Glucocorticoids and the Brain after Critical Illness

Abstract

Treatment for critical illness typically focuses on a patient’s short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut–brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.

Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression

“…IL-10 is a marker for non-inflamed patients [ 67 ]. It has also been hypothesised that repeated endogenous glucocorticoid release in response to stress contributes to delirium development [ 80 ].…”

Dream Recall/Affect and the Hypothalamic–Pituitary–Adrenal Axis

“…Additionally, GRs can be subjected to epigenetic modulation. The GR is widely expressed in the brain, whereas the MR is expressed mostly in the limbic region [23]. Contrary to primates, the expression of GR in the human hippocampus remains mostly stable with age [24].…”

“…Steroid receptor activation may have a biphasic effect on brain synaptic plasticity. Activation, at lower levels of the MR ligands, enhances long-term potentiation, whereas with activation, at higher levels of the GR ligands, long-term potentiation in inhibited, with a decrease in the excitability of the hippocampus [23]; the latter's function is needed for "typical" dreaming and dream recall [27]. A role for the HPA and F in particular has been postulated regarding memory consolidation and subsequently for dream recall [28].…”

“…Patients in intensive care units (ICU) show a protracted stress response, with modest elevation or high total F (attributed to lowering in protein binding/F clearance/free F elevation; these changes occur usually in the absence of high ACTH, which may be downregulated by high free F). Twenty-five percent of ICU patients are treated with glucocorticoids [23]. More than half of critically ill patients may (subsequently) report disturbed dreaming experiences and nightmares during long-term ICU hospitalization, as well as after hospital discharge [42][43][44][45].…”

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

“…In some situations, however, the deleterious effects of stress and GCs in the brain can be transient, since stress-induced hippocampal atrophy and hippocampal-dependent behavior may be reversed after a stress-free period. However, a growing body of evidence suggests that high GC exposure in early life can adversely program the release of GCs and increase susceptibility to the development of metabolic, neuropsychiatric, and neurodegenerative diseases [8], as well as induce changes in brain structure-including the generation and loss of neurons and dendritic atrophy-and brain function, affecting electrophysiological activity and cellular signaling [9,10].…”