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. 2026 Jun 2;21:69–75. doi: 10.1016/j.ibneur.2026.05.012

Establishment of a novel rat model of chronic subdural hematoma: Recapitulating human pathological features through triple-component induction

Qiuyu Lu a,c,1, Renkun Zhang a,b,c,1, Yuhao Tan a,c,1, Yi Xu a,c, Yongwei Zhang a,c, Rui Zhao a,c, Qiang Li a,c, Pengfei Yang a,c, Jianmin Liu a,c,⁎, Qiao Zuo a,c,⁎
PMCID: PMC13273693  PMID: 42317428

Abstract

Objectives

This study aimed to develop a novel rat model of Chronic subdural hematoma (CSDH) that better recapitulates human pathophysiological mechanisms, enhancing clinical relevance for translational research.

Materials and Methods

The CSDH model was established using a triple-component system comprising allogeneic venous blood, cerebrospinal fluid (CSF), and cerebral microvascular endothelial cells (bEnd.3). Stereotaxic surgery involved subdural injection of the mixture (200 µL) via a microsyringe pump, followed by two additional injections at 72-hour intervals. Subsequently, systematic validation of the model was conducted. Data were analyzed using GraphPad Prism 9. All procedures adhered to ARRIVE guidelines and ethical approval.

Results

The CSF-blood co-culture system generated mechanically stable, heterotypically remodeled clots with ultrastructural features mirroring human CSDH membranes. The optimized CSDH model exhibited crescent-shaped subdural hematomas on MRI, temporal concordance in VEGF/Ang-2/MMP-9 expression peaks (day 14), and progressive neurological recovery, closely recapitulating clinical-pathological progression.

Conclusion

This study establishes a reproducible CSDH model combining progressive subdural injection and stereotaxic localization to recapitulate chronic hematoma dynamics, validated through quantitative morphological, inflammatory, and functional profiling, thereby providing a clinically faithful platform for mechanistic and therapeutic investigation.

Keywords: Chronic subdural hematoma, Animal model, Rat, Angiogenesis, Cerebrospinal fluid-blood interaction, Glass micropipette

1. Introduction

Chronic subdural hematoma (CSDH) is a commonly encountered neurosurgical disease. The incidence of CSDH, which is particularly prevalent among the aging population, ranges from 1.72 to 20.6 per 100,000 persons annually and continues to rise due to global population aging and expanding use of anticoagulant and antiplatelet medications (Rauhala et al., 2019, Feghali et al., 2020, Kolias et al., 2014). With advances in modern diagnostic and therapeutic modalities, the understanding of CSDH pathogenesis has evolved significantly (Poppen and Strain, 1952, Paul and Adamo, 2014, Shapiro et al., 2021). The prevailing pathophysiological model proposes that CSDH develops through a self-perpetuating cycle of hemorrhage, hyperproliferation, vascular fragility, and re-hemorrhage within the dura mater's border zone (Shapiro et al., 2021). In 2017, Ellie Edlmann demonstrated the central role of inflammatory cascades and dysregulated angiogenesis in CSDH pathogenesis (Edlmann et al., 2017). Pharmacological interventions targeting distinct nodes of this pathological cascade are undergoing active investigation as potential CSDH therapies (Qiu et al., 2017, Berghauser Pont et al., 2012, Iorio-Morin et al., 2016, Huang et al., 2020).

Consensus-based clinical guidelines for CSDH management remain undefined, while therapeutic strategies demonstrate significant heterogeneity (Almenawer et al., 2014). Although burr hole drainage remains the most common surgical approach, 10–20% of patients develop postoperative recurrence requiring reoperation (Feghali et al., 2020, Almenawer et al., 2014, Lee, 2019, Gazzeri et al., 2020). Middle meningeal artery embolization (MMAE)—a minimally invasive technique demonstrating significantly lower recurrence rates compared to surgical approaches—has emerged as a promising therapeutic innovation currently undergoing rigorous evaluation in multicenter clinical trials (Feghali et al., 2020, Ironside et al., 2021, Zuo et al., 2023, Liu et al., 2024, Fiorella et al., 2024, Davies et al., 2024).

