Thermal Threshold for Localized Blood-Brain Barrier Disruption.

Abstract

The Blood-Brain Barrier (BBB) is the gatekeeper of the central nervous system, effectively shielding the brain from blood-borne threats but simultaneously representing a significant challenge for treating neurological diseases. Altering the permeability of the BBB enables increasing the local drug concentration enhancing therapeutic effects. This study aims to explore the BBB permeability alteration through localized mild temperature increases, addressing the challenge of accurately determining and monitoring thermal dosages during hyperthermia treatments. To investigate the BBB permeability alteration, an infrared laser was used applying minimal thermal doses in a highly localized manner. The necessary threshold temperature for opening the BBB was determined in rats. In an exploratory rat study, noninvasive techniques, such as dynamic contrast enhancement-magnetic resonance imaging and magnetic resonance thermometry, were employed to show and monitor the effective BBB permeability alteration and the thermal dosage. Post-mortem verification was performed using Evan's Blue dye to assess BBB disruption. The study found that a localized increase in brain temperature of approximately 6 K (from a baseline of 37 °C to 43 °C) was sufficient to effectively disrupt the BBB. This temperature threshold was verified in-vivo and was consistent with post-mortem findings from the Evan's Blue extravasation method. The findings demonstrate that BBB permeability can be altered and controlled by applying minimal, localized thermal doses improving the delivery of therapeutics to the brain. Noninvasive imaging techniques such as DCE-MRI and MRT offer precise monitoring of the temperature changes required for BBB disruption enabling better control over thermal dosages.