Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors.

Optochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.

Rapid eye movement sleep and slow wave sleep rebounded and related factors during positive airway pressure therapy.

This study aimed to investigate the clinical characteristics and predictors of increased rapid eye movement (REM) sleep or slow wave sleep (SWS) in patients with obstructive sleep apnea (OSA) following positive airway pressure (PAP) therapy. The study retrospectively analyzed data from patients with OSA who underwent both diagnostic polysomnography (PSG) and pressure titration PSG at the Tangdu Hospital Sleep Medicine Center from 2011-2016. Paired diagnostic PSG and pressure titration studies from 501 patients were included. REM rebound was predicted by a higher oxygen desaturation index, lower REM proportion, higher arousal index, lower mean pulse oxygen saturation (SpO2), higher Epworth sleepiness score and younger age (adjusted R2 = 0.482). The SWS rebound was predicted by a longer total duration of apneas and hypopneas, lower N3 duration, lower SpO2 nadir, lower REM proportion in diagnostic PSG and younger age (adjusted R2 = 0.286). Patients without REM rebound or SWS rebound had a high probability of comorbidities with insomnia and mood complaints. Some parameters (subjective and objective insomnia, excessive daytime sleepiness, age and OSA severity) indicate changes in REM sleep and SWS between diagnostic and titration PSG tests. Treatment of insomnia and mood disorders in patients with OSA may helpful to improve the use PAP.

Waking experience modulates sleep need in mice.

BACKGROUND: Homeostatic regulation of sleep is reflected in the maintenance of a daily balance between sleep and wakefulness. Although numerous internal and external factors can influence sleep, it is unclear whether and to what extent the process that keeps track of time spent awake is determined by the content of the waking experience. We hypothesised that alterations in environmental conditions may elicit different types of wakefulness, which will in turn influence both the capacity to sustain continuous wakefulness as well as the rates of accumulating sleep pressure. To address this, we compared the effects of repetitive behaviours such as voluntary wheel running or performing a simple touchscreen task, with wakefulness dominated by novel object exploration, on sleep timing and EEG slow-wave activity (SWA) during subsequent NREM sleep. RESULTS: We find that voluntary wheel running is associated with higher wake EEG theta-frequency activity and results in longer wake episodes, as compared with exploratory behaviour; yet, it does not lead to higher levels of EEG SWA during subsequent NREM sleep in either the frontal or occipital derivation. Furthermore, engagement in a touchscreen task, motivated by food reward, results in lower SWA during subsequent NREM sleep in both derivations, as compared to exploratory wakefulness, even though the total duration of wakefulness is similar. CONCLUSION: Overall, our study suggests that sleep-wake behaviour is highly flexible within an individual and that the homeostatic processes that keep track of time spent awake are sensitive to the nature of the waking experience. We therefore conclude that sleep dynamics are determined, to a large degree, by the interaction between the organism and the environment.

A pilot study on essential oil aroma stimulation for enhancing slow-wave EEG in sleeping brain.

Sleep quality is important to health and life quality. Lack of sleep can lead to a variety of health issues and reduce in daytime function. Recent study by Fultz et al. also indicated that sleep is crucial to brain metabolism. Delta power in sleep EEG often indicates good sleep quality while alpha power usually indicates sleep interruptions and poor sleep quality. Essential oil has been speculated to improve sleep quality. Previous studies also suggest essential oil aroma may affect human brain activity when applied awake. However, those studies were often not blinded, which makes the effectiveness and mechanism of aroma a heavily debated topic. In this study, we aim to explore the effect of essential oil aroma on human sleep quality and sleep EEG in a single-blinded setup. The aroma was released when the participants are asleep, which kept the influence of psychological expectation to the minimum. We recruited nine young, healthy participants with regular lifestyle and no sleep problem. All participants reported better sleep quality and more daytime vigorous after exposing to lavender aroma in sleep. We also observed that upon lavender aroma releases, alpha wave in wake stage was reduced while delta wave in slow-wave sleep (SWS) was increased. Lastly, we found that lavender oil promote occurrence of SWS. Overall, our study results show that essential oil aroma can be used to promote both subjective and objective sleep quality in healthy human subjects. This makes aroma intervention a potential solution for poor sleep quality and insomnia.

Practical and rapidly-implemented parameters for assessing APAP titration failure.

