Measurement of cerebral perfusion with arterial spin labeling: part 2. applications

Journal of the International Neuropsychological Society (2007), 13, 1–13.
Copyright 2007 INS. Published by Cambridge University Press. Printed in the USA.
DOI: 10.10170S1355617707070634
CRITICAL REVIEW
Measurement of cerebral perfusion with arterial spinlabeling: Part 2. Applications GREGORY G. BROWN,1,2 CAMELLIA CLARK,2 and THOMAS T. LIU3 1Psychology Service, VA San Diego Healthcare System, San Diego, California2Department of Psychiatry, University of California San Diego, San Diego, California3Department of Radiology, University of California San Diego, San Diego, California (Received March 30, 2006; Final Revision November 15, 2006; Accepted November 16, 2006) Abstract
Arterial spin labeling (ASL) uses magnetic resonance imaging methods to measure cerebral blood flow (CBF)non-invasively. ASL CBF validly localizes brain function and may be especially useful for studies where the timeframe of behavioral change is more than a few minutes, such as in longitudinal and treatment studies. ASL measuresof cerebral perfusion are highly accurate in detecting lesion laterality in temporal lobe epilepsy, stenotic-occlusivedisease, and brain tumors. Among lesioned patients, ASL CBF has excellent concurrent validity when correlatedwith CBF measured by Positron Emission Tomography or with dynamic susceptibility-weighted magneticresonance. ASL CBF can predict tumor grading in vivo and can predict six-month response to the surgical treatmentof brain tumors. ASL’s capability to selectively and non-invasively tag flow in major vessels may refine themonitoring of treatment of cerebrovascular disease and brain tumors. Conclusions about the utility of ASL arelimited by the small sample sizes of the studies currently in the literature and by the uncertainty caused by the effectof brain disease on transit times of the magnetic tag. As the method evolves, ASL techniques will likely becomemore widely used in clinical research and practice. (JINS, 2007, 13, 1–13.) Keywords: Magnetic resonance imaging, Functional, Regional blood flow, Brain mapping, Cerebral stroke, Brain
tumors, Epileptic seizures
INTRODUCTION
resolution of ASL CBF maps with the gyral anatomy ofcortical flow clearly visible. Part I of this paper, Alsop’s Arterial spin labeling (ASL) is a developing magnetic res- chapter, and the original sources referenced earlier provide onance method to measure cerebral perfusion (Detre et al., additional detail about ASL methods (Alsop, 2005; Liu & 1992; Alsop, 2005). ASL applies a magnetic label to the water molecules of flowing blood in a region proximal to Part II of this paper summarizes the current findings from the imaging slice. As the magnetic label enters the imaging studies using ASL to investigate pathophysiology, diagnos- slice it exchanges with tissue water and slightly alters the tic specificity, and treatment outcome in neuropsychiatric image contrast. The magnetic label is delivered to the image disorders. It also reviews the use of ASL to study normal slice at a rate determined by local cerebral blood flow (CBF) brain function. The papers involving clinical studies were (Buxton et al., 1998; Calamante et al., 1999). Typically the found by searching PubMed using the search terms “Arte- image acquired after magnetic tagging is subtracted from a rial Spin Labeling” and the clinical condition described in control image to remove the effects of static magnetization the heading of each of the later sections (www.pubmed.gov).
and to control for imaging effects of the tagging experiment Papers written in English and published through the middle unrelated to the rate of blood flow. Figure 1 shows the high of 2006 were reviewed. We report the results of all studiesinvolving patients and selected studies involving animals.
Most technical papers focusing on ASL methods identified Correspondence and reprint requests to: Gregory G. Brown, Ph.D., in the current PubMed search were discussed in Part I of Psychology Service (MC 116B), VA San Diego Healthcare System, 3350La Jolla Village Drive, La Jolla, CA, 92161. E-mail: [email protected] this review (Liu & Brown, 2007, this issue).
hemoglobin across time points of a finger-tapping task, asmeasured by near-infrared spectroscopy (Huppert et al.,2006). In these early studies the spatial and temporal prop-erties of ASL CBF correlate well with other hemodynamicmeasures of brain activity and with expected patterns ofactivation based on the known functional organization ofthe brain.
A detailed comparison of ASL perfusion and BOLD sig- nals was presented in Part I (Liu & Brown, 2007, this issue).
The papers reviewed here provide further guidance aboutwhen to use each of these methods to study healthy brainfunction. Unless corrected for physiological confounds, ASLsignals are prone to signal variation that reduce their sensi-tivity to behavioral manipulations (Restom et al., 2006).
