Acute ischemic stroke (AIS) is a leading cause of death and disability for which treatments are limited to reperfusion therapies, including intravenous thrombolytic (lytic) and endovascular thrombectomy (EVT). Many patients are not candidates for these therapies, and amongst those who receive them, the rate of excellent outcome remains low; only 20-30% are free from disability at 3 months post-stroke. Therefore, there is a critical need to develop additional novel therapies for patients with AIS. Cathodal transcranial direct current stimulation (C-tDCS) is a non-invasive inhibitory neuromodulatory technique that applies a weak electrical current via scalp electrodes. In animal models of acute cerebral ischemia, C-tDCS salvages penumbra (ischemic tissue at risk of infarction), both through direct neuroprotection by inhibiting peri-infarct excitotoxicity and through collateral perfusion enhancement by inducing vasodilation. C-tDCS has many advantages; it is a regionally directed therapy that instantly reaches maximum local concentration, and via high-definition (HD) electrode montages, electrical field’s spatial focality can be enhanced to target each patient’s ischemic tissue only. In our pilot study using HD C-tDCS, we showed that HD C-tDCS can be efficiently applied in AIS, and we observed promising signals of beneficial effects upon imaging biomarkers of neuroprotection and collateral enhancement, including penumbral salvage, improved perfusion, and cerebral blood volume enhancement. Therefore, we propose conducting a multi-site (3 sites), phase 2a, randomized, sham-controlled, dose-optimization study of HD C-tDCS as a neuroprotective and collateral enhancing treatment for AIS with and without lytic. The primary aim of the study is to identify, among six HD C-tDCS dose tiers, an optimal dose regimen that shows adequate safety and efficacy using imaging. Up to 120 AIS patients with cortical strokes and salvageable penumbra who are ineligible for EVT will be enrolled from UCLA, Johns Hopkins, and Duke. According to lytic eligibility, patients will be enrolled either in the lytic-receiving or non-lytic group and subsequently randomized 5:1 to active stimulation vs. sham. The study utilizes an adaptive Bayesian design with bivariate endpoints as its escalation-de-escalation rules. The primary imaging safety rule of radiographic intracranial hemorrhage probability ≤40% and the primary imaging biomarker rule of substantial penumbral salvage probability ≥70% will determine the pace and occurrence of escalation-de-escalation through the dose regimens. Secondary objectives include the effect of HD C-tDCS on additional imaging efficacy biomarkers of neuroprotection and collateral enhancement (hypoperfusion region volume, cerebral blood volume, and infarct growth), and other safety/tolerability endpoints. We will also explore the clinical efficacy of HD C-tDCS. The study primarily aims to find an optimal dose that meets an adequate threshold of safety and...