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

GABA 和谷氨酸的变化是阻塞性睡眠呼吸暂停患者自主神经功能改变的基础

• 批准号: 10207743
• 负责人: Paul M Macey
• 金额: $ 73.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207743
• 关键词: Address; Adult; Affect; Age; Air Movements; Airway Resistance; Anatomy; Animal Model; Anisotropy; Anterior; Apnea; Axon; Biological Markers; Brain; Brain Injuries; Brain Pathology; Brain region; Breathing; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Characteristics; Chemicals; Chronic; Cognitive; Continuous Positive Airway Pressure; Data; Diagnosis; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Effectiveness of Interventions; Evaluation; Extracellular Space; Female; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Goals; Gold; Health; Impairment; Incidence; Injury; Insula of Reil; Interruption; Intervention; Lead; Left; Low Prevalence; Magnetic Resonance Spectroscopy; Maintenance; Measures; Mediating; Memory; Mental Depression; Moods; Morbidity - disease rate; Nature; Neurotransmitters; Newly Diagnosed; Obstructive Sleep Apnea; Outcome; Patients; Phase; Physiological; Play; Population; Regulation; Relaxation; Resolution; Role; Scanning; Severities; Sex Differences; Site; Source; Structure; Symptoms; Syndrome; Techniques; Testing; Time; Tissues; Valsalva Maneuver; Water; Woman; base; blood pressure regulation; cognitive function; common symptom; comorbidity; excitotoxicity; experience; extracellular; gamma-Aminobutyric Acid; improved; indexing; male; men; mind control; mortality; nerve injury; neurochemistry; neuroimaging; pressure; prevent; psychologic; relating to nervous system; respiratory pharmacology; response; sex; sleep regulation; symptom treatment; theories; treatment effect; two-dimensional

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.

项目摘要 至少有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 因为上呼吸道塌陷每晚都要发作几百次这种疾病伴随着心理上的 损害和心血管发病率和死亡率，但症状只有部分解决， 持续气道正压通气（CPAP），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征的健康问题。由于神经系统疾病引起的自主神经功能受损 改变是OSA症状的可能来源，因为大脑中存在结构和功能缺陷， 规范这些功能的区域。症状是性别特异性的，女性通常表现出更严重的症状 尽管患病率低于男性。然而，神经影像学发现并没有区分的性质， 脑病理学基于神经递质水平改变的结构、功能和初步发现， 在阻塞性睡眠呼吸暂停的动物模型中，我们假设大脑的改变会影响边缘系统，特别是大脑皮层。 海马在自主调节、情绪和一些认知功能中起着关键作用， 是结构中功能改变的基础。此外，由于某些症状不 用CPAP解决，即使治疗，重组可能仍然存在。我们建议测量神经递质 水平，并将这些水平与OSA中的结构和功能缺陷的程度相关联。 条件，与假设，改变的功能是与改变GABA和谷氨酸，一个理论 我们的初步数据支持。我们还将测试CPAP是否存在此类变化。我们将使用 二维磁共振波谱（MRS）测量GABA和谷氨酸，结合 对细胞大小和完整性（扩散张量成像，DTI）和含水量敏感的结构测量 (free具有T2弛豫时间的水和具有DTI衍生的游离水部分[FW]的细胞外水）。fw是 这一点很重要，因为细胞外而不是细胞内谷氨酸导致兴奋性毒性。功能将被测量 功能性磁共振成像（fMRI）在自主神经的挑战，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， 使用CPAP。我们将评估OSA与对照组相比，脑内GABA和谷氨酸是否发生了变化， 以及治疗与未治疗的患者。我们将这些神经递质水平与组织的DTI指数相关联 结构、平均扩散率（MD）和分数各向异性（FA）。我们也会将GABA和谷氨酸的水平 与自主神经刺激过程中功能磁共振成像反应的大小有关。这些发现将有助于解释 OSA的脑损伤和重组，并提出可能的治疗方案，以解决常见症状 在CPAP未解决的OSA中，包括可能通过改变GABA或 谷氨酸盐。

项目成果

Baroreflex sensitivity during rest and pressor challenges in obstructive sleep apnea patients with and without CPAP.

• DOI: 10.1016/j.sleep.2022.05.846
• 发表时间: 2022-06
• 期刊: Sleep medicine
• 影响因子: 4.8
• 作者: A. Pal;F. Martinez;R. Chatterjee;Ravi S. Aysola;R. Harper;V. Macefield;L. Henderson;P. Macey

Insular functional organization during handgrip in females and males with obstructive sleep apnea.

• DOI: 10.1371/journal.pone.0246368
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pal A;Ogren JA;Aysola RS;Kumar R;Henderson LA;Harper RM;Macey PM
• 通讯作者: Macey PM

Beat-to-beat blood pressure variability in patients with obstructive sleep apnea.

阻塞性睡眠呼吸暂停患者的逐次血压变异性。

• DOI: 10.5664/jcsm.8866
• 发表时间: 2021
• 期刊: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
• 作者: Pal,Amrita;Martinez,Fernando;Aguila,AndreaP;Akey,MargaretA;Chatterjee,Roopsha;Conserman,MerryGraceE;Aysola,RaviS;Henderson,LukeA;Macey,PaulM
• 通讯作者: Macey,PaulM

Damage to the hippocampus in obstructive sleep apnea: a link no longer missing.

阻塞性睡眠呼吸暂停对海马体的损害：不再缺失的一个环节。

• DOI: 10.1093/sleep/zsy266
• 发表时间: 2019
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Macey,PaulM

DTI-based upper limit of voxel free water fraction.

• DOI: 10.1016/j.heliyon.2018.e00700
• 发表时间: 2018-07
• 期刊: Heliyon
• 影响因子: 4
• 作者: Macey PM;Thomas MA;Henderson LA
• 通讯作者: Henderson LA