Perhaps for this reason ASL CBF is less sensitive to para-metric manipulations of task demands than is BOLD con-trast (Rao et al., 2000). ASL maps also tend to exhibit smalleractivation regions than BOLD maps (Mildner et al., 2005;Tjandra et al., 2005). The smaller spatial extent of the ASLmaps might be because of their decreased sensitivity tosmall activation changes or to their improved signal local- Fig. 1. Perfusion images from a FAIR sequence. Voxels were
ization (Liu & Brown, 2007, this issue). In some experi- resliced into 1 mm3 and smoothed by an amount of 3.44 mm full ments, the advantage of BOLD over ASL measures is width half maximum, the original in-plane pixel length. A thresh- reduced by the greater between-subject variation of BOLD old was set to emphasize cortical flow.
measures compared with ASL (Wang, et al., 2003). Eventhough BOLD contrast is typically more sensitive to changesof behavioral state than ASL CBF, especially when the ASL Healthy Brain Function
signal is uncorrected for physiological variation, the advan- Studies using ASL perfusion to localize the brain’s response tage of BOLD contrast is limited to paradigms where the to changes of behavioral status are reviewed in Table 1. The delay between the two behavioral conditions of interest is studies reviewed include behavioral validation studies of less than one minute. As the interval between two behav- ASL perfusion, studies comparing ASL perfusion with other ioral manipulations increases and exceeds two minutes, ASL functional imaging techniques, comparative studies of ASL perfusion is often more sensitive to changes in brain response and blood oxygen level dependent (BOLD) contrast as mea- than are BOLD signals (Aguirre et al., 2002; Wang et al., sures of brain response, and pharmacological studies.
2003). The relative stability of ASL perfusion to long-term Validation studies used the known functional organiza- temporal effects makes ASL an effective method to study tion of the brain to determine how well ASL perfusion meth- naturalistic longitudinal changes in mood, mental set or ods can localize brain function. Motor studies uniformly drive, or to study interventions. ASL CBF is also less prone have found ASL CBF changes in the primary motor cortex, than BOLD to false activations during overt speech para- and visual stimulation studies have found changes in the digms, apparently because ASL is less sensitive to suscep- occipital cortex (Aguirre et al., 2002; Brown et al., 2003; tibility artifacts caused by the air volume dynamics involved Garraux et al., 2005; Gollub et al., 1998; Li et al., 2000; Restom et al., 2006; Tjandra et al., 2005; Wang et al., 2003; Pharmacological manipulations, such as acetazolamide, Yongbi et al., 2002). Motor activation effects are larger at that alter brain CBF without altering brain metabolism, affect 3.0 T than at 1.5 T, presumably caused by the greater signal the magnitude of the BOLD response (Brown et al., 2003).
to noise of higher field magnets (Yongbi et al., 2002).
However, pharmacological manipulations that have little Cognitive manipulations have also produced expected lat- impact on brain blood flow, such as methylphenidate, have eralized and localized ASL CBF changes with language little impact on BOLD response in brain areas not targeted generation activating Broca’s area, visual attention activat- by the drug (Rao et al., 2000). The impact of drugs that ing anterior cingulate and right prefrontal cortex, and work- globally affect CBF and brain metabolism are more diffi- ing memory activating the prefrontal and parietal cortex culty to interpret. For example, Gollub and colleagues (Kemeny et al., 2005; Kim et al., 2006; Yee et al., 2000; Ye reported that although cocaine infusion reduced CBF by et al., 1998). The spatial activation patterns for ASL CBF 14%, BOLD response in the occipital cortex to flickering obtained during finger tapping or visual stimulation have checkerboard was not significantly altered following cocaine been shown to agree well with cerebral blood volume infusion (Gollub et al., 1998). One might conclude from changes measured by gadolinium bolus tracking (Li et al., these results that drug-induced alterations in CBF need not 2000). Moreover, ASL CBF correlates with total and oxy- affect the BOLD response. Yet, these findings are also com- Arterial spin labeling applications Table 1. Arterial spin labeling findings during behavioral challenge
The time series of the BOLD signal is dominated by low frequencies, with cycles longer than 60 s.
Perfusion time series is not dominated by low frequency oscillations.
ASL CBF has greater sensitivity than BOLD to slowlychanging behavioral conditions.
Following acetazolamide infusion, resting cerebral BOLD response dropped 35% after acetazolamide % change in CBF response during finger-thumbapposition was not affected by acetazolamide.
Slices acquired later in the sequence had less visible Despite a reduction in overall level of ASL contrast in some slices, increases in CBF were observed in all brain regions where they were predicted, from the cortical hand area through the basal ganglia to theanterior cerebellum.
Although CBF was unchanged by saline infusion, cocaine infusion reduced CBF (214.1 6 8.5%).
BOLD response in the occipital cortex did notsignificantly change after cocaine infusion.
Qualitatively the temporal profiles of the measures from the three modalities were the same.
Fractional changes in oxidative metabolism tofractional changes in blood flow were in generalagreement with previous studies of flow-metabolismcoupling.
BOLD response was more highly correlated with NIRS measure of deoxy-hemoglobin, 0.98, than with ASL measured flood flow correlated 0.91 with total hemoglobin and 0.83 with oxy-hemoglobin.
No apparent artifacts in the CBF images.
