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）是一个主要的公共卫生问题，严重影响1.5%至3%的美国成年人（300万至700万），导致严重的睡眠不足和在一天的后半部分坐着或休息时移动的冲动。工作效率下降20%，生活质量与关节炎和糖尿病等其他慢性病一样差或更差，心血管疾病风险增加。目前批准的多巴胺能治疗未能改善睡眠时间，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找到它们。目前的研究集中在感官特征上，未能解决RLS的一个重要方面;即“过度觉醒”或严重的慢性睡眠丧失，而没有明显的过度白天嗜睡。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所需的感觉和运动皮层活动，从而产生RLS症状。因此，过度觉醒导致RLS在试图休息时需要移动，并且无法维持睡眠。这种过度觉醒过程对睡眠（增加的觉醒时间）和皮质兴奋性（如经颅磁刺激（TMS）所示）的生物学后果被认为反映了兴奋性谷氨酸能活动程度的增加，因此受影响的大脑区域将在MR波谱（MRS）上显示出相对增加的谷氨酸（Glu）和谷氨酰胺（Gln）。也可能发生抑制活性和GABA的变化，但不如Glu/Gln的增加显著。我们的试点MRS数据发现了一个新的RLS异常：增加丘脑Glx（Glu + Gln），与睡眠过度觉醒的措施。Glx水平对Glu的神经递质作用没有特异性。在本项目中，将使用多导睡眠图（PSG）和TMS以及MRS的7T MRI研究RLS和匹配对照受试者，这些MRI可准确测量Gln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增加，并确定这是否也发生在运动和感觉皮质中。还将评价Glu、Gln和GABA之间的关系。其次，将评估Gln增加与对睡眠和皮层兴奋性（TMS）的过度觉醒效应之间的关系程度。这将证明，异常增加的Glu活性是RLS过度觉醒的主要原因，并从根本上改变了RLS的重点，使其更少地依赖于多巴胺，而更多地依赖于作为RLS主要特征的Glu过度觉醒。这是RLS研究和治疗开发的一个全新方向。过度觉醒的新概念为理解RLS增加了一个缺失的维度，即发现Glu异常及其与其他过度觉醒特征的中心关系。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，改变了对Glu药物的主要治疗的重点，MRS为评价药物治疗的益处提供了一个有用和可访问的措施。

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.