Cortico-limbic Interactions and Carotid Atherosclerotic Burden During Chronic Stress Exposure

Background and Aims Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis.Methods Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala).Results Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score.Conclusions In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings. Structured Graphical Abstract Multimodal imaging of the brain-heart connection. Individuals with PTSD, individuals exposed to trauma but who did not develop PTSD (trauma controls), and individuals with neither trauma exposure nor a history of psychiatric disorders (healthy controls) were recruited. Participants underwent 18F-FDG PET and MRI (including DTI MRI of the brain) to assess the function and structure of stress-associated neural tissues, leucopoietic organs (bone marrow and spleen), and the arteries. The lower panel proposes a pathway by which neural tissues may potentiate atherosclerosis. A higher metabolic activity in the amygdala relative to the vmPFC (on 18F-FDG PET), which is also linked to a disruption in their interconnection (the uncinate fasciculus) on DTI MRI, was associated with carotid atherosclerotic burden. Heightened systemic inflammation and leucopoiesis may be involved in this brain-heart connection. DTI, diffusion tensor imaging; 18F-FDG PET, 18F-fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; PTSD, post-traumatic stress disorder; SNA, stress-associated neural network activity; vmPFC, ventromedial prefrontal cortex.