Challenging the sleep homeostat: sleep in depression is not premature aging.

OBJECTIVES: The close relationship between major depression and sleep disturbances led to the hypothesis of a deficiency in homeostatic sleep pressure in depression (S-deficiency hypothesis). Many observed changes of sleep characteristics in depression are also present in healthy aging, leading to the premise that sleep in depression resembles premature aging. In this study, we aimed at quantifying the homeostatic sleep-wake regulation in young women with major depression and healthy young and older controls under high sleep pressure conditions. METHODS: After an 8-h baseline night nine depressed women, eight healthy young, and eight healthy older women underwent a 40-h sustained wakefulness protocol followed by a recovery night under constant routine conditions. Polysomnographic recordings were carried out continuously. Sleep parameters as well as the time course of EEG slow-wave activity (SWA) (EEG spectra range: 0.75-4.5 Hz), as a marker of homeostatic sleep pressure, were analyzed during the recovery night. RESULTS: Young depressed women exhibited higher absolute mean SWA levels and a stronger response to sleep deprivation, particularly in frontal brain regions. In contrast, healthy older women exhibited not only attenuated SWA values compared to the other two groups, but also an absence of the frontal SWA predominance. CONCLUSIONS: Homeostatic sleep regulation and sleep architecture in young depressed women are not equal to premature aging. Moreover, our findings demonstrate that young moderately depressed women exhibit no deficiency in the sleep homeostatic process S as predicted by the S-deficiency hypothesis, but, rather, live on an elevated level of homeostatic sleep pressure.

[Depression during pregnancy and its treatment]. / Schwangerschaftsdepression und deren Behandlung.

Approximately 11% of pregnant women suffer from major depression which requires treatment and if left untreated there are risks of preterm delivery or low birth weight. The initial difficulty lies in diagnosing the depression itself, as many symptoms of depression can be ascribed to the pregnancy. A further challenge is choosing the appropriate therapy. Treatment options are psychotherapy, antidepressants, electroconvulsive therapy (ECT) or the new possibility of light therapy. A growing number of reports on the side effects of antidepressants in pregnancy have led to uncertainties as to how to proceed. Thus, choosing the most suitable treatment needs to be made together with the pregnant woman and a careful clarification of possible risks attendant on each treatment option is essential.

[Sleep and circadian rhythms in ageing]. / Schlaf und zirkadiane Rhythmik im Alter.

With age, the consolidation of nocturnal sleep decreases, daytime napping increases, and sleep occurs earlier. Sleep regulation is dependent on the interaction between a circadian pacemaker (biological clock) and the sleep homeostat (sleep pressure increasing with duration of time awake). We have shown that in the healthy elderly, the amplitude of circadian rhythms (e. g. melatonin secretion) declines, as does slow wave sleep, parallel with an increase in afternoon sleepiness and a tendency to fall asleep in the early evening when younger subjects do not. Light is the major zeitgeber to stabilise the biological clock: older subjects require sufficient light exposure during daytime and in the evening, and should take no or only brief naps during the day to improve sleep.

Transient short free running circadian rhythm in a case of aneurysm near the suprachiasmatic nuclei.

A free running circadian rest-activity cycle is rare in sighted individuals living in a normal environment. Even more rare is a periodicity shorter than 24 hours, as observed in actigraphic recordings in a female patient during convalescence after a whiplash injury in a car accident. The documented free running period was 22.5 hours for 19 days. During the subsequent weeks re-entrainment occurred following re-establishment by a social zeitgeber, with a slightly early circadian phase of nocturnal melatonin onset relative to a late sleep period. Magnetic resonance imaging and cerebral angiography showed an aneurysm at the bifurcation of the right internal carotid artery, close to the circadian pacemaker structure (the suprachiasmatic nuclei), which was later occluded.

Seasonality in affective disorders in Switzerland.

