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Pathological Consequences of Intermittent Hypoxia in the Central Nervous System

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Intermittent hypoxia (IH) is a frequent occurrence in clinical settings. In the last decades, evidence has emerged implicating the gas exchange alterations and sleep disruption associated with those disorders in the high prevalence of cognitive and behavioral deficits afflicting these patients. In an effort to better characterize the role of IH, and to identify potential mechanisms of IH‐induced central nervous system (CNS) dysfunction, a large number of rodent models have been recently developed. The cumulative evidence confirms that IH indeed induces a heterotopic pattern of injury in the brain, particularly affecting cortical, subcortical, and hippocampal regions, ultimately leading to neuronal apoptosis and activation of microglia. These IH‐induced deleterious processes exhibit substantial variability across the lifespan, are under substantial modulatory influences of diet, physical or intellectual activity, and genetic factors, and preferentially recruit oxidative stress and inflammatory pathways. © 2012 American Physiological Society. Compr Physiol 2:1767‐1777, 2012.

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Figure 1. Figure 1.

Schematic representation of the potential interactions between intermittent hypoxia (IH), hypercapnia, and sleep fragmentation associated with sleep breathing disorders and the thus far unknown effect of duration of these processes on either preservation of homeostasis or injury in the CNS. On the left side of the scheme are examples of factors associated with either potentiation or attenuation of the IH‐induced CNS dysfunction. On the right side of the figure are representative components of the thus far elucidated cascade of pro‐oxidative stress or inflammatory pathways that contribute to IH‐associated neuronal injury.

Figure 1.

Schematic representation of the potential interactions between intermittent hypoxia (IH), hypercapnia, and sleep fragmentation associated with sleep breathing disorders and the thus far unknown effect of duration of these processes on either preservation of homeostasis or injury in the CNS. On the left side of the scheme are examples of factors associated with either potentiation or attenuation of the IH‐induced CNS dysfunction. On the right side of the figure are representative components of the thus far elucidated cascade of pro‐oxidative stress or inflammatory pathways that contribute to IH‐associated neuronal injury.

 1. Albin RL, Greenamyre JT. Alternative excitotoxic hypotheses. Neurology 42: 733‐738, 1992.
 2. Alchanatis M, Deligiorgis N, Zias N, Amfilochiou A, Gotsis E, Karakatsani A, Papadimitriou A. Frontal brain lobe impairment in obstructive sleep apnoea: A proton MR spectroscopy study. Eur Respir J 24: 980‐986, 2004.
 3. Aloia MS, Sweet LH, Jerskey BA, Zimmerman M, Arnedt JT, Millman RP. Treatment effects on brain activity during a working memory task in obstructive sleep apnea. J Sleep Res 18: 404‐410, 2009.
 4. Andersen SL, Teicher MH. Sex differences in dopamine receptors and their relevance to ADHD. Neurosci Biobehav Rev 24: 137‐141, 2000.
 5. Angermuller S, Islinger M, Volkl A. Peroxisomes and reactive oxygen species, a lasting challenge. Histochem Cell Biol 131: 459‐463, 2009.
 6. Archbold KH, Borghesani PR, Mahurin RK, Kapur VK, Landis CA. Neural activation patterns during working memory tasks and OSA disease severity: Preliminary findings. J Clin Sleep Med 5: 21‐27, 2009.
 7. Arnardottir ES, Mackiewicz M, Gislason T, Teff KL, Pack AI. Molecular signatures of obstructive sleep apnea in adults: A review and perspective. Sleep 32: 447‐470, 2009.
 8. Avale ME, Falzone TL, Gelman DM, Low MJ, Grandy DK, Rubinstein M. The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol Psychiatry 9: 718‐726, 2004.
 9. Aviles‐Reyes RX, Angelo MF, Villarreal A, Rios H, Lazarowski A, Ramos AJ. Intermittent hypoxia during sleep induces reactive gliosis and limited neuronal death in rats: Implications for sleep apnea. J Neurochem 112: 854‐869, 2010.
 10. Ayalon L, Ancoli‐Israel S, Klemfuss Z, Shalauta MD, Drummond SP. Increased brain activation during verbal learning in obstructive sleep apnea. Neuroimage 31: 1817‐1825, 2006.
 11. Bartlett DJ, Rae C, Thompson CH, Byth K, Joffe DA, Enright T, Grunstein RR. Hippocampal area metabolites relate to severity and cognitive function in obstructive sleep apnea. Sleep Med 5: 593‐596, 2004.
