Quantitation of Glymphatic Functioning in Sleep and Meditative States

摘要 脑网络功能和胶质淋巴系统成分随行为状态而变化，然而，非侵入性成像方法尚未应用于量化MM对胶质淋巴流量的影响。在这里，我们建议扩展我们正在进行的神经退行性疾病患者胶质淋巴功能障碍的研究，以测试关于健康状态下大量和血管周围流动对行为状态（清醒，睡眠和MM）的作用的基本假设。具体来说，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，但是由于缺乏这些疗法如何影响大脑生理学的客观，机械证据，这些做法并没有被所有医生广泛接受。这个问题是根本性的，因为在症状变化被定量、机制描述符证实之前，MM不会被广泛接受为治疗工具。MM被假设为基于与睡眠期间发生的类似的生理过程。最近的工作已经证明了胶质淋巴废物清除系统的作用，该系统主要在睡眠期间活跃，并用于清除大脑废物。在该系统中，从动脉周围到静脉周围空间的脑脊液（CSF）和间质液流出与潜在的脑膜和硬脑膜淋巴通道连通，以将蛋白质和废物清除到颈部淋巴结。 该系统的功能障碍最近被假设为一系列神经退行性疾病的基础。然而，胶质淋巴功能在人类中的特征仍然不完全，这主要是由于缺乏安全的方法来常规地和在不同的行为状态下量化系统成分。我们的工作重点是开发非侵入性磁共振成像方法，以量化（i）血管周围扩散，指示胶质淋巴电流;（ii）脑和外周组织血流动力学和功能;以及（iii）大量CSF流速。这些方法首先在具有已知病因的外周淋巴或脑血管功能障碍的个体中应用和验证，并且现在被用于评估胶质淋巴和相关的血管周围血流功能障碍如何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疾病患者胶质淋巴功能障碍的研究，以测试关于大量和血管周围CSF流动的作用的基本假设，以达到以下目的：（1）量化血管周围扩散，指示睡眠和觉醒期间的胶质淋巴电流;为了量化胶质淋巴流的这些测量之间的相似性，研究结果旨在告知传统和充分表征的大量CSF流动途径以及更新颖的胶质淋巴途径在MM训练期间和之后对大脑健康的相关性。研究结果应告知MM有助于活动性MM期间认知变化的机制，以及MM用作认知疗法的潜力。

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.