1. Sleep Deprivation Alters the Ultradian Coupling between Waking EEG Arousal and HPA Axis Activity Florian CHAPOTOT 1, Alain BUGUET 2 and Gabrielle BRANDENBERGER 3 1 Unité de Neurophysiologie du Stress, Centre de Recherches du Service de Santé des Armées, Grenoble, France. 2 Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France. 3 Laboratoire des Régulations Physiologiques et des Rythmes Biologiques chez l'Homme, Faculté de Médecine, Strasbourg, France. Background: Temporal coupling between brain electrical and hypothalamo-pituitary adrenal (HPA) axis activities has been demonstrated in man during nocturnal and diurnal sleep (1), as well as during wakefulness (2). During sleep, electroencephalographic (EEG) slow wave activity (SWA: power in the 0.5-3.5 Hz frequency range), a marker of sleep depth, and cortisol release oscillate reciprocally, cortisol secretion being inversely related to SWA. During rested wakefulness, cortisol release exhibits a temporal association with ultradian rhythms in EEG arousal (3), cortisol secretory rates lagging by 10-min fluctuations in EEG power of the high frequency (13-35 Hz) range. These findings suggest that ultradian synchronisation between brain and neuroendocrine activation processes may play a functionally significant role in the maintenance of physiological homeostasis. Figure 1: Individual profiles of the frontal waking EEG gamma activity (20-45 Hz absolute power) and the concomitant cortisol secretory rate with the corresponding cross-correlation plots in five subjects during daytime wakefulness between 0900-1800h. Left side: individual profiles obtained after nocturnal sleep (S). Right side: individual profiles obtained during prolonged wakefulness (W). Time series are expressed in z-scores. Results: After nocturnal sleep, a systematic daytime temporal association between the HPA axis activity and the waking EEG activity was found in all individuals, cortisol secretory rate following changes in frontal gamma (20-45 Hz) band power with a 10-min delay (average R=0.458, p<0.001). Although this temporal association remained significant (average R=0.276, p<0.05), its strength was decreased significantly in the sleep deprivation condition (p<0.05, Wilcoxon test). Compared to baseline levels, there was a significant increase in daytime cortisol plasma level, secretory rate and pulse amplitude, as well as in waking EEG power of the delta (0.5-5.5 Hz), theta (5.5- 8.5 Hz) and gamma frequency bands (all p values <0.05, Student t-tests) after sleep deprivation. The sleep deprivation-related increases in cortisol secretory rate and frontal waking EEG gamma activity were quantitatively associated (R=0.504, p<0.05). Figure 2: Average (mean±SEM) cortisol secretory parameters between 2300-1800h (panel A) and waking EEG powers of the left frontal derivation between 0900-1800h (panel B) during the nocturnal sleep (S) and prolonged wakefulness (W) sessions. Significant differences (p<0.05, Student t- test) between the two experimental sessions are indicated by a black circle (  ). Figure 3: Linear regression between the amount of changes in daytime (0900- 1800h) cortisol release and frontal waking EEG powers across the nocturnal sleep (S) and prolonged wakefulness (W) sessions. Individual changes in cortisol plasma level, secretory rate and EEG power in the different frequency bands were determined in reference to the individual mean of the two sessions. Individual changes in the S session are represented by open circles (o) and those in the W session by asterisks (*). The best-fit line and regression coefficient are represented for significant associations only. Objective: The aim of this study was to assess the degree of ultradian coupling between brain electrical and HPA axis activities in a situation where homeostasis is challenged. For this purpose, we investigated the effect of one night of sleep deprivation on the previously described (1) relationship between waking EEG and HPA axis activities. In parallel, the sleep deprivation-related changes in waking EEG and HPA axis activities allowed the assessment of their quantitative mutual relationships. Protocol, Subjects & Methods: Ten healthy young men were studied between 0900-1800h under laboratory bed rest conditions. Two experimental sessions were conducted randomly, once after nocturnal sleep (S) and once during prolonged wakefulness (W), i.e., after one night of total sleep deprivation. A n estimation of cortisol secretory profiles was obtained by deconvolution of plasma RIA measures obtained from continuous blood withdrawal with regular sampling at 10-min interval. In parallel, s pectral analysis of serial waking EEG obtained from a 1-min spot fixation task repeated every 10-min was performed using the PRANA © software package (PhiTools ®, France; website download from http://www.phitools.com ). Statistical & time series analyses: Temporal and quantitative relationships were assessed using cross- correlation and linear correlation analyses on normalised data, respectively. According to the variable under study, condition effects were determined using either a parametric or a non-parametric statistical model. Conclusions: This study extends the idea that, under physiological conditions, synchronisation of ultradian rhythms is a key feature linking brain and neuroendocrine activation processes. In addition, sleep deprivation revealed a quantitative relationship between EEG arousal and HPA axis activity, resulting in a state of physiological “hyper- arousal” probably achieved to comply with the instruction to stay awake. The partial uncoupling between brain and neuroendocrine activation processes may reflect an early sign of deregulation. This hypothesis has now to be tested in stress-related pathological conditions. References: (1) Gronfier, C. Chapotot, F. Weibel, L. Jouny, C. and Brandenberger, G. Pulsatile cortisol secretion and EEG delta waves are controlled by two independent but synchronized generators. Am. J. Physiol., 1998, 275:E97-E100. (2) Chapotot, F. Gronfier, C. Jouny, C. Muzet, A. And Brandenberger, G. Cortisol secretion is related to electroencephalographic alertness in human subjects during daytime wakefulness. J. Clin. Endocrinol. Metab., 1998, 83:4263-4268. (3) Chapotot, F. Jouny, C. Muzet, A. Buguet, A. and Brandenberger, G. High frequency waking EEG: reflection of a slow ultradian rhythm in daytime arousal. Neuroreport. 2000, 11:2223-2227.