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Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Revons-nous toute la nuit ? De quels evenements ? A quelles fins ? Pour le savoir, les scientifiques ont mis en place toutes sortes de methodes. Leurs decouvertes bousculent les idees recues.

Limb amputation is followed, in approximately 90% of patients, by “phantom limb” sensations during wakefulness. When amputated patients dream, however, the phantom limb may be present all the time, part of the time, intermittently or not at all.1 The absence of the phantom limb when dreaming has been taken as evidence for a pre-existing kinesthetic body scheme, unaffected by the amputation, that is accessible to the patient when asleep.2 Such dreaming experiences in amputees have usually been obtained only retrospectively in the morning and, moreover, dreaming is normally associated with muscular atonia so the motor counterpart of the phantom limb experience cannot be observed directly. REM sleep behaviour disorder (RBD), in which muscle atonia is absent during REM sleep and patients act out their dreams,3 allows a more direct analysis of the “phantom limb” phenomena and their modifications during sleep. A 58-year-old man had a history of erectile failure and abnormal ejaculation, a 5 year history of orthostatic hypotension and frequent somniloquy with excessive motor activity during sleep, usually accompanied by vivid striking dreams, sometimes of violent content but not causing self- or bed-partner injury. At the age of 39 years, his left arm was amputated at the level of the middle-third of the …

Reply from the Authors: We thank Dr. Stanzione et al. for their comments and for reporting the results of two cases where DBS was applied in the GPi. In their patients, parkinsonian motor signs and LIDs were both improved by pallidal stimulation. We have had similar therapeutic results and agree that the GPi can be proposed as a target for DBS. The main purpose of our study,1 however, was not to discuss the therapeutic issues of pallidal stimulation in patients with PD but to provide pathophysiologic information on this specific target. Briefly, using quadripolar …

Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of attention-deficit/hyperactivity disorder (ADHD).To evaluate iron deficiency in children with ADHD vs iron deficiency in an age- and sex-matched control group.Controlled group comparison study.Child and Adolescent Psychopathology Department in European Pediatric Hospital, Paris, France.Fifty-three children with ADHD aged 4 to 14 years (mean +/- SD, 9.2 +/- 2.2 years) and 27 controls (mean +/- SD, 9.5 +/- 2.8 years).Serum ferritin levels evaluating iron stores and Conners' Parent Rating Scale scores measuring severity of ADHD symptoms have been obtained.The mean serum ferritin levels were lower in the children with ADHD (mean +/- SD, 23 +/- 13 ng/mL) than in the controls (mean +/- SD, 44 +/- 22 ng/mL; P.001). Serum ferritin levels were abnormal (30 ng/mL) in 84% of children with ADHD and 18% of controls (P.001). In addition, low serum ferritin levels were correlated with more severe general ADHD symptoms measured with Conners' Parent Rating Scale (Pearson correlation coefficient, r = -0.34; P.02) and greater cognitive deficits (r = -0.38; P.01).These results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.

A 62-year-old man consulted the sleep clinic. He had a 20-year history of severe insomnia that was considered of psychiatric origin, although the symptoms were not alleviated by benzodiazepines (clonazepam, flunitrazepam, loflazepam), antidepressants (amitriptyline, mianserin), phenothiazine (alimemazin), amantadine, biperiden, or magnesium salts. He had frequent and long-lasting nocturnal arousals, and slept less than 4 hours a night. He had a strong feeling of discomfort (but no pain) in his legs during the night, which he was …

Background High-frequency stimulation of the subthalamic nucleus constitutes a therapeutic advance for severely disabled patients with Parkinson disease. Objective To evaluate the efficacy and safety of continuous bilateral high-frequency stimulation of the subthalamic nucleus in patients with Parkinson disease. Design A prospective study of patients with Parkinson disease treated at a university hospital. Patients and Methods Electrodes were implanted bilaterally in the subthalamic nucleus of 23 consecutive patients with Parkinson disease who responded well to levodopa but had severe motor complications. There were 16 men and 7 women (mean ± SEM age, 53 ± 2 years) who had a mean ± SEM disease duration of 14.7 ± 1.0 years. Targets were determined by 3-dimensional magnetic resonance imaging, combined with intraoperative electrophysiologic recordings and stimulation. Results Six months after surgery, motor disability, levodopa-induced motor fluctuations, dyskinesias, and the daily dose of levodopa equivalent decreased significantly by 67%, 78%, 77%, and 61%, respectively, compared with the preoperative state. No significant morbidity was observed, except transient depression in 4 patients. Conclusions The beneficial effects of subthalamic stimulation depend on (1) the criteria used for patient selection, (2) the precision with which the subthalamic nucleus is targeted (dependent on the 3-dimensional magnetic resonance imaging and the intraoperative electrophysiologic and clinical assessments), and (3) the long-term postoperative adjustment of stimulation variables.

