From pole to pole, life-long research of sleep in extreme environments.

In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of investigations in cats, I obtained my medical doctorate. Being a military physician, I was posted to Antarctica for wintering over and was initiated by Jean Rivolier into the psychology of small isolated human groups. I recorded 180 polysomnographic (PSG) nights in eight of my companions. This was my first contribution to research on human sleep under extreme environments and conditions. I then entered René Hénane's military thermophysiology laboratory, where I analyzed thermal exchanges during human sleep in the heat. Back to the cold, I spent 2 years in Canada and analyzed sleep during the Arctic winter under the direction of Manny W. Radomski, who headed the Defense and Civil Institute of Environmental Medicine and judged my PhD dissertation along with my first two mentors. Throughout my career, I worked in collaboration with Manny Radomski under the auspices of the Franco-Canadian Accord for Defence Research. We studied sleep and exercise, sleep deprivation, and recovery with and without chemical help. He also gave me support during several investigations in Africa. There, I studied normal sleep under various tropical climates (warm and dry in Niger, warm and humid in Côte d'Ivoire and Congo, temperate mid-mountain in Angola). I determined that human African trypanosomiasis, the ravaging sleeping sickness or tsetse disease, is not a hypersomnia, but a disorder of circadian rhythms, notably in the sleep-wake cycle.

Neurological patients confronting climate change: A potential role for the glymphatic system and sleep.

Interest in the health consequences of climate change (global warming, heatwaves) has increased in the neurological community. This review addresses the impact of elevated ambient temperatures and heatwaves on patients with neurological and mental health disorders, including multiple sclerosis, synucleinopathies, dementia, epilepsies, mental health, and stroke. Patients with such conditions are highly vulnerable during heatwaves because of functional disorders affecting sleep, thermoregulation, autonomic system reactivity, mood, and cognitive ability. Several medications may also increase the risk of heatstroke. Special attention is devoted to the involvement of common underlying mechanisms, such as sleep and the glymphatic system. Disease prevention and patient care during heatwaves are major issues for caregivers. Beyond the usual recommendations for individuals, we favor artificially induced acclimation to heat, which provides preventive benefits with proven efficacy for healthy adults.

Serum arginase, a biomarker of treatment efficacy in human African trypanosomiasis.

Arginase serum levels were increased in human African trypanosomiasis patients and returned to control values after treatment. Arginase hydrolyzes l-arginine to l-ornithine, which is essential for parasite growth. Moreover, l-arginine depletion impairs immune functions. Arginase may be considered as a biomarker for treatment efficacy.

Sleep and global warming: How will we sleep when the Earth is hotter?

Societal concern about climate change and global warming has grown worldwide along with the concomitant awareness that health will be impacted deeply. Among living beings, humans have quite large capacities for adaptation to varied temperature conditions. Despite their tropical origin, they live under all Earth climates, such as polar, temperate, altitude, arid, and tropical climates, using a wide range of behavioral and physiological adaptive responses. We address the adaptive abilities of human sleep-wake regulation and its interplay with thermoregulation under different natural climates. Sleep represents one-third of our living time and is also a major determinant of morbidity and mortality; shortening sleep duration increases mortality and multimorbidity. In addition, major advances in sleep neurology have occurred in the last decades. Some have been extensively reviewed, notably comparative sleep physiology among animals, allowing one to hypothesize about the functions of the different sleep states, as well as their relation to cognitive neuroscience or body biorhythms. However, the question of the sleep adaptive capacity of humans to global warming has barely been addressed. We examine "normal" sleep and thermoregulation in young adults residing in temperate conditions. We then review the sleep and thermoregulatory reactions under various climatic conditions, demonstrating the role of sleep changes as potent adaptive responses to living under natural hot climatic conditions. As a result, we show that humans are well-equipped to adapt to severe climates.

Heatwaves and human sleep: Stress response versus adaptation.

The World Meteorological Organization considers a heatwave as "a period of statistically unusual hot weather persisting for a number of days and nights". Accompanying the ongoing global climate change, sharp heatwave bouts occur worldwide, growing in frequency and intensity, and beginning earlier in the season. Heatwaves exacerbate the risk of heat-related illnesses, hence human morbidity and mortality, particularly in vulnerable elderly and children. Heat-related illnesses present a continuum from normothermic (prickly heat, heat edema, heat cramps, heat tetany) to hyperthermic syndromes (from heat syncope and heat exhaustion to lethal heat stroke). Heat stroke may occur through passive heating and/or exertional exercise. "Normal sleep", such as observed in temperate conditions, is altered during heatwaves. Brisk excessive heat bouts shorten and fragment human sleep. Particularly, deep N3 sleep (formerly slow-wave sleep) and REM sleep are depleted, such as in other stressful situations. The resultant sleep loss is deleterious to cognitive performance, emotional brain function, behavior, and susceptibility to chronic health conditions and infectious diseases. Our group has previously demonstrated that sleep constitutes an adaptive mechanism during climatic heat acclimatization. In parallel, artificial heat acclimation procedures have been proposed in sports and military activities, and for the elderly. Other preventive actions should be considered, such as education and urban heat island cooling (vegetation, white paint), thus avoiding energy-hungry air conditioning.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

