ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci USA. 2024;121(52):e2405850121. doi: 10.1073/pnas.2405850121

Brief summary: This prospective, case control study shows that the cortisol awakening response (CAR) proactively tunes large scale brain network dynamics to optimize emotional discrimination and working memory, underlining its critical role in human adaptive cognition.

Comment: As a hallmark of human endocrine activity, the cortisol awakening response (CAR), i.e. the natural rise in cortisol concentrations shortly after waking, plays a critical role in proactively modulating emotional and executive functions (1-7). This study investigated how the CAR affects the brain’s dynamic reconfiguration and supports emotional and executive functions. While CAR is thought to play a proactive role in preparing the brain for daily challenges, the underlying neural mechanisms have not been delineated.

The authors investigated large-scale brain networks involved in emotional and executive functions in 122 male volunteers; 62 participants (mean age: 22.9 years; range: 18 to 27 years) in Cohort 1 and 60 participants in Cohort 2 (21.6 years; 20 to 24 years). Participants were given low dose dexamethasone (DXM, 0.5 mg) to suppress CAR, or placebo, the night before fMRI scans. The next afternoon, they performed 3 tasks: rest, emotional discrimination, and 2 back working memory (WM), while fMRI data were analyzed using a hidden Markov model (HMM) to identify transient “brain states” across 14 large scale networks.

In terms of behavior, suppression of CAR selectively impaired emotional discrimination performance without affecting WM. Conversely, participants with robust CAR levels showed better performance across both tasks. Furthermore, CAR suppression reduced both the fractional occupancy (how often a network state is active) and mean lifetime of task relevant brain states during emotion and WM tasks. Using information theoretic measures, the authors found that lower CAR increased transition complexity, i.e., less efficient shifting, among visual sensory and salience anchored states during emotional tasks. Interestingly, the opposite pattern appeared during the WM task, where complexity decreased among executive control and visuospatial networks.

These findings show that CAR shapes the brain’s ability to dynamically allocate resources to emotional and executive processing. CAR elevates both the frequency and stability of functionally specialized brain states and refines the complexity of state-to-state transitions in a task-specific manner. By establishing a causal link between CAR and brain network dynamics, this study presents a neuroendocrine mechanism for how cortisol prepares the mind for daily emotional and cognitive demands. Furthermore, it provides evidence that the CAR proactively tunes large scale brain network dynamics to optimize emotional discrimination and working memory, underlining its critical role in human adaptive cognition. However, this study has several limitations. First, it focused on CAR in males to avoid the confounding effect of female menstrual cycles, so may not be generalizable to females. Furthermore, it did not include concurrent measures of physiologic activity and task-induced transient modulators that may interplay with CAR. Future studies with optimal design and innovative neuroimaging techniques are required to address the mechanisms underlying time-dependent effects of CAR in the morning and in the afternoon.

References: 1. McEwen B S, Akil H. Revisiting the stress concept: Implications for affective disorders. J. Neurosci. 2020: 40: 12–21.2. de Kloet ER, Joëls M, Holsboer F. Stress and the brain: From adaptation to disease. Nat. Revi. Neurosci. 2005; 6: 463–475.3. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 2009; 10: 434–445.4. Clow A, Thorn L, Evans P, Hucklebridge F. The awakening cortisol response: Methodological issues and significance. Stress 2004; 7: 29–37.5. Law R, Clow A. “Chapter 8: Stress, the cortisol awakening response and cognitive function” in International Review of Neurobiology, Clow A, Smyth N, Eds. (Academic Press, 2020), vol. 150, pp. 187–217.6. Moriarty AS, et al. Cortisol awakening response and spatial working memory in man: A U-shaped relationship. Hum. Psychopharmacol. Clin. Exp. 2014; 29: 295–298.7. Xiong B., et al. Brain preparedness: The proactive role of the cortisol awakening response in hippocampal-prefrontal functional interactions. Prog. Neurobiol. 2021; 205: 102127.