Review

Applications of Arterial Spin Labeled MRI inthe Brain

John A. Detre, MD,1–3* Hengyi Rao, PhD,1,3 Danny J.J. Wang, PhD,4

Yu Fen Chen, PhD,5 and Ze Wang, PhD3,6

Perfusion provides oxygen and nutrients to tissues and isclosely tied to tissue function while disorders of perfusionare major sources of medical morbidity and mortality. Ithas been almost two decades since the use of arterialspin labeling (ASL) for noninvasive perfusion imaging wasfirst reported. While initial ASL magnetic resonance imag-ing (MRI) studies focused primarily on technological de-velopment and validation, a number of robust ASL imple-mentations have emerged, and ASL MRI is now alsoavailable commercially on several platforms. As a result,basic science and clinical applications of ASL MRI havebegun to proliferate. Although ASL MRI can be carried outin any organ, most studies to date have focused on thebrain. This review covers selected research and clinicalapplications of ASL MRI in the brain to illustrate itspotential in both neuroscience research and clinical care.

Key Words: arterial spin labeling; cerebral blood flow;brain function; cognitive neuroscience; clinical neuro-science; magnetic resonance imagingJ. Magn. Reson. Imaging 2012;35:1026–1037.VC 2012 Wiley Periodicals, Inc.

TISSUE PERFUSION is a fundamental physiologicalparameter that is closely linked to tissue function,and disorders of perfusion are leading causes of medi-cal morbidity and mortality. While a number of flow-

related parameters can be measured using a range ofmagnetic resonance imaging (MRI) methodologies,direct measurement of tissue perfusion in classicalunits of ml/g/min requires a nominally diffusibletracer. This was first accomplished in MRI using deu-terated water (1,2) and fluorinated (3,4) tracers, andin the future hyperpolarized tracers may be used, butcurrently the most effective approach uses magneti-cally labeled arterial blood water, termed ‘‘arterial spinlabeling’’ (ASL). Feasibility of the basic ASL approachfor imaging tissue perfusion was first published in1992 as a crude single-slice image in the rat brain (5).Since that time there have been several importantmethodological advances and technical improve-ments, such that it is currently possible to obtainwhole-brain ASL data routinely in both clinical andresearch settings. With the maturation of this technol-ogy, numerous basic and clinical applications havealso been assessed. The majority of initial applica-tions have been in the brain due to its high perfusionrates relative to other organs, its spatially consoli-dated blood supply, the lack of major motion issues,and the normally tight coupling between regional cer-ebral blood flow and neural activity.

This review primarily focuses on applications ofASL, although a brief introduction to ASL methodolo-gies is also provided as background. There are cur-rently �1000 articles on ASL MRI and its applica-tions. Accordingly, this review is not intended toprovide a comprehensive summary of the literature.Instead, it attempts to illustrate the particular bene-fits of ASL MRI in selected applications in basic andclinical neuroscience where it has shown promise.

ASL METHODOLOGY

In ASL techniques, arterial blood water is magneti-cally ‘‘labeled’’ using radiofrequency (RF) irradiation.The approach is highly analogous to positron emis-sion tomography (PET) cerebral blood flow (CBF)measurements, which use 15O labeled water as theflow tracer, except that the magnetically labeled arte-rial water ‘‘decays’’ with T1 relaxation rather than theradioactive decay rate for 15O. ASL MRI measure-ments of CBF have been validated against 15O-PET(6–8) in the brain and have been shown to provide

1Department of Neurology, University of Pennsylvania, Philadelphia,Pennsylvania, USA.2Department of Radiology, University of Pennsylvania, Philadelphia,Pennsylvania, USA.3Center for Functional Neuroimaging, University of Pennsylvania,Philadelphia, Pennsylvania, USA.4Department of Neurology, UCLA, University of California, Los Angeles,California, USA.5Department of Radiology, Northwestern University, Evanston, Illinois,USA.6Department of Psychiatry, University of Pennsylvania, Philadelphia,Pennsylvania, USA.

Contract grant sponsor: National Institutes of Health; Contract grantnumbers: NS058386, NS045839, RR002305 and MH080729.

*Address reprint requests to: J.A.D., Professor, Depts. of Neurologyand Radiology, Director, Center for Functional Neuroimaging, Schoolof Medicine, University of Pennsylvania, 3 W. Gates Pav./HUP, 3400Spruce St., Philadelphia, PA 19104-4283. E-mail: detre@mail.med.upenn.edu

Received May 9, 2011; Accepted December 15, 2011.

DOI 10.1002/jmri.23581View this article online at wileyonlinelibrary.com.

