Assessment of corticospinal tract remodeling based on diffusion tensor imaging in the treatment of motor dysfunction after ischemic stroke by acupuncture: a meta-analysis study

Abstract

Currently, acupuncture therapy has been widely used in the late rehabilitation of dysfunction in patients after ischemic stroke(IS), especially motor dysfunction. The aim of this study was to investigate the efficacy of acupuncture in improving motor dysfunction after IS and to investigate the effect of acupuncture on corticospinal tract(CST) remodeling using diffusion tensor imaging. Therefore, we systematically searched the literature and performed meta-analysis. Eleven eligible RCTs involving 459 patients were eventually included. The combined evidence results showed that the acupuncture group significantly improved patients' National Institute of Health stroke scale, Fugl-Meyer Assessment Scale, and Barthel index compared with conventional medical treatment. The acupuncture group significantly promoted remodeling of the CST, as reflected by an increase in FA throughout the CST (MD=0.04, 95% CI (0.02, 0.07), P=0.001), and in addition subgroup analysis showed that the acupuncture group significantly improved Fractional Anisotropy(FA) in the infarct area compared with conventional medical treatment at around 4 weeks (MD=0.04, 95% CI (0.02, 0.07), P=0.001) and FA of the affected cerebral peduncle (MD=0.04, 95% CI (0.02, 0.07). Also, compared with conventional medical treatment, the acupuncture group significantly increased Average Diffusion Coefficient(ADC) of the affected cerebral peduncle (MD=-0.21, 95% CI (-0.28, -0.13), P<0.00001). Taken together, the results of the meta-analysis suggest that acupuncture therapy can improve the clinical manifestations of motor dysfunction in patients after IS and advance a possibly beneficial effect on CST remodeling. However, due to the number and quality of eligible studies, these findings need to be further validated in more standardized, rigorous, high-quality clinical trials.

Introduction

In recent years, stroke has become one of the leading causes of death among Chinese residents, and the lifetime risk of stroke in China is 39.3%, which is 14.4% higher than the global lifetime risk of stroke as estimated by the Global Burden of Disease Working Group. Cerebrovascular disease mortality accounts for 22% of mortality among Chinese residents, and ischemic stroke (IS) accounts for 82% of stroke patients (Wang et al. 2022). Ischemic stroke is characterized by acute onset, mainly due to impaired blood circulation, leading to localized ischemic necrosis or softening of brain tissue due to ischemia and hypoxia. Once the onset is often accompanied by irreversible damage to brain tissue, about 75% of patients are left with varying degrees of motor dysfunction (Marshall et al. 2000), which seriously affects patients' quality of life and adds a heavy burden to society and patients' families (Heuschmann et al. 2011). The corticospinal tract (CST) is an important component of the pyramidal system that translates the brain's conscious intent into observable actions and is particularly important for the motor function of the distal limb (Welniarz et al. 2017). lesions in patients with IS often involve the CST, resulting in compression, injury, or even fracture of the CST, leading to corresponding motor function impairment (Byblow et al. 2015; Maraka et al. 2014). Therefore, an adequate grasp of the infarct size and CST damage in the clinic can help to make an effective judgment of the degree of motor function impairment in patients (Li et al. 2022). MRI is an important basis for confirming the diagnosis and localization of IS in clinical practice. Among them, Diffusion Tensor Imaging (DTI) can show the morphological changes of the corticospinal tracts by processing visualization, and can accurately quantify the damage of the white matter fiber tracts by Fractional Anisotropy (FA), Average Diffusion Coefficient (ADC), etc., which can objectively reflect the degree of CST nerve damage in IS patients (Le Bihan and Johansen-Berg 2012; O'Donnell and Westin 2011). It has been demonstrated that the results of white matter integrity detection by DTI are reproducible and reliable (Albi et al. 2017). Assessment of CST integrity by DTI has also been shown to be an objective assessment and reliable in individuals with IS (Lewis et al. 2020; Snow et al. 2016).

