The Investing Fascia–Carotid Sheath Multifactorial Superposition Hypothesis: A Six-Pathway Analysis of the Pathogenesis of Primary Headaches

Abstract Primary headaches include migraine, tension-type headache, and cluster headache, among other types, and their etiology has not yet been fully elucidated. Existing mechanistic research has established the central roles of trigeminovascular system activation, calcitonin gene-related peptide release, central sensitization, cortical spreading depression, and trigeminal autonomic reflexes in the pathophysiology of primary headaches (Goadsby et al., 2017; Ashina et al., 2021). However, these mechanisms mainly explain how headaches are generated and maintained; they still lack a unified upstream explanation for why the attack threshold is significantly lowered in certain patients. Clinical observations have repeatedly found that patients with primary headaches often have neck symptoms, and objective imaging evidence of cervical myofascial abnormalities is significantly associated with headache frequency (Hvedstrup et al., 2020; Sollmann et al., 2021; Lin et al., 2022; Sedlackova et al., 2022). This article proposes the “Investing Fascia–Carotid Sheath Multifactorial Superposition Hypothesis.” The hypothesis holds that chronic forward head posture, long-term stress, aging, and chronic low-grade inflammation may synergistically drive fibrosis of the superficial layer of the deep cervical fascia—the investing fascia (Cyron and Humphrey, 2017; Pirri et al., 2023). After the loss of elastic buffering capacity, abnormal mechanical stress generated by daily micromovements of the head and neck may be transmitted through the deep cervical fascial network to the carotid sheath (Zhang and Lee, 2002; Bond et al., 2023). The carotid sheath serves as an anatomical hub where “multiple structures coexist within a single sheath,” containing the internal carotid artery, internal jugular vein, vagus nerve, and cervical sympathetic trunk, and lying in close proximity to the deep cervical lymphatics and glymphatic outflow pathways (Struthoff et al., 2024; Louveau et al., 2015). Abnormal mechanical stress may produce pathological effects through six pathways: arterial, venous, lymphatic, glymphatic, sympathetic, and vagal. These pathways may be involved simultaneously or sequentially, share an anatomical hub spatially, and amplify one another functionally, potentially creating a multifactorial superposition effect that lowers the primary headache attack threshold in some patients and promotes attack maintenance. Among these, PIEZO1 mechanotransduction may activate trigeminal nerve endings and promote CGRP release (Mikhailov et al., 2019; Della Pietra et al., 2020; Alba et al., 2025; Dolgorukova et al., 2021; Della Pietra et al., 2024), while CGRP may in turn enhance the mechanical sensitivity of PIEZO1 (Gkouzioti et al., 2025). At the same time, PIEZO1 activation may also amplify nociceptive signals through the ATP-P2X3 receptor pathway (Giniatullin and Nistri, 2023), potentially forming a multi-pathway positive feedback amplification network; CGRP signaling may also regulate cerebrospinal fluid outflow through meningeal lymphatic vessels and maintain neuroinflammation (Nelson-Maney et al., 2024); pathological changes in the myodural bridge complex may lead to chronic headache through CGRP release (Song et al., 2024); Konishi et al. (2024) detected upregulated PIEZO1 expression in myofibroblasts of carotid atherosclerotic plaques, and Tereshenko et al. (2026) detected PIEZO2-positive mechanosensitive structures and upregulated CGRP in human trapezius fascia, providing human histological evidence for the mechanosensory capacity of the investing fascia system; however, direct verification of PIEZO1 expression in the human investing fascia is still needed. This hypothesis does not replace classical mechanisms of primary headache; rather, it attempts to provide a testable upstream cervicogenic mechanical trigger layer for these mechanisms and to offer a unified explanatory framework for the clinical heterogeneity and comorbidity of migraine, tension-type headache, and cluster headache. This hypothesis is still in the hypothesis-generating stage, and its core causal chain has not yet been directly verified in patients with primary headache. This article proposes testable predictions and a phased validation framework, and explicitly states that its scope of application is limited to the subgroup of primary headache patients with forward head posture, neck symptoms, and mechanical abnormalities of the deep cervical fascia.