Sleep-wake States Research Articles

Probabilistic Sleep Staging in MSLTs across Hypersomnia Disorders.

This study aimed to identify novel markers of narcolepsy type 1 (NT1) using between-nap opportunity periods ('Lights On') and in-nap opportunity periods ('Lights Off') features of Multiple Sleep Latency Test (MSLT) recordings. We hypothesized that NT1 could be identified both from sleep-wake instability and patterns of sleepiness during wakefulness. Further, we explored if MSLTs from NT1 and narcolepsy type 2 (NT2) patients could be distinguished despite having the same diagnostic thresholds. We analyzed 'Lights On' and 'Lights Off' periods of the MSLT, extracting 163 features describing sleepiness, microsleep, and sleep stage mixing using data from 177 patients with NT1, NT2, Idiopathic Hypersomnia (IH), and Subjective Hypersomnia (sH) from three sleep centers. These features were based on automated probabilistic sleep staging, also denoted as hypnodensities, using U-Sleep. Hypersomnias were differentiated using either or both features from 'Lights On' and 'Lights Off'. Patients with NT1 could be distinguished from NT2, IH, and sH using features solely from 'Lights On' periods with a sensitivity of 0.76 and specificity of 0.71. When using features from all periods of the MSLT, NT1 was distinguished from NT2 alone with a sensitivity of 0.77 and a specificity of 0.84. The findings of this study demonstrate microsleeps and sleep stage mixing as potential markers of the sleep attacks and unstable sleep-wake states common in NT1. Further, NT1 and NT2 could be frequently distinguished using 'Lights Off' features.

Dreams interrupted: characteristics of REM sleep-associated seizures and status epilepticus.

Seizures are rare in rapid eye movement sleep (REM). However; seizures sometimes occur in REM, and a small number of focal epilepsy patients display their maximum rate of interictal epileptiform discharges in REM. We sought to systematically identify and characterize seizures in REM. We reviewed all admissions to the Epilepsy Monitoring Unit (EMU) at the Winnipeg Health Sciences Centre over 12-months in 2014-2015. American Academy of Sleep Medicine sleep-stage scoring was initially applied in the standard 30-second epochs. Then, to capture sudden changes in sleep-wake state on shorter timescales that are associated with seizure formation and propagation, we re-scored ictal and peri-ictal EEG epochs every 1 second. Patients found to have seizures in REM were subject to chart review spanning three years pre- and post-admission. REM seizures occurred in 3/63 EMU patients. Notably, one patient exhibited continuous epileptiform activity, consistent with focal nonconvulsive electrographic status epilepticus, throughout REM cycles for each night of her admission. Otherwise, discrete REM seizures constituted a small fraction of the other patients' total seizures (range 5.0-8.3%), occurred shortly after REM onset from non-REM 2, and were manifest as minor epileptic arousals. Our results confirm that REM seizures are rare, while highlighting outliers who widen the known spectrum of heterogeneous sleep effects on seizures/epilepsy. We also report the first case of paradoxical status epilepticus in REM.

Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

Efferent pathways from the suprachiasmatic nucleus to the horizontal limbs of diagonal band promote NREM sleep during the dark phase in mice

The regulation of circadian rhythms and the sleep–wake states involves in multiple neural circuits. The suprachiasmatic nucleus (SCN) is a circadian pacemaker that controls the rhythmic oscillation of mammalian behaviors. The basal forebrain (BF) is a critical brain region of sleep–wake regulation, which is the downstream of the SCN. Retrograde tracing of cholera toxin subunit B showed a direct projection from the SCN to the horizontal limbs of diagonal band (HDB), a subregion of the BF. However, the underlying function of the SCN–HDB pathway remains poorly understood. Herein, activation of this pathway significantly increased non–rapid eye movement (NREM) sleep during the dark phase by using optogenetic recordings. Moreover, activation of this pathway significantly induced NREM sleep during the dark phase for first 4 h by using chemogenetic methods. Taken together, these findings reveal that the SCN–HDB pathway participates in NREM sleep regulation and provides direct evidence of a novel SCN-related pathway involved in sleep–wake states regulation.