Covid-19: Early Cases and Disease Spread.

The emergence and global spread of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is critical to understanding how to prevent or control a future viral pandemic. We review the tools used for this retrospective search, their limits, and results obtained from China, France, Italy and the USA. We examine possible scenarios for the emergence of SARS-CoV-2 in the human population. We consider the Chinese city of Wuhan where the first cases of atypical pneumonia were attributed to SARS-CoV-2 and from where the disease spread worldwide. Possible superspreading events include the Wuhan-based 7th Military World Games on October 18-27, 2019 and the Chinese New Year holidays from January 25 to February 2, 2020. Several clues point to an early regional circulation of SARS-CoV-2 in northern Italy (Lombardi) as soon as September/October 2019 and in France in November/December 2019, if not before. With the goal of preventing future pandemics, we call for additional retrospective studies designed to trace the origin of SARS-CoV-2.

Determinants of compliance with anti-vectorial protective measures among non-immune travellers during missions to tropical Africa.

BACKGROUND: The effectiveness of anti-vectorial malaria protective measures in travellers and expatriates is hampered by incorrect compliance. The objective of the present study was to identify the determinants of compliance with anti-vectorial protective measures (AVPMs) in this population that is particularly at risk because of their lack of immunity. METHODS: Compliance with wearing long clothing, sleeping under insecticide-impregnated bed nets (IIBNs) and using insect repellent was estimated and analysed by questionnaires administered to 2,205 French military travellers from 20 groups before and after short-term missions (approximately four months) in six tropical African countries (Senegal, Ivory Coast, Chad, Central African Republic, Gabon and Djibouti). For each AVPM, the association of "correct compliance" with individual and collective variables was investigated using random-effect mixed logistic regression models to take into account the clustered design of the study. RESULTS: The correct compliance rates were 48.6%, 50.6% and 18.5% for wearing long clothing, sleeping under bed nets and using repellents, respectively. Depending on the AVPM, correct compliance was significantly associated with the following factors: country, older than 24 years of age, management responsibilities, the perception of a personal malaria risk greater than that of other travellers, the occurrence of life events, early bedtime (i.e., before midnight), the type of stay (field operation compared to training), the absence of medical history of malaria, the absence of previous travel in malaria-endemic areas and the absence of tobacco consumption.There was no competition between compliance with the different AVPMs or between compliance with any AVPM and malaria chemoprophylaxis. CONCLUSION: Interventions aimed at improving compliance with AVPMs should target young people without management responsibilities who are scheduled for non-operational activities in countries with high risk of clinical malaria. Weak associations between compliance and history of clinical malaria or variables that pertain to threat perception suggest that cognition-based interventions referencing a "bad experience" with clinical malaria could have only a slight impact on the improvement of compliance. Further studies should focus on the cognitive and behavioural predictors of compliance with AVPMs.

Cerebrospinal fluid B lymphocyte identification for diagnosis and follow-up in human African trypanosomiasis in the field.

OBJECTIVES: In human African trypanosomiasis (HAT, sleeping sickness), staging of disease and treatment follow-up relies on white cell count in the cerebrospinal fluid (CSF). As B lymphocytes (CD19 positive cells) are not found in the CSF of healthy individuals but occur in neurological disorders such as multiple sclerosis, B lymphocyte count may be useful for field diagnosis/staging and therapeutic follow-up in HAT. METHODS: Seventy-one HAT patients were diagnosed and 50 were followed-up 6-24 months after treatment. White cell counts were used for conventional staging (stage 1, < or =5 cells/microl CSF, n = 42; stage 2, > or =20 cells/microl, n = 16) and intermediate stage (6-19 cells/microl, n = 13). Slides containing 1 microl of CSF mixed with Dynabeads CD19 pan B were examined microscopically to detect B cell rosettes (bound to at least four beads). RESULTS: Stage 1 patients exhibited zero (n = 37) or one CSF rosette/microl (n = 5), contrary to most stage 2 patients (14/16: > or =2 rosettes/microl). Intermediate stage patients expressed 0 (n = 9), 1 (n = 3) or 2 (n = 1) rosettes/microl of CSF. During follow-up, rosette counts correlated with white cell count staging but were much easier to read. CONCLUSION: B cell rosettes being easily detected in the CSF in field conditions may be proposed to replace white cell count for defining HAT stages 1 and 2 and limit uncertainty in treatment decision in patients with intermediate stage.