OBJECTIVE: To estimate the prevalence of seasonal affective disorder (SAD) and its subsyndromal form (S-SAD) in Switzerland (47 degrees N). METHOD: A representative sample from all three language areas of Switzerland (n = 980) were given a structured telephone interview using the extended Seasonal Pattern Assessment Questionnaire (SPAQ+). A smaller, but also representative sample in the city of Basel filled in the SPAQ+ form as well as undergoing a structured diagnostic interview. RESULTS: In this Swiss sample, 2.2% of the population presented with symptom severity of SAD, 8.9% with S-SAD. In Basel, a much higher prevalence of SAD was found. Seasonal problems occurred more often in patients with the Diagnostic and Statistical Manual (DSM)-III diagnosis of major affective disorders than in those with pure anxiety disorders or no psychiatric diagnosis. CONCLUSION: These estimates for SAD in Switzerland are similar to those found in the Zürich Study, using other methods, and for populations in the UK, with the limitations inherent in retrospective questionnaire studies.

Role of melatonin in the regulation of human circadian rhythms and sleep.

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.

Homeostatic control of slow-wave and spindle frequency activity during human sleep: effect of differential sleep pressure and brain topography.

The impact of a 40 h sleep deprivation versus a 40 h multiple nap paradigm on topographic and temporal aspects of electroencephalographic (EEG) activity during the subsequent recovery sleep was investigated in 10 young volunteers in a controlled 'constant posture' protocol. The accumulation of sleep pressure with extended wakefulness could be significantly attenuated by intermittent naps. The differential sleep pressure conditions induced frequency- and topographic-specific changes in the EEG slow wave range (0.5-5 Hz) and in the low (LSFA, 12.25-13.25 Hz) and high spindle frequency activity range (HSFA, 13.75-16.5 Hz) during non-REM sleep. The observed increase of EEG slow-wave activity (SWA) after high sleep pressure was significantly more pronounced in the fronto-central (Fz, Cz) than in the parieto-occipital (Pz, Oz) derivations. Low sleep pressure after the nap paradigm decreased SWA with an occipital predominance. Spindle frequency activity showed a dissimilar homeostatic regulation: HSFA was significantly decreased after high sleep pressure and increased after low sleep pressure, exclusively in the centro-parietal brain region (Cz, Pz). LSFA was significantly enhanced after both manipulations. The data indicate that EEG activity, in particular frontal SWA and centro-parietal HSFA, are under a clear sleep-wake-dependent homeostatic control and imply a reciprocal relationship in the homeostatic regulation of SWA and HSFA, which however shows different spatio-temporal aspects.

Melatonin MT-1-receptor immunoreactivity in the human eye.

AIM: To examine the distribution of melatonin 1a (MT1) receptors in the human eye. METHODS: Seven normal human eyes were examined by immunohistochemical staining of paraffin sections, using an anti-MT1 primary antibody and an ABC detection system. RESULTS: MT1 receptor immunoreactivity (MT1-IR) was detected primarily in the inner segments of rods and cones and in retinal ganglion cells. In addition, MT1-IR was present in the adventitia of retinal arteries and veins, including the papillary region, but absent in ciliary and choroidal vessels. Mild staining of corneal endothelial cells and keratocytes was observed in all but two eyes. CONCLUSION: MT1-IR is present in various ocular tissues with the highest density in photoreceptor cells and ganglion cells. The physiological function of these receptors deserves further investigation.

Circadian clues to sleep onset mechanisms.

Thermoregulatory processes have long been implicated in initiation of human sleep. A meta-analysis of studies carried out under the controlled conditions of a constant routine protocol followed by nocturnal sleep revealed that heat loss, indirectly measured by the distal-proximal skin temperature gradient, was the best predictor variable for sleep onset latency (compared with core body temperature or its rate of change, heart rate, melatonin onset, and subjective sleepiness ratings). The cognitive signal of "lights out" induced relaxation, with a consequent shift in heat redistribution from the core to the periphery (as measured by an abrupt increase in skin temperatures and a rapid fall in heart rate). These thermoregulatory changes took place before sleep onset: sleep itself had minor further effects. Thus, when the confounding, long-lasting masking effects of lying down are controlled for, circadian thermoregulation initiates sleep, but does not appear to play a major role in its maintenance.

