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

Kalafatakis, Konstantinos, Russell, Georgina M., Ferguson, Stuart G., Grabski, Meryem, Harmer, Catherine J., Munafò, Marcus R., Marchant, Nicola, Wilson, Aileen, Brooks, Jonathan C. ORCID:, Thakrar, Jamini, Murphy, Patrick, Thai, Ngoc J. and Lightman, Stafford L. (2021) Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial. Psychoneuroendocrinology, 124. ISSN 0306-4530

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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 Type: Article
Additional Information: Funding Information: Funding for this work was provided by the Medical Research Council [DCS Grant MR/J0125481/1] and the Wellcome Trust [Grant 089647/Z/09/Z]. CJH was supported by the Oxford Health NIHR Biomedical Research Centre. All authors would like to declare no competing financial interests in relation to the work described. Publisher Copyright: © 2020
Uncontrolled Keywords: fmri,glucocorticoids,mood,psychophysiology,ultradian rhythm,endocrinology, diabetes and metabolism,endocrinology,endocrine and autonomic systems,psychiatry and mental health,biological psychiatry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2712
Faculty \ School: Faculty of Social Sciences > School of Psychology
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Depositing User: LivePure Connector
Date Deposited: 10 Feb 2022 09:30
Last Modified: 23 Oct 2022 03:32
DOI: 10.1016/j.psyneuen.2020.105096

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