 12. Bass JL, Corwin M, Gozal D, Moore C, Nishida H, Parker S, Schonwald A, Wilker RE, Stehle S, Kinane TB. The effect of chronic or intermittent hypoxia on cognition in childhood: A review of the evidence. Pediatrics 114: 805‐816, 2004.
 13. Bedard K, Krause KH. The NOX family of ROS‐generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 87: 245‐313, 2007.
 14. Beebe DW. Neurobehavioral morbidity associated with disordered breathing during sleep in children: A comprehensive review. Sleep 29: 1115‐1134, 2006.
 15. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: Towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 11: 1‐16, 2002.
 16. Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: A meta‐analysis of norm‐referenced and case‐controlled data. Sleep 26: 298‐307, 2003.
 17. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. J Physiol 555: 589‐606, 2004.
 18. Bliwise DL. Sleep apnea, APOE4 and Alzheimer's disease 20 years and counting? J Psychosom Res 53: 539‐546, 2002.
 19. Burckhardt IC, Gozal D, Dayyat E, Cheng Y, Li RC, Goldbart AD, Row BW. Green tea catechin polyphenols attenuate behavioral and oxidative responses to intermittent hypoxia. Am J Respir Crit Care Med 177: 1135‐1141, 2008.
 20. Castronovo V, Canessa N, Strambi LF, Aloia MS, Consonni M, Marelli S, Iadanza A, Bruschi A, Falini A, Cappa SF. Brain activation changes before and after PAP treatment in obstructive sleep apnea. Sleep 32: 1161‐1172, 2009.
 21. Catterall JR, Douglas NJ, Calverley PM, Brash HM, Brezinova V, Shapiro CM, Flenley DC. Irregular breathing and hypoxaemia during sleep in chronic stable asthma. Lancet 1: 301‐304, 1982.
 22. Cosentino FI, Bosco P, Drago V, Prestianni G, Lanuzza B, Iero I, Tripodi M, Spada RS, Toscano G, Caraci F, Ferri R. The APOE epsilon4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea. Sleep Med 9: 831‐839, 2008.
 23. Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: Neural and neurochemical substrates. Neurosci Biobehav Rev 28: 771‐784, 2004.
 24. Davies CW, Crosby JH, Mullins RL, Traill ZC, Anslow P, Davies RJ, Stradling JR. Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects. Sleep 24: 715‐720, 2001.
 25. Decary A, Rouleau I, Montplaisir J. Cognitive deficits associated with sleep apnea syndrome: A proposed neuropsychological test battery. Sleep 23: 369‐381, 2000.
 26. Decker MJ, Hue GE, Caudle WM, Miller GW, Keating GL, Rye DB. Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling. Neuroscience 117: 417‐425, 2003.
 27. Decker MJ, Jones KA, Solomon IG, Keating GL, Rye DB. Reduced extracellular dopamine and increased responsiveness to novelty: Neurochemical and behavioral sequelae of intermittent hypoxia. Sleep 28: 169‐176, 2005.
 28. Douglas NJ, Calverley PM, Leggett RJ, Brash HM, Flenley DC, Brezinova V. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1: 1‐4, 1979.
 29. Douglas RM, Miyasaka N, Takahashi K, Latuszek‐Barrantes A, Haddad GG, Hetherington HP. Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus. Am J Physiol Regul Integr Comp Physiol 292: R1254‐R1259, 2007.
 30. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 82: 47‐95, 2002.
 31. du Plessis AJ, Johnston MV. Hypoxic‐ischemic brain injury in the newborn. Cellular mechanisms and potential strategies for neuroprotection. Clin Perinatol 24: 627‐654, 1997.
 32. Duncan AJ, Heales SJ. Nitric oxide and neurological disorders. Mol Aspects Med 26: 67‐96, 2005.
 33. Farre R, Nacher M, Serrano‐Mollar A, Galdiz JB, Alvarez FJ, Navajas D, Montserrat JM. Rat model of chronic recurrent airway obstructions to study the sleep apnea syndrome. Sleep 30: 930‐933, 2007.
 34. Ficker JH, Feistel H, Moller C, Merkl M, Dertinger S, Siegfried W, Hahn EG. Changes in regional CNS perfusion in obstructive sleep apnea syndrome: Initial SPECT studies with injected nocturnal 99mTc‐HMPAO. Pneumologie 51: 926‐930, 1997.
 35. Francis PW, Muller NL, Gurwitz D, Milligan DW, Levison H, Bryan AC. Hemoglobin desaturation: Its occurrence during sleep in patients with cystic fibrosis. Am J Dis Child 134: 734‐740, 1980.
 36. Gilman S, Chervin RD, Koeppe RA, Consens FB, Little R, An H, Junck L, Heumann M. Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA. Neurology 61: 35‐39, 2003.
