Sleep Disorders: Pathogenesis and Therapeutic Interventions

Abstract

Sleep disorder significantly disrupts the quality of life for patients. Although it is clinically acknowledged, the fundamental neuropathological mechanisms are still not understood. Recent preclinical research has been directed toward understanding the fundamental mechanisms underlying the sleep deprivation and sleep/wake dysregulation. Sleep disorder is linked to changes in the structure and function of the neural basis of cognition. We reviewed the neural circuits related to sleep disorders, along with alterations in connectivity and brain region functions, based on advancements in electrophysiology and optogenetic/chemogenetic techniques. We subsequently outline the cellular and molecular modifications linked to sleep disorders in preclinical studies, primarily involving changes in neuronal metabolism, electrophysiological activity, synaptic plasticity, and glial cells. Correspondingly, on the basis of the crosstalk between the brain and peripheral organs, we elucidate the underlying mechanisms of the involvement of celiac disease and hepatic disease in the pathogenesis of sleep disorders. In this review, we mainly discussed the pathogenesis at molecular, cellular, and neural circuit levels that contribute to sleep disorder. The review also covered potential strategies for treating sleep disorders and future research avenues.

Keywords

brain / neural circuit / neuronal plasticity / neurotransmitters / sleep disorder

References

[1] S. Conley, S. Jeon, V. Lehner, D. D. Proctor, and N. S. Redeker, “Sleep Characteristics and Rest-Activity Rhythms Are Associated With Gastrointestinal Symptoms Among Adults With Inflammatory Bowel Disease,” Digestive Diseases and Sciences 66 (2021): 181–189.

[2] N. Goel, H. Rao, J. S. Durmer, and D. F. Dinges, “Neurocognitive Consequences of Sleep Deprivation,” Seminars in Neurology 29 (2009): 320–339.

[3] V. M. Thakre, M. Deshmukh, and J. Gibbs, “Effectiveness of Brain Gym Exercises Over Cognitive Behavioural Therapy in Improving Sleep Quality Among Healthcare University Students: A Comparative Study,” Cureus 16 (2024): e58463.

[4] A. Barion and P. C. Zee, “A Clinical Approach to Circadian Rhythm Sleep Disorders,” Sleep Medicine 8 (2007): 566–577.

[5] T. Roth, R. K. Bogan, L. Culpepper, et al., “Excessive Sleepiness: Under-Recognized and Essential Marker for Sleep/Wake Disorder Management,” Current Medical Research and Opinion 26, no. Suppl. 2 (2010): S3–S24. quiz S25-S27.

[6] M. Akashi, R. Sogawa, R. Matsumura, et al., “A Detection Method for Latent Circadian Rhythm Sleep-Wake Disorder,” EBioMedicine 62 (2020): 103080.

[7] M. Fornaro, C. Caiazza, G. De Simone, F. Rossano, and A. de Bartolomeis, “Insomnia and Related Mental Health Conditions: Essential Neurobiological Underpinnings Towards Reduced Polypharmacy Utilization Rates,” Sleep Medicine 113 (2024): 198–214.

[8] C. M. Morin and D. C. Jarrin, “Epidemiology of Insomnia: Prevalence, Course, Risk Factors, and Public Health Burden,” Sleep Medicine Clinics 17 (2022): 173–191.

[9] J. H. Kim, A. R. Elkhadem, and J. F. Duffy, “Circadian Rhythm Sleep-Wake Disorders in Older Adults,” Sleep Medicine Clinics 17 (2022): 241–252.

[10] W. Ruan, X. Yuan, and H. K. Eltzschig, “Circadian Rhythm as a Therapeutic Target,” Nature Reviews Drug Discovery 20 (2021): 287–307.

[11] J. Bass and M. A. Lazar, “Circadian Time Signatures of Fitness and Disease,” Science 354 (2016): 994–999.

[12] K. Wulff, S. Gatti, J. G. Wettstein, and R. G. Foster, “Sleep and Circadian Rhythm Disruption in Psychiatric and Neurodegenerative Disease,” Nature Reviews Neuroscience 11 (2010): 589–599.

[13] R. L. Rios, M. Kafashan, O. Hyche, et al., “Targeting Slow Wave Sleep Deficiency in Late-Life Depression: A Case Series With Propofol,” The American Journal of Geriatric Psychiatry 31 (2023): 643–652.

[14] S. Hassamal, “Chronic Stress, Neuroinflammation, and Depression: An Overview of Pathophysiological Mechanisms and Emerging Anti-Inflammatories,” Frontiers in Psychiatry 14 (2023): 1130989.

[15] J. Godos, R. Ferri, G. Lanza, et al., “Mediterranean Diet and Sleep Features: A Systematic Review of Current Evidence,” Nutrients 16 (2024): 282.

[16] M. Zhao, H. Tuo, S. Wang, and L. Zhao, “The Effects of Dietary Nutrition on Sleep and Sleep Disorders,” Mediators of Inflammation 2020 (2020): 3142874.

[17] G. Lanza, D. Arico, B. Lanuzza, et al., “Facilitatory/Inhibitory Intracortical Imbalance in REM Sleep Behavior Disorder: Early Electrophysiological Marker of Neurodegeneration?,” Sleep 43 (2020): zsz242.

[18] G. Donzuso, C. E. Cicero, L. Giuliano, et al., “Neuroanatomical Findings in Isolated Rem Sleep Behavior Disorder and Early Parkinson’s Disease: A Voxel-Based Morphometry Study,” Brain Imaging and Behavior 18 (2024): 83–91.

[19] S. Joza, M. T. Hu, K. Y. Jung, et al., “Progression of Clinical Markers in Prodromal Parkinson’s Disease and Dementia With Lewy Bodies: A Multicentre Study,” Brain 146 (2023): 3258–3272.

[20] C. H. Schenck, B. F. Boeve, and M. W. Mahowald, “Delayed Emergence of a Parkinsonian Disorder or Dementia in 81% of Older Men Initially Diagnosed With Idiopathic Rapid Eye Movement Sleep Behavior Disorder: A 16-Year Update on a Previously Reported Series,” Sleep Medicine 14 (2013): 744–748.

[21] J. R. Connor, X. S. Wang, R. P. Allen, et al., “Altered Dopaminergic Profile in the Putamen and Substantia Nigra in Restless Leg Syndrome,” Brain 132 (2009): 2403–2412.

[22] J. Zhu, C. Chen, Z. Li, et al., “Overexpression of Sirt6 Ameliorates Sleep Deprivation Induced-Cognitive Impairment by Modulating Glutamatergic Neuron Function,” Neural Regeneration Research 18 (2023): 2449–2458.

[23] T. Urushihata, M. Goto, K. Kabetani, et al., “Evaluation of Cellular Activity in Response to Sleep Deprivation by a Comprehensive Analysis of the Whole Mouse Brain,” Frontiers in Neuroscience 17 (2023): 1252689.

