Homeostatic forces underlying the daily pattern of sleep propensity

Previous forced desynchrony studies have highlighted the close relationship between the circadian rhythms of core body temperature (CBT) and sleep propensity. In particular, these studies have shown that a “forbidden zone” for sleep exists on the rising limb of the CBT rhythm. In these previous studies, the length of the experimental day was either ultrashort (90 min), short (20 h), or long (28 h), and the ratio of sleep to wake was normal (i.e., 1:2). The aim of the current study was to examine the relative effects of the circadian and homeostatic processes on sleep propensity using a 28-h forced desynchrony protocol in which the ratio of sleep to wake was substantially lower than normal (i.e., 1:5). Twenty-seven healthy males lived in a time-isolation sleep laboratory for 11 consecutive days. Participants completed either a control (n = 13) or sleep restriction (n = 14) condition. In both conditions, the protocol consisted of 2 × 24-h baseline days followed by 8 × 28-h forced desynchrony days. On forced desynchrony days, the control group had 9.3 h in bed and 18.7 h of wake, and the sleep restriction group had 4.7 h in bed and 23.3 h of wake. For all participants, each 30-s epoch of time in bed was scored as sleep or wake based on standard polysomnography recordings, and was also assigned a circadian phase (360° = 24 h) based on a cosine equation fitted to continuously recorded CBT data. For each circadian phase (i.e., 72 × 5° bins), sleep propensity was calculated as the percentage of epochs spent in bed scored as sleep. For the control group, there was a clear circadian rhythm in sleep propensity, with a peak of 98.5% at 5° (∼05:20 h), a trough of 64.9% at 245° (∼21:20 h), and an average of 82.3%. In contrast, sleep propensity for the sleep restriction group was relatively high at all circadian phases, with an average of 96.7%. For this group, the highest sleep propensity (99.0%) occurred at 60° (∼09:00 h), and the lowest sleep propensity (91.3%) occurred at 265° (∼22:40 h). As has been shown previously, these current data indicate that with a normal sleep-to-wake ratio, the effect of the circadian process on sleep propensity is pronounced, such that a forbidden zone for sleep exists at a phase equivalent to evening time for a normally entrained individual. However, these current data also indicate that when the ratio of sleep to wake is substantially lower than normal, this circadian effect is masked. In particular, sleep propensity is very high at all circadian phases, including those that coincide with the forbidden zone for sleep. This finding suggests that if the homeostatic pressure for sleep is sufficiently high, then the circadian drive for wakefulness can be overridden. In future studies, it will be important to determine whether or not this masking effect occurs with less severe sleep restriction, e.g., with a sleep-to-wake ratio of 1:3. (Author correspondence: charli.sargent@cqu.edu.au)

Somatic reflex response-reversal of reticular origin

Electrophysiology of the frontal granular cortex. II. Patterns of spontaneous discharges of impulses of neurons in the cortex through states of sleep and wakefulness in the monkey

Prolongation of the Q-T interval in man during sleep

Switches between global sleep and wakefulness states are believed to be dictated by top-down influences arising from subcortical nuclei. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterized by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation, an Ile102Asn substitution in the synaptic vesicular protein, VAMP2, was associated with morphological synaptic changes and specific behavioral deficits, while in vitro electrophysiological investigations with fluorescence imaging revealed a markedly diminished probability of vesicular release in mutants. Our data show that global shifts in the synaptic efficiency across brain-wide networks leads to an altered probability of vigilance state transitions, possibly as a result of an altered excitability balance within local circuits controlling sleep-wake architecture.

Understanding the detection of salient auditory stimuli by the deep layer of the superior colliculus (dSC) during REM and NREM sleep offers valuable insights into the neurophysiological mechanisms of state-dependent auditory information processing. We recorded local field potentials (LFP) from dSC, electrocorticogram (ECoG) from frontal/parietal cortical regions, and neck electromyogram (EMG) in freely moving rats during sleep and awake states under oddball paradigm auditory stimulations. Our analysis focused on mismatch negativity (MMN) responses and event-related spectral perturbation (ERSP) in slow gamma (30-60 Hz) activity (SGA) and medium gamma (60-95 Hz) activity (MGA) frequency bands in wakefulness, REM and NREM sleep using three different intensities (35-, 55-, 80-dB) of stimulation. Data were analysed using repeated-measure two-way ANOVA and Linear Mixed Model. We found that the dSC exhibited significantly increased MMN responses to salient auditory stimuli across nearly all conditions (p < 0.05), specifically in REM, compared to other vigilance states. Additionally, stimulus intensity in pure tone experiments significantly enhances the MMN peak amplitude (p < 0.0001). The dSC further illustrated state-dependent spectral dynamics: SGA (30-60 Hz) ERSP substantially increased in NREM (p < 0.0001), while MGA (60-95 Hz) ERSP increased in both REM/NREM significantly (p < 0.001). These findings demonstrate that the dSC, a key node within the auditory processing network, retains robust auditory salience detection in sleep states.

