John A. Detre

Reduced Transit-Time Sensitivity in Noninvasive Magnetic Resonance Imaging of Human Cerebral Blood Flow

Herein, we present a theoretical framework and experimental methods to more accurately account for transit effects in quantitative human perfusion imaging using endogenous magnetic resonance imaging (MRI) contrast. The theoretical transit time sensitivities of both continuous and pulsed inversion spin tagging experiments are demonstrated. We propose introducing a delay following continuous labeling, and demonstrate theoretically that introduction of a delay dramatically reduces the transit time sensitivity of perfusion imaging. The effects of magnetization transfer saturation on this modified continuous labeling experiment are also derived, and the assumption that the perfusion signal resides entirely within tissue rather than the arterial microvasculature is examined. We present results demonstrating the implementation of the continuous tagging experiment with delay on an echoplanar scanner for measuring cerebral blood flow (CBF) in normal volunteers. By varying the delay, we estimate transit times in the arterial system, values that are necessary for assessing the accuracy of our quantification. The effect of uncertainties in the transit time from the tagging plane to the arterial microvasculature and the transit time to the tissue itself on the accuracy of perfusion quantification is discussed and found to be small in gray matter but still potentially significant in white matter. A novel method for measuring T1, which is fast, insensitive to contamination by cerebrospinal fluid, and compatible with the application of magnetization transfer saturation, is also presented. The methods are combined to produce quantitative maps of resting and hypercarbic CBF.

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. Magn Reson Med 73:102–116, 2015.

Magnetic resonance perfusion imaging in acute ischemic stroke using continuous arterial spin labeling.

BACKGROUND AND PURPOSE Continuous arterial spin-labeled perfusion MRI (CASL-PI) uses electromagnetically labeled arterial blood water as a diffusible tracer to noninvasively measure cerebral blood flow (CBF). We hypothesized that CASL-PI could detect perfusion deficits and perfusion/diffusion mismatches and predict outcome in acute ischemic stroke. METHODS We studied 15 patients with acute ischemic stroke within 24 hours of symptom onset. With the use of a 6-minute imaging protocol, CASL-PI was measured at 1.5 T in 8-mm contiguous supratentorial slices with a 3.75-mm in-plane resolution. Diffusion-weighted images were also obtained. Visual inspection for perfusion deficits, perfusion/diffusion mismatches, and effects of delayed arterial transit was performed. CBF in predetermined vascular territories was quantified by transformation into Talairach space. Regional CBF values were correlated with National Institutes of Health Stroke Scale (NIHSS) score on admission and Rankin Scale (RS) score at 30 days. RESULTS Interpretable CASL-PI images were obtained in all patients. Perfusion deficits were consistent with symptoms and/or diffusion-weighted imaging abnormalities. Eleven patients had hypoperfusion, 3 had normal perfusion, and 1 had relative hyperperfusion. Perfusion/diffusion mismatches were present in 8 patients. Delayed arterial transit effect was present in 7 patients; serial imaging in 2 of them showed that the delayed arterial transit area did not succumb to infarction. CBF in the affected hemisphere correlated with NIHSS and RS scores (P=0.037 and P=0.003, Spearman rank correlation). The interhemispheric percent difference in middle cerebral artery CBF correlated with NIHSS and RS scores (P=0.007 and P=0.0002, respectively). CONCLUSIONS CASL-PI provides rapid noninvasive multislice imaging in acute ischemic stroke. It depicts perfusion deficits and perfusion/diffusion mismatches and quantifies regional CBF. CASL-PI CBF asymmetries correlate with severity and outcome. Delayed arterial transit effects may indicate collateral flow.

