Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain

摘要

Focused ultrasound (FUS) is a technology capable of delivering therapeutic levels of energy through the intact skull to a tightly localized brain region. Combining the FUS pressure wave with intravenously injected microbubbles creates forces on blood vessel walls that open the blood-brain barrier (BBB). This noninvasive and localized opening of the BBB allows for targeted delivery of pharmacological agents into the brain for use in therapeutic development. It is possible to use FUS power levels such that the BBB is opened without damaging local tissues. However, open questions remain related to the effects that FUS-induced BBB opening has on brain function including local physiology and vascular hemodynamics. We evaluated the effects that FUS-induced BBB opening has on resting state functional magnetic resonance imaging (rs-fMRI) metrics. Data from rs-fMRI was acquired in rats that underwent sham FUS BBB vs. FUS BBB opening targeted to the right primary somatosensory cortex hindlimb region (S1HL). FUS BBB opening reduced the functional connectivity between the right S1HL and other sensorimotor regions, including statistically significant reduction of connectivity to the homologous region in the left hemisphere (left S1HL). The effect was observed in all three metrics analyzed: functional connectivity between anatomically defined regions, whole brain voxel-wise correlation maps based on anatomical seeds, and spatial patterns from independent component analysis. Connectivity metrics for other regions where the BBB was not perturbed were not affected. While it is not clear whether the effect is vascular or neuronal in origin, these results suggest that even safe levels of FUS BBB opening have an effect on the physiological processes that drive the signals measured by BOLD fMRI. As such these effects must be accounted for when carrying out studies using fMRI to evaluate the effects of pharmacological agents delivered via FUS-induced BBB opening.