Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates

Introduction: Low-Intensity Focused Ultrasound (LIFU) is a promising, non-invasive technique for transiently opening the blood-brain barrier (BBB), enabling targeted drug delivery to deep brain structures. While the local effects of LIFU-mediated BBB opening (LIFU-BBBO) have been studied, the broader physiological and metabolic consequences, particularly in remote brain regions, remain unclear. Objective: This study aims to investigate the local and remote metabolic responses, measured by oxygen extraction fraction (OEF), following focal LIFU-BBBO in non-human primates, with a focus on both the targeted and homologous contralateral regions. Methods: LIFU-BBBO was performed in the striatum of four male macaques using a 500 kHz transducer and intravenously administered microbubbles. MRI-guided treatment planning and post-sonication imaging confirmed precise BBB opening. Quantitative BOLD (qBOLD) MRI was used to map OEF in both the treated and contralateral regions. Results: Focal LIFU-BBBO did not induce significant metabolic changes at the sonicated site. However, a robust and spatially specific increase in OEF was observed in the homologous contralateral striatum, particularly in the putamen. This contralateral effect was confirmed by both linear mixed-effects modeling and hierarchical Bayesian analysis, while no significant changes were found in other brain regions or when averaging across hemispheres. Conclusion: Focal LIFU-BBBO in the striatum elicits a paradoxical increase in metabolic demand in the untreated, homologous contralateral hemisphere, as indicated by elevated OEF. These findings highlight the importance of considering remote, network-level effects when evaluating the safety and efficacy of LIFU-based therapies, and underscore the need for comprehensive assessment of both local and distant physiological responses in future clinical applications.