Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Comparison and optimization of pCASL and VSASL for rat thoracolumbar spinal cord MRI at 9.4 T.

PURPOSE: To evaluate pseudo-continuous arterial spin labeling (pCASL) and velocity-selective arterial spin labeling (VSASL) for quantification of spinal cord blood flow (SCBF) in the rat thoracolumbar spinal cord. METHODS: Labeling efficiency (LE) was compared between pCASL and three VSASL variants in simulations and both phantom and in vivo experiments at 9.4 T. For pCASL, the effects of label plane position and shimming were systematically evaluated. For VSASL, the effects of composite pulses and phase cycling were evaluated to reduce artifacts. Additionally, vessel suppression, respiratory, and cardiac gating were evaluated to reduce motion artifacts. pCASL and VSASL maps of spinal cord blood flow were acquired with the optimized protocols. RESULTS: LE of the descending aorta was larger in pCASL compared to VSASL variants. In pCASL, LE off-isocenter was improved by local shimming positioned at the label plane and the anatomical level of labeling for the thoracic cord was only viable at the level of the T10 vertebra. Cardiac gating was essential to reduce motion artifacts. Both pCASL and VSASL successfully demonstrated comparable SCBF values in the thoracolumbar cord. CONCLUSION: pCASL demonstrated high and consistent LE in the thoracic aorta, and VSASL was also feasible, but with reduced efficiency. A combination of cardiac gating and recording of actual post-label delays was important for accurate SCBF quantification. These results highlight the challenges and solutions to achieve sufficient ASL labeling and contrast at high field in organs prone to motion.

Velocity-selective arterial spin labeling perfusion MRI: A review of the state of the art and recommendations for clinical implementation.

This review article provides an overview of the current status of velocity-selective arterial spin labeling (VSASL) perfusion MRI and is part of a wider effort arising from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. Since publication of the 2015 consensus paper on arterial spin labeling (ASL) for cerebral perfusion imaging, important advancements have been made in the field. The ASL community has, therefore, decided to provide an extended perspective on various aspects of technical development and application. Because VSASL has the potential to become a principal ASL method because of its unique advantages over traditional approaches, an in-depth discussion was warranted. VSASL labels blood based on its velocity and creates a magnetic bolus immediately proximal to the microvasculature within the imaging volume. VSASL is, therefore, insensitive to transit delay effects, in contrast to spatially selective pulsed and (pseudo-) continuous ASL approaches. Recent technical developments have improved the robustness and the labeling efficiency of VSASL, making it a potentially more favorable ASL approach in a wide range of applications where transit delay effects are of concern. In this review article, we (1) describe the concepts and theoretical basis of VSASL; (2) describe different variants of VSASL and their implementation; (3) provide recommended parameters and practices for clinical adoption; (4) describe challenges in developing and implementing VSASL; and (5) describe its current applications. As VSASL continues to undergo rapid development, the focus of this review is to summarize the fundamental concepts of VSASL, describe existing VSASL techniques and applications, and provide recommendations to help the clinical community adopt VSASL.

Recent Technical Developments in ASL: A Review of the State of the Art.

This review article provides an overview of a range of recent technical developments in advanced arterial spin labeling (ASL) methods that have been developed or adopted by the community since the publication of a previous ASL consensus paper by Alsop et al. It is part of a series of review/recommendation papers from the International Society for Magnetic Resonance in Medicine Perfusion Study Group. Here, we focus on advancements in readouts and trajectories, image reconstruction, noise reduction, partial volume correction, quantification of nonperfusion parameters, fMRI, fingerprinting, vessel selective ASL, angiography, deep learning, and ultrahigh field ASL. We aim to provide a high level of understanding of these new approaches and some guidance for their implementation, with the goal of facilitating the adoption of such advances by research groups and by MRI vendors. Topics outside the scope of this article that are reviewed at length in separate articles include velocity selective ASL, multiple-timepoint ASL, body ASL, and clinical ASL recommendations.

Comparison of velocity-selective arterial spin labeling schemes.

