Functional ultrasound imaging (fUS) is a medical ultrasound imaging technique for detecting or measuring changes in neural activities or metabolism, such as brain activity loci, typically through measuring hemodynamic (blood flow) changes. It is an extension of Doppler ultrasonography.
Brain activation can be directly measured by imaging electrical activity of neurons using voltage-sensitive dyes, calcium imaging, electroencephalography, or magnetoencephalography. It can also be indirectly measured hemodynamically, that is, by detecting 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, etc. [1]
Optics-based methods generally provide the highest spatial and temporal resolutions; however, due to scattering, they are limited to measuring regions close to the surface. Thus, they are often used on animal models after partially removing or thinning the skull to allow light to penetrate into brain 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, resulting in cerebral blood volume (CBV) changes. This relationship between neuronal activity and blood flow is called neurovascular coupling. 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 MRI machines can be prohibitive. Second, for fMRI to achieve a high spatial resolution necessarily decreases its time resolution and/or signal-noise ratio. As a result, it is hard to image fine spatial details of transient events such as epilepsy. Finally, fMRI is not appropriate for all clinical applications. For example, fMRI is rarely performed on infants, because infants do not stay still inside MRI machines. [2]
Like fMRI, Doppler-based functional ultrasound is based on the neurovascular coupling and are thus limited by the spatiotemporal features of neurovascular coupling, specifically 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. [3]
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. [2]
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. [4]
The temporal window is the thinnest lateral area of the skull, and it is mostly hairless. It is often used for fTCD. [5]
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. [2]
Functional ultrasound imaging was pioneered at ESPCI by Mickael Tanter 's team [6] following work on ultrafast imaging [7] and ultrafast Doppler. [8]
Ultrasensitive Doppler relies on ultrafast imaging scanners [7] able to acquire images at thousands of frames per second (~1 kHz), thus boosting the SNR of power Doppler without any contrast agents. Instead of the line by 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. Coherent Compound Beamforming 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 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), and thus increasing spatial resolution. A theoretical model demonstrates that the gain in sensitivity of the ultrasensitive Doppler method is due to the combination of the high signal-to-noise ratio (SNR) of the gray scale images, due to the synthetic compounding of backscattered echoes and the extensive signal samples averaging due to the high temporal resolution of ultrafast frame rates. [2] The sensitivity was recently further improved using multiple plane wave transmissions [9] and advanced spatiotemporal clutter filters for better discrimination between low blood flow and tissue motion. Ultrasound researchers have been using ultrafast imaging research platforms with parallel acquisition of channels and custom sequences programming to investigate ultrasensitive Doppler/fUS modalities. A custom real-time high-performance GPU beamforming code with a high data transfer rate (several GB/s) must then be implemented to perform imaging at high frame rate. Acquisitions can also typically easily provide gigabytes of data depending on acquisition duration.
Ultrasensitive Doppler has a typical 50-200 μm spatial resolution depending on the ultrasound frequency used. [2] It features temporal resolution ~10 ms, can image the full depth of the brain, and can provide 3D angiography. [10]
This signal boost enables the sensitivity required to map subtle blood variations in small arterioles (down to 1mm/s) related to neuronal activity. By applying an external stimulus such as a sensory, auditory or visual stimulation, it is then possible to construct a map of brain activation from the ultrasensitive Doppler movie.
Functional ultrasound (fUS) measures indirectly cerebral blood volume which provides an effect size close to 20% and as such is quite more sensitive than fMRI whose BOLD response is typically only a few percents. Correlation maps or statistical parametric maps can be constructed to highlight the activated areas. fUS has been shown to have a spatial resolution on the order of 100 μm at 15 MHz in ferrets [11] and is sensitive enough to perform single trial detection in awake primates. [12] Other fMRI-like modalities such as functional connectivity can also be implemented.
Commercial scanners with specialized hardware and software [13] are enabling fUS to rapidly expand behind ultrasound research labs to the neuroscience community.
4D functional ultrasound imaging (4D fUS) means fUS imaging of a 3D region of the brain over time.
Some researchers conducted 4D fUS of whole-brain activity in rodents. Currently, two different technological solutions are proposed for the acquisition of 3D and 4D fUS data, each with its own advantages and drawbacks. [14] The first is a tomographic approach based on motorized translation of linear probes. This approach proved to be a successful method for several applications such as 3D retinotopic mapping in the rodent brain [15] [16] and 3D tonotopic mapping of the auditory system in ferrets. [11] The second 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. [17]
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. 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. [6] fUS can be applied for chronic studies in animal models through a thinned-skull [18] or smaller cranial window or directly through the skull in mice.
Tonotopics or retinotopics maps [19] can be constructed by mapping the response of frequency-varying sounds [11] or moving visual targets. [15] [19] [16]
When no stimulus is applied, fUS can be used to study functional connectivity during resting state. The method has been demonstrated in rats [20] and awake mice [21] and can be used for pharmacological studies when testing drugs. [22] Seed-based maps, independent component analysis of resting states modes or functional connectivity matrix between atlas-based regions of interests can be constructed with high resolution.
