- Academic Editor
Objective: To evaluate the efficacy and safety of noninvasive therapies
in the treatment of central poststroke pain (CPSP) by network meta-analysis and
to provide an evidence-based basis for clinical practice. Methods:
PubMed, Cochrane Library, EMBASE, CNKI, Wanfang, and VIP were searched for
clinical randomized controlled studies on noninvasive therapy for CPSP. The
retrieval time limit was from the establishment of each database to July 2022.
The bias risk assessment tool recommended by Cochrane was used to evaluate the
quality of the included randomized controlled trials (RCTs). Stata 14.0 was used
for network meta-analysis, and Review Manager 5.3 software was used for
traditional meta-analysis. Results: Twelve RCTs involving 8 treatment
schemes and 641 patients were finally included. The results of the network
meta-analysis showed the following rankings in visual analysis scale (VAS): super laser injury on
stellate ganglia (SLI)
Stroke is a common cerebrovascular disease with a high disability rate that mostly occurs in elderly individuals. Stroke is often accompanied by various sequelae, such as motor, swallowing, language and cognitive dysfunction. As one of the common sequelae of patients after stroke, central poststroke pain (CPSP) can have a very significant impact on the body, mind and daily life of patients. The pathogenesis of CPSP is not clear. Previous studies have suggested that CPSP is caused by thalamic damage, which results in thalamic pain. However, subsequent studies have shown that injuries in other parts outside the thalamus, such as the posterior limb of the internal capsule, the parietal cortex of the brain stem, the medulla oblongata, the insula, the tectum and other parts, can cause pain, and CPSP has a variety of clinical manifestations, including local, hemiplegia, and crossed pain and sensory abnormalities. Many studies have suggested that the pathogenesis of CPSP is complex [1, 2, 3].
At present, the treatment goal of CPSP is mainly to alleviate symptoms, which makes a complete cure difficult to achieve. Common therapies in the clinic include drug therapy and neuromodulation therapy. Depression drugs (amitriptyline and venlafaxine), anticonvulsant drugs (gabapentin, pregabalin, and lamotrigine) and glutamatergic drugs (ketamine) are common in drug therapy. The World Association for Neuroregulation defines “neuroregulation” as a biomedical engineering technology that uses invasive or noninvasive technology to change the activity of the central and peripheral nervous systems by means of electrical stimulation or drugs, thus improving symptoms and the quality of life of patients. Neuroregulation is an emerging discipline. Compared with the original damage and removal, it focuses on regulation; that is, the process is reversible, and the treatment parameters can be adjusted in vitro [4]. For some patients with strong drug resistance, invasive neuromodulation therapy is often used for treatment, such as invasive motor cortex (M1) stimulation (MCS) [5] and deep brain stimulation (DBS) [6]. However, invasive neuromodulation therapy is more traumatic and expensive, and it easily causes postoperative neurological damage, making it difficult to apply in clinical practice. In recent years, many noninvasive complementary therapies have gradually appeared for the clinical treatment of CPSP, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). As the most commonly used noninvasive nerve regulation technology, rTMS and continuous theta burst stimulation (cTBS) use a changing magnetic field to generate an induction electric field in the cerebral cortex, thus regulating a series of physiological activities of neurons [7]. Unlike rTMS, tDCS mainly increases or decreases the excitability of neurons by inputting a weak constant direct current (DC) current into the brain, thus causing changes in brain function [8]. In addition, there are transcutaneous acupoint electrical stimulation (TAES) based on traditional Chinese medicine, super laser injury on stellate ganglia (SLI) based on laser irradiation principle and psychological therapy (like psychological training of mindfulness (PT) and music therapy (MT)). Some clinical studies [9] have confirmed their effectiveness, but the advantages and disadvantages of different noninvasive complementary therapies are rarely mentioned. Based on the frequency method of network meta-analysis, this study evaluates the clinical efficacy and safety of different noninvasive therapies in the treatment of CPSP with the visual analysis scale (VAS), clinical adverse reaction rate and total clinical effective rate as outcome indicators and ranks the related efficacy based on surface under the cumulative ranking (SUCRA).
This meta-analysis has been registered on PROSPERO, registration number CRD42022348055. PRISMA checklist is shown in Supplementary Materials.