In amyotrophic lateral sclerosis (ALS), the progressive loss of upper and lower motor neurons leads to respiratory failure, often with predominant diaphragm dysfunction, and death. Because the diaphragm is the only active inspiratory muscle during rapid eye movement (REM) sleep, there is a high theoretical risk of respiratory disorders during REM sleep in patients with ALS. To assess this hypothesis, we studied sleep characteristics (polysomnography) in 21 patients with ALS, stratified according to the presence or absence of diaphragmatic dysfunction. Diaphragmatic dysfunction was defined as an absent or delayed diaphragm response to cervical or cortical magnetic stimulation, abdominal paradox, or respiratory pulse (Group 1, 13 patients). These patients did not differ in age, clinical course, or form (bulbar or spinal) from the eight others, who did not have diaphragmatic dysfunction (Group 2). REM sleep was reduced in Group 1 (7 +/- 7% of total sleep time; mean +/- SD) and normal in Group 2 (18 +/- 6%, p = 0.004). Apneas or hypopneas were rare in both groups. In Group 1, REM sleep was absent or minimal (less than 3 min) in five patients. An unusual and remarkable preservation of phasic inspiratory sternomastoid activation during REM was associated with longer REM sleep duration in six of the other patients with diaphragmatic dysfunction. Median survival time was dramatically shorter (217 d) in Group 1 than in Group 2 (619 d, p = 0.015).

Le syndrome des apnees obstructives du sommeil se manifeste par des symptomes banals (ronflement, somnolence, mictions nocturnes, hypertension arterielle) en rapport avec des obstructions completes (apnees) ou incompletes (hypopnees) iteratives des voies aeriennes superieures. Les apnees sont a l'origine d'hypoxie, d'hypercapnie, et d'efforts respiratoires suivis d'un bref eveil salvateur. L'instabilite des voies aeriennes est entretenue par des facteurs anatomiques (etroitesse du pharynx) et neurophysiologiques. Les muscles dilatateurs du pharynx, qui s'opposent a la pression negative engendree par le diaphragme en inspiration, sont en effet controles differemment pendant l'eveil et le sommeil. Cette maladie frequente, identifiee depuis peu, affecte plus volontiers l'homme d'âge moyen en surpoids. Elle reste sous-estimee malgre une mortalite et une morbidite accrues par les troubles cardio-vasculaires et les accidents du travail et de la route.

Sleep-disordered breathing may be present in patients with degenerative diseases affecting the brainstem. Indeed, this last structure contains the executive system of rapid eye movement (REM) sleep (tegmentum of the pons), of respiratory drive (medulla oblongata and pons) and motor neurons of upper airways dilators (fifth, seventh, ninth, tenth and twelfth cranial roots). Patients with Parkinson's disease suffer frequently from insomnia, partly caused by nocturnal motor disability, and from REM sleep behavior disorder. In 20 percent of the patients, excessive daytime sleepiness is caused by a sleep apnea syndrome, with a partly levodopa-dependent upper airway dysfunction. In 40 percent of the patients, sleepiness mimics a secondary narcolepsy and may be associated with hypnagogic hallucinations. During supranuclear palsy, REM sleep is progressively curtailed with rare sleep-disordered breathing. Patients with multiple systemic atrophy may present a nocturnal stridor caused by laryngeal palsy and benefit from tracheotomy or continuous nasal positive airway pressure. Seldom sleep and respiratory studies in genetic ataxic diseases suggest a normal respiratory drive, occasional diaphragmatic dysfunction and night hypopneas. During amyotrophic lateral sclerosis, the progressive loss of phrenic nerve leads to a diaphragmatic dysfunction, dyspnea and a lesser survival. Adequate ventilation is jeopardized during REM sleep with a consequent loss of this state.

