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Effects of hypoxia on the brain: Neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea

  • SHAWN D. GALE (a1) and RAMONA O. HOPKINS (a2) (a3)


Hypoxia damages multiple organ systems especially those with high oxygen utilization such as the central nervous system. The purpose of this study was to compare the neuropathological and neuropsychological effects of hypoxia in patients with either carbon monoxide poisoning or obstructive sleep apnea. Neuroimaging revealed evidence of hippocampal atrophy in both groups although a linear relationship between hippocampal volume and memory performance was found only for selected tests and only in the sleep apnea group. There were significant correlations between hippocampal volume and performance on measures related to nonverbal/information processing. Generalized brain atrophy, as measured by the ventricle-to-brain ratio, was more common in the carbon monoxide poisoning group compared to the obstructive sleep apnea group. Performance on tests of executive function improved following treatment with nasal continuous positive airway pressure treatment in the obstructive sleep apnea group but there was no associated improvement in general intellectual function. We found that hypoxia due to obstructive sleep apnea and CO poisoning resulted in neuropathological changes and neuropsychological impairments. The observed group differences provide insight into the relationship between etiology of injury, neuropathological changes, and clinical presentation. (JINS, 2004, 10, 60–71.)


Corresponding author

Reprint requests to: Shawn D. Gale, Ph.D., ABPP-Cn, Department of Clinical Neuropsychology, Barrow Neurological Institute, 222 W. Thomas Road, Suite 315, Phoenix, Arizona 85013. E-mail:


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Agency for Health Care Policy and Research. (1998). Systematic Review of the Literature Regarding the Diagnosis of Sleep Apnea. Summary, Evidence Report/Technology Assessment: Number 1, December 1998. Rockville, MD. Retrieved from
Altman, D.G. (1991). Practical statistics for medical research. London: Chapman and Hall.
Barbe, F., Mayorala, L.R., Duran, J., Masa, J.F., Maimo, A., Montserrat, J.M., Monasterio, C., Bosch, M., Ladaria, A., Rubio, M., Rubio, R., Medinas, M., Hernandez, L., Vidal, S., Douglas, N.J., & Agusti, A.G.N. (2001). Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. Annals of Internal Medicine, 134, 10151023.
Barker, L.H., Bigler, E.D., Johnson, S.C., Anderson, C.V., Russo, A.A., Boineau, B., & Blatter, D.D. (1999). Polysubstance abuse and traumatic brain injury: Quantitative magnetic resonance imaging and neuropsychological outcome in older adolescents and young adults. Journal of the International Neuropsycholgical Society, 5, 593608.
Barth, J.T., Findley, L.J., Zillmer, E.A., Gideon, D.A., & Suratt, P.M. (1993). Obstructive sleep apnea, hypoxemia, and personality functioning: Implications for medical psychotherapy assessment. Advances in Medical Psychotherapy, 6, 2936.
Beck, A.T. (1987). Beck Depression Inventory. San Antonio, TX: The Psychological Corporation.
Beck, A.T. & Steer, R.A. (1993). Beck Anxiety Inventory. San Antonio, TX: The Psychological Corporation.
Bédard, M.A., Montplaisir, J., Malo, J., Richer, F., & Rouleau, I. (1993). Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with nasal continuous positive airway pressure (CPAP). Journal of Clinical and Experimental Neuropsychology, 15, 330341.
Bédard, M., Montplaisir, J., Richer, F., Rouleau, I., & Malo, J. (1991). Obstructive sleep apnea syndrome: Pathogenesis of neuropsychological deficits. Journal of Clinical and Experimental Neuropsychology, 13, 950964.
Beebe, D.W. & Gozal, D. (2002). Obstructive sleep apnea and the prefrontal cortex: Towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. Journal of Sleep Research, 11, 116.
Berry, D.T.R., Webb, W.B., Block, A.J., Bauer, R.M., & Switzer, D.A. (1986). Nocturnal hypoxia and neuropsychological variables. Journal of Clinical and Experimental Neuropsychology, 8, 229238.
Bigler, E.D., Lowry, C.M., Anderson, C.V., Johnson, S.C., Terry, J., & Steed, M. (2000). Dementia, quantitative neuroimaging, and apolipoprotein E genotype. American Journal of Neuroradiology, 21, 18571868.
