Excessive Daytime Sleepiness and the Pathophysiology of Narcolepsy-Cataplexy: A Laboratory Perspective

Broughton, Roger; Valley, Victoria; Aguirre, Marisa; Roberts, Janet Hatcher; Suwalski, Wlodzinierz; Dunham, Wayne

doi:10.1093/sleep/9.1.205

Cited by 132 publications

(48 citation statements)

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“…Discussion Amplitude of P300 clearly was affected by time of day. These effects are consistent with prior research (Broughton et al, 1986) assessing amplitude changes in normal subjects across the day (i.e., higher P300 amplitudes in the morning than in the afternoon). That time of day impacts on P300 amplitude is irportant in that it may reflect cognitive processes whose behavioral oeasures vary in the same direction.…”

Section: E Esupporting

confidence: 91%

“…1967) and P300 amplitude (Broughton, 1986; present study) reflect changes in cognitive capacities. Although only two test points were assessed within a 24-hour period in the present study, the direction of P300 amplitude change is consistent with others (Broughton et al 1986) and warrants further investigation of variations in P300 amplitude across 24 hours.…”

Section: E Esupporting

confidence: 48%

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Auditory and Visual Evoked Potentials as a Function of Sleep Deprivation and Irregular Sleep

Harsh¹

1989

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Section: E Esupporting

confidence: 91%

Section: E Esupporting

confidence: 48%

Auditory and Visual Evoked Potentials as a Function of Sleep Deprivation and Irregular Sleep

Harsh¹

1989

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“…Long before the discovery of orexin, Broughton hypothesized that the fundamental problem in narcolepsy was a loss of the "neurochemical glues" that help integrate neuronal activity to produce stable sleep-wake behavior (Broughton et al, 1986). Most likely, he was correct because a loss of orexin appears to lower the thresholds to transition between behavioral states, producing the fragmented wakefulness and sleep of narcolepsy.…”

Section: Behavioral State Instabilitymentioning

confidence: 99%

Behavioral State Instability in Orexin Knock-Out Mice

Mochizuki¹,

Crocker²,

Mccormack³

et al. 2004

J. Neurosci.

359

263

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Narcolepsy is caused by a lack of orexin (hypocretin), but the physiologic process that underlies the sleepiness of narcolepsy is unknown. Using orexin knock-out (KO) mice as a model of narcolepsy, we critically tested the three leading hypotheses: poor circadian control of sleep and wakefulness, inadequate activation of arousal regions, or abnormal sleep homeostasis. Compared with wild-type (WT) littermates, orexin KO mice had essentially normal amounts of sleep and wake, but wake and non-rapid eye movement (NREM) bouts were very brief, with many more transitions between all behavioral states. In constant darkness, orexin KO mice had normal amplitude and timing of sleep-wake rhythms, providing no evidence for disordered circadian control. When placed in a new, clean cage, both groups of mice remained awake for ϳ45 min, demonstrating that, even in the absence of orexin, fundamental arousal regions can be engaged to produce sustained wakefulness. After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal. These experiments demonstrate that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. Instead, the fragmented behavior of orexin KO mice may be best described as behavioral state instability, with apparently low thresholds to transition between states.

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“…1 they argued that sleepiness, cataplexy, hallucinations, and many other symptoms could be viewed as a breakdown of "whatever neurochemical 'glues' or integrative neurophysiological mechanisms exist for sleep and wake state continuity." 1 This hypothesis is compelling, but it has been difficult to examine using conventional sleep scoring methods.…”

mentioning

confidence: 99%

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

Behn

Klerman

Mochizuki

et al. 2010

Sleep

110

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Over 20 years agO, BrOughtOn and cOlleagues hypOthesized that narcOlepsy is Best cOnsidered a disease Of state BOundary cOntrOl. 1 they argued that sleepiness, cataplexy, hallucinations, and many other symptoms could be viewed as a breakdown of "whatever neurochemical 'glues' or integrative neurophysiological mechanisms exist for sleep and wake state continuity." 1 This hypothesis is compelling, but it has been difficult to examine using conventional sleep scoring methods.More recently, our understanding of narcolepsy has been greatly advanced by the discovery that narcolepsy with cataplexy is caused by a loss of functional signaling by the orexin (hypocretin) neuropeptides. 2-5 the neurons producing orexins are active during wakefulness, 6-8 and direct activation of these neurons can awaken mice from sleep. 9 in addition, orexins probably stabilize wake and sleep; narcoleptic people, dogs, and mice lacking orexins have great difficulty remaining awake for long periods and also experience fragmented sleep. [10][11][12][13] in earlier work, we found that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. 10 however, conventional sleep scoring in 10-to 30-second epochs reveals little about the process of transitioning between states as cortical activity and behavior can change quite rapidly. Furthermore, conventional scoring simply identifies discrete states, so it can overlook important variations within states, such as the distinctions between light and deep nreM sleep or between drowsy wake and high levels of arousal. Therefore, to determine how orexin deficiency causes behavioral state instability we developed a state space analysis technique to examine the dynamics of sleep/wake behavior in orexin knockout (OXKO) mice, a model of narcolepsy.The previous application of state space techniques to sleep recordings used local field potential data, but the variability in these signals prevented comparisons between animals. [14][15][16] We adapted these techniques for analysis of EEG recordings in mice and developed metrics for inter-animal comparisons. State space techniques have high temporal resolution and analyze behavior as a continuum, rather than in discrete states, thus facilitating higher dimensional examination of state transitions. this approach enabled us to determine whether the state instability in this mouse model of narcolepsy reflects abnormal sleep/wake states, faster movements between states, or abnormal transition processes. METHODS AnimalsFounder OXKO mice were on a C57BL/6J-129/SvEV background (t. sakurai, Kanazawa university), and their offspring were backcrossed with C57BL/6J mice for 8 generations. We recorded sleep/wake behavior in 7 male OXKO mice and 6 wild type (Wt) littermates, all 5-6 months old and weighing 30-35 g. all experiments were approved by the institutional animal Study Objectives: Narcolepsy with cataplexy is caused by a loss of orexin (hypocretin) signaling, bu...

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Excessive Daytime Sleepiness and the Pathophysiology of Narcolepsy-Cataplexy: A Laboratory Perspective

Cited by 132 publications

References 0 publications

Auditory and Visual Evoked Potentials as a Function of Sleep Deprivation and Irregular Sleep

Auditory and Visual Evoked Potentials as a Function of Sleep Deprivation and Irregular Sleep

Behavioral State Instability in Orexin Knock-Out Mice

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

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