Revisiting the maintenance of wakefulness test: from intra-/inter-scorer agreement to normative values in patients treated for obstructive sleep apnea.

The Maintenance of Wakefulness Test is widely used to objectively assess sleepiness and make safety-related decisions, but its interpretation is subjective and normative values remain debated. Our work aimed to determine normative thresholds in non-subjectively sleepy patients with well-treated obstructive sleep apnea, and to assess intra- and inter-scorer variability. We included maintenance of wakefulness tests of 141 consecutive patients with treated obstructive sleep apnea (90% men, mean (SD) age 47.5 (9.2) years, mean (SD) pre-treatment apnea-hypopnea index of 43.8 (20.3) events/h). Sleep onset latencies were independently scored by two experts. Discordant scorings were reviewed to reach a consensus and half of the cohort was double-scored by each scorer. Intra- and inter-scorer variability was assessed using Cohen's kappa for 40, 33, and 19 min mean sleep latency thresholds. Consensual mean sleep latencies were compared between four groups according to subjective sleepiness (Epworth Sleepiness Scale score < versus ≥11) and residual apnea-hypopnea index (< versus ≥15 events/h). In well-treated non-sleepy patients (n = 76), the consensual mean (SD) sleep latency was 38.4 (4.2) min (lower normal limit [mean - 2SD] = 30 min), and 80% of them did not fall asleep. Intra-scorer agreement on mean sleep latency was high but inter-scorer was only fair (Cohen's kappa 0.54 for 33-min threshold, 0.27 for 19-min threshold), resulting in changes in latency category in 4%-12% of patients. A higher sleepiness score but not the residual apnea-hypopnea index was significantly associated with a lower mean sleep latency. Our findings suggest a higher than usually accepted normative threshold (30 min) in this context and emphasise the need for more reproducible scoring approaches.

Predicting the loss of responsiveness when falling asleep in humans.

Falling asleep is a dynamical process that is poorly defined. The period preceding sleep, characterized by the progressive alteration of behavioral responses to the environment, which may last several minutes, has no electrophysiological definition, and is embedded in the first stage of sleep (N1). We aimed at better characterizing this drowsiness period looking for neurophysiological predictors of responsiveness using electro and magneto-encephalography. Healthy participants were recorded when falling asleep, while they were presented with continuous auditory stimulations and asked to respond to deviant sounds. We analysed brain responses to sounds and markers of ongoing activity, such as information and connectivity measures, in relation to rapid fluctuations of brain rhythms observed at sleep onset and participants' capabilities to respond. Results reveal a drowsiness period distinct from wakefulness and sleep, from alpha rhythms to the first sleep spindles, characterized by diverse and transient brain states that come on and off at the scale of a few seconds and closely reflects, mainly through neural processes in alpha and theta bands, decreasing probabilities to be responsive to external stimuli. Results also show that the global P300 was only present in responsive trials, regardless of vigilance states. A better consideration of the drowsiness period through a formalized classification and its specific brain markers such as described here should lead to significant advances in vigilance assessment in the future, in medicine and ecological environments.

Disruption of hierarchical predictive coding during sleep.

When presented with an auditory sequence, the brain acts as a predictive-coding device that extracts regularities in the transition probabilities between sounds and detects unexpected deviations from these regularities. Does such prediction require conscious vigilance, or does it continue to unfold automatically in the sleeping brain? The mismatch negativity and P300 components of the auditory event-related potential, reflecting two steps of auditory novelty detection, have been inconsistently observed in the various sleep stages. To clarify whether these steps remain during sleep, we recorded simultaneous electroencephalographic and magnetoencephalographic signals during wakefulness and during sleep in normal subjects listening to a hierarchical auditory paradigm including short-term (local) and long-term (global) regularities. The global response, reflected in the P300, vanished during sleep, in line with the hypothesis that it is a correlate of high-level conscious error detection. The local mismatch response remained across all sleep stages (N1, N2, and REM sleep), but with an incomplete structure; compared with wakefulness, a specific peak reflecting prediction error vanished during sleep. Those results indicate that sleep leaves initial auditory processing and passive sensory response adaptation intact, but specifically disrupts both short-term and long-term auditory predictive coding.

Sleepiness and the transition from wakefulness to sleep.