In China, patients with motor dysfunction after IS are mostly treated with a rehabilitation program combining Chinese and Western medicine. In recent years, acupuncture has played an important role in the rehabilitation of patients with motor dysfunction after IS, and the clinical use of acupuncture as a complementary or alternative therapy has increased worldwide (Gu et al. 2014; Li et al. 2014; Wang et al. 2017). In 2002, the World Health Organization (WHO) also recommended acupuncture as a treatment for stroke, and they concluded that acupuncture has some advantages in the treatment of post-stroke patients with dysfunction, such as motor dysfunction, sensory dysfunction, and aphasia. To date, many studies have reported the role and potential mechanisms of acupuncture in improving neurological prognosis in IS. Numerous animal studies have also shown that acupuncture exerts neuroprotective effects in IS, such as promoting neuroregeneration, angiogenesis, and neuroplasticity (Chang et al. 2018). Currently, a large number of systematic evaluations have assessed the efficacy of acupuncture for stroke. However, the available systematic evaluations have not yet evaluated the effect of acupuncture intervention on CST remodeling in patients with movement disorders. The DTI has been widely used to analyze the correlation between white matter changes and functional responses in stroke (Duru et al. 2016), to measure corticospinal integrity after stroke (Park et al. 2013), to assess white matter damage in patients who have neglected stroke (Urbanski et al. 2011), and to predict the outcome of motor function after stroke rehabilitation (Song et al. 2014). Therefore, this paper explores a clinical study of acupuncture with the aid of the DTI technique for the treatment of patients with motor dysfunction in IS. In contrast to previous systematic evaluations, the present study focused on assessing corticospinal tract remodeling after acupuncture treatment of IS. With this, the clinical efficacy of acupuncture in treating patients with motor dysfunction in IS relative to single rehabilitation treatment was evaluated, which can further provide a reference for the clinical application of acupuncture in treating IS. We present the following article by the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-691).

Materials And Methods

To increase the transparency and quality of systematic evaluation reports, this research complied with PRISMA 2020 statement and has been registered in PROSPERO (registration number: CRD42021283638).

Result

Literature search

A preliminary search of 119 studies was conducted, including 19 English and 100 Chinese studies. After removing duplicate studies and reading the titles, abstracts, and full text, the remaining 108 studies were excluded. Eleven RCTs were finally included. The flow chart of studies screening and the results are shown in Fig. 1.

Discussion

Stroke is currently the leading cause of death from disease in China. Motor dysfunction after IS is mainly due to abnormal motor function caused by damage to upper motor neurons and the absence of central neural control of the motor system in the cerebral cortex. In China, acupuncture therapy combined with conventional therapy or rehabilitation is increasingly used in the long-term treatment of motor dysfunction recovery after IS. The rationale for acupuncture therapy is not well understood, and because of the obvious differences between traditional and modern medical theory, the role of acupuncture therapy needs further comprehensive and systematic evaluation. It is currently believed that acupuncture treatment improves circulation and metabolism, and protects the vascular endothelium for circulatory perfusion, thereby reducing tissue edema, decreasing the content of calcium ions in brain tissue, avoiding or reducing neuronal necrosis, promoting a significant improvement in the ultrastructure of neuronal mitochondria in the cerebral ischemic area, and causing a significant increase in the number of neurons in the brain, significantly inhibiting ischemic neuronal apoptosis, thereby promoting the functional recovery of brain tissue, and improving the coordination of the active, antagonistic, and synergistic muscles of the affected limbs through the bidirectional regulation of acupuncture, which in turn also improves the motor function of the patient (Wong et al. 2013). However, the current evaluation of the efficacy of acupuncture is mostly performed using subjective parameters, which lack objectivity, while inconsistent criteria for evaluation lead to inconsistent judgments of the efficacy of acupuncture (Kong, et al., 2010). Multimodal MRI is currently a noninvasive means of objectively evaluating the role of needling in patients with cerebral infarction. Therefore, the present study included studies using DTI as a detection tool, which allows the use of objective factors to evaluate the effect of needling by excluding subjective factors. To our knowledge, this is the first systematic review and meta-analysis based on DTI to evaluate the efficacy of acupuncture on motor dysfunction and CST remodeling after IS. CST is the most important downstream motor conduction fiber connecting the cortical motor area and spinal cord neurons (Davidoff 1990). Previous pathological studies have shown secondary injury and degeneration in distal nerve fiber regions downstream of the lesion, in addition to the focal area, after cerebral infarction (Dziewulska et al. 2004). Among these, damage to the corticospinal tract is closely related to the recovery of distant motor function in patients (Puig et al. 2010). In the early stages of acute ischemic stroke, subtle changes in FA of the corticospinal tract downstream of the lesion can be detected using DTI imaging, which is useful for observing the extent and dynamic evolution of degeneration occurring in the corticospinal tract.