 37. Goldbart A, Cheng ZJ, Brittian KR, Gozal D. Intermittent hypoxia induces time‐dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat. Neurobiol Dis 14: 440‐446, 2003.
 38. Goldbart A, Row BW, Kheirandish L, Schurr A, Gozal E, Guo SZ, Payne RS, Cheng Z, Brittian KR, Gozal D. Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: Water maze performance correlates. Neuroscience 122: 585‐590, 2003.
 39. Goldbart AD, Row BW, Kheirandish‐Gozal L, Cheng Y, Brittian KR, Gozal D. High fat/refined carbohydrate diet enhances the susceptibility to spatial learning deficits in rats exposed to intermittent hypoxia. Brain Res 1090: 190‐196, 2006.
 40. Gozal D. Sleep‐disordered breathing and school performance in children. Pediatrics 102: 616‐620, 1998.
 41. Gozal D. Morbidity of obstructive sleep apnea in children: Facts and theory. Sleep Breath 5: 35‐42, 2001.
 42. Gozal D. Obstructive sleep apnea in children: Implications for the developing central nervous system. Semin Pediatr Neurol 15: 100‐106, 2008.
 43. Gozal D, Capdevila OS, Kheirandish‐Gozal L, Crabtree VM. APOE epsilon 4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology 69: 243‐249, 2007.
 44. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 21: 2442‐2450, 2001.
 45. Gozal D, Kheirandish L. Oxidant stress and inflammation in the snoring child: Confluent pathways to upper airway pathogenesis and end‐organ morbidity. Sleep Med Rev 10: 83‐96, 2006.
 46. Gozal D, Nair D, Goldbart AD. Physical activity attenuates intermittent hypoxia‐induced spatial learning deficits and oxidative stress. Am J Respir Crit Care Med 182: 104‐112, 2010.
 47. Gozal D, Pope DW Jr. Snoring during early childhood and academic performance at ages thirteen to fourteen years. Pediatrics 107: 1394‐1399, 2001.
 48. Gozal D, Row BW, Gozal E, Kheirandish L, Neville JJ, Brittian KR, Sachleben LR Jr, Guo SZ. Temporal aspects of spatial task performance during intermittent hypoxia in the rat: Evidence for neurogenesis. Eur J Neurosci 18: 2335‐2342, 2003.
 49. Gozal D, Row BW, Kheirandish L, Liu R, Guo SZ, Qiang F, Brittian KR. Increased susceptibility to intermittent hypoxia in aging rats: Changes in proteasomal activity, neuronal apoptosis and spatial function. J Neurochem 86: 1545‐1552, 2003.
 50. Gozal E, Gozal D, Pierce WM, Thongboonkerd V, Scherzer JA, Sachleben LR Jr, Brittian KR, Guo SZ, Cai J, Klein JB. Proteomic analysis of CA1 and CA3 regions of rat hippocampus and differential susceptibility to intermittent hypoxia. J Neurochem 83: 331‐345, 2002.
 51. Gozal E, Row BW, Schurr A, Gozal D. Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat. Neurosci Lett 305: 197‐201, 2001.
 52. Gozal E, Sachleben LR Jr, Rane MJ, Vega C, Gozal D. Mild sustained and intermittent hypoxia induce apoptosis in PC‐12 cells via different mechanisms. Am J Physiol Cell Physiol 288: C535‐C542, 2005.
 53. Gray PH, Tudehope DI, Masel JP, Burns YR, Mohay HA, O'Callaghan MJ, Williams GM. Perinatal hypoxic‐ischaemic brain injury: Prediction of outcome. Dev Med Child Neurol 35: 965‐973, 1993.
 54. Halbower AC, Degaonkar M, Barker PB, Earley CJ, Marcus CL, Smith PL, Prahme MC, Mahone EM. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury. PLoS Med 3: e301, 2006.
 55. Halliwell B. Phagocyte‐derived reactive species: Salvation or suicide? Trends Biochem Sci 31: 509‐515, 2006.
 56. Hambrecht VS, Vlisides PE, Row BW, Gozal D, Baghdoyan HA, Lydic R. Hypoxia modulates cholinergic but not opioid activation of G proteins in rat hippocampus. Hippocampus 17: 934‐942, 2007.
 57. Hambrecht VS, Vlisides PE, Row BW, Gozal D, Baghdoyan HA, Lydic R. G proteins in rat prefrontal cortex (PFC) are differentially activated as a function of oxygen status and PFC region. J Chem Neuroanat 37: 112‐117, 2009.
 58. Heales SJ, Lam AA, Duncan AJ, Land JM. Neurodegeneration or neuroprotection: The pivotal role of astrocytes. Neurochem Res 29: 513‐519, 2004.
