Publications by authors named "Jian-Sheng Lin"

71 Publications

Adenosine AR/AR Antagonists Enabling Additional HR Antagonism for the Treatment of Parkinson's Disease.

J Med Chem 2021 Jun 9;64(12):8246-8262. Epub 2021 Jun 9.

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.

Adenosine A/A receptors (AR/AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H receptor (HR) antagonists in combination with the "caffeine-like effects" of AR/AR antagonists, we designed AR/AR/HR MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl HR pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar HR affinities ( < 55 nM). Compound (, (AR) = 11.5 nM, (AR) = 7.25 nM) and (, (AR) = 11.2 nM, (AR) = 4.01 nM) were evaluated . l-DOPA-induced dyskinesia was improved after administration of compound (1 mg kg, i.p. rats). Compound (2 mg kg, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00914DOI Listing
June 2021

Orexin/Hypocretin and Histamine Cross-Talk on Hypothalamic Neuron Counts in Mice.

Front Neurosci 2021 20;15:660518. Epub 2021 May 20.

PRISM Lab, Department of Biomedical and Neuromotor Sciences, Center for Applied Biomedical Research, S. Orsola University Hospital, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed -test, = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed -test, = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals.
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http://dx.doi.org/10.3389/fnins.2021.660518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173058PMC
May 2021

Chronic Toxoplasma gondii infection and sleep-wake alterations in mice.

CNS Neurosci Ther 2021 Aug 4;27(8):895-907. Epub 2021 Jun 4.

Institut des Agents Infectieux, Parasitologie Mycologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.

Aim: Toxoplasma gondii (Tg) is an intracellular parasite infecting more than a third of the human population. Yet, the impact of Tg infection on sleep, a highly sensitive index of brain functions, remains unknown. We designed an experimental mouse model of chronic Tg infection to assess the effects on sleep-wake states.

Methods: Mice were infected using cysts of the type II Prugniaud strain. We performed chronic sleep-wake recordings and monitoring as well as EEG power spectral density analysis in order to assess the quantitative and qualitative changes of sleep-wake states. Pharmacological approach was combined to evaluate the direct impact of the infection and inflammation caused by Tg.

Results: Infected mouse exhibited chronic sleep-wake alterations over months, characterized by a marked increase (>20%) in time spent awake and in cortical EEG θ power density of all sleep-wake states. Meanwhile, slow-wave sleep decreased significantly. These effects were alleviated by an anti-inflammatory treatment using corticosteroid dexamethasone.

Conclusion: We demonstrated for the first time the direct consequences of Tg infection on sleep-wake states. The persistently increased wakefulness and reduced sleep fit with the parasite's strategy to enhance dissemination through host predation and are of significance in understanding the neurodegenerative and neuropsychiatric disorders reported in infected patients.
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http://dx.doi.org/10.1111/cns.13650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265947PMC
August 2021

Intellectual Abilities of Children with Narcolepsy.

J Clin Med 2020 Dec 17;9(12). Epub 2020 Dec 17.

Pediatric Sleep Unit, Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 69500 Lyon, France.

High cognitive functioning could be a protective factor for school difficulties, behavioral and mood impairments in children with narcolepsy. To investigate this factor, we studied the intellectual abilities of 74 children with narcolepsy (43 boys, 11.7 years old at diagnosis, 91% of cataplexies, 64% obese, 100% HLA positive for DR-DQB1*06:02). All children underwent a one-night polysomnography followed by Multiple Sleep Latency Tests, an evaluation of intelligence quotient (IQ), and filled standardized questionnaires. Thirty-eight percent had high potentialities (HP defined by IQ > 130) and 48% had school difficulties. Using non-parametric tests, we found that HP children reported less difficulties at school and tended to have less impulsivity, conduct, and learning disorders than those without HP. They also tended to be less obese and had less desaturation. Using a multivariate regression analysis, we found an association between the REM sleep percentage and the IQ. REM sleep could be involved in the dynamic changes contributing to the equilibrium of intellectual functioning. This study highlights that despite their frequent school difficulties, narcolepsy per se is unlikely to be a cause of intellectual disability in children. Prompt diagnosis and management of comorbidities such as obesity and obstructive sleep apnea (OSA) could improve cognitive and school performances in these children.
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http://dx.doi.org/10.3390/jcm9124075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766444PMC
December 2020

Tibialis anterior electromyographic bursts during sleep in histamine-deficient mice.

