From the Department of Neurology and Comprehensive Stroke Center (M.B.H., J.H., J.L.S.), David Geffen School of Medicine at UCLA.
Department of Biomedical Engineering, The City College of New York (CCNY) (M.B.).
Stroke. 2019 Oct;50(10):2892-2901. doi: 10.1161/STROKEAHA.119.025364. Epub 2019 Sep 4.
Background and Purpose- Brain electrical stimulation, widely studied to facilitate recovery from stroke, has also been reported to confer direct neuroprotection in preclinical models of acute cerebral ischemia. Systematic review of controlled preclinical acute cerebral ischemia studies would aid in planning for initial human clinical trials. Methods- A systematic Medline search identified controlled, preclinical studies of central nervous system electrical stimulation in acute cerebral ischemia. Studies were categorized among 6 stimulation strategies. Three strategies applied different stimulation types to tissues within the ischemic zone (cathodal hemispheric stimulation [CHS], anodal hemispheric stimulation, and pulsed hemispheric stimulation), and 3 strategies applied deep brain stimulation to different neuronal targets remote from the ischemic zone (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation). Random-effects meta-analysis assessed electrical stimulation modification of final infarct volume. Study-level risk of bias and intervention-level readiness-for-translation were assessed using formal rating scales. Results- Systematic search identified 28 experiments in 21 studies, including a total of 350 animals, of electrical stimulation in preclinical acute cerebral ischemia. Overall, in animals undergoing electrical stimulation, final infarct volumes were reduced by 37% (95% CI, 34%-40%; <0.001), compared with control. There was evidence of heterogeneity of efficacy among stimulation strategies (=93.1%, <0.001). Among the within-ischemic zone stimulation strategies, only CHS significantly reduced the infarct volume (27 %; 95% CI, 22%-33%; <0.001); among the remote-from ischemic zone approaches, all (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation) reduced infarct volumes by approximately half. On formal rating scales, CHS studies had the lowest risk of bias, and CHS had the highest overall quality of intervention-level evidence supporting readiness to proceed to clinical testing. Conclusions- Electrical stimulation reduces final infarct volume across preclinical studies. CHS shows the most robust evidence and is potentially appropriate for progression to early-stage human clinical trial testing as a promising neuroprotective intervention.
背景与目的-脑电刺激在促进中风康复方面的研究已经得到广泛的研究，同时也有研究报道其在急性脑缺血的临床前模型中具有直接的神经保护作用。对临床前急性脑缺血对照研究进行系统评价有助于为初始的人类临床试验规划提供依据。
方法-通过系统的 Medline 检索，确定了中枢神经系统电刺激治疗急性脑缺血的对照临床前研究。研究根据 6 种刺激策略进行分类。其中 3 种策略将不同的刺激类型应用于缺血区的组织内（阴极半球刺激[CHS]、阳极半球刺激和脉冲半球刺激），另外 3 种策略将深部脑刺激应用于远离缺血区的不同神经元靶点（小脑顶核刺激、丘脑底核血管扩张区刺激和导水管周围灰质背侧刺激）。采用随机效应荟萃分析评估电刺激对最终梗死体积的影响。使用正式的评分量表评估研究水平的偏倚风险和干预水平的转化准备情况。
结果-系统搜索确定了 21 项研究中的 28 个实验，共纳入 350 只动物。与对照组相比，电刺激组动物的最终梗死体积减少了 37%（95%CI，34%-40%；<0.001）。不同刺激策略的疗效存在显著异质性（=93.1%，<0.001）。在缺血区内刺激策略中，只有 CHS 显著降低了梗死体积（27%；95%CI，22%-33%；<0.001）；在远离缺血区的方法中，所有方法（小脑顶核刺激、丘脑底核血管扩张区刺激和导水管周围灰质背侧刺激）均使梗死体积减少了约一半。在正式的评分量表中，CHS 研究的偏倚风险最低，CHS 的干预水平证据质量总体最高，支持向临床测试推进。
结论-电刺激可降低临床前研究中的最终梗死体积。CHS 显示出最有力的证据，并且作为一种有前途的神经保护干预措施，可能适合推进到早期人类临床试验测试。
