All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and ß-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

The neural correlates of arousal: Ventral posterolateral nucleus-global transient co-activation.

Arousal and awareness are two components of consciousness whose neural mechanisms remain unclear. Spontaneous peaks of global (brain-wide) blood-oxygenation-level-dependent (BOLD) signal have been found to be sensitive to changes in arousal. By contrasting BOLD signals at different arousal levels, we find decreased activation of the ventral posterolateral nucleus (VPL) during transient peaks in the global signal in low arousal and awareness states (non-rapid eye movement sleep and anesthesia) compared to wakefulness and in eyes-closed compared to eyes-open conditions in healthy awake individuals. Intriguingly, VPL-global co-activation remains high in patients with unresponsive wakefulness syndrome (UWS), who exhibit high arousal without awareness, while it reduces in rapid eye movement sleep, a state characterized by low arousal but high awareness. Furthermore, lower co-activation is found in individuals during N3 sleep compared to patients with UWS. These results demonstrate that co-activation of VPL and global activity is critical to arousal but not to awareness.

Auditory inputs modulate intrinsic neuronal timescales during sleep.

Functional magnetic resonance imaging (fMRI) studies have demonstrated that intrinsic neuronal timescales (INT) undergo modulation by external stimulation during consciousness. It remains unclear if INT keep the ability for significant stimulus-induced modulation during primary unconscious states, such as sleep. This fMRI analysis addresses this question via a dataset that comprises an awake resting-state plus rest and stimulus states during sleep. We analyzed INT measured via temporal autocorrelation supported by median frequency (MF) in the frequency-domain. Our results were replicated using a biophysical model. There were two main findings: (1) INT prolonged while MF decreased from the awake resting-state to the N2 resting-state, and (2) INT shortened while MF increased during the auditory stimulus in sleep. The biophysical model supported these results by demonstrating prolonged INT in slowed neuronal populations that simulate the sleep resting-state compared to an awake state. Conversely, under sine wave input simulating the stimulus state during sleep, the model's regions yielded shortened INT that returned to the awake resting-state level. Our results highlight that INT preserve reactivity to stimuli in states of unconsciousness like sleep, enhancing our understanding of unconscious brain dynamics and their reactivity to stimuli.

Altered brain dynamics index levels of arousal in complete locked-in syndrome.

Complete locked-in syndrome (CLIS) resulting from late-stage amyotrophic lateral sclerosis (ALS) is characterised by loss of motor function and eye movements. The absence of behavioural indicators of consciousness makes the search for neuronal correlates as possible biomarkers clinically and ethically urgent. EEG-based measures of brain dynamics such as power-law exponent (PLE) and Lempel-Ziv complexity (LZC) have been shown to have explanatory power for consciousness and may provide such neuronal indices for patients with CLIS. Here, we validated PLE and LZC (calculated in a dynamic way) as benchmarks of a wide range of arousal states across different reference states of consciousness (e.g., awake, sleep stages, ketamine, sevoflurane). We show a tendency toward high PLE and low LZC, with high intra-subject fluctuations and inter-subject variability in a cohort of CLIS patients with values graded along different arousal states as in our reference data sets. In conclusion, changes in brain dynamics indicate altered arousal in CLIS. Specifically, PLE and LZC are potentially relevant biomarkers to identify or diagnose the arousal level in CLIS and to determine the optimal time point for treatment, including communication attempts.

Eye movements during phasic versus tonic rapid eye movement sleep are biomarkers of dissociable electroencephalogram processes for the consolidation of novel problem-solving skills.