J Sleep Res 2021 Aug 13;30(4):e13255. Epub 2020 Dec 13.

PRISM Lab, Dipartimento di Scienze Biomediche e Neuromotorie, Alma Mater Studiorum, Università di Bologna, Bologna, Italy.

Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals < 10 s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals < 10 s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling.
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http://dx.doi.org/10.1111/jsr.13255DOI Listing
August 2021

Sleep problems in Rett syndrome animal models: A systematic review.

J Neurosci Res 2021 02 28;99(2):529-544. Epub 2020 Sep 28.

INSERM - School of Medicine, University Claude Bernard, Lyon, France.

Due to the discovery of Rett Syndrome (RTT) genetic mutations, animal models have been developed. Sleep research in RTT animal models may unravel novel neural mechanisms for this severe neurodevelopmental heritable rare disease. In this systematic literature review we summarize the findings on sleep research of 13 studies in animal models of RTT. We found disturbed efficacy and continuity of sleep in all genetically mutated models of mice, cynomolgus monkeys, and Drosophila. Models presented highly fragmented sleep with distinct differences in 24-hr sleep/wake cyclicity and circadian arrhythmicity. Overall, animal models mimic sleep complaints reported in individuals with RTT. However, contrary to human studies, in mutant mice, attenuated sleep delta waves, and sleep apneas in non-rapid eye movement sleep were reported. Future studies may focus on sleep structure and EEG alterations, potential central mechanisms involved in sleep fragmentation and the occurrence of sleep apnea across different sleep stages. Given that locomotor dysfunction is characteristic of individuals with RTT, studies may consider to integrate its potential impact on the behavioral analysis of sleep.
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http://dx.doi.org/10.1002/jnr.24730DOI Listing
February 2021

Narcolepsy with cataplexy: Does age at diagnosis change the clinical picture?

CNS Neurosci Ther 2020 Aug 6. Epub 2020 Aug 6.

Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, University of Lyon 1, Lyon, France.

Objective: To compare symptoms and sleep characteristics in patients diagnosed with narcolepsy-cataplexy (NC) before and after the age of 18 years.

Methods: De novo patients with NC diagnosis completed a standardized questionnaire and interview, followed by a sleep study. The clinical and sleep measures were compared between patients diagnosed before (46 children, median age: 12 year old) and after (46 adults, median age: 28.5 year old) 18 years of age.

Results: The frequency of obesity (54% vs 17%), night eating (29% vs 7%), parasomnia (89% vs 43%), sleep talking (80% vs 34%), and sleep drunkenness (69% vs 24%) were higher in children than in adults, the frequency of sleep paralysis was lower (20% vs 55%) but the frequency of cataplexy and the severity of sleepiness were not different. Children scored higher than adults at the attention-deficit/hyperactivity disorder (ADHD) scale. Depressive feelings affected not differently children (24%) and adults (32%). However, adults had lower quality of life than children. There was no difference between groups for insomnia and fatigue scores. Quality of life was essentially impacted by depressive feelings in both children and adults. Obstructive apnea-hypopnea index (OAHI) was lower in children with higher mean and minimal oxygen saturation than in adults. No between-group differences were found at the multiple sleep latency test. The body mass index (z-score) was correlated with OAHI (r = .32).

Conclusion: At time of NC diagnosis, children have more frequent obesity, night eating, parasomnia, sleep talking, drunkenness, and ADHD symptoms than adults, even if sleepiness and cataplexy do not differ. These differences should be considered to ensure a prompt diagnosis.
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http://dx.doi.org/10.1111/cns.13438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539846PMC
August 2020

2019 Overview.

CNS Neurosci Ther 2020 03;26(3):287

Xuanwu Hospital of Capital Medical University, Beijing, China.

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http://dx.doi.org/10.1111/cns.13299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052800PMC
March 2020

A Layered Control Architecture of Sleep and Arousal.