 59. Herlenius E, Lagercrantz H. Development of neurotransmitter systems during critical periods. Exp Neurol 190(Suppl 1): S8‐S21, 2004.
 60. Hoffstein V, Herridge M, Mateika S, Redline S, Strohl KP. Hematocrit levels in sleep apnea. Chest 106: 787‐791, 1994.
 61. Hui‐guo L, Kui L, Yan‐ning Z, Yong‐jian X. Apocynin attenuate spatial learning deficits and oxidative responses to intermittent hypoxia. Sleep Med 11: 205‐212, 2010.
 62. Hung MW, Tipoe GL, Poon AM, Reiter RJ, Fung ML. Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia. J Pineal Res 44: 214‐221, 2008.
 63. Joo EY, Tae WS, Lee MJ, Kang JW, Park HS, Lee JY, Suh M, Hong SB. Reduced brain gray matter concentration in patients with obstructive sleep apnea syndrome. Sleep 33: 235‐241, 2010.
 64. Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM Jr, Mignot E. Association between apolipoprotein E epsilon4 and sleep‐disordered breathing in adults. JAMA 285: 2888‐2890, 2001.
 65. Kales A, Caldwell AB, Cadieux RJ, Vela‐Bueno A, Ruch LG, Mayes SD. Severe obstructive sleep apnea–II: Associated psychopathology and psychosocial consequences. J Chronic Dis 38: 427‐434, 1985.
 66. Kamba M, Inoue Y, Higami S, Suto Y, Ogawa T, Chen W. Cerebral metabolic impairment in patients with obstructive sleep apnoea: An independent association of obstructive sleep apnoea with white matter change. J Neurol Neurosurg Psychiatry 71: 334‐339, 2001.
 67. Kamba M, Suto Y, Ohta Y, Inoue Y, Matsuda E. Cerebral metabolism in sleep apnea. Evaluation by magnetic resonance spectroscopy. Am J Respir Crit Care Med 156: 296‐298, 1997.
 68. Kanaan A, Farahani R, Douglas RM, Lamanna JC, Haddad GG. Effect of chronic continuous or intermittent hypoxia and reoxygenation on cerebral capillary density and myelination. Am J Physiol Regul Integr Comp Physiol 290: R1105‐R1114, 2006.
 69. Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long‐term environmental enrichment. Ann Neurol 52: 135‐143, 2002.
 70. Khalyfa A, Serpero LD, Kheirandish‐Gozal L, Capdevila OS, Gozal D. TNF‐alpha gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea. J Pediatr 158(1): 77‐82, 2011.
 71. Kheirandish L, Gozal D. Neurocognitive dysfunction in children with sleep disorders. Dev Sci 9: 388‐399, 2006.
 72. Kheirandish L, Gozal D, Pequignot JM, Pequignot J, Row BW. Intermittent hypoxia during development induces long‐term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex. Pediatr Res 58: 594‐599, 2005.
 73. Kheirandish L, Row BW, Li RC, Brittian KR, Gozal D. Apolipoprotein E‐deficient mice exhibit increased vulnerability to intermittent hypoxia‐induced spatial learning deficits. Sleep 28: 1412‐1417, 2005.
 74. Kheirandish‐Gozal L, De Jong MR, Spruyt K, Chamuleau SA, Gozal D. Obstructive sleep apnoea is associated with impaired pictorial memory task acquisition and retention in children. Eur Respir J 36: 164‐169, 2010.
 75. Klein JB, Barati MT, Wu R, Gozal D, Sachleben LR Jr, Kausar H, Trent JO, Gozal E, Rane MJ. Akt‐mediated valosin‐containing protein 97 phosphorylation regulates its association with ubiquitinated proteins. J Biol Chem 280: 31870‐31881, 2005.
 76. Klein JB, Gozal D, Pierce WM, Thongboonkerd V, Scherzer JA, Sachleben LR, Guo SZ, Cai J, Gozal E. Proteomic identification of a novel protein regulated in CA1 and CA3 hippocampal regions during intermittent hypoxia. Respir Physiol Neurobiol 136: 91‐103, 2003.
 77. Kohler MJ, Lushington K, Kennedy JD. Neurocognitive performance and behavior before and after treatment for sleep‐disordered breathing in children. Nature and Science of Sleep 2: 159‐185, 2010.
 78. Krageloh‐Mann I, Toft P, Lunding J, Andresen J, Pryds O, Lou HC. Brain lesions in preterms: Origin, consequences and compensation. Acta Paediatr 88: 897‐908, 1999.