Presumably false activations in temporopolar and basal frontal regions close to the pharynx in the Results largely concur with results from studies using Visual attention increased CBF in right middle frontal gyrus, anterior cingulate0medial frontal gyri, bilateral occipital gyri.
Working memory increased CBF in left inferiorfrontal0precentral gyri, left inferior parietal lobule,anterior cingulate0medial frontal gyri, and leftoccipital gyrus.
Percent change in CBF for ASL and bolus tracking Percent change in CBF and CBV during behavioral challenge was greater than BOLD percent change.
control, BOLD blockdesign, 30 s on060 s off,N 5 8 Table 1. Continued
In some regions, CBF increased 20% to 30% during When ASL and BOLD response overlapped, the BOLD response appeared to be spatially larger.
BOLD responses in the intraparietal sulcus and frontal eye fields were observed without any CBF activation Increasing tapping rate produced a monotonic increase ASL perfusion level, %BOLD, and %CBF were unaffected by methylphenidate administration.
A statistical method that assumed that the impact of physiological noise might have differential effects on the tagged and control images improved produced a larger number of activated voxels in both the visual cortex and hippocampal region than did uncorrected data. Generally, this method outperformed the other BOLD areas of activation were larger than CBF areas.
Center of gravity of activated areas within the hand region of interest were not significantly displaced between CBF and BOLD images.
CBF appeared less variable across subjects within day.
CBF and BOLD results showed similar variabilitywithin subjects across sessions.
ASL perfusion can detect differences in motor cortex response with up to 24 hours elapsing between rest ASL perfusion contrast is superior to BOLD contrast when the interval between rest and behavioral response is greater than a few minutes.
Brain response measured by ASL perfusion has less inter-subject variation than BOLD contrast.
2 min, 4 min, 8 min and1 hr between resting andfinger tapping. N 5 6 Salivary cortisol increased during the second baseline period following stressful arithmetic.
Salivary cortisol level correlated 0.72 with change in Change in subjective stress rating between the low and high stress conditions correlated 0.65 with the change of CBF in ventral right prefrontal cortex.
Increased CBF was observed in Broca’s area during CBF reached a maximum value producing a meanincrease of 30.7% at ; 6.5 s after the noun cue waspresented.
Working memory increased CBF an average of 22 6 5 cc0100 g0min in prefrontal cortex anterior to the Arterial spin labeling applications Table 1. Continued
With vascular signal suppression, signal to noise ratios of resting perfusion was nearly 3 times greater Number of voxels showing a CBF response at 3.0 T was more than 80% greater than the number No response in supplementary motor areaAt 1.5 T; significant response at 3.0 T.
Note. ASL: Arterial spin labeling, BOLD: Blood oxygen-dependent contrast, CASL: continuous arterial spin labeling, CBF: Cerebral blood flow, CBV:Cerebral blood volume, DSWC: dynamic susceptibility weighted contrast, EPI: echoplanar imaging, FAIR: Flow-sensitive Alternating Inversion Recov-ery, PASL: pulsed arterial spin labeling, PICORE: Proximal Inversion with a Control for Off-Resonance Effects, PET: Positron Emission Tomography,Q2TIPS: QUIPSS II with thin slice TI1 periodic saturation, QUIPSS–II: Quantitative imaging of perfusion using a single subtraction–version II.
patible with a down regulation of brain metabolism, a poten- drikse et al., 2004). Patients had transient ischemic attacks tial effect of cocaine administration (Gollub et al., 1998; or minor strokes compatible with ischemia within the vas- cular territory of the occluded carotid artery. All patientshad less than 30% stenosis in the contralateral carotid artery.
Except for the two most extreme inversion times, the Neuropsychiatric Disorders
perfusion-weighted signal in gray matter was less in the The following section discusses ASL in studies of adults.
hemisphere ipsilateral to the occlusion compared with Wang and Licht’s (2006) recent review discusses ASL in the contralateral hemisphere or with control values. Curve fitting to the difference images (control minus tag) acquiredacross inversion times provided a single estimate of CBF,which was significantly lower in the ipsilateral hemisphere Cerebrovascular Disease
compared with flow in the hemisphere opposite the occlu- Studies using ASL to investigate CBF have correlated ASL sion. CBF estimated from multiple inversion times yielded values with clinical, behavioral or other imaging variables flow values comparable to values based on previously val- or have used ASL to monitor cerebrovascular surgery (See idated CBF methods (Hendrikse et al., 2004).