Existing preclinical models of CSDH exhibit limitations that hinder mechanistic investigation and therapeutic development (D'Abbondanza and Macdonald, 2014). While existing models replicate certain histopathological features of human CSDH, few adequately recapitulate the chronic hemorrhagic progression characteristic of clinical disease (Quan et al., 2015, Wang et al., 2010, Xu et al., 2021). Our study aims to develop a novel rat model of CSDH that better recapitulates human pathophysiological mechanisms, enhancing clinical relevance for translational research.

2. Materials and methods

2.1. Animals and bEnd.3 cell

SPF-grade female Wistar rats (12-month-old, 500–600 g) were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd (Zhejiang, China). Animals were maintained under controlled environmental conditions with temperature regulated at 22 ± 2°C, relative humidity between 40–60%, and a 12-hour light-dark cycle. Animals were housed in standard polycarbonate cages (maximum 3 per cage) containing autoclaved corncob bedding replaced every 48 h, with free access to food and water. All experimental protocols adhered to ARRIVE guidelines and were approved by the Ethics Committee of Lingang National Laboratory (Shanghai, China). Randomization was implemented for group assignments, with data collection performed by investigators blinded to group assignments.

Mouse brain microvascular endothelial cells (bEnd.3) were obtained from the American Type Culture Collection (ATCC, CRL−2299) and preserved in liquid nitrogen tanks. The bEnd.3 cells were used because they are a well-characterized endothelial cell line with standardized quality control (Xu et al., 2021). A comparable rat brain microvascular endothelial cell line is not commercially available. Primary rat brain microvascular endothelial cells exhibit batch-to-batch variability, which would reduce model reproducibility. Cell resuscitation, culture, passage, and cryopreservation were all strictly carried out in accordance with relevant operational requirements.

2.2. Culture and characterization of bEnd.3 cells

The bEnd.3 cells (ATCC) were cultured in Dulbecco’s Modified Eagle Medium (DMEM; Gibco, USA) supplemented with 10% fetal bovine serum (FBS; Solarbio, China) and maintained under standard culture conditions (37°C, 5% CO₂). Confluent cells were harvested using 0.25% trypsin-EDTA (Sigma-Aldrich, USA), resuspended following centrifugation (1000 × g, 5 min), and subcultured at a 1:2–1:5 split ratio (Fig. 3). For phenotypic characterization, cells seeded onto 4% poly-L-lysine-coated coverslips were fixed with 4% paraformaldehyde (PFA), permeabilized with 0.5% Triton X−100, and blocked with 5% bovine serum albumin (BSA) prior to overnight incubation at 4°C with primary antibodies targeting CD31 (Novus Biologicals, #AF3628) and von Willebrand factor (VWF; Novus Biologicals, #NB600–586). Following three washes with PBS, cells were incubated with Alexa Fluor-conjugated species-matched secondary antibodies (Invitrogen, 1:500 dilution) for 30 min at room temperature (RT), and nuclei were counterstained with 4′,6-diamidino−2-phenylindole (DAPI; Abcam, 1:1000). Fluorescence images were captured using a fluorescence microscope (Olympus, Japan).

Fig. 3.

Fig. 3

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Phenotypic characterization of bEnd.3 cells. Microscopic morphology of bEnd.3 cells, showing a cobblestone-like appearance at 24 h post-culture and (B) a subconfluent state by 72 h. (C) bEnd.3 cells formed stable vascular tubes in a tube formation assay on Matrigel, confirming their angiogenic potential. (D-I) Immunofluorescence staining. bEnd.3 cells co-expressed endothelial markers (D-F) von Willebrand factor (VWF, red) and (G-I) CD31 (green). Nuclei were counterstained with (E, H) DPI (blue). (F, I) are merged images. Scale bars = 100 µm.

2.3. Triple-component preparation

Venous blood, cerebrospinal fluid (CSF), and bEnd.3 cells (ATCC) were selected as a triple-component system. Blood was collected from the orbital veins of allogeneic rats using rigid capillary glass tubes.(Fig. 1H, I) Wistar rats of the same strain were selected, and CSF was obtained via glass capillary injection into the cisterna magna cerebellomedullaris using a microinjection pump and kit under microscopic guidance.

Fig. 1.