Determinants of compliance with malaria chemoprophylaxis among French soldiers during missions in inter-tropical Africa.

BACKGROUND: The effectiveness of malaria chemoprophylaxis is limited by the lack of compliance whose determinants are not well known. METHODS: The compliance with malaria chemoprophylaxis has been estimated and analysed by validated questionnaires administered before and after the short-term missions (about four months) in five tropical African countries of 2,093 French soldiers from 19 military companies involved in a prospective cohort study. "Correct compliance" was defined as "no missed doses" of daily drug intake during the entire mission and was analysed using multiple mixed-effect logistic regression model. RESULTS: The averaged prevalence rate of correct compliance was 46.2%, ranging from 9.6%to 76.6% according to the companies. Incorrect compliance was significantly associated with eveningness (p = 0.028), a medical history of clinical malaria (p < 0.001) and a perceived mosquito attractiveness inferior or superior to the others (p < 0.007). Correct compliance was significantly associated with the systematic use of protective measures against mosquito bites (p < 0.001), the type of military operations (combat vs. training activities, p < 0.001) and other individual factors (p < 0.05). CONCLUSIONS: The identification of circumstances and profiles of persons at higher risk of lack of compliance would pave the way to specifically targeted strategies aimed to improve compliance with malaria chemoprophylaxis and, therefore, its effectiveness.

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries.

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral attachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hypoperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis, encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World Federation of Neurology we invite national and regional neurological associations to create local databases to report cases with neurological manifestations observed during the on-going pandemic. International neuroepidemiological collaboration may help define the natural history of this worldwide problem.

Cerebral inducible nitric oxide synthase protein expression in microglia, astrocytes and neurons in Trypanosoma brucei brucei-infected rats.

To study the anatomo-biochemical substrates of brain inflammatory processes, Wistar male rats were infected with Trypanosoma brucei brucei. With this reproducible animal model of human African trypanosomiasis, brain cells (astrocytes, microglial cells, neurons) expressing the inducible nitric oxide synthase (iNOS) enzyme were revealed. Immunohistochemistry was achieved for each control and infected animal through eight coronal brain sections taken along the caudorostral axis of the brain (brainstem, cerebellum, diencephalon and telencephalon). Specific markers of astrocytes (anti-glial fibrillary acidic protein), microglial cells (anti-integrin alpha M) or neurons (anti-Neuronal Nuclei) were employed. The iNOS staining was present in neurons, astrocytes and microglial cells, but not in oligodendrocytes. Stained astrocytes and microglial cells resided mainly near the third cavity in the rostral part of brainstem (periaqueductal gray), diencephalon (thalamus and hypothalamus) and basal telencephalon. Stained neurons were scarce in basal telencephalon, contrasting with numerous iNOS-positive neuroglial cells. Contrarily, in dorsal telencephalon (neocortex and hippocampus), iNOS-positive neurons were plentiful, contrasting with the marked paucity of labelled neuroglial (astrocytes and microglial) cells. The dual distribution between iNOS-labelled neuroglial cells and iNOS-labelled neurons is a feature that has never been described before. Functionalities attached to such a divergent distribution are discussed.

Hypocretin and human African trypanosomiasis.