JOURNAL OF MAGNETIC RESONANCE IMAGING 35:1026–1037 (2012)

CME

VC 2012 Wiley Periodicals, Inc. 1026

similar image appearance and blood flow values.Because the T1 relaxation rate for water in blood ortissues is on the order of 1–2 seconds, only smallamounts of arterial spin labeled water accumulate inthe brain, and prolongation of T1 with field strengthrepresents a major benefit of high-field MRI for ASLstudies. Fortunately, 3 T MRI machines are now wide-spread. Signal gains of up to 4-fold are theoreticallyobtainable from 7 T ASL, but there are also numerouschallenges to realizing this benefit.

A consequence of the short lifetime of the magneticlabel is that perfusion measurements are very sensi-tive to the arterial transit times of the label (9). Uncer-tainties in the arterial transit time are the majorsource of error in most ASL studies, and it can bechallenging to measure blood flow in poorly perfusedtissues due to label decay during transit. Use of apostlabeling delay to reduce the transit time depend-ence of ASL was an early advance in the methodology(9), and is now routinely employed in many ASLimplementations. On the other hand, arterial transittimes derived from ASL data are potentially informa-tive by defining vascular and watershed territories(10–12) or collateral flow sources (13,14).

During ASL image acquisition, repeated label andcontrol images are typically interleaved. Perfusioncontrast is obtained by pairwise subtraction of thelabel and control acquisitions, and absolute CBF inwell-characterized physiological units of ml/100g/mincan be estimated by modeling expected signalchanges in the brain, primarily taking into accountthe tracer half-life determined by the T1 of blood andtissue (5). During the past two decades, theoreticaland experimental studies have been conducted toimprove the accuracy of CBF quantification using ASLby taking into account multiple parameters such asarterial transit time, magnetization transfer effect, T1,labeling efficiency, and capillary water permeability.Assumed values are typically used for these parame-ters since it can be time-consuming to measure themin each subject and using measured values addsnoise to the resulting CBF maps. Variations in label-ing efficiency, arterial transit time, and blood T1 arethe most significant sources of error in CBF quantifi-cation (15), particularly in clinical applications wheremajor deviations from normative values occur. Whilemany ASL quantification schemes are based on asteady-state model derived from diffusible tracertheory, kinetic models analogous to those used fordynamic susceptibility contrast perfusion MRI havealso been applied to ASL data (16,17), and are theo-retically insensitive to variations in parameters suchas arterial transit time and labeling efficiency. Bettercharacterization of the compartmentalization of ASLand the use of advanced signal processing schemes toimprove ASL quantification remain promising avenuesfor improving its sensitivity and reliability (18).Although reliable quantification of absolute CBFbased on ASL data remains challenging, similar chal-lenges and assumptions exist for other methods forquantifying CBF in vivo.

Several approaches exist for achieving ASL (Fig. 1).In continuous ASL (CASL), arterial blood water is con-

tinuously and selectively labeled as it passes througha labeling plane (19). In pulsed ASL (PASL) a short RFpulse is used to instantaneously invert blood and tis-sue, and can be applied either below the brain(20,21), or to the entire brain with subsequent selec-tive inversion of the imaging slices to produce a mag-netization difference between blood and brain water(22). A hybrid approach that simulates CASL usingmany short pulses termed ‘‘pseudocontinuous’’ or‘‘pulsed continuous’’ ASL (pCASL) combines theseschemes to provide better sensitivity and ease ofimplementation for body coil transmitters (23,24). Sev-eral methods also exist for spatially selective labeling,uniquely allowing the perfusion distribution of singlearterial territories to be measured (25–30). Velocityselective labeling has also been explored as a meansof eliminating arterial transit time dependence (31,32).More recently, time-resolved ASL has been developedas a noninvasive alternative to angiography (33).

Any imaging sequence can be used to measure thechanges in tissue magnetization due to ASL. Since theASL effect is small, it is desirable to use an imagingsequence with high signal-to-noise ratio (SNR). Muchof the data acquired to date using ASL has employedechoplanar imaging due to its high SNR and speed,which reduces the potential for motion artifactsbetween label and control scans. However, echoplanarimaging can introduce distortions in regions of highstatic susceptibility gradients that degrade imagequality. Over the past several years, 3D sequences

Figure 1. Typical whole-brain ASL MRI quantitative CBFdata obtained in 6 minutes at 3 T using PASL and pCASLwith echoplanar imaging (top and middle), adapted from(109) Chen et al, J Magn Reson Imaging 2011;33:940–949,with permission from the publisher. Below: pCASL with back-ground-suppressed 3D variable density spiral acquisitionacquired in 2 minutes at 3 T (courtesy of Dr. M. Fernandez-Seara).

