New Publication: Cytoskeletal Remodeling and Gap Junction Translocation Mediates BBB Disruption by Non‑invasive electrical brain stimulation
Annals of Biomedical Engineering. 2023. DOI: 10.1007/s10439-023-03211-3
Non-invasive electrical brain stimulation optimized for targeted and safe BBB openingNeeraj Raghuraman Rajagopalan, William-Ray Vista, Masashi Fujimori, Laurien G. P. H. Vroomen, Juan M. Jiménez, Niranjan Khadka, Marom Bikson, Govindarajan Srimathveeravalli
Abstract
High-voltage pulsed electric felds (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce of-target blood–brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the efect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 µs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this efect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without afecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein—ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase signifcantly following PEF treatment and confrmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar efect on BBB disruption characterized by electric feld strength (EFS) threshold and using a combination of two bilateral HD electrode configurations.
