User:Shenlongleon/sandbox

Functional ultrasound imaging 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, which is to some extent extension of power Doppler imaging.

Neuroengineering Background
How and where the brain is activated in response to a given function or stimulus have always been of great interest and curiosity to neuroscientists. Brain activation can either be directly measuring by imaging electrical activity of neurons using voltage sensitive dyes, calcium imaging or electroencephalography (ECG) mapping, or indirectly by detecting hemodynamic changes induced by the neurovascular which couples with surrounding activated neurons through functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or photoacoustic imaging (PAI).

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 limited for imaging these changes, because it is not sensitive enough to detect the blood flow in such small vessels.

Previous Technologies
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, in neonatal pediatric neurology, fMRI is rarely performed because of specific issues concerning infant sedation.

μDoppler
This method is based on compounded plane wave emissions which image the brain at an ultrafast frame rate (1 kHz), producing power Doppler images with higher spatial and temporal resolutions compared to traditional power Doppler techniques, which can reveal blood volumes of smaller vessels. Among multiple transmission configurations, μDoppler method is approved to be rather effective and precise. A theoretical model demonstrates that the gain in sensitivity of the μDoppler method is due to the combination of 1) the high signal-to-noise ratio (SNR) of the gray scale images, attributed from the synthetic compounding of backscattered echoes; and 2) the extensive signal samples averaging enabled by the high temporal resolution of ultrafast frame rates.

Coherent Compound Beamforming
It consists of the recombination of backscattered echoes from different illuminations achieved on the acoustic pressure field with various angles (as opposed to the acoustic intensity for the incoherent case). All images are then added coherently to obtain a final compounded image. This very addition is produced without taking the envelope of the beamformed signals or any other nonlinear procedure to ensure a coherent addition. As a result, coherent adding of several echo waves leads to cancellation of out-of-phase waveforms, narrowing the point spread function (PSF), thus increasing spatial resolution.

Neurovascular Coupling
Functional ultrasound is limited by the spatiotemporal features of  neurovascular coupling as it measures 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 (~100μm). 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.

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 measured and compared between rest and task conditions or between right and left sides when studying lateralization.

Power Doppler and Contrast Ultrasound Imaging
Power Doppler is a Doppler sequence that measures the ultrasonic energy backscattered from red blood cells in each pixel of the image. Power Doppler 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.

Ultrafast Ultrasound and fUS Imaging
fUS imaging relies on ultrafast imaging scanners able to acquire images at thousands of frames per second, thus boosting the power Doppler SNR without any contrast agents. Instead of the line per line acquisition of conventional ultrasound devices, ultra-fast ultrasound takes advantage of successive tilted plane wave transmissions that afterward coherently compounded to form images at high frame rates. The sensitivity was recently even further improved using multiple plane wave transmissions and advanced spatiotemporal clutter filters for better discrimination between low blood flow and tissue motion.

This signal boost enables the sensitivity required to map subtle blood variations in small arterioles (down to 1mm/s) related to neuronal activity. fUS neuroimaging has a typical 50-200 μm spatial resolution depending on the ultrasound frequency used. It features a temporal resolution in the tens of milliseconds, can image the full depth of the brain and can provide 3D angiography. fUS imaging requires no calibration and nearly no setup time.

fUS research platforms require custom sequences programming, dedicated high-performance GPU beamforming software with a high data transfer rate(several GBytes per second) and miniature high-frequency ultrasound probes to perform live fUS imaging. Future commercial implementations through specialized hardware and software should enable fUS to rapidly expand in utility for the neuroscience community.

Functional Photoacoustic Computed Tomography
Using laser devices, the photoacoustic effect can be leveraged to enable molecular imaging of optical contrast at the ultrasound resolution. The laser is used to illuminate the brain while the strong light absorption by red blood cells created a sharp localized temperature increase, which in turn generates ultrasonic waveforms.

Asset
• Compatibility with other techniques commonly used by physiologists, in particular electrophysiological recordings

• Inexpensive and more practical (smaller machine, transportable), compared with MRI

• Enabling study of the subcortical structures makes in-depth imaging prospective compared with optical techniques

Drawback
• Need for trepanation, could be solved by techniques of thinned-skull already developed for chronical optical imaging, or to use contrast agents to increase blood echogenicity to allow imaging through the skull.

• Capillary blood flow is on the order of 0.5 mm/s, which would be filtered out by HPF and thus could not be detected.

2D functional ultrasound imaging
Functional ultrasound imaging has a wide range of applications not only in research but also in clinical practice. Firstly, fUS can benefit in monitoring cerebral function in the whole brain which is important to understanding how the brain works on a large scale under normal or pathological conditions. Secondly, the ability to image cerebral blood volume at high spatiotemporal resolution and with high sensitivity using fUS could be of great interest for applications in which fMRI reaches its limits, such as imaging of epileptic-induced changes in blood volume. fUS could potentially be applied for chronic studies in animal models through a thinned-skull or smaller cranial window. In the future, fUS could be implemented on a portable ultrasound scanner, opening a wide range of possibilities for functional imaging. Miniaturization of the probe could enable its implantation in the brain of awake, behaving animals.

For clinical practice, µdoppler imaging can be easily applied to the neonatal brain imaging in a non-invasive manner through the fontanel window. Ultrasound is usually performed in this case, which means that the current procedures does not have to be changed. High quality angiographic images will help diagnose vascular diseases such as perinatal ischemia or ventricular hemorrhage. For adults, this method can be used in craniotomy to guide the surgeon through the vasculature and to monitor the patient's brain function. Finally, the utility of µDoppler imaging is not limited to the brain: it can also be applied to other organs to improve current diagnostics based on conventional Doppler images. Its clinical interest can be used to analyze tumor vascularization, especially in the treatment of prostate cancer or breast cancer recurrence.

4D functional ultrasound imaging
Some researchers conducted 4D functional ultrasound imaging of whole-brain activity in rodents. Their approach relies on high frequency 2D matrix array transducer technology coupled with a high channel count electronic system for fast 3D imaging. To counterbalance the intrinsically poor sensitivity of matrix elements, they devised a 3D multiplane-wave scheme with 3D spatiotemporal encoding of transmit signals using Hadamard coefficients. For each transmission, the backscattered signals containing mixed echoes from the different plane waves are decoded using the summation of echoes from successive receptions with appropriate Hadamard coefficients. This summation enables the synthetic building of echoes from a virtual individual plane wave transmission with a higher amplitude. Finally, they perform coherent compounding beamforming of decoded echoes to produce 3D ultrasonic images and apply a spatiotemporal clutter filter separating blood flow from tissue motion to compute a power Doppler volume, which is proportional to the cerebral blood volume.