Emerging Science May Help Explain Excessive Sleepiness (ES) in Patients With OSA

April 23, 2019

Studies show a connection between obstructive sleep apnea (OSA) and alterations to the brain.


This is a repost of recently circulated research by Jazz Pharmaceuticals.


Untreated OSA Is Associated With Reduced Gray Matter Concentration in Brain Regions Responsible for Wakefulness and Neurocognitive Performance1,2

As compared to healthy controls, patients with untreated OSA have been found to exhibit reduced gray matter concentration in brain regions, including those involved in wakefulness and neurocognitive performance.1-8

Gray matter concentration changes in patients with OSA compared to healthy subjects included reductions in the thalamus, anterior cingulate cortex, and frontal cortex.1,2


Areas of the brain with reduced gray matter
concentrations associated with OSA1



•These regions are involved in wakefulness and neurocognitive performance, attention, and higher-order cognitive processes (eg, executive function)3-7

One study showed that reductions of gray matter concentrations in the left hippocampus, the left parietal cortex, and the right superior frontal gyrus were also associated with untreated OSA.8


•This suggests a scenario in which the hippocampus, because of its sensitivity to hypoxia and innervation of small vessels, is the region that is most strongly and quickly affected by hypoxic and hypercapnic episodes8


-The ensuing structural hippocampal damage may result in cognitive deficits involving not only memory, but attention and executive functioning8


CPAP-Adherent OSA Patients Showed Significantly Decreased White Matter Concentration in the Sleepy Versus Nonsleepy Group9


In a study to evaluate potential white matter structural alterations, diffusion tensor imaging (DTI) was used to evaluate white matter neural tracts in OSA patients (n=29) adherent to continuous positive airway pressure (CPAP) (≥6 h/night for 30 days), with and without excessive sleepiness.9

Patients with OSA with unresolved sleepiness had significant changes in brain white matter compared to nonsleepy patients with OSA.9 

ACR=anterior corona radiata; CCG=cingulum (cingulate gyrus); EC=external capsule; PCR=posterior corona radiata; RIC=retrolenticular part of internal capsule; sCC=splenium of corpus callosum; SCR=superior corona radiata.

The DTI findings from this study showed that ES was associated with structural changes to white matter, potentially indicating compromised neuronal connectivity. Some structural changes correlated with clinical measures of ES. Demyelination of neurons found in white matter may be permanent and hinder functional recovery, despite CPAP treatment.9


Fiber Tracts Observed


Increases in regional radial diffusivity of specific fiber tracts (images) were observed in9:


•Connecting fibers in the ipsilateral hemisphere (eg, frontal white matter)

•Commissural fibers of the corpus callosum (eg, corpus callosum)

•Projecting fibers from cerebral cortex to subcortical structures (eg, corona radiata)


In patients with OSA,1,2,8,9 in addition to these causes, ES may be due to other factors such as chronic sleep loss and comorbid disorders.10


Animal studies in sleep apnea


Chronic Intermittent Hypoxia and Fragmented Sleep Caused Loss of Neurons in Wakefulness-Promoting Regions of the Brain11-13


40% loss of dopaminergic and noradrenergic neurons at 6 months*,11


*Hypoxia/reoxygenation in adult mice for 6 months, modeling severe sleep apnea.


Other wake-active neural groups (eg, other monoaminergic, cholinergic, orexinergic) were relatively spared from injury.11


Fragmented Sleep Led to Degeneration of Wake-Promoting Neurons12

50% loss of noradrenergic neurons12 (P<.001)


25% loss of orexigenic neurons12 (P<.05)


A mouse model of chronic sleep disruption was used to mimic conditions of sleep apnea. In the model, chronic sleep fragmentation caused significant (50%; P<.001) reduction in total number of noradrenergic neurons in the locus coeruleus (LC) and reduced dendrite projections in these wake-promoting neurons versus controls, which persisted even after 4 weeks of recovery.12

Learn more about ES in OSA



  1.Joo EY, Tae WS, Lee MJ, et al. Reduced brain gray matter concentration in patients with obstructive sleep apnea syndrome. Sleep. 2010;33(2):235–241.

  2.Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea. Chest. 2012;141(6):1601–1610.

  3.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. 2002;11(1):1–16.

  4.Wimmer RD, Schmitt LI, Davidson T, et al. Thalamic control of sensory selection in divided attention. Nature. 2015;526(7575):705–709.

  5.Davis KD, Hutchison WD, Lozno AM, et al. Human anterior cingulate cortex neurons modulated by attention-demanding tasks. J Neurophysiol. 2000;83(6):3575–3577.

  6.España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845–858.

  7.Gompf HS, Mathai C, Fuller PM, et al. Locus coeruleus (LC) and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci. 2010;30(43):14543–14551.

  8.Canessa N, Castronovo V, Cappa S, et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med. 2011;183:1419–1426.

  9.Xiong Y, Zhou XJ, Nisi RA, et al. Brain white matter changes in CPAP-treated obstructive sleep apnea patients with residual sleepiness. J Magn Res Imaging. 2017;45(5):1375–1378.

10.Antic NA, Catcheside P, Buchan C, et al. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111–119.

11.Zhu Y, Fenik P, Zhan G, et al. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci. 2007;27(37):10060–10071.

12.Zhu Y, Fenik P, Zhan G, Xin R, Veasey SC. Degeneration in arousal neurons in chronic sleep disruption modeling sleep apnea. Front Neurol. 2015;6:109.



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