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. 2026 Jun 8;21:152–161. doi: 10.1016/j.ibneur.2026.06.005

Traditional Chinese Manual Therapy (Tuina) relieves neuropathic pain by regulating neuroplasticity: A resting-state functional magnetic resonance imaging study

Zhiwei Wu a,1, Suhong Zhao b,1, Guangxin Guo c,1, Xin Zhou b, Xinrong Li c, Yunyi Li c, Lingjun Kong b,⁎, Qingguang Zhu d,⁎, Min Fang b,⁎
PMCID: PMC13316183  PMID: 42381889

Abstract

To determine how traditional Chinese manual therapy (Tuina) alleviates neuropathic pain (NPP) via central neuroplasticity. NPP was induced by chronic compression of the dorsal root ganglion (CCD) in male rats. From post-operative day 4 to day 28, Tuina (5 N, 2 Hz, 10 min/day) was applied at Weizhong acupoint (BL40). Behavioural tests (mechanical withdrawal threshold, MWT; paw withdrawal thermal latency, PWL) were performed on 2 and 1 day before CCD surgery and post-operative day 3, 7, 14, 21 and 28. Resting-state functional MRI was performed before CCD surgery and on postoperative days 7 and 28. CCD surgery induced persistent mechanical and thermal allodynia. Tuina reversed these deficits from day 14 onward. Compared with Sham group, the CCD group exhibited elevated regional homogeneity (ReHo) in the hippocampus, amygdala, brainstem and cerebellum. Tuina further increased ReHo in the amygdala, hippocampus, corpus callosum and temporal lobe between days 7 and 28. ReHo values in pain-related regions negatively correlated with MWT and PWL. Tuina may gradually relieve neuropathic pain by reshaping limbic and sensory-motor networks, offering a neuroplasticity-based rationale for its clinical use.

Keywords: Brain plasticity, Neuropathic pain, Traditional Chinese manual therapy (Tuina), Functional magnetic resonance imaging, Regional homogeneity

1. Introduction

Neuropathic pain (NPP) represents an aberrant pain sensation resulting from injury to the nervous system (Colloca et al., 2017). The etiology may be a direct injury of the nerve, spinal cord, or brain, or it can be a result of underlying conditions such as diabetes, herpes zoster, radiation, and chemotherapy (Alles and Smith, 2018). The pain sensations experienced by patients are commonly described as firing, burning, stinging, stabbing, numbness, or throbbing (Finnerup, Kuner, and Jensen, 2021). These sensations are accompanied by reduced sensitivity in the affected area (Rosner et al., 2023). Epidemiological studies have reported substantial geographic variation in NPP prevalence. In the United States, NPP prevalence is approximately 10–20%, with the majority being middle-aged, elderly, and female (Van Hecke et al., 2014, Boehnke et al., 2016). In Europe, the prevalence of NPP ranges from 6.9% to 8.2% with a long course and inadequate treatment and has caused serious social and family economic burden (Bouhassira et al., 2008). A cross-sectional study in China shows that the prevalence of NPP in diabetes patients is as high as 67.6% (Wang et al., 2023). Beyond physical disorders, NPP can additionally be a risk factor for sleep diseases, anxiety, depression, and suicide, significantly impacting the overall quality of life (Petrosky et al., 2018). At present, the main NPP therapeutic strategies include pharmacotherapy, neurostimulation techniques, and stem cell therapy, in which pharmacotherapy is most commonly used (Cohen and Mao, 2014). Nevertheless, the precise molecular mechanisms involved in NPP remain incompletely elucidated, thereby contributing to the limited effectiveness of existing therapeutic interventions. In addition, several studies have demonstrated that drugs are not adequately effective and can have harmful effects (Finnerup et al., 2015, Finnerup et al., 2018, Meacham et al., 2017). Conversely, Traditional Chinese non-pharmacological therapies may provide pain relief with relatively few adverse effects.

Traditional chinese manual therapy (Tuina), a conventional Chinese technique of manual manipulation, has been employed for pain management in China for millennia. Clinical and preclinical studies suggest that Tuina can alleviate several types of pain, particularly spine-related pain. Tuina incorporates a variety of methods, such as kneading, rubbing, and pressing, to meticulously work on different body parts (Field, 2016). Tuina has been clinically elucidated to be effective in managing distinct pain types (Dabbour et al., 2018, Dhanani et al., 2011). A Chinese survey reported that 66.8% of those suffering from chronic pain opted for either Tuina or cupping as treatment methods (Yongjun et al., 2020). Increasing research highlights the significant impact of Tuina on pain management, especially for spinal-related discomfort (Dhanani et al., 2011, Dabbour et al., 2018). In China, Tuina is a prevalent approach for spinal diseases (Cheng et al., 2022), which can efficiently alleviate pain symptoms in patients having cervical spondylosis and lumbar disc herniation accompanied by nerve root compression (Cao et al., 2022). Tuina's analgesic mechanism primarily involves the suppression of peripheral inflammation through the regulation of the TLR4 pathway and miRNA, the modulation of ion channels (e.g., P2X3 and piezo channels), the inhibition of glial cell activation, and the adjustment of brain functional changes (Liu et al., 2022). Due to its effectiveness, economic efficiency, simplicity in application, and the absence of toxic side effects, Tuina has gained increasing recognition and use in medical practices (Field, 2016) and is poised to offer greater benefits to patients of pain as a viable alternative treatment.

As a non-invasive neuroimaging technique, functional magnetic resonance imaging (fMRI) detects blood oxygen level-dependent signals and provides insight into pain-related brain activity. This approach provides a nuanced insight into the characteristics of pain, paving the way for the development of more efficient pain management therapies. Beyond merely measuring the amplitude of low-frequency fluctuations (ALFF) in cerebral activity, fMRI offers a window into the local regional homogeneity (ReHo) of brain function. ReHo encapsulates the synchrony of neural operations within distinct cerebral areas, shedding light on the orchestration of neuronal dynamics in these zones. Crucially, ReHo analysis in select brain regions is vital for deciphering the neural underpinnings linked to pain perception (Zhang et al., 2023, Zhang et al., 2021). Notably, some investigations have observed alterations in ReHo metrics within pain-associated neural regions during nociceptive stimuli, suggesting a shift towards either heightened coordination or desynchronization of neural processes under painful conditions (Chen et al., 2018, Ma et al., 2022, Yang et al., 2022). ReHo has emerged as a widely accepted metric for evaluating the extent of coherent neuronal activity in brain areas implicated in pain processing.

