TY - JOUR
AU - Ng, Marcus, C.
AB - Abstract Interest in orexin receptor antagonism as a novel mechanism of action against seizures and epilepsy has increased in recent years. Loss of orexinergic activity is associated with rapid eye movement (REM) sleep onset, and REM sleep is generally protective against seizures. This paper discusses the dynamic modulation of seizure threshold by orexin through a postulated “orexi-cortical” axis in which the specific type of orexinergic activity exquisitely regulates sleep–wake states to modify ascending subcortical influences on cortical synchronization with profound subsequent consequences on seizure threshold. This paper also explores the current state of research into experimental orexinergic modulation of seizure threshold and suggests possible future research directions to fully understand the promise and peril of orexinergic manipulation in seizures and epilepsy. orexin, epilepsy, seizures, rapid eye movement sleep, cortical synchronization. INTRODUCTION In recent years, there has been growing interest on the use of orexin receptor antagonism as a novel mechanism of action against seizures. Discovered at the turn of the century, orexin has become widely established as a key modulator of sleep, and sleep has been known for millennia to exert a profound impact on seizures and epilepsy. Loss of orexinergic activity has been associated with rapid eye movement (REM) sleep onset, and REM sleep is generally protective against seizures. The purpose of this paper is to discuss orexinergic modulation of seizure threshold through a postulated “orexi-cortical” axis in which subcortical orexinergic activity exquisitely regulates sleep–wake states to modify ascending subcortical influences on cortical synchronization with profound subsequent consequences on seizure threshold. This paper begins by reviewing orexinergic physiology from hypothalamic origin to downstream synchronization effects at the cerebral cortex, then the current state of research into orexinergic modulation of seizure threshold, and finally possible future research directions to fully understand the promise and peril of experimental orexinergic manipulation. FROM HYPOTHALAMUS TO CORTEX Because orexin is a subcortical neuropeptide and seizures are cortical phenomena, these two processes intersect where ascending subcortical orexinergic projections meet a hyperexcitable and hypersynchronized cerebral cortex. Starting from a mere 50000 to 80000 neurons in the human posterolateral hypothalamus, the excitatory hypothalamic peptide orexin, also known as hypocretin, is exclusively manufactured from these neurons as the precursor preproorexin.1 This precursor then becomes the 33 amino acid residue peptide orexin A, and 28 amino acid residue peptide orexin B.2 Orexin A binds to 2 types of orexin receptors, OX1R and OX2R, with equal affinity.2 Orexin B preferentially binds to OX2R.2 OX1R preferentially promotes arousal (defined as onset of wakefulness) and OX2R preferentially promotes wakefulness.2 Through excitatory mediators such as glutamate, dynorphin, and galanin, active orexinergic neurons exhibit oscillatory, phasic, and tonic firing characteristics (Figure 1).1,3 Oscillatory activity is circadian regulated and associated with a myriad of non–sleep-related functions.3 Phasic activity modulates arousals as bursts of orexinergic neuronal firing, which last 1–10 seconds at a frequency greater than 5 Hz, to precede sleep–wake transitions.2,3 Tonic activity maintains a particular state of consciousness with interruptions in tone resulting in a sudden lapse into sleep.4 Figure 1 Open in new tabDownload slide Hypothesized mechanisms of the “orexi-cortical” axis. Originating in the hypothalamus, orexinergic neuronal firing characteristics determine sleep–wake state to modulate the degree of cortical synchronization with resultant effects on seizure threshold. Figure 1 Open in new tabDownload slide Hypothesized mechanisms of the “orexi-cortical” axis. Originating in the hypothalamus, orexinergic neuronal firing characteristics determine sleep–wake state to modulate the degree of cortical synchronization with resultant effects on seizure threshold. Orexinergic tone is highest in wakefulness, mild in slow-wave sleep (SWS), and completely absent in REM sleep (Figure 1).1,5 Orexinergic neuronal silence in REM sleep is only interrupted during the transition to wakefulness when phasic burst activity ensues.6–9 In wakefulness, orexinergic tone is further increased by emotional limbic input.1,5 Orexinergic neurons sustain wakefulness by projecting to wake-promoting areas with effects on the histaminergic system via the tuberomammillary nucleus; the