Boris Matrot

Rationale: Congenital central hypoventilation syndrome (CCHS) is most commonly caused by polyalanine repeat mutations in PHOX2B. The in vivo consequences of the short five-alanine expansion and the contribution of specific hindbrain lineages to the resulting respiratory phenotype remain poorly understood. Objectives: To characterize the neonatal phenotype caused by the Phox2b ^25Ala/+ mutation and determine the contribution of the MafB lineage associated with the r5–r6 hindbrain territory. Methods: We generated a conditional Phox2b ^25Ala allele and studied mice with constitutive or MafB-lineage activation. Neonatal survival, growth, gastric milk content, ventilation, and hypercapnic responses were assessed in vivo . Respiratory-network activity and responses to extracellular acidification were recorded in E18.5 isolated brainstem–spinal cord preparations, and retrotrapezoid nucleus (RTN) development was examined histologically. Measurements and Main Results: Constitutive Phox2b ^25Ala/+ pups exhibited high neonatal mortality, markedly impaired weight gain, reduced gastric milk scores, hypoventilation, increased apnea time, and blunted ventilatory responses to CO₂. Embryonic preparations showed a slower respiratory rhythm, an impaired response to acidification, and severe RTN dysgenesis. Activation of the mutant allele in the MafB lineage was also associated with severe respiratory dysfunction, RTN dysgenesis, and early neonatal mortality. In contrast, postnatal weight gain was preserved among surviving MafB-lineage mutants, and the reduction in gastric milk scores was significantly attenuated compared with constitutive mutants. Conclusions: A short PHOX2B polyalanine expansion reproduces major respiratory features of CCHS in mice. Activating the mutant allele in the MafB lineage is sufficient to cause severe respiratory dysfunction and neonatal mortality, whereas postnatal weight gain is preserved among survivors.

Background: Sleep is essential for overall health and well-being, but assessing sleep architecture is often costly and time-consuming, relying primarily on polysomnography (PSG). While wrist-worn wearables offer alternatives, they face limitations regarding user compliance, such as battery charging and physical discomfort. Nearable devices address these burdens, but they regularly lack rigorous validation, especially in real-world settings. Objective: This study evaluates the accuracy and reliability of the Withings Sleep Analyzer (WSA), a contactless sleep monitoring device, compared to PSG in a home setting using a large and diverse cohort of healthy individuals. Methods: A total of 117 healthy volunteers (69 women; mean 39.9, SD 11.4 years), prospectively recruited from the general population, underwent home-based PSG and simultaneous WSA recording. The study was conducted under free-living conditions, without constraints on substance intake, prebedtime activity, or forced sleep schedules. The main outcomes were the device’s performance in sleep-wake distinction and sleep stage identification using accuracy, kappa, sensitivity, specificity, and the mean absolute error of sleep measures on the entire population and demographic, clinical, and environmental subgroups. Results: WSA demonstrates high sensitivity (93%, 95% CI 92%-94%) for sleep detection and moderate sensitivity (73%, 95% CI 69%-77%) for wakefulness, achieving an overall accuracy of 87% (95% CI 86%-87%) for sleep-wake distinction. The device showed consistent performance across various demographic subgroups, including different age, BMI, mattress, and sleep arrangements (with or without bed partner) categories. Challenges were noted in accurately classifying specific sleep stages, particularly in distinguishing between light and deep sleep, with a mean accuracy of 63% (95% CI 62%-65%) and a Cohen κ of 0.49 (95% CI 0.47-0.51). The WSA tended to overestimate total sleep time (20 min, 95% CI 10 min to 31 min) and light sleep (1 h 21 min, 95% CI 1 h 8 min to 1 h 36 min) while underestimating rapid eye movement (−15 min, 95% CI −23 min to −8 min) and deep sleep (−46 min, 95% CI −59 min to −34 min) durations. Disagreements between expert reviewers were mirrored in part by the WSA’s misclassifications. Participants reported altered perceived sleep quality during the night with the PSG, suggesting discomfort during sleep. Conclusions: Being contactless and placed under the mattress, the WSA offers a promising approach to long-term sleep monitoring in natural home environments. It shows competitive performance in sleep-wake and sleep stage identification compared to other consumer devices. Progress in wearable and nearable devices is necessary to enhance their accuracy to better support the monitoring of populations with impaired sleep, although limited by an imperfect gold standard. This work also emphasizes the importance of using large, diverse, and challenging datasets, as well as the need for a standardized methodology for accurate sleep stage classification.