Automatic Classification of Sleep-Wake States of Newborns Using Only Body and Face Videos

Automatic Classification of Sleep-Wake States of Newborns Using Only Body and Face Videos

Sleep and circadian rhythm activity alterations during adolescence in a mouse model of neonatal fentanyl withdrawal syndrome.

Fentanyl, a highly potent synthetic opioid, is a major contributor to the ongoing opioid epidemic. During adulthood, fentanyl is known to induce pronounced sleep and circadian disturbances during use and withdrawal. Children exposed to opioids in utero are likely to develop neonatal opioid withdrawal syndrome, and display sleep disturbances after birth. However, it is currently unknown how neonatal opioid withdrawal from fentanyl impacts sleep and circadian rhythms in mice later in life. To model neonatal opioid withdrawal syndrome, mice were treated with fentanyl from postnatal days 1 through 14, analogous to the third trimester of human gestation. After weaning, fentanyl and saline treated mice underwent non-invasive sleep and circadian rhythm monitoring during adolescence postnatal days 23 through 30. Neonatal fentanyl exposure led to reduced duration of wake and a decrease in the number of bouts of non-rapid eye movement sleep. Further, neonatally exposed mice displayed an increase in the average duration of rapid eye movement sleep bouts, reflecting an overall increase in the percent time spent in rapid eye movement sleep across days. Neonatal fentanyl exposure leads to altered sleep-wake states during adolescence in mice.

Sleep quality in patients with chronic spontaneous urticaria and relation with Orexin-A, leptin, and ghrelin.

Background: Sleep can be affected in patients with chronic spontaneous urticaria (CSU). The mechanisms of sleep regulation remain poorly understood. Orexin-A, a neuroexcitatory peptide, plays a role in coordinating sleep-wake states. Ghrelin and leptin are involved in sleep regulation through the orexin system. Objective: The effects of orexin-A, ghrelin, and leptin on sleep quality in patients with CSU have not been investigated. We aimed to determine the effects of CSU on sleep quality and the association between serum orexin-A, ghrelin, and leptin levels, and sleep quality in patients with CSU. Methods: Thirty-three patients with CSU and 34 sex- and age-matched controls were included in the study. Serum orexin-A, leptin, and ghrelin levels, and the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) scores were measured in patients with CSU and in the controls; also used were the chronic urticaria quality-of-life questionnaire score and the urticaria activity score used for 7 consecutive days. Results: Median (minimum-maximum) orexin-A, leptin, and ghrelin levels in patients were 385 pg/mL (90-495 pg/mL), 3.1 ng/mL (0-21.2 ng/mL), and 701.8 pg/mL (101.9-827.7 pg/mL), respectively. Median serum orexin-A and leptin levels were higher in the patients compared with the controls (p < 0.001 and p = 0.012, respectively), whereas the median serum ghrelin levels were similar to the controls (p = 0.616). The serum orexin-A level was positively correlated with ghrelin (r = 0.298, p = 0.014), PSQI sleep quality (r = 0.356, p = 0.003), and ESS (r = 0.357, p = 0.003). Conclusion: Serum orexin-A is associated with sleep quality in patients with CSU. Further studies are needed to elucidate the role of ghrelin and leptin on sleep quality in patients with CSU.

