Longo Valentina, Barbati Saviana Antonella, Re Agnese, Paciello Fabiola, Bolla Maria, Rinaudo Marco, Miraglia Francesca, Alù Francesca, Di Donna Martina Gaia, Vecchio Fabrizio, Rossini Paolo Maria, Podda Maria Vittoria, Grassi Claudio
Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy (V.L., S.A.B., A.R., F.P., M.B., M.R., M.G.D.D., M.V.P., C.G.).
Brain Connectivity Laboratory, Department of Neuroscience and Neurorehabilitation, IRCCS San Raffaele Roma, Italy (F.M., F.A., F.V., P.M.R.).
Stroke. 2022 May;53(5):1746-1758. doi: 10.1161/STROKEAHA.121.034200. Epub 2022 Mar 16.
BACKGROUND: More effective strategies are needed to promote poststroke functional recovery. Here, we evaluated the impact of bihemispheric transcranial direct current stimulation (tDCS) on forelimb motor function recovery and the underlying mechanisms in mice subjected to focal ischemia of the motor cortex. METHODS: Photothrombotic stroke was induced in the forelimb brain motor area, and tDCS was applied once per day for 3 consecutive days, starting 72 hours after stroke. Grid-walking, single pellet reaching, and grip strength tests were conducted to assess motor function. Local field potentials were recorded to evaluate brain connectivity. Western immunoblotting, ELISA, quantitative real-time polymerase chain reaction, and Golgi-Cox staining were used to uncover tDCS-mediated stroke recovery mechanisms. RESULTS: Among our results, tDCS increased the rate of motor recovery, anticipating it at the early subacute stage. In this window, tDCS enhanced BDNF (brain-derived neurotrophic factor) expression and dendritic spine density in the peri-infarct motor cortex, along with increasing functional connectivity between motor and somatosensory cortices. Treatment with the BDNF TrkB (tropomyosin-related tyrosine kinase B) receptor inhibitor, ANA-12, prevented tDCS effects on motor recovery and connectivity as well as the increase of spine density, pERK (phosphorylated extracellular signal-regulated kinase), pCaMKII (phosphorylated calcium/calmodulin-dependent protein kinase II), pMEF (phosphorylated myocyte-enhancer factor), and PSD (postsynaptic density)-95. The tDCS-promoted rescue was paralleled by enhanced plasma BDNF level, suggesting its potential role as circulating prognostic biomarker. CONCLUSIONS: The rate of motor recovery is accelerated by tDCS applied in the subacute phase of stroke. Anticipation of motor recovery via vicariate pathways or neural reserve recruitment would potentially enhance the efficacy of standard treatments, such as physical therapy, which is often delayed to a later stage when plastic responses are progressively lower.
背景：需要更有效的策略来促进中风后的功能恢复。在此，我们评估了双半球经颅直流电刺激（tDCS）对运动皮层局灶性缺血小鼠前肢运动功能恢复的影响及其潜在机制。 方法：在前肢脑运动区诱导光血栓性中风，中风后72小时开始，每天进行一次tDCS，连续进行3天。进行网格行走、单颗粒抓取和握力测试以评估运动功能。记录局部场电位以评估脑连接性。采用蛋白质免疫印迹法、酶联免疫吸附测定法、定量实时聚合酶链反应和高尔基-考克斯染色法来揭示tDCS介导的中风恢复机制。 结果：在我们的研究结果中，tDCS提高了运动恢复率，并在亚急性期早期就有预期效果。在此窗口期，tDCS增强了梗死灶周围运动皮层中脑源性神经营养因子（BDNF）的表达和树突棘密度，同时增加了运动皮层与体感皮层之间的功能连接。用BDNF的TrkB（原肌球蛋白相关酪氨酸激酶B）受体抑制剂ANA-12进行治疗，可阻止tDCS对运动恢复和连接性的影响，以及树突棘密度、磷酸化细胞外信号调节激酶（pERK）、磷酸化钙/钙调蛋白依赖性蛋白激酶II（pCaMKII）、磷酸化肌细胞增强因子（pMEF）和突触后密度蛋白（PSD）-95的增加。tDCS促进的恢复与血浆BDNF水平升高同时出现，表明其作为循环预后生物标志物的潜在作用。 结论：在中风亚急性期应用tDCS可加速运动恢复率。通过替代途径或神经储备募集来预期运动恢复，可能会提高标准治疗（如物理治疗）的疗效，而物理治疗通常会推迟到后期，此时可塑性反应会逐渐降低。
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