Research headed by teams at the University of Rochester Center for Translational Medicine and the University of Copenhagen describes for the first time how a spreading wave of disruption and the flow of fluid in the brain triggers headaches, detailing the connection between the neurological symptoms associated with aura and the migraine that follows.

由罗切斯特大学转化医学中心和哥本哈根大学团队领导的研究首次描述了破坏波的传播和大脑中的液体流动如何引发头痛，详细描述了与先兆相关的神经系统症状与偏头痛之间的联系。

Findings from the mouse studies identify a novel non-synaptic signaling mechanism between the brain and peripheral sensory system important for migraine. The results also identify proteins that could be responsible for headaches and may serve as targets for new migraine drugs..

来自小鼠研究的发现确定了大脑和外周感觉系统之间对偏头痛重要的新型非突触信号传导机制。研究结果还确定了可能导致头痛的蛋白质，并可能成为新偏头痛药物的靶标。。

“In this study, we describe the interaction between the central and peripheral nervous system brought about by increased concentrations of proteins released in the brain during an episode of spreading depolarization, a phenomenon responsible for the aura associated with migraines,” said Maiken Nedergaard, MD, DMSc, co-director of the University of Rochester Center for Translational Neuromedicine.

“在这项研究中，我们描述了中枢神经系统和外周神经系统之间的相互作用，这是由于扩散去极化过程中大脑中释放的蛋白质浓度增加所致，这种现象导致了偏头痛的先兆，”罗切斯特大学转译神经医学中心联合主任、医学博士梅肯·内德加德（MaikenNedergaard）说。

“These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies.” Nedergaard is lead author of the team’s published paper in Science, titled, “Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model.’.

“这些发现为我们提供了一系列抑制感觉神经激活的新靶点，以预防和治疗偏头痛，并加强现有疗法。”Nedergaard是该团队在《科学》杂志上发表的论文的主要作者，该论文题为“偏头痛模型中脑脊液溶质的流入直接激活三叉神经节神经元”。

It is estimated that one out of 10 people experience migraines, and in many of these cases the headache is preceded by an aura, a sensory disturbance that can include light flashes, blind spots, double vision, and tingling sensations or limb numbness. These symptoms typically appear five to 60 minutes prior to the headache..

据估计，每10个人中就有1个人患有偏头痛，在许多情况下，头痛之前会出现先兆，这是一种感觉障碍，可能包括闪光，盲点，复视，刺痛感或肢体麻木。这些症状通常出现在头痛前5至60分钟。。

The cause of aura, cortical spreading depression (CSD), is associated with a temporary depolarization of neurons and other cells caused by diffusion of glutamate and potassium that radiates like a wave across the brain, reducing oxygen levels and impairing blood flow. “… for a third of migraine patients, headache is preceded by aura, which is transient neurological deficits associated with CSD, a pathological depolarization of cortical tissue,” the authors wrote.

先兆的原因是皮质扩散抑制（CSD），它与谷氨酸和钾的扩散引起的神经元和其他细胞的暂时去极化有关，谷氨酸和钾像波一样在大脑中辐射，降低氧气水平并损害血流。作者写道：“对于三分之一的偏头痛患者来说，头痛之前会出现先兆，这是与CSD相关的短暂性神经功能缺损，CSD是皮质组织的病理性去极化。”。

Most frequently, the depolarization event is located in the visual processing center of the brain cortex, hence the visual symptoms that first herald a coming headache..

最常见的是，去极化事件位于大脑皮层的视觉处理中心，因此视觉症状首先预示着即将到来的头痛。。

While migraines auras arise in the brain, the organ itself cannot sense pain. During the aura phase, it is believed that waves of CSD are spontaneously triggered in the cerebral cortex or cerebellum, which, in turn, leads to the activation of pain receptors (nociceptors) in the peripheral nervous system (PNS).

虽然偏头痛先兆出现在大脑中，但器官本身无法感觉到疼痛。在先兆阶段，据信CSD波在大脑皮层或小脑中自发触发，进而导致周围神经系统（PNS）中疼痛受体（伤害感受器）的激活。

Previous research has suggested that CSD events release small molecules through the CSF that activate sensory nerve endings in the external tissues of the CNS (central nervous system), “outside” of the blood-brain barrier. These nerve endings are not exposed to cerebrospinal fluid (CSF)..

。这些神经末梢不暴露于脑脊液（CSF）。。

However, the process of communication between the brain and peripheral sensory nerves in migraines has largely remained a mystery. As the team continued, “It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons.”

然而，偏头痛患者大脑和周围感觉神经之间的交流过程在很大程度上仍然是一个谜。正如该团队继续说的那样，“目前尚不清楚皮质中的病理事件如何影响外周感觉神经元。”

Nedergaard and her colleagues at the University of Rochester and the University of Copenhagen are pioneers in understanding the flow of fluids in the brain. In 2012, the Nedergaard lab was the first to describe the glymphatic system, which uses CSF to wash away toxic proteins in the brain. In partnership with experts in fluid dynamics, the team has built detailed models of how the CSF moves in the brain and its role in transporting proteins, neurotransmitters, and other chemicals..

内德·加德（Nedergaard）和她在罗切斯特大学（University of Rochester）和哥本哈根大学（University of Copenhagen）的同事是理解大脑中液体流动的先驱。2012年，Nedergaard实验室首次描述了淋巴系统，该系统使用脑脊液洗去大脑中的有毒蛋白质。该团队与流体动力学专家合作，建立了脑脊液在大脑中如何运动及其在运输蛋白质、神经递质和其他化学物质中的作用的详细模型。。

The most widely accepted theory is that nerve endings resting on the outer surface of the membranes that enclose the brain are responsible for the headaches that follow an aura. “Current evidence suggests that migraine headache is driven by activation of sensory nerve endings in the dura mata,” the investigators noted.

最广为接受的理论是，位于大脑外膜表面的神经末梢是先兆后头痛的原因。研究人员指出：“目前的证据表明，偏头痛是由硬脑膜中感觉神经末梢的激活引起的。”。

The new study, which was conducted in mice, describes a different route and identifies proteins, many of which are potential new drug targets, that may be responsible for activating the nerves and causing pain..

这项在小鼠身上进行的新研究描述了一种不同的途径，并鉴定了可能负责激活神经和引起疼痛的蛋白质，其中许多蛋白质是潜在的新药靶标。。

As the depolarization wave spreads, neurons release a host of inflammatory and other proteins into CSF. In their series of experiments in mice, the researchers showed how CSF transports these proteins to the trigeminal ganglion, a large bundle of nerves that rests at the base of the skull and supplies sensory information to the head and face.

随着去极化波的传播，神经元将大量炎症和其他蛋白质释放到脑脊液中。在他们对小鼠进行的一系列实验中，研究人员展示了脑脊液如何将这些蛋白质转运到三叉神经节，三叉神经节是位于颅底的一大束神经，为头部和面部提供感觉信息。

To do this, the team explained, “We developed a preparation for trigeminal ganglion imaging in vivo.”.

为此，该团队解释道：“我们开发了一种体内三叉神经节成像的制剂。”。

It was assumed that the trigeminal ganglion, like the rest of the peripheral nervous system, rested outside the blood-brain barrier, which tightly controls what molecules enter and leave the brain. However, using a combination of proteomic, histological, imaging, and functional approaches in a mouse model of classical migraine, the authors have identified a signaling pathway between the CNS and PNS at the trigeminal ganglion.

据推测，三叉神经节与周围神经系统的其他部分一样，位于血脑屏障之外，血脑屏障严格控制哪些分子进入和离开大脑。。

The researchers’ studies in mice identified a previously unknown gap in the barrier that allowed CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to proteins released by the brain. The results found that “… CSF transports solutes directly into the trigeminal ganglion and activates receptors on trigeminal cells … CSF transport comprises a humoral signaling pathway between the brain and the trigeminal ganglion,” they further stated.

研究人员在小鼠身上进行的研究发现，屏障中存在一个以前未知的间隙，使脑脊液直接流入三叉神经节，使感觉神经暴露于大脑释放的蛋白质。结果发现“……脑脊液将溶质直接转运到三叉神经节并激活三叉神经细胞上的受体……脑脊液转运包括大脑和三叉神经节之间的体液信号通路”，他们进一步指出。

“… as such, this flow route effectively permits fluid-borne communication between the CNS and PNS.”.

“…因此，该流动路线有效地允许CNS和PNS之间的流体通信。”。

After inducing CSD in experimental animals the team analyzed molecules in the CSF reaching the trigeminal ganglion, and their potential role in triggering headache. They first confirmed that CSD led to changes in gene expression and CSF protein content. “Bottom-up mass spectrometry on CSF obtained from adult mice with and without exposure to CSD detected proteins from 1,425 different genes.