To extend our previous ALFF findings, we investigated ReHo alterations in pain-related brain regions and examined their associations with behavioral pain severity in CCD rats receiving Tuina. Building upon our previous research, where ALFF was used to initially probe into Tuina's brain remodeling effects in neuropathic rats, we recognized the need to delve further into the role of ReHo in this context (Wu et al., 2023). Therefore, we designed this rigorous investigation to examine how Tuina modulates pain-related brain regions in neuropathic rats and to test the association between regional ReHo and pain severity, aiming to advance mechanism-based strategies for NPP management.

2. Materials and methods

2.1. Animals

Thirty specific pathogen-free male Sprague-Dawley rats (7–8 weeks; 180–200 g) were procured from Shanghai Jihui Experimental Animal Breeding Co., Ltd. (license No. SCXK (Hu) 2017–0012) and raised under a 12-hour light/dark cycle, 22–23°C with 40% humidity. Animals were randomly allocated to sham operation (Sham, N = 10), chronic compression of the dorsal root ganglion (CCD, N = 10), or Tuina groups (Tuina, N = 10) using the Excel RAND function without replacement. Sequentially numbered, opaque envelopes containing the assignments were prepared by an independent technician who had no role in surgery or behavioural testing. The envelope was opened immediately before anaesthesia induction, keeping surgeons blind to group identity. Post-surgery, cages were labelled only with numeric codes. All behavioural testing, MRI acquisition, and data analyses were performed by investigators unaware of group assignment. The Yueyang Hospital Ethics Committee authorized the experimental procedures on October 18, 2022 (YYLAC−2022–148–5). All procedures complied with institutional guidelines and the ARRIVE guidelines. One rat in each of the Sham and CCD groups died during the experiment, so these two animals were excluded. The rest of all animals were included in all experimental procedures and data analysis.

2.2. Surgery of CCD

Rats of the CCD group and Tuina group underwent surgery for CCD when satisfactory anesthesia (40 mg/kg intraperitoneal pentobarbital sodium) was maintained. The CCD model was established as previously described, involving the insertion of a titanium alloy rod of 5 mm in length and 0.4 mm in diameter into the right intervertebral foramen of L3/4 and L4/5 (Yao et al., 2022). The Sham group rats had a skin incision and muscle separation procedure but did not have an L-type rod inserted (Fig. 1B-C).

Fig. 1.

Fig. 1

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Experimental procedure. Study design. (B) Coronal view of X-ray imaging in CCD rat model. (C) Location of L-shaped stainless-steel rods and the right intervertebral foramen in the CCD rat model. CCD: chronic compression of the dorsal root ganglion group.

2.3. Tuina treatment

Tuina was administered from post-operative day 4–28. Prior to the intervention, all rats were habituated to a custom fixator for 10 min daily on days 1–3 (Fig. 1A). During each 10-min session, the experimenter (the same individual throughout the study) applied thumb pressure and circular rubbing to the right Weizhong (BL40) along the longitudinal axis of the hindlimb. Force and rhythm were standardised at 5 ± 0.5 N and 2 Hz, respectively, using a tactile pressure recorder (Novel Pliance-X 32 Expert, Germany); these parameters were adopted from our earlier pilot work (Wu et al., 2023). To minimise bias, the Tuina operator did not participate in behavioural testing or data analysis, and both the behavioural evaluator and MRI analyst were blinded to group allocation. The pressure was applied perpendicular to the skin surface at BL40, while circular rubbing was performed along the longitudinal axis of the hindlimb from proximal to distal and then returned to the starting point in each cycle. Thus, the intervention parameters included force magnitude, stimulation frequency, point of action, and direction.

2.4. Behavioral tests

Behavioral tests were performed on 2 and 1 days before surgery and on postoperative days 3, 7, 14, 21, and 28 after surgery (Fig. 1A). The average of the two preoperative measurements was used as baseline. The rats were separately housed in Plexiglas cages from the 5th to the 3rd day before surgery for 2 h and at every time of behavioral test after surgery for 30 min to ensure acclimation. As was earlier mentioned, the middle region of the right hind paw was stimulated, and any response, such as paw withdrawal, flinching, or licking, was regarded as positive behavior (He et al. 2019).

Herein, we assessed mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWL) through an electric Von-Frey esthesiometer (Stoelting Co., Wood Dale, IL, USA) and a radiant heat device (IITC Life Science, Woodland Hills, CA, USA) (Zhang et al., 2021, Hargreaves et al., 1988). Five simultaneous stimulations were applied. The mean values of the middle three data points were used to represent the MWT and PWL measurements, with each value being recorded. All behavior tasks were completed by an experimenter blinded to groups.

2.5. Magnetic resonance imaging data acquisition

fMRI was meticulously conducted using a high-field Bruker 11.7 T MRI system (BioSpec 117/16 USR-TT) containing a wide 16.0 cm aperture alongside a robust 12 cm gradient coil at the Institute of Science and Technology for Brain-Inspired Intelligence of Fudan University. To capture comprehensive data, imaging was performed prior to the surgical procedure and subsequently on the 7th and 28th days post-operation. The radio frequency (RF) coil system comprises a 72 mm inner diameter volumetric coil (Bruker, Germany) serving as the excitation coil. In tandem, a four-channel surface coil was utilized for signal reception to ensure high-fidelity data acquisition. All rats were immobilized in a supine position in the scanner after induction with 4% isoflurane anesthesia (RWD Life Science Co., Ltd., Shenzhen, China), with the head fixed to a specific coil. The administration of dexmedetomidine hydrochloride (Sigma Aldrich, St. Louis, MO, USA) was used to maintain a continuous state of anesthesia, details were as previously described (Paasonen et al., 2018). The rectal temperature was maintained at 36–38 °C with an automatic heating pad. All experimental processes were conducted under ventilator support and respiratory monitoring. The adjustment of the scanning parameters was: matrix size = 128 × 128, the field of view = 30 × 30 mm, repetition time = 2000 ms, echo time = 12.8 ms, flip angle = 90°, slice thickness = 0.5 mm, mean value = 1. The experimenter was blinded to groups.

2.6. Regional homogeneity data preprocessing

Statistical Parametric Mapping 12 (SPM 12) toolbox (https://www.fil.ion.ucl.ac.uk/spm/software/spm12), a brain imaging data processing and analysis software relying upon the MATLAB 2017a platform (MathWorks, Natick, MA, USA), was used for fMRI data preprocessing. The implementation process was as follows: (1) DICOM-to-NIfTI conversion; (2) slice-timing correction; (3) realignment to the first volume to correct head motion (6-parameter rigid-body); (4) co-registration of the mean functional image to the T1-weighted structural image, followed by segmentation and nonlinear spatial normalisation to the MNI152 template (two-step procedure); (5) resampling to 3 mm isotropic voxels; (6) spatial smoothing was applied using 27 voxel smoothing kernels (6 mm) to minimize the impacts of low-frequency linear drive as well as high-frequency physical smoothing besides noise.