The hallmark eye movement (EM) bursts that occur during rapid eye movement (REM) sleep are markers of consolidation for procedural memory involving novel cognitive strategies and problem-solving skills. Examination of the brain activity associated with EMs during REM sleep might elucidate the processes involved in memory consolidation, and may uncover the functional significance of REM sleep and EMs themselves. Participants performed a REM-dependent, novel procedural problem-solving task (i.e. the Tower of Hanoi; ToH) before and after intervals of either overnight sleep (n = 20) or a daytime 8-hour wake period (n = 20). In addition, event-related spectral perturbation of the electroencephalogram (EEG) time-locked to EMs occurring either in bursts (i.e. phasic REM), or in isolation (i.e. tonic REM), were compared to sleep on a non-learning control night. ToH improvement was greater following sleep compared to wakefulness. During sleep, prefrontal theta (~2-8 Hz) and central-parietal-occipital sensorimotor rhythm (SMR) activity (~8-16 Hz) time-locked to EMs, were greater on the ToH night versus control night, and during phasic REM sleep, were both positively correlated with overnight memory improvements. Furthermore, SMR power during tonic REM increased significantly from the control night to ToH night, but was relatively stable from night to night during phasic REM. These results suggest that EMs are markers of learning-related increases in theta and SMR during phasic and tonic REM sleep. Phasic and tonic REM sleep may be functionally distinct in terms of their contribution to procedural memory consolidation.

Topographic-dynamic reorganisation model of dreams (TRoD) - A spatiotemporal approach.

Dreams are one of the most bizarre and least understood states of consciousness. Bridging the gap between brain and phenomenology of (un)conscious experience, we propose the Topographic-dynamic Re-organization model of Dreams (TRoD). Topographically, dreams are characterized by a shift towards increased activity and connectivity in the default-mode network (DMN) while they are reduced in the central executive network, including the dorsolateral prefrontal cortex (except in lucid dreaming). This topographic re-organization is accompanied by dynamic changes; a shift towards slower frequencies and longer timescales. This puts dreams dynamically in an intermediate position between awake state and NREM 2/SWS sleep. TRoD proposes that the shift towards DMN and slower frequencies leads to an abnormal spatiotemporal framing of input processing including both internally- and externally-generated inputs (from body and environment). In dreams, a shift away from temporal segregation to temporal integration of inputs results in the often bizarre and highly self-centric mental contents as well as hallucinatory-like states. We conclude that topography and temporal dynamics are core features of the TroD, which may provide the connection of neural and mental activity, e.g., brain and experience during dreams as their "common currency".

Sleep strengthens resting-state functional communication between brain areas involved in the consolidation of problem-solving skills.

Sleep consolidates procedural memory for motor skills, and this process is associated with strengthened functional connectivity in hippocampal-striatal-cortical areas. It is unknown whether similar processes occur for procedural memory that requires cognitive strategies needed for problem-solving. It is also unclear whether a full night of sleep is indeed necessary for consolidation to occur, compared with a daytime nap. We examined how resting-state functional connectivity within the hippocampal-striatal-cortical network differs after offline consolidation intervals of sleep, nap, or wake. Resting-state fMRI data were acquired immediately before and after training on a procedural problem-solving task that requires the acquisition of a novel cognitive strategy and immediately prior to the retest period (i.e., following the consolidation interval). ROI to ROI and seed to whole-brain functional connectivity analyses both specifically and consistently demonstrated strengthened hippocampal-prefrontal functional connectivity following a period of sleep versus wake. These results were associated with task-related gains in behavioral performance. Changes in functional communication were also observed between groups using the striatum as a seed. Here, we demonstrate that at the behavioral level, procedural strategies benefit from both a nap and a night of sleep. However, a full night of sleep is associated with enhanced functional communication between regions that support problem-solving skills.

Sleep spindles and slow waves are physiological markers for age-related changes in gray matter in brain regions supporting problem-solving skills.

