Glutamate, hyperarousal and restless legs syndrome

描述(申请人提供)：中到重度不宁腿综合症(RLS)是一个主要的公共卫生问题，严重影响1.5%到3%的美国成年人(300万到700万)，导致严重的睡眠损失和在一天中坐着或休息时的运动冲动。工作效率下降了20%，生活质量与其他慢性疾病(如关节炎和糖尿病)一样糟糕，甚至更差，心血管疾病的风险也增加了。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寻找它们。目前对感觉特征的研究未能解决RLS的一个重要方面，即没有明显白天过度困倦的“过度唤醒”或严重的慢性睡眠损失。这种高度觉醒通过压倒正常的抑制过程来产生RLS症状，而正常的抑制过程是减少休息和睡眠所需的感觉和运动皮质活动所必需的。因此，过度觉醒既产生了试图休息时需要运动的RLS，也产生了无法维持睡眠的RLS。这种高觉醒过程对睡眠(唤醒时间延长)和皮质兴奋性(如经颅磁刺激(TMS)所证明的)的生物学后果被认为反映了兴奋性谷氨酸能活动的增加，因此在磁共振波谱(MRS)上，受影响的大脑区域将显示相对增加的谷氨酸(Glu)和谷氨酰胺(Gln)。抑制活性和GABA也可能发生变化，但比Glu/Gln的增加要小。我们的试点MRS数据在RLS中发现了一个新的异常：丘脑GLX(Glu+Gln)增加，这与高度唤醒的睡眠指标有很好的相关性。Glx水平并不是Glu神经递质所特有的。在这个项目中，将使用多导睡眠图(PSG)、TMS和7T MRI对RLS和匹配对照组的受试者进行研究，MRS提供准确的Gln水平测量，这主要反映神经递质Glu的活性。第一个目标是确认谷氨酰胺在丘脑中的增加，并确定这是否也发生在运动和感觉皮质中。还将评估谷氨酸、谷氨酰胺和GABA之间的关系。其次，将评估Gln升高与过度觉醒对睡眠和皮质兴奋性(TMS)的影响之间的关系程度。这将证明，异常升高的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，减少了对多巴胺的重视，更多地将Glu-高觉醒作为RLS的主要特征。这是RLS研究和治疗发展的一个全新方向。超唤醒的新概念为理解RLS增加了一个缺失的维度，即发现了Glu异常及其与其他超唤醒特征的中心关系。它为发展新的动物和细胞RLS研究打开了机会。它为药物治疗的发展提供了新的方向，改变了最初治疗的重点向谷氨酸药物转移，MRS为评估药物治疗的益处提供了一种有用的和可获得的手段。

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.