2.7. Regional homogeneity calculation

ReHo maps were generated as follows: after slice-timing and realignment, nuisance covariates—white-matter and cerebrospinal-fluid signals, plus six motion parameters—were regressed out. Data were then band-pass filtered at 0.01–0.08 Hz to retain low-frequency fluctuations (Lv et al., 2025). The Kendall coefficient of concordance (KCC) was calculated for each voxel using a 27-voxel cubic neighborhood. Spatial smoothing was achieved using 27 voxel smoothing kernels (6 mm), mitigating the impact of deformation and noise during standardization. Subsequently, the Fisher z transform was applied, followed by a normalization procedure using mean division. This process culminated in the generation of the final ReHo brain map suitable for statistical analysis.

2.8. Statistical analysis

Our study deployed SPSS 21.0 (IBM Inc., Chicago, IL, USA) for the statistical analysis of behavioral data and the correlation between ReHo values and behavioral tests, expressing the behavioral data as mean ± standard error of the mean (SEM). The normality of data will be tested by the Kolmogorov-Smirnov test. If the data does not conform to a normal distribution, a covariance analysis will be used. The study examined the differences in MWT and PWL data among the groups at different time periods using a two-way repeated measures analysis of variance (ANOVA) alongside the Bonferroni post hoc test for pairwise multiple comparisons. The ReHo values across the groups were compared using a two-sample t-test in SPM.12 software, which was implemented in MATLAB 2017a [p < 0.001 Gaussian random field (GRF), GRF corrected, voxel-p < 0.001, cluster-p < 0.05, two-tailed (Yan et al. 2016)]. GRF correction was used to control family-wise error in voxel-wise whole-brain comparisons while accounting for spatial smoothness. The Spearman correlation coefficients between ReHo values and behavioral tests were computed through SPSS 21.0 (IBM Inc., Chicago, IL, USA). P < 0.05 indicated a statistical significance. The statistician was blinded to groups.

3. Results

3.1. Tuina ameliorates mechanical and thermal pain in CCD-triggered NPP Rats

At baseline, the findings indicated no significant differences in MWT and PWL among the three groups (p > 0.05). Post-CCD surgery, the MWT and PWL of ipsilateral hind paws of rats in the CCD and Tuina groups exhibited significant reduction on day 7 in comparison to the Sham group (p < 0.001), implying that CCD provoked a prominent mechanical and thermal allodynia. The hyperalgesia caused by CCD persisted until day 28. Tuina caused a significant elevation in the MWT and PWL from days 14–28 in comparison to the CCD group (overall p < 0.05). Altogether, Tuina alleviated the mechanical and thermal allodynia in the CCD model. The results are detailed in our previously published article (Wu et al. 2023).

3.2. CCD and Sham groups differences in ReHo values on day 28 post-surgery

Compared with sham rats, CCD rats exhibited markedly elevated ReHo bilaterally in the amygdalo-hippocampic complex (amygdala, hippocampal CA1/CA3, dentate gyrus), parasubiculum, ectorhinal cortex, and cerebellar granule and molecular layers, together with increased ReHo in the brainstem (p < 0.05, GRF-corrected; Table 1 and Fig. 2). These regions, rather than the sheer number of clusters, may be the principal sites of altered local synchrony in chronic NPP.

Table 1.

Brain regions showing ReHo differences between the CCD group and sham group 28 days after surgery.

Brain regions No. of
voxels 		Peak
t-value 		MNI coordinates (mm)
x y z
CCD > Sham L_Amygdalohyppocampic_Area 21 −7.632 −60 −72 0
R_Amygdalohyppocampic_Area 22 −7.367 63 72 −3
L_Amygdalopiriform_Cortex 48 −4.819 −75 −54 −12
R_Amygdalopiriform_Cortex 78 −6.491 72 −48 −15
L_Cornu_Ammonis_1 44 −7.015 −57 −63 6
R_Cornu_Ammonis_1 48 −8.077 63 −57 −3
L_Cornu_Ammonis_3 7 −4.851 −42 −54 0
R_Cornu_Ammonis_3 7 −4.982 42 54 0
L_Dentate_Gyrus 110 −8.126 −51 −63 3
R_Dentate_Gyrus 139 −7.275 48 −66 6
L_Ectorhinal_Cortex 22 −6.202 −78 −57 −3
R_Ectorhinal_Cortex 39 −6.836 72 −54 0
L_Granule_Cell_Level_of_the_
Cerebellum		 264 −8.076 −60 −114 −12
R_Granule_Cell_Level_of_the_
Cerebellum		 274 −6.394 60 −120 −15
L_Molecular_Layer_of_the_
Cerebellum		 142 −8.126 −63 −114 −9
R_Molecular_Layer_of_the_
Cerebellum		 211 −5.097 66 −120 −9
L_Parasubiculum 29 −8.041 −51 −66 3
R_Parasubiculum 31 −7.395 48 −66 3
L_Brainstem 107 −6.005 −39 −93 −24
R_Brainstem 127 −3.987 36 −99 −24
L_Amygdalohyppocampic_Area 37 −7.632 −60 −72 0
R_Amygdalohyppocampic_Area 19 −7.367 63 72 −3
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A one-way ANOVA with Bonferroni correction was used to identify significant voxels. The voxel-p value was set at 0.001, and the cluster-p was set at 0.05. All tests were two-tailed. The corresponding t-value was then determined by the p values. x, y, z: coordinates of the position of the primary peak in MNI space; ReHo: regional homogeneity; CCD: chronic compression of the dorsal root ganglion; L: left; R: right.

Fig. 2.

Fig. 2

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ReHo maps in rats between the CCD group and Sham group 28 days after surgery. The cold tone represents areas where ReHo values of the Sham group lower than those of the CCD group at 28 days after surgery. The numbers in the figure are the coordinates of the Z-axis in standard space. The one-way ANOVA was performed with Bonferroni correction (Voxel-p < 0.001, Cluster-p < 0.05, Two-tailed). ReHo: regional homogeneity; CCD: chronic compression of the dorsal root ganglion; L: left; R: right.

3.3. Tuina and Sham groups differences in ReHo values on day 28 post-surgery

Tuina produced the limbic-hippocampal and cerebellar increases, plus additional rises in the corpus callosum and descending corticofugal tracts (p < 0.005, GRF-corrected; Table 2 and Fig. 3).

