Circadian and homeostatic sleep-wake regulation in women : effects of age and major depressive disorder

Our intention with this work was to elucidate homeostatic and circadian aspects of sleep-wake regulation in women with respect to sleep phase preference during adolescence and its association with developmental stage as well as homeostatic and circadian sleep-wake regulation in major depression. The first part of this thesis covers an ambulatory study based on a cross-sectional chronotype survey among 1’187 females aged 5 to 51 years. We investigated the influence of age on sleep phase preference as well as its relationship to the onset of menarche, which served as physiological maturation marker. Our results confirm previous findings of age-dependent changes in sleep-wake behaviour as measured by chronotype changes. We found evidence for a new biological marker for the end of adolescence since our data point towards an abrupt change in the delayed sleep phase preference in women 5 years after the onset of menarche towards advancing the sleep-wake cycle. This heralds the beginning of adult-like sleep-wake behaviour in women. We found strong evidence for a circadian misalignment in adolescents as they experience a so-called social jet-lag between week and free days accounting for up to 3 hours at the nadir of the delayed sleep phase preference 5 years after menarche. This result is of particular importance since circadian misalignment of the sleep-wake timing and the circadian pacemaker may lead to impaired alertness and performance during wakefulness as well as to sleep disorders and depression. In the second part of this thesis we compared homeostatic and circadian aspects of sleep-wake regulation in young women suffering from a major depressive disorder with age-matched young healthy women and healthy older women under low and high sleep pressure under stringently controlled laboratory conditions (constant routine conditions). The study design comprised two study protocols starting with a 8-h baseline night and ending up with a 8-h recovery night. The time between these two nights (40 hours) either consisted of sustained wakefulness or 10 short sleep-wake cycles with alternating episodes of 75 min of sleep and 150 min of wakefulness. We investigated the sleep electroencephalogram (EEG; 0.75-25 Hz) during all scheduled sleep episodes and the homeostatic sleep response to enhanced and reduced sleep pressure by EEG slow-wave activity (SWA; spectral power in the 0.75-4.5 Hz range) during the recovery nights. Sleep analysis of the 10 nap episodes allowed to compare circadian modulation of the EEG spectra between the three groups as scheduled sleep episodes occurred at different circadian phase while constant low sleep pressure was controlled for. The homeostatic sleep pressure was overexpressed in young depressed women compared to both healthy control groups under high sleep pressure as well as under low sleep pressure conditions as indexed by significantly higher frontal EEG SWA during baseline and recovery nights. This result was endorsed by significantly enhanced subjective sleepiness in young depressed volunteers under low sleep pressure conditions and higher EEG SWA during the diurnal nap sleep episodes. A reduced melatonin amplitude in the depressed women compared to the healthy young volunteers was observed which implies a weaker signal output of the circadian pacemaker in depression. This evidence was substantiated by the occurrence of more EEG SWA during diurnal naps in depressed volunteers. In summary, this thesis provides several insights into circadian and homeostatic aspects of the sleep-wake cycle in women during maturation and in depression. We could establish an association between changes in circadian sleep phase preference during female adolescence and physiological maturation and gained insights in age-dependent female sleep-wake behaviour. Our findings have implications on possible actions in order to prevent social jet-lag in adolescents as such that a temporal delay in school start times should be equally dynamic as the sleep phase timing developments in adolescents. Our results on sleep-wake regulation in depression revealed higher levels of SWA in frontal brain areas together with an over-steering of the homeostatic response to alterations in sleep pressure levels together with a weakening of the circadian signal output. We could thus emphasize the misbalance of the opponent interaction between circadian and homeostatic sleep regulation in young moderately depressed women without major sleep disturbances, which may also have repercussions on the treatment of the illness in this endophenotype of depression. Therefore, selective slow-wave sleep and SWA deprivation and bright light therapy could lead to a readjustment of homeostatic and circadian sleep-wake processes and to mood improvement.