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A ccurate quantification of perfusion in animals and humans with the A SL techniques requires consideration o f a num ber of additional factors. Under- or over-estim ation of the CBF will often result if these issues are not taken into account in the analysis of the perfusion model and the design of the experim ent. These factors are sum m arised here:

(1) T ransit tim e effects, intravascular contam ination and M TC effects w hich have been discussed in Section 3.5. In addition to the transit time, the spatial extent of the tagged region defines an inflow time that must be considered (see Section 4.2.3) unless a m odification such as QUIPSS is implem ented.

(2) Im plem entation o f the CASL m ethod on clinical scanners: This is ham pered by the increased m agnitude o f the transit times from the tagged proxim al arteries in hum ans. Loss of the label is also intensified by the shorter longitudinal relaxation times at the typically low er field strengths.

(3) RF deposition: The lim its on the duty cycle of RF amplifiers and the specific absorption rate (SAR) o f the sequence often restrict the application of a totally continuous pulse over the required duration that is in the order of seconds (» T isat)- Instead, a pulse train is applied consisting of repeated rectangular pulses w ith a duty cycle of approxim ately 75-90% (Roberts, 1994; Ye, 1997a). CBF quantification with the procedure described in the initial analyses o f the CASL experim ent (Zhang, 1992) assum ed the com plete saturation of the m acrom olecular com partm ent (i.e. Mm=0) (Eq. [3.7(b)]). This is difficult to achieve on clinical system s and the m easured flow will be underestim ated if this is not taken into consideration (Lei, 1997). The alternative approach described in later treatm ents (M cLaughlin, 1997), norm alised the signal difference to Tisat (the T | in the presence of off-resonance relaxation) and the spin density, Mq (Eq. [3.7(c)]). This procedure does not require com plete m acrom olecular saturation and is hence, advantageous.

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(4) The degree o f inversion, Oo: An accurate m easurem ent of cxq is necessary for both continuous and pulsed methods. The m ethod of cxo determ ination em ployed in our investigation (Section 3.3.2) described in ref. (Zhang, 1993) has been criticised over the m easurem ent location and the m easurem ents’s bias tow ards the low er range o f lam inar flow velocities present in the carotid artery (M accotta, 1997). The degree of inversion is considerably m ore velocity-dependent for the C A SL technique than for the pulsed techniques (W ong, 1998b) since the fulfilm ent o f the adiabatic condition in the case of the continuous A FP pulse (Eq. [1.16]) is intrinsically related to the velocity of spin passage through the tagging gradient. Individual calibration o f the value of Oo may, therefore, be necessary for the CA SL technique.

(5) The bIood:brain partition coefficient, X: A uniform value of X is often assum ed in previous studies of CB F quantification but this may represent an unrealistic assumption. D ifferent values o f the partition coefficient have been reported for GM and W M and for varying haem atocrit levels (Herscovitch, 1985). It is also possible that the regional

values of X will vary as a consequence of evolving pathophysiology. An im aging

m ethod for X determ ination on a pixel-by-pixel basis has been described (Roberts,

1996).

(6) The assum ption o f a freely diffusable tracer: As previously discussed, the extraction fraction, E(f), is intrinsically related to the validity of this assum ption and describes the partition between the vascular and tissue com partm ents during the passage o f the blood through the vasculature in the tissue (Section 3.5.2.3). This param eter has been measured using M R I m ethods and it has been shown to decrease from 1.0 to approxim ately 0.5 at very high flow rates (-5 0 0 ml/lOOg/min). H owever, E(f) should be approxim ately unity for the normal range of physiological flows in humans and animals. The inclusion of the vascular com partm ent into the FA IR m odel that is discussed in Section 3.5.2.3, has described a m ethod of E(f) determ ination using a pair of subtraction images.