Disturbed circadian rest-activity cycles in schizophrenia patients: an effect of drugs?

The circadian rest-activity cycle of schizophrenia patients stabilized for more than a year on monotherapy with a "classical" neuroleptic (haloperidol, flupentixol) or with the atypical neuroleptic clozapine was documented by continuous activity monitoring for 3-7 weeks. In this pilot study, the three patients treated with clozapine had remarkably highly ordered restactivity cycles, whereas the four patients on classical neuroleptics had minor to major circadian rhythm abnormalities. This is the first documentation of circadian rest-activity cycle disturbances in schizophrenia related to class of drug.

Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer's disease.

The pineal hormone melatonin has two major functions: as a transducer of the circadian day-night signal across the seasons, and as a vasoactive substance regulating cerebral circulation. The vasoconstrictive effects of melatonin have been postulated to be mediated by the melatonin 1a-receptor (MT1). The objective of this study was to provide the first immunohistochemical evidence for the localization of vascular MT1 in human control hippocampus compared to Alzheimer's disease (AD) patients, since regional blood flow impairments contribute to the neurodegenerative course of the disease. Both superficial and intrahippocampal arteries revealed MT1 immunoreactivity in adventitia in controls, which was distinctly increased in AD patients. The increased MT1 in AD may indicate a regulatory response to impaired melatonin levels in those patients, contributing to the regulation of cerebral circulation.

Dynamics of frontal EEG activity, sleepiness and body temperature under high and low sleep pressure.

The impact of sleep deprivation (high sleep pressure) vs sleep satiation (low sleep pressure) on waking EEG dynamics, subjective sleepiness and core body temperature (CBT) was investigated in 10 young volunteers in a 40 h controlled constant posture protocol. The differential sleep pressure induced frequency-specific changes in the waking EEG from 1-7 Hz and 21-25 Hz. Frontal low EEG activity (FLA, 1-7 Hz) during sleep deprivation exhibited a prominent increase as time awake progressed, which could be significantly attenuated by sleep satiation attained with intermittent naps. Subjective sleepiness exhibited a prominent circadian regulation during sleep satiation, with virtually no homeostatic modulation. These extremely different sleep pressure conditions were not reflected in significant changes of the CBT rhythm. The data demonstrate that changes in FLA during wakefulness are to a large extent determined by the sleep-wake dependent process with little circadian modulation, and reflect differential levels of sleep pressure in the awake subject.

Cold feet and prolonged sleep-onset latency in vasospastic syndrome.

People with vasospastic syndrome have cold hands and feet and abnormal vasoconstriction after local cold exposure. Normally there is a circadian rhythm of distal vasodilation, with onset in the early evening, which directly influences ability to fall asleep. We gave a sleep questionnaire to 32 patients with primary vasospastic syndrome and 31 healthy controls. People with vasospasticity had significantly prolonged sleep-onset latency both at onset of night-time sleep and after nocturnal disturbance. This prolonged latency could be associated with impaired capacity for distal vasodilation.

An underlying circannual rhythm in seasonal affective disorder?

A patient diagnosed with seasonal affective disorder (SAD) carried out prospective ratings of depression weekly for nearly a decade. A winter peak of depression and benzodiazepine intake was documented. However, over the years, the depressive episodes shifted toward spring in an apparent free-running circannual rhythm (periodogram peaks at 53 and 55 weeks). This patient may have an underlying seasonal propensity to depression no longer precisely entrained to environmental cues.

Early morning melatonin administration impairs psychomotor vigilance.

The acute soporific effect of melatonin in humans has been demonstrated in a range of studies. How alertness and performance are changed after melatonin given in the morning is not yet known. In a double-blind, placebo-controlled study of nine healthy young men, melatonin was given at 0700 h under controlled conditions of a modified constant routine protocol lasting 56 h (2 days, 3 nights with sleep). A clear decrement in neurobehavioral functions as measured by the Psychomotor Vigilance Test lasted for 6 h after melatonin administration (particularly in the lapse domain and median of the reaction time) without any effect on a letter cancellation task. A subjective soporific effect was present but less pronounced. Thus, melatonin taken in the morning requires caution in situations where high attention is needed.

