Bridging the gap: molecular mechanisms, regional activity and connectivity in headache disorders

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.