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based on fast spin echo (24) or GRASE (34) havebegun to be used for image acquisition in ASL toimprove image quality. 3D sequences provideimproved SNR and greatly facilitate the use of back-ground suppression pulses to reduce the static brainsignal and increase sensitivity (35–37).

CLINICAL APPLICATIONS OF ASL

Commercial ASL sequences are now available formost major clinical MRI platforms. These vary consid-erably with regard to the specific implementationused for labeling, imaging, and quantification, butthey do allow ASL to be added to clinical imaging pro-tocols. As with many other MRI methodologies, thishas initially been most widely applied in the brain.

An obvious application of ASL MRI is in cerebrovas-cular disease, since it is a disorder of perfusion (Fig.2). A few early studies demonstrated that ASL MRIwas feasible in acute stroke (38,39), but the lack ofavailability of robust methodology, its low sensitivityfor hypoperfusion, and the requirement for severalminutes of signal averaging limited its use, so to datedynamic susceptibility contrast (DSC) perfusion MRIremains the predominant method in use for acutestroke. However, the use of background suppressionallows ASL MRI data to be reliably obtained at 3 T inless than 1 minute (36), and as this methodologybecomes available, the use of ASL MRI in acute strokeimaging protocols may increase. Nonetheless, severalcase reports demonstrate the utility of ASL in strokeand its differential diagnosis, with unexpected hyper-perfusion suggesting stroke mimics such as compli-cated migraine (40) and focal seizure (41).

While acute stroke has been the focus of much ofcerebrovascular MRI, the capability for accurate andreliable quantification of CBF with ASL provides as-yet untapped potential applications in managingchronic cerebrovascular disease. Early data demon-strated that CBF is chronically reduced in patientswith cerebrovascular disease, and ASL MRI could playan important role in monitoring CBF with medicaland surgical management changes (42–45). Vesselselective ASL may also have a role in planning andmonitoring interventional procedures (46). ASL MRIcan also be used in the diagnosis and management ofarteriovenous malformations to increase their conspi-cuity due to the accumulation of a large venous label,and potentially to quantify shunt fractions (47).

ASL MRI is appealing in pediatric populations dueto its noninvasiveness. It has been used to assessbrain tissue perfusion in children with sickle cell dis-ease, showing a significant increase of CBF in all cere-bral arterial territories, which concurred with previousPET findings (48), in acute stroke where ASL perfu-sion deficits predicted chronic infarct volumes whilenormally or hyperperfused vascular territories weregenerally associated with positive imaging outcomes(49), and in congenital heart disease where baselineCBF was found to be reduced and periventricular leu-komalacia was associated with low CBF and lack offlow response to hypercarbia (50).

Arterial occlusive disease is not limited to the brain,but because the brain is stationary and highly per-fused, it is easier to obtain good quality ASL data inbrain than in other organs. However, ASL MRI hasalso been obtained from postischemic extremities inpatients with peripheral vascular disease (51) andthere have been some preliminary feasibility studiesof ASL MRI in the heart (52). The kidneys and retinaare highly perfused tissues where ASL MRI has alsobeen used (53,54).

Another clinical area in which tissue perfusion rep-resents a key pathophysiological mechanism is neo-plastic disease and its treatment. Tumor vasculariza-tion and perfusion tends to increase with tumorgrade, and brain tumor blood flow measured by ASLMRI has been shown to be correlated with grade(55,56). Imaging tumor blood flow and metabolismcan also be used to differentiate tumor recurrencefrom radiation necrosis (57) and to monitor treatment.Finally, treatment of neoplastic disease with antian-giogenesis therapy specifically targets the mecha-nisms by which tumors increase their vascularization,and preliminary studies demonstrate that early treat-ment responses detected by ASL MRI are predictive ofsubsequent clinical responses (58).

In brain and in most other organs, changes in per-fusion are coupled with changes in metabolism. Thisprovides the physiological basis of functional MRI(fMRI) studies, which will be discussed below, butalso has clinical relevance. Several studies have

Figure 2. Transit artifact in a patient with left middle cere-bral artery stroke and a transit time map showing prolongedarterial transit to this region. Top: FLAIR images showingmultiple strokes in the left Middle cerebral artery distribu-tion. Middle: ASL CBF images show artifactual hyperperfusionin the left MCA distribution (arrows) due to delayed transit oflabel, which is imaged within leptomeningeal vessels provid-ing collateral flow. CBF in left and right MCA distributions areactually nearly identical at 43 and 42 ml/100g/min, respec-tively. Bottom: Arterial transit time map demonstrates pro-longed transit times to the left MCA distribution.