[24] L. Chen, K. Wu, J. He, et al., “Circadian Regulation of the Lactate Metabolic Kinetics in Mice Using the [(1)H-(13)C]-NMR Technique,” Molecular Neurobiology 61 (2024): 5802–5813.

[25] J. Jia, W. Tao, T. Chen, et al., “Sirt6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing Rats,” Molecular Neurobiology 61 (2024): 883–899.

[26] M. Wadhwa, A. Prabhakar, J. P. Anand, et al., “Complement Activation Sustains Neuroinflammation and Deteriorates Adult Neurogenesis and Spatial Memory Impairment in Rat Hippocampus Following Sleep Deprivation,” Brain, Behavior, and Immunity 82 (2019): 129–144.

[27] M. Wadhwa, A. Prabhakar, K. Ray, et al., “Inhibiting the Microglia Activation Improves the Spatial Memory and Adult Neurogenesis in Rat Hippocampus During 48 h of Sleep Deprivation,” Journal of Neuroinflammation 14 (2017): 222.

[28] M. Wadhwa, P. Kumari, G. Chauhan, et al., “Sleep Deprivation Induces Spatial Memory Impairment by Altered Hippocampus Neuroinflammatory Responses and Glial Cells Activation in Rats,” Journal of Neuroimmunology 312 (2017): 38–48.

[29] G. Chauhan, K. Ray, S. Sahu, et al., “Adenosine a1 Receptor Antagonist Mitigates Deleterious Effects of Sleep Deprivation on Adult Neurogenesis and Spatial Reference Memory in Rats,” Neuroscience 337 (2016): 107–116.

[30] C. Florian, C. G. Vecsey, M. M. Halassa, P. G. Haydon, and T. Abel, “Astrocyte-Derived Adenosine and a1 Receptor Activity Contribute to Sleep Loss-Induced Deficits in Hippocampal Synaptic Plasticity and Memory in Mice,” Journal of Neuroscience 31 (2011): 6956–6962.

[31] P. R. Jansen, K. Watanabe, S. Stringer, et al., “Genome-Wide Analysis of Insomnia in 1, 331, 010 Individuals Identifies New Risk Loci and Functional Pathways,” Nature Genetics 51 (2019): 394–403.

[32] A. R. Hammerschlag, S. Stringer, C. A. de Leeuw, et al., “Genome-Wide Association Analysis of Insomnia Complaints Identifies Risk Genes and Genetic Overlap With Psychiatric and Metabolic Traits,” Nature Genetics 49 (2017): 1584–1592.

[33] Q. Wang, Y. Wu, X. Wang, et al., “Genomic Correlation, Shared Loci, and Causal Relationship Between Insomnia and Psoriasis: A Large-Scale Genome-Wide Cross-Trait Analysis,” Archives of Dermatological Research 316 (2024): 425.

[34] W. C. Orr, R. Fass, S. S. Sundaram, and A. O. Scheimann, “The Effect of Sleep on Gastrointestinal Functioning in Common Digestive Diseases,” Lancet Gastroenterology & Hepatology 5 (2020): 616–624.

[35] M. Sujino, K. H. Masumoto, S. Yamaguchi, G. T. van der Horst, H. Okamura, and S. T. Inouye, “Suprachiasmatic Nucleus Grafts Restore Circadian Behavioral Rhythms of Genetically Arrhythmic Mice,” Current Biology 13 (2003): 664–668.

[36] R. Allada and J. Bass, “Circadian Mechanisms in Medicine,” New England Journal of Medicine 384 (2021): 550–561.

[37] J. R. Paul, J. A. Davis, L. K. Goode, et al., “Circadian Regulation of Membrane Physiology in Neural Oscillators Throughout the Brain,” European Journal of Neuroscience 51 (2020): 109–138.

[38] K. Xiang, Z. Xu, Y. Q. Hu, et al., “Circadian Clock Genes as Promising Therapeutic Targets for Autoimmune Diseases,” Autoimmunity Reviews 20 (2021): 102866.

[39] P. Gršković and P. Korać, “Circadian Gene Variants in Diseases,” Genes (Basel) 14 (2023): 1703.

[40] J. C. Gonzalez, H. Lee, A. M. Vincent, et al., “Circadian Regulation of Dentate Gyrus Excitability Mediated by G-Protein Signaling,” Cell Reports 42 (2023): 112039.

[41] L. Sun, H. Tian, S. Xue, et al., “Circadian Clock Genes Rev-Erbs Inhibits Granulosa Cells Apoptosis by Regulating Mitochondrial Biogenesis and Autophagy in Polycystic Ovary Syndrome,” Frontiers in Cell and Developmental Biology 9 (2021): 658112.

[42] B. Pourcet and H. Duez, “Nuclear Receptors and Clock Components in Cardiovascular Diseases,” International Journal of Molecular Sciences 22 (2021): 9721.

[43] L. Lande-Diner, C. Boyault, J. Y. Kim, and C. J. Weitz, “A Positive Feedback Loop Links Circadian Clock Factor Clock-BMAL1 to the Basic Transcriptional Machinery,” PNAS 110 (2013): 16021–16026.

[44] A. C. R. Diernfellner and M. Brunner, “Phosphorylation Timers in the Neurospora Crassa Circadian Clock,” Journal of Molecular Biology 432 (2020): 3449–3465.

[45] G. van Ooijen and A. J. Millar, “Non-Transcriptional Oscillators in Circadian Timekeeping,” Trends in Biochemical Sciences 37 (2012): 484–492.

[46] F. Llorens, J. J. Zarranz, A. Fischer, I. Zerr, and I. Ferrer, “Fatal Familial Insomnia: Clinical Aspects and Molecular Alterations,” Current Neurology and Neuroscience Reports 17 (2017): 30.

[47] Y. He, C. R. Jones, N. Fujiki, et al., “The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals,” Science 325 (2009): 866–870.

[48] K. M. Holter, B. E. Pierce, and R. W. Gould, “Metabotropic Glutamate Receptor Function and Regulation of Sleep-Wake Cycles,” International Review of Neurobiology 168 (2023): 93–175.

[49] C. Hung and A. Yamanaka, “The Role of Orexin Neuron Activity in Sleep/Wakefulness Regulation,” Peptides 165 (2023): 171007.

[50] S. Rahimi, L. Joyce, T. Fenzl, and M. Drexel, “Crosstalk Between the Subiculum and Sleep-Wake Regulation: A Review,” Journal of Sleep Research 33 (2024): e14134.