As we age, the added benefit of sleep for memory consolidation is lost. One of the hallmark age-related changes in sleep is the reduction of sleep spindles and slow waves. Gray matter neurodegeneration is related to both age-related changes in sleep and age-related changes in memory, including memory for problem-solving skills. Here, we investigated whether spindles and slow waves might serve as biological markers for neurodegeneration of gray matter and for the related memory consolidation deficits in older adults. Forty healthy young adults (20-35 yr) and 30 healthy older adults (60-85 yr) were assigned to either nap or wake conditions. Participants were trained on the Tower of Hanoi in the morning, followed by either a 90-min nap opportunity or period of wakefulness, and were retested afterward. We found that age-related changes in sleep spindles and slow waves were differentially related to gray matter intensity in young and older adults in brain regions that support sleep-dependent memory consolidation for problem-solving skills. Specifically, we found that spindles were related to gray matter in neocortical areas (e.g., somatosensory and parietal cortex), and slow waves were related to gray matter in the anterior cingulate, hippocampus, and caudate, all areas known to support problem-solving skills. These results suggest that both sleep spindles and slow waves may serve as biological markers of age-related neurodegeneration of gray matter and the associated reduced benefit of sleep for memory consolidation in older adults.

Brain activations time locked to slow wave-coupled sleep spindles correlates with intellectual abilities.

Sleep spindles (SP) are one of the few known electrophysiological neuronal biomarkers of interindividual differences in cognitive abilities and aptitudes. Recent simultaneous electroencephalography with functional magnetic resonance imaging (EEG-fMRI) studies suggest that the magnitude of the activation of brain regions recruited during spontaneous spindle events is specifically related to Reasoning abilities. However, it is not known if the relationship with cognitive abilities differs between uncoupled spindles, uncoupled slow waves (SW), and coupled SW-SP complexes, nor have the functional-neuroanatomical substrates that support this relationship been identified. Here, we investigated the functional significance of activation of brain areas recruited during SW-coupled spindles, uncoupled spindles, and uncoupled slow waves. We hypothesize that brain activations time locked to SW-coupled spindle complexes will be primarily associated to Reasoning abilities, especially in subcortical areas. Our results provide direct evidence that the relationship between Reasoning abilities and sleep spindles depends on spindle coupling status. Specifically, we found that the putamen and thalamus, recruited during coupled SW-SP events were positively correlated with Reasoning abilities. In addition, we found a negative association between Reasoning abilities and hippocampal activation time-locked to uncoupled SWs that might reflect a refractory mechanism in the absence of new, intensive hippocampal-dependent memory processing.

Simultaneous EEG + fMRI study of brain activity during an emotional Stroop task in individuals in remission from depression.

Individuals in remission from depression (MDDR) tend to experience lingering cognitive and emotional processing alterations. However, little is known about the neural profiles underlying these features. Using simultaneous EEG+fMRI, we assessed neural profiles during the emotional word Stroop task (eStroop) in people with MDDR and healthy volunteers (HVs). Event-related potentials (ERPs) were extracted (N450, N2 & P3). Assessments of brain activation, as modulated by ERPs, were carried out, as were fMRI-informed ERP analyses. A trend for greater P3 amplitudes in MDDR versus HV groups existed. HV versus MDDR groups had greater brain activation to emotional versus neutral words in various regions, including the left amygdala, inferior frontal gyrus (IFG); this appeared to be driven by elevated activity to neutral words in the MDDR group (neutral > emotional). HVs showed greater activation (emotional > neutral) modulated by N450 amplitude in various regions, while MDDRs showed greater neutral > emotional activation modulated by N450 amplitude in the left IFG and left precuneus. Our EEG+fMRI findings indicate that people with MDDR appear to have blunted neural differentiation to emotional versus neutral stimuli or elevated neural responses to neutral information processing. This might represent altered neuronal processing (i.e., underlying attention and conflict processing) during a cognitive task with an emotional component in individuals remitted from depression, or elevated neural responses to ambiguous or neutral information. In sum, subtle lingering neuronal features not accompanied by performance differences appear to exist in people with MDDR.

Age-related differences in problem-solving skills: Reduced benefit of sleep for memory trace consolidation.

We investigated the behavioural and neuronal functional consequences of age-related differences in sleep for gaining insight into novel cognitive strategies. Forty healthy young adults (20-35 years), and twenty-nine healthy older adults (60-85 years) were assigned to either nap or wake conditions. Participants were trained on the Tower of Hanoi in the AM, followed by either a 90-minute nap opportunity or period of wakefulness, and were retested afterward. Functional magnetic resonance imaging scans examined differences in brain activation from training to retest in young versus older adults as a function of sleep. Sleep enhanced performance and transformed the memory trace in young adults via hippocampal-neocortical transfer, but not older adults. This is consistent with the notion that as the consolidation of a newly formed memory trace progresses, the hippocampus becomes less involved; especially so when sleep occurs during that time. These results demonstrate a critical role for sleep in supporting problem-solving skills and suggest that the benefit of sleep for consolidation of these skills is reduced with age.

