Non-invasive 4D transcranial functional ultrasound and ultrasound localization microscopy for multimodal imaging of neurovascular response

A long-standing goal of neuroimaging is the non-invasive volumetric assessment of whole brain function and structure at high spatial and temporal resolutions. Functional ultrasound (fUS) and ultrasound localization microscopy (ULM) are rapidly emerging techniques that promise to bring advanced brain imaging and therapy to the clinic with the safety and low-cost advantages associated with ultrasound. fUS has been used to study cerebral hemodynamics at high temporal resolutions while ULM has been used to study cerebral microvascular structure at high spatial resolutions. These two methods have complementary spatio-temporal characteristics, making them ideally suited for multimodal imaging, but both suffer from limitations associated with transcranial ultrasound imaging. Here, these two methods are combined on the same data acquisition, completely non-invasively, using contrast-enhancements, which solves the dual challenges of sensitivity during transcranial imaging and the ability to implement super-resolution. From this combined approach, the cerebral blood flow, activated brain region, brain connectivity, vessel diameter, and vessel velocity were all calculated from the same data acquisition. During stimulation periods, there was a statistically significant (p<0.0001) increase in cerebral blood flow, diameter, and global velocity, but a decrease in velocity in the activated region. Additionally, the global flow increased (p=0.11) and connectivity decreased (24.7%) when compared to baseline. This multimodal approach allows for the study of the relationship between cerebral hemodynamics (30 ms resolution) and the microvasculature (14.6 μm resolution) using one ultrasound scan.