Neuroprotection by Transcranial Direct Current Stimulation in Rodent Models of Focal Ischemic Stroke: A Meta-Analysis

Abstract

Infarct size is associated with stroke severity in clinical studies, so reducing it has become an important target and research hotspot in the treatment of ischemic stroke. Some preclinical studies have shown transcranial direct current stimulation (tDCS) reduced infarct size and improved neurological deficit, but others have not found beneficial effects. Besides, the optimal pattern of tDCS for ischemic stroke remains largely unknown. To shed light on the current circumstance and future research directions, the systematic review evaluated the effect of different tDCS paradigms in reducing infarct size and improving neurological deficit in rodent models of ischemic stroke and assessed the methodological quality of current literature. We searched the MEDLINE (via PubMed), EMBASE, Web of Science, and Scopus from their inception to August 18, 2021, to identify studies evaluating the effects of tDCS in rodent models of ischemic stroke. Eight studies were included, of which seven studies were included in the meta-analysis. The results showed cathodal tDCS, rather than anodal tDCS, reduced infarct size mainly measured by tetrazolium chloride and magnetic resonance imaging (standardized mean difference: −1.13; 95% CI: −1.72, −0.53; p = 0.0002) and improved neurological deficit assessed by a modified neurological severity score (standardized mean difference: −2.10; 95% CI: −3.78, −0.42; p = 0.01) in an early stage of focal ischemic stroke in rodent models. Subgroup analyses showed effects of cathodal tDCS on infarct size were not varied by ischemia duration (ischemia for 1, 1.5, and 2 h or permanent ischemia) and anesthesia (involving isoflurane and ketamine). The overall quality of studies included was low, thus the results must be interpreted cautiously. Published studies suggest that cathodal tDCS may be a promising avenue to explore for augmenting rehabilitation from focal ischemic stroke. Considering the methodological limitations, it is unreliable to blindly extrapolate the animal data to the clinical practice. Future research is needed to investigate the mechanism of tDCS in a randomized and blinded fashion in clinically relevant stroke models, such as elderly animals, female animals, and animals with comorbidities, to find an optimal treatment protocol.

Transcutaneous Electrical Nerve Stimulation in Rodent Models of Neuropathic Pain: A Meta-Analysis

“…In addition, to obtain the most reasonable results and thereby help the future animal research design, we utilized the SYRCLE's risk of bias tool for animal studies to evaluate the quality of current studies. Besides, meta-analyses of animal studies can explore the influence of the heterogeneity (Hooijmans et al, 2014a;Huang et al, 2021;Velzen et al, 2021), an important finding of this meta-analysis is that TENS was not a timingdependent intervention, which may expand the applicability of TENS to some extent.…”

“…TENS and control data about paw withdrawal thresholds expressed as an absolute value or a percentage after TENS treatment at identical time points were extracted. When quantitative data were not explicitly reported in text and supplementary materials, we extracted the data from figures using Engauge Digitizer (Huang et al, 2021). The primary outcome mechanical threshold was used in the meta-analysis if reported and available (91% of included studies), otherwise thermal threshold or cold threshold was used as an alternative.…”

“…However, to avoid drawing wrong conclusions and thereby gain the most accurate, reliable, and reasonable findings, stratified analyses exploring the influence of the heterogeneity were conducted only if there were three or more comparable studies in a certain index. Another limitation is that the sample sizes of included studies are relatively low, which might restrict the statistical power (Hooijmans et al, 2014a;Huang et al, 2021;Velzen et al, 2021). However, The Principles of Humane Experimental Technique, also known as the "3 Rs, " called for every effort to reduce to a minimum the number of animals used in experiments (Flecknell, 2002), as such we would not overcriticize this issue.…”

“…However, The Principles of Humane Experimental Technique, also known as the "3 Rs, " called for every effort to reduce to a minimum the number of animals used in experiments (Flecknell, 2002), as such we would not overcriticize this issue. And fortunately, in metaanalyses of animal studies, it is suggested to focus on the effects direction rather than effect size itself, mainly due to the inevitable heterogeneity (Hooijmans et al, 2014a;Huang et al, 2021). Besides, some included studies did not mention the baseline data of intervention and control groups, which means we had to assess whether different groups were comparable and how this factor may influence the findings.…”

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

“…It is conceivable that external stimuli might change the contents of soluble factors released from both oligodendrocytes and neurons, activating numerous signaling pathways. Therefore, the stimuli parameters, such as the duration, current input, and frequency, need to be optimized for each disease condition [113]. With a clearer understanding of molecular mechanisms, the modulation of neural activity could become a novel therapeutic strategy for the treatment of demyelinating diseases [114].…”