Table 2). Chalela and colleagues (2000) used continuous Kimura and colleagues (2005) used continuous ASL and ASL to study the clinical correlates of flow asymmetries in CO2 PET to assess regional CBF in 11 patients with unilat- 15 patients with acute unilateral stroke. See Part 1 for a eral occlusive disease. The authors not only calculated per- discussion of continuous ASL (CASL) and pulsed ASL fusion maps for ASL and PET methods separately, but also (PASL) (Liu & Brown, 2007, this issue). Eleven of the 15 estimated transit delays from combined ASL and PET mea- patients had visible CBF deficits corresponding to the sures. For each subject, ASL CBF was correlated with PET patient’s lateralized symptoms. CBF asymmetries corre- CBF across 48 ROIs. The average correlation over subjects lated significantly with symptom severity at admission was 0.71. However, the average ASL CBF values were sig- (National Institutes of Health Stroke Scale scores) and with nificantly smaller than PET CBF within gray matter ROIs daily functioning at 30 days post-stroke (Rankin Scale) (Bon- on the affected side. An analysis of the arterial transit times ita & Beaglehole, 1988; Chalela et al., 2000).
performed by the current reviewers found that the transit Studies of patients with carotid artery occlusion or with times were significantly greater in the involved hemi- high-grade stenosis have often been used to validate CBF sphere, t(10) 5 2.80, p 5 .019. Moreover, we found that the techniques (e.g., Ewing et al., 1987; Yamauchi et al., 1996).
difference in arterial transit times between the affected and A study using CASL to measure CBF found flow asymme- non-affected hemispheres correlated 0.60, p 5 .051 with tries pointing to the involved hemisphere in all 11 patients the PET0ASL CBF difference in the involved hemisphere.
with clinically significant stenosis (Detre et al., 1998). These The underestimation of CBF by ASL in the involved hemi- results are especially encouraging when considering that sphere appears to be due longer transit times, as argued by CBF studies of carotid artery occlusion or high-grade ste- Kimura and colleagues (2005). Nonetheless, these results nosis are complicated by collateral flow, which can lengthen show fairly good agreement between ASL and PET CBF the transit-time associated with the delivery of a tracer to a measures for patients with unilateral occlusions. Similar region of interest (Ewing et al., 1987; Cosottini et al., 2005).
agreement has been reported for ASL and SPECT CBF mea- To correct for variable transit times, Hendrikse and sures in subacute infarction (Tsuchiya et al., 2000).
co-authors used single-slice, pulsed ASL to acquire flow Ances et al. (2004) used multislice, CASL to study CBF images at six inversion times ranging from 200 to 1600 in 10 symptomatic patients with carotid stenosis before and msec in nine patients with carotid artery occlusion (Hen- three months after carotid endarterectomy. Vascular regions Table 2. Arterial spin labeling findings in patients with cerebrovascular disease
Baseline CBF correlated 20.78 with %DCBF.
carotid stenosis studiedPre0Post carotidendarterectomy CBF asymmetries correlated with outcome severity.
In all 11 patients with significant carotid stenosis CBF asymmetries were greatest in the hemisphere with the Presurgical CBF and Dhemoglobin predicted DCBF Postsurgical CBF increases ipsilateral to stenosis; decreased CBF supply from contralateral to ipsilateral Significant reduction of flow in gray matter ipsilateral 15% reduction in flow volume within the territory of the bypass compared with contralateral hemisphere.
Within subject ASL CBF correlated with positron emission tomography CBF; average r 5 0.71.
Qualitatively the two methods correlated well; 4 EPISTAR studies showed no flow whereasgadolinium showed delayed flow.
CBF inversely correlated with Performance IQ.
tomography correlated well in 15 patients.
Note. ASL: Arterial spin labeling, CASL: continuous arterial spin labeling, CBF: cerebral blood flow, EPISTAR: Echo-Planar Imaging and SignalTargeting with Alternating Radiofrequency, FAIR: Flow-sensitive Alternating Inversion Recovery, PASL: pulsed arterial spin labeling, QUIPSS II:QUIPSS–II: Quantitative imaging of perfusion using a single subtraction–version II.
of interest were drawn on the CBF images. Carotid endar- recent study of carotid endarterectomy found increased CBF terectomy did not alter global blood flow. Data about CBF in the middle cerebral artery territory ipsilateral to carotid changes within the distribution of the operated carotid artery stenosis and decreased contralateral supply to the ipsilat- were not provided. The authors stated that when CBF from eral side (Jones et al., 2006). Such results call into question the anterior and middle cerebral arteries were combined, the usefulness of global CBF measures to track the hemo- baseline CBF correlated significantly (r 5 2.78) with the dynamic effects of cerebrovascular surgery.
change in CBF following surgery, whereas the correlation Hendrikse and co-authors (2005) used vessel selective of baseline flow with flow change was nonsignificant (r 5 ASL to study CBF in seven patients before and after extra- .25) in the posterior distribution. Any conclusions to be cranial to intracranial (ECIC) arterial bypass. A novel aspect drawn from these change scores must be tempered by the of this study was the selective labeling of flow within the confounding of baseline scores with simple change scores.
grafted vessel. Three patients were treated for giant aneu- Because simple change scores include the baseline in their rysms, and four were treated for symptoms related to inter- definition and because measurement error produces regres- nal carotid occlusion. A turbo transfer insensitive labeling sion to the mean, baseline scores can be inversely corre- method was used to acquire flow images at inversion times lated with change scores even if baseline scores and ranging from 200 ms to 2600 ms. ASL CBF measured within follow-up scores are randomly generated (Cohen et al., the operated and contralateral hemispheres and within the 2003). Using selective labeling of each carotid artery, a basilar circulation was within the normal range, supporting Arterial spin labeling applications PET studies that found flow normalization following ECIC from metastatic tumors (Weber et al., 2006). Brain normal- arterial bypass (Gibbs et al., 1987; Marshall et al., 2002).
ized flow within a metastasis seems to be intermediate, withflow values between those of high-grade and low-gradegliomas (Warmuth et al., 2003).
