The neurobiology, diagnosis, and treatment of narcolepsy

Scammell, Thomas E.

doi:10.1002/ana.10444

Cited by 230 publications

(126 citation statements)

References 167 publications

(205 reference statements)

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“…Hypocretin-1 decreased the percentage of time spent in NREM sleep by decreasing both the number and duration of NREM sleep episodes. The hypocretin-1-induced consolidation of wakefulness into longer episodes and the decrease in the number of state transitions is consistent with the finding that narcoleptic patients 45,46 and mice lacking hypocretin 47,48 show fragmentation of sleep and wakefulness. These results also support a recent modeling study predicting that hypocretin-1 preferentially acts on long episodes of wakefulness.…”

Section: Limitations Conclusion and Potential Clinical Significancesupporting

confidence: 88%

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Brevig

Watson²,

Lydic³

et al. 2010

Sleep

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underlies the pathophysiology of narcolepsy, 4,5 and disruption of hypocretin signaling in mouse, 6 rat, 7,8 and dog 9 leads to narcolepsy-cataplexy. Hypocretinergic neurons project to multiple areas of the brain, including those important for regulating sleep and wakefulness. 1 One such area is the pontine reticular nucleus, oral part (PnO). 1,10 The PnO is the rostral portion of the rodent pontine reticular formation 11 and contributes to the generation of wakefulness and rapid eye movement (REM) sleep. 12 Microinjection of hypocretin-1 into rat PnO causes an increase in wakefulness, 13 and microinjection of hypocretin-1 into cat pontine reticular formation increases the cortically activated states of REM sleep 14 or wakefulness. 15,16 Administering hypocretin-1 into the PnO may increase wakefulness by modulating the release of arousal-promoting neurotransmitters within the PnO. Direct administration of hypocretin-1 to the PnO of isoflurane-anesthetized rat causes a concentration-dependent increase in both acetylcholine (ACh) release 17 and GABA levels 13 within the PnO. Extracellular recording studies of PnO neurons in urethane-anesthetized rat show that iontophoretic application of hypocretin-1 causes a hyperpolarization that is blocked by prior application of bicuculline. 10 This finding indicates that the hypocretin-1-induced inhibition of PnO neurons is mediated by GABA A receptors. Identified GABAergic neurons in brainstem slices of mouse PnO have been shown to be excited by hypocretin-1, 18 and intracellular recording studies in halothane-anesthetized cat show that hypocretin-1 can also cause direct depolarization of PnO neurons and an increase in PnO neuronal firing rate. 14 Numerous studies have demonstrated that GABAergic transmission in the PnO increases wakefulness and inhibits REM sleep. 13,[19][20][21][22][23][24][25] The present study provides the first test of the hypothesis that the wakefulness-promoting effects of delivering hypocretin-1 into the PnO are mediated by GABA A receptors as well as by hypocretin receptors. This hypothesis was evaluated by determining whether (1) microinjection of hypocretin-1 into the PnO causes a concentration-dependent increase in wakefulness, (2) this increase in wakefulness is blocked by coadministration of the hypocretin receptor-1 (hcrt-r1) antagonist SB-334867, and (3) coadministration of the GABA A receptor antagonist bicuculline also blocks the wakefulness response to hypocretin-1. Portions of these data have been presented as abstracts. 26,27 MATERIALS AND METHODS Chemicals and Drug SolutionsHuman hypocretin-1 was purchased from California Peptide Research, Inc. (Napa, CA). Bicuculline methiodide was pur- Study Objectives: Hypocretin-1/orexin A administered directly into the oral part of rat pontine reticular formation (PnO) causes an increase in wakefulness and extracellular g-aminobutyric acid (GABA) levels. The receptors in the PnO that mediate these effects have not been identified. Therefore, this study tested the hypothesis that the increase in wa...

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Section: Limitations Conclusion and Potential Clinical Significancesupporting

confidence: 88%

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Brevig

Watson²,

Lydic³

et al. 2010

Sleep

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“…It is generally accepted that the hypothalamus is involved in the control of the circadian rhythm, via the suprachiasmatic nucleus and their connections including hypothalamic and diencephalic areas is relevant to the wake-sleep cycle generation 15,16 . In our patient the mechanism through which these sleep disturbances occurred is speculative.…”

Section: Discussionmentioning

confidence: 99%

Hypersomnia in Whipple disease: case report

Maia

Marta

Lopes

et al. 2006

Arq. Neuro-Psiquiatr.

