Investing Fascia Tension as a Potential Mechanical Node in Cerebral Hypoperfusion and Ocular Pathology: A Mechanistic Hypothesis with Quantitative Predictions and a Multi-Scale Validation Framework

1. Introduction

The investing fascia is the most superficial layer of the deep cervical fascia, attaching posteriorly to the ligamentum nuchae, enclosing the sternocleidomastoid and trapezius muscles anteriorly, and continuous with the pretracheal and prevertebral fasciae, together participating in the formation of the carotid sheath [1]. The systematic review by Bond et al. [1] explicitly states that the carotid sheath is a fibrous tunnel formed by the convergence of the three layers of the deep cervical fascia (investing, pretracheal, and prevertebral), extending from the skull base superiorly to the mediastinum inferiorly. Through cadaveric dissection, Komune et al. demonstrated that the dense attachment of the investing fascia to the skull base provides bony anchor points for fascial mechanical transmission [2]. Snosek et al. found continuous collagen fiber connections between the investing fascia, the pretracheal fascia, and the alar fascia, providing an anatomical basis for the potential trans-layer transmission of residual passive tension across the three layers of the deep cervical fascia [3]. Through cadaveric and radiological analyses, Schachtel et al. further confirmed the continuity and mechanical coupling of fascial layers in the lateral skull base region [4]. The investing fascia is richly supplied with blood vessels, lymphatic vessels, and multiple types of nerve endings. The systematic review by Suarez-Rodriguez et al. [5] indicates that fascial tissue contains free nerve endings (nociceptors), Pacinian corpuscles and Ruffini endings (mechanoreceptors), as well as autonomic nerve fibers, and that the number of nociceptors increases significantly under pathological conditions, suggesting that the mechanical state of the investing fascia may influence the cervical neurovascular microenvironment through neural reflex mechanisms.

Deep fascia is a highly viscoelastic connective tissue whose mechanical response exhibits nonlinear, anisotropic, and viscoelastic characteristics [6,7]. The systematic review by Holzapfel et al. [7] points out that multiple collagen-dominated soft tissues (including arteries, skin, and tendons) can be described using similar nonlinear elastic or inelastic constitutive relationships under mechanical loading. The mechanobiological framework by Cyron and Humphrey [6] indicates that load-bearing soft tissues undergo adaptation or pathological remodeling through extracellular matrix (ECM) mass turnover and prestress adjustment under sustained mechanical loading, and that a critical threshold of mechanobiological stability exists beyond which mechanical homeostasis is disrupted. The structural integrity of the investing fascia is a prerequisite for maintaining neurovascular function within the carotid sheath. On this basis, it is inferred that when this fascia develops pathologically increased tension due to chronic postural loading (such as prolonged smartphone use with head flexion), repetitive microtrauma, or inflammation, mechanical homeostasis is disrupted; the increased tension may theoretically alter the mechanical boundary conditions of the carotid sheath through mechanotransduction, thereby potentially triggering downstream pathophysiological cascades.

The anatomical study by Raja et al. [8] systematically elucidated the proximal components of the posterior myofascial chain—the deep cervical fascia connects to the epicranial aponeurosis, which in turn continues to the fascial sheath of the eyeball (Tenon's capsule), forming an anatomical fascial continuum from the cervical soft tissues to the eye. The same group also confirmed the cervical-to-thoracic fascial continuity in noncardiac chest pain [9], jointly indicating that cervical fascia serves as a systemic network hub connecting multiple distal regions. From the perspective of ligamentous cervical instability, Hauser et al. systematically articulated an etiological framework for obstruction of fluid flow into and out of the brain induced by the forward head-facedown lifestyle [10]. This framework posits that prolonged forward head posture induces slow "creep" stretching of the posterior cervical ligament complex, leading to cervical instability, straightening of the cervical curvature, and even kyphosis, which in turn causes anterior displacement of the atlas, compressing the internal jugular vein and vagus nerve within the carotid sheath. Building on this foundation, the same group further proposed the "cervical oculopathy" hypothesis, explicitly identifying cervical structural abnormalities (particularly anterior C1 atlas displacement) via internal jugular vein compression and vagus nerve involvement as two key pathways linking the neck to the eye [11]. This provides independent external theoretical reference for positioning the investing fascia as a potential upstream mechanical node in the aforementioned pathways—the two hypotheses occupy different levels of the causal chain, complementing rather than competing with each other (see Discussion).

The above-described coupling relationship raises a core question: could abnormal investing fascial tension simultaneously influence cerebral blood supply and ocular function through multi-pathway mechanisms, thereby potentially constituting a long-overlooked mechanical node underlying cerebral hypoperfusion and a spectrum of ocular disorders? The anatomical connection between the investing fascia and the carotid sheath has been confirmed by multiple studies. Zhang and Lee found that this fascia is absent between the sternocleidomastoid and trapezius muscles, leaving the carotid sheath directly exposed to subcutaneous tissue through this interval [12]—an anatomical feature suggesting that superficial soft tissue tension may provide the structural conditions for direct transmission to the carotid sheath. Deep fascia exhibits significant force transmission capacity. Through multi-axial mechanical testing, Aparici-Gil et al. demonstrated that deep fascia displays marked mechanical anisotropy under different strain conditions—under uniaxial tension, the longitudinal stress was approximately 6.6 times greater than the transverse stress (3.96 MPa vs. 0.6 MPa, at λ=1.055)—and established a coupled exponential strain-energy function constitutive model capable of simultaneously reproducing uniaxial, biaxial, and planar tensile strain states [13]. The systematic review by Zullo et al. [14] indicates that aging is accompanied by increased fascial stiffness and decreased elasticity, reduced skeletal muscle mass and strength, and impaired neuromuscular function; the structural and functional coupling among these three elements diminishes, potentially leading to decreased myofascial force transmission efficiency and impaired motor coordination.

Previous studies have established associations between the neck and brain/eye pathology from multiple perspectives: In terms of cerebral blood supply, patients with cervicogenic headache exhibit reduced middle cerebral artery blood flow velocity, and cervical mobilization can significantly increase internal carotid and vertebral artery blood flow velocity [17]; myofascial release has demonstrated significant efficacy for tension-type headache, cervicogenic headache, and migraine [18], with its neuroanatomical basis traceable to the trigemino-cervical nucleus convergence theory [19,21]. Regarding venous aspects, cervicogenic internal jugular vein compression syndrome [22] and dynamic venography-confirmed internal jugular vein compression [23] provide clinical evidence for impaired venous return affecting intracranial pressure [24]. Regarding lymphatic aspects, elevated intraocular pressure following cervical lymphadenectomy [26] and the anatomical association between aqueous outflow channels and the lymphatic system [27] suggest that cervical lymphatic status may influence ocular fluid dynamics. Regarding neurological aspects, the mechanosensory capacity of the trapezius fascia [28] and the nerve distribution around the carotid bifurcation [31] provide an anatomical foundation for the influence of cervical fascial tension on autonomic nervous function.

The above evidence all focuses on single pathways; no one has yet systematically proposed that these pathways might share a common upstream mechanical driver—namely, the tension state of the investing fascia. The present hypothesis attempts to fill this gap, proposing the investing fascia as a key node connecting multiple pathways; its anatomical basis is detailed in Level 2.

2. Hypothesis Framework

The following five-level causal chain is presented step by step: first, the potential triggers for primary fibrosis of the investing fascia (Level 1); second, the anatomical basis and theoretical conditions for trans-layer transmission (Level 2); third, the theoretical mechanotransduction mechanism involving PIEZO channels as candidate core molecular switches (Level 3); fourth, the theoretical differential effects on five downstream pathways (Level 4); and finally, the theoretical possibility of pathological positive feedback loops and their spatial propagation (Level 5). On this basis, testable predictions and a three-tiered validation framework are proposed. The following five-level causal chain is based on logical inference and reasonable extrapolation from the existing literature; each level has specific anatomical or cell biological support, but the continuous causal relationships between levels currently lack direct human validation data.

3. Core Hypothesis Statement

Based on this biomechanical coupling model, this study proposes as a working hypothesis that increased tension in the investing fascia—if it occurs and propagates as theorized—could exert biomechanical influences on cervical neurovascular structures via mechanisms that may involve PIEZO1/2-mediated mechanotransduction. This could, in principle, contribute to cerebral hypoperfusion and ocular pathologies through five distinct but interconnected pathways. This formulation is a testable mechanistic hypothesis, not a demonstrated causal pathway; each of its constituent links requires independent experimental verification.

Summary in one sentence: This hypothesis posits that following fibrosis of the investing fascia and loss of elasticity, residual passive tension may, in theory, be transmitted across the three-layer fascial network to the carotid sheath, where it may, through PIEZO channel-mediated mechanotransduction, simultaneously affect blood vessels, nerves, and lymphatics, ultimately potentially driving cerebral hypoperfusion and ocular pathology. Every link in this causal chain awaits independent validation.