Front Comput Neurosci 2020 12;14. Epub 2020 Feb 12.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Sleep and wakefulness are promoted not by a single neural pathway but via wake or sleep-promoting nodes distributed across layers of the brain. We equate each layer with a brain region in proposing a layered subsumption model for arousal based on a computational architecture. Beyond the brainstem the layers include the diencephalon (hypothalamus, thalamus), basal ganglia, and cortex. In light of existing empirical evidence, we propose that each layer have sleep and wake computations driven by similar high-level architecture and processing units. Specifically, an interconnected wake-promoting system is suggested as driving arousal in each brain layer with the processing converging to produce the features of wakefulness. In contrast, sleep-promoting GABAergic neurons largely project to and inhibit wake-promoting neurons. We propose a general pattern of caudal wake-promoting and sleep-promoting neurons having a strong effect on overall behavior. However, while rostral brain layers have less influence on sleep and wake, through descending projections, they can subsume the activity of caudal brain layers to promote arousal. The two models presented in this work will suggest computations for the layering and hierarchy. Through dynamic system theory several hypotheses are introduced for the interaction of controllers and systems that correspond to the different populations of neurons at each layer. The models will be drawn-upon to discuss future experiments to elucidate the structure of the hierarchy that exists among the sleep-arousal architecture.
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http://dx.doi.org/10.3389/fncom.2020.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028742PMC
February 2020

Cerebral organoids transplantation improves neurological motor function in rat brain injury.

CNS Neurosci Ther 2020 07 22;26(7):682-697. Epub 2020 Feb 22.

Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai, China.

Background And Purpose: Cerebral organoids (COs) have been used for studying brain development, neural disorders, and species-specific drug pharmacology and toxicology, but the potential of COs transplantation therapy for brain injury remains to be answered.

Methods: With preparation of traumatic brain injury (TBI) model of motor dysfunction, COs at 55 and 85 days (55 and 85 d-CO) were transplanted into damaged motor cortex separately to identify better transplantation donor for brain injury. Further, the feasibility, effectiveness, and underlying mechanism of COs transplantation therapy for brain injury were explored.

Results: 55 d-CO was demonstrated as better transplantation donor than 85 d-CO, evidenced by more neurogenesis and higher cell survival rate without aggravating apoptosis and inflammation after transplantation into damaged motor cortex. Cells from transplanted COs had the potential of multilinage differentiation to mimic in-vivo brain cortical development, support region-specific reconstruction of damaged motor cortex, form neurotransmitter-related neurons, and migrate into different brain regions along corpus callosum. Moreover, COs transplantation upregulated hippocampal neural connection proteins and neurotrophic factors. Notably, COs transplantation improved neurological motor function and reduced brain damage.

Conclusions: This study revealed 55 d-CO as better transplantation donor and demonstrated the feasibility and efficacy of COs transplantation in TBI, hoping to provide first-hand preclinical evidence of COs transplantation for brain injury.
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http://dx.doi.org/10.1111/cns.13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298981PMC
July 2020

Paraventricular Thalamus as A Major Thalamic Structure for Wake Control.

Neurosci Bull 2019 Oct 16;35(5):946-948. Epub 2019 Mar 16.

Departments of Neuroscience, Anatomy, Histology, and Embryology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.

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http://dx.doi.org/10.1007/s12264-019-00364-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754474PMC
October 2019

Early polysomnographic characteristics associated with neurocognitive development at 36 months of age.

Sleep Med 2019 08 5;60:13-19. Epub 2019 Jan 5.

INSERM, UMR1153, Center for Research in Epidemiology and StatisticS (CRESS), EArly life Research on later Health Team (EARoH), Univ Paris-Descartes, Paris, France.

Background: Few studies on the relationship between sleep quantity and/or quality and cognition have been conducted among preschoolers from the healthy general population. We aimed to identify, among 3-year-old children, early polysomnography (PSG) sleep factors associated with estimated intelligence quotient (IQ) using the Weschler Preschool and Primary Scale Intelligence-III test (WPPSI-III) and its indicators: full-scale (FISQ), verbal (VIQ), and performance (PIQ) intelligence quotients.

Methods: We included full-term children from the French birth-cohort AuBE with PSG recording at term (M0) and/or six months (M6), and available WPPSI-III scores at three years. Sleep and arousal characteristics of these infants were evaluated during day and night sleep periods. Relationships between IQ scores and sleep parameters were estimated using models with the child as a repeated effect adjusted for time (night/day), maturation (M0/M6), tobacco exposure (yes/no), anxiety-depressive scores during pregnancy, maternal age, duration of breastfeeding and child's gender.