cholinergic system via the laterodorsal tegmentum, pedunculopontine tegmentum, and basal forebrain; the serotonergic system via the dorsal raphe nuclei; the noradrenergic system via the locus coeruleus; and the dopaminergic system.1,4 These regions express both OX1R and OX2R with the locus coeruleus and tuberomammillary nucleus being particularly rich in OX1R and OX2R, respectively.2 GABA, noradrenaline, dopamine, and serotonin from these regions provide negative feedback.1 In contrast to active wakefulness promotion, orexinergic neurons tonically suppress REM sleep.4 For example, directly injecting orexin A into the laterodorsal tegmentum increases wakefulness but suppresses REM sleep.10 Similarly, selective orexinergic activation of the ventral periaqueductal gray circuit suppresses REM but spares non-REM (NREM) sleep.11 When orexinergic tone is lost, strong wakefulness promotion is lost, mild SWS promotion is lost, active REM sleep suppression is lost, and the net result tends toward REM sleep onset. These onsets form the clinical basis of type I narcolepsy, which is characterized by marked orexinergic neuronal loss.4 In orexin receptor knockout mice, levels of choline acetyltransferase, vesicular acetylcholine transporter, and the high-affinity choline transporter are elevated in the laterodorsal pontine tegmentum, which is the location of a main cluster of REM-on neurons responsible for the initiation of REM sleep.12,13 Ascending cholinergic inputs from REM-on neurons reach the cerebral cortex in a diffuse generalized manner en masse via the thalamus or a subthalamic basal forebrain pathway in order to activate muscarinic metabotropic cholinergic receptors.14 Activated metabotropic G-protein coupled muscarinic receptors inhibit potassium channels to shift cortical neuronal excitability from a synchronized rhythmic bursting mode of activity to a desynchronized single spike mode of action potential generation.14 The resultant sum of excitatory and inhibitory postsynaptic potentials from apical dendrites of pyramidal cells in the outer layer of the cerebral cortex is captured as voltage fields on the electroencephalogram (EEG).15 Like wakefulness, another state characterized by the presence of acetylcholine, the EEG of REM sleep is also diffusely desynchronized but to a greater degree.12 Unlike wakefulness in which other neurotransmitters are active, REM sleep is an acetylcholine-exclusive state.14 THE CORTEX AND SYNCHRONY Absence of orexinergic activity leads to REM sleep onset and diffuse cortical desynchronization, which reduces the opportunity for spatial and temporal summation of aberrant neuronal activity into interictal epileptiform discharges (IEDs) and seizures.16,17 In feline kindling models of epileptogenesis, REM sleep is the most difficult state in which to kindle the cat.16,18–20 In contrast, selective REM sleep deprivation accelerates kindling and kindling decreases REM sleep.18,21 REM sleep deprivation also increases hypocretin-1 (orexin-A) levels in cerebrospinal fluid.22 Moreover, cortical cholinergic denervation accelerates murine amygdalar kindling and septal cholinergic denervation accelerates murine hippocampal kindling.23,24 In humans, only 1% of nearly 2000 seizures in a systematic review occurred in REM sleep, including severe pediatric epileptic encephalopathies.25 When adjusted for state duration, the rate of seizures, focal and generalized IEDs, and focal high-frequency oscillations (HFOs) were all lowest in REM sleep.25,26 These findings were validated in years of implanted ambulatory electrocorticography as part of responsive neurostimulation, which found a reproducible IED nadir in the latter third of the night when REM sleep is most likely; however, the extent of intracranial implantation was limited and may not have surveyed all pertinent cerebral areas.27 Cortical desynchronization in REM sleep also suppresses seizure, IED, and HFO distribution to enhance epileptogenic zone localization.28–30 Better localization has successfully guided otherwise non-localizable epilepsy surgeries.28–30 REM sleep has also been shown to selectively and persistently rebound after successful surgery.31 These findings suggest that absence of orexinergic activity in REM sleep, which is characterized by diffuse cortical desynchronization, is overall protective against IEDs and seizures (Figure 1). In contrast to orexinergic quiescence, strong orexin tone promotes wakefulness with only mild cortical desynchronization, weak orexin tone promotes SWS with strong thalamocortical synchronization, and orexin phasic bursts promote hypersynchronized state transitions. In wakefulness, a human systematic review found 8 times