The transition from wakefulness to sleep is a progressive process that is reflected in the gradual loss of responsiveness, an alteration of cognitive functions, and a drastic shift in brain dynamics. These changes do not occur all at once. The sleep onset period (SOP) refers here to this period of transition between wakefulness and sleep. For example, although transitions of brain activity at sleep onset can occur within seconds in a given brain region, these changes occur at different time points across the brain, resulting in a SOP that can last several minutes. Likewise, the transition to sleep impacts cognitive and behavioral levels in a graded and staged fashion. It is often accompanied and preceded by a sensation of drowsiness and the subjective feeling of a need for sleep, also associated with specific physiological and behavioral signatures. To better characterize fluctuations in vigilance and the SOP, a multidimensional approach is thus warranted. Such a multidimensional approach could mitigate important limitations in the current classification of sleep, leading ultimately to better diagnoses and treatments of individuals with sleep and/or vigilance disorders. These insights could also be translated in real-life settings to either facilitate sleep onset in individuals with sleep difficulties or, on the contrary, prevent or control inappropriate sleep onsets.

Embracing sleep-onset complexity.

Sleep is crucial for many vital functions and has been extensively studied. By contrast, the sleep-onset period (SOP), often portrayed as a mere prelude to sleep, has been largely overlooked and remains poorly characterized. Recent findings, however, have reignited interest in this transitional period and have shed light on its neural mechanisms, cognitive dynamics, and clinical implications. This review synthesizes the existing knowledge about the SOP in humans. We first examine the current definition of the SOP and its limits, and consider the dynamic and complex electrophysiological changes that accompany the descent to sleep. We then describe the interplay between internal and external processing during the wake-to-sleep transition. Finally, we discuss the putative cognitive benefits of the SOP and identify novel directions to better diagnose sleep-onset disorders.

Altered reinforcement learning in Narcolepsy type I and other central disorders of hypersomnolence.

Cognitive impairments are described in central disorders of hypersomnolence (CDH), but studies remain very limited and largely focused on narcolepsy type 1 (NT1). The precise nature and origin of these cognitive impairments is poorly understood. Specifically, impaired decision making under ambiguity has been reported in NT1 and suggested to be caused by dysregulation of the direct projections of hypocretin neurons to the dopamine network. However, the decision-making tasks used previously embed different cognitive functions that are difficult to isolate. This study aims to test reinforcement learning in participants with NT1 and with other (non-hypocretin deficient) CDH in a task known to directly depend on the dopamine system. Participants with NT1 (N = 27), other CDH (N = 34, including narcolepsy type 2 and idiopathic hypersomnia, matched with NT1 participants for sleepiness severity), and healthy participants (N = 34) took part in the study. Results showed that all groups had normal and similar positive reinforcement learning, a pattern not suggestive of dopamine deficiency. However, both participants with NT1 and other CDH had decreased learning abilities to avoid losses. This decreased negative reinforcement learning in participants with CDH was associated with the alteration of vigilance. This study provides new insights into the nature of decision making impairment in people with CDH and suggests that these alterations could be minimized by restoring adequate vigilance.

Impaired Sequential but Preserved Motor Memory Consolidation in Multiple Sclerosis Disease.

Studies investigating motor learning in patients with multiple sclerosis (MS) disease highlighted that MS patients exhibit similar learning performance than healthy controls, but that learning can be hampered by the progression of MS eventually leading to impaired efficiency of subcortical-cortical networks. We aimed at investigating whether the long-term, overnight consolidation of sequential motor memories is preserved in MS disease. Thirty-one patients with MS and two healthy control groups (27 young and 14 middle age) were tested over two consecutive days using a serial reaction time task. Performance was tested (a) 20 min after the end of learning at Day 1 to monitor transient offline, short-term increase in motor and sequential performance and (b) after 24 h on Day 2 to quantify overnight delayed changes in performance reflecting memory consolidation. Besides a slower overall RT in patients with MS, motor performance similarly evolved in all groups. Sequence learning as assessed by interference effects was similar in patients with MS and both control groups on Day 1 (Learning and 20-min test). In contrast, while interference effects keep increasing on Day 2 after 24 h (Relearning) in healthy control groups, it reverted to levels reached at the end of learning for patients with MS. Long-term consolidation of sequential knowledge is impaired in patients with MS. At the motor level, learning and overnight consolidation abilities are preserved in MS disease.

Order matters: sleep spindles contribute to memory consolidation only when followed by rapid-eye-movement sleep.