Results: A total of 118 PSG recordings were obtained, representing a total of 78 unique children (38 with one PSG and 40 with two PSG). No correlations were found between night and day sleep durations at M0 or M6. Mean VIQ, PIQ, and FSIQ scores were within normal ranges. In multivariate models, longer sleep duration and higher sleep efficiency during the day were negatively associated with all IQ scores. More frequent arousals during the night were associated with lower VIQ scores.

Conclusion: Early sleep characteristics such as night sleep fragmentation or longer naps could be associated with impaired cognitive function at three years of age.
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http://dx.doi.org/10.1016/j.sleep.2018.11.026DOI Listing
August 2019

Impaired histaminergic neurotransmission in children with narcolepsy type 1.

CNS Neurosci Ther 2019 03 17;25(3):386-395. Epub 2018 Sep 17.

Integrative Physiology of the Brain Arousal System, CRNL, INSERM-U1028, CNRS, UMR5292, University Lyon1, Lyon, France.

Objective: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls.

Methods: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients.

Results: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels.

Conclusions: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.
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http://dx.doi.org/10.1111/cns.13057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488909PMC
March 2019

The unfinished journey with modafinil and discovery of a novel population of modafinil-immunoreactive neurons.

Sleep Med 2018 09 4;49:40-52. Epub 2018 Jul 4.

Department of Experimental Medicine, School of Medicine, Claude Bernard University, Lyon, France.

Modafinil, a wake-promoting compound now used worldwide in sleep medicine, was initially regarded as a sedative compound because mice were so quiet with respect to locomotion after receiving it that this behavioral state was qualified as sedation. In the early 1980's when modafinil was first assessed by polysomnography in a cat in our laboratory, surprisingly, the cat spent the whole night awake without even one minute of sleep! This initial observation resulted subsequently in a series of basic and clinical studies in order to define the pharmacological profile of modafinil and its mode of action and, notably, to identify the brain targets by which modafinil acts to promote wakefulness. These studies were undertaken using pharmacologic approach coupled with the Cerveau isolé (brain transection) preparation, c-fos labelling and knockout mouse models. It was also in this context that we have developed a purified polyclonal antibody against modafinil. We expected that using immunohistochemistry with this antibody would allow us to localize the brain distribution of modafinil dosing. Surprisingly, we found discrete modafinil immunoreactive neuronal populations in several brain areas of modafinil-naive cats, rodents and humans. The most numerous and intensely labeled modafinil-immunoreactive neurons characterized by granular staining were found in the basal forebrain. They shared the regional location with cholinergic and aspartate-containing neurons but did not colocalize with them. In summary, we here present a newly identified neuronal population located in the basal forebrain that has never previously been published and suggests that these modafinil-immunoreactive neurons might be involved in forebrain functions such as sleep-wake control and cognition. This paper briefly reviews our journey with modafinil research and presents new unpublished experimental data.
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http://dx.doi.org/10.1016/j.sleep.2018.06.008DOI Listing
September 2018

Cortico-Amygdala-Striatal Activation by Modafinil/Flecainide Combination.

Int J Neuropsychopharmacol 2018 07;21(7):687-696

Theranexus, Lyon, France.

Background: Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102).

Methods: The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-deoxy-D-glucose followed by 60-minute Positron Emission Tomography acquisition. 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography images were coregistered to a rat brain template and normalized from the total brain Positron Emission Tomography signal. Voxel-to-voxel analysis was performed using SPM8 software. Comparison of brain glucose metabolism between groups was then performed.

Results: THN102 significantly increased regional brain glucose metabolism as it resulted in large clusters of 18F-2-fluoro-2-deoxy-D-glucose uptake localized in the cortex, striatum, and amygdala compared with control or drugs administered alone. These regions, highly involved in the regulation of sleep-wake cycle, emotions, and cognitive functions were hence quantitatively modulated by THN102.

