Specific mode acupoint electrical stimulation combined with NGF for neurological recovery in ischemic stroke...

Nerve growth factor (NGF) has neurorestorative potential after ischemic stroke, but its efficacy may be limited by the blood-brain barrier (BBB). Preclinical studies suggested that specific mode acupoint electrical stimulation (SMES) may transiently increase BBB permeability and facilitate neurotrophic factor delivery. This study evaluated the efficacy and safety of SMES combined with NGF in ischemic stroke and explored treatment-associated functional brain changes.

In this multicentre, randomized, placebo-controlled trial, adults aged 30-80 years with first-ever ischemic stroke, 14 days to 6 months after onset, modified Rankin Scale (mRS) score 3-4, and MMSE score < 27 were randomly assigned (1:1:1:1) to acupuncture + placebo, acupuncture + NGF, SMES + placebo, or SMES + NGF. NGF or placebo was administered by daily intramuscular injection for 28 days, followed by acupuncture or SMES at GV20 and GV26. The primary efficacy outcome was longitudinal change in mRS score. Secondary outcomes included the Modified Barthel Index, Fugl-Meyer Assessment, Tinetti Performance-Oriented Mobility Assessment, Montreal Cognitive Assessment, and Loewenstein Occupational Therapy Cognitive Assessment. Outcomes were assessed at baseline, week 2, and week 4, with mRS and MoCA further assessed during follow-up. Exploratory rs-fMRI and fNIRS assessments were performed at baseline and week 4.

Among 324 randomized participants, 296 completed treatment and follow-up. Repeated-measures ANOVA showed significant time and group-by-time effects for mRS, indicating different recovery trajectories among groups. In factorial analysis, NGF had a significant main effect on mRS improvement (P = 0.001), whereas the SMES main effect and SMES-by-NGF interaction were not significant. Cognitive outcomes showed a clearer combined-treatment pattern: the SMES + NGF group had the greatest improvements in MoCA and LOTCA at week 4, and the SMES-by-NGF interaction for MoCA was significant at week 4 (P = 0.019) and during follow-up (P < 0.001). Exploratory neuroimaging analyses suggested treatment-associated functional brain changes. Six adverse events occurred, with no serious treatment-related adverse events.

NGF-containing interventions were associated with improved neurological disability after ischemic stroke, while SMES combined with NGF showed additional benefits for cognitive recovery. SMES combined with NGF may represent a promising adjunctive strategy for post-stroke rehabilitation.

The protocol was registered in the Clinical Trials repository under NCT05231694.