Foreword

The objective of this study is to characterize the effects of the sleep-wake cycle on neurovascular and behavioral characteristics of cortical spreading depression (CSD). There is an important bi-directional relationship between migraine and the sleep-wake cycle, but the basic mechanisms of this relationship are poorly understood. We have developed a minimally invasive microchip system to continuously monitor cerebral blood volume (CBV) with optical intrinsic signal (OIS), head movement, and multiple other physiological and behavioral parameters in freely behaving mice over weeks. Behavior is also monitored with simultaneous video recording. This system can also be used to intermittently trigger and record CSD and accompanying neurovascular and behavioral responses. CSD was triggered optically in different stages of the sleep-wake cycle. The optical stimulus threshold to trigger CSD was significantly higher in the wake state compared to sleep (stimulation duration=16.4±9.7s vs. 10.8±5.8s, p=0.037, n=6mice). CSD evoked in the wake versus sleep state produced changes in CBV that were smaller (largest relative change -4.5±5.0% ∆OIS vs. -14.3±8.5% ∆OIS, p=0.001) and shorter in duration (33:22±6:37 vs. 49:42±8:05min:s, p=0.012, n=6mice). The threshold for CSD and kinetics of associated CBV changes were correlated with the time since falling asleep or awakening (n=47 CSDs in 6mice). CSD triggered in the wake state was associated with a transient freezing behavior. CSD triggered during sleep typically caused a transient awakening and behavioral response. This was followed by a return to sleep until recovery from the sustained phase of decreased CBV that occurred 30-60min later, at which time there was consistent awakening with behaviors similar to those that occurred at CSD onset. CSD triggered in the wake state evoked a transient decrease in heart rate (from 11.9±0.8 to 9.6±0.8Hz, p=0.002, n=5), whereas when triggered in the sleep state there was a transient increase in HR (from 7.5±0.4Hz to 9.3±1.1Hz, p=0.016, n=5). The sleep-wake cycle has significant effects on CSD that may have relevance to the clinical presentations of migraine and brain injury.

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.

Abnormal Sleep Architecture and Hippocampal Circuit Dysfunction in a Mouse Model of Fragile X Syndrome

Opioids are important for pain management but have the unwanted side effect of sleep disruption in humans ( Sleep Med Clin 13:271, 2018), rats ( Sci Rep 9:14122, 2019), and mice ( Neurosci Abstr Onlin e 502.02, 2019). Dose‐response data are needed for efforts to develop countermeasures to the undesired effects of opioids. Therefore, this study is testing the hypothesis that the sleep‐disrupting effects of opioids are dose dependent. Experiments were conducted in accordance with the FASEB Statement of Principles for the use of Animals in Research and Education. Adult male B6 mice (n=8) were housed in a temperature‐ and humidity‐controlled environment and 12:12h light:dark cycle. Mice were implanted with telemeters (DSI HD‐X02) to record cortical electroencephalogram (EEG) and neck muscle electromyogram. These measures made it possible to objectively quantify the effects of opioids on states of wakefulness, rapid eye movement (REM) sleep, and non‐REM (NREM) sleep. One week after recovery from surgery, each mouse began receiving subcutaneous injections (0.3 mL) within 60 min of light onset. States of sleep and wakefulness were recorded for 4 h after each injection. Repeated injections into the same mouse were separated by 3 or 4 days. Saline (vehicle control) was followed by increasing, half log doses (mg/kg) of morphine (0.01 to 30) or fentanyl (0.001 to 3). Every 10 s of each 4‐h recording was scored by two individuals, one of whom was blinded to the treatment condition. Sleep scoring concordance between the scorers was &gt;90%. Data were analyzed using repeated measures ANOVA and Tukey's multiple comparisons test (GraphPad Prism V9). Morphine (F (8, 56) = 104.4, p &lt;0.0001) and fentanyl (F (8, 56) = 94.65, p &lt; 0.0001) dose‐dependently increased wakefulness, decreased NREM sleep (F (8, 56) = 110.2, p &lt;0.0001; F (8, 56) = 96.30, p &lt; 0.0001) and decreased REM sleep (F (8, 56) = 34.00, p &lt;0.0001; F (8, 56) = 51.80, p &lt;0.0001). The lowest dose of morphine that significantly increased wakefulness and decreased NREM sleep was 1 mg/kg (p = 0.04, p = 0.03); and 3 mg/kg for decreasing REM sleep (p = 0.0004). For fentanyl, the lowest dose that significantly increased wakefulness and decreased NREM and REM sleep was 0.3 mg/kg (p = 0.001; p = 0.0016; p = 0.0007). Higher doses of morphine and fentanyl eliminated NREM and REM sleep. Both opioids also significantly and differentially altered EEG power during wakefulness (see companion abstract by O’Brien et al.). Nonlinear regression was used to calculate the half‐maximal dose (mg/kg) for increasing wakefulness (ED 50 ) and inhibiting sleep (ID 50 ). ED 50 and ID 50 data were used to compare drug potency. Morphine ED 50 was 2.2 to increase wakefulness, ID 50 2.3 to decrease NREM sleep, and 1.3 to decrease REM sleep. Fentanyl ED 50 was 0.2 to increase wakefulness, ID 50 0.2 to decrease NREM sleep, and 0.1 to decrease REM sleep. These data demonstrate that opioid‐induced sleep disruption is dose‐dependent, and that fentanyl is more potent than morphine to disrupt sleep.

