Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, BS1 3NY Bristol, United Kingdom; Clinical Research and Imaging Centre, University of Bristol and University Hospitals Bristol NHS Foundation Trust, BS2 8DX Bristol, United Kingdom; Royal Bristol Infirmary, University Hospitals Bristol NHS Foundation Trust, BS2 8HW Bristol, United Kingdom.
Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, BS1 3NY Bristol, United Kingdom; Royal Bristol Infirmary, University Hospitals Bristol NHS Foundation Trust, BS2 8HW Bristol, United Kingdom.
Psychoneuroendocrinology. 2021 Feb;124:105096. doi: 10.1016/j.psyneuen.2020.105096. Epub 2020 Dec 1.
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.
肾上腺糖皮质激素分泌到体循环中具有复杂的节律，由一个基本的超短脉冲激素的超短周期节律形成的脉冲幅度变化组成的昼夜变化。为了阐明糖皮质激素脉动在人类中的潜在神经生物学意义，我们在 15 名健康志愿者中进行了一项随机、双盲、安慰剂对照、三向交叉临床试验，通过招募功能神经影像学、计算机化行为测试和生态瞬时评估，研究不同的糖皮质激素节律对静息状态下情绪和神经活动的影响。通过药理学抑制内源性糖皮质激素的生物合成，并通过氢化可的松替代恢复皮质类固醇的血浆水平，在三种不同的方案中，模拟激素的正常超短周期和昼夜节律、保留激素的正常昼夜节律但消除激素的超短周期节律，或采用我们目前的最佳口服替代方案，从而导致昼夜节律和超短周期节律不佳。我们的结果表明，糖皮质激素替代的时间模式变化（i）影响自我感知的活力、疲劳和注意力的早晨水平，（ii）情绪变化的昼夜模式，（iii）各种人类大脑大尺度静息状态网络的内部网络功能连接，（iv）默认模式、突显和执行控制网络与皮质边缘系统的糖皮质激素敏感节点的功能连接，以及（v）情绪变化和潜在神经网络之间的功能关系。这些发现表明，超短周期糖皮质激素节律的模式可能会影响非应激条件下的认知心理生理学，并为我们理解皮质醇脉动的神经心理影响开辟了新的途径，这与优化糖皮质激素替代策略的目标有关。
