The neurovascular response is attenuated by focused ultrasound-mediated disruption of the blood-brain barrier

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2019-11, Vol.201, p.116010-116010, Article 116010
• Main Authors: Todd, Nick, Zhang, Yongzhi, Livingstone, Margaret, Borsook, David, McDannold, Nathan
• Format: Article
• Language: English
• Subjects: Animals; Blood; Blood flow; Blood-brain barrier; Blood-Brain Barrier - radiation effects; Brain; Brain mapping; Brain research; Capillary Permeability - radiation effects; Cerebral blood flow; Cerebrovascular Circulation - radiation effects; Cortex (somatosensory); Drug delivery; Experiments; Functional magnetic resonance imaging; Functional MRI; Hemodynamic response; Magnetic Resonance Imaging; Neuroimaging; Neurovascular coupling; Neurovascular Coupling - radiation effects; Neurovascular response; Physiology; Rats; Rats, Sprague-Dawley; Somatosensory cortex; Studies; Ultrasonic imaging; Ultrasonic Waves - adverse effects; Ultrasound
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2019.116010

Focused ultrasound (FUS)-induced disruption of the blood-brain barrier (BBB) is a non-invasive method to target drug delivery to specific brain areas that is now entering into the clinic. Recent studies have shown that the method has several secondary effects on local physiology and brain function beyond making the vasculature permeable to normally non-BBB penetrant molecules. This study uses functional MRI methods to investigate how FUS BBB opening alters the neurovascular response in the rat brain. Nine rats underwent actual and sham FUS induced BBB opening targeted to the right somatosensory cortex (SI) followed by four runs of bilateral electrical hind paw stimulus-evoked fMRI. The neurovascular response was quantified using measurements of the blood oxygen level dependent (BOLD) signal and cerebral blood flow (CBF). An additional three rats underwent the same FUS-BBB opening followed by stimulus-evoked fMRI with high resolution BOLD imaging and BOLD imaging of a carbogen-breathing gas challenge. BOLD and CBF measurements at two different stimulus durations demonstrate that the neurovascular response to the stimulus is attenuated in both amplitude and duration in the region targeted for FUS-BBB opening. The carbogen results show that the attenuation in response amplitude, but not duration, is still present when the signaling mechanism originates from changes in blood oxygenation instead of stimulus-induced neuronal activity. There is some evidence of non-local effects, including a possible global decrease in baseline CBF. All effects are resolved by 24 h after FUS-BBB opening. Taken together, these results suggest that FUS-BBB opening alters that state of local brain neurovascular physiology in such a way that hinders its ability to respond to demands for increased blood flow to the region. The mechanisms for this effect need to be elucidated. •Focused ultrasound opening of the blood-brain barrier alters local neurophysiology•One of the mechanisms that make up neurovascular coupling appears to be effected•BOLD and CBF responses to external stimuli are attenuated in the targeted region•BOLD responses to changes in vessel oxygenation are attenuated•These changes are transient, resolving over 24 hours