While you were sleeping: Evidence for high-level executive processing of an auditory narrative during sleep.

During sleep we lack conscious awareness of the external environment. Yet, our internal mental state suggests that high-level cognitive processes persist. The nature and extent to which the external environment is processed during sleep remain largely unexplored. Here, we used an fMRI synchronization-based approach to examine responses to a narrative during wakefulness and sleep. The stimulus elicited the auditory network and a frontoparietal pattern of activity, consistent with high-level narrative plot-following. During REM sleep, the same frontoparietal pattern was observed in one of three participants, and partially in one other, confirming that it is possible to track and follow the moment-to-moment complexities of a narrative during REM sleep. Auditory network recruitment was observed in both non-REM and REM sleep, demonstrating preservation of low-level auditory processing, even in deep sleep. This novel approach investigating cognitive processing at different levels of awareness demonstrates that the brain can meaningfully process the external environment during REM sleep.

Anterior precuneus related to the recovery of consciousness.

The neural mechanism that enables the recovery of consciousness in patients with unresponsive wakefulness syndrome (UWS) remains unclear. The aim of the current study is to characterize the cortical hub regions related to the recovery of consciousness. In the current fMRI study, voxel-wise degree centrality analysis was adopted to identify the cortical hubs related to the recovery of consciousness, for which a total of 27 UWS patients were recruited, including 13 patients who emerged from UWS (UWS-E), and 14 patients who remained in UWS (UWS-R) at least three months after the experiment performance. Furthermore, other recoverable unconscious states were adopted as validation groups, including three independent N3 sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively). Spatial similarity of the hub characteristic with the validation groups between the UWS-E and UWS-R was compared using the dice coefficient. Finally, with the cortical regions persistently shown as hubs across UWS-E and validation states, functional connectivity analysis was further performed to explore the connectivity patterns underlying the recovery of consciousness. The results identified four cortical hubs in the UWS-E, which showed significantly higher degree centrality for UWS-E than UWS-R, including the anterior precuneus, left inferior parietal lobule, left inferior frontal gyrus, and left middle frontal gyrus, of which the degree centrality value also positively correlated with the patients' Glasgow Outcome Scale (GOS) score that assessed global brain functioning outcome after a brain injury. Furthermore, the anterior precuneus was found with significantly higher similarity of hub characteristics as well as functional connectivity patterns between UWS-E and the validation groups. The results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs in the recoverable unconscious states, especially the anterior precuneus. The identified cortical hub regions could serve as potential treatment targets for patients with UWS.

The relationship between cognitive ability and BOLD activation across sleep-wake states.

The sleep spindle, a waxing and waning oscillation in the sigma frequency range, has been shown to correlate with fluid intelligence; i.e. the ability to use logic, learn novel rules/patterns, and solve problems. Using simultaneous EEG and fMRI, we previously identified the neural correlates of this relationship, including activation of the thalamus, bilateral putamen, medial frontal gyrus, middle cingulate cortex, and precuneus. However, research to date has focussed primarily on non-rapid eye movement (NREM) sleep, and spindles per se, thus overlooking the possibility that brain activity that occurs in other sleep-wake states might also be related to cognitive abilities. In our current study, we sought to investigate whether brain activity across sleep/wake states is also related to human intelligence in N = 29 participants. During NREM sleep, positive correlations were observed between fluid intelligence and blood oxygen level dependent (BOLD) activations in the bilateral putamen and the paracentral lobule/precuneus, as well as between short-term memory (STM) abilities and activity in the medial frontal cortex and inferior frontal gyrus. During wake, activity in bilateral postcentral gyri and occipital lobe was positively correlated with short-term memory abilities. In participants who experienced REM sleep in the scanner, fluid intelligence was positively associated with midbrain activation, and verbal intelligence was associated with right postcentral gyrus activation. These findings provide evidence that the relationship between sleep and intellectual abilities exists beyond sleep spindles.