Sleep is known to benefit memory consolidation, but little is known about the contribution of sleep stages within the sleep cycle. The sequential hypothesis proposes that memories are first replayed during nonrapid-eye-movement (NREM or N) sleep and then integrated into existing networks during rapid-eye-movement (REM or R) sleep, two successive critical steps for memory consolidation. However, it lacks experimental evidence as N always precedes R sleep in physiological conditions. We tested this sequential hypothesis in patients with central hypersomnolence disorder, including patients with narcolepsy who present the unique, anti-physiological peculiarity of frequently falling asleep in R sleep before entering N sleep. Patients performed a visual perceptual learning task before and after daytime naps stopped after one sleep cycle, starting in N or R sleep and followed by the other stage (i.e. N-R vs. R-N sleep sequence). We compared over-nap changes in performance, reflecting memory consolidation, depending on the sleep sequence during the nap. Thirty-six patients who slept for a total of 67 naps were included in the analysis. Results show that sleep spindles are associated with memory consolidation only when N is followed by R sleep, that is in physiologically ordered N-R naps, thus providing support to the sequential hypothesis in humans. In addition, we found a negative effect of rapid-eye-movements in R sleep on perceptual consolidation, highlighting the complex role of sleep stages in the balance to remember and to forget.

Maintenance of wakefulness test: how does it predict accident risk in patients with sleep disorders?

STUDY OBJECTIVE: To determine whether the objective level of alertness measured by the Maintenance of Wakefulness Test (MWT) is associated with the occurrence of self-reported sleepiness-related traffic near misses and accidents related to sleepiness in patients with sleep disorders. METHODS: This case-control study was conducted over a three-year period in four French sleep centers during a 4∗40 min MWT in patients driving more than 5000 Km/year. Relationship between mean sleep latency on the MWT (MWT latency) and age, sex, driving, sleepiness-related near misses and accidents reported during the previous year, and sleep disorder characteristics was analyzed. RESULTS: Of 377 patients suffering from OSAS, idiopathic hypersomnia, narcolepsy, restless leg syndrome or insufficient sleep syndrome, 176 were included. 74 cases reported an accident or near miss related to sleepiness at the wheel in the past year, and 102 reported no accident/near miss (control patients). Thirty-one (37.8 %) cases and 9 (8.8 %) controls reported being sleepy at the wheel more than once a week (p < 0.0001). After adjusted regression analyses, patients with MWT latency between 19 and 33 minutes had a 3.2- (CI 95%[1.5; 6.8], p < 0.0001) fold increase in risk of reporting a near miss/ accident and patients with MWT latency <19 min had a 5.5- (CI 95%[2.2; 13.8], p = 0.003) fold increase in this risk, compared to the referent group (MWT latency>33 min). CONCLUSIONS: MWT latency is associated with self-reported, sleepiness-related near misses and accidents related to sleepiness in the past year in patients routinely investigated in sleep clinics. The MWT could be used to assess driving risk together with clinical interviews assessing sleepiness at the wheel.

Detection of arithmetic violations during sleep.

Can the sleeping brain develop predictions of future auditory stimuli? Past research demonstrated disrupted prediction capabilities during sleep in the context of novel, arbitrary auditory sequences, but the availability of overlearned knowledge already stored in long-term memory could still be preserved. We tested the sleeping brain capabilities to detect violations of simple arithmetic facts. Sleeping participants were presented with spoken arithmetic facts such as "two plus two is nine" and brain responses to correct or incorrect results were recorded in electro and magneto-encephalography. Sleep responses were compared to both attentive and inattentive wakefulness. During attentive wakefulness, arithmetic violations elicited a succession of N400 and P600 effects, whereas no such activations could be recorded in sleep or in inattentive wakefulness. Still, small but significant effects remained in sleep, advocating for a preserved but partial accessibility to arithmetic facts stored in long-term memory and preserved predictions of low-level and already learned knowledge. Those effects were very different from residual activities seen in inattention, highlighting the differences of information processing between the sleeping and the inattentive brain.

Alzheimer's Disease Severity is Not Significantly Associated with Short Sleep: Survey by Actigraphy on 208 Mild and Moderate Alzheimer's Disease Patients.