3.1. Level 1: Primary Event—Pathological Increase in Investing Fascial Tension and Fibrosis

Initial triggers for pathologically increased investing fascial tension may include chronic postural loading, repetitive microtrauma, local inflammation, cold environment exposure, and adverse lifestyle habits, with aging serving as a contextual synergistic factor that may confer susceptibility to fibrotic remodeling through age-related increases in fascial stiffness and decreases in elasticity [14]. The theoretical framework of Cyron and Humphrey [6] demonstrates that the remodeling of collagen-dominated soft tissues under mechanical loading follows the principles of mass turnover and prestress adjustment; beyond the threshold of mechanobiological stability, tissues transition from adaptation to pathological fibrosis. Based on this framework, this hypothesis posits that when tension persistently exceeds the physiological threshold, fascial fibroblasts may sense changes in the mechanical microenvironment, potentially upregulating the TGF-β1/YAP signaling pathway through PIEZO1-mediated Ca²⁺ influx, thereby potentially driving myofibroblast phenotypic transformation and excessive deposition of collagen (COL1A1, COL3A1). Pirri et al. redefined fascia as a mechanobiological hub and stem cell reservoir [34,35]; Huang et al. positioned it as a key integrator in health and disease from a functional systems perspective [36]; and Fede et al. clarified the spatial distribution of fibroblasts, mast cells, and sensory nerve endings within fascia [37]. At the molecular level, Kirkness and Scarlata elaborated on the mechanisms by which fascia transitions between adaptation and dysfunction, emphasizing the decisive roles of collagen cross-linking, matrix metalloproteinase activity, and hydration status in determining fascial mechanical properties [38].

The anatomical location of the investing fascia makes it the structure within the cervical fascial system most directly subjected to external mechanical loading. Unlike the pretracheal and prevertebral layers, this fascia lies immediately deep to the platysma, attaches superiorly to the skull base and mandible, continues inferiorly to the clavicle and sternum, and lacks bony protection anteriorly and laterally—an anatomical feature suggesting that the sustained tensile forces generated by prolonged forward head posture may act first upon this layer. Notably, the absence of this fascia between the sternocleidomastoid and trapezius muscles [12] allows subcutaneous tissue tension to potentially bypass this fascia and transmit directly to the deeper carotid sheath. On this basis, this hypothesis proposes that the investing fascia may be more susceptible to primary fibrotic remodeling. Shear-wave elastography (SWE) provides a reliable methodological foundation for in vivo measurement of investing fascial stiffness [39].

In a prospective controlled study (preprint) involving 84 participants, Muthukrishnan and Raja Durai [42] employed multimodal ultrasound elastography to compare the cervicothoracic fascial mechanical properties of long-term smartphone users (≥6 hours daily for ≥2 years) versus controls. They found that the cervicothoracic fascial shear modulus in the smartphone group (18.4 ± 3.2 kPa) was significantly higher than that in the control group (11.6 ± 2.1 kPa), suggesting that prolonged postural loading can lead to significantly increased cervicothoracic fascial stiffness (approximately 59% elevation). The fascial sliding displacement in the smartphone group (2.1 ± 0.8 mm) was significantly smaller than that in the control group (4.3 ± 1.2 mm), suggesting impaired inter-fascial sliding function—this precisely corresponds to the quantitative mechanical manifestation of "loss of elastic compensation" described in this hypothesis. After 12 weeks of fascia-targeted intervention therapy, fascial stiffness decreased by 22.3% (a reduction of 4.1 ± 1.8 kPa), providing intervention-based reverse evidence for the plasticity of fascial mechanical status. Of note, this study is currently published as a preprint, and its data require confirmation through formal peer review. Nevertheless, the "cervicothoracic fascia" measured anatomically corresponds to the continuation of the superficial layer of the deep cervical fascia toward the thorax, belonging to the same fascial layer as the investing fascia at a different segment, with comparable mechanical properties. The above findings provide preliminary population-based quantitative clues for the initial link of "chronic static postural loading → investing fascial fibrosis and loss of elasticity" in this hypothesis; however, given its preprint status, this evidence serves only as directional indication rather than definitive support.

Zullo et al. have positioned the Sirtuins family as key "checkpoints" in myofibroblast differentiation and profibrotic activity, revealing the upstream epigenetic regulatory mechanisms in mechanical signal-driven fibrotic processes [40]. This hypothesis posits that Sirtuins activity may determine fibroblast sensitivity to mechanical stimuli and differentiation propensity, complementing the PIEZO-YAP pathway, potentially constituting a complete molecular regulatory network from "mechanosensation" to "fibrotic execution." Kirkness et al. [38] further proposed the Ca²⁺-Hyaluronan (CHA) axis integrative framework, suggesting that after mechanical signals activate PIEZO channels, they may determine whether fascial tissue remains in a stable or remodeling state through regulation of hyaluronan metabolic molecular weight dynamics. Wang et al. systematically reviewed the pathophysiological changes in fascia within hypermobility spectrum disorders [41]. The anatomical location of the investing fascia theoretically allows its fibrotic changes to influence deeper structures through trans-layer transmission (see Level 2).

3.2. Level 2: Trans-Layer Transmission—Mechanical Continuity of the Three Fascial Layers

Based on the above anatomical evidence, this study proposes the following working hypothesis requiring mechanical experimental validation: following fibrosis of the investing fascia and loss of local elastic compensation, a portion of the residual passive tension it bears may be transmitted to deeper layers through the interconnected collagen network of the three layers of the deep cervical fascia. It must be emphasized that anatomical fibrous continuity itself does not equate to confirmation of mechanical transmission function—the adipose tissue, loose connective tissue, and neurovascular bundles between the three fascial layers may constitute mechanical buffer layers, absorbing or dissipating stress to some degree rather than serving as ideal "rigid transmission channels." Therefore, the actual efficiency and pathological significance of trans-layer transmission depend on multiple factors (including inter-fascial adhesion status, tissue hydration level, collagen cross-linking density, etc.), awaiting subsequent ex vivo mechanical experiments and FSI simulation for quantitative evaluation.

The neuraxial biomechanical framework by Frost and Barclay indicates that cervical fascial mechanical status may be directly transmitted to the central nervous system through the dura mater [43], providing a biomechanical perspective for the distal effects of "trans-layer transmission" in this hypothesis. The three layers of the deep cervical fascia constitute an integrated myofascial continuum. The review by Bond et al. [1] systematically summarizes the fascial composition of the carotid sheath—the carotid sheath is formed by the participation of all three layers of the deep cervical fascia (investing fascia laterally, pretracheal fascia anteromedially, and prevertebral fascia posteriorly), with the three layers interconnected through collagen fiber networks without physical barrier. This anatomical configuration provides the structural basis for mechanical signal transmission from the investing fascia to the carotid sheath and its contents. The anatomical study by Zhang and Lee [12] further reveals that the investing fascia is not continuous between the sternocleidomastoid and trapezius muscles; instead, there exists a space completely filled with adipose tissue, allowing the carotid sheath to be directly exposed to subcutaneous tissue through this interval. This "anatomical weak point" suggests that superficial soft tissue tension may provide the structural conditions to bypass the investing fascia and act directly on the carotid sheath.

The cadaveric study by Komune et al. [2] further reveals the skull base convergence pattern of this anatomical continuity—the three layers of the deep cervical fascia in the skull base region interconnect through the interpterygoid fascia, the tensor-vascular-styloid fascia, the stylopharyngeal fascia, and the buccopharyngeal fascia, forming a complex fascial network surrounding the internal jugular vein and internal carotid artery. The carotid sheath attaches anteriorly to the vaginal process and posteriorly to the fibrocartilaginous tissue surrounding the jugular foramen, providing bony anchor points for the transmission of residual passive tension from this fascia along the fascial network toward the skull base [2]. The recent cadaveric head dissection study by Liu et al. further clarifies the hierarchical relationships of this continuum—based on systematic dissection of 10 cadaveric head specimens, it was confirmed that the cervical fascia can be clearly divided into three layers: superficial (investing fascia), middle (pretracheal fascia), and deep (prevertebral fascia), with the prevertebral fascia identified as the key anatomical barrier separating the carotid sheath from the suboccipital muscle group [44]. This study also confirmed the presence of dense fibrous connections between the investing fascia and the prevertebral fascia at the craniocervical junction; the authors suggest that this connection is not merely a simple adjacency but may theoretically constitute an anatomical coupling interface with mechanical transmission function—when this fascia loses its elastic buffering capacity due to fibrosis, the static postural load it bears may no longer be fully dissipated by the fascia's own viscoelasticity, but may instead be transmitted to deeper structures along this anatomical coupling channel.

Snosek et al. [3] confirmed that the alar fascia spans across both carotid sheaths as an independent coronal fascial layer, and Schachtel et al. [4] revealed that the anterior carotid sheath at the skull base is formed by the fusion of four fascial layers, appearing as a recognizable low-signal line on MRI; together, these provide indirect anatomical evidence for the transmission of residual passive tension from the investing fascia to the anterior wall and bilateral sides of the carotid sheath. The cadaveric dissection by Liu et al. [44] confirmed the anatomical continuity between the three layers of the deep cervical fascia, but as noted earlier, anatomical connectivity itself does not equate to confirmation of mechanical transmission function. Using anatomical analysis and personalized finite element modeling based on 18 cervical MRI scans, Mohova et al. [45] systematically quantified the displacement patterns of each cervical fascial layer under head rotation at 20° and 50°. They demonstrated that the rotation and angular displacement of all fascial layers exhibited nonlinear characteristics, with deformation increasing sharply beyond a certain angle; inter-layer relative displacement due to angular differences between fascial layers generates shear stress on collagen fiber connections; and the farther the fascial layer from the center of the intervertebral disc, the greater the displacement—a "centrifugal amplification effect" that may explain why the most superficial investing fascia undergoes the greatest deformation during head movement, thus potentially rendering it more prone to pathological fibrosis. However, this evidence should be understood as necessary evidence for "structural channel existence" rather than sufficient evidence for "static residual tension transmission," because the mechanical modes of dynamic cyclic loading and static sustained loading are fundamentally different (the former involves periodic release of strain energy, while the latter involves sustained accumulation of residual stress following stress relaxation).

