High-Definition Cathodal Direct Current Stimulation Shows Potential as Noninvasive Treatment for Ischemic Stroke


In comparison with sham, patients on active treatment had higher rates of penumbral tissue salvage and alleviation of hypoperfused ischemic regions.

Mersedeh Bahr Hosseini, MD, a neurologist at UCLA Health

A recently published randomized clinical trial (NCT03574038) showed that high-definition cathodal direct current stimulation (HD C-tDCS) was safe in patients with acute ischemic stroke (AIS), with signals of beneficial effect upon penumbral salvage. Investigators concluded that the findings warrant testing in larger multicenter trials.

Led by Mersedeh Bahr Hosseini, MD, a neurologist at UCLA Health, the first-in-human pilot study included 10 patients, 7 of which were randomized to active treatment and 3 to sham. HD C-tDCS was delivered to the ischemic tissue using 6 individualized montages. These montages were predesigned to cover 6 vascular distribution-specific ischemic fields caused by occlusions of the middle cerebral artery (MCA) trunk, MCA superior division, MCA inferior division, posterior cerebral artery, anterior cerebral artery, and posterior inferior cerebellar artery.

Patients included were within 24 hours from AIS onset, had imaging evidence of cortical ischemic, a presence of salvageable penumbra, and were ineligible for reperfusion therapies. The first 4 patients (3 active, 1 sham) were enrolled at dose tier 1 and received 1 milliamp (mA) of HD C-tDCS for 20 minutes, while the subsequent 6 patients (4 active, 2 sham) were enrolled in tier 2 and received 2 mA of HD C-tDCS for 20 minutes. In active and sham patients, the mean entry National Institutes of Health Stroke Severity (NIHSS) score was 8 (SD, 8.5) and 7 (SD, 2.6), respectively.

The proof-of-concept’s main goal, the feasibility, safety, and tolerability of HD C-tDCS in acute stroke emergency settings, was met, with all patients completing the assigned stimulation period. No discoloration or rash was detected on skin visual inspection after the stimulation, and only 1 tier 1 patient complained of mild skin burning, which was alleviated after a short pause of the stimulation. Of note, 1 patient in tier 2 experienced symptomatic intracranial hemorrhage (sICH); however, investigators concluded the patient had stroke due to septic embolization, which did not meet the entry criteria. Enrollment in tier 2 continued on after this but was ultimately stopped at the 10th patient because of the COVID-19 pandemic.

Five patients on active and 3 patients on sham had imaging biomarkers of neuroprotection and collateral enhancement evaluated at 2 to 4 hours (early time point) and 24 to 30 hours (late time point) in a per-protocol exploratory analysis. All told, findings showed a median reduction of 100% (IQR, 46-100) in the hypoperfused region in the HD C-tDCS group vs an increase of 325% (IQR, 112-412) for those on sham. The median change in quantified relative cerebral blood volume (qrCBV) was 64% (IQR, 40-100) in the active group and –4% (IQR, –7% to 1%) in those on sham.

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One patient with bilateral ischemic of occipital lobes due to bilateral posterior cerebral artery occlusions in the active group experienced penumbral salvage, enhancement of rCBV, and early recanalization only on the stimulated side while the contralateral side, which served as an internal control, remained hypoperfused.

Hosseini et al noted that 2 mechanisms may be contributing to the findings, including "Direct anti-excitatory, anti-apoptotic, and anti-inflammatory effect of C-tDCS leading to cytoprotection of ischemic tissues; electrical field–induced collateral enhancement providing retrograde reperfusion and enhanced recanalization with orthograde reperfusion of ischemic fields. The dose-related rCBV augmentation early following stimulation provides direct support for collateral enhancement as a mechanism through which HD C-tDCS exerts its alleviating effect in acute ischemia."

Additional findings from the study showed a median penumbral salvage of 66% (IQR, 29-80.5) in the C-tDCS group compared with 0% (IQR, 0-0) in sham. A dose-response effect was observed in terms of collateral enhancement, with the highest effects observed at tier 2, and interimediate effects at tier 1 and lowest at sham. In addition, the 24-hour vessel recanalization rate was 80% in the active group vs 33% in sham. At 90 days, per-protocol exploratory analysis findings showed that 3 in the active group had modified Rankin Scale (mRS) scores between 0 and 2 and 2 others had mRS of 3. In comparison with sham, 2 patients had mRS between 0 and 2 and 1 had mRS of 6 at that time point.

1. Bahr-Hosseini M, Nael K, Unal G, et al. High-definition cathodal direct current stimulation for treatment of acute ischemic stroke: a randomized clinical trial. JAMA Netw Open. 2023;6(6):e2319231. doi:10.1001/jamanetworkopen.2023.19231
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