The retrieval strategy adopted a combination of subject words and free words and adjusted the search words according to the search results. The retrieval time was from the establishment of the database to July 2022. The search databases were PubMed, Excellent Medica Database (EMBASE), Cochrane Library, CNKI, Wanfang, and VIP. The search terms included central poststroke pain, CPSP, central neurological pain after stroke, central neurological pain after cerebrovascular disease, central neurological pain after cerebral information, central neurological pain after intracerebral haemorrhage, and thalamic pain. See the appendix for all search formulas.
(1) The study was a randomized controlled trial (RCT). (2) The subjects were identified as stroke patients by brain common therapy (CT), magnetic resonance tmaging (MRI) and other imaging examinations and were diagnosed with CPSP with a pain score of 3 or more. (3) Treatment plan: The control group was treated with routine therapy (including routine rehabilitation training) combined with routine painkillers (gabapentin, pregabalin, and lamotrigine), and the treatment group was treated with noninvasive therapy based on routine rehabilitation training. (4) Outcome indicators: the main indicator was VAS, and the secondary indicators were clinical total effective rate and clinical adverse reaction rate.
(1) Unrelated literature, review, case reports, meta-analyses and other nonrandomized controlled trials; (2) Documents with repeatedly published data, incomplete data or unavailable data; (3) Repeatedly published literature in Chinese and English.
Two researchers independently conducted literature screening and data extraction according to the inclusion and exclusion criteria and cross-checked the results. In case of disagreement, the third researcher participated in the discussion and decision. Endnote (Thomson ResearchSoft, Stanford, CT, USA) and Excel software (Microsoft, Redmond, WA, USA) were used for literature management and data extraction, mainly including the basic characteristics of cases included in the literature, intervention measures, course of treatment and outcome indicators. All continuous data are included in the difference before and after treatment (that is, the difference between indicators after treatment and before treatment). If the original text is not calculated, it will be calculated by itself. The formula is as follows: corr is usually taken as 0.5.
Mean
The quality of the included literature was evaluated according to the quality evaluation scale recommended in the Cochrane Handbook, including 6 parts: reporting bias, detection bias, performance bias, selection bias, loss of visit bias and other bias. Each part of the evaluation content can be judged as high, medium and low risk according to the standard.
This study was based on the framework of frequency. For the continuity index,
the mean difference (MD) was used as the effect quantity. If it was a binary
variable, the odds ratio (OR) was used as the effect quantity, and the
corresponding 95% confidence interval (CI) was calculated. Stata 14.0 software
(Stata Corporation, Lakeway, TX, USA) was used to draw a network evidence
relationship diagram, forest diagram, grade probability diagram, funnel diagram
and corresponding statistics. When testing the global consistency, if the
difference was not statistically significant, that is, p
A total of 2679 relevant studies were obtained in the initial examination, including 329 from CNKI, 680 from Wanfang, 178 from VIP, 597 from PubMed, 683 from EMBASE, and 212 from the Cochrane Library. They were imported into the software Endnote. After eliminating duplicate studies and strictly complying with the nanodischarge standard, 12 RCTs [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19] were finally included, all of which were double-arm trials, with a total of 641 patients. Eight treatment schemes were involved, including common therapy (CT), SLI, MT, tDCS, TAES, rTMS, PT, and cTBS. The document screening process and results are shown in Fig. 1; the basic information of the included documents is shown in Table 1 (Ref. [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]).
Flow chart of literature screening.