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supported the utility of ASL MRI for detecting patternsof regional hypoperfusion suggesting a diagnosisof Alzheimer’s dementia (59–63) or frontotemporaldementia (61,63). Although a growing number ofmolecular imaging tracers are likely to provide the ear-liest and most specific detection of Alzheimer’s neuro-pathology, there remains a role for functional imagingin predicting disease conversion (64) and monitoringdisease progression and perhaps responses to therapy.Furthermore, molecular imaging studies are costlyand not widely available, so there might also be an im-portant role for ASL MRI in screening for neurodege-nerative disease.

Epilepsy is another neurological disorder in whichfunctional imaging contributes to diagnosis and man-agement. Interictal hypoperfusion measured by ASLMRI has been shown to correlate with interictal hypo-metabolism by FDG-PET in temporal lobe epilepsy ina few preliminary studies (65–67), some showingcorrelations with PET data, and ictal hyperperfusionhas also been visualized (41,68).

BASIC SCIENCE APPLICATIONS OF ASL MRI

ASL MRI is a particularly promising MRI methodologyfor basic research because it is quantitative andbecause it is one of the few MRI contrast mechanismsfor which the biological basis is well understood. Overthe past decade, ASL MRI has been successfully used

in a variety of research applications, mainly in neuro-science, and it is now increasingly included in multi-modal neuroimaging protocols. Here we review severalof the research areas in which ASL MRI has beenassessed. ASL MRI has also been used to furtherinvestigate changes in blood oxygenation level-de-pendent (BOLD) contrast, which represents a complexinteraction between changes in blood flow, blood vol-ume, and oxygen metabolism. One such application is‘‘calibrated BOLD’’ (69), wherein relative changes inASL CBF and BOLD contrast with vasoactive stimuliare used to draw inferences about oxygen metabolismchanges with functional stimulation.

ASL for Developmental Neuroscience

ASL MRI is currently being used as a biomarker forfunctional brain development in both healthy popula-tions and developmental disorders (Fig. 3). Severalphysiological properties of the pediatric brain are ben-eficial for ASL (70). Blood flow rates are generallyhigher in children compared with adults (except innewborns) (71), which increases perfusion contrast,and the water content of the brain is also higher inchildren than adults, which yields a greater concen-tration and half-life of the tracer (blood water). Inaddition, ASL offers quantitative CBF at baselinewithout the use of external tasks, which is more

Figure 3. Top: representativeASL MRI data across humanbrain development. Below: Regionof interest data showing develop-mental trajectories of relativeCBF in cingulate and occipitalcortices. An increase in cingulateCBF is evident, while occipitalCBF remains stable.

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convenient and advantageous than performing taskactivation fMRI in infants and younger children.

The first feasibility study of pediatric ASL was car-ried out using PASL at 1.5 T (70), which demonstrateda 70% improvement in the SNR of pediatric perfusionimages as compared with those of healthy adults. Sev-eral recent studies have more systematically investi-gated developmental changes of brain perfusion,using PASL or CASL at 1.5 and 3 T (72–75). In healthychildren older than 4 to 5 years, a trend of decreasingCBF in the whole brain, gray and white matter withage has been observed (73,74), which is in agreementwith existing literature based on nuclear medicineapproaches (SPECT) (71). In terms of developmentaltrajectories of regional CBF (rCBF), relative rCBFincreases with age (after adjusting global CBF) wereobserved in the frontal cortex, cingulate cortex, angu-lar gyrus, and hippocampus (74), which may reflectthe later maturation of cortical regions associatedwith executive function, cognitive control, and integra-tive and memory function (76). In a recent study per-formed on 202 healthy children age 5–18 years, Takiet al (75) separated developmental effects on brainstructure and perfusion by calculating brain perfu-sion with adjustment for gray matter density (BP-GMD) in 22 brain regions. The correlation betweenBP-GMD and age showed an inverted U shape fol-lowed by a U-shaped trajectory in most regions. Theage at which BP-GMD peaked increased from the occi-pital to the frontal lobe via the temporal and parietallobes.

ASL MRI has also been applied to neonates andinfants. In unsedated newborns, the cortical perfusionlevel is lower than that of adults. Nevertheless, perfu-sion is significantly higher in basal ganglia than corti-cal gray and white matter (72), consistent with PETimaging results in this age group (77). Another recentstudy compared perfusion images acquired from nor-mally developing 7- and 13-month-old infants whileasleep without sedation (78). The 13-month infantgroup showed an increase of relative CBF in frontalregions as well as in the hippocampi, anterior cingu-late, amygdalae, occipital lobes, and auditory cortex.

