GABA and glutamate changes underlying altered autonomic function in obstructive sleep apnea

项目总结 至少10%的人患有阻塞性睡眠呼吸暂停(OSA)，这是一种呼吸中断的情况 由于上呼吸道的塌陷，每晚都会出现数百次。这一障碍伴随着心理 损害和心血管发病率和死亡率，但症状只有部分地通过 持续气道正压(CPAP)，黄金标准干预，表明其他机制 呼吸中断会导致阻塞性睡眠呼吸暂停综合症患者的健康问题。神经性自主神经功能受损 改变可能是阻塞性睡眠呼吸暂停综合征症状的来源，因为大脑中存在结构和功能缺陷 监管这类职能的地区。症状因性别而异，女性通常表现出更严重的症状 尽管患病率低于男性。然而，神经成像的结果并没有区分出 脑部病理学。根据结构、功能和神经递质水平改变的初步发现，以及 在阻塞性睡眠呼吸暂停综合征的动物模型中，我们假设大脑的改变影响边缘区域，特别是脑岛。 脑岛在自主神经调节、情绪和一些认知功能中起着关键作用，可能存在 是在结构中改变功能的基础上的重组。此外，由于一些症状不是 通过CPAP解决，即使接受治疗，重组也可能保留。我们建议测量神经递质 OSA中脑岛的水平，并将这些水平与OSA的结构和功能缺陷的程度联系起来 条件，假设改变的功能与改变的GABA和谷氨酸有关，一种理论 由我们的初步数据支持。我们还将测试CPAP是否存在这样的变化。我们将使用 二维磁共振波谱(MRS)联合检测GABA和谷氨酸 对细胞大小和完整性(扩散张量成像，DTI)和含水率敏感的结构措施 (具有T2弛豫时间的游离水和具有DTI派生的自由水分数的细胞外水[FW])。防火墙是 这一点很重要，因为细胞外而不是细胞内的谷氨酸会导致兴奋性毒性。功能将被测量 在自主神经挑战期间进行功能磁共振成像(FMRI)，瓦尔萨尔瓦动作。我们 将研究60名未经治疗的、新诊断的OSA、60名匹配的对照组和60名OSA患者，为期1年 符合CPAP使用要求。我们将评估与对照组相比，阻塞性睡眠呼吸暂停综合征患者脑岛中的GABA和谷氨酸是否发生了变化。 在接受治疗的患者和未接受治疗的患者中。我们将把这些神经递质水平与组织的DTI指数联系起来。 结构、平均扩散系数(MD)和分数各向异性(FA)。我们还会将GABA和谷氨酸的水平联系起来 自主神经挑战期间的fMRI反应的大小。这些发现将有助于解释机制 OSA的脑损伤和重组，并建议可能的治疗方案来解决常见症状 在未经CPAP处理的阻塞性睡眠呼吸暂停综合征中，包括通过改变GABA或 谷氨酸。

PROJECT SUMMARY At least 10% of the population has obstructive sleep apnea (OSA), a condition where breathing is interrupted hundreds of times a night due to collapse of the upper airway. The disorder is accompanied by psychological impairments and cardiovascular morbidity and mortality, but symptoms are only partially addressed with continuous positive airway pressure (CPAP), the gold standard intervention, indicating that mechanisms other than breathing interruptions contribute to health problems in OSA. Impaired autonomic function due to neural alterations is a likely source of symptoms in OSA, since structural and functional deficits are present in brain regions that regulate such functions. Symptoms are sex-specific, with females typically showing greater severity despite lower prevalence than males. However, neuroimaging findings have not distinguished the nature of the brain pathology. Based on structural, functional, and preliminary findings of altered neurotransmitter levels, and animal models of OSA, we hypothesize that brain alterations impact limbic regions, and the insula in particular. The insula plays key roles in autonomic regulation as well as mood and some cognitive functions, and there may be reorganization that underlies altered function in the structure. Furthermore, since some symptoms do not resolve with CPAP, the reorganization may remain even with treatment. We propose measuring neurotransmitter levels in the insula in OSA, and relating these levels to the extent of structural and functional deficits in the condition, with the hypothesis that the altered function is associated with altered GABA and glutamate, a theory supported by our preliminary data. We will also test whether such changes are present with CPAP. We will use two-dimensional magnetic resonance spectroscopy (MRS) to measure GABA and glutamate, in conjunction with structural measures sensitive to cellular size and integrity (with diffusion tensor imaging, DTI) and water content (free water with T2 relaxation time, and extracellular water with DTI-derived free water fraction [FW]). FW is important since extracellular rather than intracellular glutamate leads to excitotoxicity. Function will be measured with functional magnetic resonance imaging (fMRI) during an autonomic challenge, the Valsalva maneuver. We will study 60 untreated, newly-diagnosed OSA, 60 matched controls, and 60 OSA patients with 1 year of compliant CPAP use. We will assess whether GABA and glutamate in the insula are altered in OSA vs. controls, and in treated vs. untreated patients. We will relate these neurotransmitter levels to DTI indices of tissue structure, mean diffusivity (MD), and fractional anisotropy (FA). We will also relate levels of GABA and glutamate to the magnitude of fMRI responses during the autonomic challenge. The findings will help explain mechanisms of brain injury and reorganization in OSA, and suggest possible treatment options to address common symptoms in OSA not addressed by CPAP, including possible manipulation of brain function through altering GABA or glutamate.