PURPOSE: In velocity-selective (VS) arterial spin labeling, strategies using multiple saturation modules or using VS inversion (VSI) pulse can provide improved SNR efficiency compared to the original labeling scheme using one VS saturation (VSS) module. Their performance improvement, however, has not been directly compared. METHODS: Different VS labeling schemes were evaluated by Bloch simulation for their SNR efficiency, eddy current sensitivity, and robustness against B1 and B0 variation. These schemes included dual-module double-refocused hyperbolic secant and symmetric 8-segment B1 -insensitive rotation (sBIR8-) VSS pulses, the original and modified Fourier transform-based VSI pulses. A subset of the labeling schemes was examined further in phantom and in vivo experiments for their eddy current sensitivity and SNR performance. An additional sBIR8-VSS with a built-in inversion (sBIR8-VSS-inversion) was evaluated for the effects of partial background suppression to allow a fairer comparison to VSI. RESULTS: According to the simulations, the sBIR8-VSS was the most robust against field imperfections and had similarly high SNR efficiency (dual-module, dual-sBIR8-VSS) compared with the best VSI pulse (sinc-modulated, sinc-VSI). These were confirmed by the phantom and in vivo data. Without additional background suppression, the sinc-VSI pulses had the highest temporal SNR, closely followed by the sBIR8-VSS-inversion pulse, both benefited from partial background suppression effects. CONCLUSION: Dual-sBIR8-VSS and sinc-VSI measured the highest SNR efficiency among the VS labeling schemes. Dual-sBIR8-VSS was the most robust against field imperfections, whereas sinc-VSI may provide a higher SNR efficiency if its immunity to field imperfections can be improved.

Practical considerations for territorial perfusion mapping in the cerebral circulation using super-selective pseudo-continuous arterial spin labeling.

PURPOSE: This paper discusses several challenges faced by super-selective pseudo-continuous arterial spin labeling, which is used to quantify territorial perfusion in the cerebral circulation. The effects of off-resonance, pulsatility, vessel movement, and label rotation scheme are investigated, and methods to maximize labeling efficiency and overall image quality are evaluated. A strategy to calculate the territorial perfusion fractions of individual vessels is proposed. METHODS: The effects of off-resonance, label rotation scheme, and vessel movement on labeling efficiency were simulated. Two off-resonance compensation strategies (multiphase prescan, field map), cardiac triggering, and vessel movement were studied in vivo in a group of 10 subjects. Subsequently, a territorial perfusion fraction map was acquired in 2 subjects based on the mean vessel labeling efficiency. RESULTS: Multiphase calibration provided the highest labeling efficiency (P = .002) followed by the field map compensation (P = .037) compared with the uncompensated acquisition. Cardiac triggering resulted in a qualitative improvement of the image and an increase in signal contrast between the perfusion territory and the surrounding tissue (P = .010) but failed to show a significant change in temporal and spatial SNR. The constant clockwise label rotation scheme yielded the highest labeling efficiency. Significant vessel movement (>2 mm according to simulations) was observed in 50% of subjects. The measured territorial perfusion fractions showed good agreement with anatomical data. CONCLUSION: Optimized labeling efficiency resulted in increased image quality and accuracy of territorial perfusion fraction maps. Labeling efficiency depends critically on off-resonance calibration, cardiac triggering, optimal label rotation scheme, and vessel location tracking.

Optimizing MRF-ASL scan design for precise quantification of brain hemodynamics using neural network regression.

PURPOSE: Arterial Spin Labeling (ASL) is a quantitative, non-invasive alternative for perfusion imaging that does not use contrast agents. The magnetic resonance fingerprinting (MRF) framework can be adapted to ASL to estimate multiple physiological parameters simultaneously. In this work, we introduce an optimization scheme to increase the sensitivity of the ASL fingerprint. We also propose a regression based estimation framework for MRF-ASL. METHODS: To improve the sensitivity of MRF-ASL signals to underlying parameters, we optimized ASL labeling durations using the Cramer-Rao Lower Bound (CRLB). This paper also proposes a neural network regression based estimation framework trained using noisy synthetic signals generated from our ASL signal model. We tested our methods in silico and in vivo, and compared with multiple post labeling delay (multi-PLD) ASL and unoptimized MRF-ASL. We present comparisons of estimated maps for the six parameters of our signal model. RESULTS: The scan design process facilitated precise estimates of multiple hemodynamic parameters and tissue properties from a single scan, in regions of normal gray and white matter, as well as regions with anomalous perfusion activity in the brain. In particular, there was a 86.7% correlation of perfusion estimates with the ground truth in silico, using our proposed techniques. In vivo, there was roughly a 7 fold improvement in the Coefficient of Variation (CoV) for white matter perfusion, and 2 fold improvement in gray matter perfusion CoV in comparison to a reference Multi PLD method. The regression based estimation approach provided perfusion estimates rapidly, with estimation times of around 1s per map. CONCLUSIONS: Scan design optimization, coupled with regression-based estimation is a powerful tool for improving precision in MRF-ASL.