STUDY OBJECTIVE To compare sleep characteristics, rapid eye movement (REM) sleep without atonia, and REM sleep behavior disorder (RBD) in patients with progressive supranuclear palsy (tauopathy), patients with Parkinson's disease (a synucleinopathy), and control subjects. DESIGN Sleep interview, overnight polysomnography, and Multiple Sleep Latency Tests. PATIENTS Forty-five age- and sex-matched patients with probable progressive supranuclear palsy, (n=15, aged 68 +/- 8 years, 7 men), patients with Parkinson disease (n=15), and control subjects (n=15). SETTINGS Tertiary-care academic hospital. INTERVENTION N/A. RESULTS Compared to the 2 other groups, patients with progressive supranuclear palsy had a longer duration of wakefulness after sleep onset and twice as much sleep fragmentation and percentage of stage 1 sleep but had similar apnea-hypopnea indexes, periodic leg movements indexes, and mean daytime sleep latencies. REM sleep percentage was as low in patients with progressive supranuclear palsy (8% +/- 6% of total sleep time) as in patients with Parkinson disease (10% +/- 4%), versus 20% +/- 6% in controls (analysis of variance, P < .0001). Interestingly, patients with progressive supranuclear palsy had percentages of REM sleep without atonia (chin muscle activity: 33% +/- 36% of REM sleep) similar to those of patients with Parkinson disease (28% +/- 35%) and dramatically higher than those of controls (0.5% +/- 1%, analysis of variance, P = .008). Four (27%) patients with progressive supranuclear palsy had more than 50% REM sleep without atonia (as did a similar number of patients with Parkinson disease), and 2 of them (13%, vs 20% of patients with Parkinson disease) had clinical RBD. The four patients with progressive supranuclear palsy with excessive daytime sleepiness slept longer at night than the 11 patients with progressive supranuclear palsy who were alert (442 +/- 14 minutes vs 312 +/- 74 minutes, student t tests, P = .004), suggesting a primary nonnarcoleptic hypersomnia. CONCLUSION REM sleep without atonia and RBD were as frequent in patients with progressive supranuclear palsy as in patients with Parkinson disease. It suggests that the downstream cause of parkinsonism, rather than its primary neuropathology (synucleinopathy vs tauopathy), is a key factor for REM sleep behavior disorder.

Background: High prevalence of both obstructive and central sleep apnea has been reported in group 1 pulmonary arterial hypertension (PAH). Central and obstructive sleep apnea can be promoted by overnight fluid shift from the legs to the lungs and the upper airway, respectively, in fluid retaining states. PAH is characterized by fluid retention but fluid shift in PAH has not been previously evaluated. Objective: To detect the occurrence of fluid shift in PAH. Methods: We developed a questionnaire to test the frequency (0=never; 1=rarely; 2=often; 3=always) of signs/symptoms caused by fluid accumulation in lower body at the end of the day (heavy legs, socks markers and tight shoes) and in the upper body during night (orthopnea, sleep with 2 pillows or more, sleep sitting and paroxysmal nocturnal dyspnea) and in the morning (swollen hands, face, throat and obstructed nose). Sleep quality was evaluated by Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness by Epworth Sleepiness Scale (ESS), fatigue by Pichot's Fatigue Scale (PFS). Results: A total of 73 stable PAH patients and 55 control subjects matched for gender, sex and body mass index were included in this study. The total score of fluid shift was higher in PAH than in control group, in particular orthopnea (0.6±0.9 vs 0.2±0.6, p=0.002), sleep with 2 pillows or more (0.6±1.1 vs 0.2±0.6, p=0.005) and obstructed nose (1.2±1.1 vs 0.6±0.8, p

Hallucinations (mainly visual), psychosis and excessive daytime sleepiness are potential side-effects of dopaminergic treatment. They may require a reduction or suppression of dopaminergic agonists, and the prescription of atypical neuroleptic agents or vigilance-enhancing drugs. The recent description of narcolepsy-like sleep onset in rapid eye movement sleep periods synchronous with hypnagogic hallucinations in patients with dopaminergic-induced psychosis or excessive daytime sleepiness, suggests that the mesodiencephalic lesions may predispose to the psychic effects of dopaminergic treatment. Disease-related mood disorders, sexual compulsions, gambling or levodopa addiction may also be amplified by the antiparkinsonian treatment. These complications illustrate the neuro-psychic aspect of Parkinson's disease: psychic troubles may result from a subtle balance between the direct effects of drugs, the pre-morbid pathological personality and the cortical and subcortical lesions.

Measurement of mouth pressure (Pm) in response to electrical phrenic nerve stimulation (Es) provides a simple noninvasive means to assess diaphragm function. An even simpler measure would be to use the Pm twitch response (Pm,t) to cervical magnetic stimulation (CMS) rather than to Es. Because CMS coactivates the diaphragm and inspiratory neck muscles (INM), CMS-Pm,t accurately reflects diaphragm function only if the corresponding INM contraction does not produce inspiratory pressures by itself. In patients with recent-onset bilateral diaphragm paralysis, it has been demonstrated that CMS-Pm,t was indeed zero; however, INM hypertrophy could change this situation and lead CMS-Pm,t to overestimate the performance of the diaphragm. To address this issue, we studied nine patients with amyotrophic lateral sclerosis (ALS) who had evidence of diaphragmatic paralysis and compensatory hypertrophy and hyperactivity of inspiratory neck muscles. The response to CMS was described in terms of diaphragm electromyogram (EMG), Pm, and abdominal (AB) and rib cage (RC) motion. No EMG response to CMS could be observed in most cases, and CMS was always associated with AB paradox. Nevertheless, a negative Pm,t swing was recorded with an amplitude of -2.6 +/- 1.0 cm H2O (mean +/- SD). We conclude that inspiratory neck muscle hypertrophy can significantly influence the Pm response to CMS. This should be taken into account when using the CMS-Pm combination in patients with possible chronic diaphragm dysfunction.