BACKGROUND: This study aimed to show the predictive value of simple polysomnographic parameters including latency of deep sleep (nREM3), latency of rapid eye movement sleep (REM), and minimum oxygen saturation (SpO2) for predicting failure of autoadjusting positive airway pressure (APAP) titration. METHODS: Out of 1470 patients with moderate to severe obstructive sleep apnea syndrome (OSAS) who underwent APAP titration between July 1, 2016, and December 31, 2017, 22 patients with titration failure were enrolled in the study. The demographic and polysomnographic characteristics of this group were compared with 44 patients with an adequate APAP titration who were matched with the titration failure group by age, sex, and OSAS severity. The periods between the start of sleep and the start of REM and nREM3 stages were noted as REM latency and nREM3 latency, respectively. RESULTS: The between group differences in the parameters including nREM3 latency, REM latency, and minimum SpO2 during the titration test were statistically significant (p = 0.004, p = 0.008, p <0.001 respectively). Possible threshold values to predict failure of APAP titration were found as 40 min and 135 min for nREM3 and REM latencies, respectively. The best threshold for minimum SpO2 was 86% with an 86.4% of sensitivity. Despite the high negative predictive values (81% for nREM3 latency, 75% for REM latency), the sensitivities (63.6% for nREM3 latency, 54.5% for REM latency) of the prior parameters in determining titration failure were relatively low. CONCLUSION: The minimum SpO2 < 86% can be used as a readily available indicator of APAP titration failure. nREM3 and REM latencies may be regarded as supplementary indicators in detecting the patients who may need an advanced PAP device.

Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need.

Although sleep is one of the most conserved behaviors, the intracellular mechanism regulating sleep/wakefulness remains unknown. We recently identified a protein kinase, SIK3, as a sleep-regulating molecule. Mice that lack a well-conserved protein kinase A (PKA) phosphorylation site, S551, showed longer non-rapid eye movement (NREM) sleep and increased NREMS delta density. S551 of SIK3 is conserved in other members of the SIK family, such as SIK1 (S577) and SIK2 (S587). Here, we examined whether the PKA phosphorylation sites of SIK1 and SIK2 are involved in sleep regulation by generating Sik1S577A and Sik2S587A mice. The homozygous Sik1S577A mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2S587A mice showed increased NREMS delta density. Both the Sik1S577A and Sik2S587A mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1S577A mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2S587A mice that were fed either a chow or high-fat diet showed similar weight gain as the wild-type littermates. These results suggest that PKA-SIK signaling is involved in the regulation of sleep need.

Quantitative spatio-temporal characterization of epileptic spikes using high density EEG: Differences between NREM sleep and REM sleep.

In this study, we applied high-density EEG recordings (HD-EEG) to quantitatively characterize the fine-grained spatiotemporal distribution of inter-ictal epileptiform discharges (IEDs) across different sleep stages. We quantified differences in spatial extent and duration of IEDs at the scalp and cortical levels using HD-EEG source-localization, during non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, in six medication-refractory focal epilepsy patients during epilepsy monitoring unit admission. Statistical analyses were performed at single subject level and group level across different sleep stages for duration and distribution of IEDs. Tests were corrected for multiple comparisons across all channels and time points. Compared to NREM sleep, IEDs during REM sleep were of significantly shorter duration and spatially more restricted. Compared to NREM sleep, IEDs location in REM sleep also showed a higher concordance with electrographic ictal onset zone from scalp EEG recording. This study supports the localizing value of REM IEDs over NREM IEDs and suggests that HD-EEG may be of clinical utility in epilepsy surgery work-up.

End-expiratory lung volume decreases during REM sleep despite continuous positive airway pressure.

PURPOSE: Patients with obstructive sleep apnea (OSA) may experience apneas and hypopneas primarily during stage R (REM) sleep when end-expiratory lung volume (EELV) reaches its nadir. The purpose of this study was to determine if REM-related reductions in EELV persist in the presence of continuous positive airway pressure (CPAP) prescribed during non-stage REM (NREM) sleep. METHODS: We prospectively recruited 17 subjects referred to the sleep laboratory for CPAP titration. CPAP was titrated per AASM protocol to control respiratory events. The change in EELV was measured using magnetometry. RESULTS: Of the 17 subjects, 12 (71%) had moderate to severe OSA. Despite the application of CPAP, there was a significant reduction in EELV between NREM and REM sleep (- 105.9 ± 92.2 to - 325.0 ± 113.1 mL, respectively, p < 0.01). The change in EELV between non-stage R (NREM) and REM significantly correlated with overall apnea-hypopnea index (AHI) (r = 0.5, p = 0.04), the number of respiratory arousals during REM (r = 0.5, p = 0.04), and prescribed level of CPAP (r = 0.7, p < 0.01). CONCLUSION: REM-related reductions in EELV are associated with worsening sleep disordered breathing and occur despite the presence of CPAP.

