The "Biomechanical Unloading" Hypothesis for the Improvement of Motor Function in Post-Stroke Sequelae by Investing Fascia Release

1. Introduction

Stroke is the leading cause of acquired motor dysfunction in adults (Bond et al., 2023). Even with standardized rehabilitation training, patients in the sequelae phase (>6 months) often experience a plateau in motor function improvement (Bond et al., 2023). Traditional theory attributes this to structural damage of the corticospinal tract—the "disconnection model." However, this model struggles to explain a long-standing clinical conundrum: some patients can achieve a manual muscle test grade of 3 (anti-gravity, full range of motion) yet remain unable to perform independent walking or fine hand manipulation—a phenomenon of mismatch between muscle strength and motor function. This phenomenon suggests that, in addition to structural damage, there may exist a functional "output inhibition" mechanism that impedes the effective utilization of residual neural pathways.

Clinically, this phenomenon is not rare. We often observe a subset of post-stroke sequelae patients whose muscle strength recovery has reached a "usable" level (e.g., knee extension strength grade 4, elbow flexion grade 3+), yet in daily living scenarios, this strength "fails to be recruited"—patients cannot utilize this strength to perform goal-directed actions such as standing transfer or grasp-and-release. This state of "strength available but not recruitable" strongly suggests the existence of a central "gating" mechanism independent of the muscle itself. If this gating upregulation is reversible—rather than fixed structural damage—it implies the existence of a yet-to-be-fully-explored therapeutic window in the sequelae phase. It is precisely this clinical conundrum that constitutes the point of origin for the problem awareness of this hypothesis.

Clinical observation has also revealed that some post-stroke sequelae patients present with varying degrees of soft tissue bulging at the cervicothoracic junction (C7-T1 level)—in mild cases, palpation reveals local tissue thickening without obvious protrusion ("subclinical buffalo hump"), while in severe cases, a visible bulge is present ("manifest buffalo hump"). This phenomenon is essentially an external manifestation of subcutaneous adipose accumulation, deep fascial fibrotic hyperplasia, and nuchal ligament calcification in the posterior neck. It should be clearly noted that the "buffalo hump" is introduced in this paper solely as a surface visualization clue for abnormal tension in cervical soft tissues (clinical observation background); it is not itself a necessary link in the causal chain of this hypothesis; the core mechanistic reasoning below focuses on the biomechanical status of the deep investing fascia and does not depend on the presence or severity of the "buffalo hump." Patients often present with a constellation of symptoms including dizziness, head heaviness, blurred vision, dry eyes, insomnia, forgetfulness, easy awakening with excessive dreaming, anxiety, depression, and shoulder-neck soreness and distension. These symptoms highly overlap with functional mechanical disorders in the posterior circulation territory, suggesting that abnormal tension in cervical soft tissues may be an important link connecting peripheral mechanical status and central nervous system function.

The adaptive and pathological remodeling mechanisms of soft tissues under sustained mechanical loading indicate that the maintenance of mechanical homeostasis depends on the balance between extracellular matrix mass turnover and pretension adjustment (Cyron and Humphrey, 2017; Holzapfel et al., 2025). In recent years, the mechanobiological functions of fascial tissues have received increasing attention. Anatomical studies have confirmed that the investing fascia, as the most superficial layer of the deep cervical fascia, participates in the formation of the carotid sheath and has anatomical proximity to key neural structures including the cervical sympathetic trunk and the vagus nerve (Bond et al., 2023; Komune et al., 2019; Struthoff et al., 2024). Histological studies have shown that fascial tissues contain mechanoreceptors such as Pacinian corpuscles and Ruffini corpuscles, as well as autonomic nerve fibers (Hamed et al., 2024), providing the anatomical basis for sensing and conducting mechanical signals. Biomechanical studies have confirmed that deep fascia possesses high viscoelasticity and mechanical anisotropy, and can undergo fibrotic remodeling under sustained abnormal loading (Cyron and Humphrey, 2017; Holzapfel et al., 2025).

At the molecular level, PIEZO1 and PIEZO2, as mechanosensitive cation channels, have been demonstrated to convert cell membrane stretch or compression into ion influx signals (Bagriantsev et al., 2014; Xiao, 2024). Recent studies have further demonstrated that PIEZO1 plays a critical role in neuroinflammation and neural repair after stroke (Zhang et al., 2026b; Wu et al., 2026a; Wu et al., 2026b; Zhao L et al., 2026). In terms of stroke-specific mechanisms, Wu et al. (2026a) demonstrated in an ischemic stroke model that Piezo1 regulates astrocyte cytoskeletal reorganization through the Wnt7b-Ca²⁺ non-canonical signaling pathway, serving as a key molecule in modulating glial scar stiffness and influencing neural regeneration. The same team further confirmed that progressive glial scar stiffening strongly inhibits the neuronal differentiation direction of neural stem cells and impairs neurite outgrowth through the Piezo1 channel (Wu et al., 2026b). The systematic review by Shi et al. (2026) positions Piezo1 as a key integrator linking physical signals such as tissue stiffening and blood flow shear stress to neuroinflammation in the central nervous system. Fu et al. (2025) confirmed in an ischemic stroke model that Piezo1 exacerbates blood-brain barrier disruption through the Ca²⁺/CaMKII/Nrf2 pathway.

Furthermore, clinical studies have preliminarily confirmed the effectiveness of peripheral fascial interventions in improving motor function after stroke. The randomized controlled trial by Parikh et al. (2022) confirmed that tennis ball myofascial release combined with conventional physical therapy was significantly superior to conventional physical therapy alone in improving upper limb spasticity and motor function in patients with chronic stroke (P < 0.05). Rafat and Srivastav (2025) further quantified the effect sizes of direct myofascial release through a quasi-experimental design, finding large effect sizes in improving spasticity (d=1.4), upper limb motor function (d=1.86), and quality of life (d=1.07), with significant improvement observed after only 2 weeks of intervention (p=0.001), providing quantitative evidence for the rapid onset of peripheral fascial intervention. A randomized controlled trial of cervical mobilization confirmed that it significantly increases blood flow velocity in the internal carotid and vertebral arteries (Uzun et al., 2024). Dengiz and Baskan (2024) further confirmed that cervical mobilization has significant improving effects on gait parameters and balance function in post-stroke patients, suggesting that cervical mechanical intervention may affect motor output through central regulatory pathways.

However, no study to date has integrated the above findings into a unified mechanistic framework from "peripheral fascial fibrosis" to "central motor regulation." Based on the above literature evidence, this paper proposes the "biomechanical unloading" hypothesis, aiming to construct an integrative theoretical framework that couples peripheral biomechanical status, anterior and posterior circulation anatomical distribution, and central motor cortical excitability regulation.

In summary, this introduction has identified three lines of evidence supporting the hypothesis: first, the presence of the "strength-function mismatch" phenomenon in the post-stroke sequelae phase suggests a reversible central gating mechanism (clinical conundrum); second, the anatomical position of the investing fascia makes it the primary recipient of exogenous mechanical loading in the neck, and its fibrosis may alter the local mechanical environment (anatomical basis); third, studies on PIEZO channels and post-stroke glial scar mechanical regulation indicate that mechanical signals can affect central nervous system function through specific molecular pathways (molecular evidence). These three lines of evidence are independent of each other but have not yet been linked into a unified causal chain. The following Section 2 will first present the core causal chain of this hypothesis in a five-step progressive manner to help readers establish an overall picture; Section 3 will then unfold the detailed argumentation layer by layer, with each step anchored to specific literature evidence; Section 4 and Section 5 will translate the hypothesis into testable quantitative predictions and a validation framework.

(Project Note: Based on the core theoretical framework of the "investing fascia biomechanical hub," our team has concurrently conducted a series of parallel theoretical explorations. Among them, a parallel study sharing the identical upstream mechanism with this hypothesis—namely "investing fascia fibrosis → abnormal stress conduction through the three-layer collagen network of the deep cervical fascia → abnormal mechanical loading on the carotid sheath and its contents"—focuses on the mechanistic deduction of cerebral hypoperfusion and ocular pathological manifestations resulting from this abnormal stress through the vascular pathway (altered blood flow shear stress due to external compression of the extracranial carotid and vertebral arteries, venous drainage impairment, and ocular circulation disturbance); whereas this paper strictly focuses on the specific inhibitory effect of this abnormal stress on motor function output in the post-stroke sequelae phase through the neural afferent pathway (abnormal afferent tension of the vagus nerve and cervical sympathetic trunk → upregulated locus coeruleus-noradrenergic output via the nucleus tractus solitarius → GABAergic interneuron-mediated excitatory inhibition in the primary motor cortex). The two papers together constitute a multi-dimensional theoretical elaboration of the same mechanical intervention target—"investing fascia release"—serving two distinct clinical outcomes: motor rehabilitation (post-stroke secondary rehabilitation) and cerebro-ocular syndrome (cerebral hypoperfusion and visual symptoms). They are independent of and complementary to each other, both being integral components of this theoretical framework. This hypothesis only addresses the former; the vascular pathway effects involved in the latter are beyond the scope of this paper.)

2. Core Statement of the Hypothesis

This section aims to present the complete causal chain of this hypothesis in the most concise manner. Because the hypothesis spans five biological levels from fascial fibrosis to motor cortical excitability, a single linear narrative may easily cause readers to lose sight of the overall picture amidst the details. Therefore, this section adopts a five-step progressive approach, with each step stating only the core proposition without elaborating the argumentation; detailed literature anchoring and mechanistic analysis will be unfolded layer by layer in Section 3. Readers are advised to first use this section as a "roadmap" to understand the overall logic, and then proceed to Section 3 to read the specific evidence for each link.

To facilitate understanding of the complex multi-level causal chain of this hypothesis, the core mechanism is briefly described below in a five-step progressive manner:

Step 1 (Initiating Event): In the post-stroke sequelae phase, patients often adopt a forward head compensatory posture due to central motor control impairment. This abnormal posture subjects the investing fascia to sustained tensile loading beyond the physiological range. Under sustained mechanical overload, fibroblasts are activated and transform into myofibroblasts via the Piezo1-YAP/TAZ pathway, with increased collagen deposition and decreased elastic fibers, leading to fibrotic adhesion of the fascia and loss of its original elastic buffering function (Zullo et al., 2021; Tu et al., 2025; Xu et al., 2025).

Step 2 (Mechanical Conduction): After the loss of elastic buffering, the shear stress generated by daily head and neck micromovements (turning, nodding) is no longer uniformly dissipated by the fascial network, but instead is rigidly conducted deep along the three-layer collagen network of the deep cervical fascia, reaching through the adventitia of the carotid sheath directly to its contents—the adventitia of the vagus nerve, cervical sympathetic trunk, carotid artery, and internal jugular vein (Bond et al., 2023; Zhang and Lee, 2002; Pires et al., 2025).

Step 3 (Mechano-Electrical Signal Transduction): The abnormal stress continuously stretches the adventitia of nerves and blood vessels, activating the PIEZO1/2 mechanosensitive ion channels on the cell membrane (Bagriantsev et al., 2014; Xiao, 2024). These channels convert physical stretch or compression stress into cation influx (Na⁺, Ca²⁺), directly generating or enhancing abnormal discharges in afferent nerves. Recent histological evidence has demonstrated that Piezo2-positive nerve fibers and mechanosensitive structures do exist in human cervical fascia (Tereshenko et al., 2026), providing a direct histological anchor for this link.

Step 4 (Central Gating Upregulation): The abnormally enhanced afferent signals converge at the nucleus tractus solitarius (NTS) in the brainstem via vagal and sympathetic afferent fibers, which in turn activates the locus coeruleus (LC) and drives whole-brain norepinephrine (NE) release (Bogduk, 2001; Ji and Lee, 2021). In the primary motor cortex (M1), NE specifically enhances the excitability of GABAergic interneurons through α₁-adrenergic receptors (Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016), thereby elevating the discharge threshold of corticospinal tract pyramidal neurons (Sawaki et al., 2003; Kim et al., 2014; Okabe et al., 2025). This "central gating upregulation" effect makes it difficult for residual descending motor commands to exceed the threshold and be effectively conducted to the anterior horn α-motor neurons of the spinal cord.