OBJECTIVES: To detail clinical and polysomnographic characteristics in patients affected with Trypanosoma brucei gambiense (Tb.g.) human African trypanosomiasis (HAT) at different stages of evolution and to measure and compare cerebrospinal fluid (CSF) levels of hypocretin-1 with narcoleptic patients and neurologic controls. METHODS: Twenty-five untreated patients affected with T.b.g. HAT were included. The patients were evaluated using a standardized clinical evaluation and a specific interview on sleep complaints. Diagnosis of stages I and II and intermediate stage was performed by CSF cell count and/or presence of trypanosomes: 4 patients were classified as stage II, 13 stage I, and 8 "intermediate" stage. Seventeen untreated patients completed continuous 24-hour polysomnography. We measured CSF levels of hypocretin-1 in all patients at different stages and evolutions, and we compared the results with 26 patients with narcolepsy-cataplexy and 53 neurologic controls. RESULTS: CSF hypocretin-1 levels were significantly higher in T.b.g. HAT (423.2 +/- 119.7 pg/mL) than in narcoleptic patients (40.16 +/- 60.18 pg/ mL) but lower than in neurologic controls (517.32 +/- 194.5 pg/mL). One stage I patient had undetectable hypocretin levels and 1 stage II patient showed intermediate levels, both patients (out of three patients) reporting excessive daytime sleepiness but without evidence for an association with narcolepsy. No differences were found in CSF hypocretin levels between patients with HAT stages; however, the presence of major sleep-wake cycle disruptions was significantly associated with lower CSF hypocretin-1 level with a same tendency for the number of sleep-onset rapid eye movement periods. CONCLUSION: The present investigation is not in favor of a unique implication of the hypocretin system in T.b.g. HAT. However, we propose that dysfunction of the hypothalamic hypocretin region may participate in sleep disturbances observed in African trypanosomiasis.

Time of night and first night effects on arousal response in healthy adults.

OBJECTIVE: Several factors, such as homeostatic and circadian influences, may affect the density of cortical and subcortical arousals (AR). The purpose of this study was to examine the time-of-night and the first night effect on AR response. METHODS: AR were classified into microarousals (MA), phases of transitory activation (PAT), delta (D-burst) and K-complex burst (K-burst). The AR density and duration was analyzed during two consecutive nights with the analysis of sleep stage and sleep cycle in thirty-six healthy subjects. RESULTS: D- and K-burst showed a trend toward progressive decline across sleep cycles (p<0.0001). While MA rate was unaffected throughout sleep cycles, PAT index increased across the night (p=0.002). The density and duration of each group of AR exhibited reproducibility without significant differences between nights. An individual inter-night variability in AR density was found independently of night and sleep structure. CONCLUSIONS: While homeostatic and circadian influences affect nighttime subcortical and MA responses, a wakefulness drive modulates the occurrence of AR with movements. Although the pattern of AR responses was highly reliable from the first to second night, the substantial inter-individual variability suggests the existence of an individual susceptibility. SIGNIFICANCE: The first night effect on arousal response is affected by individual susceptibility and circadian and homeostatic influences.

Michel Jouvet and "exotic" sleep.

Michel Jouvet directed my medical thesis on paradoxical sleep in cats obtained in 1969, and my research on sleep in extreme environments (Antarctica, Arctic winter cold, physical exercise), which was the subject of my Ph.D. dissertation in 1984. As a military MD and scientist, I was posted in "exotic" (far away) places (Antarctica, Canada, Niger) and participated in several remote field trials (Canada, Côte d'Ivoire, Congo, Angola). Michel Jouvet supervised my research activity, allowing me the use of his laboratory facilities. He co-authored the work on sleep in Antarctica in 1987. In 1988, he was invited to Niamey (Niger) to preside on the international jury of medical doctorate dissertations. He then examined one of my patients with narcolepsy-like sleep attacks, suspect of sleeping sickness. Jouvet also co-authored our work on nitric oxide in the rat model of sleeping sickness. His scientific curiosity led him to study REM sleep eye movements in Bassari people, an isolated ethnic group in Senegal. With Monique Gessain, he co-authored a book on the Bassari oneiric activity. He was convinced that research in electricity-free villages was capital for understanding past mankind story. The present contribution recognizes the tremendous work capacity and scientific curiosity of Michel Jouvet.

Stress-induced hippocampus Npas4 mRNA expression relates to specific psychophysiological patterns of stress response.

Neuronal Per-Arnt-Sim (PAS) domain protein 4 (Npas4) is a key protein that intervenes in GABA synapse scaling and neurotrophicity enhancing. Since GABA and neurotrophicity are implicated in stress response and Npas4-deficient rodents exhibit behavioral alterations, an investigation was designed in rats to verify whether stress-induced spontaneous hippocampus Npas4 mRNA expression would be associated with specific patterns of stress response. The rats were exposed to one of three stressor levels: no stress (CTL, n = 15), exposure to a footshock apparatus (Sham, S, n = 40) and footshock (F, n = 80). After stress exposure the S and F rats were tested in an activity cage, and subsequently in an elevated plus maze (EPM), just prior to the sacrifice. Using cluster analysis, the animals already assigned to a stress level were also distributed into 2 subgroups depending on their Npas4 mRNA levels. The low (L) and high (H) Npas4 expression subgroups were identified in the S and F groups, the CTL group being independent of the Npas4 levels. The Npas4 effect was studied through the interaction between stress (S and F) and Npas4 level (L and H). The biological stress response was similar in H and L rats, except blood corticosterone that was slightly lower in the H rats. The H rats were more active in the actimetry cage and presented higher levels of exploration in the EPM. They also exhibited higher hippocampus activation, as assessed by the c-fos, Egr1 and Arc mRNA levels. Therefore high Npas4 expression favors stress management.

