echo planar imaging ( epi )   is commonly used for functional mri ( fmri ) . it finds application in most methods for blood oxygenation level dependent ( bold ) fmri   as well as other functional imaging sequences such as arterial spin labeling ( asl )   or vascular space occupancy ( vaso )   fmri . for bold fmri , gradient echo ( ge ) epi is popular as whole - brain images with high functional contrast to noise ( cnr ) can typically be acquired at a sufficiently high temporal resolution to adequately sample the bold response . an attractive alternative for fmri at high field strengths is provided by spin echo ( se ) based t2 contrast , which arises from changes in extravascular dynamic averaging and intravascular changes in the effective t2 of blood , both associated with the bold effect . signal attenuation due to dynamic averaging is diffusion - induced and , in contrast to static dephasing effects in the field inhomogeneities around larger vessels , is not refocused in the spin echo experiment as it is a random process . at higher field strengths , this leads to an intrinsically better spatial specificity , as the relative contribution of the intravascular compartment is reduced , and the signal is weighted towards the microvasculature , that is expected to be closer to the while at 1.5 t the intravascular contribution to the se fmri signal dominates , the intravascular signal nearly vanishes at ultra - high field strength such as 9.4 t . at 3 t still approximately half of the functional signal change is of intravascular origin [ 12 , 13 ] , but the increased specificity of se over ge could be demonstrated . quantitative measurement of the spatial extent of the bold response   showed a 13% narrower point spread function for se - epi , albeit at the cost of a factor 3 reduction in functional cnr . an additional advantage of se imaging is its insensitivity to through - plane susceptibility gradients which can result in substantial signal voids in ge images . it was shown in ref .   that parts of the inferior prefrontal brain activation associated with cognitive tasks could be imaged with se - epi , but not ge - epi . however , se - epi suffers from in - plane distortions , and some t2 * weighting will remain , caused by the long epi readout of typically 40 ms [ 15 , 16 ] . the severity of t2 * related artifacts increases rapidlywith field strength due to the shortened relaxation time . as pointed out in ref . t2 * effects can further lead to a broadening of the psf , causing the effective spatial resolution to be less than the voxel size in regions of short t2 * , particularly at higher field strengths ( 4 and 7 t ) as used in their study . bold fmri with pure t2 contrast , and with no epi artifacts , can be performed by using a multiply - refocused sequence , such as fast spin echo ( fse ) . this was demonstrated in an early study at 1.5 t   with a fully sampled multi - shot fse sequence at relatively high in - plane resolution ( 1.6  3.2 mm ) . the resulting long repetition time ( tr ) of > 20 s for five slices , however , only allowed use of very long block stimuli . at the field strength of 1.5 t the fse sequence was mainly sensitive to intravascular bold effects , but it was suggested in   that by adjusting the echo spacing the sensitivity could be tuned towards a specific range of vessel sizes . at 3 t , the increased contribution of extravascular dynamic averaging effects can be utilized . if for a given te the echo train for signal acquisition is preceded by a preparation period with a long refocusing interval , the relative contribution from the extravascular compartment , and thus the more desirable portion of the bold contrast can be increased . as in se - epi , the centre of k - space should be acquired at a te approximately equal to t2 . sampling times can be made compatible with the requirements for fast fmri by the use of partial fourier and parallel imaging . by following this sampling strategy , repetition times comparable to that of se - epi can be realized ( see methods section ) . acquisition rates of eight slices per second can be achieved , permitting good sampling of the bold response with near whole brain coverage in about 3 s. in this paper , the value of such an approach is investigated , and comparisons are made with the more conventional , singly refocused se - epi sequence ( some authors also refer to the spin echo in this context as the hahn spin echo ) . to facilitate a conservative comparison of functional sensitivity , full k - space acquisition is used for se - epi . two practical problems must be overcome to make fast multi - slice experiments viable as an alternative to se - epi . first , image acquisition times should ideally not exceed those of a conventional se - epi experiment . second , the energy deposition of the refocusing pulses must not exceed specific absorption rate ( sar ) limits ; yet a high enough signal to noise ( snr ) must be achieved at sufficient spatial resolution . both constraints may be addressed by using a combination of partial fourier ( pf ) imaging , and parallel imaging such as smash , sense   or grappa . to reduce total acquisition time , we implemented the haste sequence ( half - fourier acquisition single shot turbo se ) with linear ascending phase - encoding sampling scheme with acceleration factor 4 and 7/8 pf . the first echo is refocused at 50 ms by a three - lobed 180 selective sinc pulse . echo spacing was adjusted such that the k - space centre is acquired at the target te of 80 ms ( at 3 t ) , giving an inter - echo te of 6.5 ms . under the conservative assumption of a tissue t2 of 80 ms the line - broadening in this sequence caused by transverse relaxation is less than one pixel . sensitivity maps were calculated from separate moderately smoothed ( fwhm 3 pixels ) full resolution flash scans , using a third order polynomial fit for extrapolation beyond the edge of the object . the acquisition parameters were as follows : matrix size 64  64 , fov= 224 mm , voxel size 3.5  3.5  5 mm , tr = 2 s , pixel bandwidth 300 hz , effective echo train length of 14 k - space lines and tacq = 130 ms per slice . fully sampled se- and ge - epi measurements were made using a singly refocused double - echo sequence , with the same geometric parameters as for haste and at a bandwidth of 2,700 hz / pixel . for the epi sequence , all data were acquired on a 3 t siemens magnetom trio system ( siemens medical solutions , erlangen , germany ) using the product eight - channel head coil . the initial 50 ms period sensitizes for bold contrast by allowing dynamic averaging . using a combination of four - fold accelerated sense and 7/8 partial fourier only 14 k - space lines are sampled , reducing total slice acquisition time to 130 ms , close to that of a typical se - epi experiment schematic of the haste sequence used for the activation studies . the initial 50 ms period sensitizes for bold contrast by allowing dynamic averaging . using a combination of four - fold accelerated sense and 7/8 partial fourier only 14 k - space lines are sampled , reducing total slice acquisition time to 130 ms , close to that of a typical se - epi experiment visual stimuli consisting of 30 s rest followed by 21 s of 8 hz inverting black and white checkerboards were shown using presentation software ( neurobehavioral systems , inc . six subjects with normal or corrected - to - normal vision were scanned , after having given written consent according to local regulations . linear trend removal and high - pass filtering of all time courses were carried out in brainvoyager 2000 ( brain innovation , the netherlands ) . t tests were performed at p < 0.0001 ( all p values uncorrected for small volumes ) . mean and maximum t - scores , as well as count of active voxels were noted . functional cnr was calculated for each subject as the average signal change divided by the mean error on the average stimulus response curve . in addition , a spatial map of pixel - wise temporal snr ( tsnr ) was calculated in one dataset to assess the effect of parallel imaging on temporal stability . two practical problems must be overcome to make fast multi - slice experiments viable as an alternative to se - epi . first , image acquisition times should ideally not exceed those of a conventional se - epi experiment . second , the energy deposition of the refocusing pulses must not exceed specific absorption rate ( sar ) limits ; yet a high enough signal to noise ( snr ) must be achieved at sufficient spatial resolution . both constraints may be addressed by using a combination of partial fourier ( pf ) imaging , and parallel imaging such as smash , sense   or grappa . to reduce total acquisition time , we implemented the haste sequence ( half - fourier acquisition single shot turbo se ) with linear ascending phase - encoding sampling scheme with acceleration factor 4 and 7/8 pf . the first echo is refocused at 50 ms by a three - lobed 180 selective sinc pulse . echo spacing was adjusted such that the k - space centre is acquired at the target te of 80 ms ( at 3 t ) , giving an inter - echo te of 6.5 ms . under the conservative assumption of a tissue t2 of 80 ms the line - broadening in this sequence caused by transverse relaxation is less than one pixel . sensitivity maps were calculated from separate moderately smoothed ( fwhm 3 pixels ) full resolution flash scans , using a third order polynomial fit for extrapolation beyond the edge of the object . the acquisition parameters were as follows : matrix size 64  64 , fov= 224 