Author | Year | Number of patients | Age (year) | Male/female | Treatment | Intervention period | Outcome indicator | |||
I | C | I | C | I | C | |||||
Zhou N [11] | 2021 | 39 | 40 | 54.26 |
51.85 |
43/26 | PT | CT | 4W | VAS, total clinical effective rate |
Chen JM [12] | 2020 | 20 | 20 | 51.5 |
55.1 |
25/15 | rTMS | CT | 2W | VAS, clinical adverse reaction rate |
Ou HN [13] | 2015 | 29 | 30 | 59.78 |
58.27 |
33/26 | TAES | CT | 2W | VAS |
Guo M [14] | 2020 | 40 | 40 | 61.2 |
59 |
43/37 | MT | CT | 4W | clinical adverse reaction rate |
He BJ [15] | 2022 | 40 | 40 | - | - | - | SLI | CT | 2W | VAS, clinical adverse reaction rate |
Sun W [16] | 2019 | 20 | 20 | 48.1 |
50.1 |
27/13 | rTMS | CT | 4W | VAS, clinical adverse reaction rate |
Duan Q [17] | 2021 | 9 | 9 | 51 |
49 |
- | cTBS | CT | 2W | VAS |
Tan J [18] | 2021 | 19 | 21 | 64.11 |
66.24 |
20/20 | tDCS | CT | 2W | VAS |
Li N [19] | 2016 | 37 | 33 | 58.3 |
58.1 |
35/35 | rTMS | CT | 4W | VAS, total clinical effective rate |
Zhao YY [20] | 2021 | 41 | 42 | 52.03 |
52.11 |
47/35 | rTMS | CT | 2W | VAS, total clinical effective rate |
Bae SH [21] | 2014 | 7 | 7 | 52.3 |
51.1 |
7/7 | tDCS | CT | 3W | VAS |
Zhao CQ [22] | 2021 | 19 | 19 | 49.55 |
21/17 | rTMS | CT | 3W | clinical adverse reaction rate |
I, intervention group; C, Control group; PT, psychological training; CT, common therapy; rTMS, repetitive transcranial magnetic stimulation; TAES, transcutaneous acupoint electrical stimulation; MT, music therapy; SLI, super laser injury; cTBS, continuous theta burst stimulation; tDCS, transcranial direct current stimulation; VAS, visual analysis scale.
The included studies were evaluated using the Cochrane manual 5.1.0 bias risk assessment tool. In terms of the random allocation method, 9 studies were low risk, and the random number table method [11, 13, 14, 15, 16, 17, 20] was used for random allocation. Two studies were high risk [18, 19] and did not mention randomization, and the remaining studies only mentioned randomization without reporting specific random allocation methods. In terms of concealment of the random allocation scheme, one study [22] mentioned that allocation concealment was low risk, and the remaining the studies did not mention it. In terms of the blind method of the random allocation scheme, two studies [11, 22] mentioned the use of the blind method, one of which was single-blinded [11] and the other double-blinded [12]. The measurement of outcome indicators was not mentioned in the literature. In terms of data integrity, the data included in the study were complete. In terms of selective reporting of research results, the included studies were all low risk. Other sources of bias were unclear. The risk assessment of bias in the included studies is shown in Fig. 2.
Risk of bias graph. (A) Risk of bias summary. (B) Risk of bias graph.
Visual Analysis Scale (VAS) was reported in 10 studies involving 7 noninvasive treatment regimens. In the figure, the dot size represents the sample size of the intervention measure, and the line thickness represents the number of RCTs using the two treatment schemes. The seven treatments are all direct comparisons, and there is no closed-loop formation. The number of studies comparing rTMS with CT treatment was the largest (4 RCTs). The VAS evidence network is shown in Fig. 3A.
Relevant processing diagram of VAS. (A) Network diagram of VAS scores. (B) Funnel diagram of FMA-UE scores. (C) Network meta-analysis of VAS scores. PT, psychological training; CT, common therapy; rTMS, repetitive transcranial magnetic stimulation; TAES, transcutaneous acupoint electrical stimulation; MT, music therapy; SLI, super laser injury; cTBS, continuous theta burst stimulation; tDCS, transcranial direct current stimulation; 95% CI, 95% confidence interval; VAS, visual analysis scale.
In this study, seven different treatment schemes were involved in the outcome indicators of VAS. Dots of different colours in the funnel chart represent the direct comparison between two different rehabilitation treatment schemes, and the number of dots represents the number of studies. Most of the dots in the funnel map of this study are symmetrically distributed on the vertical line and its two sides. Both sides are essentially symmetrical, but a certain degree of publication bias may persist. See Fig. 3B for the funnel map.