Recent progress in ASL.

This article aims to provide the reader with an overview of recent developments in Arterial Spin Labeling (ASL) MRI techniques. A great deal of progress has been made in recent years in terms of the SNR and acquisition speed. New strategies have been introduced to improve labeling efficiency, reduce artefacts, and estimate other relevant physiological parameters besides perfusion. As a result, ASL techniques has become a reliable workhorse for researchers as well as clinicians. After a brief overview of the technique's fundamentals, this article will review new trends and variants in ASL including vascular territory mapping and velocity selective ASL, as well as arterial blood volume imaging techniques. This article will also review recent processing techniques to reduce partial volume effects and physiological noise. Next the article will examine how ASL techniques can be leveraged to calculate additional physiological parameters beyond perfusion and finally, it will review a few recent applications of ASL in the literature.

Improved sensitivity and temporal resolution in perfusion FMRI using velocity selective inversion ASL.

PURPOSE: This work aims to investigate the utility of velocity selective inversion pulses for perfusion weighted functional MRI. METHODS: Tracer kinetic properties of velocity selective inversion (VSI) pulses as an input function for an arterial spin labeling (ASL) experiment were characterized in a group of healthy participants. Numerical simulations were conducted to search for a robust set of timing parameters for FMRI time series acquisition with maximal signal to noise ratio efficiency. The performance of three VSI pulse sequences with different timing parameters was compared with a pseudocontinuous ASL sequence in a simple FMRI experiment conducted on healthy participants. RESULTS: The fit to the tracer kinetic model yielded arterial CBV of 1.24% ± 0.52% and 0.45 ± 0.11% and perfusion rates of 60.8 ± 32.3 and 34.4 ± 5.4 mL/min/100 g for gray and white matter, respectively. Bolus arrival times were estimated as 75.7 ± 21 ms and 349 ± 78 ms for gray and white matter, respectively. The FMRI experiments showed that VSI pulses yield comparable sensitivity to PCASL with similar timing parameters (TR = 4 s). However, VSI pulses could be used at a faster acquisition speed (TR = 3 s) and were more sensitive to neuronal activity than PCASL pulses, as evidenced by the 31% higher Z scores obtained on average in the active regions. CONCLUSION: VSI pulses can be very beneficial for perfusion weighted functional MRI because of their tracer kinetic characteristics, which allow a faster acquisition rate while maintaining an efficient labeling input function.

Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions.

By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

MR-based detection of individual histotripsy bubble clouds formed in tissues and phantoms.

PURPOSE: To demonstrate that MR sequences can detect individual histotripsy bubble clouds formed inside intact tissues. METHODS: A line-scan and an EPI sequence were sensitized to histotripsy by inserting a bipolar gradient whose lobes bracketed the lifespan of a histotripsy bubble cloud. Using a 7 Tesla, small-bore scanner, these sequences monitored histotripsy clouds formed in an agar phantom and in vitro porcine liver and brain. The bipolar gradients were adjusted to apply phase with k-space frequencies of 10, 300 or 400 cm-1 . Acoustic pressure amplitude was also varied. Cavitation was simultaneously monitored using a passive cavitation detection system. RESULTS: Each image captured local signal loss specific to an individual bubble cloud. In the agar phantom, this signal loss appeared only when the transducer output exceeded the cavitation threshold pressure. In tissues, bubble clouds were immediately detected when the gradients created phase with k-space frequencies of 300 and 400 cm-1 . When the gradients created phase with a k-space frequency of 10 cm-1 , individual bubble clouds were not detectable until many acoustic pulses had been applied to the tissue. CONCLUSION: Cavitation-sensitive MR-sequences can detect single histotripsy bubble clouds formed in biologic tissue. Detection is influenced by the sensitizing gradients and treatment history. Magn Reson Med 76:1486-1493, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Evidence that neurovascular coupling underlying the BOLD effect increases with age during childhood.