Fig. 1

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The procedure and key components for establishing the CSDH rat model. Collection of allogeneic venous blood from the orbital veins. (B) Collection of cerebrospinal fluid (CSF) from the cisterna magna cerebellomedullaris. (C) Cultured mouse brain microvascular endothelial cells (bEnd.3). (D) Schematic diagram of the triple-component mixture (venous blood, CSF, bEnd.3 cells) injection into the subdural space via a microsyringe pump. (E) Stereotaxic coordinates for the burr hole (4 × 6 mm; centered 4 mm posterior and 5 mm lateral to bregma). (F) Stereotaxic frame and microsyringe pump apparatus used for surgery. (G) Surgical exposure of the cranial surface. (H) Glass capillaries for injection. (I) 1 mL syringe linked with a soft transparent tube and glass capillary, used for injection.

Subsequently, experiments were conducted to investigate the interaction between blood and CSF. Samples containing 1 mL of normal saline, 5% glucose solution, PBS, or CSF were prepared, and 0.2 mL of blood was added to each (Fig. 2). The CSF-blood mixture constituted the experimental group, while the other solutions served as control groups. Samples were incubated at 37°C for 24 h prior to observation. Upon formation of a blood clot-like structure, gross morphological examination was performed, followed by isolation of the structural envelope for ultrastructural analysis via scanning and transmission electron microscopy.

Fig. 2.

Fig. 2

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In vitro interaction between blood and cerebrospinal fluid (CSF). 0.2 mL of blood was added to tubes containing 1 mL of 0.9% NaCl, 5% glucose solution (GS), PBS, or CSF, respectively, and incubated at 37°C for 24 h. The CSF group (far right) formed self-supporting clot-like structures. (B) Gross morphology of the clot formed from the CSF-blood mixture, showing it retained morphological integrity after mechanical perturbation (incision). (C, D) Scanning electron microscopy (SEM) images of the clot's encapsulating membrane, revealing (C) a porous matrix architecture and (D) a highly crosslinked collagen fiber network. Scale bars: (C) 50 µm; (D) 2.5 µm. (E, F) Transmission electron microscopy (TEM) images of the encapsulating membrane, showing (E) erythrocyte-derived deformable bodies and (F) lipid-like vesicles embedded within the matrix. Scale bars: (E) 1 µm; (F) 500 nm.

2.4. CSDH model

The surgical protocol for establishing the experimental model was depicted in Fig. 1. Briefly, anesthesia was induced by placing rats in an induction chamber with 5% isoflurane (RWD Life Science, Shenzhen, China) for 1 min until loss of reflex responsiveness. Anesthetized rats were transferred to a stereotaxic frame (RWD Life Science, Fig. 1F) under 2% isoflurane maintenance, with body temperature regulated at 38°C via a rectal probe-linked heating pad.

Following stereotaxic fixation of the head in a neutral position, the surgical field was depilated and disinfected with 10% povidone-iodine. Ophthalmic lubricant and tinfoil were applied to protect the eyes from intraoperative light exposure. A midline scalp incision (∼1.5 cm) was made to expose the skull, followed by blunt dissection of subcutaneous tissues to reveal the cranial surface (Fig. 1G).

A burr hole (4 × 6 mm; centered at −4 posterior, −5 lateral to bregma) was drilled using a stereotaxically mounted cranial drill (RWD Life Science, Fig. 1E). After dural puncture with a 0.2-mm glass capillary, a 200 μL mixture of venous blood (150 μL) and cerebrospinal fluid containing 1 × 10⁶ bEnd.3 cells (50 μL) were injected into the subdural space at 20 μL/min via a microsyringe pump (RWD Life Science,Fig. 1A ∼ D). The needle was retained for 10 min post-injection to minimize backflow. The burr hole was sealed with bone wax (Sanhe Sanyou Medical Instrument Factory, China), and the incision was closed with surgical adhesive. Two additional injections (200 μL each) were delivered at 72-hour intervals under identical conditions. Sham-operated rats underwent craniotomy without injection. All procedures adhered to strict aseptic protocols.

2.5. Systematic validation of CSDH model

2.5.1. Macropathological and histopathological evaluation

To evaluate macropathological features, rats were transcardially perfused 24 h after the third injection, followed by cranial bone removal to observe hematoma morphology. Brains were harvested and sectioned coronally for hematoxylin-eosin (HE) staining to localize the hematoma depth for histopathological analysis (Fig. 3).