The "loss of elastic compensation" as defined herein refers specifically to a reduction in the stress-relaxation capacity of the fascia under sustained loading (i.e., an increase in the equilibrium stress ratio within the stress-relaxation curve and prolongation of the relaxation time constant), resulting in strain energy that cannot be dissipated viscously and is instead stored within the collagen network as residual elastic potential energy. To bridge the logical gap between dynamic interlayer coupling evidence and static residual tension transmission, this hypothesis specifically designs an ex vivo fascial strip serial tensile experiment within the validation protocol (see "Future Validation Protocol"), aimed at directly testing the stress transmission efficiency between the three fascial layers under static loading. The tissue-specific mechanical parameters obtained will serve as direct material inputs for the FSI finite element model and will also provide biomechanical reference data for interpreting the ex vivo findings in relation to subsequent in vivo intervention studies. The mechanical testing protocol for this experiment references the multi-axial mechanical testing standards established by Aparici-Gil et al. [13], thus forming a complementary chain of evidence from ex vivo parameter acquisition to in vivo simulation validation. Yang et al. quantified hemodynamic parameter changes across different carotid segments and stenosis severities using computational fluid dynamics (CFD), providing methodological reference for the quantitative analysis of cerebral perfusion changes under varying degrees of compression predicted by the FSI model in this hypothesis [49]. Mechanical signals transmitted to the middle and deep layers ultimately need to be sensed and transduced at the cellular level. PIEZO channels, as mechanosensitive cation channels on the cell membrane, may theoretically serve as the candidate apparatus for completing this mechanical-biological signal conversion.

3.3. Level 3: Molecular Transduction—PIEZO Channels as Candidate Core Molecular Switches

Early in the discovery of PIEZO channels, Bagriantsev et al. systematically elucidated the multiple functions of Piezo proteins as regulators of mechanosensation [50]. PIEZO1 and PIEZO2 are embedded in the cell membrane as unique "three-bladed propeller-shaped" bowl structures: in the resting state, the center is concave and the channel is closed; when the membrane is stretched or compressed, it flattens, the bowl structure is forced open, and the channel opens, allowing Ca²⁺ and Na⁺ influx. Based on experimental evidence from non-cervical tissues (primarily pulmonary fibrosis models, skin fibrosis models, and in vitro microtissue systems), this study extrapolates the following molecular hypothesis awaiting validation: if investing fascial fibroblasts express functional PIEZO1 channels—the expression of which has not yet been directly confirmed in human investing fascia—then mechanical signals reaching through trans-layer transmission may theoretically activate TGF-β1 through Ca²⁺ influx and, via YAP nuclear translocation, potentially upregulate COL1A1/COL3A1 expression.

Xu et al. demonstrated in a pulmonary fibrosis model that PIEZO1 mediates myofibroblast activation [51]; Ezzo et al. found that integrin-Piezo1 mechanically activates fibroblasts [52]. In nanostructured 2D and 3D fibrosis models, Rashidi et al. confirmed that PIEZO1-mediated mechanotransduction can independently regulate COL1A1/COL3A1 collagen synthesis and participates in vivo in wound contraction and scar thickening in response to mechanical loading [53]. The expression of PIEZO1 in tendons and spinal tissues has been documented [54,55]; the regulation of its distribution by membrane curvature [56] and thin-layer tissue SWE measurement methods [57] provide complementary perspectives for understanding the tissue-specific mechanotransduction of PIEZO channels. In HEK293 cells and mouse models, Zhang et al. revealed that phosphorylation of Piezo1 at Ser-1612 can regulate its mechanosensitivity and in vivo mechanotransduction function [58], suggesting how identical mechanical stimuli may produce differential cellular responses across pathological contexts. PIEZO2 on nerve endings within the carotid sheath may theoretically sense sheath deformation and mechanical compression, generating action potentials that ascend to the central nervous system, thereby participating in pain reflexes and autonomic regulation. Sonkodi proposed that PIEZO2 proton affinity and availability may regulate mechanical pain sensitivity, potentially driving central sensitization and neurodegeneration [59], thereby extending PIEZO2 from a "mechanical sensor" to a "mechano-chemical signal integrator." Ji and Lee systematically reviewed molecular sensors of temperature, pressure, and pain, providing a comparative perspective on the role of PIEZO2 in pain transmission [60]. Pirri further positioned PIEZO channels as "gatekeepers" of neuroimmune crosstalk in mechano-inflammation [61], suggesting that PIEZO-mediated mechanical signals may simultaneously activate fibroblast fibrotic programs and immune cell inflammatory responses—the same mechanical input may simultaneously drive tissue remodeling and neuroimmune activation through PIEZO channels.

The recent review by Kirkness and Scarlata builds upon this foundation to propose the "calcium-hyaluronan (Ca²⁺-Hyaluronan, CHA) axis" integrative framework, which links the activation of PIEZO1 and other channels, intracellular calcium signaling, dynamic changes in hyaluronan metabolism, and differential signaling output through CD44/RHAMM receptors into a unified mechanobiological feedback loop, proposing a model in which fascial tissue oscillates dynamically between "Quiet" (stable) and "Riot" (remodeling/repair) states. The framework indicates that high-molecular-weight hyaluronan binding to CD44 promotes tissue stability, whereas low-molecular-weight hyaluronan fragments activating RHAMM drive tissue remodeling; the balance between these two states depends on the intensity, frequency, and duration of mechanical signals, providing a mechanistic basis for understanding how the CHA axis orchestrates fascial adaptation versus pathological fibrosis. This framework provides a novel molecular perspective for understanding the transition of the investing fascia between physiological adaptation and pathological fibrosis—when mechanical stimuli on this fascia remain within the physiological range, the CHA axis may theoretically maintain the "Quiet" state and fascial tissue remains stable; when mechanical stimuli exceed physiological thresholds and persist, the CHA axis may shift toward the "Riot" state, hyaluronan metabolism skews toward low-molecular-weight species, RHAMM signaling is activated, potentially driving fibroblast-to-myofibroblast transformation and collagen deposition.

Of note, PIEZO1-mediated mechanical signals may not only drive local fibroblast collagen synthesis [53] but also propagate over long distances through the extracellular matrix network via paratensile signaling, activating distal fibroblasts [63]. This hypothesis posits that this dual mode of "local sensing—remote propagation" may allow localized tension abnormalities in the investing fascia to spread toward the middle and deep layers through the three-layer fascial collagen network [44], thereby affecting the mechanical microenvironment of the carotid sheath. Thus, PIEZO1/2 may theoretically constitute the molecular hub linking trans-layer residual passive tension to fibroblast fibrosis on the one hand, and to neural sensing and autonomic reflex on the other, achieving parallel conversion from mechanical signals to multi-system biological responses. Parallel to the PIEZO1-mediated direct mechano-transcriptional coupling, Walker et al. [62] demonstrated in an in vitro microtissue model that sustained mechanical stretch can maintain myofibroblast contractile phenotype and collagen secretory activity through protease-dependent activation of latent TGF-β1. This mechanism suggests that mechanical stimuli may drive fibrosis through two parallel molecular pathways: first, PIEZO1-mediated direct transcriptional regulation (a rapid-response pathway, independent of soluble factors); and second, mechanical stretch → latent TGF-β1 activation → paracrine signaling (a sustained maintenance pathway). Together, these two may respectively be responsible for the "trigger" of fibrotic initiation and the "latch" of the fibrotic state, constituting a dual-pathway amplification mechanism of mechano-fibrotic coupling.

It bears emphasizing that the above molecular evidence for PIEZO1/2 and the CHA axis is derived primarily from pulmonary fibrosis models, skin fibrosis models, in vitro microtissue models, and non-cervical deep fascial tissue studies; their specific expression, cell-type localization, and mechanical response thresholds in human investing fascial fibroblasts await direct verification through the immunohistochemistry (IHC) experiments designed in this hypothesis. Therefore, at the current stage, it is more prudent to position PIEZO channels as "candidate core molecular switches" rather than as "definitive core molecular switches."

4. Alternative Mechanotransduction Pathways

It is important to note that even if subsequent IHC experiments confirm that PIEZO1/2 are not expressed in investing fascial fibroblasts or are expressed at levels insufficient to mediate mechanotransduction, the core mechano-pathological coupling framework of this hypothesis may still receive molecular support through alternative mechanotransduction pathways. The integrin-YAP/TAZ signaling axis is a classical pathway by which connective tissue cells sense extracellular matrix stiffness; its activation does not depend on PIEZO channels and can transmit mechanical signals to the nucleus directly through reorganization of the actin cytoskeleton [73,74]. Additionally, TRPV4—another class of mechanosensitive cation channel—can sense osmotic pressure changes and shear stress in fibroblasts, functionally complementing PIEZO channels [71]. The mechanical activation of latent TGF-β1 likewise does not depend on PIEZO channels, but rather occurs through conformational changes mediated by integrins αvβ6 and αvβ8, releasing active TGF-β1 [106]. Therefore, even if PIEZO channel expression in the investing fascia is lower than anticipated, mechanical signals may still drive fibrotic programs through the aforementioned pathways. This hypothesis positions PIEZO1/2 as "candidate core molecular switches" rather than as "the sole molecular switches," precisely because of this multi-pathway redundancy. Subsequent IHC experiments will simultaneously detect integrin β1, YAP, and TRPV4 to comprehensively map the molecular mechanotransduction profile in the investing fascia.