Breathing is inherently variable due to the nonlinear dynamics of its brainstem neural control. In amphibians, a gill and a lung oscillator interact to produce breathing but the lung oscillator is necessary and sufficient to produce a mathematically complex behavior. In mammals, where the preBötzinger complex (preBötC) is considered homologous to the amphibian lung oscillator and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) homologous to the amphibian gill oscillator, the origin of ventilatory complexity is not known. We address this question by characterizing ventilation variability in Phox2b mutant mice lacking the RTN/pFRG and human patients with Phox2b mutation‐confirmed congenital central hypoventilation syndrome (CCHS). Ventilatory recordings were obtained from Phox2b ^{27 ala/+} —dying within hours after birth—and Egr2 ^cre/+ ; Phox2b ^27ala/+ mice—generally surviving until adulthood—and their wild‐type (WT) littermates, during behavioral quiescence at various developmental stages. Human data were collected from CCHS patients and healthy controls during quiet wakefulness. Variability was assessed using the coefficient of variation, complexity using noise titration (noise limit, NL), and sensitivity to initial conditions using the largest Lyapunov exponent (LLE). Mice from both mutant lineages exhibited greater variability at early developmental stages, which decreased with maturation in Egr2 ^{cre /+} ; Phox2b ^27ala/+ mice. NL was consistently higher in mutant mice than in WT, indicating preserved or even enhanced ventilatory complexity despite RTN/pFRG dysfunction. CO ₂ reduced variability but did not affect complexity. In humans, no differences were observed between patients and controls for variability, NL, or LLE. Ventilatory complexity persists in mice lacking a functional RTN/pFRG and despite Phox2b mutations in humans, suggesting that the pontomedullary rhythm and pattern generators that include the preBötC may be its principal source. This supports the analogy between mammalian and amphibian rhythm generators.

A bstract: Background: Sleep is essential for overall health and well-being, but assessing sleep architecture and quality is often costly and time-consuming, relying primarily on polysomnography (PSG). Wearable and nearable devices offer potential alternatives, but they regularly lack rigorous validation, especially in real-world settings. Objectives: This study evaluates the accuracy and reliability of Withings Sleep Analyzer (WSA), a contactless sleep monitoring device, compared to PSG in a home setting using a large and diverse cohort of healthy individuals. Methods: A total of 117 participants (69 women; 39.9 ± 11.4 years, mean ± std) underwent home-based polysomnography (PSG) and simultaneous WSA recording. Data analysis focused on evaluating sleep-wake distinction and sleep stage identification using standard classification metrics. Results: WSA demonstrates high sensitivity (93%) for sleep detection and moderate sensitivity (73%) for wakefulness, achieving an overall accuracy of 87% for sleep-wake distinction. The device showed consistent performance across various demographic subgroups, including different age, BMI, mattress and sleep arrangements (with or without bed partner) categories. Challenges were noted in accurately classifying specific sleep stages, particularly in distinguishing between light and deep sleep, with a mean accuracy of 63% and a Cohen’s Kappa of 0.49. The WSA tended to overestimate total sleep time (+20 min) and light sleep (+1h21 min) while underestimating REM (−15 min) and deep sleep (−46 min) durations. Disagreements between expert reviewers, particularly between light and deep sleep stages, mirrored in part the WSA’s misclassifications. Participants reported significantly altered perceived sleep quality during the night with the PSG, suggesting potential discomfort during sleep. Conclusions: WSA offers a promising approach to sleep monitoring in natural home environments. Being contactless and placed under the mattress, the WSA’s allows for long-term monitoring of sleep measures. It shows competitive performance in sleep-wake and sleep stage identification compared to other consumer devices. Progress in wearable and nearable devices is necessary to enhance their accuracy to better support the monitoring of populations with strongly impaired sleep, although limited by an imperfect gold standard. This work also emphasizes the importance of using large, diverse, and challenging datasets, as well as the need for a standardized methodology for accurate sleep stage classification.