Brain Tumors
The accuracy of ASL perfusion measures for the differ- MR perfusion studies have focused primarily on the use of entiation of tumor types has been compared with the accu- ASL to distinguish among tumor types and to monitor treat- racy of dynamic susceptibility weighted contrast (DSWC) ment change. The current literature on ASL studies of brain measures of perfusion and volume. DSWC involves using tumors is summarized in Table 3. ASL perfusion shows rapid MR imaging techniques to track an injected paramag- consistently higher CBF values in high-grade than low- netic contrast agent over time (Alsop, 2005). The delivery grade gliomas (Warmuth et al., 2003; Weber et al., 2006; of the contrast agent temporally decreases the MR signal on Wolf et al., 2005). The difference in flow level reliably T*2 weighted images (Alsop, 2005). Plots of the change in distinguishes low-grade and high-grade gliomas at sensitiv- signal over time provide information about mean transit ity rates ranging from 79% to 100% and specificity rates time, cerebral blood flow, and cerebral blood volume (CBV).
ranging from 50% to 100%. One study found that a relative As commonly used, DSWC measures mean transit time in measure of tumor CBF separated untreated grade III and IV absolute units, and relative values of CBF and CBV (Alsop, gliomas from grade I and II gliomas at 100% accuracy (War- 2005). DSWC has been used successfully to predict tumor muth et al., 2003). ASL CBF appeared most valid in distin- progression (Law et al., 2006). Consequently, DSWC has guishing among tumor types when flows were age-adjusted become an important criterion against which new MR flow (Warmuth et al., 2003). Increased CBF can also distinguish methods should be validated in brain tumor patients.
higher-grade gliomas from lymphomas, whereas increased As seen in Table 3, DSWC enhanced MRI values corre- lated 0.83 with PASL CBF within the tumor region (War- of glioblastomas can distinguish these primary brain tumors muth et al., 2003). DSWC correlated .88 and .89 with two Table 3. Arterial spin labeling findings in patients with brain tumors
Resting ASL maps showed that core of tumor was rostral to primary motor cortex, apparent during perfusion response to finger movement.
1. DSWC enhanced MRI correlated 0.83 with PASL 2. ASL and DSWC distinguish high and low grade gliomas at the same significance level.
1. Perfusion in healthy brain tissue correlated well across all methods of measuring CBF.
2. CBF in healthy brain tissue did not change after 1. Pre-surgical CBF did not predict tumor response.
2. Reduced CBF following treatment at 6 weeks predicted tumor response in all cases.
radiosurgery and 6 weeks,12 weeks, and 24 weekspost-surgery.
1. ASL perfusion distinguishes glioblastomas from metastases, central nervous system lymphomas and 2. ASL perfusion predicts tumor type more accurately than structural MRI and proton spectroscopy.
Maximum tumor blood flow normalized to global CBF best distinguished low-grade from high-grade tumors.
Note. ASL: Arterial spin labeling, CASL: continuous arterial spin labeling, CBF: cerebral blood flow, DSWC: dynamic susceptibility weighted contrast,FAIR: Flow-sensitive Alternating Inversion Recovery, MRI: magnetic resonance imaging, PASL: pulsed arterial spin labeling, Q2TIPS: QUIPSS II withthin-slice TI1 periodic saturation, QUIPSS–II: Quantitative imaging of perfusion using a single subtraction–version II.
different PASL methods when flows were measured in Although sites of hypoperfusion in these three studies healthy brain regions of patients with brain metastases differ somewhat—probably related to differences in brain (Weber et al., 2003). Moreover, ASL and DSWC distin- coverage—they are consistent with previous PET findings guish high and low grade gliomas at the same significance as well as the pathophysiology and neuropsychological def- level (Warmuth et al., 2003). In comparison with DSWC, icits characteristics of AD. If the MCI findings are repli- ASL provides quantitative CBF values that are unrelated to cated, ASL measures of perfusion may prove a useful the disruptions of blood-brain barrier, does not require the injection of a contrast agent, and requires little post-processing so that images are rapidly available for clinical Epilepsy
interpretation. DSWC has better signal to noise, permits theacquisition of a greater number of slices, and provides infor- ASL has been used to augment presurgical planning of epi- mation about tumor blood volume and vessel permeability lepsy patients and to explore basic questions about the cou- (Warmuth et al., 2003; Weber et al., 2003).