Using dedicated ultralight probes, it is possible to perform freely-moving experiments in rats or mice. [23] [24] The size of the probes and electromagnetic-compatibility of fUS means it can also be used easily on head-fixed setups for mice [16] or in electrophysiology chambers in primate. [12]
Thanks to its portability, fUS has also been used in clinics in awake neonates. [25] Functional ultrasound imaging can be applied to 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 could help diagnose vascular diseases such as perinatal ischemia or ventricular hemorrhage.
For adults, this method can be used during neurosurgery to guide the surgeon through the vasculature and to monitor the patient's brain function prior to tumor resection [26] [27]
Medical ultrasound includes diagnostic techniques using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints, blood vessels, and internal organs, to measure some characteristics or to generate an informative audible sound. The usage of ultrasound to produce visual images for medicine is called medical ultrasonography or simply sonography, or echography. The practice of examining pregnant women using ultrasound is called obstetric ultrasonography, and was an early development of clinical ultrasonography. The machine used is called an ultrasound machine, a sonograph or an echograph. The visual image formed using this technique is called an ultrasonogram, a sonogram or an echogram.
Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area of the brain is in use, blood flow to that region also increases.
Elastography is any of a class of medical imaging modalities that map the elastic properties and stiffness of soft tissue. The main idea is that whether the tissue is hard or soft will give diagnostic information about the presence or status of disease. For example, cancerous tumours will often be harder than the surrounding tissue, and diseased livers are stiffer than healthy ones.
Functional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions. It is primarily used as a research tool in cognitive neuroscience, cognitive psychology, neuropsychology, and social neuroscience.
In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. This coupling between neuronal activity and blood flow is also referred to as neurovascular coupling.
Medical optical imaging is the use of light as an investigational imaging technique for medical applications, pioneered by American Physical Chemist Britton Chance. Examples include optical microscopy, spectroscopy, endoscopy, scanning laser ophthalmoscopy, laser Doppler imaging, and optical coherence tomography. Because light is an electromagnetic wave, similar phenomena occur in X-rays, microwaves, and radio waves.
Functional near-infrared spectroscopy (fNIRS) is an optical brain monitoring technique which uses near-infrared spectroscopy for the purpose of functional neuroimaging. Using fNIRS, brain activity is measured by using near-infrared light to estimate cortical hemodynamic activity which occur in response to neural activity. Alongside EEG, fNIRS is one of the most common non-invasive neuroimaging techniques which can be used in portable contexts. The signal is often compared with the BOLD signal measured by fMRI and is capable of measuring changes both in oxy- and deoxyhemoglobin concentration, but can only measure from regions near the cortical surface. fNIRS may also be referred to as Optical Topography (OT) and is sometimes referred to simply as NIRS.
Transcranial Doppler (TCD) and transcranial color Doppler (TCCD) are types of Doppler ultrasonography that measure the velocity of blood flow through the brain's blood vessels by measuring the echoes of ultrasound waves moving transcranially. These modes of medical imaging conduct a spectral analysis of the acoustic signals they receive and can therefore be classified as methods of active acoustocerebrography. They are used as tests to help diagnose emboli, stenosis, vasospasm from a subarachnoid hemorrhage, and other problems. These relatively quick and inexpensive tests are growing in popularity. The tests are effective for detecting sickle cell disease, ischemic cerebrovascular disease, subarachnoid hemorrhage, arteriovenous malformations, and cerebral circulatory arrest. The tests are possibly useful for perioperative monitoring and meningeal infection. The equipment used for these tests is becoming increasingly portable, making it possible for a clinician to travel to a hospital, to a doctor's office, or to a nursing home for both inpatient and outpatient studies. The tests are often used in conjunction with other tests such as MRI, MRA, carotid duplex ultrasound and CT scans. The tests are also used for research in cognitive neuroscience.
Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Increasingly it is also being used for quantitative research studies of brain disease and psychiatric illness. Neuroimaging is highly multidisciplinary involving neuroscience, computer science, psychology and statistics, and is not a medical specialty. Neuroimaging is sometimes confused with neuroradiology.
FreeSurfer is brain imaging software originally developed by Bruce Fischl, Anders Dale, Martin Sereno, and Doug Greve. Development and maintenance of FreeSurfer is now the primary responsibility of the Laboratory for Computational Neuroimaging at the Athinoula A. Martinos Center for Biomedical Imaging. FreeSurfer contains a set of programs with a common focus of analyzing magnetic resonance imaging (MRI) scans of brain tissue. It is an important tool in functional brain mapping and contains tools to conduct both volume based and surface based analysis. FreeSurfer includes tools for the reconstruction of topologically correct and geometrically accurate models of both the gray/white and pial surfaces, for measuring cortical thickness, surface area and folding, and for computing inter-subject registration based on the pattern of cortical folds.