For the same intervention measures, no obvious source of heterogeneity was found
(tDCS vs. CT, I
Treatment | Numbers of RCTs | MD [95% CI] | I |
Z | p | Effect |
rTMS vs. CT | 4 | –1.33 [–1.67, –0.99] | 0 | 7.61 | Fixed | |
cTBS vs. CT | 1 | –1.00 [–2.58, 0.58] | - | 1.24 | 0.21 | Fixed |
SLI vs. CT | 1 | –2.12 [–2.70, –1.54] | - | 7.16 | Fixed | |
TAES vs. CT | 1 | –0.89 [–1.12, –0.66] | - | 7.64 | Fixed | |
tDCS vs. CT | 2 | –1.84 [–2.39, –1.28] | 67 | 6.44 | Random | |
PT vs. CT | 1 | –1.70 [–2.01, –1.39] | - | 10.82 | Fixed |
Numbers of RCTs, The number of studies involving comparison of such interventions included; RCTs, randomized controlled trials; MD [95% CI], mean difference [95% confidence interval]; I
Seven treatment schemes were analysed by network meta-analysis, and 10 comparisons showed significant differences. The decreases in the VASs of continuous theta burst stimulation (cTBS) (MD = –1.33, 95% CI [–1.67, 0.99]), SLI (MD = –2.12, 95% CI [–2.70, –1.54]), TAES (MD = –0.89, 95% CI [–1.12, –0.66]), tDCS (MD = –1.84, 95% CI [–2.39, –1.28]), PT (MD = –1.70, 95% CI [–2.01, –1.39]) were significantly larger than that of CT; compared with rTMS, the decrease in VAS for SLI (MD = –0.79, 95% CI [–1.47, –0.12]) was larger than that for rTMS, and the decrease in VAS for TAES (MD = 0.44, 95% CI [0.03, 0.85]) was larger than that for rTMS. The decrease in VAS for TAES (MD = 1.23, 95% CI [0.61, 1.85]) was larger than that for SLI. Compared with TAES, tDCS (MD = –0.95, 95% CI [–1.55, –0.34]) and PT (MD = –0.81, 95% CI [–1.19, –0.43]) had larger VAS decreases. Other comparisons did not show significant differences, as shown in Fig. 3C.
Three studies reported the total clinical efficacy, including three noninvasive treatment regimens. The three treatments were all directly compared, and no closed loop formed. The number of studies comparing rTMS with CT treatment was the largest (2 RCTs). Few studies included this research index, and a traditional meta-analysis and funnel analysis consequently were not performed. The evidence network is shown in Fig. 4A.
Relevant processing diagram of total clinical effective rate. (A) Network diagram of the total clinical effective rate. (B) Network meta-analysis of the total clinical effective rate score.
Three treatment schemes were analysed by network meta-analysis, and one comparison had a significant difference. Compared with CT, the total clinical effective rate of rTMS (OR = 2.73, 95% CI [1.38, 5.38]) was significantly higher than that of CT, and no significant difference was detected in other comparisons, as shown in Fig. 4B.
Among all included studies, five studies [12, 14, 15, 16, 22] reported adverse reactions, which were mainly mild adverse reactions, such as mild headache, fatigue, dizziness, dizziness, drowsiness, dry mouth, temporary scalp numbness or facial muscle twitching. See Table 3 (ref. [12, 14, 15, 16, 22]) for the occurrence of adverse reactions/events.
Author | Treatment | I | C |
Chen JM 2020 [12] | rTMS vs. CT | 3 cases of mild headache | 1 case of mild headache |
Guo M 2020 [14] | MT vs. CT | 2 cases of fatigue, 1 case of dizziness and 2 cases of lethargy | 1 case of fatigue, 1 case of dizziness and 3 cases of lethargy |
He BJ 2022 [15] | SLI vs. CT | 1 case of sleepiness, 1 case of dry mouth, 1 case of dizziness | 3 cases of sleepiness, 4 cases of dry mouth, 3 cases of dizziness |
Sun W 2019 [16] | rTMS vs. CT | 1 case of transient mild headache | None |
Zhao CQ 2021 [22] | rTMS vs. CT | 3 cases of short-term scalp numbness or facial muscle twitch | None |
I, intervention group; C, Control group.
Five studies reported the clinical adverse reaction rate, including four noninvasive treatment regimens. All four treatments were directly compared, and no closed loop formed. The number of studies comparing rTMS with CT treatment was the largest (3 RCTs). Few studies included this research index, and traditional meta-analysis and funnel analysis were consequently not performed. The evidence network is shown in Fig. 5A.
Relevant processing diagram of clinical adverse reaction rate. (A) Network diagram of the clinical adverse reaction rate. (B) Network meta-analysis of clinical adverse reaction rate.