在实验动物中诱导CSD后，研究小组分析了CSF中到达三叉神经节的分子及其在引发头痛中的潜在作用。他们首先证实CSD导致基因表达和CSF蛋白含量的变化。“从成年小鼠获得的脑脊液自下而上的质谱法检测到1425种不同基因的蛋白质，无论是否暴露于CSD。

The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression. “After CSD, the expression of 155 of these proteins (11%) changed, and of these 155 proteins, 67 changed by more than twofold (21 up-regulated and 46 down-regulated) … We next sought to evaluate whether humoral agents within the CSD proteome could potentially drive headache by activating receptive cells.”.

皮质扩散抑制后，脑脊液中发现的几种蛋白质的浓度增加了一倍以上。“CSD后，这些蛋白质中的155种（11%）的表达发生了变化，在这155种蛋白质中，67种变化了两倍以上（21种上调，46种下调）……我们接下来试图评估CSD蛋白质组中的体液因子是否可能通过激活接受细胞来驱动头痛。”。

Their analyses identified within the up-regulated CSD proteome 12 protein ligands pairing with 28 distinct receptors in the ganglion. One of the proteins, calcitonin gene-related peptide (CGRP), is already the target of a new class of CGRP inhibitor drugs in development to treat migraine. “CGRP is encoded by the gene Calca, and the CSF transport of CGRP to the trigeminal ganglion could be directly involved in the development of migraine headache,” they wrote.

他们的分析在上调的CSD蛋白质组中鉴定出12种蛋白质配体与神经节中的28种不同受体配对。其中一种蛋白质降钙素基因相关肽（CGRP）已经成为正在开发的治疗偏头痛的新型CGRP抑制剂药物的靶标。他们写道：“CGRP由基因Calca编码，CGRP向三叉神经节的脑脊液转运可能直接参与偏头痛的发展。”。

“CGRP has also been found elevated in the CSF of migraine patients without aura, suggesting that in these patients as well, the trigeminal CSF pathway could drive headache.” Other identified proteins are known to play a role in other pain conditions, such as neuropathic pain, and are likely important in migraine headaches as well.

“在没有先兆的偏头痛患者的脑脊液中也发现CGRP升高，这表明在这些患者中，三叉神经-脑脊液通路也可能导致头痛。”已知其他已鉴定的蛋白质在其他疼痛状况（如神经性疼痛）中起作用，并且可能在偏头痛中也很重要。

“Several of the ligands and receptors had previously been shown to be involved in processes such as hyperalgesia and inflammation,” the scientists further pointed out..

。。

“We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system,” said first author Martin Kaag Rasmussen, PhD, a postdoctoral fellow at the University of Copenhagen. “Among the identified molecules are those already associated with migraines, but we didn’t know exactly how and where the migraine-inducing action occurred.

第一作者、哥本哈根大学博士后马丁·卡格·拉斯穆森博士说：“我们已经发现了一种新的信号通路和几种激活周围神经系统感觉神经的分子。”。“在已确定的分子中，有一些已经与偏头痛有关，但我们不知道偏头痛诱导作用是如何以及在何处发生的。

Defining the role of these newly identified ligand-receptor pairs may enable the discovery of new pharmacological targets, which could benefit the large portion of patients not responding to available therapies.”.

定义这些新发现的配体-受体对的作用可能有助于发现新的药理学靶点，这可能有利于大部分对可用疗法无反应的患者。”。

The researchers also observed that the transport of proteins released in one side of the brain reaches mostly the nerves in the trigeminal ganglion on the same side, potentially explaining why pain occurs on one side of the head during most migraines. “This signaling route may therefore account for the unilaterality of migraine headache, as well as the typical delay between aura and headache onset.”.

研究人员还观察到，大脑一侧释放的蛋白质的运输主要到达同一侧三叉神经节的神经，这可能解释了为什么在大多数偏头痛期间疼痛发生在头部的一侧。“因此，这种信号通路可能解释了偏头痛的单侧性，以及先兆和头痛发作之间的典型延迟。”。

“Our data indicate that CSF transports solutes from the cortex to the trigeminal ganglion and, by so doing, establishes a nonsynaptic route of communication between the CNS and PNS that underlies the pathogenesis of classical migraine,” they concluded in their paper. “… defining the role of the ligand-receptor pairs identified in the CSD proteome may enable the discovery of new pharmacological targets, to the benefit of the large portion of patients not responding well to currently available therapies.”.

他们在论文中总结道：“我们的数据表明，脑脊液将溶质从皮质转运到三叉神经节，从而建立了中枢神经系统和PNS之间的非突触通讯途径，这是经典偏头痛发病机制的基础。”。“…定义CSD蛋白质组中鉴定的配体-受体对的作用可能有助于发现新的药理学靶标，这有利于大部分对目前可用疗法反应不佳的患者。”。

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新脑脊液偏头痛周围神经系统