Conclusion: Data presented here provide the first evidence of a regional brain activation induced by THN102, currently being tested in a phase II clinical trial in narcoleptic patients.
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http://dx.doi.org/10.1093/ijnp/pyy027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031015PMC
July 2018

Maturation of arousals during day and night in infants with non-smoking and smoking mothers.

Early Hum Dev 2017 12 9;115:46-50. Epub 2017 Sep 9.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, University Lyon1, 8, avenue Rockefeller, 69373 Lyon, France; Pediatric Sleep Unit, Department of Pediatric Epilepsy, Sleep and Neurological Functional Explorations, Women's Mother's Children's Hospital, 59, boulevard Pinel, 69500 Lyon, University of Lyon 1, France. Electronic address:

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http://dx.doi.org/10.1016/j.earlhumdev.2017.08.006DOI Listing
December 2017

Low cerebrospinal fluid hypocretin levels during sudden infant death syndrome (SIDS) risk period.

Sleep Med 2017 05 8;33:57-60. Epub 2017 Feb 8.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, CNRS UMR5292, University Lyon 1, Lyon, France; Centre de biologie et d'anatomopathologie, Groupement Hospitalier Est, Lyon, France. Electronic address:

Objectives: The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2-6 months, which is the age of peak incidence for SIDS, to both younger and older children.

Method: Hypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0-2 months, 2-6 months, 1-5 years, 5-10 years, and 10-18 years.

Results: Hypocretin levels were not significantly different between 1-5 years, 5-10 years, and 10-18 years. Therefore, these three groups were pooled into a single one (1-18 years) for further analysis. Between the 0-2 month, 2-6 month, and 1-18 year groups, a significant difference in CSF hypocretin levels existed (p = 0.001). Simple comparisons showed that CSF hypocretin levels in the 2-6 month age group were significantly lower than hypocretin levels in both the 0-2 month and 1-18 year group (p < 0.001 and p = 0.008, respectively), but not significantly between 0-2 month and 1-18 year children.

Conclusions: The CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age.
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http://dx.doi.org/10.1016/j.sleep.2016.12.027DOI Listing
May 2017

Neuropeptide S reduces propofol- or ketamine-induced slow wave states through activation of cognate receptors in the rat.

Neuropeptides 2017 Jun 14;63:59-66. Epub 2017 Feb 14.

Departments of Neuroscience, Anatomy, Histology, and Embryology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China. Electronic address:

Intracerebroventricular injection of NPS reduces the duration of the ketamine- or thiopental-induced loss of the righting reflex in rats. But the specific EEG activities are unknown. We therefore sought to examine the effects of the NPS-NPSR system on anesthetic-induced characteristics of EEG power spectra and sleep-wake profiles. NPS alone or together with an NPSR antagonist was injected intracerebroventricularly, whereas the propofol (50mg/kg) or ketamine (100mg/kg) was administrated intraperitoneally. NPS (1 or 2nmol) significantly reduced the amount of propofol-induced EEG delta activity and slow wave states (SWS). NPS (1 or 5nmol) significantly reduced the amount of ketamine-induced SWS and EEG delta activity. Cortical EEG power spectral analysis showed that, in saline-pretreated rats, propofol induced a marked increase in delta (0.5-4Hz) activity, decrease in theta (4.5-8.5Hz) activity, and decrease in high frequency activity (14.5-60Hz), while, in rats pretreated with 1nmol of NPS, the duration of delta activity was reduced, while its spectral pattern was not changed. Whereas injection of ketamine into saline-pretreated rats induced a marked increase in delta (0.5-4Hz) activity, a moderate increase in theta (4.5-8.5Hz) activity, and a marked decrease in high frequency (14.5-60Hz) activity. However, delta activity was reduced while theta activity increased under pretreatment with 1nmol of NPS. The inhibitory effect of NPS on anesthetic-induced SWS was characterized by a reduced SWS episode duration with no significant change in either episode number or latency to SWS. [D-Val]NPS, an NPSR antagonist (20nmol), significantly attenuated the arousal-promoting effect of 1nmol of NPS, but had no effect on SWS when injected alone. We speculate that NPS significantly reduces anesthetic-induced SWS and EEG slow activity by selective activation of the NPSR, which, in turn, would trigger subsequent arousal pathways.
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http://dx.doi.org/10.1016/j.npep.2017.02.081DOI Listing
June 2017

Early features associated with the neurocognitive development at 36 months of age: the AuBE study.