Table 2.

Brain regions showing ReHo differences between the Tuina group and sham group 28 days after surgery.

Brain regions No. of
voxels 		Peak
t-value 		MNI coordinates (mm)
x y z
Tuina > Sham L_Amygdalohyppocampic_Area 21 −7.125 −60 −72 0
R_Amygdalohyppocampic_Area 19 −6.863 63 −72 −3
L_Amygdalopiriform_Cortex 75 −5.256 −75 −54 −12
R_Amygdalopiriform_Cortex 83 −6.095 72 −48 −15
L_Cornu_Ammonis_1 49 −6.918 −63 −57 −6
R_Cornu_Ammonis_1 44 −7.748 63 −57 −15
L_Cornu_Ammonis_3 6 −4.500 −42 −54 0
R_Cornu_Ammonis_3 6 −4.519 48 −54 0
L_Dentate_Gyrus 120 −7.941 −51 −63 3
R_Dentate_Gyrus 157 −7.183 48 −66 6
L_Ectorhinal_Cortex 29 −5.797 −78 −57 −3
R_Ectorhinal_Cortex 23 −6.681 72 −54 0
L_Granule_Cell_Level_of_the_Cerebellum 247 −7.956 −60 −114 −12
R_Granule_Cell_Level_of_the_Cerebellum 284 −6.649 60 −120 −15
L_Molecular_Layer_of_the_Cerebellum 132 −8.126 −63 −114 −9
R_Molecular_Layer_of_the_Cerebellum 212 −8.041 66 −120 −9
L_Parasubiculum 33 −7.799 −51 −69 6
R_Parasubiculum 31 −8.126 48 −66 3
L_Brainstem 35 −5.672 −39 −96 −24
L_Corpus_Callosum_and_Associated_Subcortical_White_Matter 7 −7.870 −63 −51 −6
R_Corpus_Callosum_and_Associated_Subcortical_White_Matter 9 −7.672 66 −63 0
L_Descending_Corticofugal_Pathways_and_Globus_Pallidum 6 −4.026 −27 −63 −15
R_Descending_Corticofugal_Pathways_and_Globus_Pallidum 18 −4.353 33 −63 −3
L_Middle_Cerebellar_Peduncle 37 −4.445 −45 −93 −12
R_Middle_Cerebellar_Peduncle 2 −4.511 45 −96 3
L_Inferior_Olive/PyramidalDecusation/SP5 9 −3.807 −21 −69 −24
L_Brachium_Pontis 9 −3.946 −21 −69 −21
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A one-way ANOVA with Bonferroni correction was used to identify significant voxels. The voxel-p value was set at 0.001, and the cluster-p was set at 0.05. All tests were two-tailed. The corresponding t-value was then determined by the p values. x, y, z: coordinates of the position of the primary peak in MNI space; ReHo: regional homogeneity; L: left; R: right.

Fig. 3.

Fig. 3

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ReHo maps in rats between the Tuina group and Sham group 28 days after surgery. The cold tone represents areas where ReHo values of the Sham group lower than those of the Tuina group at 28 days after surgery. The numbers in the figure are the coordinates of the Z-axis in standard space. The one-way ANOVA was performed with Bonferroni correction (Voxel-p < 0.001, Cluster-p < 0.05, Two-tailed). ReHo: regional homogeneity; L: left; R: right.

3.4. ReHo differences between Tuina and CCD groups on post-operative day 28

On day 28 post-surgery, Tuina-treated rats exhibited significantly higher ReHo than CCD controls in four key regions: the left lateral entorhinal cortex, left subiculum, left primary motor cortex, and right cerebellar molecular layer (p < 0.05, GRF-corrected).

3.5. ReHo values of the CCD group between days 7 and 28 post-surgery

The right presubiculum and retrosplenial dysgranular cortex displayed higher ReHo on day 28 than on day 7 (p < 0.05, GRF-corrected; Table 3 and Fig. 4).

Table 3.

Brain regions showing ReHo differences of CCD group between 7 days and 28 days after surgery.

Brain regions No. of
voxels 		Peak
t-value 		MNI coordinates (mm)
x y z
D28 >D7 R_Presubiculum 6 −3.720 39 −81 42
R_Retosplenial_Dysgranular_
Cortex		 17 −3.949 30 −81 48
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A one-way ANOVA with Bonferroni correction was used to identify significant voxels. The voxel-p value was set at 0.001, and the cluster-p was set at 0.05. All tests were two-tailed. The corresponding t-value was then determined by the p values. x, y, z: coordinates of the position of the primary peak in MNI space; ReHo: regional homogeneity; CCD: chronic compression of the dorsal root ganglion; R: right.

Fig. 4.

Fig. 4

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ReHo maps of the CCD group between 7 days and 28 days after surgery. The cold tone represents areas where ReHo values of the CCD group at 7 days after surgery lower than those 28 days after surgery. The numbers in the figure are the coordinates of the Z-axis in standard space. The one-way ANOVA was performed with Bonferroni correction (Voxel-p < 0.001, Cluster-p < 0.05, Two-tailed). ReHo: regional homogeneity; CCD: chronic compression of the dorsal root ganglion; R: right.

3.6. ReHo values of the Tuina group between days 7 and 28 post-surgery

Between days 7 and 28 post-surgery, ReHo increased in the left amygdalo-hippocampic area, bilateral dentate gyrus, subiculum, parasubiculum, ectorhinal cortex, and corpus callosum (p < 0.05, GRF-corrected; Table 4 and Fig. 5).

Table 4.

Brain regions showing ReHo differences of Tuina group between 7 days and 28 days after surgery.

Brain regions No. of
voxels 		Peak
t-value 		MNI coordinates (mm)
x y z
D28 >D7 L_Amygdalohyppocampic_Area 6 −4.700 −60 −72 0
L_Cornu_Ammonis_1 7 −3.578 −57 −63 6
L_Dentate_Gyrus 61 −4.265 −48 −66 6
R_Dentate_Gyrus 38 −4.391 48 −66 6
L_Ectorhinal_Cortex 9 −3.774 −66 −72 15
L_Parasubiculum 33 −5.215 −51 −72 6
R_Parasubiculum 30 −4.582 48 −69 6
L_Subiculum 82 −4.887 −54 −72 6
R_Subiculum 51 −4.563 54 −66 0
L_Corpus_Callosum_and_Associated_Subcortical_White_Matter 7 −3.761 −60 −72 15
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A one-way ANOVA with Bonferroni correction was used to identify significant voxels. The voxel-p value was set at 0.001, and the cluster-p was set at 0.05. All tests were two-tailed. The corresponding t-value was then determined by the p values. x, y, z: coordinates of the position of the primary peak in MNI space; ReHo: regional homogeneity; L: left; R: right.