 79. Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem 285: 667‐674, 2010.
 80. Kumar R, Macey PM, Cross RL, Woo MA, Yan‐Go FL, Harper RM. Neural alterations associated with anxiety symptoms in obstructive sleep apnea syndrome. Depress Anxiety 26: 480‐491, 2009.
 81. Lavie L. Obstructive sleep apnoea syndrome–an oxidative stress disorder. Sleep Med Rev 7: 35‐51, 2003.
 82. Li J, Savransky V, Nanayakkara A, Smith PL, O'Donnell CP, Polotsky VY. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 102: 557‐563, 2007.
 83. Li JM, Shah AM. Endothelial cell superoxide generation: Regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287: R1014‐R1030, 2004.
 84. Li R, Bao G, el‐Mallakh RS, Fletcher EC. Effects of chronic episodic hypoxia on monoamine metabolism and motor activity. Physiol Behav 60: 1071‐1076, 1996.
 85. Li RC, Row BW, Gozal E, Kheirandish L, Fan Q, Brittian KR, Guo SZ, Sachleben LR Jr, Gozal D. Cyclooxygenase 2 and intermittent hypoxia‐induced spatial deficits in the rat. Am J Respir Crit Care Med 168: 469‐475, 2003.
 86. Li RC, Row BW, Kheirandish L, Brittian KR, Gozal E, Guo SZ, Sachleben LR Jr, Gozal D. Nitric oxide synthase and intermittent hypoxia‐induced spatial learning deficits in the rat. Neurobiol Dis 17: 44‐53, 2004.
 87. Lou HC. Etiology and pathogenesis of attention‐deficit hyperactivity disorder (ADHD): Significance of prematurity and perinatal hypoxic‐haemodynamic encephalopathy. Acta Paediatr 85: 1266‐1271, 1996.
 88. Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: Identification of a cellular activation mechanism. Exp Neurol 171: 29‐45, 2001.
 89. Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, Harper RK, Yan‐Go FL, Harper RM. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 166: 1382‐1387, 2002.
 90. Macey PM, Kumar R, Woo MA, Valladares EM, Yan‐Go FL, Harper RM. Brain structural changes in obstructive sleep apnea. Sleep 31: 967‐977, 2008.
 91. McGuire M, Zhang Y, White DP, Ling L. Effect of hypoxic episode number and severity on ventilatory long‐term facilitation in awake rats. J Appl Physiol 93: 2155‐2161, 2002.
 92. Mill J, Caspi A, Williams BS, Craig I, Taylor A, Polo‐Tomas M, Berridge CW, Poulton R, Moffitt TE. Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention‐deficit/hyperactivity disorder: Evidence from 2 birth cohorts. Arch Gen Psychiatry 63: 462‐469, 2006.
 93. Mill J, Fisher N, Curran S, Richards S, Taylor E, Asherson P. Polymorphisms in the dopamine D4 receptor gene and attention‐deficit hyperactivity disorder. Neuroreport 14: 1463‐1466, 2003.
 94. Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Oda N, Tanaka A, Yamamoto M, Ohta S, O'Donnell CP, Adachi M. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med 175: 612‐617, 2007.
 95. Miyashita Y. Cognitive memory: Cellular and network machineries and their top‐down control. Science 306: 435‐440, 2004.
 96. Mohammed AH, Henriksson BG, Soderstrom S, Ebendal T, Olsson T, Seckl JR. Environmental influences on the central nervous system and their implications for the aging rat. Behav Brain Res 57: 183‐191, 1993.
 97. Morrell MJ, Twigg G. Neural consequences of sleep disordered breathing: The role of intermittent hypoxia. Adv Exp Med Biol 588: 75‐88, 2006.
 98. Muralikrishna Adibhatla R, Hatcher JF. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40: 376‐387, 2006.
 99. Nishibayashi M, Miyamoto M, Miyamoto T, Suzuki K, Hirata K. Correlation between severity of obstructive sleep apnea and prevalence of silent cerebrovascular lesions. J Clin Sleep Med 4: 242‐247, 2008.
 100. Nowak M, Kornhuber J, Meyrer R. Daytime impairment and neurodegeneration in OSAS. Sleep 29: 1521‐1530, 2006.
 101. Nyakas C, Buwalda B, Kramers RJ, Traber J, Luiten PG. Postnatal development of hippocampal and neocortical cholinergic and serotonergic innervation in rat: Effects of nitrite‐induced prenatal hypoxia and nimodipine treatment. Neuroscience 59: 541‐559, 1994.