Susceptibility weighted imaging (SWI), originally called BOLD venographic imaging, is an MRI sequence that is exquisitely sensitive to venous blood, hemorrhage and iron storage. SWI uses a fully flow compensated, long echo, gradient recalled echo (GRE) pulse sequence to acquire images. This method exploits the susceptibility differences between tissues and uses the phase image to detect these differences. The magnitude and phase data are combined to produce an enhanced contrast magnitude image. The imaging of venous blood with SWI is a blood-oxygen-level dependent (BOLD) technique which is why it was referred to as BOLD venography. Due to its sensitivity to venous blood SWI is commonly used in traumatic brain injuries (TBI) and for high resolution brain venographies but has many other clinical applications. SWI is offered as a clinical package by Philips and Siemens but can be run on any manufacturer's machine at field strengths of 1.0 T, 1.5 T, 3.0 T and higher.
Connectomics is the production and study of connectomes: comprehensive maps of connections within an organism's nervous system. More generally, it can be thought of as the study of neuronal wiring diagrams with a focus on how structural connectivity, individual synapses, cellular morphology, and cellular ultrastructure contribute to the make up of a network. The nervous system is a network made of billions of connections and these connections are responsible for our thoughts, emotions, actions, memories, function and dysfunction. Therefore, the study of connectomics aims to advance our understanding of mental health and cognition by understanding how cells in the nervous system are connected and communicate. Because these structures are extremely complex, methods within this field use a high-throughput application of functional and structural neural imaging, most commonly magnetic resonance imaging (MRI), electron microscopy, and histological techniques in order to increase the speed, efficiency, and resolution of these nervous system maps. To date, tens of large scale datasets have been collected spanning the nervous system including the various areas of cortex, cerebellum, the retina, the peripheral nervous system and neuromuscular junctions.
Preclinical imaging is the visualization of living animals for research purposes, such as drug development. Imaging modalities have long been crucial to the researcher in observing changes, either at the organ, tissue, cell, or molecular level, in animals responding to physiological or environmental changes. Imaging modalities that are non-invasive and in vivo have become especially important to study animal models longitudinally. Broadly speaking, these imaging systems can be categorized into primarily morphological/anatomical and primarily molecular imaging techniques. Techniques such as high-frequency micro-ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) are usually used for anatomical imaging, while optical imaging, positron emission tomography (PET), and single photon emission computed tomography (SPECT) are usually used for molecular visualizations.
Magnetic resonance imaging of the brain uses magnetic resonance imaging (MRI) to produce high-quality two- or three-dimensional images of the brain, brainstem, and cerebellum without ionizing radiation (X-rays) or radioactive tracers.
Resting state fMRI is a method of functional magnetic resonance imaging (fMRI) that is used in brain mapping to evaluate regional interactions that occur in a resting or task-negative state, when an explicit task is not being performed. A number of resting-state brain networks have been identified, one of which is the default mode network. These brain networks are observed through changes in blood flow in the brain which creates what is referred to as a blood-oxygen-level dependent (BOLD) signal that can be measured using fMRI.
Functional magnetic resonance spectroscopy of the brain (fMRS) uses magnetic resonance imaging (MRI) to study brain metabolism during brain activation. The data generated by fMRS usually shows spectra of resonances, instead of a brain image, as with MRI. The area under peaks in the spectrum represents relative concentrations of metabolites.
An MRI pulse sequence in magnetic resonance imaging (MRI) is a particular setting of pulse sequences and pulsed field gradients, resulting in a particular image appearance.
Arterial spin labeling (ASL), also known as arterial spin tagging, is a magnetic resonance imaging technique used to quantify cerebral blood perfusion by labelling blood water as it flows throughout the brain. ASL specifically refers to magnetic labeling of arterial blood below or in the imaging slab, without the need of gadolinium contrast. A number of ASL schemes are possible, the simplest being flow alternating inversion recovery (FAIR) which requires two acquisitions of identical parameters with the exception of the out-of-slice saturation; the difference in the two images is theoretically only from inflowing spins, and may be considered a 'perfusion map'. The ASL technique was developed by John S. Leigh Jr, John A. Detre, Donald S. Williams, and Alan P. Koretsky in 1992.
The neurovascular unit (NVU) comprises the components of the brain that collectively regulate cerebral blood flow in order to deliver the requisite nutrients to activated neurons. The NVU addresses the brain's unique dilemma of having high energy demands yet low energy storage capacity. In order to function properly, the brain must receive substrates for energy metabolism–mainly glucose–in specific areas, quantities, and times. Neurons do not have the same ability as, for example, muscle cells, which can use up their energy reserves and refill them later; therefore, cerebral metabolism must be driven in the moment. The neurovascular unit facilitates this ad hoc delivery and, thus, ensures that neuronal activity can continue seamlessly.
Ultrasound Localization Microscopy (ULM) is an advanced ultrasound imaging technique. By localizing microbubbles, ULM overcomes the physical limit of diffraction, achieving sub-wavelength level resolution and qualifying as a super-resolution technique.