Neuroanatomical and functional outcomes of pediatric obstructive sleep apnea

描述(申请人提供)：儿童阻塞性睡眠呼吸暂停(OSA)与执行功能受损有关，临床表现为学习、注意力、记忆和学习表现的障碍，以及神经心理发育异常。成人OSA与功能性脑激活的局部改变(增加和减少)、基于体素的形态计量学的皮质灰质体积减少以及弥散张量成像的皮质下白质完整性改变有关。目前尚不清楚OSA对发育中的大脑的影响是否相似，以及这些后果是否可逆。中心假设是儿童阻塞性睡眠呼吸暂停导致直接脑损伤，导致皮质灰质丢失、白质完整性改变、静息状态相互作用受损和任务相关的功能性脑激活。此外，这些异常情况可能不会轻易逆转。实验性睡眠片断导致海马区记忆和神经发生的长期增强受损，而睡眠不足进一步导致细胞应激。低氧可导致细胞丢失，促进细胞凋亡，激活神经元损伤的多种机制。破坏正常的-lt；1赫兹缓慢的皮质神经元振荡可以改变突触中的钙动力学，并可能阻止假定的突触降低睡眠的功能。阻塞性睡眠呼吸暂停综合征可能导致严重的神经元、髓鞘和突触损伤。我们研究的长期目标是确定OSA对大脑发育和儿童认知疾病的影响，以及作为成年后执行和情感障碍的危险因素。我们的研究将使用基于前沿磁共振成像(MRI)的解剖和功能神经成像技术，测量标准的多导睡眠图和神经心理变量，并计算标准和新的睡眠质量和睡眠呼吸指数。我们这项应用的具体目标是展示儿科OSA对1)皮质灰质和皮质下白质的影响，使用3特斯拉的高分辨率解剖磁共振成像；2)工作记忆(执行网络，包括外侧前额叶皮质)和编码(编码网络，包括海马体)任务相关激活的功能MRI。静息状态的大脑激活评估将补充上述方法。我们将评估健康年龄、体重指数、性别和Tanner分期匹配的对照组、治疗前和治疗后6个月(扁桃体切除术或正压)的差异。神经解剖学指标(皮质厚度、各向异性分数、纤维长度、表观扩散系数)和执行网络区域(例如，背外侧前额叶、顶叶后、前扣带回)的功能激活体积和血氧水平依赖的信号变化的相关性将与神经心理表现、神经解剖异常、功能成像异常和多导睡眠图疾病严重程度相关。 公共卫生相关性：睡眠呼吸暂停与睡眠期间气流反复受阻有关，导致睡眠中断和睡眠期间氧气下降。有人担心，这种变化可能会损害发育中的大脑。这项研究项目将使用磁共振成像，这是一种使用强大但安全的磁场来观察大脑结构和功能的技术，以研究睡眠呼吸暂停对儿童(8-13岁)大脑的影响。

DESCRIPTION (provided by applicant): Pediatric obstructive sleep apnea (OSA) is associated with impaired executive function, and manifests clinically as impairments in learning, attention, memory, and school performance, along with abnormal neuropsychological development. OSA in adults has been associated with regional alterations (both increases and decreases) in functional brain activation, cortical grey matter volume reductions on voxel-based morphometry, and altered subcortical white matter integrity on diffusion tensor imaging. It is unknown if the effects of OSA on a developing brain are similar, and if these consequences are reversible. The central hypothesis is that pediatric OSA causes direct brain injury that result in cortical grey matter loss, altered white matter integrity, impaired resting state interactions, and task-related functional brain activation. Moreover, these abnormalities may not be readily reversible. Experimental sleep fragmentation causes impaired hippocampal long-term potentiation of memory and neurogenesis, while sleep deprivation further leads to cellular stress. Hypoxia can cause cell loss, enhance apoptosis and activate multiple mechanisms of neuronal injury. Disruption of the normal < 1 Hz slow cortical neuronal oscillation can alter calcium kinetics in the synapses and perhaps prevent a putative synaptic downscaling function of sleep. OSA can plausibly result in significant neuronal, myelin, and synaptic injury. The long-term goals of our research are to determine the impact of OSA on brain development and pediatric cognitive morbidity, and as a risk factor for executive and affective dysfunction in adulthood. Our research will use cutting edge magnetic resonance imaging (MRI) based anatomical and functional neuroimaging techniques, measure standard polysomnographic and neuropsychological variables, and compute standard and novel sleep quality and sleep-breathing indices. Our specific aims for this application are to demonstrate the impact of pediatric OSA on 1) cortical grey matter and subcortical white matter, using high resolution anatomical magnetic resonance imaging at 3 Tesla; 2) working memory (executive network including the lateral prefrontal cortex) and encoding (encoding network including the hippocampus) task- related activation on functional MRI. Resting state brain activation assessments will complement the above approaches. We will assess differences from healthy age, body mass index, gender, and Tanner stage matched controls, pre and 6-months post treatment (tonsillectomy or positive airway pressure). Correlations of neuroanatomical indices (cortical thickness, fractional anisotropy, fiber length, apparent diffusion coefficient) and functional activation volumes and % blood oxygen level dependent signal change, in areas of the executive network (e.g., dorsolateral prefrontal, posterior parietal, anterior cingulate) will be explored in relation to neuropsychological performance, neuroanatomical abnormalities, functional imaging abnormalities, and polysomnographic disease severity. PUBLIC HEALTH RELEVANCE: Sleep apnea is associated with repeated obstructions of airflow during sleep, resulting in sleep disruption and drops in oxygen during sleep. There is concern that such changes can harm the developing brain. This research project will use magnetic resonance imaging, a technique that uses powerful but safe magnetic fields to look at brain structure and function, to study the impact of sleep apnea on the child's (age 8-13 years) brain.