[51] A. Eban-Rothschild, J. C. Borniger, G. Rothschild, W. J. Giardino, J. G. Morrow, and L. de Lecea, “Arousal State-Dependent Alterations in VTA-GABAergic Neuronal Activity,” Eneuro 7 (2020):

[52] A. Eban-Rothschild, G. Rothschild, W. J. Giardino, J. R. Jones, and L. de Lecea, “VTA Dopaminergic Neurons Regulate Ethologically Relevant Sleep-Wake Behaviors,” Nature Neuroscience 19 (2016): 1356–1366.

[53] E. L. Sutton, “Insomnia,” Annals of Internal Medicine 174 (2021): Itc33–Itc48.

[54] M. Nedergaard and S. A. Goldman, “Glymphatic Failure as a Final Common Pathway to Dementia,” Science 370 (2020): 50–56.

[55] S. A. Kashchenko, A. A. Eranova, and E. V. Chuguy, “Glymphatic Dysfunction and Sleep Disorders: Indirect Effects on Slzheimer’s Disease,” Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova 124 (2024): 7–12.

[56] A. Scott-Massey, M. K. Boag, A. Magnier, D. Bispo, T. K. Khoo, and D. L. Pountney, “Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease,” International Journal of Molecular Sciences 23 (2022): 12928.

[57] J. J Avilez-Avilez, M. F Medina-Flores, and B. Gómez-Gonzalez, “Sleep Loss Impairs Blood-Brain Barrier Function: Cellular and Molecular Mechanisms,” Vitamins and Hormones 126 (2024): 77–96.

[58] M. Bishir, A. Bhat, M. M. Essa, et al., “Sleep Deprivation and Neurological Disorders,” BioMed Research International 2020 (2020): 5764017.

[59] J. Wang, Y. Tian, C. Qin, et al., “Impaired Glymphatic Drainage Underlying Obstructive Sleep Apnea Is Associated With Cognitive Dysfunction,” Journal of Neurology 270 (2023): 2204–2216.

[60] J. Christensen, G. R. Yamakawa, S. R. Shultz, and R. Mychasiuk, “Is the Glymphatic System the Missing Link Between Sleep Impairments and Neurological Disorders? Examining the Implications and Uncertainties,” Progress in Neurobiology 198 (2021): 101917.

[61] J. I. Shenker and G. Singh, “Sleep and Dementia,” Missouri Medicine 114 (2017): 311–315.

[62] A. R. Eugene and J. Masiak, “The Neuroprotective Aspects of Sleep,” MEDtube Science 3 (2015): 35–40.

[63] T. T. Bobić, A. Šečić, I. Zavoreo, et al., “The Impact of Sleep Deprivation on the Brain,” Acta Clinica Croatica 55 (2016): 469–473.

[64] N. I. Bohnen, A. J. Yarnall, R. S. Weil, et al., “Cholinergic System Changes in Parkinson’s Disease: Emerging Therapeutic Approaches,” Lancet Neurology 21 (2022): 381–392.

[65] M. A. Bedard, M. Aghourian, C. Legault-Denis, et al., “Brain Cholinergic Alterations in Idiopathic REM Sleep Behaviour Disorder: A PET Imaging Study With (18)F-FEOBV,” Sleep Medicine 58 (2019): 35–41.

[66] R. Mehta, R. Bhattacharya, and B. N. Mallick, “Sleep and Neuroimmunomodulation for Maintenance of Optimum Brain Function: Role of Noradrenaline,” Brain Sciences 12 (2022): 1725.

[67] R. Mehta, S. Giri, and B. N. Mallick, “Rem Sleep Loss-Induced Elevated Noradrenaline Could Predispose an Individual to Psychosomatic Disorders: A Review Focused on Proposal for Prediction, Prevention, and Personalized Treatment,” EPMA Journal 11 (2020): 529–549.

[68] J. M. Monti, H. Jantos, and P. Lagos, “Activation of Serotonin 5-HT(1B) Receptor in the Dorsal Raphe Nucleus Affects REM Sleep in the Rat,” Behavioural Brain Research 206 (2010): 8–16.

[69] R. Mehta, A. Singh, I. Bókkon, and B. Nath Mallick, “REM Sleep and Its Loss-Associated Epigenetic Regulation With Reference to Noradrenaline in Particular,” Current Neuropharmacology 14 (2016): 28–40.

[70] K. B. Andersen, A. K. Hansen, M. Sommerauer, et al., “Altered Sensorimotor Cortex Noradrenergic Function in Idiopathic REM Sleep Behaviour Disorder—A PET Study,” Parkinsonism & Related Disorders 75 (2020): 63–69.

[71] Z. C. Luo and T. M. Gao, “Dopamine Switches Affective States Under Acute Sleep Deprivation,” Neuroscience Bulletin 40 (2024): 1205–1208.

[72] N. D. Volkow, G. J. Wang, F. Telang, et al., “Sleep Deprivation Decreases Binding of [11C]Raclopride to Dopamine D2/D3 Receptors in the Human Brain,” Journal of Neuroscience 28 (2008): 8454–8461.

[73] M. Wu, X. Zhang, S. Feng, et al., “Dopamine Pathways Mediating Affective State Transitions After Sleep Loss,” Neuron 112 (2024): 141–154.e148.

[74] M. G. Stokholm, A. Iranzo, K. Østergaard, et al., “Extrastriatal Monoaminergic Dysfunction and Enhanced Microglial Activation in Idiopathic Rapid Eye Movement Sleep Behaviour Disorder,” Neurobiology of Disease 115 (2018): 9–16.

[75] P. Cai, F. D. Wang, J. Yao, et al., “Regulation of Wakefulness by Gabaergic Dorsal Raphe Nucleus-Ventral Tegmental Area Pathway,” Sleep 45 (2022): zsac235.

[76] S. Ren, C. Zhang, F. Yue, et al., “A Midbrain Gabaergic Circuit Constrains Wakefulness in a Mouse Model of Stress,” Nature Communications 15 (2024): 2722.

[77] S. Han, J. Wang, W. Zhang, and X. Tian, “Chronic Pain-Related Cognitive Deficits: Preclinical Insights Into Molecular, Cellular, and Circuit Mechanisms,” Molecular Neurobiology 61 (2024): 8123–8143.

[78] Y. Oishi and M. Lazarus, “The Control of Sleep and Wakefulness by Mesolimbic Dopamine Systems,” Neuroscience Research 118 (2017): 66–73.

[79] J. M. Monti and D. Monti, “The Involvement of Dopamine in the Modulation of Sleep and Waking,” Sleep Medicine Reviews 11 (2007): 113–133.

[80] X. Yu, W. Li, Y. Ma, et al., “GABA and Glutamate Neurons in the VTA Regulate Sleep and Wakefulness,” Nature Neuroscience 22 (2019): 106–119.

[81] S. L. Reitz, A. Z. Wasilczuk, G. H. Beh, A. Proekt, and M. B. Kelz, “Activation of Preoptic Tachykinin 1 Neurons Promotes Wakefulness Over Sleep and Volatile Anesthetic-Induced Unconsciousness,” Current Biology 31 (2021): 394–405.e394.

