Non-invasive 4D transcranial contrast-enhanced functional ultrasound imaging in mice with Alzheimer’s Disease during vibrotactile stimulation (Part 18)

Functional ultrasound (fUS) is an imaging technique that can measure changes in cerebral blood flow (CBF). However, transcranial ultrasound imaging is challenging due to the aberration and reverberation of sound due to the skull. Microbubble contrast-enhancement can overcome sensitivity limitations. Here, we propose a completely non-invasive 4D contrast-enhanced fUS approach to image brain hemodynamics at high spatial (200 um) and temporal resolutions (20 ms), providing a method to better study the localized changes in brain activity. The capabilities of this technique are demonstrated in Alzheimer's Disease (AD), a neurodegenerative disorder that is one of the leading causes of disability and death. Compared to conventional neuroimaging tools that are used for diagnosis and monitoring the proposed technique has higher spatial and temporal resolution. To demonstrate the capabilities of this contrast-enhanced fUS technique to transcranially image volumetric cerebral hemodynamics, it was applied to five wild-type (WT) mice and five mice with AD at rest (baseline) during vibrotactile stimulation of the front or hind paw. WT mice, on average, experienced 10.7-23.9 % higher mean CBF for each stimulation case but 17.0-20.3 % lower mean connectivity than mice with AD. Five specific regions were highlighted in this comparison that are known to be affected by AD. These were the entorhinal cortex, hippocampus, thalamus, parietal cortex, and frontal cortex. AD mice exhibited hyper-connectivity in the hippocampus, one of the first regions affected by AD in this mouse model, and lower CBF in all five regions. Both the CBF and connectivity results from this technique agree with published gold-standard fMRI AD findings that account for the age of the animals. In summary, it is demonstrated that 4D fUS can non-invasively detect and monitor changes in cerebral hemodynamics associated with AD with high temporal resolution, enabling longitudinal functional assessments of these effects in rodent AD models.