Hallucinations (mainly visual), psychosis and excessive daytime sleepiness are potential side-effects of dopaminergic treatment. They may require a reduction or suppression of dopaminergic agonists, and the prescription of atypical neuroleptic agents or vigilance-enhancing drugs. The recent description of narcolepsy-like sleep onset in rapid eye movement sleep periods synchronous with hypnagogic hallucinations in patients with dopaminergic-induced psychosis or excessive daytime sleepiness, suggests that the mesodiencephalic lesions may predispose to the psychic effects of dopaminergic treatment. Disease-related mood disorders, sexual compulsions, gambling or levodopa addiction may also be amplified by the antiparkinsonian treatment. These complications illustrate the neuro-psychic aspect of Parkinson's disease: psychic troubles may result from a subtle balance between the direct effects of drugs, the pre-morbid pathological personality and the cortical and subcortical lesions.

Background Exogenous gamma-hydroxybutyrate (GHB) increases slow-wave sleep and reduces daytime sleepiness and cataplexy in patients with primary narcolepsy. Objective To examine nighttime sleep and daytime sleepiness in a 13-year-old girl homozygous for succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare recessive metabolic disorder that disrupts the normal degradation of 4-aminobutyric acid (GABA), and leads to an accumulation of GHB and GABA within the brain. Methods Sleep interview, nighttime polysomnography, Multiple Sleep Latency Tests, and continuous 24-hour in-lab recordings in the patient; overnight polysomnography in her recessive mother and in a 13-year-old female control. Results During quiet wakefulness, background electroencephalographic activity was slow and composed of 7-Hz activity. Sleep stage 3/4 was slightly increased (28.1% of total sleep period, norms 15%-28%), and the daytime mean sleep latency was short in the patient (3 minutes 42 seconds, norms > 8 minutes). Stage 2 spindles were infrequent in the child (0.18/minute, norms: 1.2-9.2/minute) and her mother (0.65/minute) but normal (4.6/minute) in the control. At the beginning of the second night, a tonic-clonic seizure occurred, followed by a dramatic increase in stage 3/4 sleep, that lasted 46.3 % of the total sleep period, double the normal value. The mother showed a reduced total sleep time and rapid eye movement sleep percentage. Discussion This suggests that a chronic excess of GABA and GHB induces subtle sleep abnormalities, whereas increased slow-wave sleep evoked by a sudden event (here an epileptic seizure) may be caused by a supplementary increase in GABA and GHB.

There has been renewed interest in functional surgery as treatment for Parkinson's disease (PD). Although pallidotomy and chronic pallidal stimulation are highly effective in suppressing levodopa-induced dyskinesia (LID), both methods also seem to be effective in reducing parkinsonian disability. However, the simultaneous improvement of LID and motor signs is hard to explain with the classic model of basal ganglia circuitry. Taking advantage of the fact that deep brain stimulation is reversible and that implanted electrodes contain four discrete stimulation sites, we investigated the effect of stimulation on different sites of the globus pallidus (GP) in five PD patients. Stimulation in the dorsal GP (upper contact) significantly improved gait, akinesia, and rigidity and could induce dyskinesia when patients were in the "off" state. In contrast, stimulation in the posteroventral GP (lower contact) significantly worsened gait and akinesia, although the reduction in rigidity remained. For patients in the "on" state, stimulation in the posteroventral GP dramatically reduced LID but, as in the "off" state, worsened gait and akinesia, thus canceling out the antiparkinsonian effect of levodopa. Our results indicate that stimulation had a striking different effect on parkinsonism and dyskinesia when applied at two different loci of the GP and that stimulation applied in the posteroventral GP produced opposite effects on rigidity and on akinesia. We conclude that parkinsonian signs and LID are a reflection of at least two different anatomofunctional systems within the GP and that this functional organization of the GP needs to be considered when determining the optimal target for surgical treatment of PD.