(7) M ulti-slice data acquisition: The standard continuous technique (Section 3.3) is only am enable to im plem entation on a single slice due to the necessity of acquiring a control im age for M TC correction. A two-coil m odification of this technique largely elim inates the M TC contribution and, thereby, enables m ulti-slice acquisition (Zhang, 1995). A lternatively, use of an am plitude m odulated RF pulse in order to obtain the

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control im age has been recently proposed to allow m ultiple slice data collection, but the resultant overall degree of inversion is im paired (Alsop, 1998a). The P A S L techniques are im m ediately am enable to m ulti-slice acquisitions but the pulsed m ethods are especially susceptible to slice-order-related signal contam ination (W ong, 1997; Kim, 1997a) and to slice profile im perfections (Frank, 1997; W ong, 1998b). The variable transit tim es to the m ultiple slices m ust be considered for both continuous and pulsed methods. Im plem entation o f the modified sequences with reduced transit time sensitivity or with use o f a m eans of sim ultaneous slice acquisition (Kao, 1998), is recom m ended.

(8) Im age orientation: A tagging plane that is perpendicular to the direction o f the main feeding carotid arteries is the natural choice for the tagging experim ent. The standard im plem entation o f both classification o f m ethods com plicates the acquisition of non-axial scans since the im aging plane has to be parallel to the tagging plane in order to reduce the transit tim e and to elim inate the static signal with an effective distal control. H owever, the m ulti-slice im plem entation of CA SL (Alsop, 1998a) allows the sim ple acquisition of non-axial im ages due to the coincidence of the labelling plane in both the tagged and control experim ents. The tagging and im aging planes are consequently independent o f each other.

(9) B O L D contrast: Sim ultaneous flow and To^-contrast inform ation can be extracted from a gradient-echo based A SL experim ent. Several groups have, thereby, em ployed FA IR (Kim, 1997b; Kim, 1997c, Zhu, 1998) and QUIPSS (W ong, 1997) techniques in studies of the com bined flow and blood oxygenation level dependent (BOLD) responses to functional activation paradigm s. For flow quantification studies using gradient-echo or spin-echo im age acquisition, the respective T2*- and T i-w eighting of the signal (that

is incorporated within the m easured spin density, Mq in for exam ple, Eq. [3.8]) must be extracted (see Section 3.5.2.2), and this procedure is usually based upon baseline m easurem ents (Kim, 1995).

(10) C SF contam ination: The partial volume effect of CSF, which is exacerbated with

the larger voxel sizes used in clinical imaging, can result in significant underestim ation of the flow m easurem ents. K w ong et al. predicted an underestim ation o f approxim ately 30% for a G M :C SF volum e fraction of 50% :50% (Kwong, 1995). A perfusion m easurem ent given in the standard units norm alised to the tissue mass are, therefore, unrealistic in this context unless a means of determ ining the volum e fractions can be

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im plem ented. This error can be reduced with the use of increased resolution and CSF suppression.

(11) T he T i o f blood, Tia: Q uantitative PA SL techniques are based on a biexponential expression containing both the T | values of tissue and blood (Eq. [3.8]). The corresponding CA SL m easurem ent is a m onoexponential fit to the tissue T | but relaxation during the transit tim e follows Tia. The m easurem ent of flow with both classifications of techniques, therefore, requires a determ ination o f Tia. The m ajority of previous reports have obtained a value of this param eter by extrapolation from published in-vitro data. The dependence of T|a on factors such as oxygenation, haem atocrit and vessel size and environm ent may be significant and requires further study.

(12) V en ous contam ination: The blood in the venous circulation during the experim ent m ay have been labelled by the control or tagging experim ents. This will largely depend upon the treatm ent of the distal area relative to the im aging slice which differs between the A S L techniques. This effect may, therefore, provide an unw anted contribution to the subtraction signal although if the blood had been tagged while in the arterial circulation, the label should have decayed by a significant extent by the tim e it reaches the venous circulation.

