DBS-relevant electric fields increase hydraulic conductivity of in vitro endothelial monolayers

Deep brain stimulation (DBS) achieves therapeutic outcome through generation of electric fields (EF) in the vicinity of energized electrodes. Targeted brain regions are highly vascularized, and it remains unknown if DBS electric fields modulate blood-brain barrier (BBB) function, either through electroporation of individual endothelial cells or electro-permeation of barrier tight junctions. In our study, we calculated the intensities of EF generated around energized Medtronic 3387 and 3389 DBS leads by using a finite element model. Then we designed a novel stimulation system to study the effects of such fields with DBS-relevant waveforms and intensities on bovine aortic endothelial cell (BAEC) monolayers, which were used as a basic analog for the blood-brain barrier endothelium. Following 5 min of stimulation, we observed a transient increase in endothelial hydraulic conductivity (Lp) that could be related to the disruption of the tight junctions (TJ) between cells, as suggested by zonula occludens-1 (ZO-1) protein staining. This 'electro-permeation' occurred in the absence of cell death or single cell electroporation, as indicated by propidium iodide staining and cytosolic calcein uptake. Our in vitro results, using uniform fields and BAEC monolayers, thus suggest that electro-permeation of the BBB may occur at electric field intensities below those inducing electroporation and within intensities generated near DBS electrodes. Further studies are necessary to address potential BBB disruption during clinical studies, with safety and efficacy implications.