Bigler, E.D., Blatter, D.D., Anderson, C.V., Johnson, S.C., Gale, S.D., Hopkins, R.O., & Burnett, B. (1997). Hippocampal volume in normal aging and traumatic brain injury. American Journal of Neuroradiology, 18, 1123.
Biomedical Imaging Resource. (1993). ANALYZE 6.0 [Computer software]. Rochester, MN: Mayo Foundation.
Blatter, D.D., Bigler, E.D., Gale, S.D., Johnson, S.C., Anderson, C.V., Burnett, B.M., Ryser, D., Macnamara, S.E., & Bailey, B.J. (1997). MRI based brain and CSF quantification following traumatic brain injury: Correlation with neuropsychological outcome. American Journal of Neuroradiology, 18, 110.
Blatter, D.D., Bigler, E.D., Gale, S.D., Johnson, S.C., Anderson, C.V., Burnett, B.M., Parker, N., Kurth, S., & Horn, S.D. (1995). Quantitative volumetric analysis of brain MRI: Normative database spanning five decades of life. American Journal of Neuroradiology, 16, 241251.
Bliwise, D.L., King, A.C., & Harris, R.B. (1994). Habitual sleep durations and health in a 50–65 year old population. Journal of Clinical Epidemiology, 47, 3541.
Caine, D. & Watson, J. (2000). Neuropsychological and neuropathological sequelae of cerebral anoxia: A critical review. Journal of the International Neuropsychological Society, 6, 8699.
Cheshire, K., Engleman, H., Deary, I., Shapiro, C., & Douglas, N.J. (1992). Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome. Archives of Internal Medicine, 152, 538541.
Choi, I.S. (1983). Delayed neurologic sequelae in carbon monoxide intoxication. Archives of Neurology, 40, 433435.
Davis, H.P., Tribuna, J., Pulsinelli, W.A., & Volpe, B.T. (1986). Reference and working memory of rats following hippocampal damage induced by transient forebrain ischemia. Physiology and Behavior, 37, 387392.
Derogatis, L.R. (1994). Symptom Checklist–90–Revised (3rd ed.). Minneapolis, MN: National Computer Systems Inc.
Engleman, H.M., Martin, S.E., Deary I.J., &Douglas N.J. (1997). Effect of CPAP therapy on daytime function in patients with mild sleep apnoea/hypopnoea syndrome. Thorax, 52, 114119.
Findley, L.J., Barth, J.T., Powers, D.C., Wilhoit, S.C., Boyd, D.G., & Suratt, P.M. (1986). Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest, 90, 686690.
Gale, S.D., Hopkins, R.O., Weaver, L.K., Bigler, E.D., Booth, E.D., & Blatter, D.D. (1999). MRI, quantitative MRI, SPECT, and neuropsychological findings following carbon monoxide poisoning. Brain Injury, 13, 229243.
Gale, S.D., Hopkins, R.O., Weaver, L.K., Walker, J.M., Bigler, E.D., & Cloward, T.V. (2000). Hippocampal atrophy following sleep apnea and carbon monoxide poisoning: Similarities and differences. Journal of the International Neuropsychological Society, 6, 154.
Gale, S.D., Johnson, S.C., Bigler, E.D., & Blatter, D.D. (1995). Nonspecific white matter degeneration following traumatic brain injury. Journal of the International Neuropsychological Society, 1, 1728.
Geffen, G., Moar, K.J., O'Hanlon, A.P., Clark, C.R., & Geffen, L.B. (1990). Performance measures of 16- to 86-year old males and females on the auditory verbal learning test. Clinical Neuropsychologist, 4, 4563.
Greenberg, G.D., Watson, R.K., & Deptula, D. (1987). Neuropsychological dysfunction in sleep apnea. Sleep, 10, 254262.
Guilleminault, C., van den Hoed, J., & Mitler, M.M. (1978). Clinical overview of the sleep apnea syndromes. In C. Guilleminault & W.C. Dement (Eds.), Sleep apnea syndromes (pp. 112). New York: Alan R. Liss.