ASL for Cognitive Neuroscience

Over the last two decades, fMRI based on BOLD hasbecome a standard tool to visualize regional brainactivation in response to various sensorimotor or cog-nitive tasks. However, because BOLD signal is theresult of a complex interaction between a number ofphysiological variables changes accompanying neuralactivity including CBF, cerebral blood volume (CBV),and cerebral oxygenation metabolic rate, task-specificBOLD signal changes cannot be directly quantified inphysiological units. Instead, BOLD signal changes areusually expressed as a relative percentage signalchange or as a statistical significance level based on astatistical model. ASL perfusion MRI can be used tomonitor task-correlated CBF changes in a mannersimilar to BOLD fMRI. Although task-correlated per-centage signal changes in ASL MRI are weaker thanBOLD changes, there is evidence that ASL CBF

changes are better localized than BOLD changes bothspatially (79) and temporally (80,81). However, thesebenefits have yet to be realized in significant applica-tions. Instead, the principal benefits of ASL MRI forbrain mapping relate to the quantitative relationshipbetween ASL MRI signal changes and CBF.

ASL data are typically obtained from successivepairwise subtractions between images acquired withand without ASL. This paired subtraction dramati-cally changes the noise properties of ASL comparedwith BOLD fMRI by eliminating low-frequency noise(82), thereby increasing sensitivity over longer timescales (83). The superior low-frequency sensitivity ofASL perfusion over BOLD fMRI has been well demon-strated in a sensorimotor study showing that reliableCBF activation in motor cortex could be detected withup to 24 hours interval between rest and finger tap-ping, while BOLD activation diminished with a fewminutes interval (84), as shown in Fig. 4. Because ofits long-term stability, ASL perfusion fMRI providesan appealing alternative to BOLD fMRI for imagingbrain activations during long time scale processesand more ecological paradigms such as motor learn-ing (85), emotion or mental states (86–88), moodchanges (89,90), and natural vision (91). Further,although the sensitivity and temporal resolution ofASL are generally lower than routine BOLD fMRI,there is some evidence that ASL sensitivity to groupeffects is increased, which may be due to reducedbetween-subject variation in the CBF changes as com-pared with BOLD signal changes (83,84).

Because ASL MRI provides absolute quantificationof CBF, which is coupled to regional neural activity(84), it can also be used to measure resting brainfunction independent of any specific sensorimotor orcognitive task. Indeed, it is thought that the vast ma-jority of brain metabolism does not vary with exoge-nous stimuli, but rather reflects ‘‘state’’ or ‘‘trait’’ func-tions (92), which can be measured with ASL MRI.Using a latent trait-state model on ASL CBF dataobtained over several weeks with eyes open or eyesclosed, a recent study confirmed that �70% of theCBF variance was attributable to individual differen-ces on a latent physiological trait, with �20% attribut-able to ‘‘state’’ effects and the remaining variance at-tributable to measurement errors (93).

Several recent reports have begun to use ASL MRIto demonstrate genotype and phenotype ‘‘trait’’ effects(Fig. 5). For example, ASL perfusion fMRI has beenused to examine the effect of 5-HTTLPR (serotonintransporter) genetic variations on resting brain func-tion and mood regulation of healthy individuals(89,94,95). The results showed that the homozygousshort allele (s/s) group has increased resting CBF inthe amygdala compared with the homozygous long al-lele (l/l) group, which could not be accounted for byvariations in brain anatomy, personality, or self-reported mood (94). Moreover, regional CBF in theamygdala showed positive correlations with depres-sion scores and stressful life events in the s/s groupbut negative correlations in the l/l group (95,96).These findings complement existing literature onshort allele related amygdala hyperactivity and

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suggest an additional neurobiological mechanismwhereby 5-HTTLPR is associated with individual dif-ferences in vulnerability to mood disorder. Other

groups have also shown that resting baseline CBFcorrelates with habitual emotion regulation scores(97), working memory capacity (98), and predicts

Figure 5. Demonstration of genotype and phenotype effects in resting ASL MRI data. Left: Increased perfusion of amygdalain patients with a serotonin transporter genotype that confers an increased risk of depression and anxiety. Right: Restingperfusion in right medial frontal cortex predicts subsequent time-on-task fatigability. Adapted from (88) Lim et al, Neuro-Image 2010;49:3426–3435, (94) Rao et al, Biol Psychiatry 2007;62:600–606, with permission from the publishers.