 102. Nyakas C, Buwalda B, Luiten PG. Hypoxia and brain development. Prog Neurobiol 49: 1‐51, 1996.
 103. Nyakas C, Markel E, Schuurman T, Luiten PG. Impaired learning and abnormal open‐field behaviours of rats after early postnatal anoxia and the beneficial effect of the calcium antagonist nimodipine. Eur J Neurosci 3: 168‐174, 1991.
 104. O'Brien LM, Mervis CB, Holbrook CR, Bruner JL, Smith NH, McNally N, McClimment MC, Gozal D. Neurobehavioral correlates of sleep‐disordered breathing in children. J Sleep Res 13: 165‐172, 2004.
 105. O'Donoghue FJ, Briellmann RS, Rochford PD, Abbott DF, Pell GS, Chan CH, Tarquinio N, Jackson GD, Pierce RJ. Cerebral structural changes in severe obstructive sleep apnea. Am J Respir Crit Care Med 171: 1185‐1190, 2005.
 106. O'Hara R, Schroder CM, Kraemer HC, Kryla N, Cao C, Miller E, Schatzberg AF, Yesavage JA, Murphy GM Jr. Nocturnal sleep apnea/hypopnea is associated with lower memory performance in APOE epsilon4 carriers. Neurology 65: 642‐644, 2005.
 107. Owens JA, Mehlenbeck R, Lee J, King MM. Effect of weight, sleep duration, and comorbid sleep disorders on behavioral outcomes in children with sleep‐disordered breathing. Arch Pediatr Adolesc Med 162: 313‐321, 2008.
 108. Ozaki M, Haga S, Zhang HQ, Irani K, Suzuki S. Inhibition of hypoxia/reoxygenation‐induced oxidative stress in HGF‐stimulated antiapoptotic signaling: Role of PI3‐K and Akt kinase upon rac1. Cell Death Differ 10: 508‐515, 2003.
 109. Palmer LJ, Redline S. Genomic approaches to understanding obstructive sleep apnea. Respir Physiol Neurobiol 135: 187‐205, 2003.
 110. Partinen M, Kaprio J, Koskenvuo M, Putkonen P, Langinvainio H. Genetic and environmental determination of human sleep. Sleep 6: 179‐185, 1983.
 111. Partinen M, Telakivi T. Epidemiology of obstructive sleep apnea syndrome. Sleep 15: S1‐S4, 1992.
 112. Patel SR. The search for apnea genes. Sleep 32: 1414‐1415, 2009.
 113. Payne RS, Goldbart A, Gozal D, Schurr A. Effect of intermittent hypoxia on long‐term potentiation in rat hippocampal slices. Brain Res 1029: 195‐199, 2004.
 114. Perez‐Chada D, Perez‐Lloret S, Videla AJ, Cardinali D, Bergna MA, Fernandez‐Acquier M, Larrateguy L, Zabert GE, Drake C. Sleep disordered breathing and daytime sleepiness are associated with poor academic performance in teenagers. A study using the Pediatric Daytime Sleepiness Scale (PDSS). Sleep 30: 1698‐1703, 2007.
 115. Perry JC, D'Almeida V, Antunes IB, Tufik S. Distinct behavioral and neurochemical alterations induced by intermittent hypoxia or paradoxical sleep deprivation in rats. Prog Neuropsychopharmacol Biol Psychiatry 32: 87‐94, 2008.
 116. Perry JC, D'Almeida V, Lima MM, Godoi FR, Vital MA, Oliveira MG, Tufik S. Intermittent hypoxia and sleep restriction: Motor, cognitive and neurochemical alterations in rats. Behav Brain Res 189: 373‐380, 2008.
 117. Pichiule P, Chavez JC, Boero J, Arregui A. Chronic hypoxia induces modification of the N‐methyl‐D‐aspartate receptor in rat brain. Neurosci Lett 218: 83‐86, 1996.
 118. Prabhakar NR. Oxygen sensing during intermittent hypoxia: Cellular and molecular mechanisms. J Appl Physiol 90: 1986‐1994, 2001.
 119. Prabhakar NR, Kline DD. Ventilatory changes during intermittent hypoxia: Importance of pattern and duration. High Alt Med Biol 3: 195‐204, 2002.
 120. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol 99: 1998‐2007, 2005.
 121. Rae C, Bartlett DJ, Yang Q, Walton D, Denotti A, Sachinwalla T, Grunstein RR. Dynamic changes in brain bioenergetics during obstructive sleep apnea. J Cereb Blood Flow Metab 29: 1421‐1428, 2009.
 122. Ramanathan L, Gozal D, Siegel JM. Antioxidant responses to chronic hypoxia in the rat cerebellum and pons. J Neurochem 93: 47‐52, 2005.
