Reduced Regional Grey Matter Volumes in Pediatric Obstructive Sleep Apnea

Mona F Philby, Paul M Macey, Richard A Ma, Rajesh Kumar, David Gozal, Leila Kheirandish-Gozal, Mona F Philby, Paul M Macey, Richard A Ma, Rajesh Kumar, David Gozal, Leila Kheirandish-Gozal

Abstract

Pediatric OSA is associated with cognitive risk. Since adult OSA manifests MRI evidence of brain injury, and animal models lead to regional neuronal losses, pediatric OSA patients may also be affected. We assessed the presence of neuronal injury, measured as regional grey matter volume, in 16 OSA children (8 male, 8.1 ± 2.2 years, AHI:11.1 ± 5.9 events/hr), and 200 control subjects (84 male, 8.2 ± 2.0 years), 191 of whom were from the NIH-Pediatric MRI database. High resolution T1-weighted whole-brain images were assessed between groups with voxel-based morphometry, using ANCOVA (covariates, age and gender; family-wise error correction, P < 0.01). Significant grey matter volume reductions appeared in OSA throughout areas of the superior frontal and prefrontal, and superior and lateral parietal cortices. Other affected sites included the brainstem, ventral medial prefrontal cortex, and superior temporal lobe, mostly on the left side. Thus, pediatric OSA subjects show extensive regionally-demarcated grey matter volume reductions in areas that control cognition and mood functions, even if such losses are apparently independent of cognitive deficits. Since OSA disease duration in our subjects is unknown, these findings may result from either delayed neuronal development, neuronal damaging processes, or a combination thereof, and could either reflect neuronal atrophy or reductions in cellular volume (neurons and glia).

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Brainstem regions of significantly lower…
Figure 1. Brainstem regions of significantly lower regional grey matter volume in OSA (n = 16) over control (n = 200) subjects (P < 0.01), colored according to significance level.
Background is the average of the 216 subjects’ normalized T1-weighted brain scans. Slice locations are in MNI coordinates.
Figure 2. Cortical regions with significantly lower…
Figure 2. Cortical regions with significantly lower regional grey matter volume in 16 OSA compared to 200 control subjects (P < 0.01), colored according to significance level.
Background is the average anatomical of 216 subjects. Slice locations are in MNI coordinates. Key: L left, R right, FC frontal cortex, PFC prefrontal cortex, VMPFC ventral medial prefrontal cortex.
Figure 3. Cortical regions of significantly reduced…
Figure 3. Cortical regions of significantly reduced regional grey matter volume in OSA over control subjects (P < 0.01) displayed in yellow on the cortical surface on a single subject in MNI space.