pling of CBF and metabolism during interictal epileptic Weber and colleagues (2004) used FAIR Q2TIPS, a type discharges. Using continuous ASL, one study found abnor- of pulsed ASL, and DSWC to measure CBF prior to stereo- mal asymmetries of medial temporal lobe flow in patients tactic radiosurgery and 6, 12, and 24 weeks post-surgery in with intractable temporal lobe epilepsy (Wolf et al., 2001).
a sample of 25 patients with brain metastasis. Patients were Seizure laterality was determined by surface and intracra- divided into those showing tumor remission, tumor stabil- nial electroencephalograms, PET 18F-fluorodeoxyglucose ity or tumor progression at six months. Baseline regional scans, and surgical outcome. When the sign of an ASL per- CBF did not predict tumor response. However, a reduction fusion asymmetry index obtained in the medial temporal in the ratio of tumor CBF to contralateral gray matter CBF lobe was used to predict the laterality of the temporal lobe at six weeks predicted tumor responders with 100% sensi- seizure, relative hypoperfusion correctly predicted lesion tivity and specificity (Weber et al., 2004). ASL was more laterality in 11 of the 12 cases. The one patient whose ASL accurate in predicting outcome than were MRI measure- measure predicted lesion laterality opposite from the surgi- ments of tumor volume. DSWC had sensitivity and speci- cal hemisphere was not seizure free after the surgery. Diag- ficity values similar to ASL values. In a related study, ASL nostic reading of presurgical magnetic resonance images CBF measured in healthy brain tissue did not change after correctly identified seizure laterality in only nine patients, stereotactic radiosurgery to treat metastatic tumors (Weber and an asymmetry index based on hippocampal volume mea- et al., 2003). Although the results of the Weber et al. (2004) sured from structural MR images correctly lateralized 8 of study confirmed ASL’s potential to predict and to monitor 11 cases. The ASL measure of temporal lobe perfusion asym- treatment response in brain tumor, only three patients were metry correlated .79 with the asymmetry measure derived non-responders, thereby limiting the study’s generalizability.
from the 18F-fluorodeoxyglucose PET scans. In this smallstudy, ASL measures of asymmetry outperformed all othermethods except FDG-PET, which was used to define the Alzheimer’s Disease
optimal side for surgery and, therefore, formed part of the A preliminary study using pulsed ASL demonstrated prediction criterion (Wolf et al., 2001). Another study of decreased parieto-occipital and temporo-occipital perfu- patients with temporal lobe epilepsy found a significant sion compared with controls. Moreover, parieto-occipital correlation of .75 between a pulsed ASL measure of asym- hypoperfusion correlated with increasing dementia severity metrical perfusion and an asymmetry measure of CBF ob- (Sandson et al., 1996). A subsequent ASL study demon- O PET perfusion imaging (Liu et al., 2001).
strated significant temporal, parietal, frontal, and posterior The use of ASL flow measures to identify temporal lobe cingulate hypoperfusion in AD subjects. In this cohort, pos- regions containing abnormal neural tissue assumes that the terior parietal and posterior cingulate hypoperfusion corre- coupling of flow and neural metabolism is not disrupted by lated with increasing dementia severity (Alsop et al., 2000).
epilepsy. CBF and regional metabolism in an epileptic focus More recently, pulsed ASL revealed hypoperfusion in AD increase during the early phase of seizure activity, then patients bilaterally in the inferior parietal and inferior fron- decrease with nerve cell death (Duncan, 1997; Henry et al., tal cortex, as well as the posterior cingulate (Johnson et al., 1993; Ingvar, 1986; Weinand & Carter, 1994). Studies of 2005). Compared with healthy controls, subjects with mild interictal flow and metabolism in focal epilepsy have pro- cognitive impairment (MCI) showed decreased perfusion duced mixed results, with evidence supporting both com- (albeit less robust than in the AD group) in an area of the promised (Breier et al., 1997; Fink et al., 1996) and preserved inferior right parietal lobe similar to the region of most (Franck et al., 1989; Kuhl et al., 1980) coupling of CBF severely reduced perfusion in the AD group (Johnson et al., and metabolism. Stefanovic and colleagues (2005) used com- 2005). One limitation of the Johnson study was that it tagged bined ASL and BOLD measures to study the coupling of arterial spins at the level of the circle of Willis. Thus, the CBF and cerebral oxygen utilization in seven patients with area imaged excluded relevant inferior portions of the brain idiopathic generalized epilepsy studied during performance such as medial temporal lobes and inferior frontal areas of a motor task and while experiencing interictal epileptic discharges. Interictal epileptic activity typically involved Arterial spin labeling applications several dozen bursts of spike and wave discharges each sion (Buchsbaum et al., 1997; Mayberg et al., 1999; Wu lasting less than four seconds. The interictal epileptic dis- et al., 1999; Drevets et al., 2002).