ABSTRACT‘How much sleep does one need?’ is a critical question that has been difficult to answer. The long history of sleep research has culminated in population‐derived normative values of 7 to 9 h of sleep per night to avoid dysfunction. Such a wide range is sufficiently large that one cannot know what is required for any given individual. ‘Sleep need’ cannot currently be directly measured, might not be represented by one number (given the multiple functions that sleep subserves), and likely varies from individual‐to‐individual and from day‐to‐day. This said, the concept should be embraced and can be considered alongside more easily operationalised and routinely measured constructs of ‘sleep opportunity’ (e.g., time in bed) and ‘sleep ability’ (i.e., the obtained sleep, such as sleep duration). Considering the dynamics of all three constructs together may drive greater understanding about sleep health, sleep insufficiency, and sleep disorder pathology. In this article, we describe a new theory called Sleep Opportunity, Need, and Ability and provide a rationale for why this theory has both theoretical and clinical value.

Primary central alveolar hypoventilation (CAHV) is a rare disorder described in newborns, children, and adults. We report a 2 9/12 year old child with CAHV of unknown etiology. The evaluation of her ventilatory control system showed abnormalities awake and in the different sleep states. Hypoventilation was found to be more severe during non-REM sleep than during REM sleep and awake state. She had central apnea, an irregular respiratory rhythm in the non-REM sleep too, and diminished ventilatory response to inhaled 5%-6% CO2 in both REM and non-REM sleep. Her ventilation decreased when she was breathing 50% and 100% oxygen. During breathing 15% oxygen she did not arouse in spite a transcutaneous pO2 of 10 mmHg. She was first treated with mechanical ventilation during sleep and has now received bilateral simultaneous phrenic pacemaker support during quiet sleep for about one year. With the phrenic pacemaker she has normal minute volume and transcutaneous blood gases during sleep. During a respiratory infection she needed again mechanical ventilation via her tracheostoma 24 hours a day for one week. This case of a CAHV demonstrates a dysfunction of the central and partially also of the peripheral chemoreceptors. The abnormalities of the ventilation were demonstrable not only in the non-REM sleep but also in the REM sleep and awake state.

The purpose of this study is to detect the characteristic features of the oscillatory electrical activity of the brain in early postnatal development, depending on the gestational age of newborns. Methods. The study is based on automatic processing of clinical data from electroencephalography of newborns on the third day after birth. Behavioral characteristics assessed periods of sleep and wakefulness, without a precise division into stages of sleep and various states of wakefulness. The processing of multichannel electroencephalography signals was carried out on the basis of the method of modifying the continuous wavelet transform (CWT), which makes it possible to estimate the average characteristics of the number, duration and energy of oscillatory components (patterns) developing in different frequency ranges. Results. A paradoxical picture has been demonstrated describing the state of sleep and wakefulness in weakly preterm infants. For this group of children, the number and average energy of patterns detected in the frequency ranges from 1 to 20 Hz behave in a reflected way during sleep compared to children born at the usual time. At the same time, the average duration of oscillatory patterns remains unchanged. Conclusion. In the first days of a child’s life, it is possible to detect significant differences in the activity of the brain of newborns with slightly different gestational age during sleep/wake behavioral states. Quantitative estimates of the parameters of oscillatory CWT patterns are promising for use as the basis for systems for automatic processing of neonatal brain activity, additional to amplitude electroencephalography estimates. Such systems may be relevant for the search for early signs of anomalies in the development of the central nervous system.

Do all animals sleep?