High-Definition Transcranial Direct Current Stimulation (HD-tDCS) Enhances Cognitive Recovery After Traumatic Brain...

Traumatic brain injury (TBI) often leads to long-term cognitive deficits. High-definition transcranial direct current stimulation (HD-tDCS) is a non-invasive neuromodulation approach with potential to enhance cognitive recovery. However, the underlying mechanisms by which tDCS influences neural synapses following mild TBI remain unclear. In this study, we aimed to identify the optimal HD-tDCS intervention cycle for improving cognition after repetitive mild TBI (rmTBI) in mice and to elucidate synaptic mechanisms.

Male C57BL/6J mice underwent mild closed-head injury and received HD-tDCS (0.5 mA, 20 min/day) over the right parietal cortex. Cognitive performance was evaluated after 5, 10, and 15 days of stimulation using Y-maze and novel object recognition tests. Synaptic protein expression (PSD-95, SYN, NMDAR, GluA1) and BDNF/TrkB/CREB signaling pathway components were assessed via Western blot, while c-Fos expression was examined by immunofluorescence staining. Dendritic spine density was examined using Golgi staining. In addition, exploratory molecular modeling was performed to assess potential interactions between electric fields and the BDNF-TrkB complex. Separately, to contextualize our experimental findings, we also analyzed the public single-cell RNA-sequencing dataset GSE180862 as part of the study design.

HD-tDCS improved learning and memory performance, with the 15-day protocol showing the most robust effects among the tested schedules at the same post-injury endpoint. Behavioral improvements were accompanied by increased expression of BDNF-associated signaling proteins, elevated synaptic marker levels, and enhanced dendritic spine density in the hippocampus. In the 15-day stimulation group, a numerical trend toward sustained cognitive benefit was observed at 2 weeks after the end of stimulation, although the difference did not reach statistical significance. Molecular modeling suggested potential field-protein interactions but did not establish direct conformational modulation in vivo.

Cognitive recovery improved following HD-tDCS intervention, accompanied by upregulation of BDNF/TrkB/CREB pathway-related proteins, synaptic markers, and dendritic spine density. These findings suggest a close association between repeated HD-tDCS and plasticity-related molecular changes after brain injury, although causal evidence for pathway activation requires further investigation.