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

Neuroimage. 2019 Nov 1;201:116010. doi: 10.1016/j.neuroimage.2019.116010. Epub 2019 Jul 11.

Abstract

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.

Keywords: Brain; Drug delivery; Functional MRI; Hemodynamic response; Neuroimaging; Neurovascular coupling; Neurovascular response; Somatosensory cortex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood-Brain Barrier / radiation effects*
  • Capillary Permeability / radiation effects*
  • Cerebrovascular Circulation / radiation effects*
  • Magnetic Resonance Imaging
  • Neurovascular Coupling / radiation effects*
  • Rats
  • Rats, Sprague-Dawley
  • Ultrasonic Waves / adverse effects*