P.050 Spike source localizations between the three non-REM sleep stages: resemblances to wakefulness and distinctions from REM sleep

Background: Sleep-wake states (SWS) affect the expression of interictal epileptiform discharges (“spikes”), which affects resultant source localization calculations used in epilepsy evaluation. We hypothesize that spike localizations from non-REM sleep 1-3 are most concordant with one another. Methods: We used Standardized low-resolution brain electromagnetic tomography (sLORETA) in Curry 8 software to calculate source localization voxels of spikes in N1-3, REM, or wakefulness (W). We assessed voxel concordance between N1-N2-N3/N1-N2-W/N1-N3-W/N2-N3-W/REM-N1-N2/REM-N1-N3/REM-N2-N3/REM-N1-W/REM-N2-W/REM-N3-W. We classified concordances into those containing and not containing a SWS (e.g. N1 vs. not-N1 = N1-N2-N3/N1-N2-W/N1-N3-W/REM-N1-N2/REM-N1-N3/REM-N1-W vs. REM-N2-W/REM-N3-W/REM-N2-N3/N2-N3-W) for comparison. Results: Concordances did not differ for N1-3 or W. However, concordances with REM were lower than those without REM as a fraction of source localization space (median 32.1% vs. 56.1%, p&lt;0.001) and cortical grey matter (median 20.4% vs. 27.3%, p=0.003). Conclusions: As expected, source localizations from spikes in N1, N2, and N3 did not significantly differ from one another because these three states are constituent members of non-REM sleep. Surprisingly, however, source localizations derived from awake spikes – not a constituent of non-REM sleep – also did not differ. In contrast, REM was most different by reproducibly exhibiting the least three-way concordance. These findings reinforce the unique localizing ability of REM sleep.

Effect of Intravenous Delivery of N,N Dimethyltryptamine on Sleep-Wake States in Rat

Psychedelics, including N, N, Dimethyltryptamine (DMT), are being increasingly explored for therapeutic potential to treat psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder. These and other psychiatric conditions have a bidirectional relationship with sleep patterns but the impact of psychedelics, particularly DMT, on sleep architecture is incompletely understood. Therefore, in this study, we determined the effect of intravenous DMT administration on sleep-wake states in male and female rats. Under surgical isoflurane anesthesia, adult Sprague Dawley rats (n=10, 5 male, 5 female) were instrumented with electrodes to record electroencephalogram (EEG) from across the cortex and electromyogram (EMG) from dorsal nuchal muscles. In addition, a chronic catheter was positioned in jugular vein for the infusion of DMT or 0.9% saline (as vehicle control). Each rat received an intravenous bolus (100 uL/min over 5 min) of either one of two doses of DMT (low dose: 3.75 mg/kg, high dose: 7.5 mg/kg) or 0.9% saline. The DMT and saline infusions were performed 30-minutes after the start of the lights-ON period (8:00 am) after which EEG and EMG data were recorded for 24h across the light and dark cycle. EEG and EMG data were manually scored (SleepSign, Kissei Comtec) in 4-second intervals and classified as wakefulness, slow-wave sleep, or rapid eye movement sleep, then averaged in 3h bins across the 24h recording period. A linear mixed model was used to compare the changes in percent time spent in each state, mean duration per episode for each state, and mean number of episodes for each state, between vehicle control and DMT infusion sessions. There was a statistically significant increase in the time spent in wakefulness in the first 3h bin after DMT infusion (p&lt;0.02 for low dose, p&lt;0.03 for high dose). In the same 3h bin, a significant decrease in slow-wave sleep (p&lt;0.02 for low and high dose DMT) was observed. DMT infusion produced a significant increase in the latency to the onset of rapid eye movement sleep (p&lt;0.01), but no statistical effect was observed on the time spent in rapid eye movement sleep during the light period. Our results with DMT align with previous reports showing an increase in wakefulness after administration of serotonergic psychedelics. Further analysis of neurophysiologic data is needed to understand the neural dynamics associated with DMT-induced increases in wakefulness. Department of Anesthesiology, University of Michigan. RS was partly supported by Magnificent Michigan Summer Undergraduate Research fellowship, University of Michigan. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Inactivation of Prefrontal Cortex on Sleep-Wake States in Rat