(13) G eom etrical layout o f the tagged vasculature: The C A SL technique assumes a

tagging plane that is perpendicular to the direction of the feeding artery, and the inversion efficiency will be com prom ised of this is not the case. For both pulsed and continuous techniques, the less direct path of the blood to the im aging slice in this situation will be reflected as a longer transit time. The techniques are not sensitised to blood that remains in vessels running parallel to the im aging plane during the course of the experim ent.

(14) A lternative causes o f signal variation: The inherent, theoretical flow sensitivity o f the standard CASL technique is greater than that o f the PA SL m ethods by a factor of e ~ 2.718. However, it has been shown that on im plem entation of the equivalent sequences with reduced transit tim e sensitivity, the SN R -per-unit-tim e of the two classifications of m ethods are approxim ately equal (W ong, 1998b). The techniques produce a flow -induced m agnetisation difference o f approxim ately 1-5% at standard field strengths and this places significant demands on the detection procedure. Any

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alternative origin for the signal difference such as im perfections in the RF pulse profile (Frank, 1997; see Section 3.6), eddy currents (Pekar, 1996), radiation dam ping (Zhou, 1998), or the quality o f the shim, m ay result in a system atic offset in the subtraction image. Therefore, attem pts m ust be made to elim inate these effects. In addition, the interleaving of control and tagged experim ents is recom m ended in order to m inim ise errors resulting from hardw are instability and tem perature variations. The CASL techniques operate under steady state conditions, and cannot, therefore, be im plem ented in this way in a time efficient m anner.

(15) Sensitivity to low flows: The A SL techniques are especially susceptible to

inaccuracies in the quantification procedure at low er flow values due to the lim ited SNR and the sensitivity to the transit tim e effect. This may severely ham per the clinical im plem entation of the spin tagging m ethods since the need to m easure C B F is of greatest im portance in such conditions. The w ider variation of transit and outflow times across the brain and a general increase in the transit tim e to the affected area com bine to com plicate the im plem entation of the m odified AST methods that have been designed to reduce the transit tim e sensitivity (Section 3.5.1). The delay tim es of these techniques that create the insensitivity can be increased in order to cover the variability in the expected transit times. However, this will be accom panied by a corresponding loss of perfusion signal. Instead, sufficient subtraction images can be acquired such that the transit tim e may be obtained from the data by fitting to the theoretical expressions derived by analysis of the perfusion models discussed in Section 3.2. Experim ental determ inations of the transit time have thus been obtained for C A SL (Ye, 1997a) and PA SL (W ong, 1997) techniques. O ther authors have reported further m odifications to the A SL techniques that allow sim ilar transit time fitting (Barbier, 1998; Branch, 1998). Buxton et al. have suggested the use of a tw o-point scheme for the PA SL m ethods with subtraction images acquired at two TI delays (Buxton, 1998). The early part o f the AM(t) relationship provides an approxim ately linear expression for flow with the intercept on the time axis of the profile representing the transit delay (see Fig. 3.9). The acquisition of m ultiple time points are, however, beneficial since the 2-point m ethod relies on a chosen initial T I delay that is greater then the longest expected transit time.

D etre et al. have recently suggested a novel use o f the intrinsic transit time sensitivity o f the standard A SL m ethods to provide useful pathological inform ation (Detre, 1998, Alsop, 1998b). Bright, artefactual areas of signal were observed in the CB F maps

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obtained from patients with regions of im paired flow using the C A SL delay-m odified sequence. These regions appeared am ongst areas o f dam aged vascularity and seem ed to reflect the presence of intralum inal spins with an excessive transit time.

T he optim al experimental schem e for accurate quantification of im paired perfusion is expected to be provided by a com bined approach of transit time quantification with the previously m entioned procedure, and with slice profile optim isation to m inim ise the m agnitude and the variation o f the transit times. The lim ited tem poral resolution o f such m easurem ents restricts the im plem entation of the schem e but will be am eliorated by im proved pulse (see Section 3.3) and coil design, and by optim ised sequence time efficiency (see Section 4.2).

A num ber of studies were undertaken relating to the m ethodology and im plem entation of the A S L techniques. These are now described in the follow ing three sections.