Heaton, R.K., Grant, I., & Matthews, C.G. (1991). Comprehensive norms for an expanded Halstead-Reitan Battery: Demographic corrections, research findings and clinical applications. Odessa, FL: Psychological Assessment Resources, Inc.
Hopkins, R.O., Gale, S.D., Johnson, S.D., Anderson, C.V., Bigler, E.D., Blatter, D.D., & Weaver, L.K. (1995a). Severe anoxia with and without concomitant brain atrophy and neuropsychological impairments. Journal of the International Neuropsychological Society, 1, 501509.
Hopkins, R.O., Weaver, L.K., & Kesner, R.P. (1993). Long term memory impairments and hippocampal magnetic resonance imaging in carbon monoxide poisoned subjects. Abstracts, Undersea and Hyperbaric Society Annual Scientific Meeting, Vol. 20 (Suppl.), 15.
Hopkins, R.O., Kesner, R.P., & Goldstein, M. (1995b). Item and order recognition memory in subjects with hypoxic brain injury. Brain and Cognition, 27, 180201.
Jarrard, L.E. & Meldrum, B.S. (1993). Selective excitotoxic pathology in the rat hippocampus. Neuropathology and Applied Neurobiology, 19, 381389.
Johnson, R.A. & Wichern, D.W. (2002). Applied multivariate statistical analysis (5th ed.). Upper Saddle River, NJ: Prentice Hall.
Kelly, D.A., Claypoole, K.H., & Coppel, D.B. (1990). Sleep apnea syndrome: Symptomatology, associated features, and neurocognitive correlates. Neuropsychology Review, 1, 323342.
Kesler, S.R., Hopkins, R.O., Weaver, L.K., Blatter, D.D., Edge-Booth, H., & Bigler, E.D. (2001). Verbal memory deficits associated with fornix atrophy in carbon monoxide poisoning. Journal of the International Neuropsychological Society, 7, 640646.
Kesner, R.P. & Hopkins, R.O. (2001). Short-term memory for duration and distance in humans: Role of the hippocampus. Neuropsychology, 15, 5868.
Manns, J.R., Hopkins, R.O., Reed, J.M., Kitchener, E.G., & Squire, L.R. (2003). Recognition memory and the human hippocampus. Neuron, 37, 171180.
Meyers, J.E. & Meyers, K.R. (1995). Rey Complex Figure Test and Recognition Trial. Lutz, FL: PAR Inc.
Mittenberg, W., Burton, D.B., Darrow, E., & Thompson, G.B. (1992). Normative data for the Wechsler Memory Scale–Revised: 25- to 34-year-olds. Psychological Assessment, 4, 363368.
Neubauer, J.A. (2001). Physiological and genomic consequences of intermittent hypoxia, invited review: Physiological and pathophysiological responses to intermittent hypoxia. Journal of Applied Physiology, 90, 15931599.
Okeda, R., Funata, N., Takano, T., Miyazaki, Y., Higashino, F., Yokoyama, K., & Manabe, M. (1981). The pathogenesis of carbon monoxide encephalopathy in the acute phase-physiological and morphological correlation. Acta Neuropathologica, 54, 110.
Piantadosi, C.A. (1987). Carbon monoxide, oxygen transport, and oxygen metabolism. Journal of Hyperbaric Medicine, 2, 2744.
Piantadosi, C.A., Schmechel, D.E., & Zhang, J. (1995). Is neuronal degeneration mediated by apoptosis after carbon monoxide poisoning. Undersea and Hyperbaric Medicine, 22, 1516.
Piantadosi, C.A., Zhang, J., Levin, E.D., Folz, R.J., & Schmechel, D.E. (1997a). Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat. Experimental Neurology, 147, 103114.
Piantadosi, C.A., Zhang, J., & Demchenko, I.T. (1997b). Production of hydroxyl radical in the hippocampus after CO hypoxia or hypoxic hypoxia in the rat. Free Radical Biology and Medicine, 22, 725732.
Raub, J.A., Mathieu-Nolf, M., Hampson, N.B., & Thom, S.R. (2000). Carbon monoxide poisoning—a public health perspective. Toxicology, 145, 114.
