Ramin Khatami

A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans

Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and declines during sleep. Animal studies suggested that sleep need is genetically controlled, yet the physiological mechanisms remain unknown. Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep. In contrast, a distinct polymorphism of the adenosine A2A receptor gene, which was associated with interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers, affects the electroencephalogram during sleep and wakefulness in a non-state-specific manner. Our findings indicate a direct role of adenosine in human sleep homeostasis. Moreover, our data suggest that genetic variability in the adenosinergic system contributes to the interindividual variability in brain electrical activity during sleep and wakefulness.

A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep.

Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self‐rated caffeine‐sensitive individuals, but not in caffeine‐insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine‐sensitive and ‐insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine‐induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.

Caffeine Attenuates Waking and Sleep Electroencephalographic Markers of Sleep Homeostasis in Humans

Prolonged wakefulness increases electroencephalogram (EEG) low-frequency activity (<10 Hz) in waking and sleep, and reduces spindle frequency activity (∼12–16 Hz) in non-rapid-eye-movement (nonREM) sleep. These physiologic markers of enhanced sleep propensity reflect a sleep–wake-dependent process referred to as sleep homeostasis. We hypothesized that caffeine, an adenosine receptor antagonist, reduces the increase of sleep propensity during waking. To test this hypothesis, we compared the effects of caffeine and placebo on EEG power spectra during and after 40 h of wakefulness. A total of 12 young men underwent two periods of sleep deprivation. According to a randomized, double-blind, crossover design, they received two doses of caffeine (200 mg) or placebo after 11 and 23 h of wakefulness. Sleep propensity was estimated at 3-h intervals by measuring subjective sleepiness and EEG theta (5–8 Hz) activity, and polysomnographic recordings of baseline and recovery nights. Saliva caffeine concentration decreased from 15.7 μmol/l 16 h before the recovery night, to 1.8 μmol/l 1 h before the recovery night. Compared with placebo, caffeine reduced sleepiness and theta activity during wakefulness. Compared with sleep under baseline conditions, sleep deprivation increased 0.75–8.0 Hz activity and reduced spindle frequency activity in nonREM sleep of the recovery nights. Although caffeine approached undetectable saliva concentrations before recovery sleep, it significantly reduced EEG power in the 0.75–2.0 Hz band and enhanced power in the 11.25–20.0 Hz range relative to placebo. These findings suggest that caffeine attenuated the build-up of sleep propensity associated with wakefulness, and support an important role of adenosine and adenosine receptors in the homeostatic regulation of sleep.

Adenosinergic Mechanisms Contribute to Individual Differences in Sleep Deprivation-Induced Changes in Neurobehavioral Function and Brain Rhythmic Activity

Large individual differences characterize the changes induced by sleep deprivation on neurobehavioral functions and rhythmic brain activity. To investigate adenosinergic mechanisms in these differences, we studied the effects of prolonged waking and the adenosine receptor antagonist caffeine on sustained vigilant attention and regional electroencephalogram (EEG) power in the ranges of theta activity (6.25–8.25 Hz) in waking and the slow oscillation (<1 Hz) in sleep. Activity in these frequencies is functionally related to sleep deprivation. In 12 subjectively caffeine-sensitive and 10 -insensitive young men, psychomotor vigilance task (PVT) performance and EEG were assessed at 3 h intervals before, during, and after one night without sleep. After 11 and 23 h waking, subjects received 200 mg caffeine and placebo in double-blind, cross-over manner. In the placebo condition, sleep deprivation impaired PVT speed more in caffeine-sensitive than in caffeine-insensitive men. This difference was counteracted by caffeine. Theta power in waking increased more in a frontal EEG derivation than in a posterior derivation. Caffeine attenuated this power gradient in caffeine sensitive subjects. Sleep loss also differently affected the power distribution <1 Hz in non-rapid eye movement sleep between caffeine sensitive and insensitive subjects. Also, this difference was mirrored by the action of caffeine. The effects of sleep deprivation and caffeine on sustained attention and regional EEG power in waking and sleep were inversely related. These findings suggest that adenosinergic mechanisms contribute to individual differences in waking-induced impairment of neurobehavioral performance and functional aspects of EEG topography associated with sleep deprivation.