BACKGROUND: In epidemiological surveys, cognitive decline has been found to be associated with both short and long sleep duration. OBJECTIVE: Our goal was to objectively determine how total sleep time (TST) at night was associated or not with apathy or severity scores in patients with Alzheimer 's disease (AD). METHODS: During an observational first step of a clinical trial, sleep was assessed in institutionalized patients with mild or moderate AD using actigraphy (MW8, Camtech, Cambridge, UK) for 14 consecutive 24-hour periods. Sleep parameters analyzed were: TST, time in bed (TIB), wake after sleep onset (WASO), sleep efficiency (SE) defined by the ratio TST/TIB, in percentage), the number and length of awakenings, the night fragmentation index, the interdaily stability, and intradaily variability indexes. Statistical association analyses were tested between these values and AD apathy and severity scores. RESULTS: 208 individuals coming from 82 centers worldwide (France, Germany, Spain, Italy, Portugal, Poland, United States, Canada, and Australia) and≥50 years old participated. Their average TST was 7 hours and 35 minutes and the average WASO 58 minutes. TST and SE were significantly higher in patients with apathy and the number of awakenings was significantly lower. TST was also positively associated with functional disability (ADCS-ADL scores), but it was not found significantly greater in patients with a moderate AD severity compared to the mild. CONCLUSION: Despite several and long awakenings, TST was not shorter in patients with AD. TST was even significantly increased with disability and apathy.

Sound level intensity severely disrupts sleep in ventilated ICU patients throughout a 24-h period: a preliminary 24-h study of sleep stages and associated sound levels.

BACKGROUND: It is well recognized that sleep is severely disturbed in patients in intensive care units (ICU) and that this can compromise their rehabilitation potential. However, it is still difficult to objectively assess sleep quantity and quality and the determinants of sleep disturbance remain unclear. The aim of this study was therefore to evaluate carefully the impact of ICU sound intensity levels and their sources on ICU patients' sleep over a 24-h period. METHODS: Sleep and sound levels were recorded in 11 ICU intubated patients who met the criteria. Sleep was recorded using a miniaturized multi-channel ambulatory recording device. Sound intensity levels and their sources were recorded with the Nox-T3 monitor. A 30-s epoch-by-epoch analysis of sleep stages and sound data was carried out. Multinomial and binomial logistic regressions were used to associate sleep stages, wakefulness and sleep-wake transitions with sound levels and their sources. RESULTS: The subjects slept a median of 502.2 [283.2-718.9] min per 24 h; 356.9 [188.6-590.9] min at night (22.00-08.00) and 168.5 [142.5-243.3] during daytime (8 am-10 pm). Median sound intensity level reached 70.2 [65.1-80.3] dBC at night. Sound thresholds leading to disturbed sleep were 63 dBC during the day and 59 dBC during the night. With levels above 77 dBC, the incidence of arousals (OR 3.9, 95% CI 3.0-5.0) and sleep-to-wake transitions (OR 7.6, 95% CI 4.1-14) increased. The most disturbing noises sources were monitor alarms (OR 4.5, 95% CI 3.5-5.6) and ventilator alarms (OR 4.2, 95% CI 2.9-6.1). CONCLUSIONS: We have shown, in a small group of 11 non-severe ICU patients, that sound level intensity, a major disturbance factor of sleep continuity, should be strictly controlled on a 24-h profile.

Imaging 'top-down' mobilization of visual information: a case study in a posterior split-brain patient.

During visual perception, automatic bottom-up and controlled top-down processes occur simultaneously and interact in a complex way, making them difficult to isolate and characterize. In rare neurological conditions, such a dissociation can be achieved more easily. In the present work, we studied a patient (AC) with a posterior lesion of the corpus callosum (CC), using a combination of behavioural, structural MRI and high-density scalp EEG measures. Given the complete disruption of the posterior half of the CC, we speculated that inter-hemispheric transfer of visual information was only possible through top-down mobilization across the preserved anterior segment of the CC. We designed a matching-to-sample visual task during which this patient was randomly presented with two successive numerical targets (T1 and T2) flashed with either a short or a long stimulus-onset asynchrony (SOA), each presented within one visual hemifield (HF). Intra-hemispheric processing of visual stimuli was essentially preserved. In sharp contrast, patient's performance was massively impaired during inter-HFs trials with a short-SOA, confirming the lack of fast inter-hemispheric transfer. Crucially, patient AC spontaneously improved his performance in inter-HFs trials with a long-SOA. This behavioral improvement was correlated with a mid-frontal ERP effect occurring during the T1-T2 interval, concomitant with an increase of functional connectivity of this region with distant areas including occipital regions. These results put to light a slow, non-automatic, and frontally mediated route of inter-hemispheric transfer dependent on top-down control.