Non-rapid Eye Movement Sleep States Research Articles

State-dependent and region-specific alterations of cerebellar connectivity across stable human wakefulness and NREM sleep states

Sleep regulation and functioning may rely on systematic coordination throughout the whole brain, including the cerebellum. However, whether and how interactions between the cerebellum and other brain regions vary across sleep stages remain poorly understood. Here, using simultaneous EEG-fMRI recordings captured from 73 participants during wakefulness and non-rapid eye movement (NREM) sleep, we constructed cerebellar connectivity among intrinsic functional networks with intra-cerebellar, neocortical and subcortical regions. We uncovered that cerebellar connectivity exhibited sleep-dependent alterations: slight differences between wakefulness and N1/N2 sleep and greater changes in N3 sleep than other states. Region-specific cerebellar connectivity changes between N2 sleep and N3 sleep were also revealed: general breakdown of intra-cerebellar connectivity, enhancement of limbic-cerebellar connectivity and alterations of cerebellar connectivity with spatially specific neocortices. Further correlation analysis showed that functional connectivity between the cerebellar Control II network and regions (including the insula, hippocampus, and amygdala) correlated with delta power during N3 and beta power during N2 sleep. These findings systematically reveal altered cerebellar connectivity among intrinsic networks from wakefulness to deep sleep and highlight the potential role of the cerebellum in sleep regulation and functioning.

Effect of magnesium sulfate on baroreflex during acute hypoxemia in chronically instrumented fetal sheep.

To investigate the effects of magnesium sulfate on fetal baroreflex in normoxemia or acute fetal hypoxemia. Fetal baroreflex response was elicited using phenylephrine (30 μg) in saline and magnesium sulfate in 8 chronically treated and instrumented fetal sheep. Hypoxemia was induced using nitrogen gas inflow for 30 min. Baroreflex, calculated as the ratio of the fetal heart rate change to the mean arterial pressure, was monitored after magnesium sulfate administration and in rapid and nonrapid eye movement (NREM) sleep states. Baroreflex was assessed in response to hypoxemia in control groups in both the rapid and NREM sleep states. Baroreflex was not significantly affected by saline, magnesium sulfate and rapid or NREM sleep states in normoxemic sheep. Hypoxemia increased the baroreflex in the saline-treated group (hypoxemic vs normoxemic rapid eye movement sleep: 4.37 ± 2.48 vs 2.72 ± 0.83; P < 0.05; hypoxemic vs normoxemic NREM sleep: 4.30 ± 1.47 vs 3.15 ± 0.83; P < 0.001). Magnesium sulfate decreased the baroreflex in the hypoxemic fetuses (magnesium sulfate hypoxemic vs. control normoxemic fetuses: 1.42 ± 0.92 vs 3.15 ± 0.83, P < 0.05). The hypoxemic fetal sheep, from the ewes that were receiving magnesium sulfate, showed a significantly reduced in the baroreflex response. In clinical practice, baroreflex-related decelerations in hypoxemic fetuses of mothers receiving magnesium sulfate should be carefully interpreted.

Strong correlation of novel sleep electroencephalography coherence markers with diagnosis and severity of posttraumatic stress disorder

Objective biomarkers of the presence and severity of posttraumatic stress disorder (PTSD) are elusive, yet badly needed. Electroencephalographic (EEG) coherence represents a promising approach to identifying and understanding brain biomarker activity in PTSD. Overnight polysomnography data containing EEG across sleep and wake states was collected in n = 76 Veterans with and without PTSD from a single site under IRB approval. Brain coherence markers (BCM) were calculated from EEG signals using a novel approach to produce one index for PTSD diagnosis (PTSDdx), and another index for PTSD severity (PTSDsev). PTSDdx showed strong sensitivity to the presence of PTSD in the awake state, during non-rapid eye movement (NREM) stage N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. PTSDsev showed a strong correlation with PTSD symptom severity (using the PTSD Checklist 5, or PCL5 survey) in the awake state, during N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. Thus, sleep EEG-based brain coherence markers can be utilized as an objective means for determining the presence and severity of PTSD. This portable, inexpensive, and non-invasive tool holds promise for better understanding the physiological mechanisms underlying PTSD and for tracking objective responses to treatment.