[82] J. T. Moore, J. Chen, B. Han, et al., “Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis,” Current Biology 22 (2012): 2008–2016.

[83] G. Vanini, M. Bassana, M. Mast, et al., “Activation of Preoptic GABAergic or Glutamatergic Neurons Modulates Sleep-Wake Architecture, but Not Anesthetic State Transitions,” Current Biology 30 (2020): 779–787.e774.

[84] J. Smith, A. Honig-Frand, H. Antila, et al., “Regulation of Stress-Induced Sleep Fragmentation by Preoptic Glutamatergic Neurons,” Current Biology 34 (2024): 12–23.e15.

[85] A. Mondino, V. S Hambrecht-Wiedbusch, D. Li, et al., “Glutamatergic Neurons in the Preoptic Hypothalamus Promote Wakefulness, Destabilize NREM Sleep, Suppress REM Sleep, and Regulate Cortical Dynamics,” Journal of Neuroscience 41 (2021): 3462–3478.

[86] S. Teng, F. Zhen, L. Wang, et al., “Control of Non-REM Sleep by Ventrolateral Medulla Glutamatergic Neurons Projecting to the Preoptic Area,” Nature Communications 13 (2022): 4748.

[87] J. J. Maurer, A. Lin, X. Jin, et al., “Homeostatic Regulation of Rapid Eye Movement Sleep by the Preoptic Area of the Hypothalamus,” Elife 12 (2024): RP92095.

[88] G. Miracca, B. Anuncibay-Soto, K. Tossell, et al., “NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep,” Journal of Neuroscience 42 (2022): 5389–5409.

[89] Y. C. Saito, T. Maejima, M. Nishitani, et al., “Monoamines Inhibit GABAergic Neurons in Ventrolateral Preoptic Area That Make Direct Synaptic Connections to Hypothalamic Arousal Neurons,” Journal of Neuroscience 38 (2018): 6366–6378.

[90] K. Prokofeva, Y. C. Saito, Y. Niwa, et al., “Structure and Function of Neuronal Circuits Linking Ventrolateral Preoptic Nucleus and Lateral Hypothalamic Area,” Journal of Neuroscience 43 (2023): 4075–4092.

[91] X. Guo, X. Gao, B. T. Keenan, et al., “RNA-seq Analysis of Galaninergic Neurons From Ventrolateral Preoptic Nucleus Identifies Expression Changes Between Sleep and Wake,” BMC Genomics [Electronic Resource] 21 (2020): 633.

[92] H. B. Xiang, C. Liu, T. T. Liu, and J. Xiong, “Central Circuits Regulating the Sympathetic Outflow to Lumbar Muscles in Spinally Transected Mice by Retrograde Transsynaptic Transport,” International Journal of Clinical and Experimental Pathology 7 (2014): 2987–2997.

[93] T. K. Lee, J. H. Lois, J. H. Troupe, T. D. Wilson, and B. J. Yates, “Transneuronal Tracing of Neural Pathways That Regulate Hindlimb Muscle Blood Flow,” American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 292 (2007): R1532–R1541.

[94] J. Gao, F. Zhang, H. J. Sun, et al., “Transneuronal Tracing of Central Autonomic Regions Involved in Cardiac Sympathetic Afferent Reflex in Rats,” Journal of the Neurological Sciences 342 (2014): 45–51.

[95] Q. Ye, J. Nunez, and X. Zhang, “Oxytocin Receptor-Expressing Neurons in the Paraventricular Thalamus Regulate Feeding Motivation Through Excitatory Projections to the Nucleus Accumbens Core,” Journal of Neuroscience 42 (2022): 3949–3964.

[96] Q. Ye, J. Nunez, and X. Zhang, “Multiple Cholinergic Receptor Subtypes Coordinate Dual Modulation of Acetylcholine on Anterior and Posterior Paraventricular Thalamic Neurons,” Journal of Neurochemistry 168 (2024): 995–1018.

[97] L. R. Barrett, J. Nunez, and X. Zhang, “Oxytocin Activation of Paraventricular Thalamic Neurons Promotes Feeding Motivation to Attenuate Stress-Induced Hypophagia,” Neuropsychopharmacology 46 (2021): 1045–1056.

[98] C. B. Saper, T. C. Chou, and T. E. Scammell, “The Sleep Switch: Hypothalamic Control of Sleep and Wakefulness,” Trends in Neuroscience (TINS) 24 (2001): 726–731.

[99] D. Ono and A. Yamanaka, “Hypothalamic Regulation of the Sleep/Wake Cycle,” Neuroscience Research 118 (2017): 74–81.

[100] M. Patel and B. Joshi, “Development of the Sleep-Wake Switch in Rats During the P2-P21 Early Infancy Period,” Frontiers in Network Physiology 3 (2023): 1340722.

[101] S. Ren, Y. Wang, F. Yue, et al., “The Paraventricular Thalamus Is a Critical Thalamic Area for Wakefulness,” Science 362 (2018): 429–434.

[102] Y. D. Li, Y. J. Luo, W. Xu, et al., “Ventral Pallidal GABAergic Neurons Control Wakefulness Associated With Motivation Through the Ventral Tegmental Pathway,” Molecular Psychiatry 26 (2021): 2912–2928.

[103] A. B. Dos Santos, L. K. Skaanning, E. Mikkelsen, et al., “Α-Synuclein Responses in the Laterodorsal Tegmentum, the Pedunculopontine Tegmentum, and the Substantia Nigra: Implications for Early Appearance of Sleep Disorders in Parkinson’s Disease,” Journal of Parkinson’s Disease 11 (2021): 1773–1790.

[104] C. Gallea, C. Ewenczyk, B. Degos, et al., “Pedunculopontine Network Dysfunction in Parkinson’s Disease With Postural Control and Sleep Disorders,” Movement Disorders 32 (2017): 693–704.

[105] M. A. Khanday, B. I. Somarajan, R. Mehta, and B. N. Mallick, “Noradrenaline From Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM Sleep and Induces Its Loss-Associated Effects in Rats,” Eneuro 3 (2016):

[106] C. Liu, D. W. Ye, X. H. Guan, R. C. Li, H. B. Xiang, and W. Z. Zhu, “Stimulation of the Pedunculopontine Tegmental Nucleus May Affect Renal Function by Melanocortinergic Signaling,” Medical Hypotheses 81 (2013): 114–116.

[107] Y. Hao, X. B. Tian, T. T. Liu, C. Liu, H. B. Xiang, and J. G. Zhang, “Mc4r Expression in Pedunculopontine Nucleus Involved in the Modulation of Midbrain Dopamine System,” International Journal of Clinical and Experimental Pathology 8 (2015): 2039–2043.

