A two-night comparison in the sleep laboratory as a tool to challenge the relationship between sleep initiation, cardiophysiological and thermoregulatory changes in women with difficulties initiating sleep and thermal discomfort.

Cardiovascular and thermophysiological changes accompany the decision to fall asleep. A relationship between core body temperature and heart rate variability (HRV) especially during the sleep onset episode is suggested, but only few data are available, investigating a relationship between skin temperature and HRV at this time span. This study was aimed to elucidate the pattern of body temperature (i.e. distal and proximal skin temperature), heart rate and its variability in a specific population of ten healthy women having both, thermal discomfort from cold extremities and difficulties initiating sleep for two subsequent nights in the laboratory. Furthermore, changes in sleep, temperature or cardiac regulation were examined after 16-h of constant posture conditions. Due to a faster decline of arousals, the build-up of sleep stage 2, slow wave sleep and hence delta power is promoted in the second night compared to the first. Both, proximal and distal skin temperatures show an increase after lights out. Distal skin temperature around lights out is already higher during the second night. Proximal skin temperature starts at the same temperature level for both nights but was significantly reduced in the second hour after lights out during the second night. The distal-proximal skin temperature gradient (DPG), as a measure for distal dilatation of the skin vasculature, starts with a lower level after lights out in the first night, compared to the second. Different dynamics and differences between the two nights in skin temperature or sleep variables, but not in heart rate and HRV variables were found during the sleep initiation episode. Thus, a direct causality between these functions seems rather unlikely in the present study sample. The described differences between both nights might occur from delayed relaxation, reflected in a slower decrease of arousals, prolonged sleep onset latency and a lower DPG at the first night. Especially the latter finding confirms nicely the statement that warm extremities promote a rapid onset of sleep.

Resting energy expenditure in vasospastic subjects and its potential relevance in glaucoma.

BACKGROUND: Peripheral vasospastic syndrome is frequently encountered in normal tension glaucoma patients. We tested the hypothesis as to whether peripheral vascular spastic tendency is due to an attempt to preserve body heat in subjects with reduced resting energy expenditure. PATIENTS AND METHODS: Twenty healthy non-smoking female individuals were enrolled into the study. Subjects were classified as having vasospasm (10 subjects) if they related a clear history of frequent cold hands, and as normal subjects (10 subjects) if they denied such a history. Sample size calculation was based on a power of 80 % to find a difference of 20 %. Resting energy expenditure (REE) was assessed by indirect calorimetry and corrected for fat-free mass (FFM), which was assessed by bioelectric impedance analysis. RESULTS: REE was 1198 +/- 155 kilocalories (kcal) in vasospastics and 1169 +/- 122 in controls (Mann-Whitney U-test: p = 0.62). FFM was 39.6 +/- 3.3 kg in vasospastics and 41.1 +/- 2.3 kg in controls (Mann-Whitney U-test: p = 0.16). REE adjusted for FFM was 30.2 +/- 2.5 kcal/kg in vasospastics and 28.4 +/- 2.3 kcal/kg in controls (Mann-Whitney U-test: p = 0.08). CONCLUSIONS: Peripheral vasospastic syndrome seems not to be a secondary response to insufficient resting energy expenditure. The results of the present study rather indicate an opposite tendency which deserves further investigation.

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.

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.

Assisted suicide as conducted by a "Right-to-Die"-society in Switzerland: a descriptive analysis of 43 consecutive cases.

BACKGROUND AND METHODS: The Swiss "Right-to-Die"-society EXIT enables assisted suicide by providing terminally ill members with a lethal dosage of barbiturates on request. This practice is tolerated by Swiss legislation. EXIT insists on its assumption that people with serious illness and suffering have the competency to take such a decision. The case of two patients who committed suicide a short time after their release from a psychiatric clinic raised some doubts about the practice of EXIT. The files of all 43 cases of suicide assisted by EXIT between 1992 and 1997 in the region of Basle kept in the Institute of Forensic Medicine were examined for accuracy of the medical data. This sample was compared for age, gender-ratio and prior psychiatric treatment with 425 ordinary suicides in the same region. An attempt was made to assess whether only terminally ill and people with intolerable suffering had been assisted with suicide and what efforts EXIT had made to rule out psychiatric illnesses or poor social conditions as the reason for the wish to die. RESULTS: A medical report of the treating doctor(s) was in the files in only five cases. The "EXIT" cases where older than the "ordinary"-sample. Among those over 65 years old there were almost twice as many women as men. 16 of the 24 women older than 65 years were widowed. There were 20 cases of cancer; but in eleven cases medical files revealed no apparent medical condition to explain a death-wish. Five of the patients declared a social loss or fear of such loss as the reason for their wish to die. Six persons had formerly been in psychiatric care, though this was not mentioned in the files. CONCLUSIONS: Due to the scarcity of information in the files as regards previous palliative care, the high proportion of old women and the high percentage of people not suffering from a terminal illness compared to the literature we conclude that psychiatric or social factors are not an obstacle for EXIT to assist with suicide.