5. Integration of the Molecular Temporal Sequence Model

Based on the above experimental evidence from non-cervical tissues, this hypothesis attempts to construct a cross-timescale theoretical sequence model of the mechano-molecular signaling cascade (for subsequent experimental testing only): immediately upon mechanical loading (milliseconds), PIEZO1 channels may theoretically undergo conformational changes and channel opening, with Ca²⁺ and Na⁺ influx initiating intracellular calcium signaling; after seconds to minutes of sustained stimulation, elevated intracellular Ca²⁺ may trigger downstream signaling cascades, with YAP dephosphorylation and nuclear translocation initiating transcription of early response genes; over tens of minutes to hours, YAP and TEAD transcription factors may synergistically upregulate TGF-β1 expression, and TGF-β1 in an autocrine/paracrine manner further activates Smad signaling, while Sirtuins family members (particularly SIRT1 and SIRT3) may be recruited to fibroblast nuclei during this phase, modulating the epigenetic state of histones and transcription factors through deacetylation, determining the long-term propensity of fibroblasts toward myofibroblast differentiation; over hours to days, the Sirtuins checkpoint described by Zullo et al. [40] may theoretically complete the "licensing" decision—if Sirtuins activity is inhibited by oxidative stress, the TGF-β1/Smad signaling pathway gains full activation, driving α-SMA expression and stable transformation to the myofibroblast phenotype; over days to weeks, excessive COL1A1 and COL3A1 may deposit in the extracellular matrix, accompanied by increased collagen cross-linking and downregulated matrix metalloproteinase activity, completing the structural changes of fibrotic remodeling.

Important Limitation: The time parameters (milliseconds, minutes, hours, days) for the above molecular events are all derived from studies on non-investing fascial tissues (including pulmonary fibroblasts, skin fibroblasts, and engineered tissues); their actual timing in human investing fascia may differ significantly. This model is intended to provide a conceptual framework and intervention window hypotheses for subsequent research, not an established timeline. All temporal parameters await calibration or revision through investing fascia-specific experiments. If this temporal sequence model receives subsequent validation, it may provide a conceptual framework for understanding molecular intervention windows at different pathological stages: acute/hyperacute stage may target the PIEZO1 channel itself (milliseconds to seconds), subacute stage may target YAP nuclear translocation and TGF-β1 expression (minutes to hours), and chronic stage may target Sirtuins activity and collagen metabolic balance (hours to days), offering a theoretical basis for designing temporal-sequence combination pharmacological intervention strategies. However, it must be reiterated that the specific temporal parameters of each molecular event in human investing fascia currently lack direct experimental data; this model is a reasonable extrapolation based on non-cervical tissue studies and awaits calibration in investing fascia-specific experiments.

Level 4: Five Downstream Pathways—Diversified Effects of Neurovascular Compression

The downstream effects of the five pathways are distinct—involving blood perfusion, fluid pressure, immune clearance, vasomotor tone, and autonomic balance, respectively—but the mechanical source is theoretically inferred to be the same upstream event: abnormal investing fascial tension may reach the carotid sheath and its adjacent structures through trans-layer transmission. Raja et al. explicitly described the anatomical continuity from the deep cervical fascia through the epicranial aponeurosis to the fascial sheath of the eyeball (Tenon's capsule); this fascial continuum provides a direct anatomical pathway for mechanical transmission of residual passive tension from this fascia to ocular structures. This pattern of "homologous mechanical input, multisystem output" distinguishes this hypothesis from previous single-pathway theories. The relative contributions of the five pathways may vary dynamically with disease stage. Based on available literature, this study proposes the following prior hypothesis spectrum (awaiting subsequent validation): in the early disease stage (duration <1 year), sympathetic stimulation (intraocular pressure fluctuation) and vagus nerve compression (autonomic imbalance) may predominate, manifesting as functionally reversible changes; in the subacute stage (1–3 years), arterial compression leading to cerebral hypoperfusion and venous compression leading to intracranial pressure elevation may progressively worsen, entering a structural compensation phase; in the chronic late stage (>3 years), impaired lymphatic drainage leading to sustained intraocular pressure elevation and positive feedback loops (self-amplifying fibrosis) may become dominant, resulting in structural damage.

Evidence Strength Note for Each Pathway: The literature support for the following five pathways differs substantially in strength. The arterial and venous pathways have more extensive human clinical studies (Doppler ultrasound, RCTs, ONSD studies), with relatively higher levels of evidence; the lymphatic pathway relies primarily on indirect evidence (intraocular pressure changes following cervical lymphadenectomy) and case reports, with lower evidence levels; the sympathetic and vagal pathways rely primarily on animal experiments and clinical observations, with limited direct human evidence. Readers should give due consideration to this uneven evidence distribution when evaluating the contribution of each pathway.

6. Arterial Pathway

This hypothesis posits that residual passive tension from the investing fascia, transmitted through the carotid sheath to the common and internal carotid arteries, may cause vascular compression and luminal narrowing, potentially leading to cerebral hypoperfusion and ocular ischemia. This mechano-hemodynamic coupling relationship has received multi-level evidence support. At the population level, the RCT by Uzun et al. [17] in 25 patients with cervicogenic headache demonstrated that six weeks of cervical mobilization significantly increased internal carotid and vertebral artery blood flow velocity (p<0.05) while simultaneously significantly reducing headache intensity, providing direct Doppler ultrasound evidence that cervical manual therapy improves cerebral blood flow. Of note, this was a six-week cumulative effect, which limits its value for extrapolating immediate mechanical effects; hence this hypothesis separately proposes Prediction 1b to specifically test the acute time window. The network meta-analysis by Xu and Ling [19], incorporating 14 studies with 1,297 patients, confirmed that cervical manipulation was most effective for relieving cervicogenic headache pain (surface under the cumulative ranking curve [SUCRA] 98.9%). The systematic review and meta-analysis by Lu et al. additionally confirmed that myofascial release demonstrated significant efficacy for tension-type headache, cervicogenic headache, and migraine [18]. The multicenter prospective cohort study by Yang et al. [20] further demonstrated that anterior cervical decompression and fusion significantly improved headache and cervical function at the 12-month follow-up. Bogduk's classic review [21] provides a neuroanatomical explanation for headache improvement following cervical intervention, based on the trigemino-cervical nucleus convergence.

At the biomechanical level, the FSI study by Shakya et al. systematically compared the hemodynamic differences between carotid artery compression by external pressure and atherosclerotic stenosis, finding that external pressure-induced luminal deformation exhibits a hemodynamic response pattern distinct from intrinsic stenosis [64]. This finding provides a computational biomechanical basis for distinguishing between "extrinsic compressive stenosis" (caused by residual passive tension from the investing fascia) and "intrinsic stenosis" (caused by atherosclerosis), further strengthening the methodological foundation for the FSI simulation validation plan in this hypothesis. Within the classical framework of hemodynamic regulation, the "vascular waterfall" theory proposed by Permutt and Riley states that when external pressure on a collapsible vessel exceeds intravascular pressure, flow depends on upstream driving pressure and is no longer influenced by downstream pressure [65]. Through ultrasound measurements, Holmlund et al. confirmed that the human internal jugular vein exhibits significant posture-dependent collapse in the upright position, and that this collapse directly participates in postural intracranial pressure regulation [66]. When fascial tension abnormalities cause venous compression within the carotid sheath, increased venous return resistance may elevate intracranial venous pressure, thereby affecting the stable maintenance of cerebral perfusion pressure through the waterfall effect. The above evidence—from clinical hemodynamics, computational biomechanics, and classical physiology—collectively suggests that the causal chain of "investing fascial residual passive tension → extrinsic carotid artery compression → cerebral and ocular hypoperfusion" is plausible.

7. Lymphatic Pathway

This hypothesis posits that residual passive tension from the investing fascia may indirectly compress the deep lymphatic vessels and lymph nodes anterior to the prevertebral fascia through trans-layer transmission—since tension changes in this fascia must be transmitted through the middle fascial layer to affect these structures—thereby potentially obstructing lymphatic drainage of aqueous humor and exacerbating intraocular fluid retention. Do et al. reported a high prevalence of myofascial trigger points in migraine and tension-type headache [73], suggesting that local fascial pathological changes may influence autonomic tone through reflex mechanisms, indirectly participating in lymphatic return and intraocular pressure regulation. Complementing the findings of Kim et al. [26], the case report by Pereira de Godoy et al. demonstrated that a bilateral glaucoma patient whose intraocular pressure remained 35–40 mmHg despite four classes of ocular hypotensive agents experienced a reduction in IOP to below 20 mmHg following cervical lymphatic manual therapy, a response that was maintained for approximately 48 hours; when the treatment interval was extended to 3 days, IOP rebounded with blurred vision [74]. This phenomenon suggests that "improved lymphatic drainage → decreased IOP" and "impaired lymphatic drainage → elevated IOP" together indicate, from both directions, that cervical lymphatic drainage status may directly regulate intraocular pressure. The complete anatomical-physiological pathway for this association was revealed by Xu et al.: CSF pressure in the optic nerve sheath is lower than intracranial pressure under physiological conditions and drains directly to deep cervical lymph nodes through intrathecal lymphatic vessels, independent of retrograde intracranial flow [75]. This finding provides the first human evidence that optic nerve CSF possesses an independent lymphatic drainage system ultimately draining to deep cervical lymph nodes and simultaneously suggests that when cervical lymphatic vessels are obstructed by external compression, increased outflow resistance of optic nerve CSF may elevate sheath pressure and consequently raise intraocular pressure—thereby providing anatomical-physiological support for the causal chain of "investing fascial residual passive tension → compression of deep cervical lymphatics → impaired optic nerve CSF/aqueous lymphatic drainage → intraocular fluid retention and elevated IOP" [75].