The three treatment schemes were analysed by network meta-analysis, and the two comparisons had significant differences. The clinical adverse reaction rate of SLI (OR = 0.24, 95% CI [0.06, 0.96]) was significantly lower than that of CT. The clinical adverse reaction rate of SLI (OR = 0.06, 95% CI [0.01, 0.48]) was significantly lower than that of rTMS. No significant difference was detected in other comparisons, as shown in Fig. 5B.
According to the results of SUCRA, SLI may be the most effective intervention to
reduce VAS. The SUCRA probability ranking results were as follows: SLI (92.4%)
Cumulative probability ranking plot. (A) VAS. (B) Total clinical effective rate. (C) Clinical adverse reaction rate.
The results of SUCRA suggest that PT may be the most effective intervention to
increase the total clinical effective rate. The SUCRA probability ranking results
were as follows: PT (89.9%)
According to the results of SUCRA, SLI may be the safest intervention. The SUCRA
probability ranking results were as follows: rTMS (95.9%)
Central Poststroke Pain (CPSP) is one of the most common complications after stroke, and clinical
first-line central analgesics often have poor curative effects for patients with
strong drug resistance. Invasive neuromodulation therapy is not only expensive
but may also be accompanied by serious irreversible sequelae. Therefore,
noninvasive complementary therapy has become a research hotspot in the clinical
treatment of CPSP. In addition to conventional therapy, this study involved seven
noninvasive therapies, which can be roughly divided into ① electric
stimulation therapy: rTMS, cTBS, tDCS, and TAES. rTMS and cTBS are two modes of
TMS that have a good analgesic effect on neuropathic pain [22]. tDCS is a
noninvasive technology that uses a constant, low-intensity direct current
(1~2 mA) to regulate the activity of neurons in the cerebral
cortex. Studies have also confirmed its effectiveness in the treatment of CPSP
[23]. TAES, a new acupuncture treatment method combining transcutaneous
electrical nerve stimulation (TENS) with acupuncture and acupoint therapy, has
been proven to have analgesic effects and peripheral and central mechanisms
similar to acupuncture [24]; ② laser therapy: SLI. As a new technology,
SLI is used to alleviate neuropathic pain based on the principle of affecting the
stellate ganglion [25]. ③ Psychology therapy: MT and PT. As two branches
of psychotherapy, music therapy and mindfulness psychotherapy have gradually
begun to receive attention in the clinical treatment of CPSP. The results of this
study show ranked the VAS as follows: SLI
The VAS has obvious advantages in evaluating subjective factors. This method was first used in psychological research [26, 27]. Later, VAS scores ranging from 0 to 10 were used to judge the degree of pain [28]. During the evaluation, patients are asked to select the score according to their own feelings. A higher score indicates a more severe degree of subjective pain, and the score value can be accurate. The clinical manifestations of CPSP are diverse, but the main characteristics are pain and sensory disorders. At present, the diagnosis of the disease lacks specificity, and the diagnosis largely depends on the subjective feelings of patients. Therefore, VAS is widely used in the pain assessment of CPSP. The results of this study show that among all noninvasive interventions, SLI is most effective in improving the VAS indicators of patients. The stellate ganglion is the main pathway of the sympathetic nerve. Blocking the stellate ganglion is generally believed to be able to expand the blood vessels in the area dominated by the stellate ganglion. More studies have shown that [29] stellate ganglion block (SGB) therapy can alleviate many drug-resistant headaches and reduce the original dosage of drugs. Invasive stellate ganglion block has achieved a good curative effect, while noninvasive stellate ganglion irradiation, as an alternative therapy for stellate nerve block, is safe and practical [25], but relevant studies on the clinical effect of treating CPSP are scarce. The VAS results of the main indicators in this study suggest that the pain relief effect of SLI is the best, but only one study was included. Therefore, this result is limited to the data analysis of the included literature and cannot completely explain the advantages and disadvantages of each clinical efficacy. Nevertheless, the results rain significance for clinical guidance. The secondary indicator of this study is the total clinical effective rate. The results suggest that PT has the best curative effect. Many CPSP patients often have a certain degree of anxiety and depression when drug efficacy is poor, and anxiety is often accompanied by prostaglandins, bradykinins and other secretions that exacerbate pain, leading to a decrease in the pain threshold. This effect results in emotional fluctuations and a loss of confidence in treatment and prognosis. Therefore, mindfulness psychotherapy, a type of systematic psychotherapy, can have a positive effect on the treatment of central neuralgia and limb rehabilitation of stroke patients by mobilizing the enthusiasm of patients and relieving tension and negative emotions, but sufficient clinical research to further confirm this hypothesis is lacking [30]. However, clinicians often note unexpected effects on CPSP patients with routine drug treatment and psychological treatment in clinical practice.
