A voxel-level brain-wide association study of cortisol at 8 a.m.: Evidence from Cushing's disease

Abstract

Cortisol, the end product of the hypothalamic–pituitary–adrenal axis, regulates cognitive function and emotion processing. Cushing's disease, which is characterized by a unique excess of cortisol upon clinical diagnosis, serve as an excellent in vivo “hyperexpression” model to investigate the neurobiological mechanisms of cortisol in the human brain. Previous studies have shown the association between cortisol and functional connectivity within an a priori brain network. However, the whole-brain connectivity pattern that accompanies endogenous cortisol variation is still unclear, as are its associated genetic underpinnings. Here, using resting-state functional magnetic resonance imaging in 112 subjects (60 patients with Cushing's disease and 52 healthy subjects), we performed a voxel-level brain-wide association analysis to investigate the functional connectivity pattern associated with a wide variation in cortisol levels at 8 a.m. The results showed that the regions associated with cortisol as of 8 a.m. were primarily distributed in brain functional hubs involved in self-referential processing, such as the medial prefrontal cortex, anterior and posterior cingulate cortex, and caudate. We also found that regions in the middle temporal, inferior parietal and ventrolateral prefrontal cortex, which is important for social communication tasks, and in the visual and supplementary motor cortex, which is involved in primary sensorimotor perception, were adversely affected by excessive cortisol. The connectivity between these regions was also significantly correlated with neuropsychiatric profiles, such anxiety and depression. Finally, combined neuroimaging and transcriptome analysis showed that functional cortisol-sensitive brain variations were significantly coupled to regional expression of glucocorticoid and mineralocorticoid receptors. These findings reveal cortisol-biased functional signatures in the human brain and shed light on the transcriptional regulation constraints on the cortisol-related brain network.

Dynamic functional connectivity changes associated with psychiatric traits and cognitive deficits in Cushing’s disease

“…Research progress on Cushing’s disease, which depends on static resting-state fMRI, revealed that patients with Cushing’s disease showed increased functional connectivity between the default mode network (DMN) and left lateral occipital cortex [ 2 ], and hippocampus [ 8 ]. Cortisol increase would induce connectivity changes within the DMN and salience network (SN) [ 9 ], and the DMN’s activity correlated with the morning cortisol level of patients with Cushing’s disease [ 10 ].…”

“…For example, the network-connectivity changes between SN and DMN [ 20 , 21 ], SN and CEN [ 22 ] corresponded to increased cortisol levels. Furthermore, our previous studies also identified that CD patients would show dysregulations of resting-state functional connectivity patterns with DMN [ 10 , 23 ]. Since CD patients also suffer from cognitive impairment and neuropsychological symptoms, including depression and anxiety, which DMN, SN, and CEN mainly modulate, we hypothesized that these three networks are critical to understanding Cushing’s disease and its comorbidity.…”