Effect of glucocorticoid depletion on heat-induced Hsp70, IL-1beta and TNF-alpha gene expression.

When exposed to heat, conscious naive rats may develop lethal heatstroke, depending on heat load, i.e., time spent at high body core temperature. The occurrence of heatstroke was hypothesized to result from a defective glucocorticoid secretion related to altered heat-stress responses. We thus investigated the potential involvement of glucocorticoids in heat tolerance and its consequences on physiological responses, heat shock protein 70 (Hsp70), and cytokine mRNA expressions. Two hours before heat exposure, the animals were injected either with metyrapone, an inhibitor of corticosterone synthesis, or with its vehicle. Heat exposure lasted for 15, 30, 45 or 60 min. Thereafter, the rats were distributed into three groups according to their heat load: null, moderate (without any lethal risk) and intense (with lethal risk). Physiological responses were evaluated with colonic temperature, plasma lactate and hematocrit. Brain responses were assessed in frontal cortex through Hsp70, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) mRNA expressions. The animals with a severe heat load exhibited a high hematocrit, increased plasma lactate level and enhanced brain IL-1beta and Hsp70 mRNA expressions. Independent of the heat load, Metyrapone rats showed the same thermophysiological responses and IL-1beta and Hsp70 mRNA expressions when compared with vehicle rats. However, the Metyrapone rats experiencing an intense heat load exhibited an increased TNF-alpha mRNA expression. In conclusion, these data (i) confirm that heat load is important in the calibration of the risk attached to heat exposure; and (ii) suggest that corticosterone synthesis inhibition may favor TNF-alpha mRNA expression without any effect on Hsp70 mRNA expression.

Sleep under extreme environments: effects of heat and cold exposure, altitude, hyperbaric pressure and microgravity in space.

Human sleep is sensitive to the individual's environment. The present review examines current knowledge of human sleep patterns under different environments: heat exposure, cold exposure, altitude, high pressure and microgravity in space. Heat exposure has two effects. In people living in temperate conditions, moderate heat loads (hot bath, sauna) prior to sleep provoke a delayed reaction across time (diachronic reaction) whereby slow-wave sleep (SWS) augments in the following night (neurogenic adaptive pathway). Melanoids and Caucasians living in the Sahel dry tropical climate experience diachronic increases in SWS throughout seasonal acclimatization. Such increases are greater during the hot season, being further enhanced after daytime exercise. On the contrary, when subjects are acutely exposed to heat, diachronic decreases in total sleep time and SWS occur, being often accompanied by synchronic (concomitant) diminution in REM sleep. Stress hormones increase. Nocturnal cold exposure provokes a synchronic decrease in REM sleep along with an activation of stress hormones (synchronic somatic reaction). SWS remains undisturbed as it still occurs at the beginning of the night before nocturnal body cooling. Altitude and high pressure are deleterious to sleep, especially in non-acclimatized individuals. In their controlled environment, astronauts can sleep well in microgravity. Exercise-induced sleep changes help to understand environmental effects on sleep: well-tolerated environmental strains may improve sleep through a neurogenic adaptive pathway; when this "central" adaptive pathway is overloaded or bypassed, diachronic and synchronic sleep disruptions occur.

Sleep patterns in villagers and urban African volunteers in a humid tropical climate: Influence of accessibility to electric light?

Recent publications focusing on sleep-wake alternation, using actigraphic recordings in hunter-gatherers, stressed the existence of a potential effect of electricity availability on sleep habits. These reports prompted us to achieve a new analysis of the polysomnographic data already obtained in healthy African volunteers in equatorial Africa during two different investigations. Comparison of the 24-h polysomnographic sleep patterns were done between 9 volunteers sleeping in a laboratory in Abidjan (Abidjan cohort) and 11 villagers living in electricity-free bush villages (Sinfra cohort). Sleep was lighter in the villagers, with more stage 1 and less slow wave sleep (SWS). Latency to SWS was also shorter. Total sleep time, however, was not different between the two groups. There were no indications as to whether the observed differences were attributable to the availability of electrical power. Reactivity of human sleep structure to the environment was discussed in terms of multifactorial influences such as daylight length, temperature, humidity, electromagnetic field, time of sleep onset, thermoregulatory mechanisms, stress or anxiety.