mm , voxel size 3.5  3.5  5 mm , tr = 2 s , pixel bandwidth 300 hz , effective echo train length of 14 k - space lines and tacq = 130 ms per slice . fully sampled se- and ge - epi measurements were made using a singly refocused double - echo sequence , with the same geometric parameters as for haste and at a bandwidth of 2,700 hz / pixel . for the epi sequence , all data were acquired on a 3 t siemens magnetom trio system ( siemens medical solutions , erlangen , germany ) using the product eight - channel head coil . the initial 50 ms period sensitizes for bold contrast by allowing dynamic averaging . using a combination of four - fold accelerated sense and 7/8 partial fourier only 14 k - space lines are sampled , reducing total slice acquisition time to 130 ms , close to that of a typical se - epi experiment schematic of the haste sequence used for the activation studies . the initial 50 ms period sensitizes for bold contrast by allowing dynamic averaging . using a combination of four - fold accelerated sense and 7/8 partial fourier only 14 k - space lines are sampled , reducing total slice acquisition time to 130 ms , close to that of a typical se - epi experiment visual stimuli consisting of 30 s rest followed by 21 s of 8 hz inverting black and white checkerboards were shown using presentation software ( neurobehavioral systems , inc . six subjects with normal or corrected - to - normal vision were scanned , after having given written consent according to local regulations . linear trend removal and high - pass filtering of all time courses were carried out in brainvoyager 2000 ( brain innovation , the netherlands ) . t tests were performed at p < 0.0001 ( all p values uncorrected for small volumes ) . mean and maximum t - scores , as well as count of active voxels were noted . functional cnr was calculated for each subject as the average signal change divided by the mean error on the average stimulus response curve . in addition , a spatial map of pixel - wise temporal snr ( tsnr ) was calculated in one dataset to assess the effect of parallel imaging on temporal stability . stable sense reconstruction of the t2 prepared haste images could be achieved despite the high acceleration factor . figure 2 shows ge - epi , se - epi and haste images for comparison . figure 3a and b show corresponding slices from se - epi and haste experiments in one functional subject . temporal snr of the two preprocessed time courses is shown in fig . 3c and d. in the occipital cortex , tsnr of haste is comparable to that of se - epi , but lower in other regions . the spatial noise variation not only shows the expected dependence on tissue type , but also clearly resembles that of the g - map ( fig . the g - factor is the coil geometry related noise increase caused by the use of parallel imaging . figure 3f illustrates that the visual cortex is not strongly affected by g - noise ; typical values here are between 2.0 and 2.6 . 2five brain slices spanning from inferior to superior brain , acquired with ge - epi ( top ) , se - epi ( middle ) and t2-prepared haste ( bottom ) . the signal voids due to through - plane dephasing that are clearly present in the ge - epi are absent in se - epi , but in - plane distortions remain and are particularly severe in the inferior brain . in both cases nyquist ghosting can be observed . these epi artifacts are not present in the haste images , however the effect of coil sensitivity variations ( e.g. , in the left frontal regions ) appears more pronounced . traces of weak residual foldover that resembles the pattern of the g - map ( see fig . 3e ) can be seen in the third and fourth slices . in no instance , however , did this result in a projection of artifactual visual activation into other brain areasfig . 3typical se - epi ( a ) and haste ( b ) images with activation overlays at p < 0.0001 ( color scale represents t - scores ) . subfigures ( c ) and ( d ) show tsnr maps of the se - epi and haste data , respectively . spatial variation in the latter the overlay of g - map on haste image ( f ) illustrates that visual areas are not strongly affected by g - noise five brain slices spanning from inferior to superior brain , acquired with ge - epi ( top ) , se - epi ( middle ) and t2-prepared haste ( bottom ) . the signal voids due to through - plane dephasing that are clearly present in the ge - epi are absent in se - epi , but in - plane distortions remain and are particularly severe in the inferior brain . in both cases nyquist ghosting can be observed . these epi artifacts are not present in the haste images , however the effect of coil sensitivity variations ( e.g. , in the left frontal regions ) appears more pronounced . traces of weak residual foldover that resembles the pattern of the g - map ( see fig . 