Fig. 5.

Fig. 5

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ReHo maps of the Tuina group between 7 days and 28 days after surgery. The cold tone represents areas where ReHo values of the Tuina group at 7 days after surgery lower than those 28 days after surgery. The numbers in the figure are the coordinates of the Z-axis in standard space. The one-way ANOVA was performed with Bonferroni correction (Voxel-p < 0.001, Cluster-p < 0.05, Two-tailed). ReHo: regional homogeneity; L: Left; R: right.

3.7. Correlation between ReHo values and behavioral test

Spearman correlation analysis showed that ReHo values in predefined pain-related regions were negatively associated with MWT and PWL. The MWT is negatively correlated with ReHo values of brainstem (r = −0.285, p < 0.001), hippocampus (r = −0.273, p < 0.05), internal capsule (r = −0.243, p < 0.05), sensory-motor (r = −0.426, p < 0.001), somatosensory system (r = −0.267, p < 0.05) and temporal system (r = −0.318, p < 0.001). Meanwhile, PWL is negatively correlated with ReHo values of the brainstem (r = −0.31, p < 0.001), hippocampus (r = −0.229, p < 0.05), sensory-motor (r = −0.44, p < 0.001) and temporal system (r = −0.316, p < 0.001) (Fig. 6).

Fig. 6.

Fig. 6

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Spearman correlation between the ReHo values and MWT and PWL. The analysis of all date indicated a negative correlation between the brainstem (r = −0.285, p < 0.001), hippocampus (r = −0.273, p < 0.05), internal capsule (r = −0.243, p < 0.05), sensory-motor (r = −0.426, p < 0.001), somatosensory system (r = −0.267, p < 0.05), temporal system (r = −0.318, p < 0.001) and MWT. While the ReHo values of brainstem (r = −0.31, p < 0.001), hippocampus (r = −0.229, p < 0.05), sensory-motor (r = -0.44, p < 0.001) and temporal system (r = −0.316, p < 0.001) is negatively correlated with PWL. ReHo: regional homogeneity; MWT: Mechanical withdrawal threshold; PWL: paw withdrawal thermal latency.

4. Discussion

Repeated Tuina alleviated mechanical and thermal hypersensitivity in CCD rats and was accompanied by marked ReHo alterations in distributed pain-related brain regions. Compared with the Sham group, CCD induced robust increases in ReHo within the amygdalo-hippocampal complex, parasubiculum, ectorhinal cortex, brainstem, and cerebellar layers, indicating substantial reorganization of local neural synchrony during persistent neuropathic pain. Tuina treatment was further associated with increased ReHo in the entorhinal-subicular circuit, primary motor cortex, corpus callosum, and cerebellum, together with progressive changes between postoperative days 7 and 28 in the amygdalo-hippocampal area, dentate gyrus, subiculum, parasubiculum, ectorhinal cortex, and corpus callosum. Collectively, these findings suggest that Tuina does not simply suppress brain activity globally, but rather reshapes local synchronization within distributed pain-processing networks.

At the peripheral and spinal levels, Tuina analgesia has been linked to anti-inflammatory signaling, mechanosensitive ion channels, and glial regulation (Liu et al., 2022) (Yang et al., 2024) (Song et al. 2018). At the supraspinal level, our previous ALFF study (Wu et al., 2023) and other resting-state fMRI studies suggest that manual therapy can remodel pain-related brain activity and connectivity (Xing et al., 2021) (Ma et al., 2023). Consistent with this, the present ReHo findings extend earlier work by showing that repeated Tuina is associated not only with behavioral improvement, but also with regionally specific reorganization of local neural synchrony in chronic neuropathic pain.

ReHo is a widely used index of local neural synchrony in pain neuroimaging (Wang et al., 2015). Abnormal ReHo has been reported in limbic and sensorimotor regions in migraine(Chen et al., 2019) (Shi et al., 2022), in prefrontal, hippocampal, insular, and temporal regions in primary dysmenorrhea (Jin et al., 2017), and in multiple supraspinal regions after acute spinal cord injury (Zhu et al., 2015). In the present study, the most prominent ReHo shifts were found in the amygdala, hippocampus, dentate gyrus, subiculum, parasubiculum, and ectorhinal cortex. Because these structures are closely related to affective salience, contextual memory, and pain persistence, the observed changes likely reflect reorganization of affective-memory circuitry rather than a simple change in nociceptive intensity alone.

This interpretation is supported by recent small-animal neuroimaging studies. Chi et al. reported that neuropathic pain in rats was associated with dynamic changes in brain activity and functional connectivity over time (Chi et al., 2024). Zhou et al. further demonstrated structural and functional alterations in the hippocampal system under chronic pain conditions, including dentate gyrus-related changes detected by resting-state fMRI and DTI (Zhou et al., 2024). Together with our findings, these studies support the view that neuropathic pain engages maladaptive plasticity in limbic-hippocampal circuits and that Tuina-related analgesia may be accompanied by gradual reorganization of these affective-memory networks.

Another notable finding is the involvement of sensorimotor, brainstem, and cerebellar systems. Chronic pain is increasingly recognized as a distributed network disorder involving sensory-discriminative, affective-motivational, and descending modulatory systems. Consistent with this view, a recent rat fMRI study showed that different pain entities produce distinct cerebral hypersensitivity network signatures involving S1, M1, hippocampus, piriform cortex, and cingulate cortex (Kreitz et al., 2025). Clinical manual-therapy imaging studies have likewise shown that pain relief can be accompanied by functional remodeling in salience and sensorimotor networks (Isenburg et al., 2021; Yang et al., 2022). In this context, the higher ReHo observed in the primary motor cortex and cerebellar molecular layer after Tuina may reflect altered sensorimotor integration and compensatory recruitment within pain-modulatory circuits. Importantly, the negative correlations between ReHo and MWT/PWL in the brainstem, hippocampus, sensory-motor, and temporal systems indicate that local synchrony in these regions was behaviorally relevant. However, the direction of ReHo change should be interpreted cautiously: higher ReHo may indicate maladaptive hypersynchrony in some nodes of the pain network, whereas Tuina-related increases in other regions may represent adaptive reorganization and restoration of network integration.