There is a large body of literature to support subcortical regulation of sleep-wake states, but there have been limited studies to investigate the role of cortex in sleep-wake regulation. Previously, we have demonstrated that cholinergic stimulation of prefrontal cortex can reverse general anesthesia and promote wakefulness in unanesthetized rats, and there is emerging evidence to suggest that the prefrontal cortex might be a critical node in arousal state control. To better understand the direct role of prefrontal cortex in the regulation of sleep-wake states, we quantified the effect of prefrontal cortex inactivation, via local tetrodotoxin (156 μM) infusion, on sleep architecture. Under surgical isoflurane anesthesia, adult Sprague Dawley rats (n=7 male) were instrumented with electrodes to record electroencephalogram (EEG) from frontal and parietal cortices, and electromyogram (EMG) from dorsal nuchal muscles. In addition, a bilateral guide cannula was implanted aimed at the medial prefrontal cortex for tetrodotoxin infusion. After at least a week of post-surgical recovery and conditioning to the recording chambers, rats received bilateral microinjection (500 nL) of either 156 μM tetrodotoxin or 0.9% saline (vehicle control). The tetrodotoxin and 0.9% saline infusions were performed 30-minutes before the start of lights-OFF period (8:00 pm) after which EEG and EMG data were recorded for 24h across dark and light cycles. The EEG and EMG data were manually scored (SleepSign, Kissei Comtec Inc.) in 4-second intervals into wakefulness, slow-wave sleep, and rapid eye movement sleep, and then averaged in 3h bins across 24h recording period. A linear mixed model was used to compare the changes in percent time spent in each state, mean duration per episode for each state, and mean number of episodes for each state, between the vehicle control and tetrodotoxin-infusion sessions. Inactivation of prefrontal cortex via tetrodotoxin infusion produced long-lasting statistically significant increase in slow-wave sleep (p&lt;0.05 for 0-3h, 4-6h, 7-9h, 10-12h, 13-15, 16-18, 22-24) and decrease in wakefulness (p&lt;0.05 for 0-3h, 4-6h, 10-12h) and rapid eye movement sleep (p&lt;0.05 for 7-9h, 10-12h, 13-15h). These data further support a causal contribution of prefrontal cortex in regulating arousal states. This work was supported by the National Institutes of Health (Bethesda, MD, USA) grant (R01 GM111293) to GAM and DP, and funding from the Department of Anesthesiology, University of Michigan Medical School, Ann Arbor. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sleep pressure modulates single-neuron synapse number in zebrafish

Sleep is a nearly universal behaviour with unclear functions1. The synaptic homeostasis hypothesis proposes that sleep is required to renormalize the increases in synaptic number and strength that occur during wakefulness2. Some studies examining either large neuronal populations3 or small patches of dendrites4 have found evidence consistent with the synaptic homeostasis hypothesis, but whether sleep merely functions as a permissive state or actively promotes synaptic downregulation at the scale of whole neurons is unclear. Here, by repeatedly imaging all excitatory synapses on single neurons across sleep–wake states of zebrafish larvae, we show that synapses are gained during periods of wake (either spontaneous or forced) and lost during sleep in a neuron-subtype-dependent manner. However, synapse loss is greatest during sleep associated with high sleep pressure after prolonged wakefulness, and lowest in the latter half of an undisrupted night. Conversely, sleep induced pharmacologically during periods of low sleep pressure is insufficient to trigger synapse loss unless adenosine levels are boosted while noradrenergic tone is inhibited. We conclude that sleep-dependent synapse loss is regulated by sleep pressure at the level of the single neuron and that not all sleep periods are equally capable of fulfilling the functions of synaptic homeostasis.

0364 The Role of Hyperarousal in Sleep-wake State Discrepancy in Youths with Insomnia

0364 The Role of Hyperarousal in Sleep-wake State Discrepancy in Youths with Insomnia

Automatic sleep-wake classification and Parkinson's disease recognition using multifeature fusion with support vector machine.

