Non-invasive 4D transcranial contrast-enhanced functional ultrasound imaging in mice with Alzheimer’s Disease during vibrotactile stimulation (Part 17)

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.

功能性超声（fUS）是一种可测量脑血流量（cerebral blood flow, CBF）变化的成像技术。然而，经颅超声成像面临挑战，原因是颅骨导致的声波畸变和混响。微泡造影增强（Microbubble contrast-enhancement）可克服灵敏度限制。在此，我们提出一种完全无创的4D造影增强fUS方法，能够以高空间分辨率（200 μm）和时间分辨率（20 ms）成像脑血流动力学（brain hemodynamics），为更深入研究脑活动的局部变化提供手段。该技术的性能在阿尔茨海默病（Alzheimer's Disease, AD）中得到验证——AD是一种神经退行性疾病（neurodegenerative disorder），也是导致残疾和死亡的主要原因之一。与用于诊断和监测的传统神经影像学工具（neuroimaging tools）相比，该技术具有更高的空间和时间分辨率。为验证这种造影增强fUS技术在经颅成像容积脑血流动力学（volumetric cerebral hemodynamics）方面的能力，研究人员将其应用于5只野生型（WT）小鼠和5只AD小鼠，分别在静息状态（基线）及前爪或后爪振动触觉刺激（vibrotactile stimulation）时进行成像。野生型小鼠在各刺激情况下的平均CBF比AD小鼠高10.7%-23.9%，但平均连接性（connectivity）却低17.0%-20.3%。本研究重点比较了已知受AD影响的5个特定脑区，包括内嗅皮层（entorhinal cortex）、海马（hippocampus）、丘脑（thalamus）、顶叶皮层（parietal cortex）和额叶皮层（frontal cortex）。AD小鼠在海马区表现出超连接性（hyper-connectivity），而海马区是该小鼠模型中最早受AD影响的脑区之一；此外，AD小鼠在所有5个脑区的CBF均较低。该技术获得的CBF和连接性结果与已发表的、考虑动物年龄因素的金标准功能磁共振成像（fMRI）AD研究结果一致。综上，研究表明4D fUS能够以高时间分辨率无创检测和监测与AD相关的脑血流动力学变化，从而可对啮齿类（rodent）AD模型中这些效应进行纵向功能评估（longitudinal functional assessments）。