Patients with Parkinson's disease experience prominent difficulties in maintaining sleep, painful night-time abnormal movements, and daytime sleepiness, sometimes culminating in sleep attacks. Recent insights into the pathophysiology of sleep disorders in PD points to a complex interaction between movement disorders, side-effects of dopamine agents and lesions in sleep-wake regulating systems. Treatment with dopamine agonists provides a twice higher risk of daytime sudden sleep episodes than levodopa, with no difference between ergotic and non ergotic compounds. Insomnia can be improved by a better control of night-time disability, restless legs syndrome and dystonia using subthalamic nucleus stimulation or night-time levodopa. A specific REM sleep disorder contributes to REM sleep behavior disorder and also to hallucinations (suggesting they could be awake dreams) and excessive daytime sleepiness. The management of sleep and alertness problems requires to analyze their potential causes, to monitor night-time and daytime sleep, and to subtly adjust psychotropic and dopaminergic treatment.

The video-polysomnographic criteria of REM sleep behavior disorder (RBD) have not been well described. We evaluated the between-night reproducibility of phasic and tonic enhanced muscle activity during REM sleep as well as the associated behaviors and vocalizations of the patients.Fifteen patients with clinical RBD underwent two consecutive video-polysomnographies. The amount of excessive phasic and tonic chin muscle activity during REM sleep was measured in 15 patients in 3-sec mini-epochs. The time spent with motor (minor, major, complex, and scenic) or vocal (sounds, mumblings, and comprehensible speeches) events was measured in 7 patients during REM sleep.There was a good between-night agreement for tonic (Spearman rho = 0.55, p = 0.03; Kendall tau = 0.48, p = 0.01) but not for phasic (rho = 0.47, p = 0.1; tau = 0.31, p = 0.1) excessive chin muscle activity. On the video and audio recordings, the minor RBD behaviors tended to occur more frequently during the second night than the first, whereas the patients spoke longer during the first than the second night.The excessive tonic activity during REM sleep is a reliable marker of RBD. It could represent the extent of dysfunction in the permissive atonia systems. In contrast, the more variable phasic activity and motor/vocal events could be more dependent on dream content (executive systems).

To review evidence on the association between restless legs syndrome (RLS) and attention-deficit/hyperactivity disorder (ADHD), to discuss the hypothetical mechanisms underlying this association, and to consider the potential interest for common pharmacologic treatments of RLS and ADHD when co-occurring.A PubMed search.In clinical samples, up to 44% of subjects with ADHD have been found to have RLS or RLS symptoms, and up to 26% of subjects with RLS have been found to have ADHD or ADHD symptoms. Several mechanisms may explain this association. Sleep disruption associated with RLS might lead to inattentiveness, moodiness, and paradoxical overactivity. Diurnal manifestations of RLS, such as restlessness and inattention, might mimic ADHD symptoms. Alternatively, RLS might be comorbid with idiopathic ADHD. Subjects with RLS and a subset of subjects with ADHD might share a common dopamine dysfunction. Limited evidence suggests that some dopaminergic agents, such as levodopa/carbidopa, pergolide, and ropinirole, may be effective in children with RLS associated with ADHD symptoms.Although still limited, evidence from clinical studies demonstrates an association between RLS and ADHD or ADHD symptoms. Further clinical studies using standard criteria and procedures are needed to better estimate the degree of association. Epidemiologic studies are required to assess the relationship between ADHD and RLS symptoms in nonclinical samples. Further investigations should address the mechanisms underlying the relationship between RLS and ADHD. Several dopaminergic agents seem to be promising treatment for RLS associated with ADHD symptoms. To date, however, the absence of randomized and blinded controlled studies does not allow evidence-based recommendations.

Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopatherapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease. © 2001 Movement Disorder Society.