The temporal profile of our data also deserves emphasis. Behavioral improvement emerged from postoperative day 14 onward, whereas rs-fMRI was acquired only on days 7 and 28. Therefore, the current data support a suggestive, rather than definitive, two-stage trajectory of Tuina-induced neuroplasticity. Early changes may be dominated by altered nociceptive processing, whereas later changes may involve broader limbic-hippocampal and interregional remodeling. This interpretation is broadly consistent with longitudinal rodent imaging studies of pain chronification and central sensitization (Wu et al., 2018), Spisák et al., 2017 Chi et al., 2024). At the same time, the standardized parameters used here (5 N, 2 Hz, 10 min/day) improved experimental reproducibility, but they should not be regarded as directly equivalent to clinical Tuina. Future studies should combine quantitative force-control systems with behavioral and neuroimaging endpoints to clarify dose-response relationships and improve translational relevance (Liu et al., 2022; Wu et al., 2023).

The anesthesia regimen should also be considered when interpreting these findings. Dexmedetomidine or medetomidine-based protocols are widely used in rodent rs-fMRI because they help preserve resting-state network organization better than deeper volatile anesthesia alone (Paasonen et al., 2018). Recent work has further shown that stable and reproducible resting-state networks can be identified in anesthetized rats and that combined ISO/MED protocols can provide relatively stable brain states for rs-fMRI acquisition after an appropriate equilibration period (Dai et al., 2023, Pradier et al., 2021). Nevertheless, anesthesia remains a potential confound because spontaneous neural activity and neurovascular coupling are still modified in a dose- and time-dependent manner. Accordingly, the present results should be interpreted as pain-related and Tuina-related differences observed within a standardized anesthetized state, rather than as exact equivalents of awake brain function.

5. Limitations

Several limitations should be acknowledged. First, the present design did not include a sham Tuina or non-acupoint stimulation group, and therefore the acupoint specificity of BL40 stimulation cannot be distinguished from non-specific tactile input. Second, although behavioral analgesia became evident on postoperative day 14, rs-fMRI was performed only on days 7 and 28, which limits precise characterization of intermediate neuroplastic changes. Third, ReHo is a correlational measure and cannot establish causality between altered local synchrony and analgesic outcome. Fourth, only evoked pain behaviors were assessed; future studies should include affective and spontaneous pain-related behavioral assays to better capture the emotional dimension of neuropathic pain. Finally, because the current experiment was conducted under dexmedetomidine-based anesthesia and in male rats only, caution is warranted when generalizing these findings across physiological states and sexes.

6. Conclusion

Repeated Tuina alleviated CCD-induced neuropathic pain and was associated with ReHo alterations in limbic, sensorimotor, brainstem, and cerebellar regions. These findings suggest that central neuroplasticity may contribute to Tuina analgesia, although causal and acupoint-specific mechanisms require further investigation.

CRediT authorship contribution statement

Qingguang Zhu: Writing – review & editing, Methodology. Lingjun Kong: Writing – review & editing, Methodology. Min Fang: Supervision, Methodology, Funding acquisition. Yunyi Li: Formal analysis. Xinrong Li: Data curation. Xin Zhou: Investigation. Zhiwei Wu: Writing – original draft, Methodology, Funding acquisition, Data curation. Suhong Zhao: Writing – original draft, Investigation, Data curation. Guangxin Guo: Investigation, Formal analysis.

Ethics approval

This study was approved by Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. The study was conducted in accordance with the local legislation and institutional requirements.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82205302, 82030121), Demonstration Project of Surface Electromyography Application (No. 23SHS05400), Shanghai Key Laboratory of Tuina Techniques on Musculoskeletal Disorders (No. 24dz2260200).

Declaration of Competing Interest

All authors declare that they have no conflict of interest. This study was approved by Yueyang Hospital Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (YYLAC−2022–148–5). The study was conducted in accordance with the local legislation and institutional requirements.

Contributor Information

Lingjun Kong, Email: chunyong01@163.com.

Qingguang Zhu, Email: zhuqingguang@126.com.

Min Fang, Email: fm-tn0510@shutcm.edu.cn.