Phase advance after one or three simulated dawns in humans.

A specially designed apparatus that can simulate the waveform of the dawn or dusk signal at any latitude and any day of the year has been shown to phase shift the circadian pacemaker in rodents and primates at a fraction of the illuminance previously used. Until recently, it was considered that rather high illuminances or rather long exposure episodes to room light were necessary to phase shift human circadian rhythms. This experiment shows that, under controlled conditions of a modified constant routine protocol, a single dawn signal is sufficient to phase advance the timing of the onset of secretion of the pineal hormone melatonin. The significant phase advance of salivary melatonin of 20 minutes, which is enhanced to 34 minutes after three consecutive dawn signals, is small, but appears to be of sufficient magnitude to entrain the human circadian pacemaker, which has an endogenous period of about 24.2h.

The human circadian pacemaker can see by the dawn's early light.

The authors' previous experiments have shown that dawn simulation at low light intensities can phase advance the circadian rhythm of melatonin in humans. The aim of this study was to compare the effect of repeated dawn signals on the phase position of circadian rhythms in healthy participants kept under controlled light conditions. Nine men participated in two 9-day laboratory sessions under an LD cycle 17.5:6.5 h, < 30:0 lux, receiving 6 consecutive daily dawn (average illuminance 155 lux) or control light (0.1 lux) signals from 0600 to 0730 h (crossover, random-order design). Two modified constant routine protocols before and after the light stimuli measured salivary melatonin (dim light melatonin onset DLMOn and offset DLMOff) and rectal temperature rhythms (midrange crossing time [MRCT]). Compared with initial values, participants significantly phase delayed after 6 days under control light conditions (at least -42 min DLMOn, -54 min DLMOff, -41 min MRCT) in spite of constant bedtimes. This delay was not observed with dawn signals (+10 min DLMOn, +2 min DLMOff, 0 min MRCT). Given that the endogenous circadian period of the human circadian pacemaker is slightly longer than 24 h, the findings suggest that a naturalistic dawn signal is sufficient to forestall this natural delay drift. Zeitgeber transduction and circadian system response are hypothesized to be tuned to the time-rate-of-change of naturalistic twilight signals.

EEG and subjective sleepiness during extended wakefulness in seasonal affective disorder: circadian and homeostatic influences.

BACKGROUND: Seasonal affective disorder (SAD) may reflect a disturbance of circadian phase relationships or a disturbance of sleep-wake dependent processes, both of which change daytime energy and sleepiness levels. METHODS: Under the unmasking conditions of a 40-hour constant routine protocol (CR), self-rated sleepiness and waking electroencephalogram (EEG) power density were assessed in women with SAD (n = 8) and in age-matched healthy control subjects (n = 9). RESULTS: There was no significant effect of season or light treatment in any of the measures. The time course of subjective sleepiness was characterized by a circadian modulation and an overall increase during extended wakefulness in both SAD patients and control subjects. A prominent circadian rhythm of subjective sleepiness was not different in SAD patients and control subjects; however, the progressive buildup of sleepiness, as quantified by nonlinear regression analysis, was significantly reduced in SAD patients, mainly because they were sleepier than control subjects during the first 12 hours of the CR. The time course of waking EEG theta-alpha activity showed a more rapid increase during the first 10 hours of the CR in SAD patients. In contrast to control subjects who showed a progressive increase in the course of the 40-hour episode of extended wakefulness, EEG theta-alpha activity in SAD patients did not further increase over the remainder of the CR. CONCLUSIONS: The data suggest that SAD patients may have a trait (rather than state) deficiency in the homeostatic buildup of sleep pressure during extended wakefulness as indexed by subjective sleepiness and EEG theta-alpha activity.