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-Whipple disease (WD) is a rare systemic infection caused by Tropheryma whippelii. Neurological involvement has been recognised in 40% of patients, either as initial manifestations or during the course of the disease. We report on a 45 years-old man with WD with initial, persistent and irresistible episodes of daytime somnolence. The patient was HLA-DQB1*0602 positive (genetic marker for narcolepsy). WD diagnosis was suspected on clinical and MRI basis and confirmed by histological and immunohistochemical study of duodenal biopsy. Forty months later all clinical features improved, narcoleptic-like episodes disappeared and cerebral MRI and CSF normalised. Longitudinal neurophysiological studies revealed persistent sleep pattern abnormalities with sleep fragmentation, paucity of slow wave and of REM sleep. The disruption of the hypocretin circuitry in the hypothalamic -diencephalic region triggered by the infection was the probable cause of the hypersomnia and narcopleptic symptoms. WD should be added to the list of causes of secondary hypersomnia.KEY WORDS: Whipple disease, hypersomnia, multiple sleep latency test, HLA (DQB1*0602). Hipersónia na doença de Whipple: relato de casoRESUMO -A doença de Whipple (DW) é infecção sistémica rara causada pelo Tropheryma whippelii. Cerca de 40% dos doentes apresentam envolvimento neurológico, seja como manifestação inicial da doença, seja durante o seu curso. Apresentamos o caso de um homem de 45 anos com doença de DW com episó-dios iniciais, persistentes e irresistíveis de sonolência durante a actividade diurna. O doente era positivo para o HLA-DQB1*0602 (marcador genético de narcolepsia). A suspeita do diagnóstico de DW foi levantada com base na clínica e RM e confirmada por estudo imunocitoquímico do material de biópsia jejunal. Quarenta meses mais tarde, todas as manifestações clínicas melhoraram, os episódios narcolépticos desapareceram, e a RM e o LCR normalizaram. Os estudos neurofisiológicos seriados do sono revelaram alterações persistentes caracterizadas por fragmentação do sono, escassez de ondas lentas e sono REM. A perturbação do circuito da hipocretina na região hipotálamo-diencefálica, causada pela infecção, foi a causa provável da hipersónia num doente geneticamente susceptível. A DW deve ser incluída nas causas de hipersónia secundária. PALAVRAS-CHAVE: doença de Whipple, hipersónia, teste de latências múltiplas, HLA (DQB1*0602).When George H Whipple first described in 1907 the autopsy findings of a case of "intestinal lipodystrophy" no neurological manifestations were reported and pathology of central nervous system (CNS) was not described. Whipple disease (WD) was born. It is now believed that the CNS is the major extra-intestinal site of involvement 1,2 . Data in the literature report a variable frequency of neurological symptomatology of 5-40% with only 5% with exclusive CNS involvement 1-4 . WD is caused by Tropheryma whippelii (TW) and it is generally accepted that both the presence of the bacillus and the host response are responsible for the ...

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“…1,2 Loss of these essential signaling molecules results in chronic daytime sleepiness, cataplexy, and other REM sleep associated phenomena. 3 In addition, considerable research indicates that the hypocretin system enhances signaling in the mesolimbic pathways that regulate reward processing and addiction, and hypocretin is now considered a key factor in of the neural mechanisms of drug addiction. 4,5 In response to drugs of abuse and other rewarding stimuli, neurons of the ventral tegmental area (VTA) release dopamine in the nucleus accumbens (NAc).…”

Section: S C I E N T I F I C I N V E S T I G a T I O N Smentioning

confidence: 99%

Reward-Seeking Behavior in Human Narcolepsy

Dimitrova

Fronczek

Ploeg

et al. 2011

Journal of Clinical Sleep Medicine

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Study Objectives: The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk-and reward-seeking behaviors, including substance abuse. Design: Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). Setting: Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). Patients: Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. Interventions: None. Measurements and Results: There was no difference in risktaking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. Conclusions:We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety were higher in all narcoleptic subjects. However, using the current methods, no evidence could be found to support the hypothesis that hypocretin deficiency would affect reward-processing in humans. Keywords: Narcolepsy, cataplexy, hypocretin, orexin, risktaking, addiction, reward-seeking, substance abuse, sleep, sleepiness Citation: Dimitrova A; Fronczek R; Van der Ploeg J; Scammell T; Gautam S; Pascual-Leone A; Lammers GJ. Rewardseeking behavior in human narcolepsy. S C I E N T I F I C I N V E S T I G A T I O N SN arcolepsy with cataplexy is caused by an extensive loss of the neurons producing the hypocretin (orexin) neuropeptides. 1,2 Loss of these essential signaling molecules results in chronic daytime sleepiness, cataplexy, and other REM sleep associated phenomena. 3 In addition, considerable research indicates that the hypocretin system enhances signaling in the mesolimbic pathways that regulate reward processing and addiction, and hypocretin is now considered a key factor in of the neural mechanisms of drug addiction. 4,5 In response to drugs of a...

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The neurobiology, diagnosis, and treatment of narcolepsy

Cited by 230 publications

References 167 publications

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Hypersomnia in Whipple disease: case report

Reward-Seeking Behavior in Human Narcolepsy

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