8. Sympathetic Pathway

This hypothesis posits that residual passive tension from the investing fascia may stimulate the cervical sympathetic trunk deep to the prevertebral fascia, activating sympathetic outflow and potentially leading to ocular vasoconstriction and intraocular pressure fluctuations. The systematic review of fascial innervation [5] indicates that fascia contains tyrosine hydroxylase-positive sympathetic nerve fibers, CGRP- and substance P-positive nociceptive sensory fibers, and S100 protein-positive glial support structures. This neural composition suggests that tension changes in the investing fascia may not only be directly sensed by sensory nerve endings but may also influence autonomic tone through sympathetic and parasympathetic fibers. The cervical sympathetic trunk lies deep to the prevertebral fascia and posterior to the carotid sheath, containing superior, middle, and inferior ganglia; its postganglionic fibers enter the cranium via the internal carotid plexus, form the cavernous plexus within the cavernous sinus, and then give rise to ocular branches through the ciliary ganglion to innervate the pupillary dilator muscle—an anatomical pathway that allows mechanical signals anterior to the prevertebral fascia to potentially transmit through the fascial barrier to the deep cervical sympathetic trunk.

In a classic study, Langham and Rosenthal demonstrated that stimulation of the cervical sympathetic trunk causes uveal vasoconstriction, significantly reducing ocular blood flow [76]. Gallar and Liu further found that cervical sympathetic nerve stimulation increases intraocular pressure; in conscious rabbits, 5 Hz electrical stimulation of the cervical sympathetic nerve for 1 hour doubled aqueous humor norepinephrine concentration and elevated IOP [77]. Belmonte et al. found that resection of the superior cervical sympathetic ganglion in rabbits eliminated drug-induced IOP elevation, further suggesting a key role for the cervical sympathetic nerve in IOP regulation [78]. The effects of sympathetic nerve stimulation on aqueous humor dynamics exhibit temporal complexity. Sustained sympathetic stimulation produces an immediate sharp decrease in IOP, followed by a gradual return to pre-stimulation levels over 60–90 minutes—a dynamic pattern suggesting that sympathetic regulation of IOP is not a simple pressor or depressor effect, but rather involves multiple regulatory mechanisms of aqueous humor production and outflow resistance. With respect to β-adrenergic effects, sustained sympathetic stimulation can reduce aqueous humor production rate. This bidirectional, time-dependent regulatory pattern suggests that chronic sustained sympathetic stimulation by fascial tension abnormalities may produce pathological effects distinct from those of acute experimental stimulation—transitioning from compensatory regulation in the acute phase to decompensation and functional disturbance in the chronic phase.

The clinical association between sympathetic dysfunction and ocular pathology is also noteworthy. Patients with sympathetic cervical spondylosis, due to abnormal mechanical stimulation or compression of the cervical sympathetic nerves in the prevertebral fascial region, may present with ocular symptoms including eye distension and blurred vision. Cervical degenerative disease compressing the cervical sympathetic nerves may trigger sympathetic nervous system disturbances, leading to pupillary abnormalities, elevated IOP, and dilated fundus vessels. These clinical observations provide indirect support from clinical medicine for the causal chain of "cervical fascial tension abnormality → cervical sympathetic trunk stimulation → ocular functional disturbance." Zhang et al. systematically reviewed the morphology, physiology, developmental biology, and pathology of the myodural bridge complex, emphasizing the mechanical coupling between cervical fascia and intracranial structures [79]. Research indicates that retinal and choroidal vascular systems are regulated by complex interactions among local autoregulatory mechanisms, systemic blood pressure, IOP, and autonomic tone, and the close anatomical proximity of the cervical sympathetic chain to the cervical spine and carotid artery allows cervical mechanical stimulation to regulate ocular perfusion through sympathetic pathways. Integrating the above anatomical, experimental physiological, and clinical observational evidence, the transmission of residual passive tension from the investing fascia through the fascial layers to the cervical sympathetic trunk deep to the prevertebral fascia, driving ocular vasoconstriction and IOP fluctuations through sympathetic activation, constitutes yet another biologically grounded potential pathway from cervical fascial mechanical abnormality to ocular pathology.

9. Vagus Pathway

Similarly, residual passive tension from the investing fascia may theoretically compress the vagus nerve within the carotid sheath, inhibiting parasympathetic function and potentially leading to autonomic imbalance. Schachtel et al. [4] found that the glossopharyngeal nerve traverses the multilayered fascial structure of the anterior carotid sheath approximately 9 mm below the skull base, suggesting that cervical fascial tension may directly compress or irritate lower cranial nerves passing through the sheath. Noseda et al. revealed non-trigeminal nociceptive innervation of the posterior dura mater [80], suggesting that cervical mechanical signals may directly participate in headache signaling through cervical nerves. Song et al. provided direct evidence that pathological changes in the myodural bridge complex induce chronic headache [81], indicating that the anatomical connection between cervical fascia and the spinal dura mater can mediate mechanical signal transmission to the intracranial compartment. In their cervicogenic encephalopathy framework [10], Hauser et al. likewise emphasized the central role of vagus nerve compression in autonomic dysfunction; their subsequent cervical oculopathy hypothesis [11] similarly identified vagus nerve involvement as a core mechanism underlying ocular autonomic dysfunction, forming independent external corroboration for the vagal pathway described in this hypothesis. Della Pietra et al. systematically reviewed the role of Piezo channels in migraine pain, noting that Piezo expression in peripheral sensory neurons and the trigeminovascular system makes them key molecular substrates for mechanically triggered mechanisms [82]. The anatomical convergence point of the five pathways is the carotid sheath—a fascial conduit formed with participation of the investing fascia, simultaneously accommodating the carotid artery, internal jugular vein, and vagus nerve. Based on this model, this hypothesis posits that fascial tension changes may simultaneously affect all three structures.

Level 5: Positive Feedback Loop—Pathological Amplification and Spatial Spread

The specific molecular mechanism of fibrotic spatial expansion was systematically elucidated by Liu et al. in the Proceedings of the National Academy of Sciences (PNAS) [63]: mechanical signals propagate through the collagen fiber network over distances exceeding 70 μm in less than 1 second, mediated by PIEZO1 ion channels in a calcium-dependent manner via DDR2 and integrin signaling pathways, activating distal fibroblasts to transform into myofibroblasts and driving fibrosis expansion from the original injury site to surrounding normal tissue. This study introduced the concept of "paratensile signaling" and demonstrated that blocking paratensile signaling effectively inhibits fibroblast-to-myofibroblast transformation and the spread of the fibrotic boundary. The mechanobiological framework of Cyron and Humphrey [6] explains this positive feedback amplification mechanism at the tissue scale—increased stiffness of fibrotic tissue alters the local mechanical microenvironment, driving further extracellular matrix deposition, theoretically forming a "mechanical drive → tissue stiffening → mechanical re-drive" vicious cycle. This mechanism complements the molecular- and tissue-scale findings of Liu et al. [63] on paratensile signaling spatial propagation. The molecular basis of this positive feedback loop has been independently validated in a skin fibrosis model [83]. This molecular basis, together with paratensile signaling spatial propagation [63], CHA axis state switching [38], and PIEZO1-mediated collagen synthesis regulation [53], constitutes multi-layer molecular evidence for the positive feedback loop (see Level 3 for details). Snosek et al. [3] found that the alar fascia contains αSMA-positive smooth muscle-like cells and S100 protein-positive nerve fibers, suggesting that fibrotic fascial tissue may participate in the maintenance and amplification of the positive feedback loop through neuroimmune mechanisms.

The spatial propagation of this positive feedback loop is supported not only by molecular-level mechanisms [63,83] but also by anatomical channel infrastructure. Komune et al.'s cadaveric study [2] confirmed that the uppermost portion of the carotid sheath is formed by the fusion of multiple fascial layers—the tensor-vascular-styloid fascia, stylopharyngeal fascia, buccopharyngeal fascia, and prevertebral fascia—forming a thick protective covering. This fusion region provides a direct anatomical pathway for local fibrotic remodeling of the investing fascia to spread spatially to the carotid sheath and its contents. In human fetuses, Rodriguez-Vázquez et al. revealed the embryonic developmental origins of the myodural bridges, providing a developmental biological basis for their bridging role in transmitting residual passive tension from cervical fascia to intracranial structures [84]. Zhang et al. systematically reviewed the morphology, physiology, developmental biology, and pathology of the myodural bridge complex, clarifying that the myodural bridge complex acts as a "dynamic pump" in CSF circulation, with changes in its tensile force directly altering CSF secretion and reabsorption rates [79]. Through electrical stimulation of the obliquus capitis inferior muscle in beagles with simultaneous monitoring of CSF pressure at four sites, Yuan et al. directly demonstrated that the MDBC can convert muscle contraction into CSF pressure waves propagating from the occipito-atlantal cistern to the cranial cavity and spinal canal [85]. In a rat model of obliquus capitis inferior muscle hyperplasia, Li et al. found that muscle hyperplasia significantly elevates intracranial pressure, whereas surgical transection of the MDBC connection significantly reduces intracranial pressure—a bidirectional causal experiment that explicitly confirms the mechanical transmission function of the myodural bridge complex between muscle tension and intracranial pressure [86].