BACKGROUND Sleep is essential for overall health and well-being, but assessing sleep architecture and quality is often costly and time-consuming, relying primarily on polysomnography (PSG). Wearable and nearable devices offer potential alternatives, but they regularly lack rigorous validation, especially in real-world settings. OBJECTIVE This study evaluates the accuracy and reliability of Withings Sleep Analyzer (WSA), a contactless sleep monitoring device, compared to PSG in a home setting using a large and diverse cohort of healthy individuals. METHODS A total of 117 participants (69 women; 39.9 11.4 years, mean std) underwent home-based polysomnography (PSG) and simultaneous WSA recording. Data analysis focused on evaluating sleep-wake distinction and sleep stage identification using standard classification metrics. RESULTS WSA demonstrates high sensitivity (93%) for sleep detection and moderate sensitivity (73%) for wakefulness, achieving an overall accuracy of 87% for sleep-wake distinction. The device showed consistent performance across various demographic subgroups, including different age, BMI, mattress and sleep arrangements (with or without bed partner) categories. Challenges were noted in accurately classifying specific sleep stages, particularly in distinguishing between light and deep sleep, with a mean accuracy of 63% and a Cohen's Kappa of 0.49. The WSA tended to overestimate total sleep time (+20 min) and light sleep (+1h21 min) while underestimating REM (-15 min) and deep sleep (-46 min) durations. Disagreements between expert reviewers, particularly between light and deep sleep stages, mirrored in part the WSA's misclassifications. Participants reported significantly altered perceived sleep quality during the night with the PSG, suggesting potential discomfort during sleep. CONCLUSIONS WSA offers a promising approach to sleep monitoring in natural home environments. Being contactless and placed under the mattress, the WSA's allows for long-term monitoring of sleep measures. It shows competitive performance in sleep-wake and sleep stage identification compared to other consumer devices. Progress in wearable and nearable devices is necessary to enhance their accuracy to better support the monitoring of populations with strongly impaired sleep, although limited by an imperfect gold standard. This work also emphasizes the importance of using large, diverse, and challenging datasets, as well as the need for a standardized methodology for accurate sleep stage classification.

Severe obstructive sleep apnea is prevalent in neonates with Down syndrome, but neonatal breathing disorders remain unexplored in mouse models. Using the Dp(16)1Yey model, we observed prolonged obstructive apneas and lower heart rates at birth in mutant pups compared to wild-type littermates. This preclinical model provides a novel platform to study neonatal obstructive sleep apnea in Down syndrome and its contribution to neurodevelopmental disorders associated with Down syndrome.

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis (Dammann, O. and Leviton, A., Intermittent or sustained systemic inflammation and the preterm brain . Pediatr Res, 2014. 75 (3): p. 376-80). In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery (Luca, A.,et al., Birth trauma in preterm spontaneous vaginal and cesarean section deliveries: A 10-years retrospective study. PloS one,2022, 17(10), e0275726.) We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation (Favrais, G.,et al., Systemic inflammation disrupts the developmental program of white matter. Ann Neurol,2011. 70 (4): p. 550-65). This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders. Significance Statement: In a well-established mouse model of the encephalopathy of prematurity, we observed that C-section exacerbates the deleterious effects of neonatal systemic inflammation (intraperitoneal injections of IL-1β between postnatal days one and five) on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced brain functional connectivity. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem–spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5–3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4–1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3–3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1–1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.

Summary: A combination of noradrenergic and antimuscarinic agents reduces the apnea–hypopnea index (AHI) in adult patients with obstructive sleep apnoea (OSA) via reduced upper airway collapsibility, suggesting that a shift in the sympathovagal balance improves OSA. The objectives of our present case‐control study were to assess heart rate variability (HRV) indices in the stages of sleep in children with and without OSA to evaluate OSA‐induced sleep HRV modifications and to assess whether increased collapsibility measured during wakefulness is associated with reduced sympathetic activity during non‐rapid eye movement (NREM) sleep. Three groups of 15 children were matched by sex, age,z‐score of body mass index and ethnicity: non‐OSA (obstructive AHI [OAHI] n = 30) were characterised by increased compliance and no physiological parasympathetic tone increase in REM sleep. Children with increased pharyngeal compliance (n = 21) had a higher OAHI due to higher AHI in NREM sleep, whereas their sympathetic tone was lower than that of those with normal compliance (n = 24). In conclusion, children with increased pharyngeal compliance exhibit decreased sympathetic tone associated with increased AHI in NREM sleep. Therapeutics directed at sympathovagal balance modifications should be tested in childhood OSA.

Rationale: Congenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B ^{27Ala /+} mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine whether Phox2b ^{27Ala /+} mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b ^{27Ala /+} pups versus 0.6/min (0.4-1.0) in wildtypes ( P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b ^{27Ala /+} pups versus 1.7s (1.1-1.9) in wildtypes ( P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b ^{27Ala /+} preparations, the hypoglossal nucleus had fewer ( P < 0.05) and smaller ( P < 0.01) neurons, compared to wildtypes. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset ( P < 0.001). Conclusions: The Phox2b ^{27Ala /+} mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.