Vera Knoblauch

Age‐related Changes in the Circadian and Homeostatic Regulation of Human Sleep

The reduction of electroencephalographic (EEG) slow‐wave activity (SWA) (EEG power density between 0.75–4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non‐rapid eye movement (NREM) sleep consolidation reflects an age‐related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age‐related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency—the latter was phase‐advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age‐related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age‐related decrements in sleep and daytime alertness levels.

Encoding Difficulty Promotes Postlearning Changes in Sleep Spindle Activity during Napping

Learning-dependent increases in sleep spindle density have been reported during nocturnal sleep immediately after the learning session. Here, we investigated experience-dependent changes in daytime sleep EEG activity after declarative learning of unrelated word pairs. At weekly intervals, 13 young male volunteers spent three 24 h sessions in the laboratory under carefully controlled homeostatic and circadian conditions. At approximately midday, subjects performed either one of two word-pair learning tasks or a matched nonlearning control task, in a counterbalanced order. The two learning lists differed in the level of concreteness of the words used, resulting in an easier and a more difficult associative encoding condition, as confirmed by performance at immediate cued recall. Subjects were then allowed to sleep for 4 h; afterward, delayed cued recall was tested. Compared with the control condition, sleep EEG spectral activity in the low spindle frequency range and the density of low-frequency sleep spindles (11.25–13.75 Hz) were both significantly increased in the left frontal cortex after the difficult but not after the easy encoding condition. Furthermore, we found positive correlations between these EEG changes during sleep and changes in memory performance between pre-nap and post-nap recall sessions. These results indicate that, like during nocturnal sleep, daytime sleep EEG oscillations including spindle activity are modified after declarative learning of word pairs. Furthermore, we demonstrate here that the nature of the learning material is a determinant factor for sleep-related alterations after declarative learning.

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.

Circadian and wake-dependent modulation of fastest and slowest reaction times during the psychomotor vigilance task

Performance on the psychomotor vigilance task (PVT) sensitively reflects a circadian modulation of neurobehavioral functions, as well as the effect of sleep pressure developing with duration of time awake, without being confounded by a learning curve. Sixteen healthy volunteers underwent two 40-h constant posture protocols in a balanced crossover design. During these protocols, either low sleep pressure conditions were attained by an alternating cycle of 150 min of wakefulness and 75 min of sleep (NAP) protocol, or high sleep pressure conditions were achieved by total sleep deprivation (SD) protocol. During scheduled wakefulness in both protocols, the PVT was carried out every 225 min. Quantitative analysis of the lapses, slowest (90th percentile) and fastest (10th percentile) reaction times (RTs) during the protocols, indicated that the lapses and slowest RTs were sensitive to changes in homeostatic sleep pressure. Our data indicate that the difference between the fastest and slowest RTs (interpercentile range 10th-90th percentile) was particular sensitive to detect very early effects of growing sleep pressure. On the other hand, decrements in PVT performance which were related to circadian phase did not depend significantly on any categorization (such as percentiles of the RTs).

The frontal predominance in human EEG delta activity after sleep loss decreases with age.

Sleep loss has marked and selective effects on brain wave activity during subsequent recovery sleep. The electroencephalogram (EEG) responds to sleep deprivation with a relative increase in power density in the delta and theta range during non‐rapid eye movement sleep. We investigated age‐related changes of the EEG response to sleep deprivation along the antero‐posterior axis (Fz, Cz, Pz, Oz) under constant routine conditions. Both healthy young (20–31 years) and older (57–74 years) participants manifested a significant relative increase in EEG power density in the delta and theta range after 40 h of sleep deprivation, indicating a sustained capacity of the sleep homeostat to respond to sleep loss in ageing. However, the increase in relative EEG delta activity (1.25–3.75 Hz) following sleep deprivation was significantly more pronounced in frontal than parietal brain regions in the young, whereas such a frontal predominance was diminished in the older volunteers. This age‐related decrease of frontal delta predominance was most distinct at the beginning of the recovery sleep episode. Furthermore, the dissipation of homeostatic sleep pressure during the recovery night, as indexed by EEG delta activity, exhibited a significantly shallower decline in the older group. Activation of sleep regulatory processes in frontal brain areas by an extension of wakefulness from 16 to 40 h appears to be age‐dependent. These findings provide quantitative evidence for the hypothesis that frontal brain regions are particularly vulnerable to the effects of elevated sleep pressure (‘prefrontal tiredness’) and ageing (‘frontal ageing’).