more seizures, 1.11 times more focal IEDs, and 3 times more generalized IEDs than REM sleep (Figure 2).25 The greater impact of desynchronization on seizures than IEDs confirms that organization of aberrant epileptiform activity is affected more than generation of aberrant activity in the first place; in other words, cortical desynchronization makes it harder for spontaneously occurring aberrant activity to organize into an IED and then harder still for IEDs to organize into seizures. In SWS, there were 60 times more seizures, 2 times more focal IEDs, and 7 times more generalized IEDs than REM sleep (Figure 2).25,32 Aberrant activity in primary generalized epilepsy (PGE) often “hijacks” synchronization mechanisms in SWS to organize into an IED which is physically embedded within normal NREM sleep architecture that depends on thalamocortical synchrony in a phenomenon termed “dyshormia.”33 Regarding state transitions, there is often cortical synchronization, such as in hypnagogic and hypnopompic hypersynchrony.34 In the cat, kindling is easiest in the transition from REM sleep to wakefulness.16 In murine temporal lobe epilepsy (TLE), seizures are increased in transitions from SWS to REM sleep in a tetanus toxin model, which reduced inhibitory neurotransmitter release, and from REM sleep to SWS in a kainate model using repeated low-dose intraperitoneal injections to generate TLE.35,36 In humans, there is a specific PGE subtype named “generalized tonic–clonic seizures upon awakening.”37 The classic and best known PGE, juvenile myoclonic epilepsy, is characterized by morning myoclonus and generalized tonic–clonic seizures after awakening.38 These findings overall suggest that the presence of orexinergic activity in wakefulness, SWS, and state transitions, which are characterized by a relatively greater degree of cortical synchronization than REM sleep, is overall less protective against IEDs and seizures (Figure 1). However, even though wakefulness is relatively more synchronized than REM sleep, it remains the second most protective state against seizures because the cortex is still mildly desynchronized during this state. Figure 2 Open in new tabDownload slide Sleep–wake state–dependent effects on human epilepsy. (A) Interictal epileptiform discharge (IED) firing and seizure rates in wakefulness and slow-wave sleep (SWS) relative to rapid eye movement (REM) sleep. (B) Percentage of patients by sleep–wake state in which they experience the highest rate of IED firing (“peak discharge state”). Figure 2 Open in new tabDownload slide Sleep–wake state–dependent effects on human epilepsy. (A) Interictal epileptiform discharge (IED) firing and seizure rates in wakefulness and slow-wave sleep (SWS) relative to rapid eye movement (REM) sleep. (B) Percentage of patients by sleep–wake state in which they experience the highest rate of IED firing (“peak discharge state”). While diffuse cortical desynchronization in REM sleep usually prevents epileptiform activity from organizing due to destructive interference, random constructive interference may lead to paradoxical synchronization. For example, there is a unique synchronized focal theta rhythm in the hippocampus that is associated with focal seizures during REM sleep onset in a murine TLE model.35 In contrast, infusing carbachol (a synthetic long-acting muscarinic cholinergic receptor full agonist) into the pontine reticular formation forces REM sleep onset and hippocampal theta rhythm, which abruptly aborts seizures in a pentylenetetrazol model of generalized epilepsy in the rat.39,40 In humans, IED firing rates are overall lowest in REM sleep but these rates are subject to individual variability. In a systematic review, 11% of patients with focal epilepsy experienced the highest rate of IED firing in REM sleep (Figure 2).25 However, no patients in a systematic review of generalized epilepsy experienced the highest rate of IED firing in REM sleep (Figure 2).25 These findings suggest that paradoxical focal cortical synchronization in REM sleep activates appropriately situated focal epileptiform activity in both animals and humans but generalized epileptiform activity remains resistant to the effects of paradoxical focal synchronization. OREXINERGIC MANIPULATION The effects of experimental orexinergic modulation generally mirror physiologic state-dependent orexinergic effects on seizure threshold via effects on cortical synchronization. Direct orexinergic agonism mirrors phasic orexin bursts during state transitions when seizure propensity is high. In a murine penicillin epilepsy model, direct application of orexin to cerebral cortex exacerbates seizures.41 On the cellular level, intraventricular