Abstract
Burst-mode focused ultrasound (FUS) induces microbubble cavitation in the vasculature and temporarily disrupts the blood-brain barrier (BBB) to enable therapeutic agent delivery. However, it remains unclear whether FUS-induced BBB opening is accompanied by neuromodulation. Here we characterized the functional effects of FUS-induced BBB opening by measuring changes in somatosensory evoked potentials (SSEPs) and blood-oxygen-level dependent (BOLD) responses. Rats underwent burst-mode FUS (mechanical index (MI) of 0.3, 0.55 or 0.8) to the forelimb region in the left primary somatosensory cortex to induce BBB opening. Longitudinal measurements were followed for up to 1 week to characterize the temporal dynamics of neuromodulation. We observed that 0.8-MI FUS profoundly suppressed SSEP amplitude and prolonged latency, and this effect lasted 7 days. 0.55-MI FUS resulted in minimal and short-term suppression of SSEP for less than 60 minutes and didn’t affect latency. BOLD responses were also suppressed in an MI-dependent manner, mirroring the effect on SSEPs. Furthermore, repetitive delivery of 0.55-MI FUS every 3 days elicited no accumulative effects on SSEPs or tissue integrity. This is the first evidence that FUS-induced BBB opening is accompanied by reversible changes in neuron responses, and may provide valuable insight toward the development of FUS-induced BBB opening for clinical applications.
Highlights
The 0.3-mechanical index (MI) Focused ultrasound (FUS) is lower than the threshold that induces blood-brain barrier (BBB) opening (MI = 0.46)24, 0.55-MI FUS is considered within the safe range, and 0.8-MI FUS induces BBB opening and red blood cell (RBC) extravasation[9,11]
Two more control groups were included: the first control group received microbubbles without FUS; the second control group received 0.8-MI FUS for 120 s without the presence of microbubbles (0.8-MI FUS-alone). This group was included to determine whether neuromodulation was induced by ultrasound alone and whether it was accompanied by BBB opening
We demonstrated neuromodulation accompanying FUS-induced BBB opening, as evidenced by changes in SSEPs and BOLD responses following FUS
Summary
FUS-alone enhances neuronal activity in the motor cortex, but suppresses activity in the visual cortex[16], indicating that the effects of FUS differ across cortical areas. The exposure condition of FUS used for BBB opening is different from that used in the aforementioned FUS-induced neuromodulation, so it is important to assess whether FUS-induced BBB opening is accompanied by brain modulation. We measured somatosensory evoked potentials (SSEPs) and blood-oxygen-level-dependent (BOLD) responses to assay neuromodulation that might accompany FUS-induced BBB opening. Stimulus-driven SSEPs17,18 and BOLD responses[19,20] are widely used to measure cortical neuromodulation[16,21]. Repetitive FUS-induced BBB opening was performed to evaluate accumulative functional and histological effects
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