Each night, we cross a bridge that connects the waking and sleeping worlds. We know very little about this bridge (symbolizing the sleep-onset period), as our passage is brief and leaves only a few fragmented memories behind. Moreover, sleep researchers have largely overlooked this twilight period, certainly owing to its ‘in-between’ and fleeting nature. However, upon closer examination, the sleep-onset period appears as a rich and dynamic time during which our body and mind undergo significant changes. Brain activity slows, muscles relax, and reality gradually distorts: dreamlike images begin to dance before the eyelids. In contrast to the research community, many scientists and artists, such as Thomas Edison and Salvador Dali, were fascinated by this rich period, seeing in it great potential, particularly for increasing their creativity. They even devised methods for capturing creative inspirations from this ‘genius gap’ before they vanished into the limbo of sleep. They would take naps while holding an object that dropped noisily as they dozed off, awakening them just in time to record some of their discoveries/ideas. Is there any truth in this seductive story? In other words, is the sleep-onset period conducive to creativity? This question will serve as the central theme of this thesis. Our main hypothesis was that hybrid states, at the borderland between wakefulness and sleep, would promote creativity. We tested this hypothesis by examining both a physiological state in which sleep and wakefulness coexist (the sleep-onset period, specifically the first sleep stage, named N1) and a sleep disorder, narcolepsy, in which the line between the two vigilance states is even finer than usual. We first demonstrated an increased creative potential in patients with narcolepsy, suggesting an (indirect) link between a privileged access to the sleep-onset period (caused by excessive daytime sleepiness) and the gradual development of creativity over time. Second, we found a direct link between the N1 stage and creativity, given that a single minute of N1 was sufficient to triple the probability of discovering a hidden shortcut to solve a task compared to a period of wakefulness. Additionally, this beneficial effect of the N1 stage disappeared when the subjects reached a deeper sleep (N2). We substantiated these results using spectral analyses and discovered an optimal cocktail for creativity (above and beyond sleep stages), consisting of an intermediate level of alpha (a marker of the wake-to-sleep transition) and a low level of delta (which signs sleep depth). We thus unraveled the existence of a ‘creative sweet spot’ within the sleep-onset period. Hitting this zone requires striking a balance between falling asleep easily and sleeping too deeply. Finally, we investigated the relationship between memory and creativity during sleep onset, using a newly-designed task that allowed us to evaluate these two cognitive functions within a single experimental design. Regrettably, the creative task was too difficult (not enough solvers) to assess the link between memory and creative problem-solving. However, we found that subjects who slept exclusively in N1 exhibited a 10% forgetting of previously encoded individual memory traces, whereas subjects who transitioned to the N2 stage showed less forgetting. Intriguingly, these last two studies both show distinct behavioral effects between two seemingly close sleep stages (N1 and N2). These parallel findings may suggest a link between memory processing (and possibly the pruning of irrelevant information) and the N1-induced boost in creativity. But more importantly, they emphasize the importance of distinguishing the N1 and N2 stages in future research, as they appear to have distinct effects on cognition. Overall, our findings indicate that critical cognitive processes occur during sleep onset. Notably, we found that this period constitutes a doorway into creativity, which neuroscientists [...], Chaque nuit, nous empruntons un pont qui nous emmène du monde éveillé au monde du sommeil. De ce pont (symbolisant la phase d'endormissement), nous ne savons pas grand-chose, et pour cause. Sa traversée est furtive, et ne laisse que peu de souvenirs. De plus, les chercheurs du sommeil se sont désintéressés de cet état à la frontière entre éveil et sommeil, sans doute en raison de sa nature hybride et insaisissable. Pourtant, à y regarder de plus près, la phase d'endormissement apparaît comme une période riche et dynamique au cours de laquelle notre organisme subit d'importants changements. L'activité cérébrale ralentit, les muscles se détendent, et la réalité commence progressivement à se déformer, laissant alors place à des images oniriques qui se mettent à danser derrière les paupières. D'ailleurs, contrairement aux chercheurs, de nombreux scientifiques et artistes, parmi lesquels Thomas Edison et Salvador Dali, étaient fascinés par cette période en laquelle ils voyaient une réelle source d'inspiration. Ces derniers ont même imaginé une méthode pour capturer cet état intermédiaire et ses inspirations créatives avant qu'elles ne disparaissent dans les limbes du sommeil. Pour ce faire, ils réalisaient des siestes en tenant un objet dans leur main afin que ce dernier tombe bruyamment à l'endormissement, les réveillant ainsi à temps pour noter leurs idées/découvertes. Y a-t-il un semblant de vérité dans cette belle histoire ? Autrement dit, la phase d'endormissement est-elle propice à la créativité ? Cette question a constitué le fil conducteur de cette thèse. Notre hypothèse principale était que les états hybrides, à la frontière entre éveil et sommeil, favoriseraient la créativité. Nous avons testé cette hypothèse en examinant à la fois un état physiologique dans lequel le sommeil et l'éveil co-existent (la période d'endormissement, plus précisément le premier stade du sommeil, nommé N1), et un trouble du sommeil, la narcolepsie, dans lequel la frontière entre les deux états est encore plus fine qu'à l'accoutumée. Nous avons tout d'abord démontré l'existence d'une créativité plus élevée chez les patients narcoleptiques, suggérant un lien (indirect) entre un accès privilégié à la phase d'endormissement (causé par la somnolence diurne excessive des narcoleptiques) et le développement d'une créativité accrue au fil du temps. Par la suite, nous avons trouvé un lien direct entre le stade N1 et la créativité, puisqu'une seule minute de N1 suffisait à tripler la probabilité de découvrir un raccourci caché pour résoudre une tâche par rapport à une période d'éveil. De plus, cet effet bénéfique du stade N1 disparaissait lorsque les sujets atteignaient un sommeil plus profond (N2). Nous avons confirmé ces résultats par des analyses spectrales et découvert un ‘cocktail’ idéal pour la créativité (au-delà des stades de sommeil), composé d'un niveau intermédiaire d'alpha (un marqueur de la transition veille-sommeil) et d'un niveau faible de delta (qui signe la profondeur du sommeil). Nous avons ainsi révélé l'existence d'une zone propice à la créativité au sein de la période d'endormissement. L'atteindre nécessite de réussir à s'endormir aisément, mais pas trop profondément. Enfin, nous avons essayé d'étudier le lien théorique entre retraitement des souvenirs et créativité, en utilisant une nouvelle tâche conçue pour pouvoir évaluer ces deux fonctions cognitives au sein d'un même protocole expérimental. Malheureusement, la tâche créative s'est révélée être trop difficile (pas assez de solveurs) pour examiner le devenir de traces mnésiques suite à la résolution de problèmes. Néanmoins, nous avons constaté que les sujets qui avaient dormi uniquement en N1 présentaient un taux d'oubli de 10% des traces mnésiques préalablement encodées, alors que les sujets qui étaient passés en N2 montraient moins d'oubli. Étonnamment, ces deux dernières études mettent en lumière l'existence d'effets comportementaux distincts entre deux stades de sommeil [...]