Step 5 (Mechanical Unloading and Functional Release): Investing fascia release, by physically cutting off the abnormal stress conduction pathway, could theoretically achieve "mechanical unloading" of the central nervous system—aberrant afferent signals decrease abruptly, NTS-LC-NE output declines, the cortical inhibition mediated by M1 GABAergic interneurons is relieved, the discharge threshold is restored, residual descending commands exceed the threshold, and motor function is released.

To help readers grasp the progressive relationship of the above five steps as a whole, the complete causal chain of this hypothesis can be summarized by the following simplified formula:

Forward head compensatory posture → Investing fascia fibrosis (initiation) → Daily head and neck micromovements generate abnormal shear stress (mechanical loading) → Stress is rigidly conducted deep through the three-layer network of the deep cervical fascia (mechanical conduction) → The adventitia of the carotid sheath contents (nerves, blood vessels) is subjected to force (target arrival) → PIEZO1/2 channels are activated, converting physical stress into abnormal neural discharges (mechano-electrical transduction) → NTS-LC-NE pathway is continuously activated (central gating upregulation) → Cortical inhibition mediated by M1 GABAergic interneurons is enhanced (output threshold elevation) → Residual motor commands are blocked, and motor function cannot be effectively expressed (functional inhibition) → Investing fascia release cuts off the stress pathway → The above process is reversed (mechanical unloading and functional release)

This causal chain can be regarded as a series of "dominoes" in sequence: the establishment of each link is the prerequisite for the next, and the disruption of any link will lead to the failure of the hypothesis. It is precisely this serial structure that endows the hypothesis with a high degree of falsifiability—testing any single link can challenge the whole.

Based on this deduction, in the post-stroke sequelae phase (>6 months), the fibrotic and adhered investing fascia becomes a conduction pathway for abnormal shear stress during daily head and neck micromovements; this abnormal stress is conducted deep through the three-layer collagen network of the deep cervical fascia, acting on the adventitia of the carotid sheath and its contents, and is converted through PIEZO1/2 channel-mediated mechano-electrical signal transduction into abnormally enhanced afferent signals, which continuously activate whole-brain NE output via the NTS-LC pathway, specifically upregulate the excitability of M1 GABAergic interneurons, elevate the discharge threshold of corticospinal tract pyramidal neurons, thereby suppressing residual motor function output. Investing fascia release, by cutting off the abnormal stress conduction pathway, may achieve mechanical unloading of the central nervous system, allowing the discharge threshold to return to baseline and motor function to be released.

The clinical boundary of this effect may be determined by the anatomical distribution of the anterior and posterior circulations (Bond et al., 2023): the extracranial segment (neck) is the mechanically accessible region, among which the posterior circulation vertebral artery V1-V3 segment may become the optimal mechanical response target due to its anatomical proximity to the investing fascia (Zhang et al., 2026a; Yuan et al., 2025); the intracranial segment (within the cranium) is a structural damage region beyond the range of mechanical conduction, where structural necrosis of the thalamus and brainstem nuclei is irreversible and beyond the biological limits of this intervention.

3. Hierarchical Exposition of the Hypothesis

This section will elaborate on the detailed argumentation for each link in the five-step causal chain from Section 2. Each subsection corresponds to one causal link, following a unified argumentation structure of "statement of proposition → presentation of supporting literature → explanation of mechanism → identification of evidence gaps." For those with sufficient evidence, the discussion will be more detailed; for those with insufficient evidence, the limitations will be clearly pointed out while deducing their theoretical plausibility. Readers may choose to read according to their interests: those who wish to understand the overall framework may focus on Section 2 and Section 4; those who wish to examine the strength of the argumentation may scrutinize the relationship between literature and reasoning section by section.

3.1. Initiating Event: Investing Fascia Fibrosis and Loss of Elastic Buffering

The investing fascia, as the most superficial layer of the deep cervical fascia, forms a continuous fibrous sleeve encircling the entire neck, attaching superiorly to the skull base and inferiorly to the clavicle and sternum, and laterally directly receiving the tension of the platysma and subcutaneous tissues (Bond et al., 2023). This fascial layer is absent between the sternocleidomastoid and trapezius muscles, allowing subcutaneous tissue tension to directly act on the deep carotid sheath (Zhang and Lee, 2002)—an anatomical feature suggesting that it may be the primary recipient of exogenous mechanical loading in the neck.

Under physiological conditions, the viscoelasticity of the investing fascia can buffer the shear stress generated by daily head and neck micromovements, uniformly dissipating it through the collagen-elastin network (Cyron and Humphrey, 2017; Holzapfel et al., 2025). Ex vivo biomechanical studies have further confirmed that deep fascia exhibits complex nonlinear mechanical responses under uniaxial, biaxial, and planar tension, with its multiaxial mechanical properties providing direct experimental evidence for understanding the stress dissipation function of the investing fascia (Aparici-Gil et al., 2025). However, chronic postural loading (such as forward head posture) can induce fibrotic remodeling—activation of the TGF-β1/YAP pathway, increased collagen deposition, and decreased elastic fibers (Zullo et al., 2021; Kirkness and Scarlata, 2026). In the stroke population, forward head posture is particularly common. The systematic review and meta-analysis by Hao et al. (2024) confirmed that spinal mobilization can significantly improve forward head posture in stroke patients (SMD: 1.00, 95% CI: 0.53 to 1.46, p < 0.001), suggesting that forward head posture is an intervenable mechanical risk factor after stroke, providing evidence-based medical support for the initiating event of abnormal loading on the investing fascia. Ley et al. (2025) systematically verified the reliability of stiffness measurements in skin, fascia, and superficial and deep muscles using shear wave elastography (SWE), demonstrating that SWE has higher reliability at the fascia than in muscle tissue, providing a methodological basis for objective assessment of fascial stiffness. Creze et al. (2025) further directly quantified the mechanical properties of the human thoracolumbar fascia and erector spinae aponeurosis through ex vivo mechanical tensile testing combined with SWE, providing ex vivo-in vivo cross-validation for SWE assessment of fascial stiffness. Zandi et al. (2025) further focused on the posterior cervical fascia, demonstrating excellent test-retest reliability of SWE in measuring cervical fascial stiffness (ICC ≥ 0.90), and that fascial thickness in chronic pain patients was significantly greater than in healthy controls (p=0.002), providing a direct methodological basis for SWE assessment of the investing fascia as a neck-specific fascia. In stroke patients, ultrasound imaging studies have also confirmed that the fascial thickness on the affected side is significantly greater than that on the unaffected side (anterior: 0.96±0.14 mm vs. 0.72±0.08 mm, p<0.001) (Choi et al., 2024), suggesting that peripheral fascia can undergo structural fibrotic thickening after stroke, providing stroke-specific population evidence for the above deduction.

In addition to morphological thickening, the in vivo mechanical properties of peripheral soft tissues also undergo significant changes after stroke. Chardon et al. (2020) directly measured the passive mechanical properties of musculotendon units in chronic stroke survivors using ultrasound indentation technology, finding that the affected-side tissue no longer undergoes normal strain during stretching, but instead translates as a rigid body; the study clearly indicated that the underlying mechanism is extracellular matrix (ECM) fibrotic remodeling. This in vivo mechanical evidence independently corroborates the above morphological findings at the functional level—fibrosis not only thickens the fascia but fundamentally alters its mechanical response pattern—jointly supporting the conclusion that peripheral connective tissues undergo structural fibrotic changes after stroke.

Tu et al. (2025) applied cyclic mechanical stretch to fibroblasts using PDMS stretch membranes and a uniaxial cell stretching system, establishing for the first time in vitro a complete evidence chain of mechanical stretch → Piezo1 upregulation → YAP pathway activation → fibroblast proliferation and migration enhancement, confirming that Piezo1 is the key molecular bridge connecting mechanical signals to the fibrotic execution program. Xu et al. (2025) further validated this pathway in vivo in a Postn⁺ myofibroblast-specific knockout mouse model, demonstrating that Piezo1 deficiency can significantly inhibit fibrosis progression. Yu et al. (2025) revealed another parallel mechanism in osteoarthritic synovial tissue—mechanical stress overload simultaneously drives inflammation and fibrosis through the Piezo1/NF-κB/NLRP3 signaling cascade. These three studies together constitute a multi-pathway convergent evidence chain of "mechanical signal → Piezo1 → (YAP/Yap-Taz/NF-κB-NLRP3) → fibrosis." At the deep fascia level, Pirri et al. (2023) directly confirmed the expression of Yes-associated protein (YAP) in human deep fascia, providing fascia tissue-specific molecular localization evidence for the above deduction of the mechanical signal → YAP pathway.

Based on this, this hypothesis deduces that after the loss of fascial elastic buffering, the shear stress from daily head and neck micromovements is no longer dissipated but instead conducted deep along collagen fibers, forming focal stress concentration (Cyron and Humphrey, 2017; Ley et al., 2025). Zullo et al. (2021) positioned the Sirtuin family as a key regulatory node for myofibroblast differentiation and profibrotic activity. Kirkness and Scarlata (2026) further proposed the calcium-hyaluronan (CHA) axis integrative framework, pointing out that after mechanical signals activate PIEZO channels, the dynamic regulation of hyaluronan molecular weight metabolism determines whether fascial tissue maintains a steady state or undergoes remodeling (Kirkness and Scarlata, 2026). The review by Lei et al. (2025) published in FRONTIERS IN IMMUNOLOGY systematically proposed the "mechanotransduction-immune axis" conceptual framework, pointing out that matrix stiffness, shear stress, and mechanical stretch simultaneously activate pro-fibrotic signals in stromal cells and reprogram immune cell phenotypes through mechanosensors such as integrins, FAK, Piezo1, and TRPV4, with the two mutually amplifying to form a positive feedback loop. The above mechanisms together constitute a complete molecular regulatory network from mechanical sensing to fibrotic execution (Pirri, 2025; Zullo et al., 2021; Lei et al., 2025).

This subsection focuses on the "initiating event"—that is, under what conditions the investing fascia undergoes fibrosis and why it loses its elastic buffering function. The argumentation strategy is: first, establish that "the investing fascia is anatomically the primary recipient of exogenous mechanical loading in the neck" (anatomical localization); second, argue that "sustained abnormal loading can induce fascial fibrosis" (biomechanical and molecular mechanisms); and finally, anchor this to the stroke-specific population using ultrasound evidence of increased fascial thickness in stroke patients (disease relevance). The three lines of evidence come from anatomy, biomechanics, and clinical ultrasound respectively, independent but convergent in their conclusions, jointly supporting the proposition that "investing fascia fibrosis is a detectable pathological change in the post-stroke sequelae phase." This argumentation structure will be reused in subsequent sections—the "anatomical basis → mechanical mechanism → disease-specific evidence" triad—to maintain consistency in the overall argumentation style.

3.2. Mechanical Conduction Pathway: Stress Transmission Through the Three-Layer Fascial Network

The investing fascia is not a mechanical island. However, it should be noted that the anatomical continuity of the investing fascia is not without controversy in the academic community—Nas et al. (2005), based on gross anatomical observations of the neck, questioned the complete existence of the most superficial layer of the deep cervical fascia in the anterior cervical triangle, suggesting that it may not be a complete continuous membranous structure. This controversy is mainly concentrated in the anterior cervical region (anterior to the trachea and esophagus); in the posterolateral wall of the carotid sheath and the posterolateral region between the sternocleidomastoid and trapezius muscles, the functional continuity of the investing fascia as a mechanical conduction interface is still widely recognized (Zhang and Lee, 2002; Bond et al., 2023). Based on this, the mechanical conduction pathway on which this hypothesis relies—that is, the transmission of stress from the superficial investing fascia through the carotid sheath adventitia to the deep neurovascular contents—has a reasonable anatomical basis for its existence.

Widely accepted anatomical views confirm that the investing fascia is interconnected with the pretracheal fascia and prevertebral fascia through a collagen network, jointly forming the carotid sheath (Bond et al., 2023; Snosek et al., 2021; Zhang and Lee, 2002); the investing fascia has dense fibrous connections with the prevertebral fascia at the craniocervical junction (Komune et al., 2019); the alar fascia spans across the bilateral carotid sheaths (Snosek et al., 2021); the fascial network at the skull base converges around the internal jugular vein and internal carotid artery (Komune et al., 2019); and MRI can detect interfascial fusion at the skull base (Schachtel et al., 2023). The above anatomical continuity suggests the existence of a mechanical conduction chain from the superficial investing fascia through the carotid sheath to its contents (nerves and blood vessels) (Bond et al., 2023; Zhang and Lee, 2002; Struthoff et al., 2024). Mohova et al. (2023) quantified that the superficial fascia undergoes greater deformation than the deep fascia during head and neck rotation, confirming that dynamic loading is preferentially received by the superficial layer and conducted downward (Mohova et al., 2023). Pires et al. (2025) quantified that an average force of 6.06±0.186 N/cm² is sufficient to produce effective mechanical transmission from the superficial layer to the deep cervical fascia (Pires et al., 2025).

Based on the above evidence, this hypothesis deduces three specific stress conduction sub-pathways:

Sub-pathway A (Nerve Adventitia Conduction): Abnormal stress may directly stretch the adventitia of the vagus nerve and cervical sympathetic trunk traveling within the carotid sheath through the carotid sheath adventitia (Bond et al., 2023; Struthoff et al., 2024). The nerve adventitia, as a collagenous connective tissue sheath, has mechanical properties continuous with the fascia and could theoretically transmit tensile stress to the perineurium and even the axolemma (Hamed et al., 2024; Struthoff et al., 2024).

Sub-pathway B (Vascular Adventitia Conduction): Abnormal stress may stretch the adventitia of the carotid artery and internal jugular vein (Bond et al., 2023; Lan et al., 2024). The vascular adventitia is also rich in collagen and mechanoreceptors (Hamed et al., 2024). The study by Lan et al. (2024) published in the JOURNAL OF THE AMERICAN HEART ASSOCIATION further revealed how Piezo1 perceives oscillatory shear stress and activates endothelial inflammation through the Ca²⁺/CaM/CaMKII-FAK/Src-YAP axis, providing a molecular-level mechanistic framework for understanding how external compression affects the vascular wall through mechanosensitive channels.

Sub-pathway C (Dural-Myodural Bridge Conduction): Prevertebral fascial stress may be transmitted to the spinal dura mater through the myodural bridge (Zhang et al., 2026a; Yuan et al., 2025). Zhang et al. (2026a) systematically reviewed the morphology, physiology, developmental biology, and pathology of the myodural bridge complex (Zhang et al., 2026a). Li et al. (2022) further revealed the association between the myodural bridge and intracranial pressure, finding that suboccipital muscle hyperplasia can affect intracranial pressure fluctuations through the myodural bridge, providing direct evidence for understanding the pathophysiological significance of the myodural bridge as a mechanical conduction hub. Yuan et al. (2025) directly confirmed through electrical stimulation of the obliquus capitis inferior muscle in beagle dogs that the myodural bridge complex can convert muscle contraction into cerebrospinal fluid pressure waves propagating from the cisterna magna to the cranial cavity and spinal canal (Yuan et al., 2025). Zhang et al. (2025) further confirmed in a rat model that Integrin α7 (ITGA7) is a key molecular bridge for myodural bridge development, and that ITGA7 knockout significantly impairs the development and maturation of the myodural bridge, demonstrating that the mechanical force of the suboccipital muscles fundamentally affects the differentiation and maturation of the myodural bridge (Zhang et al., 2025).

The above three sub-pathways are not mutually exclusive competitive hypotheses, but are more likely parallel mechanical conduction channels operating simultaneously. Nerve adventitia conduction (Sub-pathway A) directly mediates the transmission of mechanical signals to nerve fibers and is the primary pathway for "mechano-electrical signal transduction" in this hypothesis; vascular adventitia conduction (Sub-pathway B) may trigger local inflammatory responses through mechanosensitive channels in the vascular wall, indirectly enhancing the sensitivity of afferent nerves—the two pathways form a synergy at the anatomical convergence point of the carotid sheath; the myodural bridge conduction (Sub-pathway C) provides another conduction pathway that does not pass through the carotid sheath and may participate in the generation of posterior circulation-related symptoms (such as dizziness and balance disorders). The relative contributions of the three pathways depend on the direction, intensity, and frequency distribution of the specific mechanical loading, and their weights currently cannot be quantified. This hypothesis primarily relies on Sub-pathways A and B for deduction in subsequent discussions, with Sub-pathway C serving mainly as an auxiliary explanatory pathway for posterior circulation effects.

3.3. Mechano-Electrical Signal Transduction: From Physical Stress to Neuronal Excitability Changes

After abnormal stress reaches the adventitia of nerves and blood vessels, this hypothesis deduces that it is converted into neural signals through two mechanisms:

Mechanism A (Direct Mechano-Electrical Signal Transduction): Sustained stretching of the nerve adventitia may increase the open probability of PIEZO1 and PIEZO2 channels (Bagriantsev et al., 2014; Xiao, 2024). As mechanosensitive cation channels, PIEZO channels, once opened, allow Na⁺ and Ca²⁺ influx, directly altering the neuronal resting membrane potential (Bagriantsev et al., 2014; Xiao, 2024). Bagriantsev et al. (2014) systematically elucidated the multiple functions of Piezo proteins as regulators of mechanosensation (Bagriantsev et al., 2014). Rashidi et al. (2025) demonstrated in nanostructured 2D and 3D fibrosis models that PIEZO1-mediated mechanotransduction can independently regulate COL1A1 and COL3A1 collagen synthesis (Rashidi et al., 2025).

Huang et al. (2025) identified a population of CD34⁺ membranous cells (CMCs) in subcutaneous fascia, which highly express mechanosensitive channels such as PIEZO2 and form a "distributed sensing network" within the fascia through Cx43⁺ gap junctions and tunneling nanotubes (TNTs), and can directly interact with adjacent nerve endings, providing a direct cytological basis for the fascia tissue itself to convert physical stress into neural signals.

The review by Hamed et al. (2024) published in THE JOURNAL OF PHYSIOLOGY explicitly positions PIEZO channels as force sensors of the interoceptive nervous system, elucidating how PIEZO1/2 convert mechanical signals from visceral and muscular activities into neural signals. The review by Pirri (2025) published in DISEASES further positions PIEZO channels as context-dependent gatekeepers in the "mechano-inflammation-neuroimmune crosstalk," systematically pointing out that PIEZO1 regulates calcium-dependent pro-inflammatory activation through pathways such as NF-κB and STAT1 in immune cells, fibroblasts, and endothelial cells, while PIEZO2 is enriched in sensory neurons and participates in the mechanical perception and amplification of inflammatory pain; both channels are mechanistically involved in neuroinflammation, glial cell activation, blood-brain barrier dysfunction, and connective tissue fibrosis.

Recent histological evidence has demonstrated that Piezo2-positive nerve fibers and mechanosensitive structures such as Pacinian corpuscles and Ruffini corpuscles can be detected in human trapezius fascia (Tereshenko et al., 2026). Although this fascia is anatomically distinct from the investing fascia, it belongs to the same deep cervical fascial system, providing a direct histological anchor for PIEZO channel-mediated mechano-electrical signal transduction in human cervical fascia.

In the absence of direct confirmation of PIEZO1 and PIEZO2 expression in human investing fascia, the integrin-YAP/TAZ pathway and mechanically activated TGF-β1 (Walker et al., 2020) may serve as compensatory mechanotransduction pathways. The study by Xue et al. (2025) published in NATURE COMMUNICATIONS, using a mouse controlled tissue expansion model combined with single-cell sequencing and spatial transcriptomics, directly confirmed the core coordinating role of Piezo1 in the mechano-metabolism-inflammation crosstalk, finding that Piezo1, upon sensing skin tension, drives glycolysis (upregulation of Glut1 and Aldoa) and immune cell infiltration (macrophages and monocytes), providing functional evidence for PIEZO channels as mechanical signal integration hubs. Furthermore, the "fascial capacitor model" proposed by Kimura and Kobayashi (2026) provides a theoretical framework independent of PIEZO channels for the fascia itself to generate electrical signals through collagen nanoscale piezoelectric effects—the alternating arrangement of collagen sublayers and hyaluronan-rich loose layers in stacked fascia constitutes a multi-layer biological capacitor; the RC time constant of fibrotic or densified fascia can be prolonged by several orders of magnitude, reaching the millisecond range (Kimura and Kobayashi, 2026). Zhang et al. (2026b) systematically reviewed the role of the ECM-PIEZO1 axis in the central nervous system, pointing out that PIEZO1 mediates neuroinflammation and blood-brain barrier function regulation through pathways such as NF-κB, YAP/TAZ, and CaMKII by sensing mechanical signals including ECM stiffness, viscoelasticity, and shear stress (Zhang et al., 2026b).

Mechanism B (Tension-Excitability Threshold Modulation): Sustained tension on the nerve adventitia may, through cytoskeleton-ion channel coupling, upregulate voltage-gated sodium channel expression or alter their activation curves, making nerves more sensitive to subthreshold stimuli and generating ectopic discharges (Hamed et al., 2024; Struthoff et al., 2024).

The final common pathway of the two mechanisms: the afferent fibers of the cervical sympathetic trunk and vagus nerve—theoretically carrying abnormally elevated background discharges—converge toward the brainstem. Sympathetic afferents ascend via the spinothalamic tract to the medullary level and form synaptic connections with the nucleus tractus solitarius (NTS) (Bogduk, 2001); vagal afferents project directly to the NTS (Ji and Lee, 2021). As a convergence relay station for brainstem mechanical signals, the NTS, after its excitability is abnormally elevated, may drive whole-brain norepinephrine release through the NTS-locus coeruleus (LC) projection (Ji and Lee, 2021; Noseda et al., 2019).

Mechanism A (PIEZO channel-mediated direct transduction) and Mechanism B (tension-excitability threshold modulation) are not mutually substitutive but may operate synergistically on different time scales. Mechanism A provides "immediate" mechano-electrical signal transduction—physical stress generates ion influx through PIEZO channel opening within milliseconds; Mechanism B may involve a "delayed" effect—sustained tension, through cytoskeletal remodeling and channel upregulation, alters the intrinsic excitability of neurons, with effects that may manifest on a time scale of minutes to hours. Both can elevate the background discharge of afferent nerves in the absence of structural damage, providing two parallel mechanisms for the "reversible" central gating upregulation in this hypothesis.

In terms of evidence strength, the evidence presented in this section exhibits a hierarchical distribution: the highest level is the immunohistochemical evidence of PIEZO in the human carotid sinus and superior cervical ganglion by Alba et al. (2025) (direct human anatomical evidence); the second level is the Piezo2-positive fibers detected in the human trapezius fascia by Tereshenko et al. (2026) (belonging to the same deep cervical fascial system, but not the investing fascia itself); the third level is the cytological evidence in subcutaneous fascia by Huang et al. (2025) (different anatomical site); and the lowest level is PIEZO expression in the investing fascia itself (currently pending confirmation, explicitly noted as a limitation by the authors). This evidence hierarchy indicates that although the core role of PIEZO channels in mechano-electrical signal transduction is well supported, their direct expression in the investing fascia itself still requires further investigation and confirmation.

3.4. Central Effect: Abnormal Mechanical Signals Suppress Motor Output

Based on the above deduction, the sustained elevation of NTS-LC norepinephrine output may inhibit motor output in the primary motor cortex (M1) through the following stepwise mechanisms. The following is elaborated step by step from five levels: molecular localization, synaptic function, stroke pathology, human imaging, and the latest neural circuit mechanisms.

First, at the molecular localization level, Papay et al. (2006), using a transgenic mouse model (alpha1A-AR-EGFP), determined the cellular localization of the α1A-adrenergic receptor (α₁A-AR) in the brain at the protein level, finding that α1A-AR is significantly expressed in cortical neurons and co-localizes with GAD (glutamate decarboxylase) and GABA, confirming that α1A-AR is directly expressed in GABAergic interneurons. This finding provides a direct molecular structural basis for NE-mediated regulation of the GABAergic system.

Second, at the synaptic function level, Araneda and Firestein (2006) provided direct electrophysiological evidence using ex vivo brain slice patch-clamp recordings. The study found that norepinephrine (NA, 10 μM) could sharply increase the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) from 0.9±0.2 Hz to 8.8±2.3 Hz (p < 0.001). This effect could be completely mimicked by the α1 receptor agonist phenylephrine (PE, 30 μM) (increased to 8.5±2.2 Hz, p < 0.001), and completely blocked by the α1 receptor antagonist prazosin (returned to 0.5±0.2 Hz), while α2 or β receptor agonists were ineffective. This clearly confirms that NE specifically enhances GABAergic synaptic transmission strength through pre- and post-synaptic α1 receptors. Although these data are from the accessory olfactory bulb, the α1 receptor-mediated inhibitory synaptic enhancement mechanism is highly conserved in the central nervous system, providing direct synaptic-level evidence for similar regulation in the M1 region.

Furthermore, in the context of stroke pathology, Hiu et al. (2016), using a mouse photothrombotic stroke model, found that in the peri-infarct cortex during the repair phase, layer 5—the layer containing the cell bodies of corticospinal tract pyramidal neurons—exhibited a significant increase in the number of GABAergic synapses containing α1 receptor subunits (confirmed by array tomography: 0.064 vs 0.036 synapses/μm³), and the efficacy of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) on pyramidal neurons in this layer was enhanced, indicating that M1 output neurons are in a state of abnormally elevated α1-GABAergic inhibition after stroke.

At the human imaging level, Kim et al. (2014) used [¹⁸F]flumazenil ([¹⁸F]FMZ) PET to conduct longitudinal follow-up of ischemic stroke patients, finding that from 1 month to 3 months after stroke, GABA_A receptor availability in the bilateral cerebral cortex and cerebellum significantly decreased, and the magnitude of decrease in GABA_A receptor availability in the bilateral M1 region was positively correlated with the improvement in Fugl-Meyer scores at 3 months. This study provides direct human evidence for a causal association between cortical GABAergic status and motor outcomes after stroke—that is, the reduction of cortical GABAergic inhibition is an important neuroplasticity mechanism for motor function recovery.

At the level of clinical reverse validation, Sawaki et al. (2003) found in healthy subjects that a single oral dose of the α1-adrenergic antagonist prazosin could significantly reduce the capacity for training-dependent plasticity induced by motor training, suggesting that α1-adrenergic signaling is a necessary neuromodulatory pathway for motor training-dependent plasticity. The study further noted that caution should be exercised when using α1-adrenergic blockers in the rehabilitation setting after brain injury.

The latest evidence at the neural circuit level further strengthens the above conclusions. The study by Okabe et al. (2025) published in NATURE COMMUNICATIONS found that rehabilitation training can selectively enhance the synaptic formation between parvalbumin (PV)-expressing GABAergic interneurons in the forelimb motor area and specific stroke-projection neurons, and that PV interneuron activation during training is essential for motor function recovery; pharmacological enhancement of PV interneuron function can directly improve motor recovery, mimicking the effect of rehabilitation training. This study directly demonstrates that GABAergic interneurons—particularly the PV subtype—are a core target for regulating motor function recovery after stroke, and are mechanistically highly complementary to the above deduction that α1-GABAergic pathway enhancement leads to gating upregulation.

Synthesizing the above multi-level evidence from receptor expression (Papay et al., 2006) to synaptic transmission (Araneda and Firestein, 2006), to stroke pathology (Hiu et al., 2016), human imaging (Kim et al., 2014), clinical reverse validation (Sawaki et al., 2003), and the latest neural circuit mechanisms (Okabe et al., 2025), NE specifically enhances the inhibitory input of GABAergic interneurons onto pyramidal neurons through α1 receptors on these interneurons, thereby elevating the discharge threshold of corticospinal tract pyramidal neurons. This "central gating upregulation" effect makes it difficult for residual descending motor commands to be effectively conducted to the anterior horn α-motor neurons of the spinal cord. This means that even if the corticospinal tract is anatomically intact, its descending commands may be blocked by the abnormally elevated discharge threshold, failing to effectively activate the anterior horn α-motor neurons—which may provide a mechanistic explanation for the mismatch between muscle strength and motor function.

Based on this framework, this hypothesis deduces: if the release procedure can cut off the abnormal stress conduction, peripheral afferent abnormal discharges drop sharply, NTS-LC-NE output declines, the cortical inhibition mediated by M1 GABAergic interneurons is relieved, residual descending commands exceed the threshold, and motor function is released. The entire process theoretically does not depend on structural remodeling, and therefore may take effect within a relatively short time (Cyron and Humphrey, 2017; Holzapfel et al., 2025). The clinical study by Rafat and Srivastav (2025) provides phenomenological support for this deduction—significant motor function improvement was observed after only 2 weeks of myofascial release intervention (p=0.001, d=1.86).

This subsection is one of the most "deductive" links in the causal chain of the hypothesis. Although the NTS-LC-NE pathway (Bogduk, 2001; Ji and Lee, 2021) and NE enhancement of GABAergic interneuron excitability through α1 receptors (Papay et al., 2006; Araneda and Firestein, 2006) are both supported by literature, and post-stroke α1-GABAergic synaptic enhancement (Hiu et al., 2016), the correlation between decreased GABA inhibition confirmed by human PET and motor recovery (Kim et al., 2014), and the impairment of motor plasticity by α1 receptor blockade (Sawaki et al., 2003) have all been experimentally confirmed, and the key role of PV interneurons in rehabilitation (Okabe et al., 2025) has also received the latest independent validation, these links have not yet been directly concatenated and validated in the specific context of "peripheral fascial abnormal stress → central motor inhibition." The value of this section's deduction lies in its provision of a clear, TMS-measurable intermediate phenotype (elevated RMT) and a testable causal prediction (RMT decreases after release); even if the specific pathways have room for revision, the core logic of "peripheral mechanical abnormality → reversible central gating upregulation" remains independently valid.

It should be noted that the stroke-specific evidence cited in this section mainly originates from animal models and human imaging studies in the repair phase (Hiu et al., 2016) or the 1-3 month recovery period (Kim et al., 2014), whereas this hypothesis focuses on the sequelae phase (>6 months). Although the neuroplastic mechanism of enhanced GABAergic inhibition may be persistent across different time windows, whether the NTS-LC-NE pathway still maintains the same intensity of activation in the sequelae phase currently lacks direct validation. Therefore, the causal chain deduction in this section still requires specific validation through indicators such as TMS-RMT in sequelae-phase patients in the temporal dimension.

3.5. Anterior and Posterior Circulation Shunting: Anatomical Boundaries of the Mechanical Unloading Effect

This hypothesis deduces that the possible effects of the biomechanical unloading mechanism are not uniform, but may be limited by the anatomical distribution of the anterior and posterior circulations (Bond et al., 2023). If the previous four sections answered the question of "how the hypothesis works," this section answers the question of "where the hypothesis applies." The shunting model is based on a core anatomical limitation—the range of mechanical conduction is strictly limited by the physical boundary of the skull-dural barrier. The vertebral artery V1-V3 segments travel within the cervical soft tissue spaces, closely adjacent to the deep fascia and suboccipital muscles, possessing anatomical contact conditions for mechanical conduction (deduced as the optimal mechanical response zone); although the internal carotid artery also travels within the carotid sheath, its intracranial segment, after entering the carotid canal, is surrounded by bony structures, and external fascial tension cannot cross this bony barrier to directly act on intracranial vessels and nerves (deduced as a partial response zone); once entering the cranial cavity, deep nuclei such as the thalamus and brainstem are under complete bony protection, and external mechanical signals have no anatomical pathway to be conducted here (deduced as structural damage zones beyond the range of mechanical conduction). This anatomical limitation is the fundamental basis for the subsequent stratified predictions.

3.5.1. Anatomical Definition of the Anterior and Posterior Circulations

Anterior circulation (internal carotid artery system): arising from the common carotid artery → internal carotid artery, entering the cranium through the carotid sheath, giving off the ophthalmic artery, anterior cerebral artery, and middle cerebral artery, supplying the anterior two-thirds of the brain (frontal lobe, parietal lobe, lateral temporal lobe) and the basal ganglia region (internal capsule, putamen) (Bond et al., 2023).

Posterior circulation (vertebral-basilar artery system): the bilateral vertebral arteries ascend through the cervical transverse foramina (C6-C1), enter the cranium through the foramen magnum, and converge to form the basilar artery, supplying the posterior one-third of the brain (occipital lobe, medial temporal lobe, thalamus, brainstem, cerebellum) (Bond et al., 2023).

The key division between the extracranial and intracranial segments: the mechanical action range of the investing fascia and the deep cervical fascia is limited to the extracranial segment (neck). Once blood vessels penetrate the skull, they are surrounded by bony structures, and external fascial tension may no longer be able to exert direct mechanical influence on them (Bond et al., 2023; Zhang and Lee, 2002).

3.5.2. Anterior and Posterior Circulation Shunting of the Investing Fascia Release Effect

Extracranial segment of the posterior circulation (vertebral artery V1-V3): the deduced optimal mechanical response zone

The extracranial segment of the vertebral artery (V1-V3) has three mechanically vulnerable links anatomically: (1) the V1 segment (from its origin to the C6 transverse foramen) is adjacent to the longus colli muscle and prevertebral fascia, connecting to the mechanical conduction pathway of the investing fascia (Bond et al., 2023; Pires et al., 2025); (2) the V2 segment (within the C6-C1 transverse foramina) is surrounded by the sympathetic plexus, and abnormal prevertebral fascial tension may affect the vertebral artery wall tension through fascial attachment points around the transverse foramina (Zhang et al., 2026a); (3) the V3 segment (from the C1 transverse foramen to the foramen magnum) travels through the suboccipital triangle, where the myodural bridge constitutes a fascia-muscle-dura-central nervous system mechanical conduction hub (Zhang et al., 2026a; Yuan et al., 2025). The study by Zhang et al. (2025) further confirmed that the Integrin α7-mediated mechanotransduction mechanism is the molecular basis for the normal development and functional maintenance of the myodural bridge (Zhang et al., 2025).

Based on this, this hypothesis deduces: in the sequelae phase, investing fascia fibrosis → loss of elastic buffering → abnormal shear stress generated by head and neck micromovements is conducted through the investing fascia-prevertebral fascia-vertebral artery adventitia pathway to the adventitia of the vertebral artery V1-V3 segments → abnormal stress, through the perivascular sympathetic plexus or by directly altering vertebral artery wall tension, transmits abnormal mechanical background signals to posterior circulation-supplied regions such as the brainstem vestibular nuclei and cerebellum → brainstem functional mechanical disturbance → clinical manifestations may include dizziness, head heaviness, blurred vision, dry eyes, and balance instability (Hamed et al., 2024; Bogduk, 2001; Zhang et al., 2026a; Yuan et al., 2025).

Extracranial segment of the anterior circulation (internal carotid artery): the deduced partial mechanical response zone

The extracranial segment of the internal carotid artery travels within the carotid sheath and has a clear anatomical proximity to the investing fascia (Bond et al., 2023; Zhang and Lee, 2002). However, the internal carotid artery has no branches in the neck and directly penetrates the skull (carotid canal), and its intracranial segment (ophthalmic artery, anterior and middle cerebral arteries) is surrounded by bony structures, potentially exceeding the mechanical action range of the investing fascia (Bond et al., 2023).

Mechanistic deduction: investing fascia fibrosis → increased tension on the carotid sheath adventitia → mechanical force on the wall of the extracranial segment of the internal carotid artery → may affect anterior circulation function through improved collateral circulation compensation (opening of Willis circle communicating branches). The study by Lan et al. (2024) suggests that abnormal blood flow shear stress caused by external tension may affect vascular function through the Piezo1-mediated endothelial inflammation pathway (Lan et al., 2024).

Intracranial segment of the posterior circulation (vertebral artery V4 and basilar artery perforating branches): structural damage zone beyond the range of mechanical conduction

The V4 segment of the vertebral artery after penetrating the foramen magnum and the basilar artery perforating branches are completely located within the skull, surrounded by cerebrospinal fluid and bony structures. Abnormal stress from the investing fascia may have no anatomical pathway to be conducted here (Zhang et al., 2026a). Mechanistic deduction: infarction of the brainstem (vestibular nuclei, nucleus tractus solitarius, nucleus ambiguus) and thalamus (VPL, VPM nuclei) → neuronal necrosis → irreversible structural damage (Bond et al., 2023).

3.5.3. Clinical Prediction Model of Anterior and Posterior Circulation Shunting

Based on the above anatomical deduction (Bond et al., 2023; Zhang and Lee, 2002; Zhang et al., 2026a; Yuan et al., 2025), this hypothesis proposes the following stratified predictions: the extracranial segment of the posterior circulation (vertebral artery V1-V3 compression and tension abnormality) is a mechanically accessible region (optimal target zone), and if functional mechanical signal abnormalities exist, immediate improvement may be anticipated after release; the extracranial segment of the anterior circulation (internal carotid sheath tension abnormality) is a mechanically accessible region, and if blood flow regulation abnormalities or collateral circulation limitation exist, moderate improvement may be anticipated after release; the cerebral cortex and basal ganglia (intracranial segment of the anterior circulation) are regions beyond the range of mechanical conduction, and due to neuronal necrosis (structural), only partial improvement may be anticipated after release; the thalamus and brainstem (intracranial segment of the posterior circulation) are regions beyond the range of mechanical conduction, and due to irreversible neuronal necrosis, minimal or no improvement may be anticipated after release (Bond et al., 2023).

The core clinical value of this model is that it predicts not whether efficacy exists, but where efficacy exists. This model proposes a directly testable hypothesis—patients with lesions located in the posterior circulation extracranial segment supply area (e.g., lateral medulla, cerebellar hemisphere) should have significantly better postoperative functional improvement than patients with lesions of comparable severity located in the thalamus or brainstem nuclei. Because the degree of corticospinal tract involvement may be matched between the two groups (both are posterior circulation supply areas), but the mechanical accessibility of the lesions differs, this comparison can, to some extent, control for the confounding factor of corticospinal tract integrity. If this prediction is falsified—that is, there is no significant difference in postoperative improvement between the two groups—then the anterior-posterior circulation shunting hypothesis will face fundamental challenge.

3.5.4. Spatial Logical Bridging Between the Shunting Model and Central Gating

It should be particularly noted that the above anatomical boundary model of the anterior-posterior circulation shunting does not contradict the M1 central gating mechanism described in Section 3.4. Although the primary motor cortex (M1) belongs to the anterior circulation in terms of vascular supply, the NTS-LC-NE pathway on which this hypothesis relies possesses the neuroanatomical feature of whole-brain diffuse projection (Bogduk, 2001; Ji and Lee, 2021). The nucleus tractus solitarius (NTS), as a convergence relay station for brainstem mechanical signals, drives locus coeruleus (LC) noradrenergic output that is not limited to the posterior circulation supply area, but rather affects the whole-brain excitability tone through a widespread cortical projection system, including the anterior circulation-supplied M1 region (Noseda et al., 2019). Based on this deduction: the mechanical unloading of the posterior circulation extracranial segment (vertebral artery V1-V3) by investing fascia release, by reducing abnormal excitatory afferent input to the brainstem NTS, can downregulate the background noradrenergic output tone from the LC to the whole brain (including the M1 region), thereby relieving the cortical inhibition mediated by M1 GABAergic interneurons. Therefore, patients with lesions located in the mechanically accessible posterior circulation region may also achieve motor function improvement through this indirect "brainstem-whole brain projection" pathway—this is precisely the underlying logic by which the shunting model makes spatially specific predictions rather than negating the M1 gating mechanism.

3.6. From Vicious Cycle to Beneficial Remodeling: Breaking the Mechanical Positive Feedback

Based on literature evidence, this hypothesis deduces that a mechanical-functional-postural vicious cycle may exist in the sequelae phase (Cyron and Humphrey, 2017; Ley et al., 2025; Zhang et al., 2025; Xue et al., 2025; Lei et al., 2025):

Forward head compensatory posture → abnormal loading on investing fascia → fibrosis and loss of elastic buffering (Ley et al., 2025) → head and neck micromovements trigger abnormal stress conduction → mechanical signals drive glycolytic reprogramming and immune infiltration through Piezo1 (Xue et al., 2025) → persistent NTS-LC activation (Ji and Lee, 2021; Noseda et al., 2019) → enhanced cortical inhibition mediated by M1 GABAergic interneurons (Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Sawaki et al., 2003; Kim et al., 2014; Okabe et al., 2025) → worsening motor dysfunction → further reliance on compensatory posture → persistent abnormal fascial loading (Cyron and Humphrey, 2017; Zhang et al., 2025)

Lei et al. (2025) systematically integrated the above mechanisms into the "mechanotransduction-immune axis" framework, pointing out that mechanical signals simultaneously activate pro-fibrotic signals in stromal cells and reprogram immune cell phenotypes through mechanosensors such as Piezo1, with the two mutually amplifying to form positive feedback that drives fibrosis progression. Investing fascia release theoretically cuts off the abnormal mechanical conduction link in this cycle (Cyron and Humphrey, 2017; Zhang and Lee, 2002; Pires et al., 2025). Zhang et al. (2025) confirmed in a rat model that Integrin α7 (ITGA7) is a key molecular bridge for myodural bridge development, and that ITGA7 knockout significantly impairs the development and maturation of the myodural bridge, demonstrating that the mechanical force of the suboccipital muscles fundamentally affects the differentiation and maturation of the myodural bridge (Zhang et al., 2025). The study by Xue et al. (2025) further confirmed that mechanical signals can simultaneously drive metabolic reprogramming (upregulation of glycolysis-related genes Glut1 and Aldoa) and immune cell infiltration (macrophages and monocytes) through Piezo1, revealing how mechanical signals coordinate tissue remodeling and inflammatory responses through PIEZO channels (Xue et al., 2025). Based on this deduction, if cortical inhibition is relieved, patients may be able to complete rehabilitation training more effectively, reinforce correct movement patterns, and reduce compensatory posture, thereby reducing abnormal fascial loading and achieving beneficial remodeling (Cyron and Humphrey, 2017; Zhang et al., 2025).

The above deduction of the vicious cycle suggests a clinical reality that is easily overlooked: functional stagnation in the sequelae phase may not be a simple "recovery plateau," but rather a state of functional inhibition maintained by mechanical-neural positive feedback. In this steady state, abnormal mechanical signals continuously reinforce postural compensation through central gating upregulation, and postural compensation further exacerbates mechanical abnormalities—forming a closed, self-reinforcing cycle. If this deduction holds, it means that breaking any key link in the cycle (such as cutting off mechanical conduction through investing fascia release) may be sufficient to shift the entire system out of the pathological steady state and onto a trajectory of beneficial remodeling. This "nonlinear" recovery mode—rather than linear progressive improvement—may explain why some patients experience unexpectedly large functional improvements after receiving a single mechanical intervention.

4. Testable Predictions

Based on this hypothesis, the following quantitatively testable predictions are proposed:

Prediction 1 (Mechano-Electrophysiological Coupling): Preoperative SWE measurements of the investing fascia should theoretically be positively correlated with the resting motor threshold (RMT) of the ipsilesional M1 (r > 0.6). The stiffer the fascia (the greater the mechanical loading), the higher the central output threshold may be (Liao et al., 2023; Xiao, 2024). The correlation between SWE and histological fibrosis has been confirmed by Dapper et al. (2026) (r = 0.78, p < 0.001) (Dapper et al., 2026). Ley et al. (2025) further confirmed the reliability of SWE in measuring fascial stiffness, while Zandi et al. (2025) provided evidence for the specific reliability of SWE measurements in cervical fascia (ICC ≥ 0.90).

This prediction aims to verify the cross-level association between the first link (peripheral mechanical abnormality) and the fourth link (central gating upregulation) of the hypothesis's causal chain. If there is no significant correlation between preoperative SWE values and RMT, it would imply that the coupling between peripheral mechanical status and central excitability regulation may not exist—this would be the most direct challenge to the hypothesis. The threshold of r > 0.6 was set with reference to the effect size of the correlation between SWE and histological fibrosis in Dapper et al. (2026) (r = 0.78), meaning that the expected effect size should not be lower than this reference standard. Validating this prediction does not require intervention, only cross-sectional measurements, and has the lowest implementation threshold; it is recommended as the starting point for hypothesis validation.

Prediction 2 (Immediate Electrophysiological Effect of Mechanical Unloading): If mechanical unloading is effective, the ipsilesional RMT may decrease by ≥10% within 24 hours after release, and the magnitude of decrease should be positively correlated with preoperative SWE values (Liao et al., 2023; Xiao, 2024; Dapper et al., 2026).

This prediction is a longitudinal extension of Prediction 1—not only validating the correlation, but also validating the causal relationship of the intervention. Observing RMT changes within 24 hours is intended to examine the immediate neurophysiological effects of mechanical unloading rather than long-term rehabilitation outcomes. If postoperative RMT decreases by ≥10%, it would indicate that central gating inhibition is rapidly relieved after mechanical unloading—a time scale consistent with the hypothesis's deduction that the effect "does not depend on structural remodeling." The prediction that the magnitude of decrease is positively correlated with preoperative SWE values implies that patients with stiffer preoperative fascia derive greater unloading benefits, which is consistent with the basic logic of "greater mechanical loading → more significant unloading effect."

Prediction 3 (Physical Measurability of Stress Conduction): Finite element modeling may show that the peak von Mises stress in the carotid sheath region decreases by ≥30% after release, and the magnitude of simulated stress decrease may be positively correlated with the magnitude of postoperative RMT decrease (Shakya et al., 2023; Lan et al., 2024). The fluid-structure interaction study by Shakya et al. (2023) systematically compared the hemodynamic differences between external carotid compression and atherosclerotic stenosis (Shakya et al., 2023).

Prediction 4 (Hemodynamic Validation): If the posterior circulation extracranial compression hypothesis holds, in patients with preoperative transcranial Doppler (TCD) showing reduced blood flow velocity in the extracranial vertebral artery (V2-V3), the vertebral artery systolic peak flow velocity (Vs) may increase by ≥15% within 24 hours after release, and the increase may be negatively correlated with improvement in dizziness VAS scores (r < -0.5) (Uzun et al., 2024; Lan et al., 2024). The randomized controlled trial by Uzun et al. (2024) confirmed that cervical mobilization can significantly increase blood flow velocity in the internal carotid and vertebral arteries (Uzun et al., 2024).

This prediction directly tests the posterior circulation branch of the anterior-posterior circulation shunt model. The choice of the extracranial vertebral artery segment (V2-V3) rather than the intracranial segment (V4) as the measurement target is based on the core logic of the anatomical boundary—only the extracranial segment lies within the mechanically accessible range. If vertebral artery Vs increases after release but dizziness symptoms do not improve (r does not show a negative correlation), it would suggest that the association between changes in blood flow velocity and clinical symptoms may not be a direct causal relationship, and the symptom improvement prediction of the posterior circulation shunt model would need to be revised. The threshold of ≥15% increase was set with reference to the magnitude of change in vertebral artery blood flow velocity after cervical mobilization in Uzun et al. (2024).

Prediction 5 (Hand Perfusion Validation): If upper limb hypoperfusion originates from upstream compression, the ipsilesional SpO₂ may increase by ≥5% within 30 minutes after release (Lan et al., 2024).

Prediction 6 (Anatomical-Effect Association): In patients with preoperative brain MRI showing lesions confined to functional ischemia in the posterior circulation extracranial supply area, the postoperative improvement in Fugl-Meyer scores may be significantly greater than in patients with structural infarction in the thalamus or brainstem nuclei (between-group difference >20 points, p < 0.01) (Bond et al., 2023; Zhang et al., 2026a).

This is the most direct test of the anterior-posterior circulation shunt model. If there is no significant difference in postoperative functional improvement between the two groups, the anatomical boundary hypothesis of the anterior-posterior circulation shunt will be overturned. The between-group difference threshold of ≥20 points was set with consideration of the minimal clinically important difference (MCID) of the Fugl-Meyer scale, ensuring that the statistical difference also has clinical significance. The implementation difficulty of this prediction lies in the need to precisely localize lesions on preoperative MRI and determine their vascular supply territory.

Prediction 7 (Language Function Validation): In patients with preoperative expressive aphasia (damage to the left middle cerebral artery territory), the improvement in language function scores after release may be positively correlated with the increase in TCD blood flow velocity in the M1 segment of the left middle cerebral artery (Uzun et al., 2024; Bond et al., 2023).

The above seven predictions cover the various causal links of the hypothesis from different perspectives, but differ in validation priority and operability. Readers are advised to understand them at three levels: Level 1 (Core Validation) includes Predictions 1 and 2, which directly test the cross-level coupling relationship of "peripheral mechanical abnormality-central excitability regulation," representing the most core proposition of the hypothesis; Level 2 (Mechanistic Deepening) includes Predictions 3 and 4, which provide independent validation from the perspectives of computational mechanics and hemodynamics, respectively; Level 3 (Clinical Translation) includes Predictions 5, 6, and 7, which focus on specific clinical outcomes and patient stratification, providing a basis for subsequent translational research. The three levels are not sequentially dependent but rather represent cross-validation of the same causal chain from different angles. The falsification of any prediction would require revision or qualification of the hypothesis.

5. Validation Framework

This hypothesis proposes a three-level validation pathway (Liao et al., 2023; Shakya et al., 2023; Dapper et al., 2026):

Level 1: Biomechanical-Electrophysiological Coupling Validation (Clinical, Highest Priority). It is recommended to enroll post-stroke sequelae patients (>6 months), stratified by preoperative brain MRI/DTI into a tract-intact group (FA > 0.4) and a tract-damaged group (FA < 0.3), with measurements taken preoperatively, at 24 hours postoperatively, at 1 week postoperatively, and at 4 weeks postoperatively for: (a) investing fascia SWE stiffness (Liao et al., 2023; Dapper et al., 2026; Ley et al., 2025; Zandi et al., 2025); (b) ipsilesional M1 RMT (Xiao, 2024); (c) TCD blood flow velocity of the extracranial vertebral artery (Uzun et al., 2024); (d) ipsilesional finger SpO₂ (Lan et al., 2024); (e) Fugl-Meyer motor function scores and VAS scores for dizziness and dry eye.

The core logic of this level of validation is "correlation testing"—observing whether SWE measurements change synchronously with changes in RMT and clinical symptoms. Stratifying patients into the tract-intact group (FA > 0.4) and tract-damaged group (FA < 0.3) is intended to test the prerequisite for the applicability of the hypothesis—that "residual tract function" is a necessary condition for mechanical unloading to exert its effects. If the tract-intact group shows a significant postoperative decrease in RMT while the damaged group shows no change, this would support the premise; if neither group changes or both change, the role of corticospinal tract integrity in the mechanical unloading effect would need to be re-examined.

Level 2: Computational Mechanics Simulation Validation (Mechanistic Deepening). It is recommended to construct patient-specific finite element models based on cervical MRI to simulate the stress distribution in the carotid sheath region under two mechanical boundary conditions: preoperative (fibrotic fascia) and postoperative (post-release) (Shakya et al., 2023; Lan et al., 2024). Correlation analyses should be performed between simulated stress values and preoperative SWE measurements and postoperative RMT reduction magnitudes (Liao et al., 2023; Xiao, 2024; Dapper et al., 2026).

The value of this level of validation lies in directly correlating macroscopic clinical manifestations (SWE, RMT) with the local mechanical environment (von Mises stress). If simulated stress values are positively correlated with SWE measurements and positively correlated with RMT reduction magnitude, this would provide independent physical validation for the "mechanical conduction" link in the hypothesis. The advantage of finite element simulation is that it can quantify stress distributions in the carotid sheath region that cannot be directly measured—however, modeling accuracy depends on the spatial resolution of MRI and the accuracy of material constitutive models, which represent a methodological bottleneck.

Level 3: Prospective Interventional Validation (Long-term). It is recommended to design a single-arm prospective observational study, stratifying patients by preoperative lesion location (posterior circulation extracranial segment, anterior circulation extracranial segment, intracranial segment) (Bond et al., 2023), and comparing postoperative changes in RMT, Fugl-Meyer scores, SpO₂, and VAS scores across strata to validate the predictive performance of the anterior-posterior circulation shunt model (Uzun et al., 2024; Bond et al., 2023; Liao et al., 2023; Xiao, 2024; Dapper et al., 2026; Lan et al., 2024).

This level of validation directly tests the clinical prediction of the anterior-posterior circulation shunt model (Prediction 6). The recommendation to use a single-arm prospective observational design rather than a randomized controlled trial is based on considerations of the high heterogeneity of the post-sequelae patient population and the diversity of lesion types—stratified analysis can preliminarily validate the model's spatially specific predictions without requiring a large sample size. If preliminary results support the shunt model, they can serve as the basis for subsequent RCT design.

6. Discussion

6.1. Relationship with Existing Theories

This hypothesis and previously proposed cervicogenic brain dysfunction hypotheses occupy different levels of the causal chain. Previous hypotheses have primarily originated from cervical spine structural abnormalities (such as anterior subluxation of C1), whereas this hypothesis originates from investing fascia fibrosis; the two are complementary rather than competitive, jointly constructing a complete causal chain from cervical spine structural abnormality → fascial tension abnormality → carotid sheath compression → brain dysfunction.

6.2. External Supporting Evidence

The PIEZO1/2-mediated mechano-electrical signal transduction mechanism deduced by this hypothesis has received independent anatomical validation in the carotid sinus and superior cervical ganglion. Alba et al. (2025), using immunohistochemistry and immunofluorescence combined with laser confocal microscopy, systematically investigated the distribution of PIEZO1 and PIEZO2 in the human carotid sinus, carotid body, glossopharyngeal nerve petrosal ganglion, and superior cervical ganglion. The results showed that: in the carotid sinus and carotid artery wall, PIEZO1- and PIEZO2-positive nerve fibers form sensory nerve endings of different morphologies; in the petrosal ganglion, approximately 25% of neurons express PIEZO1 and approximately 85% express PIEZO2; in the superior cervical ganglion, approximately 71% of neurons express PIEZO1 and approximately 86% express PIEZO2. This study clearly indicated that PIEZO1 and PIEZO2 may participate in mechanosensory conduction in the human carotid sinus (Alba et al., 2025).

Huang et al. (2025) identified a population of CD34⁺ membranous cells in subcutaneous fascia, which highly express mechanosensitive ion channels such as PIEZO, can convert physical stimuli into intracellular calcium signals, and form a "distributed sensing network" within the fascia through gap junctions. This finding provides direct cytological evidence that fascial tissue itself possesses mechanical signal sensing capability (Huang et al., 2025).

Hamed et al. (2024) explicitly positioned PIEZO channels as force sensors of the interoceptive nervous system, systematically elucidating how PIEZO1/2 convert mechanical signals from visceral and muscular activities into neural signals, providing a theoretical framework for understanding how peripheral mechanical signals enter the central nervous system through PIEZO channels (Hamed et al., 2024). Pirri (2025) further positioned PIEZO channels as gatekeepers of "mechano-inflammation-neuroimmune crosstalk," systematically integrating the multiple functions of PIEZO in immune cells, sensory neurons, and connective tissue (Pirri, 2025).

In terms of stroke-specific mechanisms, Wu et al. (2026a) demonstrated in an ischemic stroke model that Piezo1 regulates astrocyte cytoskeletal reorganization through the Wnt7b-Ca²⁺ non-canonical signaling pathway, serving as a key molecule in modulating glial scar stiffness and influencing neural regeneration. The same team further confirmed that progressive glial scar stiffening strongly inhibits the neuronal differentiation direction of neural stem cells and impairs neurite outgrowth through the Piezo1 channel (Wu et al., 2026b). The systematic review by Shi et al. (2026) positions Piezo1 as a key integrator linking physical signals such as tissue stiffening and blood flow shear stress to neuroinflammation in the central nervous system (Shi et al., 2026). Fu et al. (2025) further confirmed in an ischemic stroke model that Piezo1 exacerbates blood-brain barrier disruption through the Ca²⁺/CaMKII/Nrf2 pathway (Fu et al., 2025). The study by Xue et al. (2025) provided in vivo functional evidence for the core role of PIEZO channels in mechano-metabolism-inflammation crosstalk, revealing through a skin expansion model how Piezo1 coordinates glycolysis and immune infiltration (Xue et al., 2025).

Regarding the α1-adrenergic receptor-mediated central gating mechanism, six independent studies have provided systematic support for this hypothesis from different levels. Papay et al. (2006) confirmed in a transgenic mouse model that α1A-AR is directly expressed on cortical GABAergic interneurons; Araneda and Firestein (2006) demonstrated through ex vivo electrophysiological recordings that NE increases GABAergic mIPSC frequency by nearly 10-fold through α1 receptors; Hiu et al. (2016) confirmed in a stroke model that the number and function of α1-GABAergic synapses in layer 5 of the peri-infarct cortex during the repair phase are enhanced; Kim et al. (2014) demonstrated in humans using PET that decreased GABA_A receptor availability is positively correlated with motor recovery; Sawaki et al. (2003) confirmed in humans that α1 receptor blockade impairs motor training-dependent plasticity; Okabe et al. (2025), in their latest study published in NATURE COMMUNICATIONS, confirmed that PV interneuron activation is essential for rehabilitation-induced functional recovery, and that pharmacological enhancement of PV interneuron function can mimic the effects of rehabilitation training. These six studies, progressing layer by layer from receptor expression to synaptic function, from stroke pathology to human imaging, from clinical reverse validation to the latest neural circuit mechanisms, jointly support the core deduction in the hypothesis of "abnormal NE signal → α1 receptor → enhanced GABAergic inhibition → elevated motor output threshold."

These independent lines of evidence from peripheral mechanotransduction and central neural regulation—from anatomical localization (Alba et al., 2025), cytological basis (Huang et al., 2025), interoceptive framework (Hamed et al., 2024), neuroimmune gating framework (Pirri, 2025), molecular regulatory mechanisms (Wu et al., 2026a; Wu et al., 2026b), integrative theoretical frameworks (Shi et al., 2026; Lei et al., 2025), blood-brain barrier disruption mechanisms (Fu et al., 2025), ECM-PIEZO1 axis signaling pathways (Zhang et al., 2026b), metabolic-inflammatory coordination functions (Xue et al., 2025), the fascial capacitor model for electrical signal generation in fascia itself (Kimura and Kobayashi, 2026), and the multi-level validation of α1-GABAergic central gating (Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Kim et al., 2014; Sawaki et al., 2003; Okabe et al., 2025)—form multi-level mechanistic complementarity with this hypothesis, collectively pointing toward the complete biological pathway of "peripheral mechanical signal → Piezo channel → NTS-LC-NE output → α1-GABAergic gating upregulation → motor function inhibition."

However, the direct expression of PIEZO channels in the investing fascia itself still awaits further investigation and confirmation (Xue et al., 2025; Kimura and Kobayashi, 2026; Zhang et al., 2026b; Alba et al., 2025; Huang et al., 2025; Fu et al., 2025; Pirri, 2025).

The external evidence presented in this section can be summarized into three levels: the anatomical-molecular level (Alba et al.'s 2025 PIEZO expression in human carotid artery, Huang et al.'s 2025 fascial CD34⁺ membranous cells, Papay et al.'s 2006 localization of α1A-AR on GABAergic interneurons); the mechanistic pathway level (Wu et al.'s 2026a/b glial scar mechanical regulation, Fu et al.'s 2025 blood-brain barrier disruption, Xue et al.'s 2025 metabolic-inflammatory coordination, Araneda and Firestein's 2006 α1 receptor-mediated GABAergic synaptic enhancement, Hiu et al.'s 2016 post-stroke α1-GABAergic synaptic remodeling, Okabe et al.'s 2025 PV interneuron rehabilitation mechanism); and the theoretical integration and clinical translation level (Hamed et al.'s 2024 interoceptive framework, Pirri et al.'s 2025 neuroimmune gating, Shi et al.'s 2026 systematic review, Kimura and Kobayashi's 2026 fascial capacitor model, Kim et al.'s 2014 GABA PET human evidence, Sawaki et al.'s 2003 α1 receptor blockade impairment of motor plasticity). All three levels independently point to PIEZO channels and the α1-adrenergic signaling pathway as core hubs of mechano-neural signal transduction, but none of them constitute direct evidence generated in the specific context of "investing fascia-post-stroke sequelae-motor function." This "non-specific but convergent" evidence pattern suggests that each link of the hypothesis has independent support, but their overall concatenation still requires validation.

6.3. Clinical Significance

This hypothesis provides a new perspective for secondary rehabilitation in the post-stroke sequelae phase, targeting peripheral biomechanics and bounded by anatomical distribution (Bond et al., 2023; Zhang and Lee, 2002):

- A clear intervenable target: fibrotic adhesion of the investing fascia may not be an irreversible sequela, but rather an intervenable mechanical factor that can be improved through surgical release (Zhang and Lee, 2002; Ley et al., 2025).

- Delineation of therapeutic boundaries: through the anterior-posterior circulation anatomical distribution model (Bond et al., 2023), the applicable population is limited to the subgroup of patients with reversible mechanical abnormalities in the extracranial (cervical) large vessels.

- Provision of testable predictions: the above predictions can all be validated through existing clinical examination modalities (SWE, TMS, TCD, DTI, SpO₂) (Uzun et al., 2024; Liao et al., 2023; Xiao, 2024; Dapper et al., 2026; Zandi et al., 2025), rendering this hypothesis falsifiable.

6.4. Theoretical Deduction of Preventive Potential

The above causal chain (Section 3.1, Section 3.2, Section 3.3, Section 3.4, Section 3.5 and Section 3.6) focuses on the mechanism by which abnormal mechanical signals suppress residual motor function output through the neural pathway (NTS-LC-M1). However, the same upstream mechanical abnormality—fibrosis of the investing fascia and abnormal shear stress—can also produce independent pathological effects through the vascular pathway. The external tension of the investing fascia can be conducted to the carotid sheath through the three-layer collagen network of the deep cervical fascia, directly acting on the walls of the extracranial large vessels (Bond et al., 2023; Zhang and Lee, 2002; Pires et al., 2025). Based on this anatomical foundation, this hypothesis further deduces that investing fascia release may have two preventive implications—one acting on blood vessels (reducing thrombotic risk) and the other on neural function (preventing functional deterioration), with the two also distinguished on a temporal scale: the manifestation of vascular effects may require a longer observation period, while the prevention of neural effects may appear earlier in conjunction with rehabilitation training.

(1) Potential Preventive Effects on Cerebral Infarction and Cerebral Thrombosis

Based on the above anatomical and mechanobiological evidence, this hypothesis deduces that the abnormal shear stress generated by investing fascia fibrosis can be conducted to the carotid sheath through the three-layer fascial network, producing sustained external tension on the common carotid artery and the extracranial segment of the internal carotid artery (Bond et al., 2023; Zhang and Lee, 2002; Pires et al., 2025). Keshelava (2026), in a systematic review published in ANNALS OF VASCULAR SURGERY, clearly indicated that mechanical external compression of the extracranial carotid artery is a rare but treatable cause of cerebral ischemia, which can manifest as transient ischemic attack, ischemic stroke, and carotid artery thrombosis (Keshelava, 2026). This review proposed a mechanism-based three-part classification—positional compression, anatomical compression, and volumetric compression (Keshelava, 2026)—providing a direct clinical classification framework for understanding the pathological mechanisms of investing fascia-derived external compression. This clinical evidence, together with the fluid-structure interaction simulation by Shakya et al. (2023) and the Piezo1-mediated endothelial inflammation mechanism by Lan et al. (2024), jointly constitutes a complete evidence chain of "external compression → hemodynamic alteration → Piezo1 activation → endothelial inflammation → atherosclerosis or thrombosis."

At the molecular level, PIEZO1 has been confirmed to be a core mechanosensitive channel for sensing abnormal shear stress and tissue stiffness. The study by Lan et al. (2024) published in the JOURNAL OF THE AMERICAN HEART ASSOCIATION revealed that Piezo1 directly perceives oscillatory shear stress generated by disturbed blood flow and activates endothelial inflammation through the Ca²⁺/CaM/CaMKII-FAK/Src-YAP axis, promoting atherosclerotic plaque progression (Lan et al., 2024). The study by Atcha et al. (2024) published in PNAS NEXUS further confirmed that Piezo1 enables macrophages to sense changes in tissue stiffness and mediates the uptake of oxidized low-density lipoprotein (oxLDL), promoting foam cell formation and atherosclerosis (Atcha et al., 2024). At the platelet level, Wang et al. (2025), in the BRITISH JOURNAL OF PHARMACOLOGY, confirmed that Piezo1 is highly expressed in platelets and is a core molecule for sensing pathological high shear stress; platelet-specific Piezo1 deficiency can significantly reduce high shear rate-induced platelet activation and aggregation, and attenuate arterial thrombosis (Wang et al., 2025). Zhao et al. (2021), in the JOURNAL OF THROMBOSIS AND HAEMOSTASIS, further confirmed that in hypertension, a disease characterized by an abnormal mechanical microenvironment, Piezo1 is aberrantly activated, initiating platelet hyper-reactivity and accelerating arterial thrombosis (Zhao et al., 2021). The study by Xue et al. (2025) further revealed, from the perspective of metabolic-inflammatory integration, how Piezo1 coordinates tissue responses to mechanical stimuli by driving glycolysis and immune infiltration, providing a new metabolic-level perspective for understanding the pro-inflammatory role of Piezo1 in abnormal mechanical microenvironments (Xue et al., 2025). The above five studies together construct a complete molecular evidence chain of "abnormal shear stress or tissue stiffness → Piezo1 activation → (endothelial inflammation + macrophage foam cell formation + platelet activation + metabolic reprogramming) → atherosclerosis or thrombosis."

Based on this deduction, the local blood flow shear stress abnormality and tissue stiffness caused by investing fascia-derived external compression may increase the risk of vascular inflammation and thrombosis through the Piezo1-mediated pathways described above. Release surgery, by cutting off the abnormal stress conduction pathway, could theoretically relieve the external mechanical constraint on the extracranial large vessels and restore normal hemodynamic status (Shakya et al., 2023; Pires et al., 2025). The randomized controlled trial by Uzun et al. (2024) has confirmed that cervical mobilization can significantly increase blood flow velocity in the internal carotid and vertebral arteries (Uzun et al., 2024), providing clinical evidence for "mechanical intervention → cerebral blood flow improvement." Based on this, this hypothesis deduces that investing fascia release may, by improving the hemodynamics of extracranial large vessels and reducing local tissue stiffness and abnormal shear stress, thereby reduce Piezo1-mediated vascular inflammation and pro-thrombotic signals, theoretically potentially reducing the mechanical risk factors for thrombosis.

It should be clearly understood that release surgery does not directly act on the classical risk factors for cerebral infarction and cerebral thrombosis, such as atherosclerosis, hypertension, hyperlipidemia, and diabetes. It exerts its effects by relieving the external mechanical constraint on the extracranial large vessels and restoring the normal mechanical microenvironment of the vessel wall. Therefore, it should be regarded as a potential mechanical supplement to, rather than a replacement for, traditional secondary prevention (antihypertensive therapy, lipid-lowering therapy, antiplatelet therapy, and lifestyle intervention).

(2) The "Buffalo Hump" as a Surface Marker of Cervical Mechanical Abnormalities and Its Association with Stroke Risk

The above mechanisms focus on the molecular pathway by which investing fascia fibrosis leads to thrombosis through direct vascular compression. At the clinical level, the surface manifestation of the same mechanical abnormality—the "buffalo hump"—provides another perspective for understanding the epidemiological association between cervical soft tissue abnormalities and cerebrovascular disease risk. The "buffalo hump" is essentially a composite soft tissue alteration comprising subcutaneous adipose accumulation, deep fascial fibrotic hyperplasia, and nuchal ligament calcification in the posterior neck. It is noteworthy that the presence and severity of the "buffalo hump" exhibit considerable individual variation: some patients have no visible protrusion, but palpation reveals local tissue thickening and significantly increased fascial tension, accompanied by typical symptoms including dizziness, head heaviness, blurred vision, dry eyes, insomnia, forgetfulness, anxiety, depression, and shoulder-neck soreness and distension—these patients with "subclinical buffalo hump" may be clinically overlooked due to the lack of visible signs, but their abnormal cervical soft tissue tension may similarly affect central nervous system function through the mechanical conduction pathways described in this paper.

Epidemiological studies have provided quantitative evidence for the association between cervical adipose accumulation and cerebrovascular disease risk. A multicenter prospective cohort study based on 18,796 adults in northeastern China found that neck circumference was independently and positively correlated with cardiovascular disease mortality risk. Compared with the lowest quartile group of neck circumference, the highest quartile group had a 1.83-fold increased risk of overall cardiovascular disease mortality (95% CI: 1.29–2.61) and a 2.40-fold increased risk of coronary heart disease mortality (95% CI: 1.45–4.00) (Li et al., 2024). Notably, larger neck circumference was significantly associated with ischemic stroke mortality risk, but not with hemorrhagic stroke mortality—a distinction that is highly consistent with this hypothesis's focus on ischemic cerebrovascular events. For each 1-standard-deviation increase in neck circumference, the risks of overall cardiovascular disease mortality, stroke mortality, and coronary heart disease mortality increased by approximately 1.21- to 1.25-fold, demonstrating a clear dose-response relationship.

A 12-year prospective community study from South Korea, enrolling 3,662 adults, further confirmed that the incidence of cerebrovascular disease increased from 2.2% in the lowest neck circumference quartile to 5.0% in the highest quartile; among women, the highest neck circumference quartile had a 4.71-fold increased risk of stroke compared with the lowest quartile (95% CI: 1.50–14.77) (Han et al., 2022). This finding suggests that the relationship between neck circumference and cerebrovascular disease exhibits significant sex differences, with women potentially being more sensitive to the vascular effects of cervical adipose accumulation.

At the postural mechanics level, forward head posture (FHP)—the typical abnormal posture that causes sustained tension on the investing fascia—has an independent association with posterior circulation ischemic stroke. Behzadi et al. (2024), in a case-control study enrolling 206 subjects, found that the severity of forward head posture in patients with posterior circulation ischemic stroke was significantly greater than that in matched controls (C0-C2 angle: 30.7° vs. 23.2°, P = 0.002; sagittal vertical axis offset: 35.4 mm vs. 25.3 mm, P < 0.001), with no significant differences between the two groups in traditional stroke risk factors such as hypertension, hyperlipidemia, diabetes, and smoking. The study indicated that forward head posture may increase posterior circulation ischemia risk through chronic alteration of the hemodynamics of the vertebral-basilar artery system.

Synthesizing the above epidemiological and postural mechanics evidence, both cervical adipose accumulation and forward head posture—which together constitute the anatomical and mechanical basis for the formation of the "buffalo hump"—have independent and quantifiable associations with cerebrovascular disease risk. However, a clear distinction needs to be made between "association" and "causation": existing evidence supports cervical adipose accumulation as a surface marker of systemic metabolic disorders, indirectly increasing stroke risk through classical pathways such as hypertension and insulin resistance; forward head posture may directly affect posterior circulation blood supply through chronic hemodynamic alterations. The improvement of cervicogenic symptoms such as dizziness, headache, and blurred vision following investing fascia release suggests that it may exert symptomatic relief by relieving abnormal cervical soft tissue tension and improving the hemodynamics of the extracranial vertebral artery; however, this observational phenomenon cannot be directly extrapolated to a reduction in stroke risk, and its long-term cerebrovascular protective effects still require validation through prospective cohort studies.

(3) Preventive Effects on Further Deterioration of Motor Function

More direct and with a stronger deductive basis is the prevention of functional deterioration. The hypothesis points out that the long-term presence of abnormal mechanical signals can lead to sustained central gating upregulation (Ji and Lee, 2021; Noseda et al., 2019; Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Kim et al., 2014; Sawaki et al., 2003; Okabe et al., 2025), suppressing residual motor function output. Even if patients receive standardized rehabilitation training, its effects may be partially counteracted by gating inhibition. Release surgery, by removing the source of abnormal mechanical signals and restoring normal central gating levels, could theoretically provide more favorable neuroplasticity conditions for rehabilitation training, thereby preventing further functional decline.

It should be emphasized that the above preventive effects are currently still theoretical deductions based on the hypothesis and have not yet been validated by prospective clinical studies. Their confirmation would require well-designed prospective cohort studies or randomized controlled trials to observe whether the incidence of cerebral infarction and cerebral thrombosis, and the rate of motor function decline during long-term follow-up after release, are significantly lower than in control groups. This hypothesis provides a testable theoretical framework and specific predictive indicators for the above studies.

The discussion on preventive potential in this section is the most "speculative" part of the entire hypothesis. It logically depends on two premises: (1) the external tension of the investing fascia can indeed affect the hemodynamics of extracranial large vessels through the vascular adventitia conduction pathway; and (2) the resulting abnormal blood flow shear stress is sufficient to activate Piezo1-mediated pro-inflammatory and pro-thrombotic pathways. The former has support from anatomy (Bond et al., 2023) and finite element simulation (Shakya et al., 2023), while the latter has independent molecular-level evidence (Lan et al., 2024; Atcha et al., 2024; Wang et al., 2025). However, there remains a substantial evidence gap between "molecular pathway activation" and "clinical event (stroke) occurrence"—particularly the lack of prospective cohort studies directly examining the association between investing fascia fibrosis and stroke recurrence risk. Therefore, the deduction in this section should be understood as a theoretical extrapolation based on the same upstream mechanism, rather than evidence-based conclusions drawn from clinical outcome data. This hypothesis positions this section as a "secondary deduction," with a lower level of confidence than the core causal chain deduction in Section 2, Section 3 and Section 4.

6.5. Boundaries and Limitations of the Hypothesis

This hypothesis does not attempt to explain all post-stroke sequelae (Bond et al., 2023; Zhang et al., 2026a). Its applicable prerequisites are: (a) the corticospinal tract maintains anatomical continuity (DTI FA > 0.4); (b) the investing fascia exhibits detectable fibrotic thickening (SWE values >30% higher than the contralateral side) (Liao et al., 2023; Dapper et al., 2026; Zandi et al., 2025); and (c) the lesion is located in the mechanically accessible extracranial region, or although intracranial, residual tract function remains (Bond et al., 2023). For patients with complete corticospinal tract disruption, complete infarction of the posterior circulation intracranial segment (thalamus, brainstem) with no residual conduction function, mechanical unloading cannot restore central pathways that have been physically severed or irreversibly necrosed—these are anatomically defined regions beyond the range of mechanical conduction (Bond et al., 2023; Zhang et al., 2026a).

The main limitations of this hypothesis include: the expression of PIEZO1 and PIEZO2 in human investing fascia has not yet been directly confirmed by immunohistochemistry (Bagriantsev et al., 2014; Xiao, 2024; Kimura and Kobayashi, 2026; Zhang et al., 2026b; Wu et al., 2026a; Wu et al., 2026b; Shi et al., 2026; Fu et al., 2025; Alba et al., 2025; Huang et al., 2025; Xue et al., 2025; Pirri, 2025); the efficiency of trans-layer static tension transmission still awaits ex vivo mechanical experimental validation (Zhang and Lee, 2002; Pires et al., 2025); and the relative contribution weights of the five downstream pathways are unknown (Bond et al., 2023; Struthoff et al., 2024; Hamed et al., 2024; Lan et al., 2024). Furthermore, although Papay et al. (2006) confirmed the expression of α1A-AR on GABAergic interneurons, Araneda and Firestein (2006) validated that NE enhances GABAergic synaptic transmission through α1 receptors, Hiu et al. (2016) demonstrated the structural and functional enhancement of α1-GABAergic synapses after stroke, Kim et al. (2014) provided human PET-level evidence for the association between GABA inhibition and motor recovery, Sawaki et al. (2003) confirmed in humans that α1 receptor blockade impairs motor plasticity, and Okabe et al. (2025) demonstrated the key role of PV interneurons in rehabilitation, none of the above evidence constitutes direct evidence generated in the specific context of "investing fascia abnormal stress → central motor inhibition." The causal concatenation between NTS-LC-NE pathway activation and M1 α1-GABAergic gating upregulation currently remains a theoretical deduction, awaiting direct validation through indicators such as TMS-RMT in post-stroke sequelae patients.

The above statement of limitations is not simply a "disclaimer." In hypothesis-type papers, proactively identifying evidence gaps serves a positive academic function—it indicates key directions for subsequent research: (1) the direct expression of PIEZO channels in the investing fascia can be directly verified through immunohistochemistry or in situ hybridization on human autopsy or surgical specimens; (2) trans-layer tension transmission efficiency can be quantified through ex vivo mechanical tensile experiments on fascia-carotid sheath complexes; (3) the relative contributions of the five downstream pathways can be distinguished through selective pharmacological blockade (e.g., vagotomy, sympathetic ganglion blockade) combined with electrophysiological recordings; and (4) the causal concatenation between the NTS-LC-NE pathway and M1 α1-GABAergic gating can be validated in animal models or humans through TMS-RMT combined with pharmacological manipulations (e.g., observation of acute effects of α1 receptor agonists/antagonists). The solvability of these limitations itself constitutes a specific task list for hypothesis validation studies.

Furthermore, this hypothesis adopts a serial causal structure, and its explanatory power logically depends on the stepwise establishment of each link. However, it should be emphasized that a serial structure is not equivalent to an "all-or-nothing" fragility—if the molecular mediator of a certain intermediate link (such as the direct expression of PIEZO channels in the investing fascia) is not confirmed, it would only require revision of the specific molecular pathway of that link (such as replacing it with the integrin-YAP/TAZ pathway or the fascial piezoelectric effect), without the need to overturn the core logical framework of "peripheral mechanical abnormality suppresses motor function through central gating upregulation." This theoretical resilience of "core logic unchanged, local mediators replaceable" reserves sufficient space for local revision of the hypothesis based on new evidence in subsequent validation, and also prevents the entire theoretical framework from being prematurely abandoned due to temporarily insufficient evidence for a single link.

6.6. Statement of Theoretical Positioning

The "biomechanical unloading" hypothesis proposed in this paper is a theoretical deduction based on existing literature evidence, aimed at providing a testable mechanistic framework for motor dysfunction in the post-stroke sequelae phase. All conclusions are based on logical reasoning and literature synthesis, and have not been validated by clinical studies. This hypothesis does not represent a promotion of this surgical procedure as a treatment method for post-stroke sequelae; each link of its causal chain requires further validation through animal experiments and prospective clinical studies.

7. Conclusion

Based on a systematic integration of existing literature, this paper proposes the "biomechanical unloading" hypothesis (Bond et al., 2023; Zhang and Lee, 2002): fibrotic investing fascia may generate abnormal shear stress during head and neck micromovements (Cyron and Humphrey, 2017; Ley et al., 2025), which is conducted deep through the cervical fascial collagen network to the carotid sheath and the vagus and sympathetic nerves within it (Bond et al., 2023; Zhang and Lee, 2002; Struthoff et al., 2024), and may be converted into abnormal afferent signals through PIEZO channel-mediated mechano-electrical signal transduction (Bagriantsev et al., 2014; Xiao, 2024; Rashidi et al., 2025; Alba et al., 2025; Huang et al., 2025; Hamed et al., 2024; Pirri, 2025), upregulating cortical inhibition mediated by M1 GABAergic interneurons through the NTS-LC pathway—a link that has received multi-level evidence support from receptor expression to clinical translation (Bogduk, 2001; Ji and Lee, 2021; Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Kim et al., 2014; Sawaki et al., 2003; Okabe et al., 2025)—thereby potentially suppressing motor output. Investing fascia release could theoretically physically cut off the stress conduction pathway, achieve mechanical unloading of the central nervous system, and restore normal motor cortical excitability regulation (Cyron and Humphrey, 2017; Holzapfel et al., 2025). Based on the anatomical distribution of the anterior and posterior circulations (Bond et al., 2023), this hypothesis deduces the effect boundaries of this intervention—the extracranial segment of the posterior circulation may be the optimal mechanical response zone (Zhang et al., 2026a; Yuan et al., 2025), while the intracranial segment (thalamus, brainstem) is a structural damage zone beyond the range of mechanical conduction (Bond et al., 2023).

External evidence from multiple levels—anatomical localization (Alba et al., 2025), cytological basis (Huang et al., 2025), interoceptive framework (Hamed et al., 2024), neuroimmune gating (Pirri, 2025), stroke glial scar mechanisms (Wu et al., 2026a; Wu et al., 2026b; Shi et al., 2026; Fu et al., 2025), multi-level validation of α1-GABAergic central gating (Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Kim et al., 2014; Sawaki et al., 2003; Okabe et al., 2025), mechanically driven fibrosis (Tu et al., 2025; Xu et al., 2025; Yu et al., 2025), and force-dependent development of the myodural bridge (Zhang et al., 2025)—forms mechanistic complementarity with this hypothesis, collectively pointing toward the biological pathway of "mechanical signal → Piezo channel → NTS-LC-NE output → α1-GABAergic gating upregulation → motor function inhibition." At the vascular pathway level, the systematic review by Keshelava (2026) provides clinical evidence for "external compression → carotid artery thrombosis → cerebral ischemia," while Lan et al. (2024), Atcha et al. (2024), Wang et al. (2025), Zhao et al. (2021), and Xue et al. (2025) have revealed PIEZO1-mediated molecular mechanisms from four levels: endothelial inflammation, macrophage foam cell formation, platelet activation, and metabolic-inflammatory coordination. Epidemiological evidence further supports the association between cervical soft tissue abnormalities and cerebrovascular disease risk: a multicenter prospective cohort study from China demonstrated that neck circumference is an independent predictor of cardiovascular disease mortality (Li et al., 2024); a 12-year follow-up cohort from South Korea confirmed a dose-response relationship between neck circumference and cerebrovascular disease incidence (Han et al., 2022); and a case-control study directly found that forward head posture is independently associated with posterior circulation ischemic stroke (Behzadi et al., 2024).

This hypothesis provides a biomechanics-centered, anatomy-oriented, testable explanatory framework for the mismatch between muscle strength and motor function in the post-stroke sequelae phase, with each link of its causal chain independently verifiable through SWE (Liao et al., 2023; Dapper et al., 2026; Ley et al., 2025; Zandi et al., 2025), TMS (Xiao, 2024), TCD (Uzun et al., 2024), DTI (Bond et al., 2023), and finite element simulation (Shakya et al., 2023).

The core contributions of this hypothesis can be summarized at four levels: First, at the problem level—it raises the clinical conundrum of "strength available but not recruitable" and positions it as a phenomenological manifestation of reversible central gating upregulation. Second, at the mechanistic level—it constructs a five-step causal chain from investing fascia fibrosis to M1 cortical inhibition, providing a complete explanation for this conundrum from molecules to systems, in which the α1-GABAergic gating upregulation link has received multi-level literature support from receptor expression to the latest neural circuit mechanisms (Papay et al., 2006; Araneda and Firestein, 2006; Hiu et al., 2016; Kim et al., 2014; Sawaki et al., 2003; Okabe et al., 2025). Third, at the boundary level—it delineates the spatial boundaries of the mechanical unloading effect based on anterior-posterior circulation anatomical distribution, giving the hypothesis a clear scope of applicability. Fourth, at the validation level—it provides seven testable quantitative predictions and a three-tier validation framework, endowing the hypothesis with Popperian falsifiability.