Multimodal circadian phenotyping reveals distinct mechanisms of photic entrainment failure in two sighted patients with non-24-hour sleep-wake disorder.
Aug 2026· Sleep Medicine· Vol 148, pp.
109204
· 0 citations· 20 references
Medicine
TL;DR
This first multimodal characterization of sighted N24SWD reveals distinct pathophysiological mechanisms underlying failure of photic circadian entrainment and suggests that N24SWD in sighted individuals should not be considered a unitary disorder but rather a heterogeneous condition resulting from dysfunction at different levels of the circadian photic entrainment pathway.
Abstract
Non-24-h sleep-wake disorder (N24SWD) is a rare circadian rhythm disorder in sighted patients whose underlying pathophysiology remains poorly understood. Here, we aimed to investigate the mechanisms of impaired circadian entrainment by combining assessments of retinal and melanopsin function, circadian light responsiveness and endogenous circadian rhythmicity. Two sighted patients with confirmed N24SWD underwent comprehensive circadian phenotyping targeting three complementary components of the circadian system: retinal and melanopsin-mediated photoreception, endogenous circadian timing, and circadian responsiveness to light. Retinal function was assessed using full-field electroretinography and chromatic pupillometry with measurement of the post-illumination pupil response (PIPR). Endogenous circadian phase and period were characterized through continuous core body temperature monitoring and hourly plasma melatonin and cortisol sampling during a 25-h multiple-nap protocol conducted under modified constant-routine conditions. Circadian light responsiveness was evaluated using three 15-min light exposures delivered at different irradiance levels and circadian phases across three consecutive nights, with simultaneous assessment of light-induced melatonin suppression. The first subject exhibited preserved melanopsinergic response as indicated by a normal PIPR, but showed no melatonin suppression regardless of light timing or illuminance levels. The intrinsic circadian period of melatonin and temperature was markedly prolonged (≈25 h). In contrast, the second patient exhibited impaired melanopsinergic response, reflected by reduced PIPR, while retaining melatonin suppression across all light conditions. His intrinsic period remained within the upper physiological range (24.20 h). This first multimodal characterization of sighted N24SWD reveals distinct pathophysiological mechanisms underlying failure of photic circadian entrainment. These observations suggest that N24SWD in sighted individuals should not be considered a unitary disorder but rather a heterogeneous condition resulting from dysfunction at different levels of the circadian photic entrainment pathway. Such mechanistic phenotyping may provide a foundation for personalized therapeutic strategies targeting the specific component of the circadian system that is impaired.
Skin temperature showed promising feasibility for in-field circadian rhythm estimation after only three days, potentially facilitating research on circadian rhythms and health and validation against core body temperature and melatonin sampling is warranted.
Vaida T R Verhoef, K.C.H.J. Smolders, Geert Peeters et al.· Chronobiology International· 0 citations
BACKGROUND
Light is the primary environmental cue synchronizing circadian rhythms, yet the lighting conditions in neonatal intensive care units (NICUs) often deviate from natural light-dark cycles. This study aimed to quantify circadian-relevant light exposure in NICUs and examine its potential association with neonatal melatonin production.
METHODS
In this prospective multicenter study, ambient and procedural illuminance were measured at patient and caregiver eye level using a portable light meter across eight NICUs in four tertiary hospitals. In a single-center substudy, a dosimeter continuously recorded illuminance and correlated color temperature (CCT). Urinary 6-sulfatoxymelatonin (aMT6s) was collected every four hours on days 1, 2, 3, 5, and 7 from 37 preterm and term neonates.
RESULTS
Among 1022 measurements, 82.3% (neonates) and 81.8% (caregivers) were exposed to <100 lx at eye-level. Examination lamps displayed significant variability, with maximum intensities ranging from 3747 to 25,720 lx. Across 314 patient-days, median daytime illuminations never exceeded 100 lx, whereas nighttime exposure exceeding 100 lx for more than 10 min occurred on 24.4% of days. CCT values remained near 4000 K throughout the 24-h cycle, showing minimal spectral variation. Urinary aMT6s showed no diurnal rhythm and did not differ between term and preterm infants.
CONCLUSION
NICU lighting conditions were characterized by low daytime illuminance, limited day-night spectral variation, and recurrent nocturnal exposure to artificial light with higher correlated color temperatures. These environmental lighting patterns may be potentially unfavorable for circadian entrainment in neonates and warrant further investigation regarding their biological relevance for hospitalized infants and healthcare staff within the same environmental setting.
IMPLICATIONS FOR CLINICAL PRACTICE
Integrating circadian-aware lighting concepts into daily nursing workflows, including optimized daytime illumination and reduced nocturnal light exposure during care activities, may represent a practical strategy to support neonatal adaptation and improve NICU lighting environments.
Benedikt Bonsau, E. A. Alsat, A. Kribs et al.· Intensive & Critical Care Nu...· 0 citations
OBJECTIVE
Rapid eye movement (REM) sleep is implicated in fear inhibition processes critical for trauma recovery. However, prior experimental models of REM sleep disruption have lacked ecological validity by manipulating sleep without accounting for circadian timing. Circadian misalignment frequently occurs in occupations at high risk of trauma exposure. The present study examined the relationship between REM sleep and fear inhibition in the context of experimentally induced circadian misalignment.
METHOD
A total of 42 healthy adults (Mage = 24.89, SD = 5.11) were randomized to one of three conditions for four nights: (a) normal control (n = 18), (b) circadian disruption with placebo administration (n = 14), or (c) circadian disruption with melatonin (3 mg) administration (n = 10). Circadian disruption consisted of two consecutive 4-hr phase advances. Fear inhibition was measured via the fear-potentiated startle task. Degree of circadian misalignment was measured via the phase angle between peak urinary 6-sulfatoxymelatonin and scheduled wake time.
