tDCS has been used to treat various brain disorders and its mechanism of action (MoA) was found to be neuronal polarization. Since the blood-brain barrier (BBB) tightly regulates the neuronal microenvironment, we hypothesized that another MoA of tDCS is direct vascular activation by modulating the BBB structures to increase its permeability (P). To test this hypothesis, we used high resolution multiphoton microscopy to determine P of the cerebral microvessels in rat brain. We found that 20 min 0.1-1 mA tDCS transiently increases P to a small solute, sodium fluorescein (MW 376) and to a large solute, Dextran-70k, with a much higher increase in P to the large solute. By pretreating the vessel with a nitric oxide synthase inhibitor, we revealed that the tDCS-induced increase in P is NO dependent. A transport model for the BBB was further employed to predict the structural changes by the tDCS. Comparing model predictions with the measured data suggests that tDCS increases P by temporarily disrupting the structural components forming the paracellular pathway of the BBB. That the transient and reversible increase in the BBB permeability also suggests new applications of tDCS such as a non-invasive approach for brain drug delivery through the BBB.
Keywords: Multiphoton microscopy; NG-monomethyl-L-arginine (L-NMMA); Nitric oxide synthase (NOS) inhibition; Non-invasive; Rat; Structural mechanisms; Transport model across the blood–brain barrier.