Key Points Question Can electroencephalography (EEG), combined with clinical, biological, and magnetic resonance imaging (MRI) analyses, help to better characterize patients with neurologic coronavirus disease 2019 (COVID-19) and diagnose specific COVID-19–related encephalopathy? Findings Neurologic manifestations, biological findings, EEG findings, and brain MRI images were analyzed in a cohort study of 78 adult patients with COVID-19. Nine patients had no identified cause of brain injury, as revealed by biological and MRI findings; their injury was defined as COVID-19–related encephalopathy. Meaning This study suggests that, although neurologic manifestations, EEG findings, and MRI findings may appear heterogeneous and nonspecific, multimodal monitoring may better identify patients with COVID-19–related encephalopathy and guide treatment strategy., Importance There is evidence of central nervous system impairments associated with coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Multimodal monitoring of patients with COVID-19 may delineate the specific features of COVID-19–related encephalopathy and guide clinical management. Objectives To investigate clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with COVID-19, and to better refine the features of COVID-19–related encephalopathy. Design, Setting, and Participants This retrospective cohort study conducted in Pitié-Salpêtrière Hospital, Paris, France, enrolled 78 hospitalized adults who received a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and underwent EEG between March 30 and June 11, 2020. Exposures Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription–polymerase chain reaction assay or, in the case of associated pneumonia, on a computed tomography scan of the chest. Main Outcomes and Measures Data on the clinical and paraclinical features of the 78 patients with COVID-19 were retrieved from electronic patient records. Results Of 644 patients who were hospitalized for COVID-19, 78 (57 men [73%]; mean [SD] age, 61 [12] years) underwent EEG. The main indications for EEG were delirium, seizure-like events, and delayed awakening in the intensive care unit after stopping treatment with sedatives. Sixty-nine patients showed pathologic EEG findings, including metabolic-toxic encephalopathy features, frontal abnormalities, periodic discharges, and epileptic activities. Of 57 patients who underwent brain MRI, 41 showed abnormalities, including perfusion abnormalities, acute ischemic lesions, multiple microhemorrhages, and white matter–enhancing lesions. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG. The results of cerebrospinal fluid analysis were negative for SARS-Cov-2 for all tested patients. Nine patients who had no identifiable cause of brain injury outside COVID-19 were further isolated; their brain injury was defined as COVID-19–related encephalopathy. They represented 1% (9 of 644) of patients with COVID-19 requiring hospitalization. Six of these 9 patients had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter–enhancing lesions. Conclusions and Relevance The results from this cohort of patients hospitalized with COVID-19 suggest there are clinical, EEG, and MRI patterns that could delineate specific COVID-19–related encephalopathy and guide treatment strategy., This cohort study investigates clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with coronavirus disease 2019 (COVID-19) and refines the features of COVID-19–related encephalopathy.