[108] D. Ye, Q. Guo, J. Feng, et al., “Laterodorsal Tegmentum and Pedunculopontine Tegmental Nucleus Circuits Regulate Renal Functions: Neuroanatomical Evidence in Mice Models,” Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban 32 (2012): 216–220.

[109] N. D. Volkow, D. Tomasi, G. J. Wang, et al., “Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain,” Journal of Neuroscience 32 (2012): 6711–6717.

[110] M. Guo, Y. Wu, D. Zheng, et al., “Preoperative Acute Sleep Deprivation Causes Postoperative Pain Hypersensitivity and Abnormal Cerebral Function,” Neuroscience Bulletin 38 (2022): 1491–1507.

[111] Y. Murata, A. Oka, A. Iseki, et al., “Prolonged Sleep Deprivation Decreases Cell Proliferation and Immature Newborn Neurons in Both Dorsal and Ventral Hippocampus of Male Rats,” Neuroscience Research 131 (2018): 45–51.

[112] Y. Wang, Y. Tian, Z. Long, et al., “Volume of the Dentate Gyrus/CA4 Hippocampal Subfield Mediates the Interplay Between Sleep Quality and Depressive Symptoms,” International Journal of Clinical and Health Psychology 24 (2024): 100432.

[113] E. Y. Joo, H. Kim, S. Suh, and S. B. Hong, “Hippocampal Substructural Vulnerability to Sleep Disturbance and Cognitive Impairment in Patients With Chronic Primary Insomnia: Magnetic Resonance Imaging Morphometry,” Sleep 37 (2014): 1189–1198.

[114] P. Meerlo, R. E. Mistlberger, B. L. Jacobs, H. C. Heller, and D. McGinty, “New Neurons in the Adult Brain: The Role of Sleep and Consequences of Sleep Loss,” Sleep Medicine Reviews 13 (2009): 187–194.

[115] H. Dong, Z. K. Chen, H. Guo, et al., “Striatal Neurons Expressing Dopamine D(1) Receptor Promote Wakefulness in Mice,” Current Biology 32 (2022): 600–613.e604.

[116] Y. J. Luo, Y. D. Li, L. Wang, et al., “Nucleus Accumbens Controls Wakefulness by a Subpopulation of Neurons Expressing Dopamine D(1) Receptors,” Nature Communications 9 (2018): 1576.

[117] Y. Li, X. Zhang, Y. Li, Y. Li, and H. Xu, “Activation of Ventral Pallidum Camkiia-Expressing Neurons Promotes Wakefulness,” Neurochemical Research 48 (2023): 2502–2513.

[118] Y. J. Luo, J. Ge, Z. K. Chen, et al., “Ventral Pallidal Glutamatergic Neurons Regulate Wakefulness and Emotion Through Separated Projections,” Iscience 26 (2023): 107385.

[119] D. Yang, B. B. Nie, J. G. He, et al., “Exploring Cerebral Structural and Functional Abnormalities in a Mouse Model of Post-Traumatic Headache Induced by Mild Traumatic Brain Injury,” Zoological Research 45 (2024): 648–662.

[120] A. K Bouzier-Sore, P. Voisin, V. Bouchaud, E. Bezancon, J. M. Franconi, and L. Pellerin, “Competition Between Glucose and Lactate as Oxidative Energy Substrates in Both Neurons and Astrocytes: A Comparative NMR Study,” European Journal of Neuroscience 24 (2006): 1687–1694.

[121] M. Wu, S. Minkowicz, V. Dumrongprechachan, P. Hamilton, and Y. Kozorovitskiy, “Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms,” Biological Psychiatry 89 (2021): 1096–1105.

[122] H. Wu, N. K. Savalia, and A. C. Kwan, “Ketamine for a Boost of Neural Plasticity: How, but Also When?,” Biological Psychiatry 89 (2021): 1030–1032.

[123] M. Ogiue-Ikeda, N. Tanabe, H. Mukai, et al., “Rapid Modulation of Synaptic Plasticity by Estrogens as Well as Endocrine Disrupters in Hippocampal Neurons,” Brain Research Reviews 57 (2008): 363–375.

[124] H. Gao, Y. Zhang, D. Luo, et al., “Activation of the Hippocampal DRD2 Alleviates Neuroinflammation, Synaptic Plasticity Damage and Cognitive Impairment After Sleep Deprivation,” Molecular Neurobiology 60 (2023): 7208–7221.

[125] S. Giri, R. Mehta, and B. N. Mallick, “REM Sleep Loss-Induced Elevated Noradrenaline Plays a Significant Role in Neurodegeneration: Synthesis of Findings to Propose a Possible Mechanism of Action From Molecule to Patho-Physiological Changes,” Brain Sciences 14 (2023): 8.

[126] C. Ma, B. Li, D. Silverman, et al., “Microglia Regulate Sleep Through Calcium-Dependent Modulation of Norepinephrine Transmission,” Nature Neuroscience 27 (2024): 249–258.

[127] H. Liu, C. Yang, X. Wang, et al., “Propofol Improves Sleep Deprivation-Induced Sleep Structural and Cognitive Deficits via Upregulating the BMAL1 Expression and Suppressing Microglial M1 Polarization,” CNS Neuroscience & Therapeutics 30 (2024): e14798.

[128] T. Sun, H. Du, Z. Li, et al., “Decoding the Contributions of Gut Microbiota and Cerebral Metabolism in Acute Liver Injury Mice With and Without Cognitive Dysfunction,” CNS Neuroscience & Therapeutics 29, no. Suppl. 1 (2023): 31–42.

[129] T. Sun, M. Feng, A. Manyande, H. Xiang, J. Xiong, and Z. He, “Regulation of Mild Cognitive Impairment Associated With Liver Disease by Humoral Factors Derived From the Gastrointestinal Tract and MRI Research Progress: A Literature Review,” Frontiers in Neuroscience 17 (2023): 1206417.

[130] N. X. Huang, H. W. Huang, Q. Y. Dong, et al., “Metabolic Alterations in the Right Anterior Insula Among Patients With Cirrhosis Without Overt Hepatic Encephalopathy: A Magnetic Resonance Spectroscopy Study,” Frontiers in Neurology 14 (2023): 1291478.

[131] Z. He, Y. Liu, Z. Li, et al., “Gut Microbiota Regulates Circadian Oscillation in Hepatic Ischemia-Reperfusion Injury-Induced Cognitive Impairment by Interfering With Hippocampal Lipid Metabolism in Mice,” Hepatology International 17 (2023): 1645–1658.

[132] R. A. de Graaf, G. F. Mason, A. B. Patel, K. L. Behar, and D. L. Rothman, “In Vivo 1H-[13C]-NMR Spectroscopy of Cerebral Metabolism,” NMR in Biomedicine 16 (2003): 339–357.

