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The breadth of brain disorders and functions reported responsive to transcranial direct current stimulation (tDCS) suggests a generalizable mechanism of action. Prior efforts characterized its cellular targets including neuron, glia and endothelial cells. We propose tDCS also modulates the substance transport in brain tissue. High resolution multiphoton microscopy imaged the spread across rat brain tissue of fluorescently-labeled solutes injected through the carotid artery after tDCS. The effective solute diffusion coefficient of brain tissue (D eff ) was determined from the spatio-temporal solute concentration profiles using an unsteady diffusion transport model. 5–10 min post 20 min–1 mA tDCS, D eff  increased by ~ 10% for a small solute, sodium fluorescein, and ~ 120% for larger solutes, BSA and Dex-70k. All increases in D eff  returned to the control level 25–30 min post tDCS. A mathematical model for D eff  in the extracelluar space (ECS) further predicts that this dose of tDCS increases D eff  by transiently enhancing the brain ECS gap spacing by ~ 1.5-fold and accordingly reducing the extracellular matrix density. The cascades leading ECS modulation and its impact on excitability, synaptic function, plasticity, and brain clearance require further study. Modulation of solute diffusivity and ECS could explain diverse outcomes of tDCS and suggest novel therapeutic strategies.

Modulation of solute diffusivity in brain tissue as a novel mechanism of transcranial direct current stimulation (tDCS)