Adrenergic reactions during N3 sleep arousals in sleepwalking and sleep terrors: The chicken or the egg?

To understand the mechanisms of N3 sleep interruptions in patients with sleepwalking episodes and/or sleep terrors (SW/ST), we evaluated whether autonomic reactions preceded or accompanied behavioural arousals from NREM sleep stage N3. In 20 adult patients with SW/ST and 20 matched controls without parasomnia, heart rate and pulse wave amplitude were measured beat-to-beat during the 10 beats preceding and during the 15 beats succeeding a motor arousal from N3 sleep. Respiratory rate and amplitude were measured during the same 25 successive beats. In patients with SW/ST, the N3 arousals were associated with a 33% increase in heart rate, a 57% decrease in pulse wave amplitude (indicating a major vasoconstriction), a 24% increase in respiratory rate and a doubling of respiratory amplitude. Notably, tachycardia and vasoconstriction started 4 s before motor arousals. A similar profile (tachycardia and vasoconstriction gradually increasing from the 4 s preceding arousal and post-arousal increase of respiratory amplitude, but no polypnea) was also observed, with a lower amplitude, during the less frequent 38 quiet N3 arousals in control subjects. Parasomniac arousals were associated with greater tachycardia, vasoconstriction and polypnea than quiet arousals, with the same pre-arousal gradual increases in heart rate and vasoconstriction. Autonomic arousal occurs 4 s before motor arousal from N3 sleep in patients with SW/ST (with a higher adrenergic reaction than in controls), suggesting that an alarming event during sleep (possibly a worrying sleep mentation or a local subcortical arousal) causes the motor arousal.

Evolución atípica del síndrome de Panayiotopoulos a síndrome de punta-ondas continuas durante el sueño lento / Atypical evolution of Panayiotopoulos syndrome to continuous spikes and wave's syndrome during slow sleep

Introducción: Las epilepsias focales idiopáticas constituyen uno de los grupos de epilepsias más frecuentes en la infancia. Excepcionalmente los pacientes con este tipo de epilepsias tienen evoluciones atípicas que constituyen un reto diagnóstico y terapéutico. Objetivo: Ilustrar la evolución atípica de la epilepsia focal idiopática tipo Panayiotopoulos. Presentación del caso: Adolescente de 13 años que presentó su primera crisis epiléptica a los 5 años de edad, de breve duración, mientras dormía tuvo apertura ocular, desviación de los ojos a la izquierda, abundante salivación y presentó un vómito. En tres años tuvo solo tres crisis. No recibió tratamiento con fármacos antiepilépticos hasta después de la tercera crisis, que fue más prolongada. Tras iniciar tratamiento con carbamazepina comenzó a presentar dificultades en el aprendizaje y marcada hiperactividad. Un electroencefalograma interictal de sueño demostró descargas de punta-ondas continuas en el sueño lento. Después de dos años de tratamiento se alcanzó la normalidad en el estudio electroencefalográfico de sueño, con retirada inicial de la carbamazepina, e introducción progresiva de clobazam y valproato de magnesio. Evolutivamente el paciente mantuvo las dificultades en el aprendizaje, con mejoría notable de su hiperactividad, sin recurrencia de crisis epilépticas. Conclusiones: El caso presentado constituye un ejemplo infrecuente de un paciente con una epilepsia focal idiopática con evolución atípica, probablemente inducida por la carbamazepina, con cuadro clínico-electroencefalográfico de más de dos años de duración, con mejoría favorecida por el tratamiento finalmente empleado, la evolución natural del síndrome o el efecto de ambos (AU)

