Role of the Locus Coeruleus in Response to Threat in Anxiety Disorders and Posttraumatic Stress Disorder: An Ultra-High-Field 7T Functional Magnetic Resonance Imaging Study.

Background: By harnessing the enhanced spatial resolution and signal power of high-field 7T magnetic resonance imaging (MRI), we assessed the functional involvement of the locus coeruleus (LC), together with the broader threat circuitry, in anxious arousal among individuals with anxiety disorders and posttraumatic stress disorder (PTSD). Methods: Sixty-nine individuals with and without anxiety disorders or PTSD completed a modified no (N), predictable (P), and unpredictable (U) (NPU) threat task during a 7T functional MRI scan. Anxious arousal was measured using the Mood and Anxiety Symptom Questionnaire anxious arousal subscale. Individual data-driven LC segmentations were derived from ultra-high-resolution magnetization transfer contrast scans. We conducted LC functional activation and whole-brain data analyses during the NPU task using both transdiagnostic (Research Domain Criteria-based) and categorical (DSM-5-based) approaches. Results: Greater LC activation during unpredictable threat was positively correlated with anxious arousal across all participants. In whole-brain analyses, the posterior cingulate cortex/precuneus and the subgenual anterior cingulate cortex were significantly activated during unpredictable threat, whereas the posterior insula was significantly activated during predictable threat. Greater activation within key structures of the threat circuitry, including the brainstem, the left hippocampus/amygdala, and the insula was positively correlated with anxious arousal across conditions and participants. Conclusions: This translational and dimensional work advances our understanding of the role of the LC system and threat circuitry in pathological anxiety. Using 7T MRI, this study highlights the functional role of the LC in processing unpredictable threat in association with anxious arousal in individuals with anxiety disorders and PTSD.