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

Importance The 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 differentDSM-IVdiagnoses within a category. For example, anxiety disorders comprise aDSM-IVcategory that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. WhetherDSM-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. Objective To 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 Participants This 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. Exposures A 2-day threat conditioning and extinction protocol. Main Outcomes and Measures Skin 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 primaryDSM-IVdiagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning. Results This 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 categoricalDSM-IV–based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 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, ηp2 = 0.21;P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12;P = .02). The direct comparison ofDSM-IV–based vs Research Domain Criteria–based results did not yield significant findings (ηp2values ranged from 0.02 to 0.078;Pvalues ranged from .09 to .98), suggesting no overlap between the approaches. Conclusions and Relevance The 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.