The vicious cycle described by Hauser et al. [10] provides corroboration at the macro-mechanical level: forward head posture → creep of cervical posterior ligaments → cervical instability → carotid sheath compression → cerebral symptoms → patient further flexes forward to alleviate discomfort → worsening cervical structural disruption. This macroscopic cycle and the local mechano-fibrotic positive feedback loop [63,83] of the investing fascia may theoretically reinforce each other across different scales. Of note, the above findings derive respectively from pulmonary fibrosis models [63], skin fibrosis models [83], in vitro engineered models [53], and theoretical integrative frameworks [38]; their co-existence and synergy in human investing fascia await direct immunohistochemical and ex vivo mechano-molecular coupling experiments for confirmation. Each step of the above vicious cycle has corresponding experimental evidence supporting its plausibility: the cadaveric dissection study by Liu et al. [44] confirmed the anatomical continuity between the investing fascia and the prevertebral fascia, providing the structural basis for trans-layer tension transmission; Rashidi et al. [53], in 2D and 3D fibrosis models, demonstrated that PIEZO1 directly regulates collagen synthesis, providing direct molecular evidence for fibroblasts depositing collagen in response to mechanical stimuli; Xu et al. [75] discovered that optic nerve sheath CSF drains through lymphatic vessels to deep cervical lymph nodes, providing a complete anatomical-physiological pathway for lymphatic involvement in IOP regulation; Zandi et al. [87], in chronic neck pain populations, validated the reliability of SWE for measuring fascial stiffness, providing an operable tool for clinical detection of investing fascial mechanical status; Kirkness and Scarlata [38], through the CHA axis framework, integrated PIEZO channels, hyaluronan metabolism, and CD44/RHAMM receptor signaling into a unified "Quiet vs. Riot" model, providing a theoretical framework for understanding the transition between fascial adaptation and fibrosis; He et al. [83], in a skin fibrosis model, confirmed the existence of a PIEZO1-Wnt2/Wnt11-CCL24 positive feedback loop, providing molecular evidence for mechanical signal-driven self-amplification of fibrosis independent of the TGF-β pathway. The quantitative study by Pires et al. [46] further provided a mechanical feasibility threshold (approximately 6 N/cm²) for trans-layer transmission, giving the mechanical transmission link of this hypothesis direct experimental data support. The above literature, from anatomical structure [44], molecular mechanisms [53,83], physiological pathways [75], detection methods [87], mechanical thresholds [46], and theoretical frameworks [38], jointly constitutes the multi-level plausibility basis for this hypothesis. Based on the above evidence, this hypothesis proposes the following theoretical possible pathway for the complete vicious cycle: primary fibrosis of the investing layer → loss of elasticity → trans-layer transmission of residual passive tension → secondary fibrosis of middle/deep layers → carotid sheath narrowing compressing veins → elevated tissue hydrostatic pressure reversely exacerbates deep layer fibrosis → restricted cervical motion further stretches the investing fascia. The superposition of this multi-line evidence elevates the vicious cycle from macroscopic mechanical inference to a testable theoretical model with multi-level molecular biological support.

10. Testable Predictions

This hypothesis proposes the following five testable predictions, providing clear directions for subsequent empirical research.

10.1. Prediction 1 (Mechano-Coupling Hypothesis)

If this model holds, investing fascial stiffness (SWE) should be negatively correlated with ipsilateral carotid artery peak systolic velocity—that is, increased residual passive tension in this fascia may reduce cerebral blood supply via carotid compression. Using a multi-layered phantom model, Bartsch et al. evaluated the reliability and validity of stiffness measurement tools, providing a methodological foundation for SWE measurement [88]. Liao et al. further validated the reliability of shear-wave elastography for measuring cervical fascial stiffness in the human neck [39]. Zandi et al. extended this validation to the clinical target population, demonstrating excellent test-retest reliability of SWE for fascial stiffness and thickness measurements in patients with chronic neck and low back pain [87]. The imaging-based arterial stiffness estimation method by Celi et al. can extend this prediction to arterial wall-investing fascia stiffness coupling analysis [89]. In the clinical assessment of cervical fibrosis, Dapper et al. [90] recently validated shear-wave elastography for layer-specific quantitative assessment of fibrosis in patients with radiation-induced cervical fibrosis, demonstrating that SWE-measured fascial stiffness significantly positively correlated with histological fibrosis scores (r=0.78, p<0.001), thereby providing additional independent evidence supporting the application of SWE technology in pathological cervical fascial stiffness measurement and further consolidating its methodological foundation as a core detection tool in this hypothesis.

10.2. Prediction 1b (Diagnostic Time Window)

If residual passive tension of the investing fascia is the direct cause of arterial compression, then within 30 minutes following standardized release of this fascia, a detectable immediate increase in ipsilateral middle cerebral artery peak systolic velocity should occur. The RCT by Uzun et al. [17] demonstrated that cervical mobilization can increase internal carotid and vertebral artery blood flow velocity, but that study was a six-week long-term intervention; its immediate effect time window remains to be established. Based on the coefficient of variation (CV≈8–12%) for flow velocity measured by transcranial Doppler (TCD) in cervicogenic headache populations, this study preselects a response threshold of ≥12% elevation from baseline as meaningful for detection; oral vasodilators typically peak 2–4 hours after administration. This time window difference may serve as an operational basis for distinguishing mechanical extrinsic compressive stenosis from primary vasogenic pathology.

10.3. Prediction 2 (Intraocular Pressure Reduction Hypothesis)

If this model holds, intraocular pressure (IOP) should decrease within 30 minutes to 24 hours following release of the investing fascia [26,74,86].

10.4. Prediction 3 (Optic Nerve Sheath Diameter Reduction Hypothesis)

If this model holds, optic nerve sheath diameter (ONSD) should decrease following release of this fascia. ONSD is an effective noninvasive imaging indicator for intracranial pressure. Hladky and Barrand systematically outlined the regulatory principles of CSF volume and intracranial pressure, identifying venous return resistance as a key factor influencing intracranial pressure fluctuations [70]—a causal chain—internal jugular vein compression → elevated intracranial pressure → increased ONSD—that gains physiological plausibility within this framework. At the human empirical level, through a self-controlled experiment in which healthy volunteers wore cervical collars, Woster et al. [71] directly demonstrated that static external cervical compression (30 min) significantly increases ONSD (p<0.001), providing direct static mechanical model evidence for "sustained cervical compression → increased ONSD." Using a cervical hyperextension (>30°) model, Ersoy Karka et al. [72] further demonstrated that dynamic cervical positional changes similarly decrease internal jugular vein flow velocity and increase deoxyhemoglobin (indicating acute cerebral congestion), while ONSD significantly increases from baseline (p<0.001)—a finding that, together with the static compression model of Woster et al. [71], confirms the causal chain of cervical mechanical state → impaired venous return → elevated ICP/ONSD from two complementary mechanical modes. Together, the static compression model of Woster et al. [71] and the dynamic hyperextension model of Ersoy Karka et al. [72] confirm, from two complementary mechanical modes, the causal chain of cervical mechanical state → impaired venous return → elevated ICP/ONSD, providing dual human empirical support for Prediction 3.

10.5. Prediction 4 (Autonomic Function Hypothesis)

If this model holds, investing fascial stiffness should be negatively correlated with heart rate variability parameters that reflect parasympathetic activity (RMSSD, high-frequency power HF) [5,28,59,83]. The systematic evidence on fascial innervation [5] supports the hypothesis that changes in fascial stiffness may influence autonomic tone through nociceptors and autonomic nerve fibers.

10.6. Prediction 5 (Layer-Specificity Hypothesis—Excluding the Generalization Hypothesis)

If the causal chain of "primary fibrosis of investing layer → trans-layer transmission → secondary fibrosis of deep layers" holds, then the increase in investing fascial SWE values should temporally precede the increase in SWE values of the deep fascial layers (pretracheal fascia, prevertebral fascia) over the disease course. Specific validation design: In cross-sectional studies, SWE values should be compared between patients with mild neck pain or early-stage disease and those with severe neck pain or advanced brain-eye symptoms; it is expected that investing fascial SWE values are already significantly elevated above healthy controls at the mild stage, whereas significant increases in deep fascial SWE values should only be observed at the severe/advanced stage. In longitudinal observational studies, patients with early-stage neck pain should be followed for 2–3 years; it is expected that investing fascial SWE values begin to rise significantly early in follow-up (e.g., 6–12 months), whereas significant increases in deep fascial SWE values do not emerge until later follow-up (e.g., 24–36 months). If this prediction holds, it supports the causal direction of "investing layer primary → trans-layer transmission." Conversely, if SWE values of the three fascial layers rise synchronously without significant temporal gradient differences, this would suggest synchronous fibrosis of the three layers under the same mechanical environment (the "generalization hypothesis"), requiring revision of the hypothesis to a parallel pathogenic model of "three-layer deep cervical fascia synergistic fibrosis jointly constituting altered mechanical boundary conditions of the carotid sheath," thereby downgrading the investing fascia's "initiating" role to "key participant."

11. Plausibility Argumentation

11.1. Anatomical Plausibility

The anatomical connections between the investing fascia and the carotid sheath have been detailed in the Introduction and in Level 2 (1,2,3,4,8,12). The interlacing of collagen fibers among the three layers of the deep cervical fascia constitutes the structural basis for trans-layer transmission of residual passive tension [3]. The histological study by Snosek et al. [3] further reveals that the alar fascia contains αSMA-positive smooth muscle-like cells and S100 protein-positive nerve fibers, suggesting that it may participate in dynamic regulation of fascial tension through active contraction and neural reflexes. The cadaveric dissection by Liu et al. [44] confirms that the prevertebral fascia is the key anatomical barrier separating the carotid sheath from the suboccipital muscle group. The MRI findings of Schachtel et al. [4] suggest that the mechanical coupling of fascial layers in the lateral skull base region can be identified in vivo. Raja et al. [8,9] further extended this fascial network to the ocular and thoracic regions, supporting the systemic and cross-regional nature of the fascial network. The systematic review by Xiao on PIEZO channel mechanotransduction mechanisms and physiological functions provides a comprehensive molecular biological framework for understanding the role of PIEZO in cervical fascial tension sensing [91].

11.2. Neuroanatomical Plausibility

The innervation of the investing fascia equips it with the capacity to sense and transmit mechanical signals. The systematic review by Suarez-Rodriguez et al. [5] confirms that fascial tissue contains free nerve endings (nociceptors), Pacinian corpuscles and Ruffini endings (mechanoreceptors), and tyrosine hydroxylase-positive autonomic nerve fibers, with innervation being significantly increased under pathological conditions—providing direct neuroanatomical support for the causal chain of "fascial tension abnormality → neural sensing and reflexes → autonomic dysfunction."