In the assessment of patients' clinical performance, we selected NIHSS, BI, and FMA as indicators for evaluation. As an evaluation of the degree of neurological deficit, the NHISS has the best reliability and validity criteria (Cheng et al. 2021). Although the NIHSS can quickly make a judgment about the degree of neurological deficit after stroke, the scale is less sensitive to reflect the patient's coordination, gait impairment, cortical sensory function, and distal motor function (Lyden 2017). Therefore, we combined the BI and FMA to objectively represent the efficacy of acupuncture treatment in improving motor function in patients. The BI assessment is simple, with high reliability and sensitivity, and is currently the most widely used disability scale in the world to predict treatment outcome, length of hospital stay, and prognosis (Prodinger et al. 2017). The scale is used to evaluate the degree of neurological disuse by the completion of daily living abilities in patients with cerebral infarction, and it can be used for prognostic speculation in the acute phase of stroke (Zhou et al. 2021). In patients after IS, the most common motor dysfunction is in the upper and lower extremities (Bonnyaud et al. 2016), and the FMA can be used to infer motor performance and quality of movement in individuals with different degrees of chronic post-stroke injury and is particularly good at assessing motor performance in the upper and lower extremities (Rech et al. 2020). In this study, we found that acupuncture interventions improved patients' NIHSS compared to conventional treatment or rehabilitation. Three of these studies showed that patients improved better than controls in NIHSS just after two weeks of acupuncture treatment. This suggests that acupuncture interventions may have a positive effect on neurological improvement in a short period. Three studies reported improvements in limb movements after acupuncture at 2 and 4 weeks, with one study finding better NIHSS, FMA, and BI than the control group after three months of follow-up. Four studies reported better improvements in BI scores in patients than in the control group after two weeks of acupuncture treatment. This suggests that the patient's ability to perform daily living activities with acupuncture interventions may be better recovered with the aid of acupuncture in combination with rehabilitation. In conclusion, the improvement of clinical performance of acupuncture in patients with motor dysfunction in IS is positive.

For the improvement of brain microstructure, this study focuses on summarizing the studies related to observing the changes of corticospinal tracts under pinpoint intervention after cerebral infarction. Currently, DTI is the only noninvasive imaging method that can display the white matter fiber tracts of the brain in vivo. DTI can detect lesions of the CST in IS and can visually and clearly show the compression, tortuosity, and deformation of the CST, as well as clarify the relationship between the lesions and the white matter fiber tracts. The observation of nerve fiber bundle lesions and the appearance of functional impairment is important to clarify the exact anatomical location of the lesion and to assess the function (Carey et al. 2004; Stieltjes et al. 2001). The anisotropy in the cerebral cortex is low, while the anisotropy in the white matter is high, and the more compact the white matter fiber bundles are, the more significant the white matter anisotropy is. The microstructural damage to brain tissue caused by IS lesions is mainly in the central and limbic brain tissue due to ischemia and hypoxia, with secondary inflammatory reactions causing degeneration of axons and myelin sheaths of nerve fiber bundles or secondary degeneration of axons and myelin sheaths of fiber bundles distal to the lesion, resulting in a decrease in white matter fiber bundle anisotropy (Shereen et al. 2011). The various anisotropies of diffusion can be achieved by quantitative metrics, such as FA, ADC, and MD. Currently, the most commonly used parameter for quantification is FA (Assemlal et al. 2011).FA images provide better gray-white matter contrast and easy identification of lesion sites, making the measured FA more accurate. Also, FA does not change with the direction of rotation of the coordinate system, and FA are physical characteristics of the tissue, and the values obtained at different times, with different imaging devices, and between different subjects for the same object are comparable (Durrleman et al. 2011). Li J et al. found that there was no significant difference between the treated and control groups in the mean FA values of the whole-segment CST after acupuncture treatment, which may be since the mean values of the whole-segment fiber bundles do not fully reflect the specific details of the changing CST remodeling, which may obscure potentially important information (Li et al. 2020). Therefore, cerebral peduncle was additionally selected as the primary anatomical location for this study. The long axis of CST in this area is vertical, which can ensure the integrity of the target spinal tracts; the CST in this area are closely arranged and easily distinguishable from other neighboring fiber tracts; the fibers are reconstructed by applying two ROIs at the same time are the fibers that pass through both areas, which ensures the authenticity of the reconstructed fiber tracts. In this study, after 4 weeks of treatment, the FA values in the corresponding areas of the treatment group increased compared to the control group, suggesting that nerve fiber bundle reorganization and repair occurred, indicating that after 4 weeks of acupuncture combined with conventional rehabilitation treatment resulted in nerve fiber bundle remodeling, axon regeneration, and thus functional recovery in the lesion area. Yang FX et al. used the DTI technique to visualize some areas through which the CST passes and evaluated the relevant parameters FA and ratio of FA and found that both the acupuncture and control groups improved the spatial structural remodeling of the CST in the infarct focus area and the affected posterior limb of the internal capsule, cerebral peduncle, and pons, and both correlated with motor function, but the improvement was more significant in the acupuncture group. This is consistent with the findings of many international rehabilitation scholars (Yang et al. 2021; Oey, et al., 2019).

