Obstructive sleep apnea (OSA) occurs in close to 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe cardiovascular and neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and there are few clinical guidelines for treating symptoms other breathing support with positive airway pressure (PAP);that support assists ventilation, but does little to restore sympathetic dysfunction, one factor that likely contributes to hypertension and other cardiovascular sequelae in the syndrome. Since sympathetic outflow is regulated by the brain, a possible contribution to the cardiovascular sequelae is impaired regulation due to neural injury from the intermittent hypoxia and other characteristics of OSA. We showed such injury in OSA together with deficient cardiovascular control in many brain regions, including the insular cortex, an area that integrates higher brain processing and sensory input to modulate brainstem and hypothalamic autonomic outflow. Our R21 data show that female OSA patients have an even greater extent of insular cortex injury and dysfunction than male OSA patients. We therefore hypothesize that in OSA patients, the insular cortex has impaired function due to injury, resulting in less effective cardiovascular regulation, and these effects are especially severe in female OSA patients. We will evaluate brain structure with diffusion tensor imaging, brain function with functional magneti resonance imaging (fMRI), and cardiovascular function with heart rate measurements during three autonomic challenges, an inspiratory apnea, Valsalva maneuver, and static hand grip. We will localize the insular cortex subdivisions involved in sympathetic modulation from high-resolution MRI scans. We will study 144 people across four age-matched groups: newly-diagnosed OSA females and males matched for disease severity, and healthy control females and males. Females will be assessed for menopausal and hormonal status, with the aim of balancing the numbers of pre- and post-menopausal women, and including hormonal factors in statistical models. In males and females, the findings will show whether disrupted neural regulation of sympathetic activity occurs in OSA, whether that dysfunction is paralleled by brain injury, and whether cardiovascular responsiveness is also impaired. We will also perform an exploratory assessment of the effects of 3 months of PAP treatment on autonomic function in 15 male and 15 female patients, and gather evidence as to whether autonomic central function can recover, at least in the short term. A lack of recovery would suggest additional treatments to PAP should be investigated. Findings of worse effects of OSA in women would highlight the need to broaden OSA treatment, which currently solely focuses on resolving breathing disruptions for moderate and severe OSA, and is typically ignored in mild OSA in women, despite evidence that mild OSA in females is accompanied by severe cardiovascular characteristics.

Public Health Relevance

We will investigate a possible cause of the cardiovascular and neuropsychological symptoms that women with Obstructive Sleep Apnea (OSA) show to a greater degree than men. We will test whether brain function in the insula, a region controlling blood pressure and mood, is abnormal in female OSA patients by using magnetic resonance imaging, and look at brain damage as a possible cause of this dysfunction, as well as looking at the cardiovascular consequences, and in a subset of patients the influence of treatment. This study will help show whether impaired brain function in the insula due to injury is associated with poor cardiovascular control, whether women are more physically affected by OSA than men, and whether treatment for the sleep disorder may improve brain and cardiovascular function.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Research Project (R01)
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Nursing and Related Clinical Sciences Study Section (NRCS)
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Matocha, Martha F
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University of California Los Angeles
Schools of Nursing
Los Angeles
United States
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Sarma, Manoj K; Macey, Paul M; Nagarajan, Rajakumar et al. (2016) Accelerated Echo Planer J-resolved Spectroscopic Imaging of Putamen and Thalamus in Obstructive Sleep Apnea. Sci Rep 6:31747
Macey, Paul M; Sarma, Manoj K; Nagarajan, Rajakumar et al. (2016) Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex. J Sleep Res 25:390-4
Samy, Lauren; Macey, Paul M; Sarrafzadeh, Majid (2015) A gender-aware framework for the daytime detection of obstructive sleep apnea. Conf Proc IEEE Eng Med Biol Soc 2015:7683-7
Macey, Paul M; Ogren, Jennifer A; Kumar, Rajesh et al. (2015) Functional Imaging of Autonomic Regulation: Methods and Key Findings. Front Neurosci 9:513
Macey, Paul M (2015) Altered Resting Cerebral Blood Flow in Obstructive Sleep Apnea: A Helpful Change or Not? Sleep 38:1345-7
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Fatouleh, Rania H; Hammam, Elie; Lundblad, Linda C et al. (2014) Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea. Neuroimage Clin 6:275-83
Macey, Paul M; Kumar, Rajesh; Ogren, Jennifer A et al. (2014) Global brain blood-oxygen level responses to autonomic challenges in obstructive sleep apnea. PLoS One 9:e105261
Harper, Ronald M; Kumar, Rajesh; Macey, Paul M et al. (2014) Affective brain areas and sleep-disordered breathing. Prog Brain Res 209:275-93
Sarma, M K; Nagarajan, R; Macey, P M et al. (2014) Accelerated echo-planar J-resolved spectroscopic imaging in the human brain using compressed sensing: a pilot validation in obstructive sleep apnea. AJNR Am J Neuroradiol 35:S81-9

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