charges occurred in the absence of clinical signs of a sei-zure. Multislice, pulsed ASL obtained by a PICORE QUIPSSII protocol was used to measure CBF (Stefanovic et al., Anxiety Disorders and Stress
2005; Wong et al., 1998). A standard gradient echo, T*2weighted sequence was used to obtain BOLD signal mea- PubMed searches that combined the terms “Anxiety Disor- surements. Both CBF and BOLD images were obtained der,” “ Post-traumatic Stress Disorder,” or “ Phobia” indi- during a block design experiment comparing rest with a vidually with “Arterial Spin Labeling” did not locate any pinch-grip of a pressure bulb and, in a separate experiment, papers. We did find one study using CASL to study changes during graded exposure to carbon dioxide (hypercapnia).
in cerebral perfusion related to the stress induced by The percent change in the cerebral metabolic rate of oxy- performance-monitored mental arithmetic (Wang et al., 2005). The authors chose CASL perfusion methods over BOLD measures using the deoxyhemoglobin dilution model BOLD because of the former method’s long-term stability (Davis et al., 1998). The hypercapnia experiment provided (Liu & Brown, 2007, this issue). CBF in the right ventral a calibration constant that defined the maximum BOLD prefrontal cortex, right insular-putamenal region, and ante- signal change possible given the specific hardware and pulse rior cinglulate showed sustained activation among individ- sequences used. See Liu and Brown (2007) or Davis et al.
uals showing high stress responses to mental arithmetic.
(1998) for a discussion of the calibrated BOLD method.
Moreover, baseline CBF in the ventral, right prefrontal cor- The CBF response to the pinch-grip condition was linearly tex and right orbitofrontal cortex correlated with changes in physiological measures of stress induced by mental arith- 2 , with a slope equal to 0.46 6 0.05.
The coupling was very similar to the value observed by metic. This study shows the usefulness of combining base- these authors in a previously published group of healthy line perfusion with activation data to support inferences controls, where the slope equaled .44 6 0.04 (Stefanovic about brain systems that mediate stress responses.
et al., 2005). In only two subjects did any areas of BOLDresponse to interictal epileptic discharges overlap with CBF Substance Use Disorders
changes. Across these small areas of overlap, %DCBF and%DCMRO2 were linearly related with a slope equal to 0.48 6 A study contrasting the relationship between BOLD and 0.17, a value very similar to those observed in the pinch- ASL measures during IV cocaine and placebo (saline) infu- sion found that BOLD signal intensity (measured during Stefanovic and colleagues interpreted their results as sup- visual stimulation) did not change significantly with cocaine porting the coupling of flow and metabolism during behav- infusion, even though IV cocaine produced a 14% decrease ioral activation tasks in patients with epilepsy (Stefanovic in global cortical gray matter perfusion. (Gollub et al., 1998).
et al., 2005). It will be important to confirm this coupling A pulsed ASL study showed decreased prefrontal and left with other behavioral paradigms, especially those that acti- parietal perfusion in young alcohol dependent women com- vate temporal lobe function. Their data on the coupling of pared with women who were not alcohol dependent (Clark flow and metabolism during interictal epileptic discharges et al., in press). In both cases, ASL findings were consistent is less convincing. The regression analysis Stefanovic and with PET and SPECT findings (Moselhy et al., 2001; Demir colleagues reported involved only two patients, and one et al., 2002; Gottschalk & Kosten 2002). A recent paper patient contributed more than one data point to the regres- reported that chronic cigarette smoking in alcohol depen- sion. Moreover, the BOLD and CBF t-value maps Ste- dent individuals is associated with reduced ASL-measured fanovic and colleagues (2005) published showed areas where CBF in frontal and parietal cortex (Gazdzinski et al., 2006).
epileptic discharges appeared to have altered BOLD signalswithout altering flow, suggesting an uncoupling of metab-olism and flow. Thus, whether CBF and BOLD signals Human Immunodeficiency Virus
remain coupled during interictal epileptic discharges remainsan open question.
Continuous ASL has also been successfully used to studyHIV patients (Ances et al., 2006). Compared with HIV neg-ative controls, the HIV-associated neurocognitive impair- Affective Disorders
ment (HNCI) group showed significantly decreased blood In the only study to utilize ASL in affective disorders, hyper- flow in the caudate nucleus, a structure preferentially affected perfusion measured by pulsed ASL in ventral anterior cin- in HIV infection. HIV patients with subsyndromal neuro- gulate and amygdala predicted antidepressant response to cognitive findings showed a mild decrease in caudate per- partial sleep deprivation among individuals with major fusion compared with healthy controls ( p 5 .070). Reduced depression (Clark et al., 2006a, 2006b). These results were caudate perfusion may be a useful biomarker for sub- consistent with previous PET and SPECT studies of sleep sequent studies of neurocognitive decline in HIV positive deprivation and antidepressant medication in major depres- “anxiety disorders,” “obsessive-compulsive disorders,”“post-traumatic stress disorder,” “phobia,” or “schizophre- Arterial spin labeling appears to be a valid method for the nia” were identified in our PubMed search (www.pubmed.
