Functional connectivity of the locus coeruleus in anxiety and posttraumatic stress disorder reveals convergent mapping to the cingulate cortex and insula using ultra-high field 7 Tesla MRI

Abstract Cortical and subcortical correlates of anxiety and stress disorders have been well defined over recent decades. However, the role of the locus coeruleus (LC), which is responsible for synthesizing and releasing a majority of the brains’ norepinephrine, has been less widely studied. Here, we used ultra-high field 7T imaging with 400 μm³ voxel resolution to individually segment the LC. We performed a functional connectivity analysis to elucidate the relationship between LC connectivity across the whole brain and measures of anxiety and stress, with a particular focus on anxious arousal, a core feature of pathological anxiety. We assessed 77 individuals with and without anxiety or posttraumatic stress disorder (PTSD). We found that higher anxious arousal was robustly associated with higher LC connectivity to the dorsal anterior cingulate cortex (dACC). A conjunction analysis utilizing additional measures of anxiety and stress revealed consistent mapping of LC connectivity to the dACC and the insula (all p cluster < 0.05, FWE whole-brain corrected). This study leveraged high resolution functional connectivity mapping and individualized segmentation of the LC to demonstrate a consistent neuropathological phenotype of LC hyper-connectivity with dACC and insula across anxiety disorders and PTSD. These findings suggest that functional interactions between LC and dACC and insula represent a core aspect of pathological anxiety.