[133] T. Ziegs, L. Ruhm, A. Wright, and A. Henning, “Mapping of Glutamate Metabolism Using 1H FID-MRSI After Oral Administration of [1-13C]GLC at 9.4 T,” Neuroimage 270 (2023): 119940.

[134] R. A. Waniewski and D. L. Martin, “Preferential Utilization of Acetate by Astrocytes Is Attributable to Transport,” Journal of Neuroscience 18 (1998): 5225–5233.

[135] R. Chibbar and L. A. Dieleman, “The Gut Microbiota in Celiac Disease and Probiotics,” Nutrients 11 (2019): 2375.

[136] G. Pennisi, G. Lanza, S. Giuffrida, et al., “Excitability of the Motor Cortex in De Novo Patients With Celiac Disease,” PLoS ONE 9 (2014): e102790.

[137] H. Reinke and G. Asher, “Circadian Clock Control of Liver Metabolic Functions,” Gastroenterology 150 (2016): 574–580.

[138] Z. Zwighaft, H. Reinke, and G. Asher, “The Liver in the Eyes of a Chronobiologist,” Journal of Biological Rhythms 31 (2016): 115–124.

[139] D. J. Stenvers, F. Scheer, P. Schrauwen, S. E. la Fleur, and A. Kalsbeek, “Circadian Clocks and Insulin Resistance,” Nature Reviews Endocrinology 15 (2019): 75–89.

[140] S. Montagnese, C. De Pittà, M. De Rui, et al., “Sleep-Wake Abnormalities in Patients With Cirrhosis,” Hepatology 59 (2014): 705–712.

[141] M. Bruyneel and T. Sersté, “Sleep Disturbances in Patients With Liver Cirrhosis: Prevalence, Impact, and Management Challenges,” Nature and Science of Sleep 10 (2018): 369–375.

[142] K. Wijarnpreecha, C. Thongprayoon, P. Panjawatanan, and P. Ungprasert, “Short Sleep Duration and Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis,” Journal of Gastroenterology and Hepatology 31 (2016): 1802–1807.

[143] S. De Cruz, J. R. Espiritu, M. Zeidler, and T. S. Wang, “Sleep Disorders in Chronic Liver Disease,” Seminars in Respiratory and Critical Care Medicine 33 (2012): 26–35.

[144] T. Marjot, D. W. Ray, F. R. Williams, J. W. Tomlinson, and M. J. Armstrong, “Sleep and Liver Disease: A Bidirectional Relationship,” Lancet Gastroenterology & Hepatology 6 (2021): 850–863.

[145] S. Tordjman, S. Chokron, R. Delorme, et al., “Melatonin: Pharmacology, Functions and Therapeutic Benefits,” Current Neuropharmacology 15 (2017): 434–443.

[146] Y. B. Liu and M. K. Chen, “Epidemiology of Liver Cirrhosis and Associated Complications: Current Knowledge and Future Directions,” World Journal of Gastroenterology 28 (2022): 5910–5930.

[147] C. D. Byrne and G. Targher, “NAFLD: A Multisystem Disease,” Journal of Hepatology 62 (2015): S47–S64.

[148] S. L. Friedman, B. A Neuschwander-Tetri, M. Rinella, and A. J. Sanyal, “Mechanisms of NAFLD Development and Therapeutic Strategies,” Nature Medicine 24 (2018): 908–922.

[149] C. Gofton, Y. Upendran, M. H. Zheng, and G. J. Mafld, “How Is It Different From NAFLD?,” Clinical and Molecular Hepatology 29 (2023): S17–S31.

[150] Z. Younossi, Q. M. Anstee, M. Marietti, et al., “Global Burden of NAFLD and NASH: Trends, Predictions, Risk Factors and Prevention,” Nature Reviews Gastroenterology & Hepatology 15 (2018): 11–20.

[151] J. Zhou, F. Zhou, W. Wang, et al., “Epidemiological Features of NAFLD From 1999 to 2018 in China,” Hepatology 71 (2020): 1851–1864.

[152] J. V. Lazarus, H. E. Mark, Q. M. Anstee, et al., “Advancing the Global Public Health Agenda for NAFLD: A Consensus Statement,” Nature Reviews Gastroenterology & Hepatology 19 (2022): 60–78.

[153] E. E. Powell, V. W. Wong, and M. Rinella, “Non-Alcoholic Fatty Liver Disease,” Lancet 397 (2021): 2212–2224.

[154] E. Paschetta, P. Belci, A. Alisi, et al., “OSAS-Related Inflammatory Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease,” Mediators of Inflammation 2015 (2015): 815721.

[155] G. Musso, C. Olivetti, M. Cassader, and R. Gambino, “Obstructive Sleep Apnea-Hypopnea Syndrome and Nonalcoholic Fatty Liver Disease: Emerging Evidence and Mechanisms,” Seminars in Liver Disease 32 (2012): 49–64.

[156] G. Musso, M. Cassader, C. Olivetti, F. Rosina, G. Carbone, and R. Gambino, “Association of Obstructive Sleep Apnoea With the Presence and Severity of Non-Alcoholic Fatty Liver Disease. A Systematic Review and Meta-Analysis,” Obesity Reviews 14 (2013): 417–431.

[157] R. Lv, X. Liu, Y. Zhang, et al., “Pathophysiological Mechanisms and Therapeutic Approaches in Obstructive Sleep Apnea Syndrome,” Signal Transduction and Targeted Therapy 8 (2023): 218.

[158] D. J. Gottlieb and N. M. Punjabi, “Diagnosis and Management of Obstructive Sleep Apnea: A Review,” JAMA 323 (2020): 1389–1400.

[159] J. V. Rundo, “Obstructive Sleep Apnea Basics,” Cleveland Clinic Journal of Medicine 86 (2019): 2–9.

[160] S. C. Veasey and I. M. Rosen, “Obstructive Sleep Apnea in Adults,” New England Journal of Medicine 380 (2019): 1442–1449.

[161] C. Türkay, D. Ozol, B. Kasapoğlu, I. Kirbas, Z. Yıldırım, and R. Yiğitoğlu, “Influence of Obstructive Sleep Apnea on Fatty Liver Disease: Role of Chronic Intermittent Hypoxia,” Respiratory Care 57 (2012): 244–249.

[162] L. A. Barnes, Y. Xu, A. Sanchez-Azofra, et al., “Duration of Intermittent Hypoxia Impacts Metabolic Outcomes and Severity of Murine NAFLD,” Frontiers in Sleep 2 (2023): 1215944.

[163] O. A. Mesarwi, R. Loomba, and A. Malhotra, “Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease,” American Journal of Respiratory and Critical Care Medicine 199 (2019): 830–841.

[164] G. Musso, M. Cassader, F. Rosina, and R. Gambino, “Impact of Current Treatments on Liver Disease, Glucose Metabolism and Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic Review and Meta-Analysis of Randomised Trials,” Diabetologia 55 (2012): 885–904.