Figure 4. Temporal stabilityof ASL perfusion fMRI. Suc-cessful demonstration ofmotor cortex activation withbilateral finger tapping isobserved even when task andactivation are carried out onsuccessive days, 24 hoursapart. The experimental designis shown above. Adapted from(84) Wang et al, Magn ResonMed 2003;49:796–802, withpermission from the publisher.

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individual differences in the blood pressure responseto a stress-eliciting task administered after MRI (99).Taken together, these studies indicate the potential ofASL perfusion fMRI for imaging the neural correlatesof behavioral traits or states, and as such can be con-sidered complementary to BOLD fMRI studies thatfocus more on evoked responses.

The ability to measure static brain function alsoproves an alternative approach to elucidating brain–behavior relationships to task activation by correlat-ing regional CBF measures in the absence of a specificcognitive task with measures in other domains madeoutside of the MRI scanner. This approach relies onindividual difference across the study cohort to pro-vide image contrast, and its most effective userequires quantitative neuroimaging measures thatcan be effectively compared across subjects and scan-ning sessions. To date, this approach has mainlybeen used with structural MRI and termed ‘‘voxelbased morphometry (VBM)’’ (100), but it can equallybe applied to brain function using ASL MRI. Thisstrategy of deriving brain–behavior relationshipsavoids the performance confound that is inherent intask activation data, which can be particularly prob-lematic when studying populations with performancedeficits.

ASL MRI as a Biomarker of PharmacologicalActions

Pharmacological imaging offers in vivo visualization ofdrug actions and can be applied in both preclinicalmodels and human subjects. The most widely appliedpharmacological imaging method to date has beenPET, which allows the distribution of radiotracer ana-logs of drugs or drug targets to be imaged. While thisprovides a very specific biomarker for drug penetranceand actions, it requires expensive development foreach compound as well as exposure to ionizing radia-tion. Nonspecific PET markers of neural activity suchas 15O-PET and FDG-PET have also been used, andmore recently pharmacological MRI (phMRI) hasbegun to be used for this purpose. These nonspecificapproaches rely on a coupling between drug actionson neural activity and changes in CBF and metabo-lism. PhMRI based on BOLD contrast has been themost commonly used phMRI technique, but sinceBOLD does not provide a quantitative baseline it isprimarily applicable to studying the short-term effectsof intravenously administered drugs or drug effects ontask-induced activations The complex interplay ofphysiological properties that give rise to BOLD con-trast can also make interpretation difficult, especiallywhen examining the effects of drugs that modulateboth neural activity and blood flow.

One such substance is caffeine, a nonspecific aden-osine antagonist that has the dual effect of decreasingCBF and increasing neural activity. Depending on thebalance between these two effects, BOLD response inthe presence of caffeine may either increase ordecrease, likely the reason why earlier BOLD studieson caffeine often had seemingly contradictory results(101–104). Using simultaneous ASL and BOLD

acquisitions to ‘‘calibrate’’ the BOLD response,Perthen et al (105) demonstrated that caffeine signifi-cantly alters CBF and cerebral oxygen consumptioncoupling (CMRO2) at rest, with a higher degree ofintersubject variation when compared with visualstimulation. This result was extended by Chen andParrish (106), who used calibrated BOLD to show thatcaffeine not only alters baseline hemodynamics, butalso decreases CBF:CMRO2 coupling in both motorand visual tasks (107). The vasoconstrictive effects ofcaffeine also alter the temporal dynamics of the BOLDresponse (103,108), potentially due to the increasedvascular tone of the constricted blood vessels. Thesestudies highlight how ASL and BOLD can providecomplementary information in the rapidly growingfield of phMRI.

ASL MRI offers several advantages as a potentialbiomarker of drug actions. First, ASL has been shownto have high reproducibility over periods of day,weeks, or months (109–111), making it suitable forstudying oral drugs and chronic treatment. Its abilityto quantify CBF, a biological parameter, means that itshould also be suitable for multisite studies involvingdiffering scanning platforms, although this capabilityhas not yet been fully validated and dealing with cur-rent variations in ASL implementations across scan-ner platforms remains a challenge. Several recentstudies have begun to demonstrate the utility of ASLMRI as a biomarker of pharmacological actions in thebrain. Finally, ASL can be used to disentangle thecomplexity of BOLD contrast. In fact, a few studieshave used a combination of both techniques to pro-vide complementary information about brain activity(105,107). As ASL continues to gain in popularity andavailability, such combined studies are expected tobecome increasingly common. The use of ASL MRI tomonitor the effects of pharmacological treatment fortobacco addiction is described in the followingsection.