2.5.2. Neuroimaging and hematoma quantification

At 1, 7, 14, and 21 days post-modeling, hematoma progression was monitored via 9.4 T MRI (Bruker BioSpin, Germany). Hematoma volume was quantified using MRI segmentation and spectrophotometric hemoglobin content measurements (Fig. 4).

Fig. 4.

Fig. 4

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Macropathological, histopathological, and neuroimaging validation of the CSDH model. 24 h after the third injection, craniectomy revealed a fan-shaped subdural hematoma over the ipsilateral hemisphere, while the contralateral hemisphere showed intact dura mater. (B) Gross coronal sections of the fixed brain. The ipsilateral hemisphere shows a well-demarcated subdural hematoma, whereas the contralateral hemisphere retains normal neuroanatomy. (C) H&E staining confirmed the subdural localization of the hematoma without parenchymal invasion or significant edema. Top: Contralateral; Bottom: Ipsilateral. (D-G) 9.4 T MRI T2-weighted coronal images on post-modeling days 1, 7, 14, and 21. MRI shows (D) a crescent-shaped hematoma, which (E-G) progressively resolved over time, though residual hematoma persisted at 21 days.

2.5.3. Molecular and functional assessments

Angiogenesis-related proteins (VEGF, Ang−2, MMP−9) were analyzed by Western blot (WB) using standard protocols (Fig. 5A, B). Neurological and cognitive functions were assessed on days 1, 7, 14, and 21 post-modeling via the modified Neurological Severity Score (mNSS) and Foot-fault motor performance tests (Fig. 5C, D). Detailed protocols are provided in the Supplemental materials.

Fig. 5.

Fig. 5

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Molecular and functional assessments of the CSDH model. Western blot (WB) analysis and (B) quantification of angiogenesis-related proteins (VEGF, Ang−2, and MMP−9) in the hematoma capsule at 7, 14, and 21 days post-modeling. Protein levels in the CSDH group showed a time-dependent increase compared to the Sham group, peaking at day 14. (C) Modified Neurological Severity Score (mNSS) assessment. mNSS scores were significantly elevated in the CSDH group versus Sham at all timepoints, with progressive improvement over time. (D) Foot-fault motor performance test. The CSDH group exhibited persistent motor deficits, with gradual functional recovery observed over time. (B, C, D) Data are expressed as mean ± SD. **** P < 0.0001, CSDH group vs. Sham group.

2.6. Statistical analysis

All experimental data were analyzed and visualized using GraphPad Prism 9 (GraphPad Software, USA), with results expressed as mean ± standard deviation (SD). Intergroup comparisons were performed using an independent Student’s t-test for normally distributed data or the Mann-Whitney U test for nonparametric data; one-way ANOVA with Tukey’s post hoc test was applied for multigroup comparisons. Statistical significance was defined as P < 0.05.

3. Results

3.1. Rat CSF collection

The stereotaxic apparatus-based CSF collection protocol achieved a 100% procedural success rate without mortality. Using glass micropipettes coupled with a microinjection pump, CSF samples were consistently harvested (single-sample volume: 150 μL), with an operator-induced mortality rate of 0%.

3.2. In vitro blood-CSF interaction experiments

The experimental group (CSF-blood) exhibited marked heterotypic remodeling: unlike the stable sedimentation observed in controls, self-supporting clot-like structures with autonomous stability formed in the experimental group (Fig. 2A). Following mechanical perturbation (oscillation or blade incision), these structures retained morphological integrity, indicating the presence of a mechanically stable encapsulating membrane (Fig. 2B). Ultrastructural analysis revealed that the encapsulating membrane comprised a porous matrix architecture (Fig. 2C), predominantly composed of a highly crosslinked collagen fiber network under scanning electron microscopy (Fig. 2D). Transmission electron microscopy further identified erythrocyte-derived deformable bodies and lipid-like vesicles embedded within the matrix (Fig. 2E, F).

3.3. Phenotype validation of bEnd.3 cells

Cobblestone-like morphology was observed at 24 h post-culture (Fig. 3A), progressing to a subconfluent state by 72 h (Fig. 3B). In a low-growth-factor Matrigel system, these cells formed stable vascular tubes in a tube formation assay, confirming their angiogenic potential (Fig. 3C). Dual immunofluorescence labeling demonstrated 100% co-expression of CD31 and VWF, consistent with the canonical endothelial phenotype(Fig. 3D ∼ I).