Introduction: Idiopathic focal epilepsies are one of the most frequent epilepsy groups in childhood. Exceptionally, patients with this type of epilepsy have atypical evolutions that constitute a diagnostic and therapeutic challenge. Objective: To illustrate the atypical evolution of idiopathic focal epilepsy, type Panayiotopoulos. Case presentation: A 13-year-old adolescent who presented his first epileptic seizure at 5 years old, of short duration, while he slept had an eye opening, deviation of the eyes to the left, abundant salivation and vomiting. In three years he had only three seizures. He did not receive treatment with antiepileptic drugs until after the third seizure, which was longer. After starting treatment with carbamazepine, he began to have learning difficulties and marked hyperactivity. A sleep's interictal electroencephalogram showed continuous spikes and wave's discharges during the slow sleep. After two years of treatment, the normalization of the sleep electroencephalogram was achieved, with withdrawal of carbamazepine, and progressive introduction of clobazam and magnesium valproate. The patient remained evolutionarily with learning difficulties, with significant improvement in hyperactivity, without recurrence of seizures. Conclusions: The case presented is an infrequent example of a patient with idiopathic focal epilepsy with atypical evolution, probably induced by carbamazepine, with clinical-electroencephalographic symptoms during more than two years, with improvement favored by the final treatment used, the natural evolution of the syndrome or the effect of both(AU)

A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep.

How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states. VIDEO ABSTRACT.

c-Fos expression in the limbic thalamus following thermoregulatory and wake-sleep changes in the rat.

A cellular degeneration of two thalamic nuclei belonging to the "limbic thalamus", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (Ta, - 10 °C) and in the first hours of the subsequent recovery period at normal laboratory Ta (25 °C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation.

The neural tides of sleep and consciousness revealed by single-pulse electrical brain stimulation.

Wakefulness and sleep arise from global changes in brain physiology that may also govern the flow of neural activity between cortical regions responsible for perceptual processing versus planning and action. To test whether and how the sleep/wake cycle affects the overall propagation of neural activity in large-scale brain networks, we applied single-pulse electrical stimulation (SPES) in patients implanted with intracranial EEG electrodes for epilepsy surgery. SPES elicited cortico-cortical spectral responses at high-gamma frequencies (CCSRHG, 80-150 Hz), which indexes changes in neuronal population firing rates. Using event-related causality (ERC) analysis, we found that the overall patterns of neural propagation among sites with CCSRHG were different during wakefulness and different sleep stages. For example, stimulation of frontal lobe elicited greater propagation toward parietal lobe during slow-wave sleep than during wakefulness. During REM sleep, we observed a decrease in propagation within frontal lobe, and an increase in propagation within parietal lobe, elicited by frontal and parietal stimulation, respectively. These biases in the directionality of large-scale cortical network dynamics during REM sleep could potentially account for some of the unique experiential aspects of this sleep stage. Together these findings suggest that the regulation of conscious awareness and sleep is associated with differences in the balance of neural propagation across large-scale frontal-parietal networks.

Extracellular adenosine and slow-wave sleep are increased after ablation of nucleus accumbens core astrocytes and neurons in mice.

Sleep and wakefulness are controlled by a wide range of neuronal populations in the mammalian brain. Activation of adenosine A2A receptor (A2AR)-expressing neurons in the nucleus accumbens (NAc) core promotes slow-wave sleep (SWS). The neuronal mechanism by which activation of NAc A2AR neurons induces SWS, however, is unknown. We hypothesized that the ability of NAc activation to induce sleep is mediated by the classic somnogen adenosine, which can be formed by various processes in all types of cells. Here, to investigate whether astrocytes are involved in the ability of the NAc to regulate SWS, we ablated glial fibrillary acidic protein (GFAP)-positive cells in the NAc core of mice by virus-mediated expression of diphtheria toxin (DT) receptors and intraperitoneal administration of DT. Analysis of electroencephalogram and electromyogram recordings of DT-treated wild-type mice revealed that SWS was remarkably increased at 1 week after DT treatment, whereas sleep-wake behavior was unchanged in DT-treated A2AR knockout mice. Cell ablation was associated with an increased number of GFAP-positive cells and activation of microglia in the NAc. In-vivo microdialysis revealed significantly increased levels of extracellular adenosine in the NAc at 1 week after DT treatment. Our findings suggest that elevated adenosine levels in the NAc core promote SWS by acting on A2ARs and provide the first evidence that adenosine is an endogenous candidate for activating NAc A2AR neurons that have the ability to induce SWS.