References

  1. Alles S.R.A., Smith P.A. Etiology and Pharmacology of Neuropathic Pain. Pharmacol. Rev. 2018;70:315–347. doi: 10.1124/pr.117.014399. [DOI] [PubMed] [Google Scholar]
  2. Boehnke K.F., Litinas E., Clauw D.J. Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. J. Pain. 2016;17:739–744. doi: 10.1016/j.jpain.2016.03.008. [DOI] [PubMed] [Google Scholar]
  3. Bouhassira D., Lanteri-Minet M., Attal N., Laurent B., Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136:380–387. doi: 10.1016/j.pain.2007.08.013. [DOI] [PubMed] [Google Scholar]
  4. Cao B., Zhou X., Zhang S.P., Zhu Q.G., Kong L.J., Fang M. Effect of traditional Chinese manual therapy on alleviating pain and dysfunction of lumbar disc herniation: a randomized controlled pilot study. Am. J. Transl. Res. 2022;14:6941–6952. [PMC free article] [PubMed] [Google Scholar]
  5. Chen J., Wang Z., Tu Y., Liu X., Jorgenson K., Ye G., Lin C., Liu J., Park J., Lang C., Liu B., Kong J. Regional Homogeneity and Multivariate Pattern Analysis of Cervical Spondylosis Neck Pain and the Modulation Effect of Treatment. Front. Neurosci. 2018;12:900. doi: 10.3389/fnins.2018.00900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen C., Yan M., Yu Y., Ke J., Xu C., Guo X., Lu H., Wang X., Hu L., Wang J., Ni J., Zhao H. Alterations in Regional Homogeneity Assessed by fMRI in Patients with Migraine Without Aura. J. Med. Syst. 2019;43:298. doi: 10.1007/s10916-019-1425-z. [DOI] [PubMed] [Google Scholar]
  7. Cheng Z.J., Zhang S.P., Gu Y.J., Chen Z.Y., Xie F.F., Guan C., Fang M., Yao F. Effectiveness of Tuina Therapy Combined With Yijinjing Exercise in the Treatment of Nonspecific Chronic Neck Pain: A Randomized Clinical Trial. JAMA Netw. Open. 2022;5 doi: 10.1001/jamanetworkopen.2022.46538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chi X.-T., Yang W., Zhang J.-B., et al. A Cross-Sectional and Longitudinal Integrated Study on Brain Functional Changes in a Neuropathic Pain Rat Model. eNeuro. 2024;11(3) doi: 10.1523/ENEURO.0272-23.2024. ENEURO.0272-23.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen S.P., Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ. 2014;348:f7656. doi: 10.1136/bmj.f7656. [DOI] [PubMed] [Google Scholar]
  10. Colloca L., Ludman T., Bouhassira D., Baron R., Dickenson A.H., Yarnitsky D., Freeman R., Truini A., Attal N., Finnerup N.B., Eccleston C., Kalso E., Bennett D.L., Dworkin R.H., Raja S.N. Neuropathic pain. Nat. Rev. Dis. Prim. 2017;3 doi: 10.1038/nrdp.2017.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dabbour R.Y., Hassan T.A., Faqawi M.S., Bottcher B. Pain management during labour at the El-Emarati Hospital: a clinical audit. Lancet. 2018;391(2):S35. doi: 10.1016/S0140-6736(18)30401-X. [DOI] [PubMed] [Google Scholar]
  12. Dai T., Seewoo B.J., Hennessy L.A., et al. Identifying reproducible resting state networks and functional connectivity alterations following chronic restraint stress in anaesthetized rats. Front. Neurosci. 2023;17 doi: 10.3389/fnins.2023.1151525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dhanani N.M., Caruso T.J., Carinci A.J. Complementary and alternative medicine for pain: an evidence-based review. Curr. Pain. Headache Rep. 2011;15:39–46. doi: 10.1007/s11916-010-0158-y. [DOI] [PubMed] [Google Scholar]
  14. Field T. Massage therapy research review. Complement. Ther. Clin. Pract. 2016;24:19–31. doi: 10.1016/j.ctcp.2016.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Finnerup N.B., Attal N., Haroutounian S., McNicol E., Baron R., Dworkin R.H., Gilron I., Haanpaa M., Hansson P., Jensen T.S., Kamerman P.R., Lund K., Moore A., Raja S.N., Rice A.S., Rowbotham M., Sena E., Siddall P., Smith B.H., Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162–173. doi: 10.1016/S1474-4422(14)70251-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Finnerup N.B., Haroutounian S., Baron R., Dworkin R.H., Gilron I., Haanpaa M., Jensen T.S., Kamerman P.R., McNicol E., Moore A., Raja S.N., Andersen N.T., Sena E.S., Smith B.H., Rice A.S.C., Attal N. Neuropathic. Pain. Clin. Trial. Factors Assoc. decreases Estim. Drug. Effic. Pain. 2018;159:2339–2346. doi: 10.1097/j.pain.0000000000001382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Finnerup N.B., Kuner R., Jensen T.S. Neuropathic Pain: From Mechanisms to Treatment. Physiol. Rev. 2021;101:259–301. doi: 10.1152/physrev.00043.2019. [DOI] [PubMed] [Google Scholar]
  18. Hargreaves K., Dubner R., Brown F., Flores C., Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77–88. doi: 10.1016/0304-3959(88)90026-7. [DOI] [PubMed] [Google Scholar]
  19. He L., Xu R., Chen Y., Liu X., Pan Y., Cao S., Xu T., Tian H., Zeng J. Intra-CA1 Administration of Minocycline Alters the Expression of Inflammation-Related Genes in Hippocampus of CCI Rats. Front. Mol. Neurosci. 2019;12:248. doi: 10.3389/fnmol.2019.00248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Isenburg K., Mawla I., Loggia M.L., Ellingsen D.M., Protsenko E., Kowalski M.H., Swensen D., O'Dwyer-Swensen D., Edwards R.R., Napadow V., Kettner N. Increased Salience Network Connectivity Following Manual Therapy is Associated with Reduced Pain in Chronic Low Back Pain Patients. J. Pain. 2021;22:545–555. doi: 10.1016/j.jpain.2020.10.006. [DOI] [PubMed] [Google Scholar]
  21. Jin L., Yang X., Liu P., Sun J., Chen F., Xu Z., Qin W., Tian J. Dynamic abnormalities of spontaneous brain activity in women with primary dysmenorrhea. J. Pain. Res. 2017;10:699–707. doi: 10.2147/JPR.S121286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kreitz S., Pradier B., Segelcke D., et al. Distinct functional cerebral hypersensitivity networks during incisional and inflammatory pain in rats. Curr. Res. Neurobiol. 2025;8 doi: 10.1016/j.crneur.2024.100142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liu Z.F., Wang H.R., Yu T.Y., Zhang Y.Q., Jiao Y., Wang X.Y. Tuina for peripherally-induced neuropathic pain: A review of analgesic mechanism. Front. Neurosci. 2022;16 doi: 10.3389/fnins.2022.1096734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lv D., Yan H.H., Zhang C.G., Li X.L., Zhang L.Y., Liang J.Q., Tang C.H., Wu W.B., Deng W., Xie G.J., Guo W.B. Kcc-ReHo and Cohe-ReHo in bipolar disorder: their associated genes and potential for diagnosis and treatment prediction. Neuropharmacology. 2025;278 doi: 10.1016/j.neuropharm.2025.110575. [DOI] [PubMed] [Google Scholar]
  25. Ma J., Hua X.Y., Zheng M.X., Wu J.J., Huo B.B., Xing X.X., Feng S.Y., Li B., Xu J.G. Surface-based map plasticity of brain regions related to sensory motor and pain information processing after osteonecrosis of the femoral head. Neural Regen. Res. 2022;17:806–811. doi: 10.4103/1673-5374.322471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ma S.J., Zhang J.P., Hua X.Y., Wu J.J., Zheng M.X., Xu J.G. Tuina therapy promotes behavioral improvement and brain plasticity in rats with peripheral nerve injury and repair. Brain Behav. 2023;13 doi: 10.1002/brb3.3174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Meacham K., Shepherd A., Mohapatra D.P., Haroutounian S. Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr. Pain. Headache Rep. 2017;21:28. doi: 10.1007/s11916-017-0629-5. [DOI] [PubMed] [Google Scholar]