A Theoretical and Experimental Investigation of the Tagging Efficiency of Pseudocontinuous Arterial Spin Labeling

Arterial spin labeling (ASL) is capable of noninvasively measuring blood flow by magnetically tagging the protons in arterial blood, which has been conventionally achieved using instantaneous (PASL) or continuous (CASL) RF pulses. As an intermediate method, pseudocontinuous ASL (pCASL) utilizes a train of discrete RF pulses to mimic continuous tagging that is often unavailable on imagers due to the requirement of continuous RF transmit capabilities. In the present study, we implemented two versions of pCASL (balanced and unbalanced gradient waveforms in tag and control scans) for both transmit/receive coils and array receivers. Experimental data show a 50% ± 4% increase of signal‐to‐noise ratio (SNR) compared with PASL and a higher tagging efficiency than amplitude‐modulated (AM) CASL (80% vs. 68%). Computer simulations predict an optimal tagging efficiency of 85% for flow velocities from 10 to 60 cm/s. It is theoretically and experimentally demonstrated that the tagging efficiency of pCASL is dependent upon the resonance offset and flip angle of the RF pulse train. We conclude that pCASL has the potential of combining the merits of PASL, including less hardware demand and higher tagging efficiency, and CASL, which includes a longer tagging bolus and thus higher SNR. These improvements provide a better balance between tagging efficiency and SNR. Magn Reson Med 58:1020–1027, 2007.

Assessment of cerebral blood flow in Alzheimer's disease by spin‐labeled magnetic resonance imaging

To evaluate the utility of arterial spin‐labeled blood flow magnetic resonance imaging for the detection of cerebral blood flow abnormalities in Alzheimers disease, arterial spin‐labeled blood flow images in 16 contiguous 5‐mm axial sections were acquired in 18 patients diagnosed with probable Alzheimers disease and 11 age‐matched controls. Blood flow images from all subjects were transformed to a standard anatomical space for voxel‐by‐voxel statistical analysis. High quality blood flow images were obtained from all but 1 subject. Statistical analysis demonstrated significant flow decreases relative to control subjects in temporal, parietal, frontal, and posterior cingulate cortices. Increased severity of disease, as measured by Mini‐Mental State Examination, correlated with posterior parietal and posterior cingulate decreases but not temporal decreases. Arterial spin‐labeled magnetic resonance imaging was found to be an effective tool for characterizing flow decreases accompanying Alzheimers disease. The absence of ionizing radiation or injection and the ability to obtain high quality anatomical images within the same scanning session make arterial spin labeling an attractive technique for the study of Alzheimers disease, for the evaluation of pharmacological therapies, and, possibly, for early diagnosis. Ann Neural 2000; 47:93–100

Comparison of quantitative perfusion imaging using arterial spin labeling at 1.5 and 4.0 Tesla

High‐field arterial spin labeling (ASL) perfusion MRI is appealing because it provides not only increased signal‐to‐noise ratio (SNR), but also advantages in terms of labeling due to the increased relaxation time T1 of labeled blood. In the present study, we provide a theoretical framework for the dependence of the ASL signal on the static field strength, followed by experimental validation in which a multislice pulsed ASL (PASL) technique was carried out at 4T and compared with PASL and continuous ASL (CASL) techniques at 1.5T, both in the resting state and during motor activation. The resting‐state data showed an SNR ratio of 2.3:1.4:1 in the gray matter and a contrast‐to‐noise ratio (CNR) of 2.7:1.1:1 between the gray and white matter for the difference perfusion images acquired using 4T PASL, 1.5T CASL, and 1.5T PASL, respectively. However, the functional data acquired using 4T PASL did not show significantly improved sensitivity to motor cortex activation compared with the 1.5T functional data, with reduced fractional perfusion signal change and increased intersubject variability. Possible reasons for these experimental results, including susceptibility effects and physiological noise, are discussed. Magn Reson Med 48:242–254, 2002.