Sleep disturbance is a prevalent nonmotor symptom of Parkinson's disease (PD), however, assessing sleep conditions is always time-consuming and labor-intensive. In this study, we performed an automatic sleep-wake state classification and early diagnosis of PD by analyzing the electrocorticography (ECoG) and electromyogram (EMG) signals of both normal and PD rats. The study utilized ECoG power, EMG amplitude, and corticomuscular coherence values extracted from normal and PD rats to construct sleep-wake scoring models based on the support vector machine algorithm. Subsequently, we incorporated feature values that could act as diagnostic markers for PD and then retrained the models, which could encompass the identification of vigilance states and the diagnosis of PD. Features extracted from occipital ECoG signals were more suitable for constructing sleep-wake scoring models than those from frontal ECoG (average Cohen's kappa: 0.73 vs. 0.71). Additionally, after retraining, the new models demonstrated increased sensitivity to PD and accurately determined the sleep-wake states of rats (average Cohen's kappa: 0.79). This study accomplished the precise detection of substantia nigra lesions and the monitoring of sleep-wake states. The integration of circadian rhythm monitoring and disease state assessment has the potential to improve the efficacy of therapeutic strategies considerably.

Changed nocturnal levels of stress-related hormones couple with sleep-wake states in the patients with chronic insomnia disorder: A clinical pilot study

ObjectivesTo explore the relationship between nocturnal levels of stress-related hormones and different sleep-wake states in chronic insomnia disorder (CID) patients. MethodsThirty-three CID patients and 34 good sleepers were enrolled and completed assessment of sleep log, Pittsburgh Sleep Quality Index and Insomnia Severity Index. During a-overnight polysomnography monitoring, the patients' vein bleeds were continually collected at different time points (pre-sleep, deep-sleep, 5-min or 30-min waking, and morning waking-up). The control subjects’ bleeds were collected only at 22:00 and morning waking-up. The serum hormones were detected using enzyme-linked immunosorbent assay. ResultsCompared with at pre-sleep, the level of cortisol was significantly higher at morning waking-up respectively in two-group subjects (Ps < 0.001), with insignificant inter-group differences in cortisol, corticotropin releasing hormone and copeptin at the two time-points. In the patients, the nocturnal secretion curves of three hormones were similar, with the highest concentration at morning waking-up, followed by 30-min waking, 5-min waking, pre-sleep, and deep-sleep. The patients' cortisol (Z = 79.192, P < 0.001) and copeptin (Z = 12.333, P = 0.015) levels were statistically different at different time-points, with higher cortisol at morning waking-up relative to deep-sleep, pre-sleep and 5-min waking (Ps < 0.05), and at 30-min waking relative to deep-sleep and pre-sleep (Ps < 0.05), and higher copeptin at morning waking-up relative to deep-sleep (P < 0.05). ConclusionsIn CID, the nocturnal wakes were instantaneously accompanied by high level, and deep sleep was accompanied by the lowest levels, of stress-related hormones, especially in cortisol, supporting the insomniac hypothesis of increased nocturnal pulse-release of cortisol.

Abstract WP9: Ischemic Stroke Progression After Witnessed Onset in Daytime vs Night-Time

Introduction: Early neurologic deterioration (END) and poor functional outcomes are more frequent with night than daytime onset of ischemic stroke. This variation may be related to: 1) circadian variation endogenous bodily rhythms and/or 2) extrinsic environmental time cues. Methods: To assess the contribution of extrinsic environmental time to ischemic stroke course, we evaluated patients with acute cerebral ischemia (ACI) onset within last 2h, enrolled in the NIH FAST-MAG trial of prehospital neuroprotection, consisting of patients with witnessed/wake onset. Results: Among 1235 ACI patients (ischemic stroke 1033, TIA 202), age was 70.8 [±13.2], 45.3% female, initial NIHSS 7 (IQR 2-15), LKW to randomization 59 mins (IQR 46-80), and 473 (38%) treated with IV lytics. Onset occurred during clock daytime (07:00-22:59) in 1147 (92.9%) and night-time (23:00-06:59) in 88 (7.1%). Patients were similar in 18 baseline characteristics, but night-onset had higher initial SBP (162 vs 155, p=0.01) and longer onset to paramedic times (33m vs 23m, p = 0.0002). Among non-lytic patients, both unadjusted and adjusted clinical outcomes were similar in night vs daytime patients, including END (13.6% vs 16.4%), 90d mRS 0-2 (63.6% vs 58.5%), and 90d mortality (10.2% vs 12.8%). Among lytic patients, clinical outcomes were also similar in night vs daytime onset patients, including unadjusted END (36% vs 21.7%), 90d mRS 0-2 (52% vs 46.9%), and 90d mortality (12% vs 17.4%). Night vs daytime onset did not modify the effect of magnesium vs placebo on outcome among either non-thrombolytic or thrombolytic-treated patients (Figure). Conclusion: Among acute cerebral ischemia patients, efficacy, safety, and neuroprotective agent response outcomes were not modified by witnessed onset during active versus inactive phase clock times. These findings suggest biological wake-sleep state rather than chronologic clock time is the driver of known circadian rhythmicity in stroke course.