3.4. Systematic validation of the CSDH animal model

3.4.1. Macropathological and histopathological evaluation

At 24 h post-modeling, craniectomy revealed a subdural hematoma on the ipsilateral hemisphere, displaying a fan-shaped distribution across the cortical surface and mimicking human CSDH morphology, while the contralateral hemisphere showed intact dura mater and no hematoma (Fig. 4A). After 24 h fixation in 4% paraformaldehyde, the ipsilateral hemisphere exhibited a well-demarcated subdural hematoma with preserved dura mater, whereas the contralateral hemisphere retained normal neuroanatomy (Fig. 4B). H&E staining confirmed the hematoma’s subdural localization without parenchymal invasion, cortical contusion, or significant edema (Fig. 4C).

3.4.2. Neuroimaging and hematoma quantification

At 24 h post-modeling, MRI confirmed hematoma localization between the skull and cerebral cortex, exhibiting a crescent-shaped morphology with heterogeneous signal intensity and predominantly moderate hyperintensity (Fig. 4D). Longitudinal MRI revealed progressive hematoma resolution; however, residual hematoma persisted at 21 days post-modeling, with complete absorption requiring over 3 weeks (Fig. 4E ∼ G).

3.4.3. Molecular and functional assessments

Western blot analysis of the hematoma capsule assessed temporal changes in angiogenesis-related factors (VEGF, Ang−2, and MMP−9) at postoperative intervals of 7, 14, and 21 days. Compared to the Sham group, VEGF, Ang−2, and MMP−9 protein levels in the CSDH group exhibited a time-dependent increase, peaking at day 14, followed by a decline at day 21 (Fig. 5A, B)—a trend paralleling hematoma resolution observed via MRI. mNSS were significantly elevated in the CSDH group versus Sham at all timepoints (p < 0.05), with progressive improvement in neurological function over time (Fig. 5C). Foot-fault assay results indicated persistent motor deficits in the CSDH group, while temporal assessment revealed gradual functional recovery (Fig. 5D).

4. Discussion

Current research on chronic subdural hematoma (CSDH) focuses predominantly on clinical investigations, including technical innovations, novel therapeutic strategies, risk factor profiling, and biomarker identification. However, preclinical studies utilizing CSDH animal models remain limited. Existing CSDH animal models encompass blood-injection models, clot-placement models, vascular avulsion models, and spontaneous hematoma models (Goodell and Mealey, 1963, Watanabe et al., 1972, Aikawa and Suzuki, 1987). Nevertheless, these models exhibit inherent limitations that hinder their translational applicability and academic consensus.

Large-animal models (e.g., nonhuman primates, canines) demonstrate partial recapitulation of human pathophysiology but face critical constraints, including high costs, technical complexity, and poor reproducibility, limiting their utility for large-scale studies. In contrast, murine models (rats/mice) offer procedural simplicity, cost-effectiveness, and genomic homology to humans, rendering them superior for large-scale investigations into CSDH pathophysiology and drug screening. Earlier murine models were constrained by methodological limitations, such as crude surgical techniques and elevated mortality rates, compromising their reliability. Furthermore, single-injection protocols failed to replicate the chronic hematoma expansion dynamics characteristic of human CSDH, resulting in suboptimal pathophysiological fidelity.

Quan et al. (2015) pioneered a rat CSDH model involving two sequential autologous blood injections via a cranial burr hole at 72-hour intervals, using an intravenous catheter (Quan et al., 2015). This model achieved hematoma persistence beyond 3 weeks and validated the critical roles of angiogenesis and inflammatory cascades in CSDH pathogenesis. Subsequently, Xu et al. (2021) established a rat CSDH model by subdurally administering a Matrigel-bEnd.3 cell mixture, demonstrating progressive hemorrhage akin to human CSDH (Xu et al., 2021). These models marked substantial improvements over prior methodologies in mimicking key pathological features of human CSDH. Despite these advances, critical limitations persist. In rodent models, the limited cranial cavity volume and reliance on burr hole-based injections result in failure to reliably differentiate the dura mater from adjacent tissues, compromising subdural localization accuracy and risking iatrogenic parenchymal injury. Moreover, the relatively large diameter of intravenous catheters predisposes to blood leakage during injection, undermining inter-model homogeneity. Furthermore, exclusive use of Matrigel-bEnd.3 cell mixtures, excluding blood components, fails to recapitulate the hematoma fluid-dominated pathophysiology of clinical CSDH.