Black et al (112) employed a placebo-controlled,repeated-measure, crossover study design to investi-gate the mechanism of a novel adenosine A2A antago-nist, SYN115, in 21 Parkinson disease patients withlevodopa infusion. Subjects were scanned with thecommercial Siemens PASL sequence after a week ofSYN115 treatment, taken twice a day. After a 1-weekwashout period, the experiment was repeated with aweek’s treatment of placebo. A subset of the subjectswas assigned to 20 mg (n ¼ 12) and 60 mg (n ¼ 14)dose of SYN115 to facilitate quantification of a dose–response curve. In addition to a small decrease inglobal CBF (4% and 7% for 20 mg and 60 mg, respec-tively), the authors reported a significant decrease inthalamic CBF, consistent with the expected disinhibi-tion of basal ganglia pathway by A2a antagonists. Thisis also supported by earlier studies on treatment ofParkinsonian symptoms with A2a antagonists. Thisstudy was one of the first that uses ASL to investigatemechanism of a novel drug, as well as provide a quan-titative dose–response curve.

Chen et al (113) tested the feasibility of pseudocon-tinuous ASL (pCASL) to detect the effect of a single,oral dose of citalopram on CBF. Twelve healthy

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subjects were randomized to receive either placebo or20 mg of citalopram, with a week’s washout periodbetween the two. Baseline pCASL scans were collectedbefore drug intake, as well as 30 minutes, 1 hour,and 3 hours postmedication. Using a support vectormachine (SVM), the authors reported significant drug-induced CBF decreases in regions including the amyg-dala, fusiform, insula, and orbitofrontal cortex. Mixedeffects analysis on CBF data extracted from selectedregions of interest revealed a significant drug effect inthe serotonergic regions. Combined with findings ofelevated CBF in the same regions of depressedpatients as well as subjects genetically prone todepression, these results suggest a potential mecha-nism for the clinical efficacy of citalopram in the treat-ment of depression.

Fernandez-Seara et al (114) also demonstrated thefeasibility of using ASL to detect single oral drug dose,in this case 10 mg of metoclopramide or placebo wasgiven to 18 healthy subjects. pCASL scans wereacquired both before and 1 hour postmedication. Tominimize variability due to inaccurate pCASL labelingefficiency, this study employed an additional phase-contrast scan to estimate the labeling efficiency ineach subject (115) rather than using an assumed lit-erature value. The authors reported bilateral increasesin regional CBF in the putamen, globus pallidus, andthalamus, as well as decreased regional CBF in bilat-eral insula, extending to the anterior temporal lobes.These results are consistent with findings in other an-tipsychotic drug studies using PET, and are furthersupported by pathological hyperperfusion in similarareas observed in Parkinson’s disease patients.

Tolentino et al (116) used PASL to investigate theeffect of alcohol ingestion on CBF in a large number ofsubjects comprised of those at high and low risks foralcohol use disorders. Eighty-eight young, healthy sub-jects were divided into matched pairs of high and lowlevels of response (LR) to alcohol, and assigned inrandomized order to receive either 0.7–0.75 mL/kg ofethanol or placebo (in the form of a noncaffeinated bev-erage). PASL scans were acquired 22 minutes after bev-erage ingestion. Consistent with earlier reports usingother CBF measuring methodologies (PET, SPECT, and133Xe inhalation), the authors observed CBF increasesin the frontal regions. Additionally, this CBF increasewas smaller in subjects with low LR to alcohol, which isalso in agreement with earlier fMRI studies.

ASL MRI in Neuropsychiatry

ASL MRI provides a versatile tool for quantifying re-gional brain function associated with ‘‘states,’’ ‘‘traits,’’evoked responses, and pharmacological actions, all ofwhich may be manifested by changes in regional CBF.These properties are particularly valuable in the inves-tigation of neuropsychiatric disorders and their treat-ment. Initial studies have demonstrated the utility ofASL in several areas including tobacco addiction.

Franklin et al (117) used the temporal stability ofASL MRI to compare brain function during smokingversus nonsmoking cues while controlling for with-drawal effects by having subjects smoke a cigarette

before each measurement. CBF in preselected limbicregions including ventral striatum, amygdala, orbito-frontal cortex, hippocampus, medial thalamus, andleft insula was higher during smoking versus non-smoking cues, while cue-induced craving scores posi-tively correlated with CBF changes in the dorsolateralprefrontal cortex and posterior cingulate. This patternof activation was consistent with prior preclinical dataon the neural correlates of conditioned drug reward.In a subsequent report, the effects of dopamine trans-porter (DAT) polymorphisms on the observed effectswere examined (118). Correlations between brain ac-tivity and craving were strong in one genotype sub-group and absent in the other, providing evidencethat genetic variation in the DAT gene contributes tothe neural and behavioral response variations elicitedby smoking cues.

