Local REM sleep-N1-wake sleep stage mixing in narcolepsy type 1

Type 1 narcolepsy (NT1), a disorder caused by the loss of hypocretin/orexin transmission, is characterized by daytime sleepiness and symptoms where Rapid Eye Movement (REM) sleep, a state normally occurring from middle to late in the night, can intermingle with wakefulness. This results in cataplexy and sleep paralysis, episodes of muscle paralysis when awake, or in the generation of dream-like hallucinations and vivid dreaming, periods of visual imagery or sensory experiences that occur while awake, notably when falling asleep (hypnagogic hallucinations) or lingering dreams with over-realistic recall. Using deep learning of nocturnal sleep polysomnography (PSG) signals (EEG, EMG and EOG) applied to sleep stage scoring, we found that NT1 shows abnormally short wake to REM sleep transitions and occurrences of abnormal sleep stages probabilities of wake, REM sleep and N1 (very light NREM) sleep abnormally co-occurs (sleep stage mixing). Interestingly, although presence of these during sleep enables NT1 diagnosis with performances similar to gold standard diagnostic procedure, the multiple sleep latency test (MSLT), the cortical localization of these dissociations remains unclear. In this work, we used electrode specific predictions of sleep stages to explore if these are global or observed at the local cortical level. Surprisingly, although sleep stage mixing was preeminent between REM sleep, N1 and wake across all electrodes, it was found to fluctuate across locations, with stronger fluctuations found in frontal and central locations, notably in the dominant (left) hemisphere. The strongest single discriminator for NT1 was N1-REM stage mixing across central electrodes (C3-C4), showing 4.3-fold higher dissociation in NT1 patients (Cohens d = 0.61). Analysis of sleep stage dissociations across varying time scales revealed that windows lasting several minutes were most predictive of NT1 status, aligning with the duration of clinically reported symptoms of dissociated REM sleep in narcolepsy. Local N1-W-REM sleep dissociations correlated with CSF orexin/hypocretin levels and severity as measured using MSLT. The predominance of stage mixing in frontal and central regions, areas typically associated with executive and motor control, may contribute to the partial preservation of awareness during dissociated REM phenomena. Further, self-reports of hypnagogic hallucinations correlated best with dissociations involving occipital locations, in agreement with its usual visual content. Coherence analysis was also conducted but did not reveal additional insight. These results suggest that orexin deficiency destabilizes REM sleep organization across cortical projection area contributing both to REM sleep dissociation and to abnormal state transitions observed in NT1.