11.3. Biomechanical Plausibility

The viscoelasticity of deep fascia allows it to adapt to mechanical loading within physiological ranges, but mechanical homeostasis is disrupted when tension persistently exceeds elastic thresholds [6,7,13]. The mechanobiological theory of Cyron and Humphrey [6] indicates that once collagen-dominated soft tissues surpass mechanobiological stability thresholds, their remodeling shifts from adaptive to pathological. Through multi-axial mechanical testing, Aparici-Gil et al. [13] systematically quantified the mechanical anisotropy of deep fascia, with longitudinal stiffness significantly higher than transverse stiffness (approximately 6.6:1 under uniaxial tension), suggesting that the distribution of residual passive tension after fibrosis may be direction-dependent. Using an algometer combined with ultrasound imaging, Pires et al. [46] directly measured the mechanical pressure required to reach the deep cervical fascia in 43 healthy subjects, finding that an average of only 6.06 ± 0.186 N/cm² was sufficient to produce effective mechanical transmission. The dynamic interlayer displacement and shear stress confirmed by Mohova et al. [45] provide indirect evidence of interlayer mechanical coupling for the static residual tension transmission pathway. On this basis, this hypothesis posits that following localized loss of elasticity due to fascial fibrosis, stress may be forced to redistribute along the fascial plane, generating residual passive tension [13,41,92]. Berardo et al. [93] confirmed that superficial fascia exhibits significant site-specificity, suggesting that the mechanical properties of the investing fascia should be measured directly rather than extrapolated from other regions.

11.4. Molecular Mechanism Plausibility

The molecular mechanisms underlying the proposed mechano-fibrotic coupling have been systematically elaborated in Level 3 (see "Level 3: Molecular Transduction"), where the PIEZO-YAP pathway, the CHA axis framework, and latent TGF-β1 activation were discussed in detail [38,50,51,52,53,54,55,56,57,58,59,60,61,62,71,73,74,83,106]. Caroccia et al. [94] demonstrated that angiotensin II can promote deep fascia remodeling through YAP activation, offering a molecular pathway analogy for understanding the interplay between mechanical and humoral factors within the deep fascial system. The systematic elaborations by Hinz et al. [95,97,98] and Zent and Guo [96] on the mechanical regulation of myofibroblast phenotypic transformation and collagen contraction provide cell biological foundations for the molecular chain of "mechanical signal → fibroblast activation → fibrosis" in this hypothesis. The Sirtuins checkpoint identified by Zullo et al. [40] complements the PIEZO-YAP pathway, together constituting a complete regulatory network from "mechanosensation" to "fibrotic execution." However, the specific expression of PIEZO1/2 in human investing fascia awaits immunohistochemical verification [91].

12. Discussion

12.1. Comparison with Previous Fascial Mechanobiological Models and Innovations

This hypothesis integrates the fascial fibrosis and mechanotransmission models of Zullo et al. [14,40,68], Schleip et al. [92,99], Plaut [33,100], and Stecco and Pavan [101], distinguishing itself from integrative models focused on pain neurophysiology [102,103] by attempting to incorporate mechanotransmission, fibrosis, and brain-eye pathology into a unified framework. The core innovations are twofold: first, integration rather than replacement—this hypothesis does not conflict with the "jugular vein hypothesis" [23] or the "cervical oculopathy" hypothesis [11]; rather, it builds upon them by asking "what is the common upstream cause of these compressions," integrating single-pathway theories into a more explanatory framework. The two hypotheses occupy different positions in the causal chain, mutually complementing each other. Second, molecular mechanism deepening—this is the first attempt to introduce PIEZO1/2 channels into the conceptual framework of investing fascial pathology (positioned as candidate core molecular switches), and through the CHA axis framework [38], paratensile signaling [63], and Wnt positive feedback [83], constructs a complete molecular chain from mechanosensation to cellular response, as well as a temporal sequence model from millisecond-scale channel opening to week-scale collagen deposition [38,50,51,52,53,54,55,56,57,58,59,60,61,62,83,63,71,73,74,106].

12.2. Refined Elaboration on "Initiation" vs. "Exacerbation"

This hypothesis positions investing fascial tension abnormality as a potential mechanical node in cerebral hypoperfusion and ocular diseases. In patients with significant cervical structural abnormalities, fascial tension elevation may be secondary to cervical instability, with its role closer to an "exacerbating factor"; in patients without significant cervical structural abnormalities, the tension elevation caused by primary fibrosis of this fascia may theoretically serve as an independent "initiating factor." The relative contributions of these two mechanisms in individuals may exhibit a continuous spectrum distribution, awaiting subsequent subgroup analysis for testing.

12.3. Competing Hypotheses and Discriminative Conditions

(1) Pure Vasogenic Hypothesis—Discriminative condition: if the correlation between fascial SWE values and cerebral perfusion indicators disappears after adjusting for vascular factors, this would support the vasogenic hypothesis.

(2) Pure Neurogenic Hypothesis—Discriminative condition: if the improvement of ocular symptoms following fascial release is completely blocked by local anesthesia, this would support the neurogenic hypothesis. This hypothesis predicts that fascial release should simultaneously produce both mechanical (improved blood flow velocity) and neural (HRV changes) effects; if only one type of effect exists, the integrative advantage of this hypothesis would be weakened.

13. Limitations

First, this work is a theoretical hypothesis rather than an empirical study; it does not provide FSI simulation data or IHC evidence directly validating the proposed fascial tension-driven cascade—this constitutes the most fundamental limitation of the present work.

Second, the mechanotransduction roles of PIEZO1/2 and YAP/TAZ are inferred from previously published literature (primarily derived from non-cervical tissues, including pulmonary fibrosis models, skin fibrosis models, and in vitro microtissue systems) and currently lack direct validation in human tissues from patients with cervicogenic headache—this is a core limitation of the molecular-level argumentation in this hypothesis (see the limitation statement in Level 3).

Third, this biomechanical coupling model simplifies the complex craniocervical anatomy. Individual anatomical variation (e.g., variations in fascial thickness, density, and attachment patterns) has not been quantitatively incorporated into this theoretical framework.

Fourth, this hypothesis cannot exclude other known pathogenic mechanisms of cervicogenic headache. Other well-recognized pathological pathways (such as direct trigeminal afferent activation, cervical root irritation, and myofascial trigger point mechanisms) may coexist and interact with the fascial tension-centric cascade described herein.

Fifth, investing fascia-specific research is insufficient, and direct evidence for PIEZO1/2 expression in this fascia is lacking [51,53,83]. That said, even if PIEZO channel expression is negative, this hypothesis may still maintain the core logic of mechano-fibrotic coupling through three alternative pathways—the integrin-YAP axis [73,74], TRPV4 channels [71], and mechanical activation of latent TGF-β1 [106]—in which case the "candidate molecular switch" would be adjusted from PIEZO channels to a "multi-pathway redundant mechanotransduction network."

Sixth, the relative contribution weights of the five pathways are unknown, and standardized protocols for fascial release and SWE measurement have yet to be established. The a priori weight spectrum proposed in Level 4 is a working assumption that requires empirical validation.

14. Discriminative Framework for Initiation vs. Exacerbation Factors

In the subsequent human mechanistic validation cohort, the following discriminative framework is prespecified:

15. Conditions Supporting the "Initiating Factor" Designation

After adjustment for cervical structural abnormalities (e.g., degree of C1 anterior displacement, cervical curvature index, and sagittal balance parameters), investing fascial SWE values should remain independently and significantly associated with primary endpoints (TCD flow velocity, IOP, and ONSD).

In the subgroup of patients without clearly defined cervical structural abnormalities (i.e., excluding those with C1 anterior displacement and other bony etiologies described by Hauser et al. [11]), fascial release should still independently influence the direction of change in TCD flow velocity and IOP.

In longitudinal follow-up, early elevation of investing fascial SWE values should predict subsequent decline in TCD flow velocity or elevation in IOP, with this predictive relationship remaining independent of baseline cervical structural parameters.

16. Conditions Supporting the "Exacerbating Factor" or "Modulating Factor" Designation

After adjustment for cervical structural abnormalities, the correlation between investing fascial SWE and primary endpoints should disappear or be significantly attenuated.

Elevation of investing fascial SWE values should be observed only in patients with significant cervical structural abnormalities, with no significant elevation in patients with normal cervical structure.

The effect of fascial release should be observable only in patients with cervical structural abnormalities, and not in those without.

This discriminative framework will be implemented in prespecified subgroup analyses of the prospective human mechanistic validation cohort. If validation results support the "exacerbating factor" designation rather than the "initiating factor" designation, the core proposition of this hypothesis will require revision—the fascial tension abnormality should then be considered an intermediary link between cervical structural abnormalities and brain/eye pathology, rather than an independent etiological starting point.

17. Pathways of Hypothesis Revision

To ensure the falsifiability of this hypothesis, the following revision pathways are prespecified corresponding to each prediction:

If Prediction 1 (negative correlation between fascial stiffness and carotid flow velocity) is not supported, the core mechano-coupling hypothesis requires reexamination—fascial tension may influence cerebral blood supply not through mechanical arterial compression but through reflex vasomotor regulation or diffusion of inflammatory mediators. This would shift the theoretical framework from a "direct mechanical compression" model to an "indirect neuromodulatory" model.

If Prediction 1b (immediate flow velocity increase after fascial release) is not supported, the acute mechanical causality would be weakened, suggesting that the hemodynamic effects of fascial tension may require longer time scales to manifest (e.g., via inflammatory or remodeling pathways), or that the TCD measurement window requires adjustment.