Functional differences in cerebral activation between slow wave-coupled and uncoupled sleep spindles.

Spindles are often temporally coupled to slow waves (SW). These SW-spindle complexes have been implicated in memory consolidation that involves transfer of information from the hippocampus to the neocortex. However, spindles and SW, which are characteristic of NREM sleep, can occur as part of this complex, or in isolation. It is not clear whether dissociable parts of the brain are recruited when coupled to SW vs. when spindles or SW occur in isolation. Here, we tested differences in cerebral activation time-locked to uncoupled spindles, uncoupled SW and coupled SW-spindle complexes using simultaneous EEG-fMRI. Consistent with the "active system model," we hypothesized that brain activations time-locked to coupled SW-spindles would preferentially occur in brain areas known to be critical for sleep-dependent memory consolidation. Our results show that coupled spindles and uncoupled spindles recruit distinct parts of the brain. Specifically, we found that hippocampal activation during sleep is not uniquely related to spindles. Rather, this process is primarily driven by SWs and SW-spindle coupling. In addition, we show that SW-spindle coupling is critical in the activation of the putamen. Importantly, SW-spindle coupling specifically recruited frontal areas in comparison to uncoupled spindles, which may be critical for the hippocampal-neocortical dialogue that preferentially occurs during sleep.

Differential Effects of a Nap on Motor Sequence Learning-Related Functional Connectivity Between Young and Older Adults.

In older adults, motor sequence learning (MSL) is largely intact. However, consolidation of newly learned motor sequences is impaired compared to younger adults, and there is evidence that brain areas supporting enhanced consolidation via sleep degrade with age. It is known that brain activity in hippocampal-cortical-striatal areas is important for sleep-dependent, off-line consolidation of motor-sequences. Yet, the intricacies of how both age and sleep alter communication within this network of brain areas, which facilitate consolidation, are not known. In this study, 37 young (age 20-35) and 49 older individuals (age 55-75) underwent resting state functional magnetic resonance imaging (fMRI) before and after training on a MSL task as well as after either a nap or a period of awake rest. Young participants who napped showed strengthening of functional connectivity (FC) between motor, striatal, and hippocampal areas, compared to older subjects regardless of sleep condition. Follow-up analyses revealed this effect was driven by younger participants who showed an increase in FC between striatum and motor cortices, as well as older participants who showed decreased FC between the hippocampus, striatum, and precuneus. Therefore, different effects of sleep were observed in younger vs. older participants, where young participants primarily showed increased communication in the striatal-motor areas, while older participants showed decreases in key nodes of the default mode network and striatum. Performance gains correlated with FC changes in young adults, and this association was much greater in participants who napped compared to those who stayed awake. Performance gains also correlated with FC changes in older adults, but only in those who napped. This study reveals that, while there is no evidence of time-dependent forgetting/deterioration of performance, older adults exhibit a completely different pattern of FC changes during consolidation compared to younger adults, and lose the benefit that sleep affords to memory consolidation.

Sleep and Second-Language Acquisition Revisited: The Role of Sleep Spindles and Rapid Eye Movements.

