Cerebral blood flow (CBF) provides critical information of brain physiology in preclinical and clinical studies. CBF can be measured quantitatively by using Xenon-133, PET, and MRI, or qualitatively with single photon emission computed tomography (SPECT), laser Doppler flowmetry (1). Arterial spin labeling (ASL) (2-7) and dynamic susceptibility contrast MRI (DSC-MRI) (8,9) techniques are the most common perfusion MRI approaches for quantitative CBF measurement with high temporal and/or spatial resolution. Perfusion MRI has been routinely used in preclinical and clinical studies of various neurological diseases like stroke (10,11). In addition, CBF-based functional MRI (fMRI) is spatially more specific to the neural activity site and has less inter-subject variation than the blood-oxygenation-level-dependent (BOLD) fMRI (12-15).
Non-human primates (NHPs) resemble most aspects of humans in brain physiology and anatomy in comparison with other animal species and are excellent animal models in neuroscience, biomedical and pharmaceutical research, and vaccine development (16-18). Both DSC-MRI and ASL perfusion MRI techniques have been developed to examine the functionality and physiological conditions in the NHP brain. In comparison with DSC-MRI, ASL uses magnetically labelling endogenous water in the arterial blood as freely diffusible tracer and does not require the administration of contrast agents. Therefore it is a completely non-invasive MRI technique. In particular, as the labeled water has a short half-life (~blood T1), ASL-based perfusion MRI can be repeatedly conducted to detect the temporal homodynamic changes in the brain with/without task activation or quantitatively measure basal or resting CBF with high spatial resolution. In this article, current ASL-based perfusion MRI techniques are described and their application and limitations in NHP studies are discussed as well.
ASL perfusion MRI techniques
ASL perfusion MRI is usually achieved with the continuous arterial spin labeling (CASL) technique (3,19-21) in which a separate neck coil is placed under the neck for labeling the arterial blood water. It can also be conducted using pulsed arterial spin labeling (PASL) (2,4,5), amplitude-modulated CASL technique (22), pseudo-continuous arterial spin labeling (pCASL) technique (23), in which the blood water labelling and brain imaging are implemented using the same imaging coil. Compared to PASL, CASL allows for continuous supply of labeled arterial blood water into tissue of interest, offering greater detection sensitivity and large volume coverage for CBF measurement. Current CASL techniques for NHP studies are described and discussed below.
CASL perfusion MRI with a separate labeling coil
Compared to regular single-coil ASL techniques, CASL with a separate labeling coil uses a long RF pulse (up to couple seconds) to adiabatically invert the flowing spins in the arterial blood locally (normally in the neck area where the labeling coil is placed). Therefore, it has greater signal to noise ratio (SNR) and reduced specific absorption rate (SAR), particularly in small animals (like rodents) which have short arterial transit time (ATT) (24,25). Also, magnetization-transfer (MT) effect can be eliminated when the RF transmission, imaging, and labeling coils are properly decoupled with each other (26). Such CASL technique is usually available on research scanners for small animals and dedicated research scanners for NHPs (27). A few conventional clinical scanners have been developed for CBF measurement with a separate labeling coil in humans (19,20) and NHPs (28,29). In the three-coil ASL setting (28), a receive-only surface coil is used for imaging, allowing for maximal sensitivity in measuring CBF of the macaque monkey brain (Figure 1). This novel setting has particular advantage to examine the local hemodynamic changes of the cortex in fMRI studies of NHPs (27). However, the CBF maps may be biased in deep brain regions due to the inherent SNR heterogeneity of a surface coil. In addition, it is not an ideal setting for multi-parameter MRI of the whole brain as some MRI modalities like diffusion tensor imaging (DTI) or diffusion spectrum imaging (DSI) are susceptible to the inhomogeneous sensitivity of a surface coil and novel parallel imaging and multiband MRI techniques cannot be performed due to the lack of multiple channels. In contrast, a two-coil setting in which a transmit/receive phased-array volume coil is employed for imaging can be used to collect homogeneous CBF maps with the tradeoff of reduced SNR (Figure 2), allowing for multi-parameter MRI measures of the whole brain performed in a single scanning session. In particular, many MRI modalities using novel parallel imaging and multiband MRI techniques can be explored in NHP studies on such two-coil setting (30-34). The repetition effect of ASL data acquisition is illustrated also (Figure 2). Our experiences suggest 4–6 repetitions of ASL data acquisition (each repetition lasts 5 minutes) provide suitable CBF maps of anesthetized macaque monkeys, and longer data acquisition does not substantially improve the quality of CBF maps by image averaging.