In subsequent work, three weeks of treatment withthe smoking cessation medication varenicline wasfound to reduce cue-induced craving as well as reac-tivity to smoking cues in reward-activating ventralstriatum and medial orbitofrontal cortex (119). In theabsence of smoking cues, varenicline treatment alsoincreased CBF in reward-evaluating lateral orbitofron-tal cortex, suggesting that varenicline may have dualeffects that contribute to its efficacy. A similar neuralresponse was observed after 3 weeks of treatmentwith baclofen (120), which also decreased CBF in ven-tral striatum and medial orbitofrontal cortex (Fig. 6)and increased CBF in lateral orbitofrontal cortex.Baclofen additionally diminished CBF in the insula, aregion where infarction has been reported to result inspontaneous smoking cessation.

A related study examined brain–behavior relation-ships in the absence of smoking cues. Wang et al(121) studied a cohort of smokers under conditions ofsatiety and overnight abstinence. Smoking abstinencewas associated with increased CBF anterior cingulatecortex, medial orbitofrontal cortex (Fig. 6), and leftorbitofrontal cortex. Abstinence-induced cravings tosmoke were predicted by CBF increases in the brain’svisuospatial and reward circuitry, including in theright orbitofrontal cortex, right dorsolateral prefrontal

Figure 6. Increase in orbitofrontal cortex CBF after overnightabstinence in smokers (left) and reduction in CBF in this regionafter treatment with baclofen (right). Adapted from (121) Wanget al, J Neurosci 2007;27:14035–14040, (120) Franklin et al,Drug Alcohol Depend 2011;117:176–183, with permission fromthe publishers.

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cortex, occipital cortex, anterior cingulate cortex, ven-tral striatum/nucleus accumbens, thalamus, amyg-dala, bilateral hippocampus, left caudate, and rightinsula. This craving response was subsequently corre-lated with functional genetic variants previously asso-ciated with nicotine dependence (122). Significantmodulations in the correlation between CBF and crav-ing were observed with D2 receptor and catechol-o-methyl transferase genotype variations, suggesting aneural mechanism whereby these genetic variantsmay be linked with nicotine dependence.

ASL MRI has also begun to be applied to other neu-ropsychiatric syndromes. In affective disorders suchas depression (123,124) and schizophrenia (125), hy-poperfusion of prefrontal cortex has been observedand ASL MRI has been used in conjunction with othermodalities to monitor treatment effects (126). Normal-ization of hyperperfusion in cortical and subcorticalregions with stimulant therapy in a small cohort ofpatients with attention deficit hyperactivity disorderwas also demonstrated using ASL MRI (127). Veryrecently, serial ASL MRI studies have been used todemonstrate objective neural correlates of postsurgi-cal pain by performing imaging before and after den-tal extractions (128).

SUMMARY

Over the past two decades ASL MRI has evolved fromfeasibility to practical utility and, concomitant withthe maturation of this technology, diverse applicationsof ASL MRI have also emerged. While most applica-tions of ASL have been in basic and clinical neuro-science, ASL MRI can also be performed in other tis-sues, and applications outside of the brain areexpected to emerge in the near future. ASL is nearlyunique among MRI contrast mechanisms in that itsbiological basis, perfusion, is known. The ability toprovide absolute quantification of a key biological pa-rameter also makes it a very useful biomarker forboth longitudinal and cross-sectional studies. CBF isa versatile biomarker of both normal and pathologicalbrain function, as illustrated by the findings summar-ized above, and inclusion of ASL in large cross-sec-tional and longitudinal databases will likely lead tovaluable new insights into the neural basis for a widerange of behaviors and disorders. Use of ASL as a bio-marker of drug actions and neural responses to ther-apy is also likely to contribute significantly to the de-velopment and validation of new therapies for braindisorders as well as disorders outside of the brain.

Given the utility of CBF measurement in clinicalmanagement, it is perplexing that ASL MRI has notreally found its way into routine clinical practice. Theexplanation for this is likely multifactorial. First, ASLMRI is based on weak signals, and ASL methodologiesare somewhat more complex than other MRI methodsin routine use. Second, the utility and benefits of ASLhave been eclipsed by related technologies such asdynamic susceptibility contrast perfusion MRI andBOLD fMRI that are more widely available. Finally,clinicians are not accustomed to being able to quan-

tify CBF easily, so rarely demand it. Hopefully, theavailability and dissemination of truly robust ASLMRI implementations and a growing literature ofapplications demonstrating its utility will lead to itsmore widespread use for the betterment of bothpatient care and biomedical research.

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