Reitan, R.M. & Wolfson, D. (1985). The Halstead-Reitan Neuropsychological Test Battery: Theory and clinical interpretation (2nd ed.). Tucson, AZ: Neuropsychology Press.
Rey, A. (1941). L'examen psychologique dans les cas d'encéphalopathie traumatique [Psychological examination of cases of traumatic encephalopathy]. Archives de Psychologie, 28, 286340.
Rey, A. (1964). L'examen cliniaue en psychologie [The clinical examination in psychology]. Paris: Presses Universitaires de France.
Reynolds, C.R., Hopkins, R.O., & Bigler, E.D. (1999). Continuing decline of memory skills with significant recovery of intellectual function following severe carbon monoxide exposure: Clinical, psychometric, and neuroimaging findings. Archives of Clinical Neuropsychology, 14, 235249.
Roehrs, T., Merrion, M., Pedrosi, B., Stepanski, E., Zorick, F., & Roth, T. (1995). Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep, 18, 382388.
Rourke, S.B. & Adams, K.M. (1996). The neuropsychological correlates of acute and chronic hypoxemia. In I. Grant & K. Adams (Eds.), Neuropsychological assessment of neuropsychiatric disorders (2nd ed., pp. 379402). New York: Oxford University Press.
Scott, J.G., Krull, K.R., Williamson, D.J., Adams, R.L., & Iverson, G.L. (1997). Oklahoma premorbid intelligence estimation (OPIE): Utilization and clinical samples. Clinical Neuropsychologist, 11, 146154.
Stevens, J. (1996). Applied multivariate statistics for the social sciences (3rd ed.). Mahwah, NJ: Lawrence Erlbaum Associates.
Thom, S.R. (1990). Carbon monoxide-mediated brain lipid peroxidation in the rat. Journal of Applied Physiology, 68, 9971003.
Thom, S.R., Taber, R.L., Mendiguren, I.I., Clark, J.M., Hardy, K.R., & Fisher, A.B. (1995). Delayed neurologic sequelae following carbon monoxide poisoning: Prevention by treatment with hyperbaric oxygen. Annals of Emergency Medicine, 25, 474480.
Tombaugh, T.N., Kozak, J., & Rees, L. (1999). Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming. Archives of Clinical Neuropsychology, 14, 167177.
Uemura, K., Harada, K., Sadamitsu, D., Tsuruta, R., Takahashi, M., Aki, T., Yasuhara, M., Maekawa, T., & Yoshida, K. (2001). Apoptotic and necrotic brain lesions in a fatal case of carbon monoxide poisoning. Forensic Science International, 116, 213219.
Valencia-Flores, M., Bliwise, D.L., Guilleminault, C., Cilveti, R., & Clerk, A. (1996). Cognitive function in patients with sleep apnea after acute nocturnal nasal continuous positive airway pressure (CPAP) treatment: Sleepiness and hypoxemia effects. Journal of Clinical and Experimental Neuropsychology, 18, 197210.
Walker, J.M., Cloward, T.V., Gale, S.D., Hopkins, R.O., Brooks, M., & Farney, R.J. (1999). Hippocampal atrophy and long-lasting neuropsychological deficits in patients with severe obstructive sleep apnea. Abstracts, American Journal of Respiratory and Critical Care Medicine, 159, A770.
Weaver, L.K., Hopkins, R.O., Chan, K.J., Churchill, S., Clemmer, T.P., Elliott, C.G., Orme, J.F., Jr., Thomas, F.O., & Morris, A.H. (2002). Hyperbaric oxygen for acute carbon monoxide poisoning. New England Journal of Medicine, 347, 10571067.
Wechsler, D. (1981). Manual for the Wechsler Adult Intelligence Scale–Revised. San Antonio, TX: The Psychological Corporation.
Wechsler, D. (1987). Wechsler Memory Scale–Revised. San Antonio, TX: The Psychological Corporation.
Young, T., Palta, M., Dempsey, J., Skatrud, J., Weber, S., & Badr, S. (1993). The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine, 328, 12301235.
Zola-Morgan, S., Squire, L.R., Rempel, N.L., Clower, R.P., & Amaral, D.G. (1992). Enduring memory impairment in monkeys after ischemic damage to the hippocampus. Journal of Neuroscience, 12, 25822596.



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