CASL perfusion MRI with a single coil
The ASL technique with a separate labeling coil is an ideal setting for CBF measurements of NHPs using a research or conventional clinic scanner (27-29). However, such CASL technique is not accessible in most clinical scanners as it requires additional RF hardware and software. In contrast, the pCASL MRI technique allows for using the same RF coil for labeling and imaging. Accordingly CBF measurement can be carried out without installing additional hardware on the scanner (35-38). With pCASL, the continuous labeling of the spins in the arterial blood water is implemented by using a train of rapid repeating short RF pulses (usually <1 ms) with alternating sign magnetic field gradients to mimic the spin-labeling scheme in CASL with a separate labeling coil. To date, pCASL technique has been implemented by most scanner manufactures, providing a robust and convenient means to measure CBF of NHPs using a standard clinical setting (Figure 3). As expected, the SNR of the CBF maps is reduced compared to those acquired with a separate labeling coil (Figures 1,2). Multi-parameter MRI with parallel imaging techniques allows for multiple MRI parameters to be measured from one subject within a single scanning session and is becoming an effective tool to characterize the tissue injury and function recovery in stroke and other diseases (31,40,41). Therefore, such single-coil setting allows for pCASL-based perfusion MRI to be conducted together with other modalities such as T1, T2-weighted, spectroscopy, fMRI, DTI on a standard clinical scanner. Among the single coil ASL techniques, amplitude-modulated CASL techniques (22) and pCASL techniques (36,42) have been successfully implemented for brain perfusion studies in macaque models of neuro-AIDS (43) and healthy adult macaque monkeys (39).
Multiple numerical models have been developed for CBF quantification (44). Single-compartment (6,45,46) is a simplified but popular model in which water is assumed to be a freely diffusible tracer and the exchange of the tracer with the tissue water is instantaneous. In contrast, some two-compartment models take into account of the effects of capillary wall permeability for restricted water exchange (47-49).
The regional difference in ATT is usually not considered in simplified CBF calculation (50), or a single ATT value in grey matter (GM) is used for the entire brain CBF calculation (28). Prior studies suggest that ASL-based CBF is sensitive to the changes of ATT (45,51,52). It has been suggested that ATT needs to be taken into account to obtain quantitatively accurate CBF maps (53,54). In particular, the perfusion quantification in white matter (WM) can be strongly biased as the ATT of WM is longer than that in GM (55). Since rodents have little WM, using a fixed ATT value may not cause significant error in CBF quantification of rodents. However, it may introduce severe bias in quantification of WM CBF in NHP or human brains as the WM can fill up to ~60 percent of the brain.
The model proposed by Alsop and colleagues considers the contribution from the tissue compartment and vascular compartment (45,56). With this model, CBF and ATT maps can be estimated pixel by pixel from CASL measurements with different post-labeling delays. The CBF calculation with this formula requires multi-parameter non-linear curve fitting. Because of the lack of the prior knowledge about these parameters and the low SNR of ASL signals during the fitting procedure, the CBF and ATT maps can be severely biased. The multiresolution data analysis approach has been demonstrated previously to improve quantification of in vivo MR spectroscopy and MRI (57-59). Briefly, the multiresolution strategy consists of constructing a multiresolution pyramid dataset of re-sampled spatial resolution from coarse to fine in which the coarse dataset has smaller data matrix but improved SNR in each pixel due to the average effect across the corresponding neighbor pixels in the finer level. Therefore, the initial fitting parameters are estimated firstly by fitting the dataset on the top of pyramid in which the data has highest SNR. Then these parameters are used as prior knowledge for fitting the data set at the next finer resolution. This procedure is repeated until the original resolution is reached. The multiresolution or multiscale processing strategy has been explored for CBF and ATT estimation as reported in our preliminary study (60), in which CBF and ATT maps were derived using the numerical model for CBF quantification (56) and a modified equation for the elimination of magnetization transfer effect using a separate labeling coil is utilized as shown in Eq. :
In which is the equilibrium magnetization, α is the labeling efficiency, f is the CBF in mL/g/s. λ is the brain-blood partition coefficient, T1tis is the tissue T1, and T1a is the blood T1. δa (or ATT) is the transit time from the labeling plane to the arterial compartment, δ is the transit time from the labeling plane to the imaging slice, w is the post-labeling-delay. λ=0.9, α=92%, T1a=1.66 s at 3T, and T1 map was obtained using an echo-planar imaging (EPI)-based inversion recovery measurement as described in the previous report (28).