Functional MRI using blood-oxygen-level-dependent (BOLD) imaging has provided unprecedented insights into the maturation of the human brain. Task-based fMRI studies have shown BOLD signal increases with age during development (ages 5-18) for many cognitive domains such as language and executive function, while functional connectivity (resting-state) fMRI studies investigating regionally synchronous BOLD fluctuations have revealed a developing functional organization of the brain from a local into a more distributed architecture. However, interpretation of these results is confounded by the fact that the BOLD signal is directly related to blood oxygenation driven by changes in blood flow and only indirectly related to neuronal activity, and may thus be affected by changing neuronal-vascular coupling. BOLD signal and cerebral blood flow (CBF) were measured simultaneously in a cohort of 113 typically developing awake participants ages 3-18 performing a narrative comprehension task. Using a novel voxelwise wild bootstrap analysis technique, an increased ratio of BOLD signal to relative CBF signal change with age (indicative of increased neuronal-vascular coupling) was seen in the middle temporal gyri and the left inferior frontal gyrus. Additionally, evidence of decreased relative oxygen metabolism (indicative of decreased neuronal activity) with age was found in the same regions. These findings raise concern that results of developmental BOLD studies cannot be unambiguously attributed to neuronal activity. Astrocytes and astrocytic processes may significantly affect the maturing functional architecture of the brain, consistent with recent research demonstrating a key role for astrocytes in mediating increased CBF following neuronal activity and for astrocyte processes in modulating synaptic connectivity.

Controlling cavitation-based image contrast in focused ultrasound histotripsy surgery.

PURPOSE: To develop MRI feedback for cavitation-based, focused ultrasound, tissue erosion surgery (histotripsy), we investigate image contrast generated by transient cavitation events. METHODS: Changes in GRE image intensity are observed while balanced pairs of field gradients are varied in the presence of an acoustically driven cavitation event. The amplitude of the acoustic pulse and the timing between a cavitation event and the start of these gradient waveforms are also varied. The magnitudes and phases of the cavitation site are compared with those of control images. An echo-planar sequence is used to evaluate histotripsy lesions in ex vivo tissue. RESULTS: Cavitation events in water cause localized attenuation when acoustic pulses exceed a pressure threshold. Attenuation increases with increasing gradient amplitude and gradient lobe separation times and is isotropic with gradient direction. This attenuation also depends upon the relative timing between the cavitation event and the start of the balanced gradients. These factors can be used to control the appearance of attenuation while imaging ex vivo tissue. CONCLUSION: By controlling the timing between cavitation events and the imaging gradients, MR images can be made alternately sensitive or insensitive to cavitation. During therapy, these images can be used to isolate contrast generated by cavitation.

Arterial cerebral blood volume-weighted functional MRI using pseudocontinuous arterial spin tagging (AVAST).

PURPOSE: Neurovascular regulation, including responses to neural activation that give rise to the blood oxygenation level-dependent (BOLD) effect, occurs mainly at the arterial and arteriolar level. The purpose of this study is to develop a framework for fast imaging of arterial cerebral blood volume (aCBV) signal suitable for functional imaging studies. METHODS: A variant of the pseudocontinuous arterial spin tagging technique was developed in order to achieve a contrast that depends on aCBV with little contamination from perfusion signal by taking advantage of the kinetics of the tag through the vasculature. This technique tailors the tagging duration and repetition time for each subject. The proposed technique, called AVAST, is compared empirically with BOLD imaging and standard (perfusion-weighted) arterial spin labeling (ASL) technique, in a motor-visual activation paradigm. RESULTS: The average Z-scores in the activated area obtained over all the subjects were 4.25, 5.52, and 7.87 for standard ASL, AVAST, and BOLD techniques, respectively. The aCBV contrast obtained from AVAST provided 80% higher average signal-to-noise ratio and 95% higher average contrast-to-noise ratio compared with that of the standard ASL measurements. CONCLUSION: AVAST exhibits improved activation detection sensitivity and temporal resolution over the standard ASL technique, in functional MRI experiments, while preserving its quantitative nature and statistical advantages. AVAST particularly could be useful in clinical studies of pathological conditions, longitudinal studies of cognitive function, and studies requiring sustained periods of the condition.

Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia.