orexin led to excitatory changes in hippocampal CA1 pyramidal neurons.42,43 In contrast, orexinergic antagonism mirrors orexin neuronal silence in REM sleep when seizure propensity is low. In humans, supraphysiologic doses of a clinical dual orexin receptor antagonist (suvorexant) increased REM sleep duration in addition to increasing total sleep time, NREM sleep duration, and sleep efficiency.44 In murine pentylenetetrazol models, intrahippocampal and intraventricular injections of a single orexin receptor antagonist reduce seizure severity and duration.45,46 On the cellular level, injection of intrahippocampal orexin receptor antagonist in mice decrease regional glutamate.45 In Kcna1 knockout mice, the dual orexin receptor antagonist almorexant shortens REM sleep latency, which correlates with decreased seizures.47 These studies are overall consistent with a proconvulsant effect of experimental orexinergic agonism, which mirrors physiologic phasic orexin bursts during state transitions when seizure propensity is high, and an anticonvulsant effect of experimental orexinergic antagonism, which mirrors physiologic orexin neuronal silence in REM sleep when seizure propensity is low (Figure 1). However, many studies on orexin and epilepsy do not measure sleep, and it is possible that REM sleep-independent influences, such as sleep fragmentation and sleep deprivation, may account for study findings instead. For example, injections of a ventricular orexin receptor antagonist in mice partially reverse dentate gyrus cellular proliferation and hippocampal CA3 neuronal injury secondary to sleep deprivation.46 While consistent with the presumed orexi-cortical axis, one is unfortunately forced to assume that the quantity and quality of sleep is the same through the entire study in order for these data to be valid. Another example is almorexant, which increased NREM sleep quantity in Kcna1 knockout mice (a generalized epilepsy model), but this finding did not correlate with seizure burden even though strong diffuse thalamocortical synchronization in SWS lowers seizure threshold.47 One possible explanation is that stages N1 and N2 sleep were promoted more than, or instead of, SWS (stage N3 sleep), which is a much more synchronized state; however, data directly correlating seizures with state and cortical synchrony were not available to confirm or refute this possibility. Similarly, a recent human case series of type I narcolepsy, marked by orexinergic neuronal loss and frequent lapses into REM sleep, found a greater than chance association with juvenile myoclonic epilepsy (a PGE syndrome).48 Although this observation agrees with frequent state transitions marked by diffuse cortical hypersynchrony exacerbating seizures, one may have also expected seizure reduction due to more REM sleep bouts with cortical desynchronization impairing seizure formation. Although paradoxical REM sleep synchronization may have activated seizures, generalized epileptiform activity should remain resistant to the effects of paradoxical focal synchronization. Without data correlating seizures with state and cortical synchrony, clarifying these findings to yield potentially novel insights into the orexinergic influence on seizures and epilepsy is not possible. FUTURE DIRECTIONS To refine our understanding of orexinergic effects on seizures and epilepsy, future studies should routinely incorporate EEG and hypnography to measure sleep. As it stands, there is already a need for more studies in animals and humans to rigorously assess the relationship between seizures and orexin receptor antagonists, some of which are already in clinical use. Further animal and human studies are also needed to verify the clinical association between narcolepsy, PGE, and other epilepsy types. There is also a need for orexinergic studies in a variety of epilepsy types as different epilepsies likely have different vulnerabilities to orexinergic influence. More basic science is needed to examine the impact of single and double orexin receptor agonists and antagonists on fundamental mechanisms of epileptogenesis at the cellular and network levels, including further basic science into the extent to which fundamental metabotropic cholinergic mechanisms in REM sleep may be altered in epilepsy. These studies can clarify whether observed effects on seizure threshold are reproducible and transcend the species barrier. Incorporating EEG and hypnography into future research can immediately translate these purely observational studies into mechanistic studies by simultaneously correlating seizures with data on cortical synchrony and the states from which seizures emerge. These data can repeatedly