References

    1. Bixler E. O. et al.. Sleep disordered breathing in children in a general population sample: prevalence and risk factors. Sleep, 32, 731–736 (2009).
    1. Kheirandish-Gozal L. & Gozal D. Sleep disordered breathing in children: a comprehensive clinical guide to evaluation and treatment. New York: Humana Press; (2012).
    1. Hunter S. et al.. Effect of sleep-disordered breathing severity on cognitive performance measures in young school-aged children. Am J Resp Crit Care Med 194, 739–47 (2016).
    1. Galland B., Spruyt K., Dawes P., McDowall P. S., Elder D. et al.. Sleep disordered breathing and academic performance: A meta-analysis. Pediatrics 136, e934–946 (2015).
    1. O’Brien L. M. et al.. Neurobehavioral correlates of sleep-disordered breathing in children. Journal of sleep research 13, 165–172 (2004).
    1. Giordani B. et al.. Neuropsychological and behavioral functioning in children with and without obstructive sleep apnea referred for tonsillectomy. J Int Neuropsychol Soc 14, 571–581 (2008).
    1. Owens J. A. Neurocognitive and behavioral impact of sleep disordered breathing in children. Pediatr Pulmonol 44, 417–422 (2009).
    1. Kheirandish-Gozal L., De Jong M. R., Spruyt K., Chamuleau S. A. & Gozal D. Obstructive sleep apnoea is associated with impaired pictorial memory task acquisition and retention in children. Eur Respir J 36, 164–169 (2010).
    1. Gottlieb D. J. et al.. Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children. J. Pediatr 145, 458–464 (2004).
    1. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics 102, 616–620 (1998).
    1. Weissbluth M., Davis A. T., Poncher J. & Reiff J. Signs of airway obstruction during sleep and behavioral, developmental, and academic problems. J Dev Behav Pediatr 4, 119–121 (1983).
    1. Montgomery-Downs H. E., Crabtree V. M. & Gozal D. Cognition, sleep and respiration in at-risk children treated for obstructive sleep apnoea. Eur Respir J 25, 336–342 (2005).
    1. Friedman B. C. et al.. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep 26, 999–1005 (2003).
    1. Marcus C. L. et al.. Childhood Adenotonsillectomy T. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med 368, 2366–2376 (2013).
    1. Kheirandish-Gozal L., Yoder K., Kulkarni R., Gozal D. & Decety J. Preliminary functional MRI neural correlates of executive functioning and empathy in children with obstructive sleep apnea. Sleep 37, 587–592 (2014).
    1. Gozal D. CrossTalk proposal: the intermittent hypoxia attending severe obstructive sleep apnoea does lead to alterations in brain structure and function. J Physiol 591, 379–381 (2013).
    1. Gozal E., Row B. W., Schurr A. & Gozal D. Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat. Neurosci Lett 305, 197–201 (2001).
    1. Kumar R. et al.. Altered global and regional brain mean diffusivity in patients with obstructive sleep apnea. J Neurosci Res 90, 2043–2052 (2012).
    1. Cross R. L. et al.. Neural Alterations and Depressive Symptoms in Obstructive Sleep Apnea Patients. Sleep 31, 1103–1109 (2008).
    1. Macey P. M. et al.. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 166, 1382–1387 (2002).
    1. Macey P. M. K. et al.. Brain structural changes in obstructive sleep apnea. Sleep 31, 967–977 (2008).
    1. Macey P. M., Kumar R., Yan-Go F. L., Woo M. A. & Harper R. M. Sex differences in white matter alterations accompanying obstructive sleep apnea. Sleep 35, 1603–1613 (2012).
    1. Fatouleh R. H. et al.. Reversal of functional changes in the brain associated with obstructive sleep apnoea following 6 months of CPAP. NeuroImage Clinical 7, 799–806 (2015).
    1. Canessa N. et al.. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 183, 1419–1426 (2011).
    1. Berry R. B. et al.. American Academy of Sleep M. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 8, 597–619 (2012).
    1. Montgomery-Downs H. E., O’Brien L. M., Gulliver T. E. & Gozal D. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics 117, 741–753 (2006).
    1. Elliott C. D. Differential Ability Scales: introductory and technical handbook. San Antonio: Psychological Corp.: Harcourt Brace Jovanovich (1990).
    1. Elliott C. D. The Nature and Structure of Childrens Abilities - Evidence from the Differential Ability Scales. J Psychoeduc Assess 8, 376–390 (1990).
    1. Celle S. et al.. Desperately seeking grey matter volume changes in sleep apnea: A methodological review of magnetic resonance brain voxel-based morphometry studies. Sleep Med Rev 25, 112–120 (2016).
    1. Ashburner J. & Friston K. J. Voxel-Based Morphometry–The Methods. NeuroImage 11, 805–821 (2000).
    1. Ashburner J. & Friston K. J. Unified segmentation. NeuroImage 26, 839–851 (2005).
    1. Ashburner J. A fast diffeomorphic image registration algorithm. NeuroImage 38, 95–113 (2007).
    1. Good C. D. et al.. A Voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage 14, 21–36 (2001).
    1. Friston K. J. et al.. Analysis of fMRI time-series revisited. NeuroImage 2, 45–53 (1995).
    1. Chan K. C. et al.. Neurocognitive dysfunction and grey matter density deficit in children with obstructive sleep apnoea. Sleep Med 15, 1055–1061 (2014).
    1. Fox N. C. & Schott J. M. Imaging cerebral atrophy: normal ageing to Alzheimer’s disease. Lancet 363, 392–394 (2004).
    1. Bray S., Krongold M., Cooper C. & Lebel C. Synergistic effects of age on patterns of white and gray matter volume across childhood and adolescence. eNeuro 2 (2015).
    1. Gozal D. & Kheirandish-Gozal L. Neurocognitive and behavioral morbidity in children with sleep disorders. Curr Opin Pulm Med 13, 505–509 (2007).
    1. Jou R. J., Frazier T. W., Keshavan M. S., Minshew N. J. & Hardan A. Y. A two-year longitudinal pilot MRI study of the brainstem in autism. Behav Brain Res 251, 163–167 (2013).
    1. Brain Development Cooperative G. Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development. Cereb Cortex 22, 1–12 (2012).
    1. Gozal D. et al.. Cognitive function in prepubertal children with obstructive sleep apnea: a modifying role for NADPH oxidase p22 subunit gene polymorphisms? Antioxid Redox Signal 16, 171–177 (2012).
    1. Huynh N. T., Prilipko O., Kushida C. A. & Guilleminault C. Volumetric brain morphometry changes in patients with obstructive sleep apnea syndrome: Effects of CPAP treatment and literature review. Frontiers in neurology 5, 58 (2014).

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever