Sympathetic Neural Coupling with the Investing Fascia, Deep Cervical Fascia, and Carotid Sheath: A Hypothesis

1. Introduction

The deep cervical fascial system consists of three layers: the investing fascia (superficial layer of the cervical fascia), the pretracheal fascia (middle layer), and the prevertebral fascia (deep layer). The investing fascia, as the most superficial layer, forms a continuous fibrous sleeve encircling the entire neck. The carotid sheath is generally considered a fibrous tunnel formed with the participation of the deep cervical fascia, containing the internal carotid artery, internal jugular vein, vagus nerve, and cervical sympathetic fibers. However, its specific fascial origin, fusion relationships, and attachment points remain controversial [1,2,3,4].

Bond et al. [1] systematically reviewed the fascial composition of the carotid sheath and pointed out that descriptions of its fascial attachments are contradictory and inconsistent. This review noted that the carotid sheath is located in the cervical region and forms part of the deep cervical fascia, with its main function being to enclose the neurovascular structures of the neck. However, descriptions of the fascial composition of the carotid sheath by various authors are complex, varied, and inconsistent. This finding confirms that the fascial composition of the carotid sheath is itself a controversial issue in the anatomical literature, and it also constitutes an essential prerequisite that cannot be omitted when this hypothesis argues for the structural basis of cross-layer tension transmission. Zhang et al. [5] used the C6 cross-section as a reference, systematically annotated the spatial relationships of the three layers of the deep cervical fascia, and clearly confirmed that the sympathetic trunk runs along the anterior surface of the longus colli and is covered by the prevertebral fascia, while the carotid sheath is located anterolaterally to the prevertebral fascia. This provides an accurate anatomical reference for the fascial spaces of the adult neck.

Recent clinical observations suggest that chronic forward head posture or sustained cervical stress may contribute to fibrotic remodeling of the investing fascia, resulting in abnormally elevated passive tension. How this mechanical change affects deep neurovascular structures through the fascial network currently lacks a systematic theoretical framework. This hypothesis aims to integrate existing evidence from anatomy, histology, biomechanics, molecular biology, pathology, electrophysiology, clinical epidemiology, alternative mechanism controls, and negative control evidence to propose a possible transmission pathway from mechanical abnormality of the investing fascia to sympathetic dysfunction, and to define the boundary conditions of its effects. Relevant anatomical foundations are described in studies by Chen et al. [6], Civelek et al. [7], Yin et al. [8], and Struthoff et al. [9]. The cellular and molecular mechanisms of fascial fibrosis can be found in the frameworks of Hinz [10], Gallardo et al. [11,12], and Miki and Manresa [13]. The ultrasound quantification methods for pathological fascial thickening can be found in the study by Langevin et al. [14].

2. Anatomical Basis

2.1. Fascial Composition and Histology of the Carotid Sheath

The investing fascia is the most superficial layer of the deep cervical fascia, covering the entire cervical region and enclosing the sternocleidomastoid, trapezius, and infrahyoid muscles. Its collagen fibers interweave with the pretracheal fascia and the prevertebral fascia, potentially forming the structural basis for cross-layer mechanical conduction.

The carotid sheath is not an independent structure; rather, it is generally considered a tubular fascial compartment formed with the participation of the layers of the deep cervical fascia. However, its specific fascial origin and fusion relationships remain controversial [1,2]. The systematic review by Bond et al. [1] pointed out that histological studies have shown that the carotid sheath is composed of fibrous tissue, elastic tissue, varying amounts of adipose tissue, and small nerves and microvessels within the sheath wall. The carotid sheath contains circular and oblique collagen fibers, and a clear demarcation plane exists between the outer sheath wall and surrounding cervical tissues. This review also emphasized that a correct understanding of the anatomy and structural relationships of the carotid sheath is crucial for optimizing surgical approaches and intraoperative localization.

Piffer [3] performed mesoscopic and microscopic observation of 40 human bilateral carotid sheath specimens, providing independent original histological evidence. This study demonstrated that the carotid sheath is always present, forming a complete capsule around the neurovascular complex, and exhibits sublayers that enclose the internal jugular vein, internal carotid artery, glossopharyngeal nerve, vagus nerve, external branch of the accessory nerve, and internal carotid nerve. Microscopic observation showed that the carotid sheath has a fibroelastic composition, with variable wall thickness. Fibrous bundles connect the wall of the first segment of the internal jugular vein to the inner surface of the carotid sheath, and fibrous extensions anchor the sheath superiorly at the margins of the jugular foramen and the carotid canal. This finding provides independent histological support for the core premise of the hypothesis that the sheath wall itself is a continuous fibrous structure capable of transmitting tension.

Palliyalil et al. [4] performed independent validation using modern histopathological methods on carotid sheath specimens from 30 patients with oral squamous cell carcinoma. This study demonstrated that the carotid sheath is composed of fibroadipose tissue and scattered nerve fascicles, representing a “strong fibroelastic tissue barrier,” and that no tumor cell infiltration was found in any specimen. This modern methodological evidence, with a larger sample size and more rigorous pathological criteria, independently reconfirmed Piffer’s [3] core finding regarding the fibroelastic composition of the sheath wall.

However, Hayashi [2], through histological observation of semi-serial sections from five cadavers (eight sides), presented findings that differed from previous descriptions. This study explicitly stated that the common sheath of the carotid sheath does not fuse with the superficial or pretracheal layers of the cervical fascia, but often fuses with the visceral fascia to form a thick plate. The alar fascia is generally considered one of the multiple layers posterior to the cervical viscera, but it is difficult to identify it as a separate distinct lamina. This finding implies that the pathway in the hypothesis by which investing fascial tension is transmitted through the sheath wall to the sympathetic trunk may need to be reexamined. Tension may not be transmitted through direct fusion between the investing fascia and the sheath wall, but rather indirectly through intermediate interfaces such as the visceral fascia. The independent histological evidence from Piffer [3], Palliyalil et al. [4], and Hayashi [2] collectively indicates that the fibroelastic structure of the carotid sheath is established, but controversy remains regarding the details of its specific fusion relationships with the surrounding fascial layers. Zhang et al. [5] used the C6 cross-section as a reference, further confirming that the sympathetic trunk runs along the anterior surface of the longus colli and is covered by the prevertebral fascia, thereby providing an adult neck anatomical reference for the above pathway.

Zhao et al. [15] used 20 New Zealand white rabbits to systematically track changes in the fascial architecture surrounding the neurovascular structures within the carotid sheath across four developmental stages. This study confirmed that the carotid sheath consistently exhibits a three-layered fascial architecture: an inner fascial layer, a middle zone, and an outer fascial layer. The inner fascial layer on the arterial side appears earliest and is the thickest, forming a dense, multilayered fibrous structure; the inner fascial layers of the vein and nerve are relatively thin. The outer fascial layer shows potential fusion between adjacent structures, reflecting external mechanical interactions. This finding suggests from a developmental perspective that the fascial architecture of the carotid sheath is not a static description but a dynamic structure formed in synchrony with mechanical stress, and that arterial-side fascial thickening may be the initiating and dominant component of sheath wall thickening, with sheath wall thickening possibly exhibiting a spatial gradient extending from the arterial side toward the posterior aspect. It should be noted that this study was performed in a rabbit model at a developmental stage and cannot directly prove that pathological fibrotic thickening causes compression of the sympathetic trunk.

McGrath and Shankar [16] provided visualization evidence of fibrosis in the region adjacent to the carotid sheath using in vivo human imaging. This case report described a patient with postradiation fibrosis in whom ultrasound evaluation showed a significant hyperechoic fibrotic region beneath the sternocleidomastoid muscle and adjacent to the carotid sheath, and pain was successfully managed with ultrasound-guided adhesiolysis. Dapper et al. [17] further used shear-wave elastography to quantify changes in cervical fascial stiffness in 16 postradiation patients and 16 matched controls, and found that fascial stiffness increased significantly from 22.7 kPa to 46.4 kPa after radiation. These two lines of evidence collectively provide an in vivo anchor for hypothesis node 3, “fibrotic thickening of the sheath wall,” from qualitative visualization to quantitative measurement. However, the pathological mechanism involves postradiation fibrosis, which may differ from chronic postural fibrosis. Okamoto et al. [18] reported a case of sclerosing inflammatory pseudotumor in which histology confirmed marked fibrotic tissue around the carotid artery, accompanied by extensive lymphocyte and plasma cell infiltration, and the fibrotic tissue was in close proximity to the sympathetic trunk. Surgical resection included the sympathetic trunk, and persistent Horner syndrome occurred postoperatively. Farage et al. [19] reported a case of idiopathic inflammatory pseudotumor of the carotid sheath in a 47-year-old man. CT and MRI showed a mass encasing and narrowing the common carotid artery, and biopsy confirmed a fibroproliferative lesion with chronic inflammatory cell infiltration. After corticosteroid treatment, significant radiological and clinical improvement occurred within eight days. These two case reports collectively confirm that space-occupying lesions characterized primarily by fibrosis can occur in the carotid sheath region and that such lesions have a spatial effect of encasing the carotid artery. The treatment response in Farage et al. [19] suggests that such fibrotic lesions may be reversible in the early stage.

2.2. Spatial Relationship of the Cervical Sympathetic Trunk with the Carotid Sheath and Longus Colli

The cervical sympathetic trunk is located posterior to the carotid sheath and runs deep to the prevertebral fascia. This spatial relationship is a key node in the mechanical chain of this hypothesis. Chen et al. [6], through systematic anatomical measurements of 42 formalin-fixed adult cadaver specimens, clearly confirmed the following core findings: the cervical sympathetic trunk was closely attached to the posterior aspect of the carotid sheath in all specimens, and above C7, the cervical sympathetic trunk was closely attached to the posterior aspect of the alar fascia and could not be easily separated by blunt dissection. The primary aim of this study was to understand the anatomical relationship between the cervical sympathetic trunk and the cervical fascia and to provide a more reliable method for avoiding injury to the cervical sympathetic trunk during the anterolateral cervical spine surgical approach.

Civelek et al. [7], through systematic dissection of 30 fresh cadavers (within 12–24 hours after death), further provided precise quantitative anatomical parameters for the mechanical chain of this hypothesis. This study showed that the cervical sympathetic trunk is located posteromedially to the carotid sheath and anterior to the longus colli, coursing longitudinally on the surface of the longus colli and deep to the prevertebral fascia. Its mean distance from the medial border of the longus colli at the C6 level was 11.6 ± 1.6 mm, the mean diameter of the cervical sympathetic trunk at the C6 level was 3.3 ± 0.6 mm, and the superior cervical ganglion was located at the C4 level in all specimens. These quantitative data provide a precise spatial parameter basis for the mechanical analysis in the hypothesis of posterior wall of the carotid sheath thickening leading to mechanical compression of the sympathetic trunk.

Yin et al. [8], through systematic dissection of 32 adult Chinese cadaveric specimens, provided key data on anatomical variations of the cervical sympathetic trunk. This study found that the middle cervical ganglion was present in only 28.1% of specimens, with two cases of unilateral duplicate middle cervical ganglia; the inferior cervical ganglion was present in 25.0% of specimens. The mean angle of the cervical sympathetic trunk relative to the midline of the cervical spine was 11.2° ± 1.8° on the left and 10.3° ± 1.4° on the right. The study explicitly stated that when the longus colli is transected or excessively retracted, the cervical sympathetic trunk is at high risk, especially at the C6 and C7 levels. These variation data have important implications for the clinical predictions of the hypothesis. If there is significant interindividual variation in the anatomical position of the cervical sympathetic trunk, then the mechanical effect of posterior wall of the carotid sheath thickening leading to mechanical compression of the sympathetic trunk may also differ significantly among individuals in terms of both probability of occurrence and severity.

Park et al. [20], through a systematic review and meta-analysis, integrated data from 8 studies and 273 cases of the middle cervical ganglion. The core findings were as follows: the detection rate of the middle cervical ganglion was approximately 50.4% (95% CI 34.5–66.4%); the middle cervical ganglion is usually located posterior to the carotid sheath and anterior to the longus colli, at the C3–C7 vertebral levels; and one variant exists in which the cervical sympathetic trunk lies on the posterior wall of the carotid sheath and adheres to the sheath wall. This integrated evidence indicates that the middle cervical ganglion is not present in all individuals and that its attachment to the posterior wall of the carotid sheath varies, suggesting that the mechanical effect of sheath wall thickening on the cervical sympathetic trunk may differ significantly because of individual anatomical differences.

Lyons and Mills [21] found in dissections of 12 cadaveric neck specimens that in two specimens the cervical sympathetic trunk was located inside the carotid sheath rather than posterior to the sheath, as is typically described. This finding further expands the range of anatomical variations of the cervical sympathetic trunk, suggesting that in some individuals, fibrotic thickening of the sheath wall may directly compress the sympathetic trunk within the sheath. This would not require the indirect pathway of posterior wall of the carotid sheath thickening leading to compression of the sympathetic trunk posterior to the sheath. This provides a testable and individualized prediction for the hypothesis: individuals in whom the sympathetic trunk is located within the sheath may be at higher risk of sympathetic symptoms due to sheath wall fibrosis.

Salazar-Orellana et al. [22] reported a case in which compensatory dilation of the right internal jugular vein compressed the second-order sympathetic neurons of the cervical sympathetic trunk, causing Pourfour du Petit syndrome (ocular sympathetic overactivity). This case provides, for hypothesis node 3, an alternative compression mechanism within the sheath other than sheath wall thickening: venous dilation within the sheath can also directly compress the sympathetic trunk and cause sympathetic overactivity, consistent with the direction predicted by the hypothesis of chronic compression leading to abnormal sympathetic activation. However, this study was a single case report, and its level of evidence is limited.

Struthoff et al. [9] used immunofluorescence analysis to quantitatively detect nerve distribution and density at the human carotid bifurcation, with the core finding being an overall nerve density of 46 ± 51 nerves per cm². The study also confirmed that along the internal carotid artery segment, nerve fibers gradually approach the vessel lumen and ultimately lie approximately 2.5 mm from the intimal surface, and that dense tyrosine hydroxylase-positive sympathetic nerve fibers are present at the carotid bifurcation. This finding provides direct histological validation on the arterial side for the coupling pathway from the sympathetic trunk to the carotid sheath and carotid artery in the hypothesis.

Lee et al. [23] used a 3-T MRI system to evaluate the normal imaging appearance of the superior cervical sympathetic ganglion (SCSG). The core findings were that 3-T MRI successfully localized a definite SCSG in 73% of cervical locations, typically appearing as a T2 hyperintense, markedly enhancing, longitudinal fusiform or oval structure located medial to the internal carotid artery and lateral to the longus colli, between the C2–C4 vertebral levels; intraganglionic low signal is a characteristic feature. However, 27% of SCSGs were not located in the typical positions described in the literature and may be located anterior to the longus colli, lateral to the internal carotid artery, or even posterior to it. These in vivo imaging variation data are consistent with the cadaveric anatomical variation data of Yin et al. [8], confirming in vivo the significant interindividual differences in the anatomical position of the cervical sympathetic ganglia.

Deshmukh et al. [24] systematically tracked the relative position of the cervical sympathetic trunk (ST) from the superior cervical ganglion to its course within the carotid sheath alongside the vagus nerve (VN) in a rat model, using microCT and immunohistochemistry to assess the co-localization rate of ST fibers with the cervical VN. The core findings were that the ST ran closely parallel to the VN within the carotid sheath and even interwoven at the typical location for placement of a nerve epineural cuff; crossing connection branches existed between the ST and VN. This study confirmed the anatomical relationship in which the cervical sympathetic trunk and vagus nerve enter the carotid sheath in parallel. It provides an anatomical basis for the parallel neural relationship within the sheath in the hypothesis that sheath wall thickening may simultaneously affect the sympathetic trunk and vagus nerve. However, this study was conducted in a rat model and did not involve sheath wall thickening, so caution is warranted when extrapolating to humans.

Taken together, the above anatomical evidence supports the following understanding. The cervical sympathetic trunk lies immediately posterior to the posterior sheath wall formed by structures such as the visceral fascia. Tension in the investing fascia may be transmitted indirectly to the posterior sheath wall through intermediate interfaces such as the visceral fascia, rather than directly through the fusion site between the investing fascia and the sheath wall. The qualitative and quantitative data from Chen et al. [6], Civelek et al. [7], Yin et al. [8], Struthoff et al. [9], Lee et al. [23], and Deshmukh et al. [24] collectively provide a spatial parameter basis for this pathway. In contrast, Lyons and Mills [21], Park et al. [20], and Salazar-Orellana et al. [22] suggest that some individuals may have anatomical and pathological variations such as a sympathetic trunk within the sheath, absence of the middle cervical ganglion, or compression by venous dilation within the sheath. Using the C6 cross-section as a reference, Zhang et al. [5] further confirmed that the sympathetic trunk runs along the anterior surface of the longus colli and is covered by the prevertebral fascia, providing an adult cervical anatomical reference for the above pathway. The case reported by Lee et al. [25] clinically confirmed that scarring of the cervical soft tissues can directly compress and tether the cervical sympathetic trunk, causing Horner syndrome, providing direct human evidence for the pathway from cervical soft tissue pathological change to mechanical compression of the sympathetic trunk.

3. Histological and Biomechanical Basis

3.1. Multilayered Collagen Fiber Architecture of the Deep Fascia

The mechanical chain of this hypothesis assumes that abnormal tension in the investing fascia may be transmitted deeply through the interwoven collagen fiber network among the layers of the deep cervical fascia. The histological premise of this hypothesis is that the deep fascia itself has a multilayered collagen fiber architecture, with differing fiber orientations among layers, enabling it to transmit tension.

Stecco et al. [26] systematically investigated the collagen fiber arrangement, elastic fiber distribution, and innervation density of the deep fascia by performing histological and immunohistochemical staining on the brachial fascia and forearm fascia from 20 upper limb specimens. This study clearly demonstrated that fascia is composed of numerous layers of undulating collagen fiber bundles. Within each layer, fibers run parallel to one another, whereas adjacent layers show different orientations. Each layer is separated by a thin layer of adipose tissue, forming a laminated structure. The fascia also contains abundant elastic fibers and various free and encapsulated nerve endings, suggesting that the deep fascia has proprioceptive function. The study further noted that layered collagen fibers allow tension to be transmitted along different lines of force. The gliding capacity between collagen layers may change in overuse syndromes, trauma, or surgery. This can lead to loss of the fascial buffering mechanism for nerve endings and cause abnormal activation of nerve receptors within the fascia. It should be noted that the specimens in this study were upper limb fascia, and caution is warranted when extrapolating to the deep cervical fascia.

Martínez-Sanz et al. [27] performed serial histological sectioning of the middle layer of the deep cervical fascia from 17 human embryos at 6–8 weeks and 20 fetuses at 9–14 weeks. This study was the first to systematically reveal the developmental stages and histological composition of the middle layer of the deep cervical fascia. It clearly confirmed that during the formation stage, fibroblast-like cells and collagen fibers appeared in the primordium of the epimysium and the middle layer of the deep cervical fascia. Development of the middle layer of the deep cervical fascia proceeded in synchrony with mechanical activity in the cervical region. This finding provides histological evidence from the cervical fascia itself for the hypothesis of investing fascial tension leading to deep cervical fascia and cross-layer transmission, rather than relying on extrapolation from upper limb fascia. It is complementary to Stecco et al. [26]. The latter confirmed the multilayered collagen architecture of upper limb fascia, whereas the former confirmed that the middle layer of the cervical fascia contains collagen fibers and fibroblasts. Together, they support the histological basis of the hypothesis from different anatomical regions. However, the investing fascia itself still requires direct study.

The developmental study by Zhao et al. [15] further suggests that the carotid sheath itself has a three-layered fascial architecture and that each layer is related to the mechanical stress environment. This finding, together with those of Stecco et al. [26] and Martínez-Sanz et al. [27], indicates that the deep fascial system in the cervical region may also possess a layered structure and tension-transmitting function. However, direct histological studies of the adult cervical investing fascia are needed for verification.

3.2. Ex Vivo Biomechanical Properties of Human Fascia

The mechanical chain of this hypothesis involves a quantitative mechanical analysis of transmission of investing fascial tension through the layers of the deep cervical fascia. However, this analysis requires ex vivo tensile mechanical parameters of human fascial tissue as a constitutive basis. Zwirner et al. [28] performed uniaxial tensile tests on 74 samples of human temporal muscle fascia and systematically measured the elastic modulus (36 ± 19 MPa), ultimate tensile strength (3.6 ± 1.7 MPa), maximum force (16 ± 8 N), maximum strain (13 ± 4%), and failure strain (17 ± 6%). These parameters provide a source of raw material data for biomechanical modeling of the hypothesis of cross-layer tension transmission. It should be noted that the specimens in this study were temporal muscle fascia rather than cervical investing fascia. Although both belong to the head and neck fascial system anatomically and are dense connective tissue histologically, differences may exist in collagen fiber orientation, thickness, and mechanical properties. When extrapolating the mechanical parameters of the temporal muscle fascia to the cervical investing fascia, they should be described as approximate reference values for fascial tissues in the same region, rather than direct substitute values.

Aparici-Gil et al. [29] performed uniaxial, biaxial, and planar tensile tests on human deep fascia and established a constitutive model capable of simultaneously reproducing these strain states. Core quantitative results included: mean uniaxial longitudinal stress of 3.96 MPa and transverse stress of 0.6 MPa; planar tensile longitudinal stress of 0.43 MPa and transverse stress of 0.11 MPa; equibiaxial longitudinal stress of 3.16 MPa and transverse stress of 1.2 MPa; and a longitudinal/transverse anisotropy ratio of approximately 6.6. This study provides multiaxial mechanical data for quantitative modeling of cross-layer tension transmission in the deep fascia that are closer to the true loading state than the uniaxial parameters of the temporal muscle fascia. However, the specimens were fascia lata rather than cervical investing fascia, and site differences must still be declared when extrapolating to the cervical region.

Bonaldi et al. [30] further performed uniaxial tensile tests on human fascia lata, confirming strongly anisotropic behavior, with collagen fiber layer angles typically ranging from 75° to 80°, and established a constitutive model capable of simulating intralayer and interlayer interactions. Compared with Aparici-Gil et al. [29], the latter described the overall mechanical response under multiaxial loading, whereas the former described the layered structure and its interactions. For quantitative modeling of hypothesis node 2, cross-layer tension transmission, interlayer sliding and interlayer interactions are key parameters, and Bonaldi et al. [30] provided original data for this dimension. However, the specimens in this study were also fascia lata, and site differences must be declared when extrapolating to the cervical investing fascia.

Pires et al. [31] used a pressure gauge combined with ultrasound imaging to directly measure the mechanical pressure required to reach the deep cervical fascia. The mean value was 6.06 ± 0.186 N/cm² in the cervical region and approximately 6 N/cm² in the lumbar/thoracolumbar region. These data provide a mechanical pressure threshold required to reach the deep fascia when applied to the body surface for hypothesis node 2, cross-layer tension transmission. They are complementary to the intrinsic mechanical parameters of fascial material provided by Zwirner et al. [28], Aparici-Gil et al. [29], and Bonaldi et al. [30]. The former describes the mechanical input conditions of the transmission pathway, whereas the latter describe the constitutive properties of the material. However, this study measured the threshold for external pressure to reach the deep fascia, not the process by which abnormal tension within the investing fascia is transmitted to the carotid sheath wall. The subjects were healthy individuals; therefore, this finding can serve only as indirect quantitative supporting evidence for node 2.

Myers et al. [32] developed a mechanical testing protocol for large-strain uniaxial tension and compression along three orthogonal anatomical directions, systematically measured the anisotropic and asymmetric tension-compression behavior of human cervical tissue, and confirmed that collagen orientation determines the directionality of the mechanical response. Shi et al. [33] subsequently established a three-dimensional anisotropic hyperelastic constitutive model based on Langevin statistical mechanics, simultaneously accounting for collagen fiber orientation, fiber bundle dispersion, and the entropic elasticity of wavy cross-linked collagen molecules, and explicitly stated that the model can be applied to other fibrous tissues. Nuckley et al. [34] further provided developmental biomechanical data for the human cervical spine under six loading directions—tension, compression, flexion-extension, lateral bending, and rotation—confirming that the mechanical response of the cervical spine exhibits significant age dependence and segmental specificity. These three studies collectively provide a methodological reference for soft tissues in the cervical region, a transferable constitutive framework, and multiaxial mechanical background for quantitative modeling of hypothesis node 2. Langevin et al. [14] used B-mode ultrasound to confirm that perimuscular connective tissue thickness and echogenicity in patients with chronic low back pain were approximately 25% greater than in controls, providing a methodological precedent for ultrasound quantification of pathological fascial thickening. However, the measurement site was the lumbar region, and the index was morphological rather than mechanical stiffness.

3.3. Sympathetic Innervation and Mechanosensory Cells in Deep and Superficial Fascia

The title of this hypothesis explicitly includes sympathetic neural coupling, and its core proposition is that abnormal tension in the investing fascia affects sympathetic nerves through the carotid sheath. However, whether the fascia itself contains sympathetic nerve fibers and whether fascial cells possess mechanosensory capacity are key to determining whether this proposition can hold on the fascial side.

Fede et al. [35] performed transmission electron microscopy and free-floating immunohistochemistry on the thoracolumbar fascia and gluteal fascia of seven adult C57-BL mice. Antibodies used in the study included anti-S100, anti-tyrosine hydroxylase (TH; a specific marker of sympathetic nerve fibers), and anti-PGP. Core findings were that a dense neural network was present within the fascial tissue; the density of autonomic nerve fibers was the same in both fasciae (0.08%); and no nerve corpuscles were found in the thoracolumbar fascia. This finding confirms that the deep fascia itself contains sympathetic nerve fibers, providing a neuroanatomical basis on the fascial side for the core designation of the hypothesis, sympathetic neural coupling with the fascia. However, this study was performed in a mouse model, and caution is warranted when extrapolating to humans.

Fede et al. [36] further validated this finding in human superficial fascia. The study used human abdominal and thigh superficial fascia specimens and performed immunohistochemical staining with an anti-tyrosine hydroxylase antibody, confirming the presence of the sympathetic autonomic nervous system within the fascia. The study quantitatively measured the relative percentage of autonomic innervation in the superficial fascia as 33.82%, and explicitly stated that chronic stress may affect the basal tension of the fascia by activating the autonomic nervous system. This direct immunohistochemical evidence from human fascia fills the gap in extrapolating Fede et al. [35] from a mouse model to humans, providing direct validation of the core proposition of sympathetic neural coupling with the fascia on the fascial side in humans. However, this study examined superficial fascia, and direct validation in the human cervical investing fascia is still needed.

Tereshenko et al. [37] detected PIEZO2 expression in human trapezius fascia and found that sympathetic nerve fibers (TH-positive) were significantly increased in the fascia of patients with occipital neuralgia, whereas they were absent in controls. The trapezius fascia corresponds to the cervicothoracic fascial-adipose complex, which is close to the posterior cervical investing fascia region described in the hypothesis. This study moved the evidence for PIEZO expression from the ganglion to the fascia itself, suggesting that fascial cells may directly participate in mechanical transduction. In addition, the selective increase in sympathetic nerve fibers within the fascia under pathological conditions echoes the core proposition of sympathetic neural coupling with the fascia on the fascial side in humans. However, this study focused on occipital neuralgia, and its pathological background differs from chronic postural fibrosis; therefore, caution is warranted when extrapolating to the specific mechanism of the hypothesis.

Huang et al. [38] identified a novel type of CD34+ membranous cells (CMCs) in the subcutaneous fascia of the abdominal midline in rats. These cells highly express mechanosensitive genes such as PIEZO2 and integrin β3 (Itgb3) and participate in mechanical signal coordination through the Rho pathway. This study provides a direct candidate cell type for cellular-level mechanical transduction between hypothesis node 1 and node 2, and it is complementary to the PIEZO2 expression evidence of Tereshenko et al. [37]. The latter confirmed that the fascia expresses PIEZO2, whereas the former suggests the presence of a specific mechanosensory cell type within the fascia. However, this study was performed in rat abdominal fascia, and caution is warranted when extrapolating to the human cervical investing fascia.

At the level of fibrotic molecular mechanisms, Hinz [10] systematically described the differentiation and maintenance mechanisms of myofibroblasts under the synergistic action of sustained mechanical tension and TGF-β1, and revealed a positive feedback loop from myofibroblast contractile activity to latent TGF-β1 activation and further fibrosis. Gallardo et al. [11] further confirmed that TGF-β activates YAP/TAZ through the SMAD3 pathway, thereby determining the differentiation fate of fibro-adipogenic progenitors toward myofibroblasts; inhibition of YAP/TAZ can reduce TGF-β1-dependent differentiation. Gallardo et al. [12] further revealed that denervation itself can drive YAP/TAZ activation, suggesting that innervation status directly influences the fate of fascial fibrosis. Miki and Manresa [13] systematically integrated fibroblast phenotypic heterogeneity and pointed out that extracellular matrix (ECM) stiffness, hypoxia, and the metabolic microenvironment jointly regulate fibroblast function. Together, these lines of evidence provide a complete molecular framework for hypothesis node 1, spanning from mechanical tension to cellular phenotypic conversion.

4. Mechanical Coupling Hypothesis

The core mechanism of this hypothesis can be divided into four sequential, progressive nodes.

4.1. Node 1: Investing Fascial Fibrosis

Chronic forward head posture or sustained cervical stress may lead to fibrotic remodeling of the investing fascia, with altered collagen fiber arrangement and increased passive tension. The posterior wall of the fibrotic investing fascia shortens and thickens, potentially disrupting the anteroposterior tension balance of the neck. Liao et al. [39] confirmed in 16 healthy adults that the shear modulus of the nuchal fascia was significantly higher in the forward head posture than in the neutral position, and that the reliability of shear-wave elastography for measuring the nuchal fascia was intra-rater ICC = 0.63–0.89 and inter-rater ICC = 0.54–0.82. Zandi et al. [40] further validated the test-retest reliability of shear-wave elastography for measuring cervical and lumbar fascial stiffness in 30 participants, with ICC [1,3] values ≥ 0.90. Dapper et al. [17] confirmed in patients with postradiation fibrosis that cervical fascial stiffness increased significantly from 22.7 kPa to 46.4 kPa, providing direct quantitative data for Node 1 under pathological fibrotic conditions. Gao et al. [41] validated in 158 adults the significant correlation between shear-wave elastography-assessed shear-wave velocity of the upper trapezius and cervical somatic dysfunction (R² = 0.69), and confirmed that shear-wave velocity decreased significantly after osteopathic manipulative treatment. This provides large-sample methodological evidence for shear-wave elastography as a tool for assessing cervical soft tissue mechanics. However, the measurement target was the upper trapezius rather than the investing fascia itself, and dedicated studies are needed to extrapolate to the investing fascia. Langevin et al. [14] used B-mode ultrasound to confirm that perimuscular connective tissue thickness and echogenicity in patients with chronic low back pain were approximately 25% greater than in controls, providing a methodological precedent for ultrasound quantification of pathological fascial thickening. However, the measurement site was the lumbar region, and the index was morphological rather than mechanical stiffness. At the cellular and molecular level, Hinz [10], Gallardo et al. [11,12], and Miki and Manresa [13] collectively provided the mechanistic chain from mechanical tension to TGF-β1, SMAD3, YAP/TAZ, myofibroblast differentiation, and extracellular matrix (ECM) deposition, explaining why fibrosis persists and intensifies. These studies collectively provide integrated evidence for Node 1, from phenomenological description to methodology and from pathological quantification to molecular mechanisms. However, the pathological mechanism in Dapper et al. [17] was postradiation fibrosis, which may differ from chronic postural fibrosis.

4.2. Node 2: Cross-Layer Tension Transmission

Abnormal tension in the investing fascia may be transmitted deeply through the interwoven collagen fiber network among the layers of the deep cervical fascia, or through intermediate interfaces such as the visceral fascia. Stecco et al. [26] confirmed that the multilayered collagen fiber architecture of the deep fascia has a tension transmission function, and that the different orientations of fibers in each layer allow tension to be transmitted along multiple lines of force. However, the specimens in this study were upper limb fascia. Martínez-Sanz et al. [27] confirmed that the middle layer of the deep cervical fascia contains collagen fibers and fibroblasts, and that its development is synchronized with mechanical activity in the cervical region. However, the specimens were embryos and fetuses. Zwirner et al. [28], Aparici-Gil et al. [29], and Bonaldi et al. [30] provided uniaxial, multiaxial, and interlayer mechanical parameters of human fascia, respectively, providing a constitutive basis for quantitative modeling of cross-layer tension transmission. However, the specimens were temporal muscle fascia and fascia lata, and caution is warranted when extrapolating to the cervical investing fascia. Pires et al. [31] measured the mechanical pressure required to reach the deep cervical fascia, which was approximately 6 N/cm², providing a reference for the mechanical feasibility of cross-layer tension transmission. However, these data describe the threshold for external pressure to reach the deep fascia, not direct evidence that abnormal tension within the investing fascia is transmitted to the sheath wall. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] provided an anisotropic testing protocol for soft tissues in the cervical region, a transferable three-dimensional constitutive model, and multiaxial developmental biomechanical data, respectively, providing a methodological basis more relevant to the cervical region for quantitative modeling of Node 2. Using the C6 cross-section as a reference, Zhang et al. [5] confirmed that the thoracic fascia forms a physiological connection with the posterior cervical fascia via the prevertebral fascia, providing an adult cervical anatomical reference for the transmission of investing fascial tension along fascial interfaces to deep and distal regions. The CD34+ membranous cells identified by Huang et al. [38] provide a candidate cell type for mechanosensory signaling within the fascia. However, this study was performed in rat abdominal fascia. Because the fascial layers converge at or are adjacent to the carotid sheath, this mechanical transmission may ultimately act on the carotid sheath itself. However, Hayashi [2] suggested that the investing fascia and the sheath wall may not be directly fused but may instead be indirectly connected through intermediate interfaces such as the visceral fascia. Currently, direct evidence for this node is lacking. The continuous mechanical transmission pathway from the adult cervical investing fascia to the carotid sheath wall still requires direct investigation. Whether cross-layer mechanical signaling involves mechanosensitive ion channels at the cellular level remains unclear and lacks direct evidence and can be regarded as one of the testable hypotheses for future research.

4.3. Node 3: Fibrotic Thickening of the Carotid Sheath

Sustained abnormal tension stimulation may contribute to fibrotic thickening of the carotid sheath wall and surrounding tissues. Thickening of the posterior wall of the carotid sheath is particularly critical. The histological study by Hayashi [2] suggests that the fusion relationship between the sheath wall and the visceral fascia may provide a pathway for tension transmission that differs from direct fusion with the investing fascia. Piffer [3] confirmed that the carotid sheath has a fibroelastic composition, with variable wall thickness and sublayers that enclose the neurovascular bundle, providing a histological basis for the sheath wall itself to participate in mechanical transmission. Palliyalil et al. [4] independently validated the fibroelastic tissue composition of the sheath wall using 30 modern pathological specimens. Zhao et al. [15] confirmed in a rabbit model that the carotid sheath has a three-layered fascial architecture: the inner fascial layer on the arterial side appears earliest and is the thickest, and the outer fascial layer shows potential fusion between adjacent structures, suggesting that sheath wall thickening may exhibit a spatial gradient extending from the arterial side toward the posterior aspect. However, this study was performed at a developmental stage and in an animal model. The case report by McGrath and Shankar [16] provided evidence that fibrosis in the region adjacent to the carotid sheath can be visualized by ultrasound in living humans, and Dapper et al. [17] further provided quantitative data on increased fascial stiffness. However, the latter involved postradiation fibrosis. The histologically confirmed evidence from Okamoto et al. [18] indicates that marked fibrosis can occur around the carotid artery and encase the carotid artery, with the fibrotic tissue in close proximity to the sympathetic trunk. The imaging and pathological evidence from Farage et al. [19] further confirmed that fibroproliferative lesions can occur in the carotid sheath region, and the effectiveness of corticosteroid therapy suggests early reversibility. Chen et al. [6] confirmed that the cervical sympathetic trunk is closely attached to the posterior aspect of the carotid sheath and the posterior aspect of the alar fascia. Civelek et al. [7] provided the quantitative distance between the cervical sympathetic trunk and the longus colli. Yin et al. [8] provided anatomical variation data for the cervical sympathetic trunk. Lyons and Mills [21] suggested that the cervical sympathetic trunk is located within the sheath in some individuals. Park et al. [20] further integrated the detection rate and variations in attachment of the middle cervical ganglion, and Salazar-Orellana et al. [22] reported a clinical case in which venous dilation within the sheath compressed the sympathetic trunk and caused sympathetic overactivity. Deshmukh et al. [24] confirmed the anatomical relationship in which the cervical sympathetic trunk and the vagus nerve enter the carotid sheath in parallel. However, this study was performed in a rat model. The anatomical review by Zhang et al. [5] further clarified the spatial relationships of the sympathetic trunk with the prevertebral fascia and the carotid sheath, providing an adult cervical anatomical reference for compression of the sympathetic trunk caused by posterior sheath wall thickening. The case reported by Lee et al. [25] confirmed that scarring of the cervical soft tissues can directly compress and tether the cervical sympathetic trunk, causing Horner syndrome, providing direct human clinical evidence for the pathway from cervical soft tissue pathological change to mechanical compression of the sympathetic trunk. These lines of evidence collectively imply that any thickening of the posterior sheath wall may exert direct mechanical effects on the sympathetic trunk and the vagus nerve, and that this effect may differ among individuals. However, there is currently no quantitative standard for the degree of sheath wall thickening required to produce clinically significant compression.

4.4. Node 4: Mechanical Compression of the Sympathetic Nerve and Functional Changes

The thickened posterior sheath wall may exert sustained mechanical compression on the cervical sympathetic trunk immediately posterior to it, thereby leading to sympathetic dysfunction. This compression may simultaneously affect the vagus nerve within the carotid sheath, causing autonomic nervous system imbalance. Two types of effects need to be distinguished. Acute or severe mechanical injury can cause loss of sympathetic function, such as Horner syndrome [42,43,44], whereas this hypothesis predicts sympathetic imbalance or abnormal activation under chronic compression. These two effects should not be directly equated. The Pourfour du Petit syndrome reported by Salazar-Orellana et al. [22] provides evidence from the opposite direction. Venous dilation within the sheath compressing the sympathetic trunk can cause ocular sympathetic hyperexcitation, suggesting that compression within the sheath may indeed cause enhanced rather than lost sympathetic function. The case reported by Lee et al. [25] provides evidence from a different perspective. Scarring of the cervical soft tissues compresses and tethers the cervical sympathetic trunk, causing Horner syndrome, further confirming that mechanical compression or tethering of the sympathetic trunk can lead to sympathetic dysfunction.

The human clinical data from Lubelski et al. [42] indicated that mechanical injury to the cervical sympathetic trunk can cause Horner syndrome, with an incidence of 0.45% in a single-center series and 0.6% in a systematic review. The most common surgical segment was C5/6 (64%), and 82% of patients experienced at least partial resolution within one year. Ying et al. [43] further confirmed at the clinical procedural level that mechanical traction on the carotid sheath can be transmitted to the cervical sympathetic trunk immediately posterior to it and cause injury. Two cases of Horner syndrome after thyroidectomy were attributed to local trauma to the sympathetic trunk during carotid sheath traction. Liu et al. [45] studied 50 patients with cervical spondylosis and hypertension and confirmed that decompressive surgery targeting the region adjacent to the cervical sympathetic trunk significantly reduced office blood pressure from 142.5/82.0 mmHg to 127.3/76.6 mmHg, directly providing human evidence that surgical intervention in the cervical sympathetic trunk region can alter blood pressure. However, this study was an observational cohort study with inherent limitations.

West et al. [44] reported a case of a patient with infectious mononucleosis in whom enlarged lymphoid tissue within the carotid sheath compressed the sympathetic nerve, causing Horner syndrome. MRI and MRA directly confirmed the compressive effect of the lesion within the sheath on the sympathetic trunk. This is one of the very few human case reports that directly confirms the chain from enlargement of structures within the carotid sheath to sympathetic nerve compression and clinical dysfunction with imaging evidence, providing direct imaging evidence of compression originating within the sheath for hypothesis Node 4. However, this case involved loss of sympathetic function rather than overactivation. Salazar-Orellana et al. [22] provided a case of venous dilation within the sheath causing sympathetic overactivity, directionally complementary to West et al. [44], collectively suggesting that the effects of compression within the sheath may depend on the nature of compression, speed, and individual anatomical differences. Ding et al. [46] confirmed in a pig model that carotid sheath surgery can cause Horner syndrome and revealed a key species difference: the cervical sympathetic trunk in pigs is located inside the carotid sheath, whereas in humans it is outside the sheath. This finding provides a necessary species-specific anatomical caveat when extrapolating animal model evidence to humans. The human anatomical variation data from Lyons and Mills [21] suggest that the cervical sympathetic trunk may also be located within the sheath in some human individuals, further indicating that both interspecies and interindividual anatomical differences must be taken into account. The case reported by Lee et al. [25] provides direct clinical evidence that scarring of the cervical soft tissues can compress and tether the sympathetic trunk.

At the molecular level, Alba et al. [47] used immunohistochemistry and immunofluorescence techniques to detect the expression of PIEZO1 and PIEZO2 in the human carotid sinus and carotid body, with expression rates as high as 71% and 86%, respectively. PIEZO1 and PIEZO2 are well-established mechanosensitive ion channels responsible for converting mechanical stimuli into electrical signals. Tereshenko et al. [37] further detected PIEZO2 expression in human trapezius fascia, shifting the evidence for mechanical transduction from the ganglion to the fascia itself. The CD34+ membranous cells identified by Huang et al. [38] in rat abdominal fascia highly express PIEZO2, providing a candidate cell type for mechanosensory perception within the fascia. Chen et al. [48] revealed the molecular mechanism by which GPR146 upregulates PIEZO1 expression through the cyclic adenosine monophosphate (cAMP)-CREB1 signaling pathway, providing an upstream pathway for mechanical signal amplification. GPR146, as a mechanosensitive G protein-coupled receptor, can directly respond to changes in hydrostatic pressure and thereby upregulate PIEZO1 transcription. Konishi et al. [49] detected upregulated PIEZO1 expression in myofibroblasts of the fibrous cap of carotid atherosclerotic plaques in 17 patients undergoing carotid endarterectomy by immunohistochemistry, and PIEZO1 expression was higher in symptomatic patients, providing human PIEZO1 expression evidence on the arterial side for the pathway from the sympathetic trunk to the carotid sheath and carotid artery in the hypothesis. Sun et al. [50] systematically integrated the molecular mechanisms and targeted therapeutic potential of PIEZO1 in cardiovascular diseases, covering pathological processes such as hypertension, atherosclerosis, and vascular remodeling, providing a systematic molecular mechanistic background for Node 4, from mechanical compression to PIEZO1 activation and sympathetic or blood pressure changes. Wang et al. [51] systematically integrated the three pathways of neural regulation, biochemical signaling, and mechanical transduction in heart-brain communication, and pointed out that autonomic imbalance is a core mediator of heart-brain comorbidities. This review provides broader framework support for the hypothesis and suggests that mechanical transduction may be involved in cross-organ pathological processes. However, as a review article, it cannot substitute for original studies that directly simulate sympathetic trunk compression caused by fibrotic thickening of the carotid sheath wall. The evidence from Alba et al. [47] provides a molecular-level candidate basis for mechanical transduction in the carotid sinus and carotid body. However, direct evidence for PIEZO expression in the cervical sympathetic ganglion is still lacking and requires further validation. Moreover, the mechanotransduction function of PIEZO in the cervical sympathetic trunk still requires in vivo experimental validation, and PIEZO expression itself does not necessarily indicate sustained activation of the channel under chronic compression conditions.

Holwerda et al. [52] evaluated muscle sympathetic nerve activity (MSNA) by microneurography and assessed common carotid artery intima-media thickness (IMT) and lumen diameter by ultrasound in 93 young and middle-aged or older adults. The core findings were as follows: MSNA and 24-hour systolic blood pressure were independent determinants of the carotid IMT-lumen ratio; after controlling for 24-hour systolic blood pressure, MSNA was significantly correlated with the IMT-lumen ratio in young men (R = 0.49, P < 0.001) and middle-aged or older women (R = 0.59, P = 0.022), whereas no such association was observed in young women. This study directly confirmed an independent association between higher sympathetic neural outflow and carotid artery wall thickness, providing direct quantitative evidence in humans for the hypothesis of sheath wall structural change leading to sympathetic activation. However, this study was a cross-sectional observation and cannot establish causality.

Dinenno et al. [53] measured MSNA and femoral artery IMT in 11 young (29 ± 1 years of age) and 13 older (63 ± 1 years of age) healthy normotensive men. The core findings were as follows: MSNA burst frequency in the older group was 70% higher than that in the young group (39 ± 1 vs. 23 ± 2 bursts/min, P < 0.001), and femoral artery IMT and the IMT/lumen ratio were approximately 75% higher (both P < 0.001); MSNA was strongly positively correlated with IMT (r = 0.82, P < 0.001); after removing the effect of MSNA, the difference in IMT between age groups was eliminated, whereas after removing the effect of age, the relationship between MSNA and wall thickness remained significant. This study provides human evidence from the age dimension for causal separation between elevated sympathetic activity and arterial wall thickening, further supporting the causal direction of the hypothesis of sympathetic overactivation leading to arterial wall structural change.

Gallego and Geijo [54] used tetrodotoxin (TTX) to induce chronic conduction block of the cervical sympathetic trunk in guinea pigs for two or four days, and then recorded synaptic efficacy in the superior cervical ganglion and stellate ganglion in vitro. The core findings were as follows: after chronic conduction block, the maximum excitatory postsynaptic potential (e.p.s.p.) amplitude of disused synapses in the superior cervical ganglion was significantly increased; the e.p.s.p. amplitude of active synapses in the stellate ganglion was also significantly increased, and the number of synaptic response steps increased, suggesting that the blocked fibers formed new synaptic connections through collateral sprouting. This study directly used the cervical sympathetic trunk as an intervention target and confirmed that chronic intervention can enhance synaptic efficacy in ganglia, providing direct mechanistic evidence at the synaptic level for the hypothesis of chronic compression of the cervical sympathetic trunk leading to ganglionic functional change. However, this model used chemical conduction block rather than mechanical compression, and species differences must be considered.

Cassaglia et al. [55] mechanically elevated blood pressure in anesthetized lambs via an intra-aortic balloon, with a 43 ± 3% increase in mean arterial pressure, and directly recorded a 53 ± 13% increase in sympathetic nerve activity (SNA) in the superior cervical ganglion (SCG), whereas SNA did not increase when blood pressure was lowered. This study was the first to directly record sympathetic nerve activity from the SCG, confirming that it can respond to changes in the mechanical environment and that the response is directionally specific. This provides direct electrophysiological evidence for hypothesis Node 4, from mechanical stimulation to changes in sympathetic nerve activity, indicating that the superior cervical ganglion is not passively compressed but can actively sense and respond to mechanical stimuli. However, this model involved acute mechanical blood pressure elevation rather than chronic sheath wall fibrotic compression, and the species was the lamb; therefore, caution is warranted when extrapolating to humans.

5. Pathophysiological Evidence

5.1. Pathological and Functional Effects of Chronic Mechanical Compression

The final effector node of this hypothesis is that the thickened posterior wall of the carotid sheath may exert mechanical compression on the cervical sympathetic trunk, leading to sympathetic dysfunction. However, whether mechanical compression alone is sufficient to cause pathological changes and functional abnormalities of the cervical sympathetic nerve requires direct experimental evidence.

Serebryakova [56] applied quantitative compression to the cervical sympathetic trunk at the base of the superior cervical ganglion in rats, performed light and electron microscopy one year after compression, and systematically measured the ratio of the number of neurons in the ganglion to the number of preganglionic myelinated fibers. The study found that the ratio was 1:210 in the intact control group and 1:173 in the age-matched control group, whereas it was as high as 1:745 in the experimental group one year after compression. These findings led to the following conclusions: normalization of the ganglionic neural connection structure did not occur, the post-traumatic regeneration process was incomplete, and the process became chronic. This study was the first to demonstrate in an animal model that mechanical compression of the cervical sympathetic trunk can cause long-term abnormalities in neural connection remodeling and that this process becomes chronic and irreversible. However, the rat model differs significantly from humans in cervical anatomy and mechanical environment.

Gu et al. [57] further provided direct evidence at the functional level that chronic mechanical compression causes abnormal discharge of the cervical sympathetic ganglion. This study established a chronic compression model of the posterior longitudinal ligament of the cervical spine in 10 healthy adult beagle dogs. Two months after modeling, abnormal discharge waveforms were recorded in the middle cervical ganglion, with waveform amplitude and waveform area per unit time significantly increased compared with those immediately after modeling, and functional spectral decomposition revealed a significant increase in the 100–250 Hz frequency band. This study directly demonstrated that chronic mechanical compression can cause abnormal functional discharge of the cervical sympathetic ganglion, advancing the causal chain of the hypothesis from structural change to functional abnormality. However, this model involved posterior longitudinal ligament compression rather than carotid sheath compression, and its mechanical pathway differs from that assumed by the hypothesis.

He et al. [58] established an atlantoaxial misalignment model in rats using an atlantoaxial implant, and within several days after surgery, all successfully modeled rats developed hypertensive symptoms; blood pressure decreased after removal of the implant. The authors explicitly stated that hypertension may be caused by stimulation of the superior cervical ganglion. Activation of the superior cervical ganglion increases norepinephrine release, constricts blood vessels, and accelerates heart rate, while acetylcholine levels decrease. Blood pressure in the left group was higher than that in the right group, consistent with the asymmetric distribution of sympathetic nerves. This study is currently the only formally published animal model that directly simulates the sequence from upper cervical mechanical misalignment to sympathetic ganglion activation and elevated blood pressure, and its causal structure is highly consistent with Prediction 1 of the hypothesis. However, the atlantoaxial anatomy of rats differs from that of humans, and the study did not directly measure mechanical compression or electrophysiological changes in the cervical sympathetic trunk or superior cervical ganglion. Cassaglia et al. [55] further confirmed at the electrophysiological level that mechanical elevation of blood pressure can directly increase sympathetic activity in the superior cervical ganglion, providing direct recording evidence for the sequence from changes in the mechanical environment to enhanced ganglionic sympathetic activity.

Little et al. [59] provided longitudinal evidence in a canine model that chronic mechanical compression leads to long-term hemodynamic changes. This study applied bilateral chronic compression to the carotid sinus of two groups of dogs using plastic clips. The first group underwent compression after carotid sinus nerve transection and clearing of the adjacent vessel wall, with continuous measurement of blood pressure and heart rate over 422–485 days. The second group underwent compression while preserving carotid sinus innervation, with continuous measurement over 593–695 days. The core findings were as follows: in the first group (denervated), chronic compression led to sustained increases in arterial systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate; in the second group (innervated), chronic compression led to sustained increases in diastolic pressure and sustained decreases in pulse pressure. This study directly confirmed over a chronic time course exceeding one year that mechanical compression can cause sustained changes in blood pressure. However, the study focused on the carotid sinus rather than the cervical sympathetic trunk.

Burstyn et al. [60] provided independent evidence from a rabbit model of chronic compression-induced hypertension. This study established a sustained hypertension model by bilaterally placing rigid casts around the carotid sinus regions over a chronic time course of weeks to months. The rigid casts simulated the sustained, irreversible mechanical compression exerted by fibrotic thickening of the sheath wall on adjacent structures, complementing the removable compression model used by Little et al. [59]. However, this model also targeted the carotid sinus region.

Liu et al. [45] directly addressed the key issue of mechanistic mismatch in chronic compression models at the human clinical level. This study used a time-series cohort design in 50 patients with cervical spondylosis and hypertension to evaluate the effect of surgical decompression targeting the region adjacent to the cervical sympathetic trunk on blood pressure. The core findings were as follows: office systolic/diastolic blood pressure decreased significantly from 142.5/82.0 mmHg before surgery to 127.3/76.6 mmHg after surgery. This study explicitly stated that surgery removed the cervical sympathetic trunk, shifting the hypothesis from an indirect analogy of carotid sinus compression to human validation of direct intervention in the cervical sympathetic trunk region. However, this study was an observational cohort study with inherent limitations, and the office blood pressure results were inconsistent with the ambulatory blood pressure results.

Lubelski et al. [42] provided complementary evidence at the human clinical level. Through a retrospective analysis of 1,116 patients who underwent anterior cervical discectomy and fusion at a single center and a systematic review of 21 studies, this study found that injury to the cervical sympathetic trunk can cause Horner syndrome, with an incidence of approximately 0.45%–0.6%, and the most common surgical segment was C5/6. The case report by Ying et al. [43] further confirmed at the procedural level that traction on the carotid sheath can cause injury to the sympathetic trunk, providing indirect validation at the clinical procedural level for the mechanical transmission pathway from sheath wall thickening to mechanical compression of the sympathetic trunk. However, this evidence involved loss of function rather than overactivity. Salazar-Orellana et al. [22] reported a case in which venous dilation within the sheath caused sympathetic overactivity, opposite in direction to Horner syndrome, further indicating that the effects of compression within the sheath may depend on the nature of the compression and individual differences. The case reported by Lee et al. [25] confirmed that scarring of the cervical soft tissues compresses and tethers the cervical sympathetic trunk, causing Horner syndrome, providing direct human clinical evidence for the pathway from cervical soft tissue pathological change to mechanical compression of the sympathetic trunk.

5.2. Physiological Effects of Cervical Sympathetic Stimulation

One of the core clinical predictions of this hypothesis is that abnormal activation of the cervical sympathetic trunk may lead to elevated blood pressure. Mills and Sampson [61] electrically stimulated the peripheral end of the cervical sympathetic nerve in 17 decerebrate, unanesthetized cats and systematically recorded respiratory and blood pressure responses. The study found that in 14 experiments, stimulation produced slight changes in blood pressure; 10 showed a decrease, and four showed an increase of no more than 10 mmHg. More importantly, all respiratory responses were eliminated after carotid sinus nerve transection, which was attributed to activation of chemoreceptor and baroreceptor afferents. The experimental subjects were decerebrate cats, and caution is warranted when extrapolating to human clinical practice.

Markman et al. [62] further validated this effect in humans. In five patients undergoing catheter ablation for atrial fibrillation, an electrophysiology catheter was advanced to the cervical level via the right vertebral vein approach to perform direct intravascular electrical stimulation of the cervical sympathetic ganglia. Each patient developed a transient increase in heart rate (ranging from 11 to 32 bpm), and three patients showed systolic blood pressure elevation (increases of 10, 17, and 32 mmHg, respectively). After cessation of stimulation, both blood pressure and heart rate returned to baseline levels, and the duration and magnitude of the effect were proportional to stimulation duration and intensity. Markman et al. [63] further reported, using the same research paradigm, the operational feasibility and dose-response relationship of this technique, confirming that acute sympathetic trunk inhibition can be titrated according to changes in hemodynamic parameters. However, the sample size was small (five cases), and the stimulation parameters differ fundamentally from the effects of chronic mechanical compression.

Joshi et al. [64] provided human experimental evidence from the perspective of external mechanical compression. This study applied external mechanical compression to the neck using a Q-collar and simultaneously measured cerebrovascular function and autonomic nervous function. The core findings were as follows: Q-collar compression significantly reduced the cross-sectional area of the carotid artery; during the Valsalva maneuver, subjects wearing the compression collar showed a significant increase in systolic blood pressure, suggesting enhanced sympathetic and adrenergic activation; in women, wearing the compression collar also significantly increased supine diastolic blood pressure and mean blood flow velocity of the middle cerebral artery. This study directly confirmed from an external compression perspective that mechanical compression of the neck can affect human sympathetic nerve activity and blood pressure. However, this model was an acute experiment, and its effects differ from the long-term effects of chronic compression.

Rea and Eckberg [65] applied graded pressure or negative pressure (+40 to −65 mmHg) via a neck pressure chamber in nine healthy subjects to compress or stretch the carotid baroreceptors for five seconds, while simultaneously recording muscle sympathetic nerve activity. The core findings were as follows: the carotid-muscle sympathetic relationship was well described by a reverse sigmoid function and was linear over a carotid distending pressure range of approximately 25 mmHg; the sympathetic response exhibited marked asymmetry, in that the increase in sympathetic activity during carotid compression was much greater than the decrease during carotid stretch. This study provides human dose-response evidence for the hypothesis regarding the relationship between degree of compression and magnitude of sympathetic activation. However, this study was an acute experiment, and whether its dose-response relationship applies to chronic compression still requires validation.

Williamson et al. [66] further refined the compression target to the unilateral carotid sinus. In 10 healthy subjects, this study used a partitioned neck collar device to apply sustained pressure of approximately 25 mmHg for five seconds to the right, left, and bilateral carotid sinuses, while simultaneously recording MSNA from the right peroneal nerve. The core findings were as follows: all MSNA indices induced by left carotid pressure were significantly greater than those on the right (P < 0.05); the sum of left and right MSNA indices was not significantly different from the value during simultaneous bilateral stimulation (P > 0.05), suggesting that the bilateral response can be approximated as the summation of unilateral responses. This study provides precise anatomical localization evidence for the hypothesis of local mechanical compression of the carotid sinus leading to MSNA activation and reveals the asymmetry of unilateral effects. However, this study was an acute experiment.

5.3. Effects of Cervical Sympathetic Activation on Cerebral Circulation

One of the clinical predictions of this hypothesis is that abnormal sympathetic activation may lead to changes in cerebrovascular resistance, affecting cerebral perfusion. Ainslie et al. [67] reflexively induced sympathetic activation via isometric handgrip exercise in 14 healthy men and simultaneously measured middle cerebral artery blood flow velocity, femoral artery blood flow, muscle sympathetic nerve activity, and mean arterial pressure. The core findings were as follows: under isocapnic conditions, sympathetic activation increased cerebrovascular resistance by 20 ± 11% while cerebral blood flow velocity remained unchanged; under hypercapnic conditions, sympathetic activation increased cerebral blood flow velocity by 13%–14% while cerebrovascular resistance remained unchanged.

In six healthy subjects, Jordan et al. [68] induced sympathetic activation by head-up tilt, induced sympathetic deactivation by ganglionic blockade, and manipulated PaCO₂ levels using hyperventilation and 5% CO₂ inhalation. The core findings were as follows: the sympathetic nervous system can attenuate CO₂-induced increases in cerebral blood flow; the regression slope of PaCO₂ versus mean flow velocity during ganglionic blockade was 2.3 ± 0.36 cm/(s·mm Hg), significantly higher than 1.6 ± 0.18 in the supine position and 1.3 ± 0.14 during head-up tilt (HUT) (P < 0.05). Through ganglionic blockade and manipulation of CO₂ levels, this study directly confirmed that the sympathetic nervous system has an effect on human cerebral blood flow regulation that is independent of CO₂. However, the sample size was six healthy subjects.

Sadoshima et al. [69] performed unilateral superior cervical ganglionectomy in spontaneously hypertensive rats and measured the wall/lumen ratio of cerebral arteries at five weeks, two months, and five months after surgery. The core findings were as follows: chronic sympathetic denervation significantly attenuated the normal development of cerebrovascular hypertrophy during the progression of hypertension, and this effect was more pronounced in small downstream vessels (diameter ≤ 100 μm). This study was conducted in a rat model, and the cerebrovascular anatomy differs from that of humans.

Wang et al. [70] further validated this effect using modern molecular biology methods. This study performed bilateral superior cervical ganglionectomy (SCGx) in spontaneously hypertensive rats (SHR) and assessed vascular remodeling four weeks later. The core findings were as follows: SCGx significantly attenuated vascular remodeling of the facial artery and superficial temporal artery in SHR, and this effect was independent of changes in blood pressure and heart rate; SCGx-treated SHR exhibited upregulated α-smooth muscle actin (α-SMA), downregulated proliferating cell nuclear antigen (PCNA), and reduced oxidative stress and inflammation. This study was conducted in a rat model.

Treggiari et al. [71] provided reverse validation from the perspective of therapeutic intervention. This study included nine patients with angiographically confirmed cerebral vasospasm and delayed ischemic neurological deficit symptoms after aneurysmal subarachnoid hemorrhage, and injected local anesthetics at the level of the superior cervical ganglion to block the cervical sympathetic trunk. The core findings were as follows: all patients showed improvement in cerebral perfusion on confirmatory angiography; except for the patient who died, all remaining patients rapidly returned to normal neurological status within 48 hours after regional treatment. This study directly confirmed that cervical sympathetic block can improve cerebral perfusion and reverse neurological deficits. However, the sample size was nine cases.

Bombardieri et al. [72] systematically integrated the clinical evidence for percutaneous cervical sympathetic block in the treatment of cerebral vasospasm and delayed cerebral ischemia, and explicitly stated that cervical sympathetic block (CSB) temporarily blocks the sympathetic innervation of cerebral arteries by injecting local anesthetics at the level of the cervical sympathetic trunk, leading to arterial vasodilation and thereby improving cerebral perfusion; they considered its results encouraging as a therapeutic approach. This study is a review article.

Gupta et al. [73] performed stellate ganglion block (SGB) in 20 patients, using transcranial Doppler ultrasound to assess ipsilateral middle cerebral artery flow velocity (MCAFV), estimated cerebral perfusion pressure (eCPP), zero flow pressure (ZFP), CO₂ reactivity, and cerebral autoregulation. The core findings were as follows: SGB resulted in a significant decrease in MCAFV, a significant increase in eCPP, and a significant decrease in ZFP, but no significant changes in CO₂ reactivity or cerebral autoregulation. This study confirmed from the perspective of therapeutic blockade that blocking the cervical sympathetic nerve can reduce cerebrovascular tone without impairing autoregulatory capacity, directly supporting the causal direction of the hypothesis of sympathetic overactivation leading to increased cerebrovascular tone. However, the sample size was 20 cases, and it was an acute intervention study.

ter Laan et al. [74] systematically integrated all available literature on the effects of electrical stimulation, chemical stimulation, and surgical intervention on the cervical sympathetic nerve on cerebral blood flow, and explicitly pointed out that the importance of sympathetic control of cerebral blood flow increases significantly under severe challenge conditions. Hamner et al. [75] confirmed in 11 healthy subjects that the effect of sympathetic blockade on the cerebral circulation was significant only at frequencies > 0.05 Hz, whereas at the lowest frequency (0.03 Hz) the cerebral circulation depended on other regulatory mechanisms, revealing the frequency dependence of sympathetic regulation of cerebral blood flow. Koep et al. [76] systematically compared the fundamental differences between the cerebral and peripheral circulations in terms of anatomical structure, adrenergic receptor distribution, and sympathetic-parasympathetic interactions, and explicitly pointed out that measurements of peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovascular system, and that cerebral sympathetic nerve activity may act in the opposite direction through changes in intracranial pressure and cerebral blood volume.

Shenkin et al. [77] performed bilateral stellate ganglionectomy in humans and directly confirmed that cerebral blood flow increased after cervical sympathetic denervation (≤20%), providing original human experimental evidence for the causal direction of the hypothesis that sympathetic overactivation leads to reduced cerebral blood flow. However, this study was published in 1951, and its methodology was relatively limited.

5.4. Boundary Definition of Alternative Mechanisms: Blood Pressure-Lowering Effect and Neural Inhibition of Carotid Sinus Compression

This hypothesis assumes that compression of the cervical sympathetic trunk leads to sympathetic activation and elevated blood pressure. However, direct compression of the carotid sinus baroreceptors is a competing explanatory pathway.

Campón-Checkroun et al. [78] performed right carotid sinus compression for 20 seconds in 64 hypertensive patients taking antihypertensive medications and found that the intervention group showed significant immediate reductions in both systolic and diastolic blood pressure after the intervention, as well as a significant decrease in heart rate, with a large clinical effect size. The reduction in systolic blood pressure persisted at five minutes, and the reduction in heart rate persisted at 60 minutes. This human evidence directly confirmed the blood pressure-lowering effect of carotid sinus compression, which is opposite in direction to the hypothesis prediction that compression leads to elevated blood pressure.

Wallin et al. [79] provided more direct evidence at the level of electrical nerve stimulation. This study recorded multiunit sympathetic nerve activity from the right peroneal nerve in four awake subjects and observed its effects over 36 carotid sinus nerve stimulation cycles. The core findings were as follows: in all 36 stimulation cycles, carotid sinus nerve stimulation inhibited muscle sympathetic nerve activity; stimulation had no discernible effect on skin sympathetic nerve activity; and sympathetic inhibition was temporally consistent with the decrease in heart rate and blood pressure. This finding confirmed the sympathetic inhibitory direction of the carotid sinus baroreceptor pathway at the neural pathway level. Therefore, the effect of posterior sheath wall thickening leading to elevated blood pressure in the hypothesis cannot be achieved through the carotid sinus baroreceptor pathway. It must instead depend on the independent pathway of cervical sympathetic trunk compression. If sheath wall thickening simultaneously compresses the carotid sinus, its effect may be opposite or mutually canceling, and this is an alternative mechanism that the present hypothesis must exclude.

5.5. Boundary of Cervical Sympathetic Trunk Intervention Effects: Negative Evidence

This hypothesis assumes that mechanical compression of the cervical sympathetic trunk can cause abnormal sympathetic activation, but whether cervical sympathetic trunk intervention necessarily leads to changes in systemic sympathetic nerve activity requires direct functional evidence. Ikeda et al. [80] recorded renal sympathetic nerve activity, arterial blood pressure, and heart rate in seven urethane-anesthetized rats 15 minutes before and 30 minutes after left cervical sympathetic trunk transection. The core findings were as follows: left cervical sympathetic trunk transection had no significant effect on renal sympathetic nerve activity, baroreceptor-unloaded renal sympathetic nerve activity, arterial blood pressure, or heart rate; and renal sympathetic nerve activity did not show a compensatory increase during cervical sympathetic trunk transection.

This negative result has important value in defining boundaries. It indicates that simply removing the afferent and efferent pathways of the cervical sympathetic trunk is not sufficient to cause compensatory changes in renal sympathetic nerve activity. This suggests that the influence of the cervical sympathetic trunk on systemic sympathetic activity may not be mediated through a simple linear pathway. It may instead depend on more complex neural circuits or abnormal activation under pathological conditions. Therefore, the causal chain of mechanical compression leading to abnormal sympathetic activation in the hypothesis cannot be simplified into a linear model of neural pathway blockade or stimulation. It should incorporate more complex mechanisms such as local inflammation, structural remodeling, and central integration. Ikeda et al. [80], together with Serebryakova [56] and Gu et al. [57], form a complementary relationship between a functional negative control and structural positive findings and functional abnormality findings. Collectively, they define the boundary of the effects of cervical sympathetic trunk intervention.

In addition, La Touche et al. [81] confirmed through a randomized controlled trial that upper cervical spine mobilization can produce a clear sympathetic excitatory response (significant increases in skin conductance, respiratory rate, and heart rate, P < 0.001), providing randomized controlled trial-level human evidence for a causal association between cervical mechanical intervention and sympathetic nervous function. However, the intervention was joint mobilization rather than fascial release, and the sample size was limited. Henley et al. [82] confirmed in 17 healthy subjects that osteopathic manipulative treatment can produce a vagal response, as assessed by heart rate variability, whereas neither the sham group nor the blank control group showed this effect. Ketelhut et al. [83] further confirmed in 20 healthy men that after a nonspecific self-myofascial release intervention, peripheral diastolic blood pressure, central diastolic blood pressure, total peripheral resistance, and the root mean square of successive differences (RMSSD) all decreased, whereas heart rate increased; during the cold pressor test, peripheral and central diastolic blood pressure also showed lower response values after self-myofascial release. However, the intervention did not target the cervical investing fascia.

6. Clinical Significance and Testable Predictions

Based on the above mechano-neural coupling pathway, this hypothesis proposes the following testable clinical predictions. Current evidence supports several of these components, but no clinical study has directly validated these predictions.

Prediction 1: Cervicogenic hypertension. Sustained mechanical compression of the cervical sympathetic trunk may lead to sympathetic overactivation, thereby causing elevated blood pressure. Experiments by Mills and Sampson [61] demonstrated that cervical sympathetic nerve stimulation can alter blood pressure regulation through the carotid body reflex pathway, and Markman et al. [62,63] further confirmed the pressor effect and dose-response relationship of cervical sympathetic nerve stimulation in humans. Little et al. [59] and Burstyn et al. [60] confirmed in canine and rabbit models, respectively, that chronic mechanical compression can lead to long-term changes in blood pressure. He et al. [58] confirmed in a rat model that atlantoaxial misalignment can cause hypertension, and blood pressure decreased after removal of the implant. Cassaglia et al. [55] confirmed in anesthetized lambs that mechanical elevation of blood pressure can directly increase sympathetic activity in the superior cervical ganglion, providing direct electrophysiological evidence for the sequence from altered mechanical environment to enhanced sympathetic ganglion activity and elevated blood pressure. The human cohort study by Liu et al. [45] confirmed that surgical decompression targeting the region adjacent to the cervical sympathetic trunk can significantly reduce office blood pressure. Joshi et al. [64] confirmed that external mechanical compression of the neck can lead to sympathetic activation and elevated blood pressure. Rea and Eckberg [65] and Williamson et al. [66] provided dose-response evidence linking the degree of carotid compression to the magnitude of sympathetic activation. The human evidence from Campón-Checkroun et al. [78] and Wallin et al. [79] defined the blood pressure-lowering effect and sympathetic inhibitory direction of carotid sinus compression, separating the effects of cervical sympathetic trunk compression from those of the carotid sinus baroreceptor pathway. Holwerda et al. [52] and Dinenno et al. [53] confirmed independent associations and causal directionality between sympathetic neural outflow and arterial wall thickness. Gallego and Geijo [54] confirmed that chronic intervention on the cervical sympathetic trunk can enhance ganglionic synaptic efficacy. Tan et al. [84] confirmed in 1,226 subjects that carotid body enlargement is positively associated with hypertension, chronic heart failure, chronic lung disease, smoking, and high body mass index (BMI), and that the cumulative number of comorbidities is associated with increased carotid body volume, providing human epidemiological evidence for an association between structural changes in the carotid bifurcation region and sympathetic-related diseases. Żera et al. [85] further integrated the pathological role of the carotid body in cardiometabolic diseases, confirming that abnormal carotid body activity leads to increased arterial chemoreflex tone and sensitivity, causing sympathetic excitation in resistant hypertension; carotid body denervation can reduce sympathetic activity and blood pressure in humans. Paton et al. [86] explicitly pointed out that carotid body excitation drives systemic sympathetic tone and receives dense sympathetic innervation from the superior cervical ganglion, providing a framework for the integrated mechanism of the cervical sympathetic trunk–carotid body axis. Sun et al. [50] systematically integrated the molecular mechanisms and targeted therapeutic potential of PIEZO1 in cardiovascular diseases, providing systematic background support for the involvement of mechanical transduction in blood pressure regulation and vascular remodeling. At the level of interventional randomized controlled trials (RCTs), the sham-controlled, double-blind trial by Simonsen et al. [87] confirmed that carotid sinus electrical stimulation can significantly reduce 24-hour ambulatory systolic blood pressure under sham-controlled conditions (−9.0 mmHg, P < 0.0001), and blood pressure rose again after the device was turned off. The sham-controlled RCT by Bakris et al. [88] confirmed that mechanical realignment of the atlas can reduce systolic blood pressure by −17 mmHg and diastolic blood pressure by −10 mmHg within eight weeks (P < 0.0001 and P = 0.002), with an effect size equivalent to combination therapy with two antihypertensive drugs. Although the three-arm parallel RCT by Plaugher et al. [89] did not show an independent effect of chiropractic adjustment on diastolic blood pressure (chiropractic group −4 mmHg, control group −4.9 mmHg), its methodological lessons—difficulty in recruiting unmedicated hypertensive patients, baseline BMI imbalance between groups, office blood pressure affected by the white-coat effect, and chiropractic intervention containing nonspecific components—provide important reference points for future RCT design. Together, these lines of evidence provide a physiological basis for this prediction, ranging from acute stimulation to chronic compression, from animals to humans, from effects to boundaries, and from qualitative to quantitative. However, all of these lines of evidence have extrapolation limitations. This mechanism may constitute a peripheral driving factor in some cases of resistant hypertension.

Prediction 2: Cerebral hypoperfusion. Abnormal sympathetic activation may lead to changes in cerebrovascular resistance and affect cerebral perfusion. Ainslie et al. [67] confirmed in humans that sympathetic activation increases cerebrovascular resistance under isocapnic conditions; Jordan et al. [68] confirmed through ganglionic blockade and CO₂ manipulation that the sympathetic effect is independent of CO₂; Hamner et al. [75] revealed the frequency dependence of this effect; and Sadoshima et al. [69] and Wang et al. [70] confirmed in rats that chronic sympathetic denervation can attenuate the development of cerebrovascular hypertrophy during the progression of hypertension. Treggiari et al. [71], Bombardieri et al. [72], and Gupta et al. [73] provided reverse validation from the perspective of clinical treatment with cervical sympathetic block, showing that blocking the sympathetic nerve can improve cerebral perfusion or reduce cerebrovascular tone. Shenkin et al. [77] directly confirmed that cerebral blood flow increases after bilateral stellate ganglionectomy. The systematic review by ter Laan et al. [74] and the mechanism-specific comparison by Koep et al. [76] further provided evidence-based integration and a mechanistic framework for the sequence from sympathetic overactivation to cerebrovascular structural remodeling and altered cerebral perfusion. This mechanism may be associated with some cases of unexplained cerebral ischemia or cognitive decline.

Prediction 3: Ocular disorders. Sympathetic nerve stimulation may lead to ocular vasoconstriction and fluctuations in intraocular pressure, whereas compression of the vagus nerve may be associated with autonomic imbalance. The Horner syndrome data from Lubelski et al. [42] indicate that mechanical injury to the cervical sympathetic trunk can produce definite ocular clinical manifestations, and Ying et al. [43] further confirmed at the clinical procedural level that traction on the carotid sheath can cause Horner syndrome. The case reported by West et al. [44] directly confirmed with imaging evidence that a lesion within the carotid sheath compressing the sympathetic trunk can cause Horner syndrome, further confirming the clinical association between the cervical sympathetic trunk and ocular function. However, these lines of evidence all involve loss of sympathetic function rather than overactivation. The Pourfour du Petit syndrome reported by Salazar-Orellana et al. [22] provides evidence from the opposite direction: venous dilation within the sheath compressing the sympathetic trunk can cause ocular sympathetic hyperexcitation. The pig model of Ding et al. [46] further suggests that carotid sheath surgery can cause Horner syndrome, but species-specific anatomical differences must be taken into account. The case reported by Lee et al. [25] confirms that scarring of the cervical soft tissues compresses and tethers the cervical sympathetic trunk, causing Horner syndrome, providing direct human clinical evidence linking this pathway to ocular disorders.

Prediction 4: Abnormal metabolic regulation. Abnormal activation of the cervical sympathetic trunk may affect glucose metabolism through the sympatho-insular axis. Alba et al. [47] confirmed that the human carotid sinus and carotid body express PIEZO mechanosensitive channels, providing a molecular basis for mechanical transduction in the carotid region. Whether the cervical sympathetic ganglion itself expresses PIEZO channels still requires direct validation. Tereshenko et al. [37] detected PIEZO2 expression in human trapezius fascia, shifting the evidence for mechanical transduction from the ganglion to the fascia itself. Huang et al. [38] found that CD34+ membranous cells in rat abdominal fascia highly express PIEZO2, providing a candidate cell type for mechanosensory perception within the fascia. Chen et al. [48] further revealed the GPR146-PIEZO1 upstream signaling pathway, providing a molecular mechanism for mechanical signal amplification. Konishi et al. [49] detected upregulated PIEZO1 expression in carotid plaques, providing human PIEZO1 expression evidence on the carotid side. Sun et al. [50] systematically integrated the role of PIEZO1 in cardiovascular diseases, providing background support for mechanical transduction involved in metabolic regulation. Wang et al. [51] suggested that mechanical transduction and autonomic imbalance are mediating mechanisms of heart-brain comorbidities. Järhult and Holst [90] confirmed in a cat model that carotid baroreceptor unloading can cause a 100% increase in blood glucose, an approximately 200% increase in glucagon, and a reduction in insulin to 50% of baseline through the sympatho-adrenal system, providing direct experimental evidence for the sequence from altered mechanical environment in the carotid region to sympathetic activation and metabolic abnormalities. However, this study was a 1978 cat model, and the intervention was baroreceptor unloading rather than sympathetic trunk compression; therefore, caution is warranted when extrapolating to the specific mechanism of the hypothesis. Zhao et al. [15] suggested that the spatial gradient of sheath wall thickening may affect the time window during which compression occurs, and the mechanical thresholds and constitutive parameters provided by Pires et al. [31], Aparici-Gil et al. [29], and Bonaldi et al. [30] may help estimate the effective dose of external mechanical intervention required to reach the deep fascia. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] further provided methodological references for soft tissue mechanical modeling in the cervical region. Langevin et al. [14] provided a methodological precedent for ultrasound quantification of pathological fascial thickening.

Positioning of Translational Maturity. This hypothesis is currently at the mechanistic hypothesis stage, and no animal model or human study has directly simulated the core causal chain. Existing interventional RCTs (Simonsen et al. [87,88,89]) and animal models (He et al. [58], Cassaglia et al. [55]) have respectively targeted carotid sinus electrical stimulation, atlas realignment, chiropractic adjustment, atlantoaxial misalignment, and mechanical blood pressure elevation, none of which directly validate the pathway from sheath wall fibrosis to sympathetic trunk compression. Therefore, the clinical translational maturity of this hypothesis should be positioned as technology readiness level (TRL) 2–3: a conceptual framework and an indirect evidence chain have been established, but direct validation has not yet been initiated.

7. Validation Framework

Validation of this hypothesis requires support from multiple levels of evidence.

Anatomical level: More independent studies are needed to replicate and verify the close attachment relationship between the cervical sympathetic trunk and the posterior wall of the carotid sheath and the alar fascia in larger samples, and to quantify its variation across populations with different ages and postural habits. Chen et al. [6] reported systematic anatomical evidence from 42 cadaver specimens; Civelek et al. [7] provided quantitative parameters from 30 cadavers; Yin et al. [8] provided variation data from 32 Chinese population specimens; Piffer [3] provided histological evidence from 40 bilateral carotid sheaths; Palliyalil et al. [4] provided independent validation from 30 modern pathological specimens; Struthoff et al. [9] provided quantitative data on nerve density at the human carotid bifurcation; Lee et al. [23] provided in vivo 3-T MRI imaging variation data for the superior cervical sympathetic ganglion (SCSG); Deshmukh et al. [24] provided anatomical evidence that the cervical sympathetic trunk runs in parallel with the vagus nerve within the sheath; Lyons and Mills [21] provided human anatomical variation evidence of the cervical sympathetic trunk located within the carotid sheath; Park et al. [20] provided meta-analysis evidence on the detection rate and attachment variations of the middle cervical ganglion; Salazar-Orellana et al. [22] provided clinical case evidence of venous dilation within the sheath compressing the sympathetic trunk; and Zhang et al. [5] provided an accurate anatomical reference for the fascial spaces of the adult neck.

The histological findings of Hayashi [2] suggest that the fascial fusion relationships of the sheath wall still require further confirmation. The rabbit model of Zhao et al. [15] suggests that the carotid sheath has a three-layered fascial architecture with preferential thickening on the arterial side, but this needs to be validated in humans. The case report by McGrath and Shankar [16] suggests that fibrosis adjacent to the carotid sheath can be visualized by ultrasound in vivo, and Dapper et al. [17] further provided quantitative data. The case reports by Okamoto et al. [18] and Farage et al. [19] provided histological and imaging evidence of fibrosis in the carotid sheath region. The species difference in cervical sympathetic trunk position between pigs and humans reported by Ding et al. [46] indicates that species-specific anatomical differences must be rigorously distinguished when extrapolating animal models to humans. The rat atlantoaxial misalignment model of He et al. [58] suggests that upper cervical mechanical misalignment can cause hypertension; the lamb model of Cassaglia et al. [55] suggests that mechanical blood pressure elevation can directly increase sympathetic activity in the superior cervical ganglion; and the case reported by Lee et al. [25] suggests that scarring of the cervical soft tissues can compress and tether the cervical sympathetic trunk. However, all three species differ from humans, and further validation in models closer to humans is needed.

Histological and biomechanical level: Histological studies of the deep cervical fascia, especially the investing fascia and prevertebral fascia, are needed to verify whether its multilayered collagen fiber architecture is consistent with the findings of Stecco et al. [26] in upper limb fascia, and to quantify the orientation and mechanical properties of fibers in each layer. Martínez-Sanz et al. [27] have confirmed that the middle layer of the deep cervical fascia contains collagen fibers and fibroblasts, but the investing fascia itself still requires direct study. Zwirner et al. [28], Aparici-Gil et al. [29], and Bonaldi et al. [30] provided uniaxial, multiaxial, and interlayer mechanical parameters of human fascia, respectively, but ex vivo mechanical data from the cervical fascia itself are still needed. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] provided methodological references for soft tissue in the cervical region, a transferable constitutive model, and multiaxial developmental biomechanical data. Pires et al. [31] provided the mechanical pressure threshold required to reach the deep cervical fascia, but further research is needed on the specific mechanical process by which tension within the investing fascia is transmitted to the sheath wall.

Fede et al. [35] and Fede et al. [36] confirmed sympathetic innervation in mouse deep fascia and human superficial fascia, respectively. Tereshenko et al. [37] detected PIEZO2 expression and increased sympathetic nerve fibers under pathological conditions in human trapezius fascia. Huang et al. [38] found CD34+ membranous cells that highly express PIEZO2 in rat abdominal fascia. However, direct validation in the human cervical investing fascia is still needed. Hinz [10], Gallardo et al. [11,12], and Miki and Manresa [13] provided a framework for the molecular mechanisms of fibrosis, but validation in the cervical fascia is needed. Alba et al. [47] confirmed that the human carotid sinus and carotid body express PIEZO mechanosensitive channels; Chen et al. [48] further revealed the GPR146-PIEZO1 upstream signaling pathway; Konishi et al. [49] detected upregulated PIEZO1 expression in carotid plaques; and Sun et al. [50] systematically integrated the role of PIEZO1 in cardiovascular diseases. Zhao et al. [15] suggested that the three-layered architecture and spatial gradient of the sheath wall need to be validated in the human carotid sheath. Creze et al. [91] confirmed in the thoracolumbar fascia that shear-wave velocity measured by shear-wave elastography was not significantly correlated with ex vivo tensile modulus, suggesting that when shear-wave elastography is used in the future to assess investing fascial stiffness, its correspondence with ex vivo mechanical properties must be separately established. Gao et al. [41] validated in 158 adults the reliability of shear-wave elastography for assessing the upper trapezius, but the measurement target was not the investing fascia itself. Langevin et al. [14] used B-mode ultrasound to confirm increased fascial thickness and echogenicity in patients with chronic low back pain, providing a methodological precedent for ultrasound quantification of pathological fascial thickening. However, the measurement site was the lumbar region, and the index was morphological rather than mechanical stiffness.

Pathological level: Findings from Serebryakova [56] regarding chronic pathological changes in the cervical sympathetic nerve caused by mechanical compression and from Gu et al. [57] regarding abnormal discharge of the cervical sympathetic ganglion caused by chronic compression need to be replicated in more animal models, and the effects of different degrees and durations of compression on neural function need to be explored. Gallego and Geijo [54] confirmed that chronic intervention on the cervical sympathetic trunk can enhance ganglionic synaptic efficacy. Little et al. [59] and Burstyn et al. [60] provided reference benchmarks for translating animal experiments to clinical practice. He et al. [58] provided direct animal model evidence for the sequence from upper cervical mechanical misalignment to sympathetic activation and hypertension. Cassaglia et al. [55] provided direct electrophysiological evidence for the sequence from changes in the mechanical environment to enhanced superior cervical ganglion activity, but the sources of compression were atlantoaxial misalignment and an intravascular balloon, respectively, rather than sheath wall fibrosis. Liu et al. [45] provided direct evidence for the blood pressure effect of decompression in the cervical sympathetic trunk region. Lubelski et al. [42] and Ying et al. [43] provided human clinical data for translating animal experiments to clinical practice. The negative results of Ikeda et al. [80] suggest that future studies need to distinguish the different effects of neural pathway blockade and pathological activation caused by mechanical compression. The species differences reported by Ding et al. [46] indicate that the choice of animal models must be made with caution. The case of Salazar-Orellana et al. [22] suggests that the effects of compression within the sheath may depend on the nature of compression. The case of Lee et al. [25] confirmed that scarring of the cervical soft tissues can compress and tether the cervical sympathetic trunk. Okamoto et al. [18] and Farage et al. [19] provided histological and imaging evidence of fibrosis in the carotid sheath region. In particular, it should be noted that no animal model or human study has directly simulated sympathetic trunk compression caused by fibrotic thickening of the carotid sheath wall. This gap is the main evidence gap of this hypothesis, and future research should prioritize the establishment of chronic animal models in which sheath wall thickness and compression degree can be precisely controlled.

Clinical level: Prospective cohort studies are needed to evaluate the correlation between abnormal investing fascial tension, which can be quantified by shear-wave elastography, and indicators of sympathetic nerve activity. The shear-wave elastography techniques validated by Zandi et al. [40], Liao et al. [39], and Dapper et al. [17] provide reliable tools for quantifying investing fascial stiffness in vivo; Gao et al. [41] further validated in 158 adults the reliability of shear-wave elastography for assessing cervical somatic dysfunction. The findings of Creze et al. [91] further suggest that there may be no direct correspondence between elastography measurements and ex vivo mechanical parameters, and future studies need to simultaneously perform ex vivo mechanical validation. The human evidence from Campón-Checkroun et al. [78] and Wallin et al. [79] suggests that future studies need to clearly distinguish the effects of carotid sinus baroreceptor compression from those of cervical sympathetic trunk compression. The human experiments of Joshi et al. [64], Rea and Eckberg [65], and Williamson et al. [66] suggest that external neck compression, graded carotid compression, and unilateral carotid sinus compression can be used as models for studying cervical mechano-sympathetic coupling. Henley et al. [82] confirmed in 17 healthy subjects that osteopathic manipulative treatment can produce a vagal response, as assessed by heart rate variability. The RCT by La Touche et al. [81] confirmed that upper cervical spine mobilization can produce a sympathetic excitatory response, providing RCT-level evidence for a causal association between cervical mechanical intervention and sympathetic function. Ketelhut et al. [83] further confirmed in 20 healthy men that after a nonspecific self-myofascial release intervention, peripheral diastolic blood pressure, central diastolic blood pressure, total peripheral resistance, and the root mean square of successive differences (RMSSD) all decreased, whereas heart rate increased.

The clinical evidence from Treggiari et al. [71], Bombardieri et al. [72], and Gupta et al. [73] suggests that cervical sympathetic block can serve as a human interventional approach for testing the causal direction of the hypothesis. The original study by Shenkin et al. [77] provided direct human evidence for the effect of sympathetic denervation on cerebral blood flow. Holwerda et al. [52] and Dinenno et al. [53] confirmed independent associations and causal directionality between sympathetic neural outflow and arterial wall thickness. The imaging study by Lee et al. [23] provided a tool for in vivo assessment of structural changes in the carotid sheath region. The anatomical study by Deshmukh et al. [24] provided direct evidence for the parallel relationship between the cervical sympathetic trunk and the vagus nerve within the sheath. The anatomical review by Zhang et al. [5] provided an adult reference for the fascial spaces of the neck and the location of the sympathetic trunk.

The above-mentioned literature provided supplementary evidence on cross-layer tension transmission, the spatial gradient of sheath wall thickening, multiaxial mechanics of the deep fascia, the heart-brain communication framework, the epidemiological association of the carotid body, the methodological boundaries of elastography, therapeutic intervention of the carotid body, the integrative framework of the carotid body–sympathetic axis, interlayer mechanics of the deep fascia, anatomical variations of the cervical sympathetic trunk, the large-sample reliability of shear-wave elastography, fascial-side PIEZO2 expression and sympathetic nerve fibers, experimental evidence of the metabolic axis, the GPR146-PIEZO1 upstream signaling pathway, integration of the anatomical features of the middle cervical ganglion, mechanosensory cells within the fascia, carotid-side PIEZO1 expression, a systematic review of PIEZO1 in cardiovascular diseases, and venous dilation within the sheath compressing the sympathetic trunk. However, none of these studies directly validated the core causal chain.

The RCT evidence from Simonsen et al. [87,88,89] further provided a methodological reference and a regional feasibility anchor for interventional research for clinical Prediction 1 of the hypothesis. The animal model of He et al. [58] provided direct causal evidence for the pathway from upper cervical mechanical misalignment to sympathetic activation and hypertension. The electrophysiological model of Cassaglia et al. [55] provided direct recording evidence for the pathway from an altered mechanical environment to enhanced sympathetic activity in the superior cervical ganglion. The case reported by Lee et al. [25] provided direct human clinical evidence for the pathway from cervical soft tissue scarring to compression and tethering of the sympathetic trunk. The cases reported by Okamoto et al. [18] and Farage et al. [19] provided histological and imaging evidence for fibrosis in the carotid sheath region. Langevin et al. [14] provided a methodological precedent for ultrasound quantification of pathological fascial thickening. Subsequent interventional studies can further test the effects of investing fascial release on the above clinical indicators.

8. Limitations and Evidence Boundaries

8.1. Core Evidence Gap

Currently, no animal model or human study has directly simulated sympathetic trunk compression caused by fibrotic thickening of the carotid sheath wall. Among the existing evidence chain, the compression models have targeted either the carotid sinus region [59,60], the posterior longitudinal ligament [57], chemical conduction block [54], atlantoaxial misalignment [58], or mechanical blood pressure elevation [55]. None has precisely simulated the pathological process of sheath wall fibrosis leading to local compression of the sympathetic trunk. This gap is the main evidence gap of this hypothesis, rather than an omission in the literature search. Future research should prioritize the establishment of chronic animal models in which sheath wall thickness and compression degree can be precisely controlled, and should conduct combined imaging and neuroelectrophysiological studies in patients with sheath wall fibrosis to directly validate the core causal chain of this hypothesis.

8.2. Cross-Tissue and Cross-Species Extrapolation Limitations

The systematic review by Bond et al. [1] has already pointed out that the fascial composition of the carotid sheath is contradictory and inconsistent in the literature, which means that the premise that the investing fascia participates in forming the carotid sheath wall itself still requires further confirmation. The histological evidence from Hayashi [2] further suggests that the investing fascia and the sheath wall may not be directly fused, but may instead be indirectly connected through intermediate interfaces such as the visceral fascia. Piffer [3] and Palliyalil et al. [4] confirmed the fibroelastic structure and sublayer composition of the sheath wall itself. Although the anatomical review by Zhang et al. [5] provides an accurate reference for the fascial spaces of the adult neck, it is a review article and does not address fascial thickening and mechanical changes under pathological conditions. The rabbit model of Zhao et al. [15] suggests that the carotid sheath has a three-layered fascial architecture with preferential thickening on the arterial side, but this study was performed at a developmental stage and in an animal model. The human anatomical and clinical variation data from Lyons and Mills [21], Park et al. [20], and Salazar-Orellana et al. [22] suggest that in some individuals the cervical sympathetic trunk is located within the sheath, the middle cervical ganglion is absent, or venous dilation within the sheath compresses the sympathetic trunk.

Chen et al. [6], Civelek et al. [7], and Yin et al. [8] confirmed the close attachment relationship between the cervical sympathetic trunk and the posterior wall of the carotid sheath and the alar fascia, and provided quantitative parameters and variation data. However, there is currently no quantitative standard for the degree of sheath wall thickening required to produce clinically significant sympathetic nerve compression. Although the histological studies by Stecco et al. [26], Martínez-Sanz et al. [27], Fede et al. [35], and Fede et al. [36] confirmed the multilayered collagen structure and sympathetic innervation of the deep fascia, their specimens were derived from upper limb fascia, embryonic cervical fascia, mouse fascia, and human superficial fascia, respectively. Zwirner et al. [28], Aparici-Gil et al. [29], and Bonaldi et al. [30] provided ex vivo tensile parameters of human fascia, but the specimens were temporal muscle fascia and fascia lata, respectively. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] provided methodological references for soft tissue mechanics in the cervical region, a transferable constitutive model, and multiaxial developmental data, but these were also not the investing fascia itself. Pires et al. [31] provided the mechanical pressure threshold required to reach the deep cervical fascia, but these data describe external compression. Dapper et al. [17] provided quantitative data from patients with postradiation fibrosis. Okamoto et al. [18] and Farage et al. [19] reported inflammatory pseudotumor-induced fibrosis, which differs etiologically from chronic postural or mechanical fibrosis. Creze et al. [91] confirmed in the thoracolumbar fascia that shear-wave elastography was not significantly correlated with ex vivo tensile modulus. Gao et al. [41] measured the upper trapezius. Langevin et al. [14] measured lumbar fascial thickness and echogenicity. Tereshenko et al. [37] provided PIEZO2 expression evidence from trapezius fascia in the context of occipital neuralgia. Huang et al. [38] provided CD34+ membranous cell evidence from rat abdominal fascia. Chen et al. [48] provided GPR146-PIEZO1 evidence from animal models and vascular smooth muscle cells. Park et al. [20] was a meta-analysis. Konishi et al. [49] was a small pilot study. Sun et al. [50] was a review. Salazar-Orellana et al. [22] was a single case report. Hinz [10], Gallardo et al. [11,12], and Miki and Manresa [13] provided fibrotic molecular mechanism evidence from skeletal muscle, skin, lung, and other tissues. Several studies involve species differences, including Serebryakova [56], Gu et al. [57], He et al. [58], Gallego and Geijo [54], Ding et al. [46], and Cassaglia et al. [55]. Lubelski et al. [42] involved loss of function rather than overactivation. Ying et al. [43] and West et al. [44] were case reports of two cases and one case, respectively. Lee et al. [25] was a single case report. Mills and Sampson [61] used decerebrate cats. Markman et al. [62,63] had a small human sample (five cases). Little et al. [59] and Burstyn et al. [60] used canine and rabbit chronic compression models, respectively. Liu et al. [45] was an observational cohort study. Joshi et al. [64] was an acute external compression model. Rea and Eckberg [65] and Williamson et al. [66] were acute experiments. Campón-Checkroun et al. [78] and Wallin et al. [79] confirmed blood pressure-lowering and sympathetic inhibitory effects of the carotid sinus pathway, opposite in direction to the pressor effect predicted by the hypothesis. The negative results of Ikeda et al. [80] suggest that simple cervical sympathetic trunk transection does not cause compensatory changes in renal sympathetic nerve activity. Zandi et al. [40], Liao et al. [39], and Dapper et al. [17] had small sample sizes in shear-wave elastography studies. Ainslie et al. [67] included 14 healthy men. Jordan et al. [68] included six healthy subjects. Hamner et al. [75] included 11 healthy subjects. ter Laan et al. [74] and Koep et al. [76] were reviews. Sadoshima et al. [69] and Wang et al. [70] were rat models. Treggiari et al. [71] included nine cases, and Bombardieri et al. [72] was a review. Struthoff et al. [9] examined the carotid bifurcation. Alba et al. [47] provided PIEZO expression data from the carotid sinus and carotid body, but the mechanotransduction function of these channels still requires in vivo validation. Wang et al. [51] was a review. Tan et al. [84] was a cross-sectional observation. Żera et al. [85] and Paton et al. [86] were reviews. Henley et al. [82] included 17 healthy subjects. La Touche et al. [81] used joint mobilization rather than fascial release. Ketelhut et al. [83] did not target the cervical investing fascia. McGrath and Shankar [16] was a single case report. Shenkin et al. [77] was published in 1951. Holwerda et al. [52] was a cross-sectional observation. Gupta et al. [73] included 20 cases. Lee et al. [23] had a limited sample size, and the SCSG localization success rate was only 73%. Deshmukh et al. [24] was a rat model. Lyons and Mills [21] examined 12 cadavers. Gao et al. [41] measured the upper trapezius rather than the investing fascia. Tereshenko et al. [37] had a small sample size (18 patients with occipital neuralgia and 10 controls). Järhult and Holst [90] was a 1978 cat model. Chen et al. [48] used animal models and vascular smooth muscle cells. Park et al. [20] was a meta-analysis. Huang et al. [38] used rat abdominal fascia. Konishi et al. [49] was a small pilot study. Sun et al. [50] was a review. Salazar-Orellana et al. [22] was a single case report. Hinz [10] was a review. Gallardo et al. [11,12] were animal experiments using skeletal muscle. Miki and Manresa [13] was a review. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] used cervical tissue and the cervical spine osteoligamentous complex, respectively. Simonsen et al. [87] included five cases, Bakris et al. [88] included 50 cases, and Plaugher et al. [89] included 23 cases. He et al. [58] was a rat model, and the atlantoaxial anatomy differs from that of humans. Zhang et al. [5] was a review and did not address fascial mechanical changes under pathological conditions. Cassaglia et al. [55] was a lamb model using acute mechanical blood pressure elevation rather than chronic sheath wall fibrotic compression. Lee et al. [25] was a single case report. Okamoto et al. [18] and Farage et al. [19] were single case reports with inflammatory pseudotumor pathology. Langevin et al. [14] measured the lumbar region and assessed morphology rather than mechanical stiffness.