RESULTS
Greater circadian misalignment on Night 4 significantly predicted larger reductions in both REM% (p = .010) and REM minutes (p = .002) that night. Controlling for changes in total sleep time and slow wave sleep, reductions in REM minutes on Night 4 significantly predicted poorer extinction recall the following day (ΔR² = .12, p = .040), whereas reductions in REM% showed a nonsignificant small-to-moderate association (p = .087).
CONCLUSIONS
Individuals experiencing greater reductions in REM sleep under circadian misalignment demonstrated poorer extinction recall. Interestingly, circadian misalignment predicted the same change in sleep (reduced REM minutes) also linked to poor extinction recall. Given the role of extinction recall in trauma-related psychopathology, these findings may have implications for frontline personnel at increased risk for posttraumatic stress disorder. However, larger samples are needed to confirm these preliminary findings. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
V. Vuong, Elise McGlashan, Sonia Birch et al.· Psychological Trauma· 0 citations
This review examines the neurobiological mechanisms governing circadian rhythm regulation and their disruption in sleep–wake disorders. Endogenous circadian clocks, coordinated by the suprachiasmatic nucleus, synchronize physiological and behavioral functions across a 24‐h cycle. Modern lifestyle factors such as artificial lighting, shift work, and irregular sleep schedules increasingly disrupt this synchronization, leading to chronic circadian misalignment. Such disruption is strongly associated with metabolic disorders, cardiovascular disease, and neuropsychiatric conditions. The review focuses on the role of key neurotransmitters, including serotonin, dopamine, GABA, glutamate, and melatonin, in maintaining circadian stability and sleep–wake regulation. Serotonin and dopamine contribute to photic and non‐photic entrainment, while GABA and glutamate regulate inhibitory‐excitatory balance and phase resetting within the suprachiasmatic nucleus. Melatonin functions as the primary hormonal signal of darkness, reinforcing circadian phase and modulating clock gene expression. Dysregulation of these neurochemical systems contributes to disorders such as insomnia, delayed sleep phase disorder, shift work disorder, and jet lag, often influenced by genetic predisposition and environmental stressors. Therapeutic approaches now target orexin signaling, melatonin pathways, and circadian timing through pharmacological, behavioral, and neuromodulatory strategies. Advances in wearable technologies and digital phenotyping enable individualized assessment and chronotherapy‐based interventions. These developments highlight the importance of integrating neurotransmitter dynamics with circadian biology to improve diagnosis and treatment strategies in sleep medicine. Precision‐based circadian interventions offer a promising direction for restoring sleep health and biological synchrony in modern populations.
Circadian rhythms have been shown to regulate sleep-wake timing across the lifespan, yet many questions remain about early childhood circadian physiology. Understanding dim light melatonin onset (DLMO) and offset (DLMOff), established markers of circadian phase, is essential for characterizing circadian rhythms in early childhood. We examined the distribution of salivary DLMO and DLMOff and their relationship with actigraphic sleep timing across 20 healthy preschoolers (M = 4.31 ± 0.34 years, 45% female). After maintaining a consistent sleep schedule for seven days, children completed an in-home circadian assessment. Children were awoken 1.5 h before habitual wake time and saliva samples were collected in 20–30 min intervals throughout the morning to determine DLMOff, then in the evening until 50 min past habitual bedtime to assess DLMO. A 4 pg/ml threshold was used to calculate each phase marker. DLMO ranged from 17:22 to 20:40 (M = 18:55 ± 0:54) and was positively associated with bedtime, sleep onset, and midsleep. In contrast, morning melatonin levels were highly variable, allowing DLMOff calculation in only eight participants. Within this small subsample, later DLMOff was associated with later chronotype (r = 0.81), sleep offset (r = 0.84), and midsleep (r = 0.80). Across the full sample, interpolated melatonin levels at habitual wake remained ≥ 4 pg/ml for 45% of children, a pattern broadly consistent with findings in adults, in which a majority of participants exhibit DLMOff after habitual wake time. These findings indicate that although evening melatonin profiles were consistently well-defined, permitting reliable calculations of DLMO across all participants, morning melatonin patterns were often irregular in young children. When able to be calculated, DLMOff showed strong associations with sleep timing, suggesting it could be a reliable marker of circadian phase. However, high variability and fluctuating morning melatonin patterns make DLMOff difficult to determine in many preschool-aged children.
L. Hartstein, S. Stowe, Kenneth P. Wright et al.· Journal of Biological Rhythm...· 0 citations
Sleep, circadian rhythms, light exposure, and environmental factors are increasingly recognized as important regulators of skin physiology. The skin contains peripheral clocks and exhibits circadian rhythmicity in barrier function, immune activity, pigmentation, temperature, blood flow, and repair processes. This review aims to summarize the current evidence linking sleep disturbances, circadian regulation, light exposure, seasonal variation, environmental temperature, and circadian desynchronization with skin physiology and some dermatoses. Sleep loss and disturbances in sleep duration may alter immune function and impair skin barrier integrity, potentially contributing to inflammatory dermatoses, including atopic dermatitis, psoriasis, and eczema. Light is the principal synchronizer of biological rhythms, whereas light at night, jet lag, and shift work may disrupt circadian organization, alter melatonin secretion, and impair central and peripheral clock regulation. These disturbances may be relevant to skin aging, impaired repair, inflammatory skin diseases, and potential skin carcinogenesis. Further studies are needed to better understand how circadian disruption influences skin homeostasis, repair processes, and disease development.
K. Biegański, S. Takamine, M. Sato et al.· Sleep Medicine Reviews· 0 citations
