Probing Cerebral Metabolism with Hyperpolarized ¹³C Imaging after Opening the Blood-Brain Barrier with Focused Ultrasound

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized ¹³C-labeled substrates in rodents: [1-¹³C]pyruvate and [1-¹³C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-¹³C]pyruvate resulted in an increase in total ¹³C signals (p = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-¹³C]lactate (lactate/total ¹³C signals, p = 0.01) and [¹³C]bicarbonate (p = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, ¹³C imaging with hyperpolarized [1-¹³C]glycerate after opening the BBB showed increased [1-¹³C]glycerate delivery to the FUS-applied region (p = 0.04) relative to the contralateral side, and [1-¹³C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized ¹³C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.