Stimulating the sleeping brain: Current approaches to modulating memory-related sleep physiology.

BACKGROUND: One of the most audacious proposals throughout the history of psychology was the potential ability to learn while we sleep. The idea penetrated culture via sci-fi movies and inspired the invention of devices that claimed to teach foreign languages, facts, and even quit smoking by simply listening to audiocassettes or other devices during sleep. However, the promises from this endeavor didn't stand up to experimental scrutiny, and the dream was shunned from the scientific community. Despite the historic evidence that the sleeping brain cannot learn new complex information (i.e., words, images, facts), a new wave of current interventions are demonstrating that sleep can be manipulated to strengthen recent memories. NEW METHOD: Several recent approaches have been developed that play with the sleeping brain in order to modify ongoing memory processing. Here, we provide an overview of the available techniques to non-invasively modulate memory-related sleep physiology, including sensory, vestibular and electrical stimulation, as well as pharmacological approaches. RESULTS: N/A. COMPARISON WITH EXISTING METHODS: N/A. CONCLUSIONS: Although the results are encouraging, suggesting that in general the sleeping brain may be optimized for better memory performance, the road to bring these techniques in free-living conditions is paved with unanswered questions and technical challenges that need to be carefully addressed.

Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function.

Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.

Automated unsupervised behavioral state classification using intracranial electrophysiology.

OBJECTIVE: Automated behavioral state classification in intracranial EEG (iEEG) recordings may be beneficial for iEEG interpretation and quantifying sleep patterns to enable behavioral state dependent neuromodulation therapy in next generation implantable brain stimulation devices. Here, we introduce a fully automated unsupervised framework to differentiate between awake (AW), sleep (N2), and slow wave sleep (N3) using intracranial EEG (iEEG) only and validated with expert scored polysomnography. APPROACH: Data from eight patients undergoing evaluation for epilepsy surgery (age [Formula: see text], three female) with intracranial depth electrodes for iEEG monitoring were included. Spectral power features (0.1-235 Hz) spanning several frequency bands from a single electrode were used to classify behavioral states of patients into AW, N2, and N3. MAIN RESULTS: Overall, classification accuracy of 94%, with 94% sensitivity and 93% specificity across eight subjects using multiple spectral power features from a single electrode was achieved. Classification performance of N3 sleep was significantly better (95%, sensitivity 95%, specificity 93%) than that of the N2 sleep phase (87%, sensitivity 78%, specificity 96%). SIGNIFICANCE: Automated, unsupervised, and robust classification of behavioral states based on iEEG data is possible, and it is feasible to incorporate these algorithms into future implantable devices with limited computational power, memory, and number of electrodes for brain monitoring and stimulation.

Slow-wave activity surrounding stage N2 K-complexes and daytime function measured by psychomotor vigilance test in obstructive sleep apnea.

STUDY OBJECTIVE: To better understand the inter-individual differences in neurobehavioral impairment in obstructive sleep apnea (OSA) and its treatment with continuous positive airway pressure (CPAP), we examined how changes in sleep electroencephalography (EEG) slow waves were associated with next-day psychomotor vigilance test (PVT) performance. METHODS: Data from 28 OSA subjects (Apnea-Hypopnea Index with 3% desaturation and/or with an associated arousal [AHI3A] > 15/hour; AHI3A = sum of all apneas and hypopneas with 3% O2 desaturation and/or an EEG arousal, divided by total sleep time [TST]), who underwent three full in-lab nocturnal polysomnographies (NPSGs: chronic OSA, CPAP-treated OSA, and acute OSA), and 19 healthy sleepers were assessed. Four 20-minute PVTs were performed after each NPSG along with subjective and objective assessment of sleepiness. Three EEG metrics were calculated: K-complex (KC) Density (#/minute of N2 sleep), change in slow-wave activity in 1-second envelopes surrounding KCs (ΔSWAK), and relative frontal slow-wave activity during non-rapid eye movement (NREM) (%SWA). RESULTS: CPAP treatment of OSA resulted in a decrease in KC Density (chronic: 3.9 ± 2.2 vs. treated: 2.7 ± 1.1; p < 0.01; mean ± SD) and an increase in ΔSWAK (chronic: 2.6 ± 2.3 vs. treated: 4.1 ± 2.4; p < 0.01) and %SWA (chronic: 20.9 ± 8.8 vs. treated: 26.6 ± 8.6; p < 0.001). Cross-sectionally, lower ΔSWAK values were associated with higher PVT Lapses (chronic: rho = -0.55, p < 0.01; acute: rho = -0.46, p = 0.03). Longitudinally, improvement in PVT Lapses with CPAP was associated with an increase in ΔSWAK (chronic to treated: rho = -0.48, p = 0.02; acute to treated: rho = -0.5, p = 0.03). In contrast, OSA severity or global sleep quality metrics such as arousal index, NREM, REM, or TST were inconsistently associated with PVT Lapses. CONCLUSION: Changes in EEG slow waves, in particular ∆SWAK, explain inter-individual differences in PVT performance better than conventional NPSG metrics, suggesting that ΔSWAK is a night-time correlate of next-day vigilance in OSA.