Five studies included in this meta-analysis mentioned adverse reactions after the intervention. The intervention measure with the highest adverse reaction rate was rTMS, which manifested as mild headache, facial twitching or numbness. The adverse reaction rate of SLI was the lowest and mainly manifested as lethargy, dry mouth, and dizziness. All adverse reactions reported in RCTs were mild or transient, and no serious adverse reactions were reported. Therefore, the psychological tension of patients is not excluded. rTMS is a noninvasive neuromodulation therapy based on achieving an analgesic effect with the application of a high-intensity pulsed magnetic field to brain tissue. According to current research, rTMS is effective in the short term and has a limited effect on poststroke central neuralgia. Thus, rTMS is generally considered to not be suitable to be used alone, and other treatment measures, such as combined drug treatment, can improve therapeutic effects [31]. However, attention should be given to evaluation before rTMS treatment in clinical practice to identify patients with intracranial metal implants, cochlear implants, and built-in pulse generators (brain pacemakers, cardiac pacemakers). In this case, rTMS easily causes the built-in pulse generator to fail. Patients with serious physical diseases, those who are using drugs that significantly reduce the threshold of seizures or those who abuse alcohol need to consider the risk-benefit ratio after receiving stimulation treatment, and the use of rTMS is recommended with caution.
In this study, the network meta-analysis method was used for the first time, which can not only compare the indirect and mixed effects between different noninvasive therapies but also compare different treatment schemes for CPSP in the absence of direct comparisons between therapies and identify the best scheme with the greatest probability. This study has the following limitations: (1) Most of the included studies were Chinese studies, and the number of studies was small. Because noninvasive therapy intervention CPSP is a relatively new clinical field, most included studies were drug trials or tested invasive therapies. When studies published in English were included, most of the clinical trials involving noninvasive therapy intervention CPSP were non-RCTs. Except for studies of rTMS, studies on noninvasive therapies are scarce, which may be because rTMS, an alternative therapy of neuromodulation, has long been studied. Consequently, it is more prevalent in the literature. Conversely, other noninvasive therapies are relatively new, and they are not well represented in the literature; (2) The overall quality of the studies was not very high. Although most studies mention random methods, others, such as allocation concealment, blinding methods and potential bias, are not mentioned. (3) The number of RCTs included in the study is insufficient, the sample size is small, with some studies reporting sample sizes of less than 10. Thus, negative results may have not been published. (4) Among the included studies, the length of intervention is somewhat inconsistent, which precludes comparisons between studies and increases clinical heterogeneity; (5) Few outcome indicators are included in this paper. Others, such as the numerical rating scale (NRS), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA), are also common outcome indicators of CPSP, but they were not included mainly because too few other outcome indicators were involved in the RCTs included, and this number was insufficient for meta-analysis; (6) Because few studies were included in this work and their quality was poor, most of the studies did not take the patient’s family genetic history as the basic research index. However, familial genetic factors play a very important role in the onset and prognosis of stroke. I hope that more studies will include the genetic history as a basic index in the future.
In summary, noninvasive complementary therapy can effectively alleviate the pain of CPSP patients, and the efficacy and safety of SLI are relatively significant. However, due to the limitations of this study, the efficacy ranking cannot fully explain the advantages and disadvantages of clinical efficacy but only serves as a clinical reference. In the future, we need to continue clinical trials on noninvasive therapy intervention for CPSP and carry out more multicentre, large sample, double-blind clinical randomized controlled trials to supplement and demonstrate the results of this study.
The datasets analyzed in this article are available upon request to: alis7718@outlook.com.
RYL and LNW designed the review. KYC and HYZcollected and analyzed the data. SAX was responsible for the result analysis and make figures. RYL and SAXsupervised the procedures. LNW wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
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This research received no external funding.
The authors declare no conflict of interest.
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