Sleep-wake state discrepancy: clinical characteristics and effect of cognitive behavioural therapy for insomnia (CBTi)

Sleep-wake state discrepancy: clinical characteristics and effect of cognitive behavioural therapy for insomnia (CBTi)

Factors associated with sleep-wake state discrepancy among healthy adults

Factors associated with sleep-wake state discrepancy among healthy adults

Revisiting the Role of Serotonin in Sleep-Disordered Breathing.

Serotonin or 5-hydroxytryptamine (5-HT) is a ubiquitous neuro-modulator-transmitter that acts in the central nervous system, playing a major role in the control of breathing and other physiological functions. The midbrain, pons, and medulla regions contain several serotonergic nuclei with distinct physiological roles, including regulating the hypercapnic ventilatory response, upper airway patency, and sleep-wake states. Obesity is a major risk factor in the development of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), recurrent closure of the upper airway during sleep, and obesity hypoventilation syndrome (OHS), a condition characterized by daytime hypercapnia and hypoventilation during sleep. Approximately 936 million adults have OSA, and 32 million have OHS worldwide. 5-HT acts on 5-HT receptor subtypes that modulate neural control of breathing and upper airway patency. This article reviews the role of 5-HT in SDB and the current advances in 5-HT-targeted treatments for SDB.

Sleep-wake state discrepancy does not impair the efficacy of cognitive behavioural therapy for insomnia: Findings from a large clinic sample.

The current study determined the extent to which sleep-wake state discrepancy impairs the efficacy of cognitive behavioural therapy for insomnia in a real-world clinical sample. Sleep-wake state discrepancy occurs when there is an inconsistency between a person's subjective and objective sleep, and is a common phenomenon amongst patients with insomnia. Limited information is available on the effectiveness of cognitive behavioural therapy for insomnia in treating patients who experience significant sleep-wake state discrepancy in "real-world" samples. In the present study, all patients with insomnia received cognitive behavioural therapy for insomnia through an outpatient insomnia program (N = 386; mean age = 51.96 years, SD = 15.62; 65.97% [N = 254] female). Prior to treatment, participants completed a polysomnography sleep study and sleep diary, which was used to calculate sleep-wake state discrepancy. At pre-treatment, post-treatment and 3-month follow-up, participants completed the Insomnia Severity Index and other questionnaires, and 1 week of sleep diaries from which sleep-onset latency, wake after sleep onset and other sleep variables were calculated. There were no differences in self-reported sleep-onset latency, wake after sleep onset or Insomnia Severity Index scores at post-treatment or 3-month follow-up between quintiles of sleep-wake state discrepancy. These results indicate that sleep-wake state discrepancy at pre-treatment does not predict treatment response to cognitive behavioural therapy for insomnia. Future research could examine multi-night assessments of sleep-wake state discrepancy to determine whether variations in discrepancy may relate to pre-treatment insomnia severity and cognitive behavioural therapy for insomnia outcomes.

Crosstalk between the subiculum and sleep-wake regulation: A review.

The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non-rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep-wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep-wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second-order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep-wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep-deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness.