下丘脑和三叉神经血管反射通路参与丛集性头痛发生的机制研究

Cluster headache (CH) includes the in-attack phase in the cluster period, the out-of-attack phase in the cluster period and the phase outside the cluster period. The studies on CH based on neuroimaging and biochemisty indicate that the hypothalamus and trigeminovascular reflex pathways are involved in the pathogenesis of CH. However, the underlying mechanism is not completely understood. Therefore, the present study will investigate the dysfunctional interacts of the hypothalamus and trigeminovascular reflex pathways in the pathophysiology of CH. The research contents in detail are mainly divided into three parts. The first part is to detect the alteration process of the brain activity, brain functional correlations and functional network coactivation among the different phases of CH separately by the regional homogeneity (ReHo), functional connectivity (FC) and independent component analysis (ICA) methods based on the resting-state functional magnetic resonance imaging (RS-fMRI) techniques. The second part is to demonstrate the RS-fMRI findings by measuring the changes of the hypocretin (HCRT), melatonin (MT) and calcitonin gene-related peptide (CGRP) levels in the cerebrospinal fluid (CSF) of CH patients during different phrases based on the biochemical techniques. The third part is to identify the pathophysiological process of the hypothalamus and trigeminovascular pathway involved in CH by the correlational analysis between the RS-fMRI results and the biochemical results. The final objective is to gain additional insight into the pathogenesis of CH, and further provide the theoretical basis for the better preventive treatment of CH.

丛集性头痛（CH）分为3个时相：丛集期内头痛发作期、丛集期内头痛缓解期、非丛集期。神经影像学及生化学研究提示下丘脑及三叉神经血管反射通路参与了CH的发生，但是，二者如何导致CH的发生尚不清楚。因此，本研究拟在前期工作基础上对CH三个时相间的演变过程进行静息状态fMRI研究，采用局部一致性、功能连接、独立成分分析方法从脑活动、脑区功能连接、脑功能网络共同活动三个方面来探究下丘脑通过何种通路参与了CH的周期性发作，下丘脑是否通过激活三叉神经血管反射进而导致CH的急性发作；同时采用放免法分析CH患者脑脊液中下丘脑泌素、褪黑素、降钙素基因相关肽的水平及其相关性的演变情况，从生化学角度验证fMRI的结果；最后采用相关性分析方法分析fMRI结果与生化学结果的相关性，确认下丘脑和三叉神经反射通路参与CH发生的机制过程。本研究旨在更深入地了解CH的发生机制，为指导CH预防性治疗的时机及办法提供理论基础。

目前神经影像学和生化学研究提示下丘脑及三叉神经血管反射通路可能参与了丛集性头痛的发生，但是，具体机制尚不清楚。因此，本研究利用静息状态功能磁共振成像（RS-fMRI）技术，采用局部一致性、功能连接、独立成分分析方法了解脑功能的变化，来推测下丘脑、三叉神经血管反射通路异常参与丛集性头痛的可能机制；利用放射免疫技术检测血浆中下丘脑泌素、褪黑素、降钙素基因相关肽、P物质的水平，从生化学角度推测下丘脑、三叉神经血管反射通路异常参与丛集性头痛的可能机制。结果发现，丛集性头痛患者急性发作期突显网络活动较自发缓解期增强，丛集性头痛患者双侧丘脑-突显网络共同活动下降，双侧下丘脑-默认网络及双侧丘脑-默认网络共同活动下降，提示三叉神经血管反射二级中枢丘脑与疼痛相关网络如突显网络、默认网络间共同活动下降，可能导致了下行抑制通路功能减弱，进而导致了丛集性头痛的发生；丛集性头痛患者丛集期内头痛缓解期较正常对照、偏头痛患者血浆下丘脑泌素-1较正常对照升高（P<0.05），褪黑素、降钙素基因相关肽、P物质无明显变化（P>0.05），偏头痛患者头痛缓解期较正常对照血浆下丘脑泌素-1、褪黑素、降钙素基因相关肽、P物质均无明显变化（P>0.05），提示丛集性头痛患者可能存在下丘脑功能异常，而偏头痛患者可能不存在下丘脑功能异常。本研究结果进一步深化认识了下丘脑和三叉神经血管反射通路参与丛集性头痛发生的可能机制，为丛集性头痛的预防和个体化治疗提供了一定的理论基础。

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