Sleep-wake habits and disorders in a series of 100 adult epilepsy patients—A prospective study

The aim of the study was to assess sleep-wake habits and disorders and excessive daytime sleepiness (EDS) in an unselected outpatient epilepsy population. Sleep-wake habits and presence of sleep disorders were assessed by means of a clinical interview and a standard questionnaire in 100 consecutive patients with epilepsy and 90 controls. The questionnaire includes three validated instruments: the Epworth Sleepiness Scale (ESS) for EDS, SA-SDQ for sleep apnea (SA), and the Ullanlinna Narcolepsy Scale (UNS) for narcolepsy. Sleep complaints were reported by 30% of epilepsy patients compared to 10% of controls (p=0.001). The average total sleep time was similar in both groups. Insufficient sleep times were suspected in 24% of patients and 33% of controls. Sleep maintenance insomnia was more frequent in epilepsy patients (52% vs. 38%, p=0.06), whereas nightmares (6% vs. 16%, p=0.04) and bruxism (10% vs. 19%, p=0.07) were more frequent in controls. Sleep onset insomnia (34% vs. 28%), EDS (ESS >or=10, 19% vs. 14%), SA (9% vs. 3%), restless legs symptoms (RL-symptoms, 18% vs. 12%) and most parasomnias were similarly frequent in both groups. In a stepwise logistic regression model loud snoring and RL-symptoms were found to be the only independent predictors of EDS in epilepsy patients. In conclusion, sleep-wake habits and the frequency of most sleep disorders are similar in non-selected epilepsy patients as compared to controls. In epilepsy patients, EDS was predicted by a history of loud snoring and RL-symptoms but not by SA or epilepsy-related variables (including type of epilepsy, frequency of seizures, and number of antiepileptic drugs).

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU‐NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders‐2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin‐1 levels, and genome‐wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep‐onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E‐07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E‐07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe

STUDY OBJECTIVE Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN Retrospective case-control study. SETTING A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Epilepsy and Obstructive Sleep Apnea

A few publications documented the coexistence of epilepsy and obstructive sleep apnea (OSA). The extent, nature, and clinical relevance of this association remain poorly understood. We retrospectively reviewed the database of our sleep center to identify patients with both sleep apnea and epilepsy. Characteristics of epilepsy, sleep history, presence of excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)] and polysomnographic data were assessed. The effect of continuous positive airway pressure (CPAP) on seizure reduction was prospectively analyzed after a median interval of 26 months (range: 2–116 months) from the diagnosis of OSA. OSA was found in 29 epilepsy patients (25 men and 4 women) with a median age of 56 years (range: 37–79). The median apnea hypopnea index was 33 (range: 10–85), the oxygen desaturation index was 12 (range 0–92), and 52% of the patients had an ESS score >10. In 27 patients, epilepsy appeared 1 month to 44 years prior to the diagnosis of OSA. In 21 patients, the appearance of OSA symptoms coincided with a clear increase in seizure frequency or the first appearance of a status epilepticus. Treatment with CPAP was continued with good compliance in 12 patients and led to a significant reduction of both ESS scores and seizure frequency in 4 patients. Our data suggest the importance of considering diagnosis and treatment of OSA in epilepsy patients with poor seizure control and/or reappearance of seizures after a seizure-free interval.

Abnormal activity in reward brain circuits in human narcolepsy with cataplexy.

Hypothalamic hypocretins (or orexins) regulate energy metabolism and arousal maintenance. Recent animal research suggests that hypocretins may also influence reward‐related behaviors. In humans, the loss of hypocretin‐containing neurons results in a major sleep‐wake disorder called narcolepsy‐cataplexy, which is associated with emotional disturbances. Here, we aim to test whether narcoleptic patients show an abnormal pattern of brain activity during reward processing.

Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation.

rancesca Poli a,2, Sebastiaan Overeemb,∗,2, Gert Jan Lammersc,2, Giuseppe Plazzia,2, ichel Lecendreuxd,2, Claudio L. Bassetti e,1,2, Yves Dauvilliers f,1,2, Daniel Keeneg,1,2, amin Khatamih,1,2, Yulin Li i,j,1,2, Geert Mayerk,1,2, Hanna Nohynekl,1,2, Barbara Pahudm,1,2, eresa Paivan,1,2, Markku Partineno,1,2, Thomas E. Scammellp,1,2, Tom Shimabukuroq,1,2, iriam Sturkenboomr,1,2, Kristy van Dinthers,1,2, Max Wiznitzer t,1,2, Jan Bonhoeffer i,j,2