[165] W. N. Hannah Jr. and S. A. Harrison, “Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease,” Clinics in Liver Disease 20 (2016): 339–350.

[166] A. F Godoy-Matos, C. M. Valério, W. S. Silva Júnior, J. M. de Araujo-Neto, and M. C. Bertoluci, “2024 Update: The Brazilian Diabetes Society Position on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in People With Prediabetes or Type 2 Diabetes,” Diabetology & Metabolic Syndrome 16 (2024): 23.

[167] T. S. Dong, W. Katzka, J. C. Yang, et al., “Microbial Changes From Bariatric Surgery Alters Glucose-Dependent Insulinotropic Polypeptide and Prevents Fatty Liver Disease,” Gut Microbes 15 (2023): 2167170.

[168] T. L. Laursen, C. A. Hagemann, C. Wei, et al., “Bariatric Surgery in Patients With Non-Alcoholic Fatty Liver Disease—From Pathophysiology to Clinical Effects,” World Journal of Hepatology 11 (2019): 138–149.

[169] K. M. Wirth, A. C. Sheka, S. Kizy, et al., “Bariatric Surgery Is Associated With Decreased Progression of Nonalcoholic Fatty Liver Disease to Cirrhosis: A Retrospective Cohort Analysis,” Annals of Surgery 272 (2020): 32–39.

[170] A. M. Brown and A. D. Pryor, “Bariatric Surgery Decreases the Progression of Nonalcoholic Fatty Liver Disease to Cirrhosis,” Annals of Surgery 272 (2020): 40–41.

[171] A. Rühle, A. T. Billeter, and B. P. Müller-Stich, “Metabolic Surgery: Paradigm Shift in Metabolic Syndrome/Diabetes Therapy,” Visceral Medicine 38 (2022): 56–62.

[172] S. Buob, A. N. Johnston, and C. R. Webster, “Portal Hypertension: Pathophysiology, Diagnosis, and Treatment,” Journal of Veterinary Internal Medicine 25 (2011): 169–186.

[173] D. A. Simonetto, M. Liu, and P. S. Kamath, “Portal Hypertension and Related Complications: Diagnosis and Management,” Mayo Clinic Proceedings 94 (2019): 714–726.

[174] S. Saab, “Portal Hypertension,” Clinics in Liver Disease 23 (2019): xiii–xiv.

[175] S. Gioia, S. Nardelli, L. Ridola, and O. Riggio, “Causes and Management of Non-Cirrhotic Portal Hypertension,” Current Gastroenterology Reports 22 (2020): 56.

[176] R. Khanna and S. K. Sarin, “Non-Cirrhotic Portal Hypertension—Diagnosis and Management,” Journal of Hepatology 60 (2014): 421–441.

[177] M. Wong and R. W. Busuttil, “Surgery in Patients With Portal Hypertension,” Clinics in Liver Disease 23 (2019): 755–780.

[178] S. H. Luo, J. G. Chu, H. Huang, G. R. Zhao, and K. C. Yao, “Targeted Puncture of Left Branch of Intrahepatic Portal Vein in Transjugular Intrahepatic Portosystemic Shunt to Reduce Hepatic Encephalopathy,” World Journal of Gastroenterology 25 (2019): 1088–1099.

[179] D. A. Iannitti and J. M. Henderson, “Surgery in Portal Hypertension,” Baillieres Clinical Gastroenterology 11 (1997): 351–364.

[180] K. Pereira, A. F. Carrion, P. Martin, et al., “Current Diagnosis and Management of Post-Transjugular Intrahepatic Portosystemic Shunt Refractory Hepatic Encephalopathy,” Liver International 35 (2015): 2487–2494.

[181] D. Thabut, C. Bouzbib, L. Meunier, et al., “Diagnosis and Management of Hepatic Encephalopathy: The French Recommendations,” Liver International 43 (2023): 750–762.

[182] J. Wiltfang, W. Nolte, J. von Heppe, et al., “Sleep Disorders and Portal-Systemic Encephalopathy Following Transjugular Intrahepatic Portosystemic Stent Shunt in Patients With Liver Cirrhosis. Relation to Plasma Tryptophan,” Advances in Experimental Medicine and Biology 467 (1999): 169–176.

[183] Y. Eso, “Questionnaire-Based Approach to Sleep-Wake Disturbance in Patients With Chronic Liver Disease,” Hepatology Research 52 (2022): 327–328.

[184] J. Samanta, R. K. Dhiman, A. Khatri, et al., “Correlation Between Degree and Quality of Sleep Disturbance and the Level of Neuropsychiatric Impairment in Patients With Liver Cirrhosis,” Metabolic Brain Disease 28 (2013): 249–259.

[185] A. Bersagliere, I. D. Raduazzo, M. Nardi, et al., “Induced Hyperammonemia May Compromise the Ability to Generate Restful Sleep in Patients With Cirrhosis,” Hepatology 55 (2012): 869–878.

[186] D. Biyyala, R. Joseph, N. Varadharajan, Y. Krishnamoorthy, and V. Menon, “Incidence and Prevalence of Depressive, Anxiety, and Insomnia Symptoms Among Adult Liver Transplant Recipients: A Systematic Review and Meta-Analysis,” General Hospital Psychiatry 80 (2023): 26–34.

[187] M. Reilly-Spong, T. Park, and C. R. Gross, “Poor Sleep in Organ Transplant Recipients: Self-Reports and Actigraphy,” Clinical Transplantation 27 (2013): 901–913.

[188] M. Riedl, A. Kuhn, I. Krämer, E. Kolbe, and G. J. Kahaly, “Prospective, Systematically Recorded Mycophenolate Safety Data in Graves’ Orbitopathy,” Journal of Endocrinological Investigation 39 (2016): 687–694.

[189] K. M. Gunn, X. Skrabal Ross, M. McLoughlin, S. McDonald, and I. Olver, “The Psychosocial Experiences and Supportive Care Preferences of Organ Transplant Recipients and Their Carers Who Live in Regional Australia,” Australian Journal of Rural Health 29 (2021): 92–105.

[190] H. Kimura, S. Kishi, H. Narita, et al., “Comorbid Psychiatric Disorders and Long-Term Survival After Liver Transplantation in Transplant Facilities With a Psychiatric Consultation-Liaison Team: A Multicenter Retrospective Study,” BMC Gastroenterology [Electronic Resource] 23 (2023): 106.

[191] S. Lim, M. Choi, H. Kim, and J. M. Kim, “Sleep Quality and Related Factors Among Liver Transplant Recipients in Korea: A Cross-Sectional Study,” The Journal of Nursing Research 31 (2023): e286.