Is Adenosine Action Common Ground for NREM Sleep, Torpor, and Other Hypometabolic States?

This review compares two states that lower energy expenditure: non-rapid eye movement (NREM) sleep and torpor. Knowledge on mechanisms common to these states, and particularly on the role of adenosine in NREM sleep, may ultimately open the possibility of inducing a synthetic torpor-like state in humans for medical applications and long-term space travel. To achieve this goal, it will be important, in perspective, to extend the study to other hypometabolic states, which, unlike torpor, can also be experienced by humans.

Atropine microdialysis within or near the pre-Bötzinger Complex increases breathing frequency more during wakefulness than during NREM sleep

Normal activity of neurons within the medullary ventral respiratory column (VRC) in or near the pre-Bötzinger Complex (preBötC) is dependent on the balance of inhibitory and excitatory neuromodulators acting at their respective receptors. The role of cholinergic neuromodulation during awake and sleep states is unknown. Accordingly, our objective herein was to test the hypotheses that attenuation of cholinergic modulation of VRC/preBötC neurons in vivo with atropine would: 1) decrease breathing frequency more while awake than during non-rapid-eye-movement (NREM) sleep and 2) increase other excitatory neuromodulators. To test these hypotheses, we unilaterally dialyzed mock cerebrospinal fluid (mCSF) or 50 mM atropine in mCSF in or near the preBötC region of adult goats during the awake (n = 9) and NREM sleep (n = 7) states. Breathing was monitored, and effluent dialysate was collected for analysis of multiple neurochemicals. Compared with dialysis of mCSF alone, atropine increased (P < 0.05) breathing frequency while awake during the day [+10 breaths (br)/min] and at night (+9 br/min) and, to a lesser extent, during NREM sleep (+5 br/min). Atropine increased (P < 0.05) effluent concentrations of serotonin (5-HT), substance P (SP), and glycine during the day and at night. When atropine was dialyzed in one preBötC and mCSF in the contralateral preBötC, 5-HT and SP increased only at the site of atropine dialysis. We conclude: 1) attenuation of a single neuromodulator results in local changes in other neuromodulators that affect ventilatory control, 2) effects of perturbations of cholinergic neuromodulation on breathing are state-dependent, and 3) interpretation of perturbations in vivo requires consideration of direct and indirect effects.

Assessing sleep state in calves through electrophysiological and behavioural recordings: A preliminary study

Adequate sleep is important for the health and well being of animals but we lack non-invasive methods to record sleep states from group-housed, freely-moving farm animals. We used electrophysiological data (electroencephalography; EEG, electromyography; EMG, and electro-oculography; EOG) to characterize sleep states in calves and examined how well observations of resting behaviour were correlated with the electrophysiological data. We obtained 20 h of EEG, EMG and EOG recordings from each of six pair-housed dairy calves using an ambulatory EEG recording device, while recording their resting posture via direct observation. Visual scoring of the electrophysiological data was used to distinguish between awake, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep during 30 s epochs. Calves were asleep for a mean (±S.D.) 25% (±2.0) of all observations in 50 (±22) bouts of 5 (±2) min per day. NREM sleep composed 55% (±7) and REM sleep 45% (±7) of the calves’ total sleep time. Both types of sleep occurred in short bouts of 2–3 min. According to electrophysiological data, calves were awake during 81% (±9) of the 30 s-epochs when the calf was standing or resting with its head lifted up and moving. Observations of “the calf resting head lifted up still” predicted 55% (±9) of the epochs of NREM sleep. The best behavioural predictor of REM sleep was “the calf resting with neck relaxed”, which predicted 61% (±9) of the epochs of REMS. The calves’ resting body postures can successfully be used to estimate calves’ total duration of time asleep and duration of time spent in REM and NREM sleep states. However, there was less success in estimating the time spent in the different phases of sleep during each 30 s epoch. Electrophysiological data can be recorded non-invasively from freely-moving, group-housed calves and observations of resting behaviour can identify when calves are asleep, although further work is needed to use behaviour to identify the phases of sleep.

Do neurotoxic lesions in rostral medullary nuclei induce/accentuate hypoventilation during NREM sleep?

