The Impact of Sleep and Hypoxia on the Brain
During obstructive apneas changes in cerebral blood flow occur and apnea-induced hypoxemia combined with reduced cerebral perfusion likely predisposes patients to nocturnal cerebral ischemia. In addition, hypoperfusion during the awake states with altered resting cerebral blood flow pattern in several regions has been shown in OSA.
Numerous clinical studies demonstrate changes in the electroencephalogram of OSA patients, including aberrant cortical excitability and an associated array of neurocognitive deficits. Taken collectively they also delineate a putative neurocircuitry fingerprint of OSA-induced brain injury and suggest the disruption of the (cerebello)-thalamocortical oscillator with involvement of the hippocampal formation. It has been previously suggested that a constellation of symptoms frequently encountered in OSA patients, such as depression, disturbances in attention, dysmetria of thought and affect, executive and verbal memory deficits, point to similarities with the spectra of two other well recognized neurological clinical syndromes, thalamocortical dysrhythmia and cerebellar cognitive affective syndrome. Correspondingly, the neuroanatomical regions most commonly reported in clinical and animal studies as affected in OSA suggest that both the cerebellar modulation of neural circuits and the normal state-dependent flow of information between thalamus (and basal ganglia) and fronto-parietal cortex are likely to be affected in susceptible patients (Fig. 1).
(Enlarge Image)
Figure 1.
Neuroanatomical changes in obstructive sleep apnea. Localized grey matter loss is shown in the right temporal lobe and cerebellum of OSA patients compared with healthy controls (a). Reproduced with permission from [30]. An aberrant, likely compensatory, interregional connectivity between hippocampus and cerebellum was demonstrated in OSA patients (b). CC, cerebellar cortex; H, hippocampus; L, left; OSA, obstructive sleep apnea; R, right; r, Pearson correlation coefficient. Reproduced with permission from [35].
Additionally, several other neuropsychiatric disorders are frequently reported comorbid or closely associated with OSA. For example, adults with epilepsy appear at increased risk of OSA, Similarly, OSA is associated with seizure exacerbation in older adults with epilepsy, and treatment with CPAP may represent an important avenue for improving seizure control in this population. Sleep apnea is also a recognized independent risk factor for stroke. It is believed to exacerbate neural damage during the stroke, as well as to increase the risk of a subsequent stroke. Moreover, an increasing body of evidence from animal studies suggests that cerebral amyloidogenesis and tau phosphorylation, two cardinal features of Alzheimer's disease, can be triggered by intermittent hypoxia. Intermittent hypoxia and reactive oxygen species, known to occur during nocturnal apnoeic episodes, were shown to initiate neuronal degeneration and axonal dysfunction in cortex and brainstems of animals. Also, the oligodendrocytes, myelin-producing cells of the CNS, were shown as selectively sensitive to hypoxia and sleep fragmentation. However, it is not clear to what extent this particular vulnerability contributes to the widely reported hypotrophic white matter changes (e.g., fornices and corpus callosum) in the brains of some OSA patients. However, and in line with preclinical findings, several clinical studies also suggested that older patients with OSA suffer accelerated brain atrophy, cognitive decline and the onset and severity of dementia. Conversely, in children with OSA, diminished learning capabilities, increased hyperactivity and incidence of attention-deficit disorders have all been documented.
Unique periods of susceptibility during the life-span, along with genetic, environmental and lifestyle conditions, appear to determine the severity of the intermittent hypoxia effects on the CNS. Some of these effects at both ends of the age spectrum may also reflect the direct and epigenetic impact of intermittent hypoxia during the heterochronus neurodevelopmental myelination process. This process in humans, unlike that in other primates, spans several decades and likely contributes to later-life cognitive gains.
Notwithstanding the above-mentioned changes, OSA-associated brain injury is commonly reported as subtle, its associated neurocognitive deficits as mild and diffuse, and their full or partial reversibility by the CPAP is debatable. The root of this discrepancy is attributed to the use of different image analysis methods in various studies over the years, varied statistical thresholds and lack of an OSA-specific battery of sensitive neurocognitive tests. Additionally, the interindividual heterogeneity to a given hypoxic stimulus during OSA and the effects of sleep on regional neuronal vulnerability are thought to contribute to this variability. Similarly, the cardiovascular and cerebrovascular protection conferred by ischemic preconditioning resulting from the nocturnal cycles of hypoxia-reoxygenation is thought to play an important role.