Sleep Med 2017 02 17;30:222-228. Epub 2016 Nov 17.

Sleep Pediatric Unit, Woman Mother Child Hospital, Lyon1 University, Lyon, France; Integrative Physiology of Brain Arousal System Research Laboratory, CRNL, INSERM-U1028, CNRS UMR5292, Lyon1 University, Lyon, France.

Background: Few studies on the relations between sleep quantity and/or quality and cognition have been conducted among preschoolers from healthy general population. We aimed at identifying, among 36 months old children, early factors associated with intelligence quotient (IQ) estimated through the Weschler Preschool and Primary Scale Intelligence-III test and its indicators: Full-Scale-, Verbal- and Performance-IQs and their subscale scores.

Methods: We included 194 children from the French birth cohort AuBE with both available Weschler Preschool and Primary Scale Intelligence-III scores at three years and sleep data. Information was collected through self-questionnaires at birth, 6, 12, 18 and 24 months. A day/night sleep ratio was calculated.

Results: Mean scores were in normal ranges for Verbal, Performance, and Full-Scale IQs ?. In multivariate models, being a third-born or more child and watching television ≥1 h/day at 24 months were negatively associated with all IQ scores, whereas collective care arrangement was positively associated. Night waking at six months and frequent snoring at 18 months were negatively associated with Performance IQ, some subscales, and Full Scale IQ contrary to day/night sleep ratio at 12 months. No association was observed between early sleep characteristics and Verbal IQ.

Conclusion: We showed that early features including infant sleep characteristics influence IQ scores at 36 months old. Some of these may be accessible to prevention.
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http://dx.doi.org/10.1016/j.sleep.2016.10.015DOI Listing
February 2017

Sleep Trajectories Among Pregnant Women and the Impact on Outcomes: A Population-Based Cohort Study.

Matern Child Health J 2017 05;21(5):1139-1146

Sleep Pediatric Unit, Hôpital Femme Mère Enfant, University Lyon1, Lyon, France.

Objectives Sleep problems and deprivation are common during pregnancy, particularly in the third trimester. Previous studies are mostly descriptive or focused on specific clinical groups and late pregnancy. We aimed to identify sleep duration trajectories during the pregnancy period, their associated factors, and impact on pregnancy and birth outcomes. Methods We studied 200 women from a mother-child cohort recruited in 2009-2011 from the French general population. We used semi-parametric models to analyze data collected through questionnaires. Results We detected three sleep duration trajectories during pregnancy: short-decreasing (<6.5h/night, 10.8% of the sample), medium-decreasing (6.5-8h/night, 57.6%), and long-increasing (>8h/night, 31.6%) trajectories. Factors associated with the short-decreasing trajectory relative to the medium-decreasing trajectory were older age (odds-ratio/year = 1.13 [95%Confidence-Interval 1.00-1.29]) and working > 28 weeks of gestational age (odds-ratio = 0.30 [0.10-0.90]). Sleep duration during pregnancy in this trajectory group was modified by insomniac symptoms (regression coefficient/trimester = -0.74 [Standard-Error 0.12]) and naps (regression coefficient/trimester = 0.58 [0.25]). Restless legs syndrome was the only factor associated with the long-increasing trajectory and decreased sleep duration (regression coefficient/trimester = -0.88 [0.25]). Assisted delivery (i.e. cesarean section and/or instrumental delivery) and post-partum depression were more frequent among women with the short-decreasing and long-increasing trajectories whereas cesarean section alone was more prevalent among those with the short-decreasing trajectory. Proportion of premature births was higher in the short-decreasing trajectory group. Birth-weight-z-score was lower in the long-increasing trajectory group. Conclusion We identified sleep trajectories among pregnant women with specific risk factors that could affect both pregnancy and birth outcomes. Taking these into consideration could improve both maternal and child health.
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http://dx.doi.org/10.1007/s10995-016-2212-9DOI Listing
May 2017

Benzyl isothiocyanate promotes apoptosis of oral cancer cells via an acute redox stress-mediated DNA damage response.

Food Chem Toxicol 2016 Nov 28;97:336-345. Epub 2016 Sep 28.

Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan. Electronic address:

Benzyl isothiocyanate (BITC) is a cruciferous vegetable-derived compound with anticancer properties in human cancer cells. However, its anticancer potential and underlying mechanisms remain absent in human oral cancer cells. Results indicate that BITC inhibits growth, promotes G/M phase arrest and triggers apoptosis of OC2 cells with a minimal toxicity to normal cells. BITC-induced cell death was completely prevented by pretreatment with thiol-containing redox compounds including N-acetyl-l-cysteine (NAC), glutathione (GSH), dithiothreitol, and 2-mercaptoethanol, but not free radical scavengers mito-TEMPO, catalase, apocynin, l-NAME and mannitol. BITC rapidly produced reactive oxygen species and nitric oxide, triggered oxidative DNA damage. BITC effectively decreased the intracellular GSH and GSH/GSSG ratio and redox balance recovery by thiol-containing redox compounds, but not by free radical scavengers. Accordingly, redox stresses-DNA damage response (DDR) activated ATM, Chk2, p53, and p21 and subsequently resulted in G/M phase arrest by inhibiting Cdc2 and cyclin B1. Notably, BITC-induced apoptosis was associated with reduced Mcl-1 and Bcl-2 expression, diminished mitochondrial membrane potential (ΔΨm), and increased PARP cleavage. These BITC-induced redox stress-mediated DDR and apoptosis could be blocked by NAC and GSH. Therefore, BITC can be a rational drug candidate for oral cancer and acted via a redox-dependent pathway.
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http://dx.doi.org/10.1016/j.fct.2016.09.028DOI Listing
November 2016

The Blind Men and the Elephant: The Risk of Misdiagnosis in Children with Developmental Disabilities.

CNS Neurosci Ther 2016 11;22(11):873-874

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028-CNRS UMR 5292, School of Medicine, Claude Bernard University, Lyon, France.

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http://dx.doi.org/10.1111/cns.12657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492881PMC
November 2016

Highly Dynamic Spatiotemporal Organization of Low-Frequency Activities During Behavioral States in the Mouse Cerebral Cortex.

Cereb Cortex 2017 12;27(12):5444-5462

INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Integrative Physiology of the Brain Arousal System Team, Lyon Cedex 08 F-69000, France.

Although low-frequency (LF < 10 Hz) activities have been considered as a hallmark of nonrapid eye movement (NREM) sleep, several studies have recently reported LF activities in the membrane potential of cortical neurons from different areas in awake mice. However, little is known about the spatiotemporal organization of LF activities across cortical areas during wakefulness and to what extent it differs during NREM sleep. We have thus investigated the dynamics of LF activities across cortical areas in awake and sleeping mice using chronic simultaneous local field potential recordings. We found that LF activities had higher amplitude in somatosensory and motor areas during quiet wakefulness and decreased in most areas during active wakefulness, resulting in a global state change that was overall correlated with motor activity. However, we also observed transient desynchronization of cortical states between areas, indicating a more local state regulation. During NREM sleep, LF activities had higher amplitude in all areas but slow-wave activity was only poorly correlated across cortical areas. Despite a maximal amplitude during NREM sleep, the coherence of LF activities between areas that are not directly connected dropped from wakefulness to NREM sleep, potentially reflecting a breakdown of long-range cortical integration associated with loss of consciousness.
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http://dx.doi.org/10.1093/cercor/bhw311DOI Listing
December 2017

High-amplitude theta wave bursts characterizing narcoleptic mice and patients are also produced by histamine deficiency in mice.

J Sleep Res 2016 10 27;25(5):591-595. Epub 2016 May 27.

Laboratory of Physiological Regulations in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whether histamine system is involved in high-amplitude theta wave burst generation during rapid eye movement sleep. The secondary aim was to assess the effects of combined histamine and orexin deficiency on high-amplitude theta wave bursts during rapid eye movement sleep in mice. Twelve histidine-decarboxylase knockout mice with congenital histamine deficiency, seven double mutant mice with combined deficiency of orexin neurons and histamine, and 11 wild-type control mice were studied with electrodes for sleep recordings and a telemetric blood pressure transducer. High-amplitude theta wave bursts during rapid eye movement sleep were detected in each of the histidine-decarboxylase knockout and double mutant mice, whereas only one burst was found in a wild-type control mouse. High-amplitude theta wave bursts occurred significantly more often and were significantly longer in double mutant than in histidine-decarboxylase knockout mice. In conclusion, it was demonstrated that, similarly to orexin, the chronic impairment of histamine entailed high-amplitude theta wave bursts during rapid eye movement sleep. The current data also suggested a synergistic role of orexin and histamine signalling on high-amplitude theta wave bursts during rapid eye movement sleep in mice.
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http://dx.doi.org/10.1111/jsr.12404DOI Listing
October 2016

Impact of Astroglial Connexins on Modafinil Pharmacological Properties.