 123. Reher C, Kuny KD, Pantalitschka T, Urschitz MS, Poets CF. Randomised crossover trial of different postural interventions on bradycardia and intermittent hypoxia in preterm infants. Arch Dis Child Fetal Neonatal Ed 93: F289‐F291, 2008.
 124. Roehrs T, Merrion M, Pedrosi B, Stepanski E, Zorick F, Roth T. Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep 18: 382‐388, 1995.
 125. Row BW. Intermittent hypoxia and behavior: Is dopamine to blame? Sleep 28: 165‐167, 2005.
 126. Row BW, Goldbart A, Gozal E, Gozal D. Spatial pre‐training attenuates hippocampal impairments in rats exposed to intermittent hypoxia. Neurosci Lett 339: 67‐71, 2003.
 127. Row BW, Kheirandish L, Cheng Y, Rowell PP, Gozal D. Impaired spatial working memory and altered choline acetyltransferase (CHAT) immunoreactivity and nicotinic receptor binding in rats exposed to intermittent hypoxia during sleep. Behav Brain Res 177: 308‐314, 2007.
 128. Row BW, Kheirandish L, Li RC, Guo SZ, Brittian KR, Hardy M, Bazan NG, Gozal D. Platelet‐activating factor receptor‐deficient mice are protected from experimental sleep apnea‐induced learning deficits. J Neurochem 89: 189‐196, 2004.
 129. Row BW, Kheirandish L, Neville JJ, Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr Res 52: 449‐453, 2002.
 130. Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 167: 1548‐1553, 2003.
 131. Sanfilippo‐Cohn B, Lai S, Zhan G, Fenik P, Pratico D, Mazza E, Veasey SC. Sex differences in susceptibility to oxidative injury and sleepiness from intermittent hypoxia. Sleep 29: 152‐159, 2006.
 132. Santos CX, Tanaka LY, Wosniak J, Laurindo FR. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: Roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal 11: 2409‐2427, 2009.
 133. Silvestri R, Gagliano A, Arico I, Calarese T, Cedro C, Bruni O, Condurso R, Germano E, Gervasi G, Siracusano R, Vita G, Bramanti P. Sleep disorders in children with Attention‐Deficit/Hyperactivity Disorder (ADHD) recorded overnight by video‐polysomnography. Sleep Med 10: 1132‐1138, 2009.
 134. Simonova Z, Sterbova K, Brozek G, Komarek V, Sykova E. Postnatal hypobaric hypoxia in rats impairs water maze learning and the morphology of neurones and macroglia in cortex and hippocampus. Behav Brain Res 141: 195‐205, 2003.
 135. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA 275: 528‐532, 1996.
 136. Spruyt K, Capdevila OS, Kheirandish‐Gozal L, Gozal D. Inefficient or insufficient encoding as potential primary deficit in neurodevelopmental performance among children with OSA. Dev Neuropsychol 34: 601‐614, 2009.
 137. Suratt PM, Barth JT, Diamond R, D'Andrea L, Nikova M, Perriello VA Jr, Carskadon MA, Rembold C. Reduced time in bed and obstructive sleep‐disordered breathing in children are associated with cognitive impairment. Pediatrics 119: 320‐329, 2007.
 138. Sweet LH, Jerskey BA, Aloia MS. Default network response to a working memory challenge after withdrawal of continuous positive airway pressure treatment for obstructive sleep apnea. Brain Imaging Behav 4: 155‐163, 2010.
 139. Tagaito Y, Polotsky VY, Campen MJ, Wilson JA, Balbir A, Smith PL, Schwartz AR, O'Donnell CP. A model of sleep‐disordered breathing in the C57BL/6J mouse. J Appl Physiol 91: 2758‐2766, 2001.
 140. Taheri S, Mignot E. The genetics of sleep disorders. Lancet Neurol 1: 242‐250, 2002.
 141. Thakre TP, Mamtani MR, Kulkarni H. Lack of association of the APOE epsilon 4 allele with the risk of obstructive sleep apnea: Meta‐analysis and meta‐regression. Sleep 32: 1507‐1511, 2009.
 142. Thomas RJ, Rosen BR, Stern CE, Weiss JW, Kwong KK. Functional imaging of working memory in obstructive sleep‐disordered breathing. J Appl Physiol 98: 2226‐2234, 2005.
 143. Tjong YW, Li M, Hung MW, Wang K, Fung ML. Nitric oxide deficit in chronic intermittent hypoxia impairs large conductance calcium‐activated potassium channel activity in rat hippocampal neurons. Free Radic Biol Med 44: 547‐557, 2008.
 144. Torasdotter M, Metsis M, Henriksson BG, Winblad B, Mohammed AH. Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus. Behav Brain Res 93: 83‐90, 1998.