8.3. Methodological Limitations

The above-mentioned literature provided supplementary evidence on cross-layer tension transmission, the spatial gradient of sheath wall thickening, multiaxial mechanics of the deep fascia, the heart-brain communication framework, the epidemiological association of the carotid body, the methodological boundaries of elastography, therapeutic intervention of the carotid body, the integrative framework of the carotid body–sympathetic axis, interlayer mechanics of the deep fascia, anatomical variations of the cervical sympathetic trunk, the large-sample reliability of shear-wave elastography, fascial-side PIEZO2 expression and sympathetic nerve fibers, experimental evidence of the metabolic axis, the GPR146-PIEZO1 upstream signaling pathway, integration of the anatomical features of the middle cervical ganglion, mechanosensory cells within the fascia, carotid-side PIEZO1 expression, a systematic review of PIEZO1 in cardiovascular diseases, and venous dilation within the sheath compressing the sympathetic trunk. However, none of these studies directly validated the core causal chain.

9. Conclusion

The hypothesis of sympathetic neural coupling with the investing fascia, deep cervical fascia, and carotid sheath provides an integrative framework linking the biomechanical state of the cervical fascia to neurovascular function within the carotid sheath. The anatomical evidence from Chen et al. [6] provides direct evidence for the core premise of this hypothesis—that the cervical sympathetic trunk is closely attached to the posterior aspect of the carotid sheath and adheres to the alar fascia. Civelek et al. [7] and Yin et al. [8] further provided quantitative distance and anatomical variation data for the cervical sympathetic trunk and the longus colli. Lyons and Mills [21] and Park et al. [20] suggested that in some individuals the cervical sympathetic trunk is located within the carotid sheath or the middle cervical ganglion is absent; Salazar-Orellana et al. [22] further suggested that venous dilation within the sheath can also compress the sympathetic trunk and cause sympathetic overactivity. Struthoff et al. [9] provided quantitative data on nerve density at the human carotid bifurcation. Lee et al. [23] provided in vivo 3-T MRI imaging variation data for the superior cervical sympathetic ganglion (SCSG). Deshmukh et al. [24] confirmed the anatomical relationship in which the cervical sympathetic trunk and the vagus nerve enter the carotid sheath in parallel. Using the C6 cross-section as a reference, Zhang et al. [5] provided an accurate anatomical reference for the fascial spaces of the adult neck.

The systematic review by Bond et al. [1] on the fascial composition of the carotid sheath provided a literature framework for the hypothesis to argue for the structural basis of cross-layer transmission. The original histological studies by Hayashi [2], Piffer [3], and Palliyalil et al. [4] revealed the fine composition of the sheath wall from different perspectives. Zhao et al. [15] further suggested that the carotid sheath may have a three-layered fascial architecture with preferential thickening on the arterial side. McGrath and Shankar [16] and Dapper et al. [17] provided clinical anchors for the visualization and quantification of fibrosis adjacent to the carotid sheath in living humans. The case reports by Okamoto et al. [18] and Farage et al. [19] provided histological and imaging evidence of fibrosis in the carotid sheath region.

Histological studies by Stecco et al. [26] and Martínez-Sanz et al. [27] revealed, from the perspectives of upper limb fascia and cervical fascia, respectively, the multilayered collagen fiber architecture of the deep fascia that enables tension transmission. Zwirner et al. [28], Aparici-Gil et al. [29], Bonaldi et al. [30], and Pires et al. [31] respectively provided uniaxial, multiaxial, and interlayer ex vivo tensile mechanical parameters of human fascia and the mechanical pressure threshold required to reach the deep cervical fascia. Myers et al. [32], Shi et al. [33], and Nuckley et al. [34] further provided methodological references for soft tissue mechanical modeling in the cervical region, a transferable constitutive model, and multiaxial developmental biomechanical data. Langevin et al. [14] provided a methodological precedent for ultrasound quantification of pathological fascial thickening. Fede et al. [35] and Fede et al. [36] further confirmed the presence of sympathetic nerve fibers within the deep fascia and superficial fascia. Tereshenko et al. [37] detected PIEZO2 expression and increased sympathetic nerve fibers under pathological conditions in human trapezius fascia. Huang et al. [38] found CD34+ membranous cells highly expressing PIEZO2 in rat abdominal fascia.

Hinz [10], Gallardo et al. [11,12], and Miki and Manresa [13] provided a complete framework for the cellular and molecular mechanisms of fascial fibrosis, from mechanical tension to the TGF-β/SMAD/YAP/TAZ pathway. Alba et al. [47] confirmed at the molecular level that the human carotid sinus and carotid body express PIEZO mechanosensitive channels. Chen et al. [48] further revealed the GPR146-PIEZO1 upstream signaling pathway. Konishi et al. [49] detected upregulated PIEZO1 expression in carotid plaques. Sun et al. [50] systematically integrated the role of PIEZO1 in cardiovascular diseases. Wang et al. [51] provided an integrative framework for mechanical transduction and autonomic imbalance as mediators of heart-brain comorbidities.

Serebryakova [56] confirmed the chronic structural pathological effects of mechanical compression on the cervical sympathetic trunk. Gu et al. [57] further confirmed abnormal functional discharge of the cervical sympathetic ganglion caused by chronic compression. Gallego and Geijo [54] confirmed that chronic intervention on the cervical sympathetic trunk enhances synaptic efficacy. Little et al. [59] and Burstyn et al. [60] confirmed in canine and rabbit models, respectively, that chronic mechanical compression leads to long-term blood pressure changes. He et al. [58] confirmed in a rat model that atlantoaxial misalignment causes hypertension and that blood pressure decreases after removal of the implant. Cassaglia et al. [55] confirmed in a lamb model that mechanical blood pressure elevation can directly increase sympathetic activity in the superior cervical ganglion. Liu et al. [45] confirmed in a human cohort study that decompression in the cervical sympathetic trunk region can significantly reduce office blood pressure. Lubelski et al. [42], Ying et al. [43], and West et al. [44] provided human clinical data confirming the clinical consequences of mechanical injury to the cervical sympathetic trunk. Lee et al. [25] confirmed that scarring of the cervical soft tissues compresses and tethers the cervical sympathetic trunk, causing Horner syndrome.

Mills and Sampson [61] and Markman et al. [62,63] revealed, in animals and humans, respectively, the mechanism by which cervical sympathetic activation affects blood pressure regulation through the carotid body reflex pathway and its dose-response relationship. Joshi et al. [64] provided human experimental evidence from external mechanical compression. Rea and Eckberg [65] and Williamson et al. [66] provided dose-response evidence and unilateral specificity for the relationship between carotid compression and sympathetic activation. Ainslie et al. [67], Jordan et al. [68], Hamner et al. [75], Sadoshima et al. [69], Wang et al. [70], ter Laan et al. [74], and Koep et al. [76] confirmed, from the dimensions of acute function, mechanistic separation, frequency dependence, chronic structure, molecular validation, evidence-based integration, and mechanistic specificity, respectively, the regulatory effects of the sympathetic nervous system on the cerebral circulation and its fundamental differences from the peripheral circulation. Treggiari et al. [71], Bombardieri et al. [72], and Gupta et al. [73] provided reverse validation from the clinical treatment perspective of cervical sympathetic block, showing that blocking the sympathetic nerve can improve cerebral perfusion or reduce cerebrovascular tone. Shenkin et al. [77] provided original human evidence that cerebral blood flow increases after bilateral stellate ganglionectomy. Campón-Checkroun et al. [78] and Wallin et al. [79] defined the blood pressure-lowering and sympathetic inhibitory effects of the carotid sinus pathway, separating the effects of the carotid sinus baroreceptor pathway from those of the cervical sympathetic trunk pathway. The negative results of Ikeda et al. [80] defined the boundary of the effects of cervical sympathetic trunk intervention. Zandi et al. [40], Liao et al. [39], and Dapper et al. [17] validated the shear-wave elastography methodology for quantifying cervical fascial stiffness in vivo and provided direct evidence of increased fascial stiffness in forward head posture and pathological fibrosis. Gao et al. [41] further validated in 158 adults the reliability of shear-wave elastography for assessing cervical somatic dysfunction. Creze et al. [91] suggested that shear-wave elastography measurements may lack direct correspondence with ex vivo mechanical parameters. Henley et al. [82], La Touche et al. [81], and Ketelhut et al. [83] confirmed in humans that osteopathic manipulative treatment, upper cervical mobilization, and nonspecific self-myofascial release can produce measurable autonomic regulatory effects. Holwerda et al. [52] and Dinenno et al. [53] confirmed independent associations and causal directionality between sympathetic neural outflow and arterial wall thickness. Tan et al. [84] provided human epidemiological evidence for an association between structural changes in the carotid bifurcation region and sympathetic-related diseases, and Żera et al. [85] and Paton et al. [86] further provided a framework for therapeutic intervention and the integrative mechanism of the carotid body–sympathetic axis. Järhult and Holst [90] provided direct experimental evidence for the sequence from altered mechanical environment in the carotid region to sympathetic activation and metabolic abnormalities. Chen et al. [48] provided the GPR146-PIEZO1 upstream pathway for mechanical signal amplification. Park et al. [20] provided integrated meta-analysis evidence for the anatomical features of the middle cervical ganglion. Huang et al. [38] provided a candidate cell type for mechanosensory perception within the fascia. Konishi et al. [49] provided human evidence for PIEZO1 expression on the carotid side. Sun et al. [50] provided a review framework for the systemic role of PIEZO1 in cardiovascular diseases. Salazar-Orellana et al. [22] provided clinical case evidence that venous dilation within the sheath compressing the sympathetic trunk causes sympathetic overactivity. Ding et al. [46] revealed species-specific anatomical differences that provide a key caveat for extrapolating animal models to humans.

The RCT evidence from Simonsen et al. [87,88,89] provided an interventional research basis for clinical Prediction 1 of the hypothesis, ranging from sham control to cervical mechanical intervention and methodological reference. The animal model of He et al. [58] provided direct causal evidence for the pathway from upper cervical mechanical misalignment to sympathetic activation and hypertension. The electrophysiological model of Cassaglia et al. [55] provided direct recording evidence for the pathway from changes in the mechanical environment to enhanced superior cervical ganglion activity. The case of Lee et al. [25] provided direct human clinical evidence for the pathway from cervical soft tissue scarring to compression and tethering of the sympathetic trunk. The cases of Okamoto et al. [18] and Farage et al. [19] provided histological and imaging evidence for fibrosis in the carotid sheath region. Langevin et al. [14] provided a methodological precedent for ultrasound quantification of pathological fascial thickening. Zhang et al. [5] provided an accurate reference for the fascial spaces of the adult neck and the location of the sympathetic trunk.

The above evidence collectively constitutes an evidence integration framework for this hypothesis, spanning anatomical structure, histological basis, biomechanical properties, molecular transduction, pathological experiments, physiological effects, human epidemiology, alternative mechanism controls, negative controls, and intervention validation. However, it must be pointed out that no animal model or human study has directly simulated sympathetic trunk compression caused by fibrotic thickening of the carotid sheath wall, which is the main evidence gap of this hypothesis. Future research should prioritize the establishment of chronic animal models in which sheath wall thickness and compression degree can be precisely controlled, and should conduct combined imaging and neuroelectrophysiological studies in patients with sheath wall fibrosis to directly validate the core causal chain of this hypothesis. Although the clinical significance of this hypothesis remains to be confirmed, it emphasizes the potential value of assessing cervical fascial tension in the diagnosis and treatment of certain complex diseases and provides testable predictions for future mechanistic research and clinical validation.