LAUSR

The orexin (ORX)/hypocretin system stabilizes sleep-wake regulation by sustaining long periods of wakefulness in humans and animals. We aimed to evaluate the relationships between cerebrospinal fluid (CSF) ORX levels and markers of nocturnal sleep stability assessed by polysomnography (PSG) in humans. Nocturnal PSG data and CSF ORX levels of 300 drug-free subjects (55% men, 29.9±15.5 years old, mean ORX levels 155.1±153.7 pg/mL) with a complaint of hypersomnolence were collected in the National Reference Center for Narcolepsy, France. Several markers of nocturnal sleep stability were analyzed: wake (WB), sleep bouts (SB), and sleep/wake transitions. Groups were categorized according to ORX levels: two categories (≤110, >110 pg/mL, the current established threshold of ORX-deficiency), and tertiles (≤26,]26;254], >254 pg/mL); and were compared using logistic regression models. Results were adjusted for age, gender and body mass index. ORX-deficient subjects had more WB, SB, and sleep-wake transitions than the others. The WB duration was longer and the SB duration shorter in ORX-deficient category. The proportion of the shortest WB (30 sec) was lower in the ORX-deficient category whereas the proportion of WB above 1 min 30 sec was higher. The proportion of SB ≤ 14min was higher among ORX-deficient patients, with opposite results for longer SB. Subsequent analyses performed in the population categorized according to tertiles of CSF ORX-A confirmed all these findings, with a strong dose-response effect of ORX levels in post-hoc comparisons. All results remained highly significant in adjusted statistical models. This study provides a strong evidence of the direct effect of ORX on nocturnal sleep stabilization in humans. WB and SB are reliable markers of nighttime sleep stability, strongly correlated to CSF ORX-A levels in a dose dependent way. These PSG biomarkers are promising to be applied in clinical and research settings. none