The experiences of our night are often described as islands of mental activity, internally generated in an ocean of unconsciousness. In the subtext of this vision, two assumptions are hidden that slow wave sleep is a model of unconsciousness and that sensory processing of the outside world in REM sleep can only be unconscious. In this work, we wanted to test these assumptions with an approach based on three complementary fields of research : consciousness, healthy and pathological sleep, and philosophy of mind. In a first study we have highlighted the existence of night "blackout": a total absence of recall of content from bedtime to awaking in Idiopathic hypersomnia. We believe that our demonstration of the existence of the blackout phenomenon is interesting because it allows, by contrast, to highlight the existence of a minimal experience of the night, as the philosophers had suggested. In two other studies we have shown the ability of narcoleptic patients (lucid or not) to treat the outside during naps using the muscles of their faces as a response. This suggests that conscious treatment in sleep can take place in REM sleep in these patients. The whole of this thesis work suggests that the idea that we lose consciousness while sleeping should be reevaluated. Indeed, a real loss of consciousness in sleep, if it exists, could be rather transitory and negligible in the face of the fabulous plurality of processes. that take lace within it., Les expériences de notre nuit sont souvent décrites comme des îlots d'activité mentale, internement générées dans un océan d'inconscience. En sous-texte de cette vision se cachent deux pré-supposés que le sommeil lent est un modèle d'inconscience et que le traitement sensoriel du monde extérieur en sommeil paradoxal ne peut être qu'inconscient. Dans cette thèse, nous avons voulu tester ces pré-supposés avec une approche empruntant à trois littératures complémentaires : celle de la conscience, celle du sommeil sain et pathologique et celle de la philosophie de l'esprit. Dans une première étude nous avons mis en évidence l'existence de "blackout' de nuit : une absence total de rappel de contenu du couche au lever dans l'hypersomnie Idiopathique. Nous pensons que notre démonstration de l'existence du phénomène de blackout est intéressante car elle permet, par contraste, de mettre en évidence l'existence d'une expérience minimale de la nuit, comme les philosophes l'avaient suggéré. Dans deux autres études nous avons montré la capacité de patients narcoleptiques (lucides ou non) à traiter l'extérieur pendant des siestes en utilisant comme réponses les muscles de leurs visages. Cela suggère qu'un traitement conscient dans le sommeil peut avoir lieu en sommeil paradoxal chez ces patients. L'ensemble de ce travail de thèse invite à penser que l'idée selon laquelle on perd conscience pendant que l'on dort serait à réévaluer. En effet, une réelle perte de conscience dans le sommeil, si elle existe, pourrait être plutôt transitoire et négligeable face à la fabuleuse pluralité des processus qui se déroulent en son sein.

Study ObjectivesTo asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy.MethodsThis open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters.ResultsPatients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case.ConclusionsLong-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.

Kleine-Levin syndrome (KLS) is a rare neuropsychiatric disease which occurs in young subjects and for wich the etiopathology is still unknown. It is characterized by recurrent episodes during several days with hypersomnia, apathy, derealization, cognitive disorders and behavioral disinhibition. Those episodes alternate with long periods of normal sleep, cognition, mood, and behavior. Are there more prolonged episodes and long-term impairment? What are the mechanisms of derealization and apathy in the KLS? To answer these questions, we used a clinical approach (interviews, questionnaires), cognitive (neuropsychological assessment) and functional brain imaging (scintigraphy) in a controlled study. Our results show that nearly one third of the patients have long episodes (over a month) and are more anxious, depressed, sleepy and tired than the others. A quarter to a third of the patients has cognitive impairment between the episodes. Cortical and subcortical hypoperfusion persists in 41 patients, especially if the duration of the episodes is long, the last episode is recent and the derealization is severe. The emergence of symptoms is associated with the hypoperfusion in the dorsal medial prefrontal cortex and in the temporoparietal junction. Those brain regions are involved in treating the information related to attention, multisensory integration, mental representations and motivation.Although the clinical expression of this disease obeys a relapsing- remitting pattern, our results suggest that those episodes could be only the tip of the "iceberg", challenging the concept of a benign disorder.; Le syndrome de Kleine-Levin (KLS) est une pathologie neuropsychiatrique rare, intermittente, du sujet jeune, dont la cause est inconnue. Les épisodes durent plusieurs jours avec hypersomnie, apathie, déréalisation, troubles cognitifs et désinhibition comportementale. Entre les épisodes, les patients retrouveraient un sommeil et un fonctionnement normal. Existe-t-il des épisodes plus prolongés et des dysfonctionnements à long terme ? Pour répondre à ces questions, nous avons utilisé une approche clinique (entretiens, questionnaires), cognitive (évaluation neuropsychologique) et d'imagerie cérébrale fonctionnelle (scintigraphie) dans une étude contrôlée. Nos résultats montrent que près d'un tiers des patients ont des longues crises et sont plus anxieux, dépressifs et fatigués que les autres. Un quart à un tiers des patients ont des difficultés cognitives entre les crises. Des hypoperfusions persistent chez 41 patients, d'autant plus que la durée des épisodes est longue, que la dernière crise est récente et que la déréalisation en crise est sévère. L'émergence des symptômes est associée à l'hypoperfusion du cortex préfrontal dorso-médian et de la jonction temporo-pariétale, qui sont impliqués dans l'attention, l'intégration multi-sensorielle, les représentations mentales et la motivation. Bien que l'expression de la maladie soit intermittente, nos résultats suggèrent que les crises soient la partie émergée d'un " iceberg ", remettant en cause le caractère bénin de la maladie.