INTRODUCTION: Second-language learning (SLL) depends on distinct functional-neuroanatomical systems including procedural and declarative long-term memory. Characteristic features of rapid eye movement (REM) and non-REM sleep such as rapid eye movements and sleep spindles are electrophysiological markers of cognitively complex procedural and declarative memory consolidation, respectively. In adults, grammatical learning depends at first on declarative memory ("early SLL") then shifts to procedural memory with experience ("late SLL"). However, it is unknown if the shift from declarative to procedural memory in early vs late SLL is supported by sleep. Here, we hypothesized that increases in sleep spindle characteristics would be associated with early SLL, whereas increases in REM activity (eg, density and EEG theta-band activity time-locked to rapid eye movements) would be associated with late SLL. METHODS: Eight Anglophone (English first language) participants completed four polysomnographic recordings throughout an intensive 6-week French immersion course. Sleep spindle data and electroencephalographic spectral power time-locked to rapid eye movements were extracted from parietal temporal electrodes. RESULTS: As predicted, improvements in French proficiency were associated with changes in spindles during early SLL. Furthermore, we observed increased event-related theta power time-locked to rapid eye movements during late SLL compared with early SLL. The increases in theta power were significantly correlated with improvements in French proficiency. DISCUSSION: This supports the notion that sleep spindles are involved in early SLL when grammar depends on declarative memory, whereas cortical theta activity time-locked to rapid eye movements is involved in late SLL when grammar depends on procedural memory.

Reversed and increased functional connectivity in non-REM sleep suggests an altered rather than reduced state of consciousness relative to wake.

Sleep resting state network (RSN) functional connectivity (FC) is poorly understood, particularly for rapid eye movement (REM), and in non-sleep deprived subjects. REM and non-REM (NREM) sleep involve competing drives; towards hypersynchronous cortical oscillations in NREM; and towards wake-like desynchronized oscillations in REM. This study employed simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) to explore whether sleep RSN FC reflects these opposing drives. As hypothesized, this was confirmed for the majority of functional connections modulated by sleep. Further, changes were directional: e.g., positive wake correlations trended towards negative correlations in NREM and back towards positive correlations in REM. Moreover, the majority did not merely reduce magnitude, but actually either reversed and strengthened in the opposite direction, or increased in magnitude during NREM. This finding supports the notion that NREM is best expressed as having altered, rather than reduced FC. Further, as many of these functional connections comprised "higher-order" RSNs (which have been previously linked to cognition and consciousness), such as the default mode network, this finding is suggestive of possibly concomitant alterations to cognition and consciousness.

Increased spindle density correlates with sleep continuity improvements following an eight-week course of a melatonin agonist in people with depression: A proof-of-concept study with agomelatine.

Sleep fragmentation and reductions in sleep spindles have been observed in individuals with depression. Sleep spindles are known to play a protective role for sleep, and there are indications that melatonin agents can enhance spindles in healthy people. Whether agomelatine, a melatonin agonist indicated for the treatment of depression, may increase spindle density sufficiently to impact sleep continuity in people with depression remains unknown. This proof-of-concept study investigated changes in spindles following agomelatine intake in young adults with depression and assessed how they may relate to potential changes in sleep continuity and depressive symptoms. This study was based on an open-label design. Fifteen participants between 17 and 28 years of age (mean = 22.2; standard deviation [SD] = 3.4) with a diagnosis of a depressive disorder underwent polysomnography before and after an intervention including a 1 hr psychoeducation session centered on sleep and circadian rhythms, and an 8-week course of agomelatine (25-50 mg) with a guided sleep phase advance. Fast spindle density significantly increased from pre- to post-intervention. This increase in spindle density significantly correlated with a reduction in wake after sleep onset, and a similar trend was found with increased sleep efficiency. There was no significant correlation between spindle parameters and depressive symptoms. These findings suggest that agomelatine may contribute to enhanced sleep consolidation, possibly in part through the modulation of spindle production. This should be confirmed by larger randomized control trials.

Sleep, Orexin and Cognition.

Orexins regulate a wide variety of biological functions, most notably the sleep-wake cycle, reward and stress processing, alertness, vigilance, and cognitive functioning. Alterations of central and peripheral orexin levels are linked to conditions such as narcolepsy, anorexia nervosa, age-related cognitive decline, and neurodegenerative disease. Preliminary studies suggest that orexin mimetics can safely promote the wake signal via orexin agonism during the day and that orexin receptor antagonists can promote the sleep signal during the night. Thus, novel orexin therapies have the potential to either improve memory, cognition, and daytime performance directly or indirectly, through promotion of good sleep. The full scope of the therapeutic potential of orexin therapies remains to be elucidated.