3e ) can be seen in the third and fourth slices . in no instance , however , did this result in a projection of artifactual visual activation into other brain areas typical se - epi ( a ) and haste ( b ) images with activation overlays at p < 0.0001 ( color scale represents t - scores ) . subfigures ( c ) and ( d ) show tsnr maps of the se - epi and haste data , respectively . spatial variation in the latter the overlay of g - map on haste image ( f ) illustrates that visual areas are not strongly affected by g - noise the average ( n = 6 ) bold response curves for se - epi and haste measurements are shown in fig . the time evolution of both curves is identical , however , the maximum signal change in se - epi ( 1.88% ) is higher than in the haste measurement ( 1.33% ) , at comparable baseline intensities . both methods show that about 9 s is required for the signal to return to baseline , followed by a bold undershoot . normalizing the activation time courses shows that both main response and undershoot of haste are proportionately reduced compared to se - epi , and the curves are almost perfectly aligned ( not shown ) . top stimulus response curve considering all active pixels , averaged over subjects ( error bars sem over subjects , they reflect variation in signal change across subjects , but not sensitivity ) . note that the average response curves of individual subjects were not normalized prior to averaging to allow comparison of the amplitude of the signal change between haste and epi . bottom mean and maximum t - scores at p < 0.0001 ( subject average , error bars sd ) . for the calculation of overlapping pixels the distortion was assumed to be negligible results of se - epi and haste bold measurements . top stimulus response curve considering all active pixels , averaged over subjects ( error bars sem over subjects , they reflect variation in signal change across subjects , but not sensitivity ) . note that the average response curves of individual subjects were not normalized prior to averaging to allow comparison of the amplitude of the signal change between haste and epi . bottom mean and maximum t - scores at p < 0.0001 ( subject average , error bars sd ) . for the calculation of overlapping pixels the distortion was assumed to be negligible at p < 0.0001 , average activation volumes are comparable in se - epi ( 332 voxels ) and haste ( 305 voxels ) . averages of mean and maximum t - scores in the haste measurements are 7.25  0.37 and 16.42  1.86 , respectively , and 7.35  0.32 and 16.12  1.72 , respectively for se - epi . considering only voxels active in both scans yields a similar picture , with 7.81  0.75 and 16.30  2.04 for haste , and 7.99  0.59 and 16.01  1.87 for se - epi . differences in t - scores are not significant ( permutation test , p < 0.05 ) and much smaller than the natural variation between subjects . calculation of functional cnr yields 16.55 ( noise 0.12 ) for se - epi , and 11.19 ( noise 0.11 ) for haste ; this means that the differences in sensitivity can be explained by the differences in signal change amplitude alone . considering the acquisition parameters used and the g - factors observed in the occipital lobe ,  within - image snr of haste would be expected to be approximately 30% lower than that of se - epi . the observation of comparable effective temporal snr of both methods ( in the visual areas ) is attributable to the contribution of physiological noise which markedly reduces the relative effect of image noise , and thus the use of parallel imaging on temporal stability . in central brain areas , however , much higher g - factors and the reduced tsnr suggest that functional sensitivity would be compromised . the g - noise can be reduced by a choosing lower acceleration factor and/or different coil array , as the g - maps are uniquely related to the combination of coil geometries with acceleration factor a , and g - values rapidly grow with the number of pixels overlapping in the foldover ( cf . 3 ) . while a protocol with acceleration factor 3 might therefore produce a  more benign g - map , it would not have allowed meeting our demands on tacq and target te of 80 ms , and required use of ambitious pf ( < 60% ) if the number of refocusing pulses were to be kept constant . on future systems this is will not be an issue as the rapidly growing number of coil elements   can yield much higher snr : the g - noise penalty for acceleration factors much smaller than the number of coils would be much lower than for the g - factors observed here . furthermore , k - space based reconstruction ( e.g. , grappa or smash ) would yield spatially almost invariant noise distributions , which might be regarded as favorable in an fmri setup . magnetization transfer effects due to off - resonance power deposition posed no problem for the 5-slice experiment in this study , but could potentially lead to signal attenuation and snr reduction for short tr and/or longer refocusing pulse trains . substantial power reductions with only moderate snr loss could be achieved by use of variable flip - angle schemes , and help improve fast multi - slice experiments . a clear advantage of haste is the absence of inhomogeneity artifacts , yielding images that are free of both dropout and distortion . the latter allows precise mapping from functional to anatomical data , and can further be expected to be beneficial for group studies . it was shown in ref .   