[192] R. Ochoa-Sanchez, F. Tamnanloo, and C. F. Rose, “Hepatic Encephalopathy: From Metabolic to Neurodegenerative,” Neurochemical Research 46 (2021): 2612–2625.

[193] P. Dellatore, M. Cheung, N. Y. Mahpour, A. Tawadros, and V. K. Rustgi, “Clinical Manifestations of Hepatic Encephalopathy,” Clinics in Liver Disease 24 (2020): 189–196.

[194] R. F. Butterworth, “Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology,” Drugs 79 (2019): 17–21.

[195] M. Bismuth, N. Funakoshi, J. F. Cadranel, and P. Blanc, “Hepatic Encephalopathy: From Pathophysiology to Therapeutic Management,” European Journal of Gastroenterology & Hepatology 23 (2011): 8–22.

[196] K. Kroupina, C. Bémeur, and C. F. Rose, “Amino Acids, Ammonia, and Hepatic Encephalopathy,” Analytical Biochemistry 649 (2022): 114696.

[197] R. S. Rahimi and D. C. Rockey, “Hepatic Encephalopathy: Pharmacological Therapies Targeting Ammonia,” Seminars in Liver Disease 36 (2016): 48–55.

[198] P. J. Parekh and L. A. Balart, “Ammonia and Its Role in the Pathogenesis of Hepatic Encephalopathy,” Clinics in Liver Disease 19 (2015): 529–537.

[199] E. A. Jones and K. D. Mullen, “Theories of the Pathogenesis of Hepatic Encephalopathy,” Clinics in Liver Disease 16 (2012): 7–26.

[200] R. T. Frederick, “Extent of Reversibility of Hepatic Encephalopathy Following Liver Transplantation,” Clinics in Liver Disease 16 (2012): 147–158.

[201] S. Kodali and B. M. McGuire, “Diagnosis and Management of Hepatic Encephalopathy in Fulminant Hepatic Failure,” Clinics in Liver Disease 19 (2015): 565–576.

[202] A. C. Anand and P. Singh, “Neurological Recovery After Recovery From Acute Liver Failure: Is It Complete?,” Journal of Clinical and Experimental Hepatology 9 (2019): 99–108.

[203] S. Sherlock, W. H. Summerskill, L. P. White, and E. A. Phear, “Portal-Systemic Encephalopathy; Neurological Complications of Liver Disease,” Lancet 267 (1954): 454–457.

[204] M. Ghabril, M. Jackson, R. Gotur, et al., “Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life,” Clinical Gastroenterology and Hepatology 15 (2017): 1271–1278.e1276.

[205] J. Córdoba, J. Cabrera, L. Lataif, P. Penev, P. Zee, and A. T. Blei, “High Prevalence of Sleep Disturbance in Cirrhosis,” Hepatology 27 (1998): 339–345.

[206] B. Mostacci, M. Ferlisi, A. Baldi Antognini, et al., “Sleep Disturbance and Daytime Sleepiness in Patients With Cirrhosis: A Case Control Study,” Neurological Sciences 29 (2008): 237–240.

[207] J. Singh, B. C. Sharma, V. Puri, S. Sachdeva, and S. Srivastava, “Sleep Disturbances in Patients of Liver Cirrhosis With Minimal Hepatic Encephalopathy Before and After Lactulose Therapy,” Metabolic Brain Disease 32 (2017): 595–605.

[208] A. T. Blei and J. Cordoba, “Practice Parameters Committee of the American College of Gastroenterology: Hepatic Encephalopathy,” American Journal of Gastroenterology 96 (2001): 1968–1976.

[209] S. Montagnese, A. Biancardi, S. Schiff, et al., “Different Biochemical Correlates for Different Neuropsychiatric Abnormalities in Patients With Cirrhosis,” Hepatology 53 (2011): 558–566.

[210] P. K. Li, K. H. Chu, K. M. Chow, et al., “Cross Sectional Survey on the Concerns and Anxiety of Patients Waiting for Organ Transplants,” Nephrology (Carlton, Vic.) 17 (2012): 514–518.

[211] E. M. Fredericks, D. Dore-Stites, S. Y. Calderon, et al., “Relationship Between Sleep Problems and Health-Related Quality of Life Among Pediatric Liver Transplant Recipients,” Liver Transplantation 18 (2012): 707–715.

[212] M. Akahoshi, T. Ichikawa, N. Taura, et al., “Sleep Disturbances and Quality of Life in Patients After Living Donor Liver Transplantation,” Transplantation Proceedings 46 (2014): 3515–3522.

[213] K. He, C. Shen, X. Chen, et al., “Health-Related Quality of Life and Sleep Among Chinese Children After Living Donor Liver Transplantation,” Pediatric Transplantation 19 (2015): 547–554.

[214] O. Ahmed, A. Lee, N. Vachharajani, et al., “Reviewing Patient-Reported Outcomes 1 Year After Orthotopic Liver Transplantation,” Journal of the American College of Surgeons 235 (2022): 69–77.

[215] S. B. Li, V. M. Damonte, C. Chen, et al., “Hyperexcitable Arousal Circuits Drive Sleep Instability During Aging,” Science 375 (2022): eabh3021.

[216] A. Vassalli and P. Franken, “Hypocretin (Orexin) Is Critical in Sustaining Theta/Gamma-Rich Waking Behaviors That Drive Sleep Need,” Proceedings of the National Academy of Sciences of the United States of America 114 (2017): E5464–E5473.

[217] M. Salemi, M. P. Mogavero, G. Lanza, L. M. Mongioi, A. E. Calogero, and R. Ferri, “Examples of Inverse Comorbidity Between Cancer and Neurodegenerative Diseases: A Possible Role for Noncoding RNA,” Cells 11 (2022): 1930.

[218] T. Xue, X. Wu, S. Chen, et al., “The Efficacy and Safety of Dual Orexin Receptor Antagonists in Primary Insomnia: A Systematic Review and Network Meta-Analysis,” Sleep Medicine Reviews 61 (2022): 101573.

[219] G. Lanza, M. Cantone, B. Lanuzza, et al., “Distinctive Patterns of Cortical Excitability to Transcranial Magnetic Stimulation in Obstructive Sleep Apnea Syndrome, Restless Legs Syndrome, Insomnia, and Sleep Deprivation,” Sleep Medicine Reviews 19 (2015): 39–50.

[220] S. K. Smith, M. Kafashan, R. L. Rios, et al., “Daytime Dexmedetomidine Sedation With Closed-Loop Acoustic Stimulation Alters Slow Wave Sleep Homeostasis in Healthy Adults,” BJA Open 10 (2024): 100276.

[221] R. L. Rios, M. Green, S. K. Smith, et al., “Propofol Enhancement of Slow Wave Sleep to Target the Nexus of Geriatric Depression and Cognitive Dysfunction: Protocol for a Phase I Open Label Trial,” BMJ Open 14 (2024): e087516.

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