Kollenburg Linda, Kurt Erkan, Mulleners Wim, Arnts Hisse, Robinson Christopher Louis, Poelen Janneke, Meier Kaare, Dominguez Moises, Ashina Sait, Vissers Kris
Department of Neurosurgery, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
The Migraine Clinic, Amsterdam 1083 HA, The Netherlands.
Brain. 2026 Mar 5;149(3):710-735. doi: 10.1093/brain/awaf361.
Chronic headache disorders have a tremendous impact on psychosocial functioning. Despite the availability of various treatment options, suboptimal management remains present in a subset of patients, leading to persistent suffering. Molecular mechanisms, regional activity patterns and connectivity pathways are crucial for understanding the pathophysiology, serving as a foundation for developing novel treatments, refining existing therapies, and ultimately optimizing the management of headache disorders. Nevertheless, articles combining fundamental and clinical aspects of the pathophysiology and treatment of headache disorders remain limited. The current literature review provides a thorough overview of the molecular mechanisms, regional activity patterns and connectivity pathways involved in migraine, cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC) and occipital neuralgia (ON), thereby bridging the gap between different fields of expertise. In this scoping review, literature on molecular mechanisms, regional activity and connectivity pathways for migraine, CH, PH, HC and ON has been collected from the PubMed, MEDLINE and EMBASE databases. Reports were also manually searched using the search function in Google Scholar, as well as reviews or references cited within the articles. In total, 130 and 97 articles, published between 1976 and 2024, are included in the analysis of the molecular mechanism and regional activity patterns/connectivity pathways, respectively. Molecular data show that the trigeminal nucleus caudalis is a central structure in headache pathology, comprising various neuropeptides and neurochemicals, including vasoactive intestinal peptide, glutamate, substance P and serotonin, and connecting the pathophysiology of these headache disorders. Sensitization of higher cortical brain areas, neuroinflammation within the trigeminal system and vasodilatation of cranial vessels seem to contribute to headache pain. Headache disorders are also associated with atypical regional activity patterns and connectivity pathways in pain processing areas, as well as the default mode network, salience network, and sensorimotor network. These abnormalities help explain the mechanisms underlying overall headache-related symptoms and additional manifestations unique to each headache disorder, including cortical spreading depression in migraine, rhythmicity of attacks in CH and autonomic symptoms in CH, PH and HC. The article fosters a deeper understanding of the molecular mechanisms, neuronal pathways and clinical symptoms involved in headache pathology across different fields of expertise. By bridging these perspectives, it provides essential insights for developing innovative treatment strategies and enhancing existing therapeutic options.
慢性头痛疾病对心理社会功能有巨大影响。尽管有多种治疗选择，但部分患者的治疗效果仍不理想，导致持续痛苦。分子机制、区域活动模式和连接通路对于理解病理生理学至关重要，为开发新疗法、改进现有疗法以及最终优化头痛疾病的管理奠定基础。然而，结合头痛疾病病理生理学和治疗的基础与临床方面的文章仍然有限。当前的文献综述全面概述了偏头痛、丛集性头痛（CH）、发作性偏侧头痛（PH）、持续性偏侧头痛（HC）和枕神经痛（ON）所涉及的分子机制、区域活动模式和连接通路，从而弥合了不同专业领域之间的差距。在这项范围综述中，从PubMed、MEDLINE和EMBASE数据库收集了关于偏头痛、CH、PH、HC和ON的分子机制、区域活动和连接通路的文献。还使用谷歌学术的搜索功能手动搜索了报告，以及文章中引用的综述或参考文献。在分子机制分析和区域活动模式/连接通路分析中，分别纳入了1976年至2024年发表的130篇和97篇文章。分子数据表明，三叉神经尾核是头痛病理学的核心结构，包含多种神经肽和神经化学物质，包括血管活性肠肽、谷氨酸、P物质和5-羟色胺，并连接这些头痛疾病的病理生理学。大脑高级皮质区域的敏化、三叉神经系统内的神经炎症和颅血管扩张似乎导致头痛疼痛。头痛疾病还与疼痛处理区域以及默认模式网络、突显网络和感觉运动网络中的非典型区域活动模式和连接通路有关。这些异常有助于解释总体头痛相关症状以及每种头痛疾病独特的其他表现的潜在机制，包括偏头痛中的皮质扩散抑制、CH发作的节律性以及CH、PH和HC中的自主神经症状。本文促进了对不同专业领域中头痛病理学所涉及的分子机制、神经元通路和临床症状的更深入理解。通过弥合这些观点，它为制定创新治疗策略和增强现有治疗选择提供了重要见解。
