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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, Russell, GM, Ferguson, SG ORCID: 0000-0001-7378-3497, Grabski, M, Harmer, CJ, Munafo, MR, Marchant, N, Wilson, Aileen, Brooks, JC, Thakrar, J, Murphy, P, Thai, NJ and Lightman, SL 2021 , 'Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial' , Psychoneuroendocrinology, vol. 124 , pp. 1-12 , doi:

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Adrenal glucocorticoid secretion into the systematic circulation is characterised by a complex rhythm, composedof the diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of shortduration hormonal pulses. To elucidate the potential neurobiological significance of glucocorticoid pulsatility inman, we have conducted a randomised, double-blind, placebo-controlled, three-way crossover clinical trial on 15healthy volunteers, investigating the impact of different glucocorticoid rhythms on measures of mood and neuralactivity under resting conditions by recruiting functional neuroimaging, computerised behavioural tests andecological momentary assessments. Endogenous glucocorticoid biosynthesis was pharmacologically suppressed,and plasma levels of corticosteroid restored by hydrocortisone replacement in three different regimes, eithermimicking the normal ultradian and circadian profile of the hormone, or retaining the normal circadian butabolishing the ultradian rhythm of the hormone, or by our current best oral replacement regime which results ina suboptimal circadian and ultradian rhythm. Our results indicate that changes in the temporal mode ofglucocorticoid 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-scaleresting state networks of the human brain, (iv) the functional connectivity of the default-mode, salience andexecutive 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 thepattern of the ultradian glucocorticoid rhythm could affect cognitive psychophysiology under non-stressfulconditions 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 Type: Article
Authors/Creators:Kalafatakis, K and Russell, GM and Ferguson, SG and Grabski, M and Harmer, CJ and Munafo, MR and Marchant, N and Wilson, Aileen and Brooks, JC and Thakrar, J and Murphy, P and Thai, NJ and Lightman, SL
Keywords: glucocorticoids, ultradian rhythm, FMRI, mood, psychophysiology
Journal or Publication Title: Psychoneuroendocrinology
Publisher: Pergamon-Elsevier Science Ltd
ISSN: 0306-4530
DOI / ID Number:
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Copyright 2020 The authorsThis is an open access article under the CC BY 4.0 license (

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