test the orexi-cortical axis hypothesis that orexinergic antagonism induces REM sleep to usually yield diffuse cortical desynchronization and increase seizure threshold (Figure 1). These data can also clarify the theoretical proconvulsant risks of orexinergic antagonism, which include inadvertent NREM sleep promotion through partial incomplete antagonism, increased sleep instability through non-sustained antagonism, and paradoxical constructive interference in REM sleep. Lastly, these data may also potentially demonstrate novel orexinergic effects on seizure propensity independent of the orexi-cortical axis through mechanisms of action yet to be discovered; for example, the role of REM sleep-independent influences, such as sleep fragmentation and sleep deprivation. Even if EEG and hypnography are fully incorporated into all future research, however, state transitions still deserve further attention. Most studies are insensitive to transitions by summating all bouts of a sleep–wake state, irrespective of proximity to onset or offset, to yield an overall propensity for that state over the course of a night.25 These studies score sleep by visual inspection (clinical gold standard) to assign a single stage to a 10- or 30-second EEG epoch (depending on whether the laboratory has a respective epilepsy or sleep emphasis). However, more recent murine studies use spectrography and power ratios to score at a finer resolution of 1 second which, while sensitive to ambiguous intermediate states, are not in official American Academy of Sleep Medicine guidelines.34,35 Nevertheless, guidelines are dynamic; for example, previously NREM sleep stages 3 and 4 are now merged into the single state N3. Future guideline revisions may want to focus on state transitions, epoch duration, spectrography, and applicability to commonly shared animal models in sleep and epilepsy research. While more studies are needed on seizure propensity during state transitions, the ultimate success of these studies depends on crisper scoring guidelines that are universally adopted among the clinical and basic science sleep and epilepsy communities. CONCLUSIONS Through unique firing characteristics, the subcortical peptide orexin exerts exquisite control over wakefulness, NREM sleep, REM sleep, and state transitions with profound consequences on cortical synchrony and the subsequent ability of aberrant epileptiform activity to organize into seizures. This orexi-cortical axis has recently been manipulated to therapeutic advantage through orexin receptor antagonism by presumably inducing REM sleep and diffuse cortical desynchronization. However, theoretical proconvulsant risks include inadvertent NREM sleep promotion, increased sleep instability, and paradoxical constructive interference in REM sleep. Future research should routinely incorporate EEG and hypnography to focus on cortical synchrony and the state from which seizures emerge, as REM sleep is likely not the whole story behind the interaction between orexin and epilepsy. Increased understanding of the orexinergic effects on seizures and epilepsy holds the exciting promise of a novel antiepileptic mechanism of action that may 1 day be translated into clinical practice. DISCLOSURE OF FUNDING University of Manitoba Vice President Research Office, University Medical Group Department of Medicine Grant. DISCLOSURE OF CONFLICTS OF INTEREST None. REFERENCES 1. Schwartz MD Kilduff TS . The neurobiology of sleep and wakefulness . Psychiatr Clin North Am . 2015 ; 38 ( 4 ): 615 – 644 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Li J Hu Z de Lecea L . The hypocretins/orexins: integrators of multiple physiological functions . Br J Pharmacol . 2014 ; 171 ( 2 ): 332 – 350 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Adamantidis A de Lecea L . Sleep and metabolism: shared circuits, new connections . Trends Endocrinol Metab . 2008 ; 19 ( 10 ): 362 – 370 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Scammell TE . Narcolepsy . N Engl J Med . 2015 ; 373 ( 27 ): 2654 – 2662 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Tsujino N Sakurai T . Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system . Pharmacol Rev . 2009 ; 61 ( 2 ): 162 – 176 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Estabrooke IV McCarthy MT Ko E et al. . Fos expression in orexin neurons varies with behavioral state . J Neurosci . 2001 ; 21 ( 5 ): 1656 – 1662 . Google Scholar PubMed WorldCat 7. Lee MG Hassani OK Jones BE . Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle . J Neurosci . 2005 ; 25 ( 28 ): 6716 – 6720 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Mileykovskiy BY Kiyashchenko LI Siegel JM . Behavioral correlates of activity in identified hypocretin/orexin neurons . Neuron . 