Limbic Activation to Cigarette Smoking Cues Independent of Nicotine Withdrawal: A Perfusion fMRI Study

Exposure to cigarette smoking cues can trigger physiological arousal and desire to smoke. The brain substrates of smoking cue-induced craving (CIC) are beginning to be elucidated; however, it has been difficult to study this state independent of the potential contributions of pharmacological withdrawal from nicotine. Pharmacological withdrawal itself may have substantial effects on brain activation to cues, either by obscuring or enhancing it, and as CIC is not reduced by nicotine replacement strategies, its neuro-anatomical substrates may differ. Thus, characterizing CIC is critical for developing effective interventions. This study used arterial spin-labeled (ASL) perfusion fMRI, and newly developed and highly appetitive, explicit smoking stimuli, to examine neural activity to cigarette CIC in an original experimental design that strongly minimizes contributions from pharmacological withdrawal. Twenty-one smokers (12 females) completed smoking and nonsmoking cue fMRI sessions. Craving self-reports were collected before and after each session. SPM2 software was employed to analyze data. Blood flow (perfusion) in a priori-selected regions was greater during exposure to smoking stimuli compared to nonsmoking stimuli (p<0.01; corrected) in ventral striatum, amygdala, orbitofrontal cortex, hippocampus, medial thalamus, and left insula. Perfusion positively correlated with intensity of cigarette CIC in both the dorsolateral prefrontal cortex (r2=0.54) and posterior cingulate (r2=0.53). This pattern of activation that includes the ventral striatum, a critical reward substrate, and the interconnected amygdala, cingulate and OFC, is consistent with decades of animal research on the neural correlates of conditioned drug reward.

Arterial spin labeling perfusion fMRI with very low task frequency

Functional magnetic resonance imaging (fMRI) has become the most widely used modality for visualizing regional brain activation in response to sensorimotor or cognitive tasks. While the majority of fMRI studies have used blood oxygenation level‐dependent (BOLD) contrast as a marker for neural activation, baseline drift effects result in poor sensitivity for detecting slow variations in neural activity. By contrast, drift effects are minimized in arterial spin labeling (ASL) perfusion contrast, primarily as a result of successive pairwise subtraction between images acquired with and without labeling. Recent data suggest that ASL contrast shows stable noise characteristics over the entire frequency spectrum, which makes it suitable for studying low‐frequency events in brain function. The present study investigates the relative sensitivities of ASL and BOLD contrast in detecting changes in motor cortex activation over a spectrum of frequencies of experimental design, where the alternating period between the resting state and activation is varied from 30 s up to 24 hr. The results demonstrate that 1) ASL contrast can detect differences in motor cortex activation over periods of minutes, hours, and even days; 2) the functional sensitivity of ASL contrast becomes superior to that of BOLD contrast when the alternating period between the resting state and activation is greater than a few minutes; and 3) task activation measured by ASL tends to have less intersubject variability than BOLD contrast. The improved sensitivity of the ASL contrast for low task frequency and longitudinal studies, along with its superior power in group analysis, is expected to extend the range of experimental designs that can be studied using fMRI. Magn Reson Med 49:796–802, 2003.

An fMRI study of sex differences in regional activation to a verbal and a spatial task.

Sex differences in cognitive performance have been documented, women performing better on some phonological tasks and men on spatial tasks. An earlier fMRI study suggested sex differences in distributed brain activation during phonological processing, with bilateral activation seen in women while men showed primarily left-lateralized activation. This blood oxygen level-dependent fMRI study examined sex differences (14 men, 13 women) in activation for a spatial task (judgment of line orientation) compared to a verbal-reasoning task (analogies) that does not typically show sex differences. Task difficulty was manipulated. Hypothesized ROI-based analysis documented the expected left-lateralized changes for the verbal task in the inferior parietal and planum temporal regions in both men and women, but only men showed right-lateralized increase for the spatial task in these regions. Image-based analysis revealed a distributed network of cortical regions activated by the tasks, which consisted of the lateral frontal, medial frontal, mid-temporal, occipitoparietal, and occipital regions. The activation was more left lateralized for the verbal and more right for the spatial tasks, but men also showed some left activation for the spatial task, which was not seen in women. Increased task difficulty produced more distributed activation for the verbal and more circumscribed activation for the spatial task. The results suggest that failure to activate the appropriate hemisphere in regions directly involved in task performance may explain certain sex differences in performance. They also extend, for a spatial task, the principle that bilateral activation in a distributed cognitive system underlies sex differences in performance.

Magnetic resonance imaging of glutamate

Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed ∼3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ∼100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.