Sağıroğlu et al. (2024) recently reported a rat CSDH model using two autologous blood injections and tested the efficacy of bevacizumab, an anti-VEGF antibody (Sağıroğlu et al., 2024). They found that bevacizumab was effective and well tolerated, with efficacy comparable to dexamethasone plus atorvastatin, while avoiding the weight loss associated with the latter. Their findings support the role of VEGF in CSDH progression and are consistent with the VEGF upregulation observed in our model. Compared with the two-injection blood-only approach used by Sağıroğlu et al., our triple-component system incorporates CSF and endothelial cells to more closely approximate the multicomponent nature of human hematoma fluid.

Building upon these insights, our optimized rat CSDH model incorporates a tripartite injectate comprising whole blood, cerebrospinal fluid, and cerebral microvascular endothelial cells, administered subdurally to emulate the multicomponent nature of human hematoma fluid. A glass micropipette-based injection technique, coupled with a 7-day modeling protocol, enables precise, gradual hematoma expansion mirroring the chronic progression of human CSDH. This standardized methodology ensures anatomical precision and reproducibility, with hematomas exhibiting characteristic crescent-shaped morphology, sustained persistence (>3 weeks), and upregulated pro-angiogenic factor expression—key hallmarks of clinical CSDH. Collectively, this model provides a robust platform for mechanistic and therapeutic investigations of CSDH.

This model has limitations that warrant further investigation. The 21-day observation window precludes full recapitulation of the multi-month chronic phase characteristic of human CSDH, necessitating extended follow-up studies beyond 8 weeks. Furthermore, the molecular mechanisms underlying CSF-mediated hematoma expansion remain unresolved; future work integrating proteomic profiling could elucidate key regulators such as TGF-β or fibrinolytic enzymes. Additionally, while the model effectively captures the acute-to-chronic transition of CSDH, it does not fully replicate long-term hematoma resolution dynamics observed clinically.Another limitation is the use of mouse-derived bEnd.3 cells in a rat model. The bEnd.3 cells were chosen because no validated rat cerebral endothelial cell line is commercially available, and primary rat cells lack standardization. Xu et al. (2021) also used bEnd.3 cells in a rat CSDH model and confirmed their angiogenic function in the subdural space despite the species mismatch (Xu et al., 2021).

5. Conclusion

The CSDH model established in this study employs a progressive injection protocol to replicate the chronic expansion dynamics of subdural hematomas, combined with a stereotaxically guided subdural localization method to ensure anatomical precision. A quantitative evaluation framework was developed to assess hematoma progression, inflammatory responses, and functional deficits. Morphological, histological, and behavioral features of the model align with clinical observations of human CSDH, including hematoma architecture, inflammatory cells infiltration, and sensorimotor impairment. This methodology provides a reproducible platform for investigating CSDH pathophysiology and screening potential therapeutics.

Funding

This research was funded by Natural Science Foundation of Shanghai Municipality, grant number: 25ZR1401398; by the "Changfeng" Talent Program of Changhai Hospital grant number: 2024-1; and by the "GuHai" Program of Changhai Hospital, grant number: H145-05.

CRediT authorship contribution statement

Jianmin Liu: Writing – review & editing. Pengfei Yang: Writing – review & editing. Qiao Zuo: Writing – review & editing, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Yongwei Zhang: Writing – review & editing. Yi Xu: Writing – review & editing. Qiang Li: Writing – review & editing. Rui Zhao: Writing – review & editing. Qiuyu Lu: Writing – review & editing, Writing – original draft, Visualization, Validation, Data curation. Yuhao Tan: Writing – original draft, Formal analysis, Data curation. Renkun Zhang: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Appendix A

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.ibneur.2026.05.012.

Contributor Information

Jianmin Liu, Email: liu118@vip.163.com.

Qiao Zuo, Email: dr_zuo@126.com.

Appendix A. Supplementary material

Supplementary material

mmc1.docx (22.3KB, docx)

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