2005 ; 46 ( 5 ): 787 – 798 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Sakurai T . The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness . Nat Rev Neurosci . 2007 ; 8 ( 3 ): 171 – 181 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Xi MC Morales FR Chase MH . Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat . Brain Res . 2001 ; 901 ( 1–2 ): 259 – 264 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Kaur S Thankachan S Begum S Liu M Blanco-Centurion C Shiromani PJ . Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice . PLoS One . 2009 ; 4 ( 7 ): e6346 . Google Scholar Crossref Search ADS PubMed WorldCat 12. España RA Scammell TE . Sleep neurobiology from a clinical perspective . Sleep . 2011 ; 34 ( 7 ): 845 – 858 . Google Scholar PubMed WorldCat 13. Kalogiannis M Grupke SL Potter PE et al. . Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons . Eur J Neurosci . 2010 ; 32 ( 1 ): 130 – 142 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Reinoso-Suárez F de Andrés I Rodrigo-Angulo ML Garzón M . Brain structures and mechanisms involved in the generation of REM sleep . Sleep Med Rev . 2001 ; 5 ( 1 ): 63 – 77 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Olejniczak P . Neurophysiologic basis of EEG . J Clin Neurophysiol . 2006 ; 23 ( 3 ): 186 – 189 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Shouse MN . State disorders and state-dependent seizures in amygdala-kindled cats . Exp Neurol . 1986 ; 92 ( 3 ): 601 – 608 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Frauscher B von Ellenrieder N Dubeau F Gotman J . EEG desynchronization during phasic REM sleep suppresses interictal epileptic activity in humans . Epilepsia . 2016 ; 57 ( 6 ): 879 – 888 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Tanaka T Naquet R . Kindling effect and sleep organization in cats . Electroencephalogr Clin Neurophysiol . 1975 ; 39 ( 5 ): 449 – 454 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Calvo JM Alvarado R Briones R Paz C Fernandez-Guardiola A . Amygdaloid kindling during rapid eye movement (REM) sleep in cats . Neurosci Lett . 1982 ; 29 ( 3 ): 255 – 259 . Google Scholar Crossref Search ADS PubMed WorldCat 20. Calvo JM . Amygdaloid kindling during wakefulness and paradoxical sleep in the cat. 1. Inhibitory influence of paradoxical sleep on kindling development . Epilepsy Res . 1991 ; 9 ( 2 ): 113 – 120 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Cohen H Thomas J Dement WC . Sleep stages, REM deprivation and electroconvulsive threshold in the cat . Brain Res . 1970 ; 19 ( 2 ): 317 – 321 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Pedrazzoli M D’Almeida V Martins PJ et al. . Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation . Brain Res . 2004 ; 995 ( 1 ): 1 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Ferencz I Leanza G Nanobashvili A Kokaia M Lindvall O . Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats . Eur J Neurosci . 2000 ; 12 ( 6 ): 2107 – 2116 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Ferencz I Leanza G Nanobashvili A Kokaia Z Kokaia M Lindvall O . Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats: comparison with noradrenergic neurons . Neuroscience . 2001 ; 102 ( 4 ): 819 – 832 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Ng M Pavlova M . Why are seizures rare in rapid eye movement sleep? Review of the frequency of seizures in different sleep stages . Epilepsy Res Treat . 2013 ; 2013 : 932790 . Google Scholar PubMed WorldCat 26. Bagshaw AP Jacobs J LeVan P Dubeau F Gotman J . Effect of sleep stage on interictal high-frequency oscillations recorded from depth macroelectrodes in patients with focal epilepsy . Epilepsia . 2009 ; 50 ( 4 ): 617 – 628 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Anderson CT Tcheng TK Sun FT Morrell MJ . Day-night patterns of epileptiform activity in 65 patients with long-term ambulatory electrocorticography . J Clin Neurophysiol . 2015 ; 32 ( 5 ): 406 – 412 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Okanari K Baba S Otsubo H et al. . Rapid eye movement sleep reveals epileptogenic spikes for resective surgery in children with generalized interictal discharges . Epilepsia . 2015 ; 56 ( 9 ): 1445 – 1453 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Ochi A Hung R Weiss S et al. . Lateralized interictal epileptiform discharges during rapid eye movement sleep correlate with epileptogenic hemisphere in children with intractable epilepsy secondary to tuberous sclerosis complex . Epilepsia . 