Experimentally induced neuronal dysfunction in respiratory regions of the rostral medulla decrease breathing more in anesthetized mammals than in awake mammals. Sleep is similar to anesthesia in that excitatory inputs to respiratory neurons are reduced compared to the awake state; thus, we hypothesized that neurotoxic lesions in rostral medullary nuclei would, relative to wakefulness (WK), induce and/or accentuate hypoventilation during non-rapid eye movement (NREM) sleep. To test the hypothesis, goats were studied between 21:00 h and 03:00 h: (1) before and 30 days after chronically implanting microtubules bilaterally into the rostral medulla and, (2) 9-15 h and 2-17 days after unilateral injections of 100 nl to 1 microl, 50 mM ibotenic acid into the vestibular, gigantocellularis reticularis, or facial nuclei, or the retrotrapezoid nucleus/parapyramidal region. Arterial blood was repeatedly sampled in all studies during WK, and NREM and rapid eye movement (REM) sleep states. There was no significant (P>0.10) change in Pa(CO(2)) between WK and NREM sleep (and REM sleep when sufficient data were obtained) before or after implantation of microtubules and in studies after creating the neurotoxic lesions. Breathing frequency also did not significantly (P>0.10) differ between states in any of the studies. The data thus did not support the hypothesis. We speculate that in goats efficient compensatory mechanisms maintain Pa(CO(2)) homeostasis during normal sleep and the same and/or other mechanisms maintain homeostasis when excitatory drive is further reduced by lesions in rostral medullary nuclei.

Graded arousal responses in infants: advantages and disadvantages of a low threshold for arousal

Objective: To review studies of upper airway protective reflexes and other aspects of arousal from sleep. Methods: Discussion of pertinant physiological studies. Conclusions: Infant arousal from sleep incorporates two systems. The first comprises a group of periodically occurring reflexes serving cardiorespiratory homeostatic functions as well as providing for several aspects of normal growth and development. The second system is organized to respond to acute threats to survival during sleep. Both systems are integrated in a single arousal network originating in the brainstem. Full arousal occurs as a progression of events occurring sequentially and manifested by various innate motor and cardiovascular responses. During an arousal, rostral progression from brainstem to cortex is retarded by increasing inhibition which serves to decrease cortical arousals thereby preserving the integrity of rapid eye movement and non-rapid eye movement sleep states. Activation of brainstem arousal reflexes alone can cause recovery from obstruction sleep apnea episodes without the need for cortical arousal, a phenomenon more characteristic of infants than adults.

Circadian rhythms and sleep have additive effects on respiration in the rat.

1. We tested two hypotheses: that respiration and metabolism are subject to circadian modulation in wakefulness, non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM) sleep; and that the effects of sleep on breathing vary as a function of time of day. 2. Electroencephalogram (EEG), neck electromyogram (EMG) and abdominal body temperature (T(b)) were measured by telemetry in six male Sprague-Dawley rats. The EEG and EMG were used to identify sleep-wake states. Ventilation (V(I)) and metabolic rate (V(CO2)) were measured by plethysmography. Recordings were made over 24 h (12:12 h light:dark) when rats were in established states of wakefulness, NREM sleep and REM sleep. 3. Statistically significant circadian rhythms were observed in V(I) and V(CO2) in each of the wakefulness, NREM sleep and REM sleep states. Amplitudes and phases of the circadian rhythms were similar across sleep-wake states. 4. The circadian rhythm in V(I) was mediated by a circadian rhythm in respiratory frequency (f(R)). Tidal volume (V(T)) was unaffected by time of day in all three sleep-wake states. 5. The 24 h mean V(I) was significantly greater during wakefulness (363.5 +/- 18.5 ml min(-1)) than during NREM sleep (284.8 +/- 11.1 ml min(-1)) and REM sleep (276.1 +/- 13.9 ml min(-1)). V(CO2) and V(T) each significantly decreased from wakefulness to NREM sleep to REM sleep. f(R) was significantly lower in NREM sleep than in wakefulness and REM sleep. 6. These data confirm that ventilation and metabolism exhibit circadian rhythms during wakefulness, and NREM and REM sleep, and refute the hypothesis that state-related effects on breathing vary as a function of time of day. We conclude that the effects of circadian rhythms and sleep-wake state on respiration and metabolic rate are additive in the rat.