This review provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ASL in Dementia consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this review, we describe the major considerations and trade-offs in implementing an ASL protocol and provide specific recommendations for a standard approach. Our conclusion is that as an optimal default implementation, we recommend pseudo-continuous labeling, background suppression, a segmented three-dimensional readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model.

Neural effects of short-term training on working memory.

Working memory training has been the focus of intense research interest. Despite accumulating behavioral work, knowledge about the neural mechanisms underlying training effects is scarce. Here, we show that 7 days of training on an n-back task led to substantial performance improvements in the trained task; furthermore, the experimental group showed cross-modal transfer, as compared with an active control group. In addition, there were two neural effects that emerged as a function of training: first, increased perfusion during task performance in selected regions, reflecting a neural response to cope with high task demand; second, increased blood flow at rest in regions where training effects were apparent. We also found that perfusion at rest was correlated with task proficiency, probably reflecting an improved neural readiness to perform. Our findings are discussed within the context of the available neuroimaging literature on n-back training.

Optimized simultaneous ASL and BOLD functional imaging of the whole brain.

PURPOSE: To compare a double-excitation combined arterial-spin labeling/blood-oxygenation level dependent (ASL/BOLD) functional imaging method to a double-echo method. ASL provides a useful complement to standard BOLD functional imaging, to map effects of cerebral hemodynamics. Whole-brain imaging is necessary to properly characterize large functional networks. A challenge of whole-brain ASL/BOLD is that images for ASL functional contrast must be acquired before significant longitudinal relaxation of the inverted spins occurs; however, a longer echo time (TE) is required for optimal BOLD functional contrast, lengthening the acquisition time. Thus, existing combined ASL/BOLD studies have only partial-brain coverage. MATERIALS AND METHODS: The proposed method allows acquisition of images for ASL contrast within a short period after the ASL labeling pulse and postinversion delay, then subsequent acquisition of images with longer TE for BOLD contrast. The technique is demonstrated using a narrative comprehension task in 35 normal children, and the double-excitation method is empirically compared with the double-echo method in 7 normal adults. RESULTS: Compared with a double-echo sequence, simulations show the double-excitation method improves ASL contrast-to-noise ratio (CNR) (∼50%) in later-acquired slices with minimal (<1%) reduction in BOLD CNR in earlier-acquired slices if reduced excitation flip angles for the ASL acquisitions are used. Empirical results from adult data are in agreement with the simulations. Group analyses from the narrative comprehension task also show greater intersubject sensitivity in BOLD versus ASL. CONCLUSION: Our method simultaneously optimizes ASL and BOLD acquisitions for CNR while economizing acquisition time.

Lateral Prefrontal Stimulation of Active Cortex With Theta Burst Transcranial Magnetic Stimulation Affects Subsequent Engagement of the Frontoparietal Network.

BACKGROUND: A critical unanswered question about therapeutic transcranial magnetic stimulation is what patients should do during treatment to optimize its effectiveness. Here, we address this lack of knowledge in healthy participants, testing the hypotheses that stimulating the left dorsolateral prefrontal cortex (dlPFC) while participants perform a working memory task will provide stronger effects on subsequent activation, perfusion, connectivity, and performance than stimulating resting dlPFC. METHODS: After a baseline functional magnetic resonance imaging session to localize dlPFC activation and the associated frontoparietal network (FPN) engaged by an n-back task, healthy participants (N = 40, 67.5% female) underwent 3 counterbalanced sessions, separated by several weeks, during which they received intermittent theta burst stimulation (iTBS) followed by magnetic resonance imaging scans as follows: 1) iTBS to the dlPFC while resting passively (passive), 2) iTBS to the dlPFC while performing the n-back task (active), and 3) iTBS to a vertex site, while not engaged in the n-back task and resting passively (control). RESULTS: We found no difference in n-back performance between the 3 conditions. However, FPN activation was reduced while performing the n-back task in the active condition relative to the passive and control conditions. There was no differential activity in the FPN on comparing passive with control conditions, i.e., there was no effect of the site of stimulation. We found no effects of state or site of stimulation on perfusion or connectivity with the dlPFC. CONCLUSIONS: In this study, the state of the brain while receiving iTBS affected FPN activation, possibly reflecting greater efficiency of FPN network activation when participants were stimulated while engaging the FPN.