study of lower and higher brain functions. ASL CBF detects gov). ASL research into these common neuropsychiatric expected patterns of brain activation predicted from the known functional organization of the motor, visual, and Although ASL provides highly valid qualitative informa- language systems of the brain. ASL CBF has strong concur- tion about CBF abnormalities, disease processes that alter rent validity as a marker of brain function when correlated the structure of the cerebrovasculature can limit the use of with dynamic susceptibility weighted contrast imaging and ASL to quantify blood flow in absolute units. Perhaps the with near infrared spectroscopy. ASL CBF more strongly most important challenge is that diseases that alter the path correlates with changes of behavioral state than do BOLD of flowing blood can change the transit times involved in signals when the changes occur over periods longer than a the delivery of tapped blood to a brain region. Variation in few minutes. ASL measures of brain response appear to be transit times, in turn, causes unwanted variation in CBF less variable across subjects than do BOLD measures. These estimates (Buxton et al., 1998). Disorders, such as vascular properties make ASL an especially useful noninvasive anomalies or stenotic-occlusive disease, that distort the method to measure CBF in longitudinal and treatment stud- geometry of cerebral vessels or interrupt the normal path of ies. ASL’s lower contrast to noise when compared with blood’s flow through the brain are known to alter blood BOLD can be improved by removing unwanted variation flow transit times (Kim et al., 2002; Matsumoto et al., 2000).
through physiological monitoring and by performing stud- Investigators and clinicians using ASL to examine CBF in ies at higher field strengths. ASL CBF seems less sensitive conditions known to alter transit times should have a firm to artifacts created by spoken responses than do BOLD understanding of how altered transit times might influence signals. ASL CBF is likely to become commonly used in quantitative CBF measures for the disorder they are study- cognitive and affective neuroscience to study slowly evolv- ing. Fitting flow equations to ASL data points from a study ing changes in psychological state, such as mood changes, involving multiple inversion times is one method to account and to help with the interpretation of BOLD findings in for variable transit times in clinical studies (Hendrikse et al., 2004). Alternatively, a relatively new ASL method, referred The literature reviewed supports the validity of ASL to as velocity-selective ASL, that tags blood based on veloc- perfusion as a marker of neuronal dysfunction in several ity as opposed to spatial position, has the potential to pro- neuropsychiatric disorders. ASL perfusion is highly accu- vide accurate CBF measures even in the presence of long rate in detecting the laterality of a lesion. In particular, transit delays (Liu & Brown, 2007; Wong et al., 2006). The asymmetry of ASL perfusion is strongly correlated with characteristics of velocity-selective ASL are under active lateralized clinical symptoms in stroke, CBF asymmetries in stenotic-occlusive disease, hemodynamic asymmetries Although ASL CBF measures correlated well with other produced by lateralized brain tumors, and lateralized tem- accepted blood flow measures, ASL has lower intrinsic sig- poral lobe abnormalities in epilepsy. Within lesioned areas, nal to noise than some other techniques (Wintermark et al., ASL measures of perfusion have excellent concurrent valid- 2005). Moreover the incremental validity of ASL perfusion ity when correlated with PET CBF or with dynamic compared with more established methods, such as PET and susceptibility-weighted MR signals. Among individuals with dynamic susceptibility-weighted MR, still remains to be stroke, ASL can provide a clearer picture of the localiza- determined. Yet, the studies reviewed suggest that ASL meth- tion of ischemic deficit underlying focal neuropsycholog- ods of measuring CBF may be as accurate as more invasive ical functions than structural MRI (Love et al., 2002).
methods. Given that ASL is repeatable, non-invasive, and Among brain tumor patients, ASL can be used to provide easily integrated with other MR methods to image brain an initial tumor grading. ASL appears to be useful when anatomy and metabolism, ASL blood flow techniques are planning epilepsy surgery and when predicting treatment likely to become more widely used in clinical research and response to brain tumor surgery. Early post-surgical changes in ASL perfusion appear to be especially accurate in pre-dicting treatment response in brain tumors. The ability ofASL to selectively and non-invasively tag flow through ACKNOWLEDGMENTS
the major vascular territories is likely to be especially use-ful when evaluating and monitoring treatment of cerebro- Preparation of this paper was supported by the VISN 22 MentalIllness Research Education and Clinical Center, a Biomedical Engi- vascular disease and brain tumors. Conclusions about ASL neering Research Grant from the Whitaker Foundation, and by must be qualified by the small sample sizes of the studies NIH grants #1 U24 RR021992 to the Function Biomedical Infor- currently in the literature. Moreover, few studies have used matics Research Network (FBIRN, http:00www.nbirn.net), 1 RO1 ASL to investigate CBF in epilepsy, mood disorders, and NS051661 to the first author, 5 K08 MH01642 and the 2006 Sleep HIV, limiting conclusions that we could draw about the Research Society Foundation J. Christian Gillin, M.D. Research utility of ASL in these disorders. Finally, no human studies Award to the second author, and 1 R01 NS367220 to Richard using ASL to study “head injury,” “traumatic brain injury,” Arterial spin labeling applications REFERENCES
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