Functional ultrasound imaging (fUS) is a medical ultrasound imaging technique of detecting or measuring changes in neural activities or metabolism, for example, the loci of brain activity, typically through measuring blood flow or hemodynamic changes. The method can be seen as an extension of Doppler imaging.
Background
Brain activation can either be directly measured by imaging electrical activity of neurons using voltage sensitive dyes, calcium imaging, electroencephalography, or magnetoencephalography, or indirectly by detecting hemodynamic changes in blood flow in the neurovascular systems through functional magnetic resonance imaging (fMRI), positron emission tomography (PET), Functional near-infrared spectroscopy (fNIRS), or Doppler ultrasonography )...
Optical based methods generally provide the highest spatial and temporal resolutions; however, due to scattering, they are intrinsically limited to the investigation of the cortex. Thus, they are often used on animal models after partially removing or thinning the skull to allow for the light to penetrate into tissue. fMRI and PET, which measure the blood-oxygen level dependent (BOLD) signal, were the only techniques capable of imaging brain activation in depth. BOLD signal increases when neuronal activation exceeds oxygen consumption, where blood flow increases significantly. In fact, in-depth imaging of cerebral hemodynamic responses by fMRI, being noninvasive, paved the way for major discoveries in neurosciences in the early stage, and is applicable on humans. However, fMRI also suffers limitations. First, the cost and size of MR machines can be prohibitive. Also, spatially resolved fMRI is achieved at the expense of a substantial drop in temporal resolution and/or SNR. As a result, the imaging of transient events such as epilepsy is particularly challenging. Finally, fMRI is not appropriate for all clinical applications. For example, fMRI is rarely performed on infants because of specific issues concerning infant sedation.
Like fMRI, Doppler based functional ultrasound approach are based on the neurovascular coupling and are thus limited by the spatiotemporal features of neurovascular coupling as they measure cerebral blood volume (CBV) changes. CBV is a pertinent parameter for functional imaging that is already used by other modalities such as intrinsic optical imaging or CBV-weighted fMRI. The spatiotemporal extent of CBV response was extensively studied. The spatial resolution of sensory-evoked CBV response can go down to cortical column (~100 µm). Temporally, the CBV impulse response function was measured to typically start at ~0.3 s and peak at ~1 s in response to ultrashort stimuli (300µs), which is much slower than the underlying electrical activity.
Conventional Doppler based functional imaging approaches
Hemodynamic changes in the brain are often used as a surrogate indicator of neuronal activity to map the loci of brain activity. Major part of the hemodynamic response occurs in small vessels; however, conventional Doppler ultrasound is not sensitive enough to detect the blood flow in such small vessels.
Functional Transcranial Doppler (fTCD) Ultrasound Doppler imaging can be used to obtain basic functional measurements of brain activity using blood flow. In functional transcranial Doppler sonography, a low frequency (1-3 MHz) transducer is used through the temporal bone window with a conventional pulse Doppler mode to estimate blood flow at a single focal location. The temporal profile of blood velocity is usually acquired in main large arteries such as the middle cerebral artery (MCA). The peak velocity is compared between rest and task conditions or between right and left sides when studying lateralization.
Power Doppler
Power Doppler is a Doppler sequence that measures the ultrasonic energy backscattered from red blood cells in each pixel of the image. It provides no information on blood velocity but is proportional to blood volume within the pixel. However, conventional power Doppler imaging lacks sensitivity to detect small arterioles/venules and thus is unable to provide local neurofunctional information through neurovascular coupling.
Ultrasensitive Doppler and functional ultrasound imaging (fUS) Functional ultrasound imaging was pioneered at ESPCI by Mickael Tanter's team following work on ultrafast imaging and ultrafast Doppler.