Multi-scale Analysis Reveals Hippocampal Subfield Vulnerabilities to Chronic Cortisol Overexposure: Evidence from Cushing's Disease

Background: Chronic cortisol overexposure plays a significant role in the development of neuropathological changes associated with neuropsychiatric and neurodegenerative disorders. The hippocampus, the primary target of cortisol, may exhibit characteristic regional responses due to its internal heterogeneity. This study explores structural and functional alterations of hippocampal subfields in Cushing's disease (CD), an endogenous model of chronic cortisol overexposure.

Methods: Utilizing structural and resting-state functional magnetic resonance imaging data from 169 participants (86 CD patients and 83 healthy controls) recruited from a single center, we investigated specific structural changes in hippocampal subfields and explored the functional connectivity alterations driven by these structural abnormalities. We also analyzed potential associative mechanisms between these changes and biological attributes, neuropsychiatric representations, cognitive function, and gene expression profiles.

Results: Compared to healthy controls, CD patients exhibited significant bilateral volume reductions in multiple hippocampal subfields. Notably, volumetric decreases in the left hippocampal body and tail subfields were significantly correlated with cortisol levels, Montreal Cognitive Assessment scores, and quality of life measures. Disrupted connectivity between the structurally abnormal hippocampal subfields and ventromedial prefrontal cortex may impair reward-based decision making and emotional regulation, with this dysconnectivity linked to structural changes in right hippocampal subfields. Additionally, another region exhibiting dysconnectivity was located in the left pallidum and putamen. Gene expression patterns associated with synaptic components may underlie these macrostructural alterations.

Conclusions: Our findings elucidate the subfield-specific effects of chronic cortisol overexposure on the hippocampus, enhancing understanding of shared neuropathological traits linked to cortisol dysregulation in neuropsychiatric and neurodegenerative disorders.