Non-linear electroencephalogram dynamics in patients with spontaneous nocturnal migraine attacks

The present study was conducted to examine non-linear electroencephalogram (EEG) measures during the development of a spontaneous migraine attack. We investigated the sleep EEG of five patients with migraine without aura in the pain-free interval and at the onset of a nocturnal attack. Sleep EEG recordings were analysed using the method of global dimensional complexity compared to conventional sleep scoring techniques. We found no divergence between classical sleep architecture and the estimated dimensional course nor any relevant short-term changes related to the onset of headache. There was, however, a loss of dimensional complexity in the first two non-rapid eye movement sleep states in the migraine night, with statistical significance during the second sleep cycle. For the first time, these results provide evidence of a global dimension decrease that is related to cortical network changes during a migraine attack.

Effects of long-term nocturnal nasal ventilation on spontaneous breathing during sleep in neuromuscular and chest wall disorders.

Nocturnal nasal intermittent positive pressure ventilation (NIPPV) is an effective means of normalizing awake blood gases in patients with respiratory insufficiency due to neuromuscular or chest wall dysfunction. However, little attention has been paid to the effects of long-term ventilation on spontaneous breathing during sleep in such patients. The purpose of this study was to determine whether spontaneous breathing during sleep improved after long-term nasal ventilation. Fourteen patients with documented nocturnal respiratory failure, who had been treated with nocturnal NIPPV for at least 6 months, were reviewed with an all night polysomnograph on a night without ventilatory support. The severity of nocturnal desaturation both in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep without nocturnal ventilation was compared to desaturation measured during the initial diagnostic study. Spontaneous daytime blood gas values (mean +/- SD) were significantly improved at follow-up compared to values obtained prior to nasal ventilation: arterial oxygen tension (Pa,O2): 7.5 +/- 1.2 to 10.2 +/- 1.3 kPa (p < 0.005); arterial carbon dioxide tension (Pa,CO2) 8.2 +/- 1.6 to 6.4 +/- 0.7 kPa (p < 0.001). Significant improvements in inspiratory muscle strength were also observed with maximal inspiratory pressure (Pl, max) increasing from a baseline value of 41 +/- 18 to 65 +/- 26% predicted measured prior to the night of ventilation withdrawal (p < 0.003). Spontaneous breathing during sleep after long-term treatment was markedly improved although still abnormal. During NREM sleep without ventilatory support, oxygen desaturation was significantly less severe compared to the initial study (arterial oxygen saturation (Sa,O2) 88 +/- 4 vs 78 +/- 8%; p < 0.001). Minimum Sa,O2 during REM sleep similarly improved from a mean value of 49 +/- 14% during the diagnostic night to 73 +/- 10% at review follow-up (p < 0.001). In 12 patients, transcutaneous carbon dioxide was measured continuously during sleep on both occasions and demonstrated significantly less CO2 retention during follow-up compared to control studies both in NREM (p < 0.003) and REM sleep states (p < 0.004). Long-term nocturnal ventilation produces improved respiratory drive both asleep and awake and improved arousal responses to abnormal blood gases.

Apnea and rapid eye movement sleep excess in the piglet during recovery from hyperthermia.

This investigation tested the hypothesis that artificially induced mild hyperthermia and recovery from hyperthermia in the developing newborn piglet (2-10 d of age) alter sleep state patterns and respiratory control. Continuous measurements of sleep state, respiratory pattern, carbon dioxide production and oxygen consumption were made before, during, and after a 3-h period of sustained hyperthermia. During hyperthermia, rectal temperatures were raised a mild 1-1.5 degree C above normal, well below the levels likely to cause severe physiologic distress in this species. This resulted in a disruption of the sleep state pattern characterized by a decrease in duration of rapid eye movement (REM) episodes, whereas immediately afterwards, during recovery, the amount of REM sleep increased. In some cases the amount of REM sleep in recovery more than doubled the basal level. Apneas were rarely observed during hyperthermia, but in recovery there was an increase in the total amount of time spent in apnea in both REM and non-rapid eye movement sleep states with a predominance in the REM state. Arousal responses to chemostimulation were not affected at this time. We conclude that the sleeping newborn piglet does indeed show marked changes in sleep state pattern (particularly REM sleep) and in the amount of apnea recorded during and immediately after only a mild increase in core temperature.