 145. Towfighi J, Mauger D, Vannucci RC, Vannucci SJ. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia‐ischemia: A light microscopic study. Brain Res Dev Brain Res 100: 149‐160, 1997.
 146. Tuor UI, Del Bigio MR, Chumas PD. Brain damage due to cerebral hypoxia/ischemia in the neonate: Pathology and pharmacological modification. Cerebrovasc Brain Metab Rev 8: 159‐193, 1996.
 147. Vannucci RC, Vannucci SJ. A model of perinatal hypoxic‐ischemic brain damage. Ann N Y Acad Sci 835: 234‐249, 1997.
 148. Veasey SC, Davis CW, Fenik P, Zhan G, Hsu YJ, Pratico D, Gow A. Long‐term intermittent hypoxia in mice: Protracted hypersomnolence with oxidative injury to sleep‐wake brain regions. Sleep 27: 194‐201, 2004.
 149. Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 9: 211‐224, 2005.
 150. Viggiano D, Ruocco LA, Arcieri S, Sadile AG. Involvement of norepinephrine in the control of activity and attentive processes in animal models of attention deficit hyperactivity disorder. Neural Plast 11: 133‐149, 2004.
 151. Viggiano D, Vallone D, Sadile A. Dysfunctions in dopamine systems and ADHD: Evidence from animals and modeling. Neural Plast 11: 97‐114, 2004.
 152. Vijay R, Kaushal N, Gozal D. Sleep fragmentation differentially modifies EEG delta power during slow wave sleep in socially isolated and paired mice. Sleep Science 2: 64‐75, 2009.
 153. Vlassara H. The AGE‐receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev 17: 436‐443, 2001.
 154. Wang Q, Tompkins KD, Simonyi A, Korthuis RJ, Sun AY, Sun GY. Apocynin protects against global cerebral ischemia‐reperfusion‐induced oxidative stress and injury in the gerbil hippocampus. Brain Res 1090: 182‐189, 2006.
 155. Waters KA, Gozal D. Responses to hypoxia during early development. Respir Physiol Neurobiol 136: 115‐129, 2003.
 156. Wei JL, Bond J, Mayo MS, Smith HJ, Reese M, Weatherly RA. Improved behavior and sleep after adenotonsillectomy in children with sleep‐disordered breathing: Long‐term follow‐up. Arch Otolaryngol Head Neck Surg 135: 642‐646, 2009.
 157. Williams GV, Castner SA. Under the curve: Critical issues for elucidating D1 receptor function in working memory. Neuroscience 139: 263‐276, 2006.
 158. Xie H, Leung KL, Chen L, Chan YS, Ng PC, Fok TF, Wing YK, Ke Y, Li AM, Yung WH. Brain‐derived neurotrophic factor rescues and prevents chronic intermittent hypoxia‐induced impairment of hippocampal long‐term synaptic plasticity. Neurobiol Dis 40: 155‐162, 2010.
 159. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L, Gozal D, Liu R. Increased oxidative stress is associated with chronic intermittent hypoxia‐mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 126: 313‐323, 2004.
 160. Yaouhi K, Bertran F, Clochon P, Mezenge F, Denise P, Foret J, Eustache F, Desgranges B. A combined neuropsychological and brain imaging study of obstructive sleep apnea. J Sleep Res 18: 36‐48, 2009.
 161. Young D, Lawlor PA, Leone P, Dragunow M, During MJ. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5: 448‐453, 1999.
 162. Zappitelli M, Pinto T, Grizenko N. Pre‐, peri‐, and postnatal trauma in subjects with attention‐deficit hyperactivity disorder. Can J Psychiatry 46: 542‐548, 2001.
 163. Zhan G, Fenik P, Pratico D, Veasey SC. Inducible nitric oxide synthase in long‐term intermittent hypoxia: Hypersomnolence and brain injury. Am J Respir Crit Care Med 171: 1414‐1420, 2005.
 164. Zhan G, Serrano F, Fenik P, Hsu R, Kong L, Pratico D, Klann E, Veasey SC. NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 172: 921‐929, 2005.
 165. Zhang K, Tarazi FI, Baldessarini RJ. Role of dopamine (D4) receptors in motor hyperactivity induced by neonatal 6‐hydroxydopamine lesions in rats. Neuropsychopharmacology 25: 624‐632, 2001.

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Shelley X.L. Zhang, Yang Wang, David Gozal. Pathological Consequences of Intermittent Hypoxia in the Central Nervous System. Compr Physiol 2012, 2: 1767-1777. doi: 10.1002/cphy.c100060