Sleep 2016 06 1;39(6):1283-92. Epub 2016 Jun 1.

Theranexus, Lyon, France.

Study Objectives: Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors.

Methods: Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices.

Results: Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-administration with flecainide.

Conclusions: Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy.

Commentary: A commentary on this article appears in this issue on page 1175.
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http://dx.doi.org/10.5665/sleep.5854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863218PMC
June 2016

Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model.

Neuropharmacology 2016 07 23;106:20-34. Epub 2015 Dec 23.

Waking Team, Integrative Physiology of the Brain Arousal Systems, CRNL, INSERM-U1028, CNRS UMR5292, School of Medicine, Claude Bernard University, Lyon, France. Electronic address:

Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/- mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/- mice. Finally, H1-/- mice showed markedly greater changes in EEG power (notably in the 0.8-5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled 'Histamine Receptors'.
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http://dx.doi.org/10.1016/j.neuropharm.2015.12.014DOI Listing
July 2016

High bicarbonate levels in narcoleptic children.

J Sleep Res 2016 Apr 17;25(2):194-202. Epub 2015 Nov 17.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, University Lyon1, Lyon, France.

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 ± 4 years, 43% boys) and 51 patients presenting de-novo narcolepsy (N) (12.7 ± 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L(-1) were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L (-1) (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice.
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http://dx.doi.org/10.1111/jsr.12357DOI Listing
April 2016

Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

PLoS One 2015 16;10(10):e0140520. Epub 2015 Oct 16.

PRISM Laboratory, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140520PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608736PMC
June 2016

Commentary: A Quest for a Novel Peripheral Biomarker for Narcolepsy.

CNS Neurosci Ther 2015 Sep;21(9):681-2

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Claude Bernard University, Lyon, France.

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http://dx.doi.org/10.1111/cns.12433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493170PMC
September 2015

Altered autonomic control in preterm newborns with impaired neurological outcomes.

Clin Auton Res 2015 Aug 8;25(4):233-42. Epub 2015 Aug 8.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, CNRS UMR5292, University Lyon 1, Lyon, France.

Purpose: Very preterm newborns are at high risk of neurological injury. The objective of this work was to study the impact of neurological aggression on the autonomic nervous system.

Methods: We studied polysomnography recordings, at term corrected gestational age, for 38 preterm infants born at less than 28 weeks or weighing less than 1 kg. These infants were seen by a neuropediatrician, average age at follow up was 54.4 months. We created two groups: one with children who did not have any neurological disorder, including cerebral palsy (CP), language or mental retardation, visual or hearing disability, and attention disorder; the second group contained children with at least one of these impairments. From the polysomnography recordings, using coarse-graining spectral analysis, we compared heart rate variability indices between preterm infants with normal and abnormal neurological outcomes.

Results: Twenty infants had an impaired neurological outcome. Regarding the clinical characteristics, there were more babies born from smoking mothers (p = 0.025), with early-onset neonatal sepsis (p = 0.04), and abnormal results on cerebral magnetic resonance imaging (p = 0.014) in the group with impaired neurological outcomes. Spectral parameters were significantly different between active and quiet sleep. Total powers, harmonic and non-harmonic powers, high frequency and low frequency powers were higher in active sleep compared with those in quiet sleep. Preterm babies with impaired neurological development, in particular those with CP, had lower total power and non-harmonic power especially in active sleep than those with normal neurological outcome.

Conclusion: These findings suggest that, in very preterm infants, perinatal neurological injuries could be associated with abnormal maturation of the autonomic nervous system.
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http://dx.doi.org/10.1007/s10286-015-0298-6DOI Listing
August 2015
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