  28. Paasonen J., Stenroos P., Salo R.A., Kiviniemi V., Gröhn O. Functional connectivity under six anesthesia protocols and the awake condition in rat brain. Neuroimage. 2018;172:9–20. doi: 10.1016/j.neuroimage.2018.01.014. [DOI] [PubMed] [Google Scholar]
  29. Petrosky E., Harpaz R., Fowler K.A., Bohm M.K., Helmick C.G., Yuan K., Betz C.J. Chronic Pain Among Suicide Decedents, 2003–2014: Findings From the National Violent Death Reporting System. Ann. Intern. Med. 2018;169:448–455. doi: 10.7326/M18-0830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pradier B., Wachsmuth L., Nagelmann N., et al. Combined resting state-fMRI and calcium recordings show stable brain states for task-induced fMRI in mice under combined ISO/MED anesthesia. NeuroImage. 2021;245 doi: 10.1016/j.neuroimage.2021.118626. [DOI] [PubMed] [Google Scholar]
  31. Rosner J., de Andrade D.C., Davis K.D., Gustin S.M., Kramer J.L.K., Seal R.P., Finnerup N.B. Central neuropathic pain. Nat. Rev. Dis. Prim. 2023;9:73. doi: 10.1007/s11916-017-0629-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shi M., Luo D., Guo J., Yang D., Li Z., Zhao H. The Function of the Autonomic Nervous System in Asian Patients With Chronic Migraine. Front. Neurosci. 2022;16 doi: 10.3389/fnins.2022.773321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Song P., Sun W., Zhang H., Fang M., Lin Z., Wu Z., Zhou X., Lv Z., Zhu Q., Jiang S., Cheng Y. Possible mechanism underlying analgesic effect of Tuina in rats may involve piezo mechanosensitive channels within dorsal root ganglia axon. J. Tradit. Chin. Med. 2018;38:834–841. [PubMed] [Google Scholar]
  34. Spisák T., Pozsgay Z., Aranyi C., Dávid S., Kocsis P., Nyitrai G., Gajári D., Emri M., Czurkó A., Kincses Z.T. Central sensitization-related changes of effective and functional connectivity in the rat inflammatory trigeminal pain model. Neuroscience. 2017;344:133–147. doi: 10.1016/j.neuroscience.2017.01.027. [DOI] [PubMed] [Google Scholar]
  35. Van Hecke O., Austin S.K., Khan R.A., Smith B.H., Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155:654–662. doi: 10.1016/j.pain.2013.11.013. [DOI] [PubMed] [Google Scholar]
  36. Wang W., Ji Q., Ran X., Li C., Kuang H., Yu X., Fang H., Yang J., Liu J., Xue Y., Feng B., Lei M., Zhu D. Prevalence and risk factors of diabetic peripheral neuropathy: A population-based cross-sectional study in China. Diabetes Metab. Res. Rev. 2023;39 doi: 10.1002/dmrr.3702. [DOI] [PubMed] [Google Scholar]
  37. Wang Y., Zhang X., Guan Q., Wan L., Yi Y., Liu C.F. Altered regional homogeneity of spontaneous brain activity in idiopathic trigeminal neuralgia. Neuropsychiatr. Dis. Treat. 2015;11:2659–2666. doi: 10.2147/NDT.S94877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wu Z., Guo G., Zhang Y., Li Y., He T., Zhu Q., Kong L., Fang M. Resting-state functional magnetic resonance imaging reveals brain remodeling after Tuina therapy in neuropathic pain model. Front. Mol. Neurosci. 2023;16 doi: 10.3389/fnmol.2023.1231374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wu J.J., Lu Y.C., Hua X.Y., Ma S.J., Xu J.G. A Longitudinal Mapping Study on Cortical Plasticity of Peripheral Nerve Injury Treated by Direct Anastomosis and Electroacupuncture in Rats. World Neurosurg. 2018;114:e267–e282. doi: 10.1016/j.wneu.2018.02.173. [DOI] [PubMed] [Google Scholar]
  40. Xing X.X., Zheng M.X., Hua X.Y., Ma S.J., Ma Z.Z., Xu J.G. Brain plasticity after peripheral nerve injury treatment with massage therapy based on resting-state functional magnetic resonance imaging. Neural Regen. Res. 2021;16:388–393. doi: 10.4103/1673-5374.290912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yan C.G., Wang X.D., Zuo X.N., Zang Y.F. DPABI: Data Processing & Analysis for (Resting-State) Brain Imaging. Neuroinformatics. 2016;14:339–351. doi: 10.1007/s12021-016-9299-4. [DOI] [PubMed] [Google Scholar]
  42. Yang Z., Wu S., Yu T., Chen J., Zhang R., Wang H., Zhang Y. Characteristics of Pain Changes in Rats with Nerve Injury within 24 h after One-Time Tuina Intervention. J. Vis. Exp. 2024 doi: 10.3791/65593. [DOI] [PubMed] [Google Scholar]
  43. Yang Y.C., Zeng K., Wang W., Gong Z.G., Chen Y.L., Cheng J.M., Zhang M., Huang Y.W., Men X.B., Wang J.W., Zhan S., Tan W.L. The Changes of Brain Function After Spinal Manipulation Therapy in Patients with Chronic Low Back Pain: A Rest BOLD fMRI Study. Neuropsychiatr. Dis. Treat. 2022;18(187-99) doi: 10.2147/NDT.S339762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yao C., Ren J., Huang R., Tang C., Cheng Y., Lv Z., Kong L., Fang S., Tao J., Fu Y., Zhu Q., Fang M. Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-kappab signaling pathway. J. Neuroinflamm. 2022;19:211. doi: 10.1186/s12974-022-02568-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yongjun Z., Tingjie Z., Xiaoqiu Y., Zhiying F., Feng Q., Guangke X., Jinfeng L., Fachuan N., Xiaohong J., Yanqing L. A survey of chronic pain in China. Libyan J. Med. 2020;15 doi: 10.1080/19932820.2020.1730550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zhang X.H., Feng C.C., Pei L.J., Zhang Y.N., Chen L., Wei X.Q., Zhou J., Yong Y., Wang K. Electroacupuncture Attenuates Neuropathic Pain and Comorbid Negative Behavior: The Involvement of the Dopamine System in the Amygdala. Front. Neurosci. 2021;15 doi: 10.3389/fnins.2021.657507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zhang S., Li H., Xu Q., Wang C., Li X., Sun J., Wang Y., Sun T., Wang Q., Zhang C., Wang J., Jia X., Sun X. Regional homogeneity alterations in multi-frequency bands in tension-type headache: a resting-state fMRI study. J. Headache Pain. 2021;22:129. doi: 10.1186/s10194-021-01341-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zhang X., Wang W., Bai X., Mei Y., Tang H., Yuan Z., Zhang X., Li Z., Zhang P., Hu Z., Zhang Y., Yu X., Sui B., Wang Y. Alterations in regional homogeneity and multiple frequency amplitudes of low-frequency fluctuation in patients with new daily persistent headache: a resting-state functional magnetic resonance imaging study. J. Headache Pain. 2023;24(14) doi: 10.1186/s10194-023-01543-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zhou J.-Z., Deng J., Luo D.-X., et al. Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study. Front. Neurosci. 2024;18 doi: 10.3389/fnins.2024.1428666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zhu L., Wu G., Zhou X., Li J., Wen Z., Lin F. Altered spontaneous brain activity in patients with acute spinal cord injury revealed by resting-state functional MRI. PLoS. One. 2015;10 doi: 10.1371/journal.pone.0118816. [DOI] [PMC free article] [PubMed] [Google Scholar]

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