta (2)(p)=0.15; P=.004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, eta (2)(p)=0.21; P=.01 and in functional magnetic resonance imaging results, eta (2)(p)=0.12; P=.02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (eta (2)(p) values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches. Conclusions and RelevanceThe data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms. This cross-sectional study uses a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and transdiagnostic dimensional (research domain criteria-based) assessments of psychophysiological, neural, and psychometric responses in adults with and without anxiety disorders.