Neural correlates of predictable and unpredictable threat in internalizing psychopathology

Converging lines of evidence suggest that heightened responding to unpredictable threat may be an important neurobiological marker of internalizing psychopathology (IP). Prior data also indicate that aversive responding to uncertainty may be mediated by hyperactivation of several brain regions within the frontolimbic circuit, namely the anterior insula (aINS) and the dorsal anterior cingulate cortex (dACC). To date, however, the majority of this research has been focused on individual diagnoses and it is unclear whether abnormal neural reactivity to unpredictable threat is observed within heterogeneous, transdiagnostic IP patient populations, as theory would suggest. The aim of the current study was to therefore examine the neural correlates of temporally unpredictable (U) and predictable (P) threat in a sample of healthy controls (n = 24) and patients with a broad range of IP diagnoses (n = 51). We also examined whether symptom severity measures of fear and distress/misery dimensions correlated with neural reactivity to U- and P-threat. All participants completed a modified version of a well-validated threat-of-shock task during functional magnetic resonance imaging (fMRI). Across all participants, U- and P-threat elicited heightened activation in the aINS and brainstem, while P-threat alone also activated the dACC. Relative to healthy controls, patients displayed greater activation in the right aINS during U-threat, and greater right brainstem activation during P-threat. In addition, we found that brainstem activity during U-threat correlated with fear, but not distress/misery, psychopathology. Taken together, these preliminary results suggest that exaggerated aINS reactivity during U-threat and brainstem reactivity during P-threat may have the potential to become important transdiagnostic biomarkers of IP; however, future research efforts are needed to corroborate and expand the present findings.