ADC has good sensitivity and specificity for the diagnosis of cerebral infarction (Fiehler et al. 2001). Since changes in ADC are related to the movement of water molecules in the body, it can describe the diffusion of water molecules in the body, and different levels of values occur at different times of cerebral infarction. The progression of stroke can now be distinguished by monitoring changes in ADC (Valnes et al. 2020). Usually, there is a significant decrease in ADC at the beginning of cerebral infarction, followed by a gradual increase as the disease progresses, and finally, it can reach near normal tissue levels (Albers et al. 2006). In this study, the comparison of ADC at the cerebral peduncle was found to be higher in the acupuncture group than in the control group, reflecting the possibility that acupuncture intervention may more significantly improve the dispersion of water molecules. All five studies included in this index had treatment periods of more than two weeks, with the longest reaching one month, and the ADC elevation may have also increased gradually with the duration of the disease. It was noted that ADC values on the focal side increased and decreased before and after acupuncture treatment, which may be due to the increase in neuronal myelin degeneration and axonal lysis, but the cellular debris generated by axonal disintegration can prevent the random diffusion of water molecules, which, together with glial cell proliferation, further restricts the diffusion of water molecules and results in a decrease. As the disease progresses, glial cell proliferation reaches a stable state and the disintegrating cellular debris is cleared by the body, the degree of water molecule diffusion restriction decreases, and ADC increases (Bhasin et al. 2021; Liao 2015). Therefore, it is suggested that the treatment time of 2 weeks of acupuncture might be significant for the ADC at the cerebral peduncle of CST that is starting to improve. Shen YX et al. concluded that ADC on the side of the lesion was lower than normal in the acute phase and gradually increased with the progression of the disease, equaling the normal value around the 4th week (Shen et al. 2012).