Subjective Well-Being Is Modulated by Circadian Phase, Sleep Pressure, Age, and Gender

Subjective well-being largely depends on mood, which shows circadian rhythmicity and can be linked to rhythms in many physiological circadian markers, such as melatonin and cortisol. In healthy young volunteers mood is influenced by an interaction of circadian phase and the duration of time awake. The authors analyzed this interaction under differential sleep pressure conditions to investigate age and gender effects on subjective well-being. Sixteen healthy young (8 women, 8 men; 20-35 years) and 16 older volunteers (8 women, 8 men; 55-75 years) underwent a 40-h sleep deprivation (high sleep pressure) and a 40-h nap protocol (low sleep pressure) in a balanced crossover design under constant routine conditions. Mood, tension, and physical comfort were assessed by visual analogue scales during scheduled wakefulness, and their average formed a composite score of well-being. Significant variations in well-being were determined by the factors “age,” “sleep pressure,” and “circadian phase.” Well-being was generally worse under high than low sleep pressure. Older volunteers felt significantly worse than the young under both experimental conditions. Significant interactions were found between “sleep pressure” and “age,” and between “sleep pressure” and “gender.” This indicated that older volunteers and women responded with a greater impairment in well-being under high compared with low sleep pressure. The time course of well-being displayed a significant circadian modulation, particularly in women under high sleep pressure conditions. The results demonstrate age- and/or gender-related modifications of well-being related to sleep deprivation and circadian phase and thus point to specific biological components of mood vulnerability.

Human sleep spindle characteristics after sleep deprivation.

OBJECTIVE Sleep spindles (12-15 Hz oscillations) are one of the hallmarks of the electroencephalogram (EEG) during human non-rapid eye movement (non-REM) sleep. The effect of a 40 h sleep deprivation (SD) on spindle characteristics along the antero-posterior axis was investigated. METHODS EEGs during non-REM sleep in healthy young volunteers were analyzed with a new method for instantaneous spectral analysis, based on the fast time frequency transform (FTFT), which yields high-resolution spindle parameters in the combined time and frequency domain. RESULTS FTFT revealed that after SD, mean spindle amplitude was enhanced, while spindle density was reduced. The reduction in spindle density was most prominent in the frontal derivation (Fz), while spindle amplitude was increased in all derivations except in Fz. Mean spindle frequency and its variability within a spindle were reduced after SD. When analyzed per 0.25 Hz frequency bin, amplitude was increased in the lower spindle frequency range (12-13.75 Hz), whereas density was reduced in the high spindle frequency range (13.5-14.75 Hz). CONCLUSIONS The observed reduction in spindle density after SD confirms the inverse homeostatic relationship between sleep spindles and slow waves whereas the increase in spindle amplitude and the reduction in intra-spindle frequency variability support the hypothesis of a higher level of synchronization in thalamocortical cells when homeostatic sleep pressure is enhanced.

Haloperidol disrupts, clozapine reinstates the circadian rest-activity cycle in a patient with early-onset Alzheimer disease.

Measurement of the circadian rest-activity cycle in a patient with early-onset Alzheimer disease for 555 days revealed marked changes in the timing and amount of nocturnal activity. After neuroleptic medication was changed to haloperidol, the rest-activity cycle became completely arrhythmic for two months, concomitant with a marked worsening of cognitive state. Circadian integrity returned together with clinical improvement when the patient was subsequently treated with clozapine. This observation suggests that the known tendency for patients with Alzheimer disease to develop sleep-wake cycle disturbances may be aggravated by a classic neuroleptic; in contrast, the atypical neuroleptic clozapine may consolidate it. Similar observations in schizophrenic patients indicate that this chronobiological finding is drug-and not illness-related.

Regional differences in the circadian modulation of human sleep spindle characteristics

Electroencephalographic oscillations in the sleep spindle frequency range (11–16 Hz) are a key element of human nonrapid eye movement sleep. In the present study, sleep spindle characteristics along the anterior–posterior axis were analysed during and outside the circadian phase of melatonin secretion. Sleep electroencephalograms were recorded during naps distributed over the entire circadian cycle and analysed with two different methodological approaches, the classical fast Fourier transform in the frequency‐domain and a new method for instantaneous spectral analysis, the fast time frequency transform that yields high‐resolution parameters in the combined time‐frequency‐domain. During the phase of melatonin secretion, spindle density was generally increased and intraspindle frequency variation reduced. Furthermore, lower spindle frequencies were promoted: peak frequencies shifted towards the lower end of the spindle frequency range, and spindle amplitude was enhanced in the low‐frequency range (11–14.25 Hz) and reduced in the high‐frequency range (∼14.5–16 Hz). The circadian variation showed a clear dependence on brain topography such that it was maximal in the parietal and minimal in the frontal derivation. Our data provide evidence that the circadian pacemaker actively promotes low‐frequency sleep spindles during the biological night with a parietal predominance.

Decline in Long-Term Circadian Rest-Activity Cycle Organization in a Patient with Dementia

Continuous measurement of the circadian rest-activity cycle for 598 days in a demented patient with probable Alzheimers disease revealed slow progressive changes in temporal organization until death. Circadian and sleep analysis of the actigraphic data provided objective documentation of the gradual insertion of wakefulness into rest and rest into wake periods. Pacing, a nonphotic zeitgeber strengthening, led to improved synchronization of the rest-activity cycle. (J Geriatr Psychiatry Neurol 2002; 15:55-59).