法国睡眠研究的历史

(Lyon Neuroscience Research Center，INSERM U1028-CNRS UMR 5292-Waking Team，University Claude Bernard，School of Medicine，Lyon，France)

The beginning

During the following 10 years，several books on sleep and sleep disorders are written.They focused on normal and pathological sleep，or more specifically on hypersomnia，insomnia and parasomnia or dreams.Especially under the impulse of Dr.Jean Lhermitte and Dr.Auguste Tournay such book-writing efforts additionally invigorated a 72-page long report on sleep，as a proceeding of the 1927 Annual Neurology conference in Paris.It consisted of two parts.A large part discussed the physiology of sleep，elaborating on its functions，the relation to nutrition，the characteristics and variations of sleep，the consequences and brain mechanisms of sleep.A smaller part dealt with the pathology of sleep.Not only two more conferences followed but also the creation of sleep labs in different universities across France became a fact.Namely，in 1963 the meeting by the Society of Electroencephalogram(EEG)and Clinical Neurophysiology of French language speakers gave platform to discuss the first EEG recordings applied during sleep.This symposium was well attended by physicians from Paris，Lyon，Marseille，Montpellier，Strasbourg，but also by physicians from Belgium，Scotland and Italy.Consequently，sleep EEG recordings were progressively applied in several diseases or symptomatologies.1975 was pivotal because of the first international symposium dedicated to narcolepsy，a sleep disorder first termed by a French physician.This symposium attracted experts from around the world，such as William C.Dement，Christian Guilleminault，Yasuo Hishikawa，Pierre Passouant，Bedrich Roth，Yasuro Takahashi and Gerard Vogel.It further resulted in a book that remains highly referenced：“Narcolepsy” by Christian Guilleminault，William C.Dement，Pierre Passouant[2].

The Jouvet-period

During the 1950-1960′s an increased interest in fundamental and clinical sleep research can be distinguished[3].The duality of sleep-wake states and how they are regulated is omnipresent.This period furthermore spawns several prominent sleep researchers across the country，while each ventures on their individual journey.

·Montpellier-Pierre PASSOUANT(1913-1983)-had a special interest in the hippocampus and cerebellum[4-5]，and might be one of the first creating in the basement of the hospital an EEG lab for experimental neurophysiology.Blocking the epileptic discharges during sleep was a primary aim，and a secondary one was the study of narcolepsy.

·Bordeaux-Jacques FAURE(1912-1986)-investigated sexual behavior and sleep-wake states.He described OBAGS，or olfacto-bucco-ano-genito-sexual behavior，in the rabbit that was considered as an isomorph of paradoxical sleep(see further).His student contributed to the development of endocrinology but foremost created a human sleep lab in 1970.

·Lyon-Michel JOUVET(1925-2017)-studied the mechanisms responsible for reticular inhibition during habituation in decorticated cats.He started with his research at University Claude Bernard Lyon 1 after spending one year in Horace W.Magoun lab in California(1954).He succeeded in performing longitudinal sleep recordings in cats.The cat had large lesions in the reticular formation，mesencephalic region or pontine.During the electromyogram(EMG)registration of muscles in the neck，he was surprised to see in the pons every 30-40 minutes a disappearance of the EMG activity.It seemed like a rhombencephalographic sleep in contrast to the slow waves of sleep.Quick thereafter he exclusively investigated sleep recordings in cats，and observed that there is cortical electrical activity that is approaching waking states but that the wakefulness threshold is very high.This was a paradoxical finding，which he thought resembled the sleep with eye movements as described by William C.Dement in the United States(US).Progressively during his career，he showed more interest in human sleep research.That is，a 30-year old subject that suffered from the chronical syndrome of decortication[6]，as well as prolonged coma patients[7]，trigged his curiosity.So，history was written!

He generated in a highly creative manner numerous fascinating findings and hypotheses regarding sleep.For instance，the 3rd state of the brain being paradoxical sleep[8].He exposed in detail brainstem structures，and the development of monoaminergic，serotoninergic，peptidergic and neural hypotheses and paradigms(e.g.[9-10]).

His work gave decennia of fruitful science.For example，the existence of waking but inhibitory systems of paradoxical sleep in the posterior hypothalamus，namely the histamine and orexin neurons.While such predictions were done in the 60′s，his pupils and close collaborators identified them in the 1980s and 1990s，respectively.

·Paris-Collete DREYFUS-BRISAC(1916-2006)-investigated the electrocortical activity and published on sensory reactivity of prematures and newborns during their sleep and wake-state[11-12](1962).Together with Nicole MONOD(in 1965)and Lilia CURZI-DASCALOVA(1975)，they formed a highly productive scientific team with many people across the world joining them for learning about sleep in newborns.

