Quantitation of Glymphatic Functioning in Sleep and Meditative States

摘要 脑网络功能和淋巴系统成分随着行为状态的不同而不同，然而，目前还没有无创的成像方法来量化MM对淋巴血流的影响。在这里，我们建议扩展我们正在进行的神经退行性变患者淋巴功能障碍的研究，以测试关于大量和血管周围血流对健康中的行为状态(觉醒、睡眠和MM)的作用的基本假设。具体地说，正念冥想(MM)和相关的冥想练习对越来越多的人的心理健康至关重要，然而由于缺乏客观的、机械的证据来证明这些疗法如何影响大脑生理，这些做法并不被所有的医生广泛接受。这个问题是根本的，因为MM不会被广泛接受为一种治疗工具，直到症状变化被定量的、机械性的描述所证实。多发性硬化症的生理过程与睡眠时相似。最近的优雅作品展示了GLYPHIC废物清除系统的作用，该系统主要在睡眠时活跃，用于清除大脑废物产品。在这个系统中，脑脊液(CSF)和间质液体从动脉周围到静脉周围流出，与潜在的脑膜和硬膜淋巴通道相连，将蛋白质和废物清除到颈部淋巴结。最近，这个系统的功能障碍被认为是一系列神经退行性疾病的基础。然而，淋巴功能在人类中仍然没有完全的特征，这主要是因为缺乏安全的方法来对系统组件进行常规和跨不同行为状态的量化。我们的工作集中在开发无创磁共振成像方法，以量化(I)血管周围扩散，指示淋巴电流；(Ii)脑和周围组织血流动力学和功能；以及(Iii)脑脊液血流速度。这些方法首先在病因已知的外周淋巴或脑血管功能障碍患者中应用和验证，现在正被用于评估淋巴和相关的血管周围血流功能障碍如何可能介导神经退行性病理生理学。在这里，我们建议扩展我们正在进行的神经退行性变患者淋巴功能障碍的研究，以测试关于大量和血管周围脑脊液流动作用的基本假设，目的是(1)量化血管周围扩散，指示睡眠和清醒期间的淋巴电流；量化这些淋巴流动测量之间的相似性，并旨在(2)睡眠和开放意识MM。研究结果旨在告知传统的和特征良好的大量脑脊液流动途径，以及更新的淋巴途径，在MM训练期间和之后对大脑健康的相关性。研究结果应该为MM在活动期MM中促进认知变化的机制提供信息，以及MM作为认知疗法的潜力。

ABSTRACT Brain network function and glymphatic system components vary with behavioral state, however non-invasive imaging methods have not been applied to quantify the impact of MM specifically on glymphatic flow. Here, we propose to extend our ongoing studies of glymphatic dysfunction in individuals with neurodegeneration to test fundamental hypotheses regarding the role of bulk and perivascular flow on behavioral state (wake, sleep, and MM) in health. Specifically, mindfulness meditation (MM) and associated contemplative exercises are fundamental to the mental health of a growing fraction of the population, however these practices are not widely accepted by all medical practitioners owing to a lack of objective, mechanistic evidence of how these therapies impact cerebral physiology. This issue is fundamental, as MM will not be widely accepted as a therapeutic tool until symptomatic changes are substantiated by quantitative, mechanistic descriptors. MM is hypothesized to be grounded in similar physiological processes as occur during sleep. Recent elegant work has demonstrated the role of a glymphatic waste clearance system, which is primarily active during sleep and serves to clear cerebral waste products. In this system, cerebrospinal fluid (CSF) and interstitial fluid efflux from periarterial to perivenous spaces acts in communication with potential meningeal and dural lymphatic channels to clear protein and waste products to cervical lymph nodes. Dysfunction of this system has recently been hypothesized to underlie a range of neurodegenerative disorders. However, glymphatic function remains incompletely characterized in humans, largely due to a lack of safe methods for quantifying system components routinely and across different behavioral states. Our work has focused on developing non-invasive magnetic resonance imaging methods to quantify (i) perivascular diffusion, indicative of glymphatic currents; (ii) cerebral and peripheral tissue hemodynamics and function; and (iii) bulk CSF flow velocity. These methods were first applied and validated in individuals with peripheral lymphatic or cerebrovascular dysfunction of known etiology and are now being used to evaluate how glymphatic and associated perivascular flow dysfunction may mediate neurodegenerative pathophysiology. Here, we propose to extend our ongoing studies of glymphatic dysfunction in individuals with neurodegeneration to test fundamental hypotheses regarding the role of bulk and perivascular CSF flow to Aim (1) quantify perivascular diffusion, indicative of glymphatic currents, during sleep and wakefulness; to quantify similarities between these measures of glymphatic flow, and Aim (2) for sleep and open awareness MM. Study findings are intended to inform the relevance of the traditional and well-characterized bulk CSF flow pathway, as well as more novel glymphatic pathway, on cerebral health during and following MM training. Study findings should inform the mechanism by which MM contributes to cognitive changes during active MM, as well as the potential of MM to be used as a cognitive therapy.