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.

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.

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.

Serum iron and ferritin in acute neuroleptic akathisia.

Acute akathisia is a common and disturbing side effect of classic antipsychotic medication. Some evidence suggests a role for iron deficiency in chronic and tardive akathisia. In acute akathisia, however, the data are contradictory. Serum iron and ferritin levels of 33 inpatients with acute akathisia during classic neuroleptic medication were compared with those of 23 patients on classic neuroleptics without this side effect. Akathisia was rated by means of the Hillside Akathisia Scale. The groups were balanced for age (mean 38.5+/-14.5), medication (butyrophenone- and phenothiazine-derived neuroleptics) and diagnosis (schizophrenia, schizoaffective disorder, psychotic affective disorder). Patients with acute akathisia had significantly lower serum ferritin levels than the patients in the control group. However, the ferritin (56. 94+/-39.54 ng/ml) and iron (88.52+/-40.0 mg/dl) levels in these patients were within the normal range (ferritin 30-300 ng/dl, iron 80-180 mg/dl). No correlations between serum iron or ferritin and akathisia ratings could be found. Although some reduction in serum ferritin was found in patients with acute akathisia compared to patients without akathisia, the difference was small and the ferritin levels were within the range of the normal population. These findings suggest a minor role for iron deficiency in acute akathisia.

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.

Functional link between distal vasodilation and sleep-onset latency?

Thermoregulatory processes have long been implicated in initiation of human sleep. The purpose of this study was to evaluate the role of heat loss in sleep initiation, under the controlled conditions of a constant-routine protocol modified to permit nocturnal sleep. Heat loss was indirectly measured by means of the distal-to-proximal skin temperature gradient (DPG). A stepwise regression analysis revealed that the DPG 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). This study provides evidence that selective vasodilation of distal skin regions (and hence heat loss) promotes the rapid onset of sleep.

Alzheimer's disease, depression and normal ageing: merit of simple psychomotor and visuospatial tasks.

INTRODUCTION: A brief psychometric test battery was used to differentiate Alzheimer's disease (AD) patients from patients with depression and healthy age-matched control subjects. The purpose was to investigate the discriminative value of simple psychomotor and visuospatial tasks that were implemented in a computer-assisted test battery. METHODS: Manumotoric coordination, discrimination reaction time and performance on a visuospatial pattern-matching task were assessed. Subjects were 30 patients with the diagnosis of probable AD (mild to moderate), 22 patients with a major depression and 15 healthy normal control subjects. RESULTS: Discrimination reaction time separated the three groups most distinctly, but general level of cognitive functioning was a significantly confounding variable. There were no differences between the AD and the depressed patients when the MMSE was used as a covariate. Substantial deficiencies in manumotoric coordination were found in both demented and depressed patients. The visual pattern-matching task yielded longer reaction times in both patient groups than in the control group. CONCLUSION: Translated into neuropsychological terms, these data suggest deficiencies in basic central operations, a slowing of central information processing and attentional deficits in AD and depressed patients. Psychomotor tasks were able to distinguish effectively healthy elderly persons from AD and depressed patients. This test battery, however, appears to be limited in differentiating AD from depression.

ELISA-quantitation of phosphorylated tau protein in the Alzheimer's disease brain.

A reliable, sensitive and specific sandwich ELISA for the quantitation of paired helical filament (PHF) tau in human brain was developed using well-defined monoclonal antibodies. We examined rapid-autopsy-derived brain tissue from 21 neuropathologically confirmed Alzheimer's disease (AD) patients and 14 nondemented controls, matched for age, sex and postmortem delay times. We demonstrated significant elevations of phosphorylated tau levels in the frontal and parietal cortex as well as in the hippocampus of AD patients as compared to the nondemented controls. No difference was observed in the cerebellum. Phosphorylated tau levels measured by ELISA were significantly correlated with the presence or absence of neurofibrillary tangles.