·Lyon but relocating to Paris-Odile BENOIT(unknown)-studied the registration of unilateral discharges in different cerebral structures of the cat.She continued her career investigating human sleep，automated analyses of sleep and pediatric sleep as well as nightshift work.

·Strasbourg-Daniel KURZ(unknown)-EEG modifications in the case of hyperammonemia and in cardiac patients.Later on，he also studied the Pickwickian syndrome and sleep apnea syndrome.An interest that remains in Strasbourg up till 2007.

·Marseille-Henri GASTAUT(1915-1995)-being interested in epilepsy，supervised two foreign students：Roger Broughton(Ottawa)studying paroxysmal non-epileptic seizures during sleep，and Carlo Alberto Tassinari(Bologne)being an EEG and epilepsy expert.Gastaut also hires Bernard Duron，a respiratory expert.Together they focused on confusional arousals，somnambulism，and night terror.

·Rouen-Dominique SAMSON-DOLLFUS(1928-2016)-works on EEG registrations/signals.She focuses on the automated analyses of the EEG and together with colleagues，they focus on ambulatory sleep recordings in young children.

·Amiens-Bernard DURON(1933-2015)works on respiratory physiology，and with the arrival of Pierre Levi-Valensi in 1988 two bedrooms for sleep registrations are in place.

·Grenoble-Claude FEUERSTEIN(unknown)-is given an old Alvar equipment(sleep recording device)by Jouvet and explores the interactions between the dopaminergic system and sleep in the rat.During his career he starts performing sleep studies in psychiatric patients，and with the help of Jean Perret in 1985 also neurological patients were included.

·Also the French army showed an interest in sleep research，i.e.，fundamental and pharmacological research by Jean-Louis VALATX(1938-2009).Jouvet recruited him as an INSERM(Institute of the French Ministries of Health and Research)researcher，and he quickly became director of sleep research with an interest in the genetics of sleep and factors that may perturb sleep such as climate changes.Other researchers joined his research objectives such as investigating sleep in extreme environmental conditions，performing sleep studies in Congo Brazzaville on patients affected by ‘sleeping sickness’ or exploring the deprivation of sleep as well as the waking effects of different substances such as modafinil.Only years later military hospitals are created.

The first diagnostic sleep recordings were done at Edouard-Herriot hospital in Lyon by Jouvet，yet soon thereafter in hospitals in Montpellier(1961)，Paris(1963)and Strasbourg(1965).Most recordings were performed in EEG boxes that overnight were converted into recording rooms for sleep，but also in meeting rooms or in the offices of the physician，this chiefly for practical reasons，e.g.，uninterrupted recordings.An analogue ambulatory system was used，and because they were not created for long-term recordings or even 24-hour recordings，many problems were faced! Each recording required a person being present the whole time but also endless meters of paper were to be analyzed per day.In the US，W.C.Dement wrote at a certain point，that his night work at Mount Sinai Hospital became intolerable for his wife.Also in France sleep experts needed to be creative to pursue their night work，not to interfere with daytime responsibilities or routines in the hospitals.

At the beginning，it was rather patients that behaved differently during sleep instead of people with actual sleep problems that were studied.Despite being labelled as diagnostic most of the studies were still highly descriptive and the know-how varied across the country.For instance，neurological disorders in Lyon; epilepsy，parasomnias and respiratory problems in Marseille; epilepsy and narcolepsy in Montpellier; prematurity，insomnia and mental health issues in Paris; cardiac and respiratory problems in Strasbourg.It is only 20-30 years later that clinical sleep consultations were executed，and at the beginning they were rather seen as auxiliary care.It would moreover involve primarily cases suffering sleep disordered breathing problems，for obvious reasons per the legend.

While the scoring of sleep recordings evolved through the years，Jouvet continued using the term ‘paradoxical’ sleep in his publications.To date，in France rapid eye movement sleep is still communicated as paradoxical sleep.So upon hearing ‘paradoxical’ sleep during conference meetings，you may certainly attribute a French connection to the speaker!

From 1970 until today sleep centers may have different set-ups.For instance，they have(separate)rooms to fill out questionnaires or perform neuropsychological assessments，(separate)rooms to prepare patients or(separate)bedrooms.But，recordings on the hospital bed were also performed as well as rooms where patients are prepared but subsequently went home exist，or altogether in home services have been provided.Lyon，considered as an important French hub for sleep，counted through history about eight clinical centers covering sleep across the lifespan! It has cultivated，and still hosts nowadays，several prominent sleep researchers.

From the second half of 1980 digitalized sleep equipment created a big shift on all aspects of sleep medicine.More parameters could be simultaneously recorded，nurses or sleep technicians were hired，multidisciplinary teams were formed.Around the same time(1979)the Diagnostic Classification of Sleep and Arousal Disorders was published，listing about 70 different sleep disorders.This publication was revised continuously，leading to the International Classification of Sleep Disorders(ICSD)in 1990，2005，2014.