Altered brain perfusion patterns in wakefulness and slow-wave sleep in sleepwalkers.

Study Objectives: The present study assessed brain perfusion patterns with single-photon emission computed tomography (SPECT) during sleepwalkers' post-sleep deprivation slow-wave sleep (SWS) and resting-state wakefulness. Methods: Following a 24 hr period of sleep deprivation, 10 sleepwalkers and 10 sex- and age-matched controls were scanned with a high-resolution SPECT scanner. Participants were injected with 99mTc-ethylene cysteinate dimer after 2 min of stable SWS within their first sleep cycle as well as during resting-state wakefulness, both after a subsequent 24 hr period of sleep deprivation. Results: When compared with controls' brain perfusion patterns during both SWS and resting-state wakefulness, sleepwalkers showed reduced regional cerebral perfusion in several bilateral frontal regions, including the superior frontal, middle frontal, and medial frontal gyri. Moreover, reduced regional cerebral perfusion was also found in sleepwalkers' left postcentral gyrus, insula, and superior temporal gyrus during SWS compared with controls. During resting-state wakefulness compared with controls, reduced cerebral perfusion was also found in parietal and temporal regions of sleepwalkers' left hemisphere, whereas the right parahippocampal gyrus showed increased regional cerebral perfusion. Conclusions: Our results reveal patterns of reduced regional cerebral perfusion in sleepwalkers' frontal and parietal areas when compared with controls, regions previously associated with SWS generation and episode occurrence. Additionally, reduced perfusion in the dorsolateral prefrontal cortex and insula during recovery SWS is consistent with the clinical features of somnambulistic episodes, including impaired awareness and reduced pain perception. Altered regional cerebral perfusion patterns during sleepwalkers' resting-state wakefulness may be related to daytime functional anomalies in this population.

Sleep State Dependence of Optogenetically evoked Responses in Neuronal Nitric Oxide Synthase-positive Cells of the Cerebral Cortex.

Slow-wave activity (SWA) in the electroencephalogram during slow-wave sleep (SWS) varies as a function of sleep-wake history. A putative sleep-active population of neuronal nitric oxide synthase (nNOS)-containing interneurons in the cerebral cortex, defined as such by the expression of Fos in animals euthanized after protracted deep sleep, may be a local regulator of SWA. We investigated whether electrophysiological responses to activation of these cells are consistent with their role of a local regulator of SWA. Using a Cre/loxP strategy, we targeted the population of nNOS interneurons to express the light-activated cation channel Channelrhodopsin2 and the histological marker tdTomato in mice. We then performed histochemical and optogenetic studies in these transgenic mice. Our studies provided histochemical evidence of transgene expression and electrophysiological evidence that the cerebral cortex was responsive to optogenetic manipulation of these cells in both anesthetized and behaving mice. Optogenetic stimulation of the cerebral cortex of animals expressing Channelrhodopsin2 in nNOS interneurons triggered an acute positive deflection of the local field potential that was followed by protracted oscillatory events only during quiet wake and slow wave sleep. The response during wake was maximal when the electroencephalogram (EEG) was in a negative polarization state and abolished when the EEG was in a positive polarization state. Since the polarization state of the EEG is a manifestation of slow-wave oscillations in the activity of underlying pyramidal neurons between the depolarized (LFP negative) and hyperpolarized (LFP positive) states, these data indicate that sleep-active cortical neurons expressing nNOS function in sleep slow-wave physiology.