2011 ; 52 ( 11 ): 1986 – 1994 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Sakuraba R Iwasaki M Okumura E et al. . High frequency oscillations are less frequent but more specific to epileptogenicity during rapid eye movement sleep . Clin Neurophysiol . 2016 ; 127 ( 1 ): 179 – 186 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Serafini A Kuate C Gelisse P et al. . Sleep before and after temporal lobe epilepsy surgery . Seizure . 2012 ; 21 ( 4 ): 260 – 265 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Kohyama J Shimohira M Tanuma N Hasegawa T Iwakawa Y . ACTH activates rapid eye movement-related phasic inhibition during REM sleep in patients with infantile spasms . Acta Neurol Scand . 2000 ; 101 ( 3 ): 145 – 152 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Niedermeyer E . Epileptiform K complexes . Am J Electroneurodiagnostic Technol . 2008 ; 48 ( 1 ): 48 – 51 . Google Scholar PubMed WorldCat 34. Badawy RA Harvey AS Macdonell RA . Cortical hyperexcitability and epileptogenesis: understanding the mechanisms of epilepsy . J Clin Neurosci . 2009 ; 16 ( 3 ): 355 – 365 . Google Scholar Crossref Search ADS PubMed WorldCat 35. Ewell LA Liang L Armstrong C et al. . Brain state is a major factor in preseizure hippocampal network activity and influences success of seizure intervention . J Neurosci . 2015 ; 35 ( 47 ): 15635 – 15648 . Google Scholar Crossref Search ADS PubMed WorldCat 36. Sedigh-Sarvestani M Thuku GI Sunderam S et al. . Rapid eye movement sleep and hippocampal theta oscillations precede seizure onset in the tetanus toxin model of temporal lobe epilepsy . J Neurosci . 2014 ; 34 ( 4 ): 1105 – 1114 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Carreño M Fernández S . Sleep-related epilepsy . Curr Treat Options Neurol . 2016 ; 18 : 23 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Wolf P Yacubian EM Avanzini G et al. . Juvenile myoclonic epilepsy: a system disorder of the brain . Epilepsy Res . 2015 ; 114 : 2 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Kumar P Raju TR . Seizure susceptibility decreases with enhancement of rapid eye movement sleep . Brain Res . 2001 ; 922 ( 2 ): 299 – 304 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Miller JW Turner GM Gray BC . Anticonvulsant effects of the experimental induction of hippocampal theta activity . Epilepsy Res . 1994 ; 18 ( 3 ): 195 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat 41. Kortunay S Erken HA Erken G et al. . Orexins increase penicillin-induced epileptic activity . Peptides . 2012 ; 34 ( 2 ): 419 – 422 . Google Scholar Crossref Search ADS PubMed WorldCat 42. Riahi E Arezoomandan R Fatahi Z et al. . The electrical activity of hippocampal pyramidal neuron is subjected to descending control by the brain orexin/hypocretin system . Neurobiol Learn Mem . 2015 ; 119 : 93 – 101 . Google Scholar Crossref Search ADS PubMed WorldCat 43. Selbach O Doreulee N Bohla C et al. . Orexins/hypocretins cause sharp wave- and θ-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling . Neuroscience . 2004 ; 127 ( 2 ): 519 – 528 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Sun H Kennedy WP Wilbraham D et al. . Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men . Sleep . 2013 ; 36 ( 2 ): 259 – 267 . Google Scholar PubMed WorldCat 45. Goudarzi E Salmani ME Lashkarbolouki T et al. . Hippocampal orexin receptors inactivation reduces PTZ induced seizures of male rats . Pharmacol Biochem Behav . 2015 ; 130 : 77 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Ni LY Zhu MJ Song Y et al. . Pentylenetetrazol-induced seizures are exacerbated by sleep deprivation through orexin receptor-mediated hippocampal cell proliferation . Neurol Sci . 2014 ; 35 ( 2 ): 245 – 252 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Roundtree HM Simone TA Johnson C et al. . Orexin receptor antagonism improves sleep and reduces seizures in Kcna1-null mice . Sleep . 2016 ; 39 ( 2 ): 357 – 368 . Google Scholar Crossref Search ADS PubMed WorldCat 48. Joshi PA Poduri A Kothare SV . Juvenile myoclonic epilepsy and narcolepsy: a series of three cases . Epilepsy Behav . 2015 ; 51 : 163 – 165 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Address correspondence to: Marcus C. Ng MD, Section of Neurology, Department of Internal Medicine, Health Sciences Centre, University of Manitoba, GF-543, 820 Sherbrook Street, Health Sciences Centre, Winnipeg, MB, Canada R3A 1R9. Telephone: (204) 787-2684; Fax: (204) 787-1486; Email: mng2@hsc.mb.ca © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.
TI - Orexin and Epilepsy: Potential Role of REM Sleep
JO - SLEEP
DO - 10.1093/sleep/zsw061
DA - 2017-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/orexin-and-epilepsy-potential-role-of-rem-sleep-fCRzRoF0Lf
VL - 40
IS - 3
DP - DeepDyve
ER -