Guilleminault-period

In 1979，Guilleminault described the apneic syndrome but also progressively documented the cardio-and cerebrovascular complications of obstructive sleep apnea.Consequently，being a public health issue，it drew a lot of attention towards sleep disorders，and more specifically obstructive sleep apnea.Which was an accomplishment but similarly pinpointed a big flaw.Namely，this medical issue required a specialist′s attention but very few had the necessary qualification to diagnose，to use the equipment，and so forth.Likewise，the French Sleep Medicine Research Society(SFRMS)started to put in place certain criteria regarding the opening of sleep centra.

Already as an intern Christian Guilleminault envisioned developing the discipline/training of sleep medicine.After fruitless attempts to launch such a medical specialty，he leaves France(01/01/1972)for Stanford(US).Guilleminault continued his career-path investigating obstructive sleep apnea syndrome in(non-)obese adults and in children.He abundantly showed the association with learning and attention problems，and with cardiovascular risks(more than 650 peer-reviewed papers).In 1982 he depicted elevated upper airway resistance syndrome in children while highlighting their problems with attention，abnormal behavior during wakefulness，learning difficulties and even co-morbid sleep problems(e.g.，sleepwalking，sleep terrors and enuresis).His lucid and highly critical mind makes him up to today an inexhaustible researcher of sleep medicine.Recently at the annual sleep conference in Paris，he stressed the significance to pay attention to abnormal breathing in young children，as it influences their craniofacial shape for life.Although he likely sighed numerous times during his career,… abnormal sleep breathing，it breathes Guilleminault!

Guilleminault′s vision for sleep medicine to become a separate discipline indeed required nearly a lifelong effort.Meanwhile in France，despite the increased interest in sleep medicine，the clinical diagnoses remain limited to certain pathologies.Yet the combination of the interest，the centers and the spotlight on abnormal breathing during sleep invoked important changes in the 80′s.

In 1987 more specifically，under the impulse of the Montpellier group，a one-week course and 48 hours of internship at centers in Lyon，Montpellier，Paris，Strasbourg led for the first time to an university degree in wakefulness and sleep.The course was a success and two years later was transformed into an interuniversity degree.The following years it was alternating between cities across France.In 2009 an interuniversity degree in sleep and its pathology is established and only taught in Paris.It involves 3 seminaries of 2 days and an internship only being available at 20 sleep centers across the country，with a minimum of 84 hours to complete.Yet in the years thereafter several other allied interuniversity degrees are created：e.g.，physiology and pathology of sleep; sleep medicine applied to the elderly; sleep/wake disorders in children，etc….Also the SFRMS has yearly a 1-day course the day before the national conference.

In addition，depending on the need of the sleep center a continued education in sleep medicine can be requested.The main aim is to distribute regionally the sleep knowledge.For instance，in analogy to the National Sleep Foundation in the US，France has the National Institute of Sleep and Vigilance(2000).They also launch large-scale surveys regarding sleep.Several other of these institutes nowadays exist aiding to promote sleep in all facets(e.g.，health-technicians).

During the same period many books，general or more specific(e.g.，dreams，pediatrics，neurology，biological rhythms)，and guides start to circulate.As a potential consequence，clinical sleep diagnoses evolve towards more research-oriented，hypothetical and deductive ‘entities’.Thus，the highly explorative-and often lacking IRB(institutional review board)regulated-assessments，quickly advanced into medical research pursued by INSERM，CRNS(French National Centre for Scientific Research)，and ANR(The French National Research Agency).In the early stages，research was done in close collaborations with hospitals and clinicians.This evolution goes hand in hand with the creation of reference centers for rare disorders(e.g.，narcolepsy).To day，there have been 363 centers labeled and created to treat and investigate rare disorders.

Likewise，the establishment of societies and professional associations took a long time，in part because few physicians had sleep medicine as their specialty.In 1982 in Jouvet′s lab，the first plan of an association of sleep labs/centers was drafted.While changing names over the years in 2017 the SFRMS counted 858 members.Yet meanwhile also other associations were formed such as la Society of Pneumologists for French language speakers.

Even today they co-host the yearly SFRMS meeting.In 1972，the European Sleep Research Society was created to promote sleep research，to improve patient care，and to disseminate information regarding sleep.This society organized several meetings in France.

The SFRMS journal had a difficult start due to existing journals，private attempts to launch a journal，but in 2014 the first journal was official.Noteworthy，the pharmaceutical companies have played a major role in financially supporting sleep and exploring sleep research endeavors through its history.

The future

It was on 21 April 2017 that a reglementatory list of university degrees included the specialty education in sleep medicine.Sleep medicine is now one of the 23 transversal educational options in medicine.That is，45-years after Guilleminault started his journey! The education in sleep medicine is now worldwide advocated and fostered，schooling young dreamers and visionaries in the world!