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

Abstract

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Improving glucocorticoid replacement profiles in adrenal insufficiency

“…Kalafatakis and colleagues recently undertook a double-blind randomized crossover study, in which they recruited 15 young males and implemented a 'block and replace' approach to cortisol using three distinct regimens to investigate the comparative effects of pulsatility on cognition, emotion and sleep. 45 These different patterns of cortisol oscillations also had differential effects on the fMRI and functional connectivity of the brain regions which process emotional responses (amygdala, dorsal striatum, insula and orbitofrontal cortex) -with parallel changes detected in attentional bias to, and recognition accuracy of emotional cues. 45 These data imply that oscillating levels of cortisol are important for physiological regulation of glucocorticoid receptors and postreceptor signalling in the brain and for the regulation of mood in man.…”

“…These different patterns of cortisol oscillations also had differential effects on the fMRI and functional connectivity of the brain regions which process emotional responses (amygdala, dorsal striatum, insula and orbitofrontal cortex) ‐ with parallel changes detected in attentional bias to, and recognition accuracy of emotional cues …”

“…However, the technological advances of new miniature nanopumps either external or with subcutaneous reservoirs will make pumps less intrusive. Kalafatakis and colleagues recently undertook a double‐blind randomized crossover study, in which they recruited 15 young males and implemented a ‘block and replace’ approach to cortisol using three distinct regimens to investigate the comparative effects of pulsatility on cognition, emotion and sleep . Participants had their endogenous cortisol secretion blocked using metyrapone and received 20 mg of hydrocortisone in three modalities: (1) a subcutaneous pulsatile mode to replicate the ultradian profile; (2) a subcutaneous continuous infusion; (3) oral thrice‐daily replacement, each for a five‐day period.…”

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy

“…37 Patients with secondary adrenal insufficiency reported a lower QoL, likely reflecting the contribution of hypopituitarism. 40 39 In addition, current regimens of glucocorticoid replacement therapy fail to replicate the ultradian cortisol rhythm which has recently been shown to be important for human cognition and behaviour.…”

“…39 In addition, current regimens of glucocorticoid replacement therapy fail to replicate the ultradian cortisol rhythm which has recently been shown to be important for human cognition and behaviour. 40…”