The systematic review found remodeling of corticospinal tracts under acupuncture intervention, a phenomenon considered to be related to the fact that acupuncture has mechanisms such as improving blood flow in ischemic areas of the brain, accelerating the establishment of collateral circulation (Hong et al. 2021; Maida et al. 2020), inhibiting the process of the inflammatory response (Khoshnam et al. 2017), promoting neurogenesis and cell proliferation and anti-apoptosis in the central system, reducing myelin damage and promoting myelin regeneration, and increasing the plasticity of nerve fibers (Zhao et al. 2017), thereby promoting the self-repair of damaged CST structures and promoting an increase in the number of fiber tracts. Lan L et al. showed that acupuncture in a rat IS model significantly increased the local anti-inflammatory effect of stroke, and they suggested that it could exert neuroprotective effects by inhibiting the release of local cellular inflammatory factors (including TNF-α, heat shock protein 70, and Toll-like receptors) to achieve control of the inflammatory response process (Lan et al. 2013). Some studies have suggested that acupuncture can reduce oxidative stress induced by cerebral ischemia (Su et al. 2020), such as Guo et al., who found that acupuncture has an antioxidant effect on cerebral ischemic injury by inhibiting NOX-mediated oxidative damage through acupuncture intervention in mice with cerebral ischemia, thus achieving neuroprotection (Guo et al. 2014). Acupuncture also increases brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). BDNF/VEGF are important nutritional mediators for the survival of neural stem cells and they stimulate the growth of new nerves and the migration of neurogenic regions. Tian X et al. after stimulating MCAO rats by electroacupuncture found that acupuncture facilitated stem cell differentiation after cerebral ischemia, increased BDNF and VEGF expression, and upregulated neuroprotective substances (Tian, et al., 2013). Acupuncture also promoted cell proliferation in ischemically injured tissues. It promotes the proliferation of astrocytes and neural stem cells by activating the Wnt/β-catenin cell signaling pathway (Chen et al. 2015); in addition, acupuncture also increases the expression of cell cycle proteins by upregulating stem cell factor, c-Kit gene, matrix metalloproteinase 9 and mRNA expression (Lu et al. 2013). In conclusion, acupuncture can exert neuroprotective effects and promote remodeling of the corticospinal tract through multiple pathways after IS, and the underlying mechanisms still need to be explored in further basic experimental studies.

This systematic review accurately and objectively presents indicators related to corticospinal tract remodeling in patients with IS after acupuncture treatment with the aid of DTI technology, but there are still some limitations to consider; first, all 12 eligible studies declared randomization, but 5 studies did not specifically describe the randomization method. Of all eligible studies, only four described specific allocation concealment methods, and the setting of blinding in acupuncture studies is critical and difficult, which may also lead to selection bias in the results. Since the studies included in this systematic review were studies related to the combination of multimodal MRI and acupuncture, their study design and methodology were relatively new, thus resulting in a small number of included studies. There is no sample size calculation method for studies related to the elucidation of the intrinsic mechanisms of acupuncture treatment with the help of multimodal MRI, and the sample sizes of the included studies were generally insignificant. Studies with multicenter and large samples of RCTs are lacking in this systematic review, thus affecting the strength of evidence and level of recommendation. Second, the control group was treated conventionally without specifying differences in the type, dose, and frequency of specific drugs, leading to increased clinical heterogeneity. The inclusion criteria did not specify the patient's infarct area, and the duration and severity of stroke may vary, which also increases clinical heterogeneity. Finally, the aim of treatment is still to improve the long-term prognosis of the patient's motor function. 2 studies were performed with follow-up, and most of them have not yet clarified the long-term efficacy of acupuncture combined with conventional treatment. Currently, because clinical studies of acupuncture treatment involve the diversity of intervention modalities and the specificity of acupuncture points, improving the design and implementation of high-quality clinical studies of acupuncture is the key to improving the level of clinical evidence. In future studies, the design of such acupuncture clinical studies should be strictly standardized, such as reasonable sample size, more rigorous methodological design, precise randomization methods, implementation of allocation concealment and blinding, use of sham acupuncture controls, and encouraging the publication of negative results.

Conclusion

Existing evidence shows that acupuncture combined with conventional treatment can prove the beneficial effect of improving motor dysfunction in patients after IS, promoting the remodeling of the corticospinal tract, and significantly improving the NIHSS, FMA, BI, FA, and ADC. However, due to the overall quality of eligible studies, more rigorous design, and standardization, high-quality randomized controlled trials are expected to further validate the clinical role of acupuncture in promoting the corticospinal tract.

Declarations

Acknowledgments

Not applicable.

Funding

This study was financially supported by a grant from the National Key R&D Program of China (NO.2018YFC1706001), the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Exploration and Innovation Project (YB202112), Taishan Scholars Program of Shandong Province (NO.tsqn201909186), and Natural Science Foundation of Shandong Province (ZR2019MH056).

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Authors' contributions

Zhihong Meng and Wei Liu contributed to the study design/planning, data interpretation, and funds collection. Weiming Zhu and Shizhe Deng contributed to the study design/planning, data collection/entry, data analysis/statistics, and data interpretation. Hailun Jiang contributed to the preparation of the manuscript and literature analysis/search. Qingqing Jia and Boxuan Li contributed to the data collection/entry. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Conflicts of Interest

There are no conflicts of interest among all authors.

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