The original data matrix size of the demonstrated perfusion images was 64×64 (Figure 4). A pyramid of three layers (from top to bottom: 16×16, 32×32, and 64×64) was constructed. The multiscale procedure was applied to generate CBF and ATT maps at each resolution level. As seen in Figure 4, GM shows much shorter ATT (~0.5 seconds) compared to those in WM (~0.9 seconds). The results suggest that multiresolution strategy is an efficient and robust approach for estimating multiple parameters from ASL data.
Technical challenges and limitations of ASL perfusion MRI in NHPs
To date, whole body high-field (3T) MRI clinical scanners are installed in most clinics or neuroimaging centers, greatly facilitating the use of novel MRI techniques in biomedical research using NHPs. In particular, the clinical scanners have spacious bore size which offers sufficient room for NHP handling in various experimental settings. Also, the related MRI findings can be readily translational compared to rodent studies with ultrahigh field scanners. As the usage of NHPs in scientific procedures is highly restrained by the ethics and rationale and cost as well (all procedures are specifically guided by the NIH guidelines for animal care and use in the United States), non-invasive in vivo MRI techniques play a unique and important role for accessing anatomical, physiological and functional information of NHP brains (61-64). The sample size in NHP neuroimaging studies is usually much smaller than that in rodents. Each scan must be carefully performed in order to obtain optimal images and minimize inter-subject variation for greater chance to reach statistical significance in the data analysis.
CASL with a separate labeling coil (two or three coil setting) provides optimal means for detection of basal CBF or function activation in NHPs. In particular, the receiving surface coil can be adjusted properly for maximal sensitivity to detect the local hemodynamic changes in the cortex with very high spatial and temporal resolution, greatly benefiting fMRI studies. In contrast, pCASL can be performed with a standard clinic setting and is currently available in most clinical scanners, largely facilitating CBF measurement in various NHP studies. pCASL can be used independently or easily combined with other MRI modalities (like DTI, structural MRI, in vivo MR spectroscopy) (31,41), providing sufficient quality data of resting CBF to examine the physiology in normal or stroke NHP brains. The labeling efficiency in pCASL is susceptible to the B0 and B1 field inhomogeneity and can vary substantially from animal to animal due to the variation in animal body size, shape and the inconsistency of experimental setting and should be calibrated in each scan. In addition, simultaneous multi-slice imaging (35), background suppression and 3D gradient and spin echo (GRASE) based ASL techniques (65) can improve image coverage and quality or offer better repeatability in ASL perfusion MRI studies and should be further explored in NHP models. The advance of ultra-high MRI (7T or above) also benefits the ASL techniques for NHP studies due to increased SNR of the MR images and longer T1 relaxation times of blood water and tissue in the brain (66).
Anesthetized animals are generally applied in MRI studies to minimize the animal motion even though MRI of awake NHPs can eliminate the adverse anesthesia effects in the brain but it requires extensive animal training and special experimental settings (67-69) which are not available in most research labs. Even though anesthetics like isoflurane substantially suppress the neural activation in the NHP brain, the brain functionality can still be evaluated with fMRI techniques (70,71). Also, the handling of anesthetized NHPs requires comprehensive physiological monitoring and professional veterinarian support to maintain animals in proper conditions and comply with the NIH guidelines of animal care and usage. The animal physiology can be altered due to adverse anesthesia effects. It is important to maintain the animal physiology in the stable condition and within normal ranges in every MRI scan in order to ensure the consistency of ASL data collection from one subject to another. The anesthesia effects can play a critical role in examining the functionality of NHPs and should be considered in experimental design and interpretation of the outcome using MRI (29,72).
CASL-based perfusion MRI allows for quantitative assessment of resting or dynamic CBF in NHPs using contemporary high field clinical scanners and has wide applications in NHP models with neurological diseases. Optimal CBF measurement in NHPs requires specific management on hardware and software, pulse sequences, data processing, and professional animal handling on a conventional clinical setting. With the advances of ASL perfusion techniques in high or ultra-high MRI, the further exploration of perfusion MRI techniques will advance the translational research using NHPs as animals keep playing a critical role in contemporary neuroscience and translational biomedical research and pharmaceutical development.
Funding: The project was funded by the National Center for Research Resources (P51RR000165) and is currently supported by the Office of Research Infrastructure Programs (OD P51OD011132).
Conflicts of Interest: The authors have no conflicts of interest to declare.
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