If Prediction 2 (IOP reduction) or Prediction 3 (ONSD reduction) is not supported, the contribution weights of the venous and lymphatic pathways should be downweighted, and the influence of this fascia on the eye may be primarily mediated through autonomic pathways (sympathetic and vagal) rather than through direct mechanical compression of venous and lymphatic structures.

If Prediction 4 (autonomic function correlation) is not supported, the neurogenic component of the hypothesis would be weakened, suggesting that the effects of fascial tension on the eye and brain may be primarily mediated through direct mechanical vascular compression rather than through autonomic reflexes.

If Prediction 5 (layer-specificity hypothesis) is not supported—that is, if SWE values of the three fascial layers increase synchronously without significant temporal gradient differences—the causal direction hypothesis of "trans-layer transmission" must be revised to a parallel model of "three-layer synergistic fibrosis," and the investing fascia's "initiating" role would be downgraded to "key participant."

This prespecification of revision pathways aims to define the falsifiability boundary of the hypothesis, preventing the theoretical framework from becoming unfalsifiable and ensuring that empirical evidence can meaningfully constrain its development.

18. Future Validation Protocol

18.1. Molecular Experiment: Immunohistochemistry (IHC)

To validate the expression and distribution of PIEZO1/2, integrin β1, YAP, TRPV4, and Sirtuins in the investing fascia and carotid sheath, IHC specimens will be collected from cervical fascial tissues resected during radical surgery for cervical malignancy (with informed consent). The study plans to collect 15 cases from the fibrosis group (SWE >20 kPa) and 15 cases from the non-fibrotic control group (SWE <12 kPa). The Ashcroft scoring system will be employed for semi-quantitative grading of fibrosis on Masson's trichrome-stained sections. Expectations: PIEZO1 should be upregulated in fibrotic fascial fibroblasts, and Sirtuins downregulation should negatively correlate with the degree of fibrosis. Pirri et al. [104] demonstrated in vitro that shockwave therapy can immediately affect fascial fibroblast activity, providing feasibility support for IHC validation.

18.2. Biomechanical Simulation: FSI Fluid-Structure Interaction Finite Element Analysis

To enable quantitative simulation of the mechanical effects of trans-layer transmission of investing fascial residual passive tension on structures within the carotid sheath, a three-dimensional finite element model—including the three fascial layers, carotid sheath, common carotid artery, internal jugular vein, and vagus nerve—will be established based on real human cervical CT/MRI data, to which different tension states will be assigned. The coupled exponential strain-energy function developed by Aparici-Gil et al. [13] can serve as the constitutive framework for parameterizing this fascial material. The mechanical threshold identified by Pires et al. [46] (approximately 6 N/cm²) will be used as a reference for load setting. The febio biphasic fluid-structure interaction framework established by Shim et al. [107], the carotid artery fluid-structure interaction stability study by Saeid Khalafvand and Han [108], and subsequent CFD/FSI series studies [109,110,111,112,113,114,115] provide methodological references for fascial-vascular coupling modeling, carotid mechanical stability assessment, and hemodynamic analysis under stenotic geometry. FSI analysis will quantitatively output carotid luminal deformation rate, internal jugular vein cross-sectional area changes, and vagus nerve stress distribution. PIEZO channel mechano-electrical coupling parameters are primarily derived from in vitro single-cell patch-clamp recordings; integrating these parameters into the tissue-scale model requires parameter sensitivity analysis and cross-scale validation. The FSI model outputs tissue-scale stress distributions, whereas PIEZO channels sense local cell membrane curvature and tension changes. To address this scale mismatch, the protocol plans to employ a representative volume element (RVE)-based homogenization method to downscale the tissue-scale strain field to local mechanical boundary conditions at the fiber-cell interface.

18.3. Human Mechanistic Validation Cohort

To distinguish acute mechanical effects from long-term chronic remodeling effects, the validation is divided into two sub-studies:

(1) Acute Mechanistic Validation Sub-study (single intervention, self-controlled): Sixty patients with cervicogenic headache and elevated intraocular pressure will be enrolled. Dynamic measurements—including TCD, IOP (Goldmann applanation tonometry), ONSD (ultrasound), and HRV—will be performed at baseline and at 5, 15, 30, and 60 minutes following the standardized fascial release intervention. The intervention protocol references the fascial manipulation standards established by Stecco et al.—patients are placed in the supine position; the operator applies sustained pressure perpendicular to the fascial plane using the thumb or finger joint at the midpoint of the posterior border of the sternocleidomastoid muscle (approximately 2–4 N), maintaining each point for 60–90 seconds, and sequentially releases 3–5 key points along the direction of the fascial course. The sham intervention consists of light touch (pressure <0.5 N).

(2) Long-term Effect Sub-study (randomized, sham-controlled): One hundred fifty patients (75 per group) will be enrolled to receive either regular fascial release or sham intervention for 8 weeks (3 times weekly), with assessments at baseline, 4 weeks, 8 weeks, and the 12-week follow-up. Primary endpoints: middle cerebral artery blood flow velocity (TCD) and IOP (Goldmann applanation tonometry). Secondary endpoints: ONSD (ultrasound/MRI), HRV, headache frequency and intensity, and cervical fascial stiffness (SWE).

Sample Size Estimation: Using a conservative effect size of d=0.5 (α=0.05, β=0.20, two-sided test), approximately 64 cases are required per group; accounting for a 15% dropout rate, 75 cases per group are needed, totaling 150 cases. The acute mechanistic sub-study, employing a paired t-test with an effect size of d=0.4, requires 52 cases; it is recommended to enroll 60 cases. An interim analysis will be conducted at 50% enrollment, with an independent statistician performing conditional power analysis and adjusting the final sample size accordingly.

Safety Considerations: Cervical manipulation carries potential risks, including carotid artery dissection, vertebral artery injury, and nerve root irritation. The manual intervention in this study protocol is intended solely as a mechanism-validation experimental tool and not as a clinical treatment recommendation.

Pre-enrollment Safety Screening (all must be passed):

Cervical vascular color Doppler ultrasound—to exclude carotid artery plaque (especially unstable plaque), carotid artery dissection, and vertebral artery developmental anomalies or stenosis.

Cervical spine X-ray (AP + lateral + flexion-extension views)—to exclude cervical instability, severe cervical spondylosis, and osteoporotic compression fractures.

TCD baseline assessment—to exclude pre-existing abnormal blood flow velocity.

Medical history screening—to exclude recent cervical trauma (within 6 months), cervical surgery history (within 12 months), coagulation disorders, and current anticoagulant use.

Safety Termination Criteria (terminate upon any occurrence):

New onset of severe headache, vertigo, nausea, or sudden visual changes during or within 24 hours after the intervention.

Post-intervention TCD showing a >20% decrease in blood flow velocity from baseline persisting for more than 10 minutes.

Any signs suggestive of carotid artery dissection (e.g., Horner's syndrome, pulsatile neck pain, or transient ischemic attack [TIA]).

The manual intervention will be performed by a rehabilitation physician with at least 5 years of clinical experience, adhering to the principles of low speed, low amplitude, and pain-free technique, within a medical institution equipped with emergency facilities. The protocol must be approved by both the Institutional Ethics Committee and the Hospital Safety Committee.

Data Analysis: Mediation Analysis: With the change in investing fascial SWE values as the independent variable, the primary endpoints as dependent variables, and carotid artery blood flow velocity, internal jugular vein cross-sectional area, RMSSD, and LF/HF ratio as candidate mediators, the Bootstrap method (5,000 resampling iterations) will be used to estimate the 95% confidence intervals for the indirect effects of each pathway.

19. Conclusions

This article proposes and argues for a theoretical model that awaits empirical testing, aiming to provide a novel biomechanical perspective for understanding brain-eye comorbidities. This hypothesis posits that increased investing fascial tension may, in theory, through five interconnected pathways—arterial compression leading to cerebral and ocular hypoperfusion; venous compression leading to intracranial hypertension and elevated intraocular pressure; lymphatic drainage obstruction leading to intraocular fluid retention; sympathetic stimulation leading to vasoconstriction and intraocular pressure fluctuations; and vagus nerve compression leading to autonomic imbalance—constitute a long-overlooked potential mechanical node underlying cerebral hypoperfusion and a spectrum of ocular disorders. This hypothesis positions PIEZO1/2 channels as candidate core molecular switches (while acknowledging the redundancy of multiple pathways, including integrin-YAP, TRPV4, and latent TGF-β1) and constructs a complete cross-scale causal chain from macroscopic mechanics to molecular mechanisms [38,50,51,52,53,54,55,56,57,58,59,60,61,62,83,63,71,73,74,106], as well as a trans-layer transmission mechanical model [1,3,44,45,46]. The neck-eye myofascial continuum [8], the RCT by Uzun et al. [17], the network meta-analysis by Xu and Ling [19], the meta-analysis by Lu et al. [18], and the mechanical threshold identified by Pires et al. [46] provide independent support for the hypothesis from anatomical, clinical, and biomechanical perspectives, respectively.

This hypothesis does not conflict with the "jugular vein hypothesis" [23] or the "cervical oculopathy" hypothesis [11]; rather, it attempts to integrate single-pathway theories into a more comprehensive framework. The five predictions and the three-tiered validation framework provide clear directions for subsequent empirical research. Of note, the fascial release in the human validation protocol serves only as an experimental tool for testing the mechanical causal hypothesis and does not constitute a clinical intervention recommendation. This hypothesis does not assert that fascial tension abnormality is the sole or sufficient cause of the aforementioned diseases, but rather proposes it as a common mechanical modulator of multiple pathways that may play a significant pathological amplifying role in a subset of patients. This hypothesis awaits further validation through computational simulation, histological, and human studies.