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Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial


Kalafatakis, K and Russell, GM and Ferguson, SG and Grabski, M and Harmer, CJ and Munafo, MR and Marchant, N and Wilson, A and Brooks, JC and Thakrar, J and Murphy, P and Thai, NJ and Lightman, SL, Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial, Psychoneuroendocrinology, 124 pp. 1-12. ISSN 0306-4530 (2021) [Refereed Article]


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Copyright 2020 The authors This is an open access article under the CC BY 4.0 license (

DOI: doi:10.1016/j.psyneuen.2020.105096


Adrenal glucocorticoid secretion into the systematic circulation is characterised by a complex rhythm, composed of the diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of short duration hormonal pulses. To elucidate the potential neurobiological significance of glucocorticoid pulsatility in man, we have conducted a randomised, double-blind, placebo-controlled, three-way crossover clinical trial on 15 healthy volunteers, investigating the impact of different glucocorticoid rhythms on measures of mood and neural activity under resting conditions by recruiting functional neuroimaging, computerised behavioural tests and ecological momentary assessments. Endogenous glucocorticoid biosynthesis was pharmacologically suppressed, and plasma levels of corticosteroid restored by hydrocortisone replacement in three different regimes, either mimicking the normal ultradian and circadian profile of the hormone, or retaining the normal circadian but abolishing the ultradian rhythm of the hormone, or by our current best oral replacement regime which results in a suboptimal circadian and ultradian rhythm. Our results indicate that changes in the temporal mode of glucocorticoid replacement impact (i) the morning levels of self-perceived vigour, fatigue and concentration, (ii) the diurnal pattern of mood variation, (iii) the within-network functional connectivity of various large-scale resting state networks of the human brain, (iv) the functional connectivity of the default-mode, salience and executive control networks with glucocorticoid-sensitive nodes of the corticolimbic system, and (v) the functional relationship between mood variation and underlying neural networks. The findings indicate that the pattern of the ultradian glucocorticoid rhythm could affect cognitive psychophysiology under non-stressful conditions and opens new pathways for our understanding on the neuropsychological effects of cortisol pulsatility with relevance to the goal of optimising glucocorticoid replacement strategies.

Item Details

Item Type:Refereed Article
Keywords:glucocorticoids, ultradian rhythm, FMRI, mood, psychophysiology
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Endocrinology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Ferguson, SG (Professor Stuart Ferguson)
ID Code:141980
Year Published:2021
Web of Science® Times Cited:6
Deposited By:Medicine
Deposited On:2020-12-07
Last Modified:2021-01-29
Downloads:20 View Download Statistics

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