Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals: study protocol for a randomised controlled trial

Abstract

BackgroundDeviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis.Methods/designThe study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18–60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain.DiscussionResults of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics.Trial registrationUK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013)

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man

“…This study follows the guidelines for reporting fMRI data suggested by Poldrack et al (78). The ROIs for the fMRI studies have been defined a priori (60). Functional and perfusion neuroimaging data analyses were carried out using FMRIB soft-ware library 5.0 (79) and Statistical Parametric Mapping version 8, and involved a number of preprocessing and postprocessing steps (SI Appendix, Figs.…”

“…Motivated by the clinical need for improved GC-based therapeutics and the preclinical evidence, we hypothesized that under normal, nonstressful, nonpathological conditions, different ultradian GC rhythms might be translated differently in relevant GC-responsive human brain regions, and that this differential processing should be detectable using well-designed experimental protocols. We have developed a "block and replace" protocol (i.e., combined metyrapone administration with hydrocortisone infusion) in which we can reliably impose definitive patterns of plasma hydrocortisone (60). This has allowed us to provide three predetermined patterns of cortisol replacement therapy: (i) normal circadian rhythmicity lacking any physiological ultradian rhythm [s.c.-continuous hydrocortisone infusion (SCC)], (ii) normal circadian and ultradian rhythmicity [s.c.-pulsatile hydrocortisone infusion (SCP)], and (iii) current optimal oral replacement therapy (PO), characterized by suboptimal circadian and ultradian rhythms.…”

“…All study-related procedures not directly available in the main text are provided in SI Appendix. Additional information is available in Kalafatakis et al (60).…”

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

“…Finally, based on earlier clinical work in similar experimental settings, using neuropharmacological challenge to probe psychological mechanisms of mood regulation and emotional processing, and functional neuroimaging to measure related neural activity ( Harmer et al, 2004 , Browning et al, 2007 , Murphy et al, 2008 ), we performed power calculations that confirmed a sample size of 15 participants per treatment arm, on whom complete data were available, would be required to give our study a 80% power at an alpha level of 5%. Further details on the study design and its rationale and limitations can be found in the study protocol, published elsewhere ( Kalafatakis et al, 2016b ).…”

MECHANISMS IN ENDOCRINOLOGY: Does circadian and ultradian glucocorticoid exposure affect the brain?

“…We created a human model of adrenal insufficiency by pharmacologically blocking GC biosynthesis (oral administration of metyrapone three times daily) and replacing the hormone in three different modes, using either (i) oral treatment (OT), (ii) constant subcutaneous infusion (SCHI) or (iii) a novel, subcutaneous, pump-based method, delivering different size pulses of hydrocortisone every 3 h, which reproduced both the natural circadian and ultradian patterns of cortisol. We then examined the neurocognitive effects of these different GC rhythms using functional neuroimaging techniques and a set of cognitive and behavioural tests, markers of sleep behaviour, working memory and emotional processing, in a randomised, double-blind, placebo-controlled, crossover study (144). We were able to demonstrate that non-pulsatile GC exposure (i.e.…”