The Neuropathology of Obstructive Sleep Apnea
During obstructive apneas changes in cerebral blood flow occur and apnea-induced hypoxemia combined with reduced cerebral perfusion likely predisposes patients to nocturnal cerebral ischemia. In addition, hypoperfusion during the awake states with altered resting cerebral blood flow pattern in several regions has been shown in OSA.
Numerous clinical studies demonstrate changes in the electroencephalogram of OSA patients, including aberrant cortical excitability and an associated array of neurocognitive deficits. Taken collectively they also delineate a putative neurocircuitry fingerprint of OSA-induced brain injury and suggest the disruption of the (cerebello)-thalamocortical oscillator with involvement of the hippocampal formation. It has been previously suggested that a constellation of symptoms frequently encountered in OSA patients, such as depression, disturbances in attention, dysmetria of thought and affect, executive and verbal memory deficits, point to similarities with the spectra of two other well recognized neurological clinical syndromes, thalamocortical dysrhythmia and cerebellar cognitive affective syndrome. Correspondingly, the neuroanatomical regions most commonly reported in clinical and animal studies as affected in OSA suggest that both the cerebellar modulation of neural circuits and the normal state-dependent flow of information between thalamus (and basal ganglia) and fronto-parietal cortex are likely to be affected in susceptible patients (Fig. 1).
(Enlarge Image)
Figure 1.
Neuroanatomical changes in obstructive sleep apnea. Localized grey matter loss is shown in the right temporal lobe and cerebellum of OSA patients compared with healthy controls (a). Reproduced with permission from [30]. An aberrant, likely compensatory, interregional connectivity between hippocampus and cerebellum was demonstrated in OSA patients (b). CC, cerebellar cortex; H, hippocampus; L, left; OSA, obstructive sleep apnea; R, right; r, Pearson correlation coefficient. Reproduced with permission from [35].
Additionally, several other neuropsychiatric disorders are frequently reported comorbid or closely associated with OSA. For example, adults with epilepsy appear at increased risk of OSA, Similarly, OSA is associated with seizure exacerbation in older adults with epilepsy, and treatment with CPAP may represent an important avenue for improving seizure control in this population. Sleep apnea is also a recognized independent risk factor for stroke. It is believed to exacerbate neural damage during the stroke, as well as to increase the risk of a subsequent stroke. Moreover, an increasing body of evidence from animal studies suggests that cerebral amyloidogenesis and tau phosphorylation, two cardinal features of Alzheimer's disease, can be triggered by intermittent hypoxia. Intermittent hypoxia and reactive oxygen species, known to occur during nocturnal apnoeic episodes, were shown to initiate neuronal degeneration and axonal dysfunction in cortex and brainstems of animals. Also, the oligodendrocytes, myelin-producing cells of the CNS, were shown as selectively sensitive to hypoxia and sleep fragmentation. However, it is not clear to what extent this particular vulnerability contributes to the widely reported hypotrophic white matter changes (e.g., fornices and corpus callosum) in the brains of some OSA patients. However, and in line with preclinical findings, several clinical studies also suggested that older patients with OSA suffer accelerated brain atrophy, cognitive decline and the onset and severity of dementia. Conversely, in children with OSA, diminished learning capabilities, increased hyperactivity and incidence of attention-deficit disorders have all been documented.
Unique periods of susceptibility during the life-span, along with genetic, environmental and lifestyle conditions, appear to determine the severity of the intermittent hypoxia effects on the CNS. Some of these effects at both ends of the age spectrum may also reflect the direct and epigenetic impact of intermittent hypoxia during the heterochronus neurodevelopmental myelination process. This process in humans, unlike that in other primates, spans several decades and likely contributes to later-life cognitive gains.
Notwithstanding the above-mentioned changes, OSA-associated brain injury is commonly reported as subtle, its associated neurocognitive deficits as mild and diffuse, and their full or partial reversibility by the CPAP is debatable. The root of this discrepancy is attributed to the use of different image analysis methods in various studies over the years, varied statistical thresholds and lack of an OSA-specific battery of sensitive neurocognitive tests. Additionally, the interindividual heterogeneity to a given hypoxic stimulus during OSA and the effects of sleep on regional neuronal vulnerability are thought to contribute to this variability. Similarly, the cardiovascular and cerebrovascular protection conferred by ischemic preconditioning resulting from the nocturnal cycles of hypoxia-reoxygenation is thought to play an important role.
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