that the application of post - hoc distortion correction to epi data not only improves coregistration with the anatomical images , but also that group statistics on functional studies improved considerably . haste acquisitions should yield the same benefits , without the difficulties associated with correction methods that rely on the use of separately acquired reference data such as field maps . in our implementation of the haste sequence , the signal acquisition is preceded by a preparation experiment for dynamic averaging that lasts 50 ms . ideally , the sequence would refocus the first echo at the optimal te of 80 ms to maximize the dynamic averaging contribution , followed by centre - out acquisition of k - space , but at the price of a much longer total acquisition time . the compromise was chosen to achieve comparable slice acquisition times for se - epi and haste and permit a conservative comparison of the two methods . while we chose to use conventional se - epi without k - space undersampling for an unbiased assessment of relative functional sensitivities , se - epi readout times this would have resulted in a g  a fold snr penalty , and hence sensitivity reduction in favor of haste , but the benefit of a - fold reduction in epi distortion / t2 * blurring . the presence of t2 * decay during the long readout train can be expected to contribute considerably to the functional signal changes in se - epi [ 15 , 16 ] . this most likely explains the majority of the observed difference between se - epi and haste . phantom studies at 1.5 t have shown that up to 37% of the se signal changes can arise due to static dephasing . in vivo data at higher fields suggest an even larger contribution of t2 * effects , approximately 60% . the amount of t2 * contribution depends on the spatial features of the activated areas , and would be largest for activation with higher spatial frequency components . quantification of this effect is , hence , object dependent and beyond the scope of this paper . a difference between se - epi and haste based t2 contrast is also likely to arise due to differences in refocusing interval : a standard se - epi protocol for fmri will have a single refocusing pulse for te 80 ms , but our haste implementation has a spin echo preparation experiment with te 50 ms , followed by multiple refocusing pulses , with the k - space centre at te 80 ms . in partially oxygenated blood the proton exchange between erythrocytes and blood plasma , or diffusion in the local fields gradients arising from the presence of deoxyhemoglobin , results in a shortening of the effective intravascular t2 with increasing deoxyhemoglobin levels and increasing refocusing interval in cpmg sequences [ 28 , 29 ] . this effect in itself forms the basis of the recently proposed verve fmri contrast mechanism . the rapid refocusing in the haste acquisitions thus implies elongation of the intravascular t2 compared to se - epi , where only a single refocusing pulse is applied , and hence a reduction in the functional sensitivity to intravascular signal changes . consequently both functional contrast mechanisms that contribute to spin - echo bold will be somewhat reduced in effect by the addition of extra refocusing pulses . it is difficult to assess the significance of this sensitivity loss , but as the difference in sensitivity between se - epi and haste in the present study is consistent with the literature regarding the t2 * sensitivity of se - epi , it may be expected to be small . these could in principle explain some of the discrepancy in signal change if they contribute differently to the two methods . however , inflow should contribute little given the se - epi acquisition parameters , and be similar as the same tr of 2 s is used in both sequences . an interesting question is raised by the fact that such a pronounced undershoot is observed in the se data , particularly the haste . while it is generally accepted that the post - stimulus undershoot is in some way caused by the complex temporal relationship between the parameters cerebral blood volume ( cbv ) , blood flow ( cbf ) and oxygen consumption ( cmro2 ) , there are two main types of explanation . first , the  balloon model family [ 31 , 32 ] , which assumes a strong coupling between cmro2 and cbf , but a temporally varying relationship between of cbv and cbf . according to this model , following stimulation , delayed vascular compliance causes cbv to return to baseline more slowly than cbf and cmro2 , leading to a negative bold signal . the second type of explanation postulates a decoupling of cbf and cmro2 : the undershoot is then caused by post - stimulus oxygen consumption that remains elevated even after cbf has returned to baseline . we observed no difference between the normalized response curves of se - epi and haste , meaning that any t2 * effects present in the se - epi data equally affect both main bold signal and undershoot . 5 . comparison of the normalized activation time courses with the ge - epi data ( not shown ) which were simultaneously acquired with the se - epi also showed no difference in the undershoot . this suggests that the same combination of contrast mechanisms must be contributing to both the main bold signal and the post - stimulus undershoot . the balloon model   predicts that the undershoot is largely due to extravascular static dephasing around the larger ( downstream ) vessels . an undershoot in the bold signal could , however , also be the result of intravascular t2 changes as would result from sustained post - stimulus oxygen metabolism . static dephasing effects are refocused by the se experiment , so if the standard balloon model hypothesis were true , then the undershoot would have to be reduced in magnitude relative to the main response . observation of the same signal contribution to both parts of the bold response thus rather excludes the interpretation of the undershoot as a downstream static dephasing effect , leaving changes in deoxyhemoglobin concentration as the more likely explanation . such post - stimulus elevation in deoxyhemoglobin could be the result of ongoing oxygen metabolism after the return of cbv and cbf back to baseline , as suggested by lu et al . . that elevated cbv alone can not be the cause for a post - stimulus signal decrease has recently been reported by yacoub et al . . 5normalization of the curves shown in fig . 4 results in both response curves being perfectly aligned , showing that haste sensitivity in the main and undershoot response scales by the same factor compared to se - epi normalization of the curves shown in fig . 4 results in both response curves being perfectly aligned , showing that haste sensitivity in the main and undershoot response scales by the same factor compared to se - epi in conclusion , the application of fast spin echo sequences to fmri was investigated . bold activation was robustly detected by haste acquisitions preceded by a preparation experiment for dynamic averaging . while the functional cnr in the occipital lobe was  30% lower than for a conventional se - epi acquisition of approximately equal tr , the absence of image artifacts makes haste a viable alternative where distortion free images are required .
at higher field strengths , spin echo ( se ) functional mri ( fmri ) is an attractive alternative to gradient echo ( ge ) as the increased weighting towards the microvasculature results in intrinsically better localization of the bold signal . 
 images are free of signal voids but the commonly used echo planar imaging ( epi ) sampling scheme causes geometric distortions , and t2 * effects often contribute considerably to the signal changes measured upon brain activation . 
 multiply refocused se sequences such as fast spin echo ( fse ) are essentially artifact free but their application to fast fmri is usually hindered due to high energy deposition , and long sampling times . in the work presented here , 
 a combination of parallel imaging and partial fourier acquisition is used to shorten fse acquisition times to near those of conventional se - epi , permitting sampling of eight slices ( matrix 64    64 ) per second . 
 signal acquisition is preceded by a preparation experiment that aims at increasing the relative contribution of extravascular dynamic averaging to the bold signal . 
 comparisons are made with conventional se - epi using a visual stimulation paradigm . while the observed signal changes are approximately 30% lower , most likely due to the absence of t2 * contamination , activation size and t - scores 
 are comparable for both methods , suggesting that haste fmri is a viable alternative , particularly if distortion free images are required . 
 our data also indicate that the bold post - stimulus undershoot is most probably attributable to persistent elevated oxygen metabolism rather than to delayed vascular compliance .