Glutamate, hyperarousal and restless legs syndrome

描述（由申请人提供）：中度至重度不宁腿综合征（RLS）是一个重大的公共卫生问题，严重影响1.5%至3%的美国成年人（300万至700万），导致严重睡眠不足，在一天的后半段坐着或休息时急于活动。工作效率下降了20%，生活质量与关节炎和糖尿病等其他慢性疾病一样差，甚至更差，心血管疾病的风险也在增加。目前批准的多巴胺能治疗不能改善睡眠时间，产生冲动行为，并可能使RLS恶化。需要新的治疗方法和新的研究方向来发现它们。目前的研究集中在感觉特征上，但未能解决RLS的一个重要方面；即“过度觉醒”或严重的慢性睡眠缺失，没有明显的白天过度嗜睡。这种过度觉醒通过压倒正常的抑制过程来减少休息和睡眠时的感觉和运动皮层活动，从而产生睡眠倒睡症症状。因此，过度觉醒会导致睡眠动动症患者在试图休息时需要移动，也会导致无法保持睡眠。这种高度觉醒过程对睡眠（清醒时间增加）和皮层兴奋性（经颅磁刺激（TMS）证明）的生物学后果被认为反映了兴奋性谷氨酸活性程度的增加，因此受影响的大脑区域在MR波谱（MRS）上显示谷氨酸（Glu）和谷氨酰胺（Gln）的相对增加。抑制活性和GABA的变化也可能发生，但不如Glu/Gln的增加明显。我们的初步MRS数据发现了睡眠倒睡症的一个新异常：丘脑Glx （Glu + Gln）的增加与过度觉醒的睡眠测量密切相关。Glx水平对Glu的神经递质作用没有特异性。在这个项目中，RLS和匹配的对照受试者将使用多导睡眠图（PSG）、TMS和7T MRI进行MRS研究，后者提供了Gln水平的准确测量，Glu水平主要反映神经递质Glu活性。第一个目的是确认谷氨酰胺在丘脑中的增加，并确定这种情况是否也发生在运动和感觉皮层中。Glu， Gln和GABA之间的关系也将被评价。其次，评估Gln增加与睡眠和皮质兴奋性（TMS）的高唤醒效应之间的关系程度。这将证明异常升高的Glu活动是导致RLS过度唤醒的主要原因，并从根本上改变了RLS对多巴胺的重视程度，更多地强调了作为RLS主要特征的Glu过度唤醒。这是RLS研究和治疗发展的一个全新方向。高唤醒的新概念为理解RLS增加了一个缺失的维度，即发现Glu异常及其与其他高唤醒特征的中心关系。它为开发新的动物和细胞RLS研究提供了机会。它为药物治疗的发展提供了新的方向，使主要治疗的重点转向Glu药物，并为评价药物治疗效果提供了一种有用的、可获得的方法。

DESCRIPTION (provided by applicant): Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound sleep loss and an urge to move during sitting or resting in the latr part of the day. Work productivity is decreased by 20%, quality of life is as bad as or worse than that for other chronic diseases, e.g. arthritis and diabetes, and there is increased cardio- vascular disease risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive behaviors and may make RLS worse. New treatments and new research directions to find them are needed. The current research focus on the sensory features has failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu- hyperarousal as a major feature of RLS. This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features. It opens the opportunity to develop new animal and cell RLS research. It provides new directions for medication treatment development, changes the emphasis for primary treatment toward Glu drugs and the MRS provides a useful and accessible measure for evaluating medication treatment benefits.