Spin-echo versus gradient-echo fMRI with short echo times

P.W. Stromana,*, V. Krausea, U.N. Frankensteina, K.L. Maliszaa, B. Tomaneka,b

aMR Technology Group, Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Manitoba, CanadabDepartment of Neurosciences, University of Calgary, Calgary, Alberta, Canada

Received 2 March 2001; accepted 10 April 2001

Abstract

Blood-oxygen level dependent signal changes in the visual cortex were investigated as a function of echo time with spin-echo andgradient-echo EPI at 1.5 T and 3 T. The linear relationship between the fractional signal change and the echo time was apparent in all cases.Relaxation rate changes determined from the slope of this linear relation agree with published values, intercept values extrapolated to anecho time of zero, however, were 0.66% to 1.0% with spin-echo EPI, and 0.11% to 0.35% with gradient-echo EPI. Spin-echo andgradient-echo EPI can therefore yield similar signal changes at sufficiently short echo times. © 2001 Elsevier Science Inc. All rights reserved.

1. Introduction

The currently accepted model of blood-oxygen leveldependent (BOLD) contrast has a linear relation betweenthe echo time (TE) and the fractional signal intensity change(DS/S) observed upon neuronal activation with T2*-weighted data [1]:

DS

S5 2 TE DS 1

T*2D (1)

The same expression can be used for T2-weighted data aswell, with the relaxation rateD(1/T2*) replaced byD(1/T2).One condition of the BOLD model is that the change inrelaxation rate,D(1/T2) should be at least a factor of 3smaller thanD(1/T2*) [2,3]. As a result, the intensitychanges observed with gradient echo techniques are ex-pected to be at least 3 times greater than those observed withspin-echo techniques. We have repeatedly observed, how-ever, that apparent BOLD changes in spin-echo fMRI dataare larger than expected from the current BOLD model asthey are greater than 1/3 the magnitude of correspondinggradient-echo fMRI data at the same echo time. In particu-lar, fMRI studies in the cervical spinal cord at 1.5 Teslahave consistently demonstrated larger spin-echo intensitychanges than expected [4,5]. Moreover, we have observedthat spin-echo intensity changes are linear with echo time,

but do not extrapolate to a value of zero as the echo timeapproaches zero [6]. This suggests that either there arecomponents of the signal change we observed upon neuro-nal stimulation that are not BOLD related, such as inflow ora change in the baseline signal intensity, or that the frac-tional signal change is not a linear function of echo time.These observations were obtained with single-shot spin-echo EPI and single-shot fast spin-echo imaging with rep-etition times greater than 6 s. We therefore conclude that thecontribution from in-flow of fully relaxed blood enhancingthe signal is insignificant and that other possible explana-tions must be considered.

In an attempt to explain this observation we thereforeinvestigated the fractional signal change as a function ofecho time in fMRI data. From these results, the slope andintercept at zero echo time were determined and comparedto the standard BOLD model. While the observations whichprompted this work were obtained in the spinal cord, wechose to carry out this investigation in the human visualcortex to rule out any “unusual” properties of the spinalcord. Moreover, the dependence of fractional signal changeon echo time was determined with two different MR sys-tems, 1.5 T and 3 T, with single-shot and segmented EPImethods in order to verify the reproducibility of our findings.

2. Methods

Studies were carried out with 12 healthy volunteers ateither 1.5 Tesla (GE Signa Horizon LX), or at 3 Tesla in a

* Corresponding author. Tel.:11-204-984-6973; fax:11-204-984-7036.E-mail address:stroman@ibd.nrc.ca (P. Stroman).

Magnetic Resonance Imaging 19 (2001) 827–831

0730-725X/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved.PII: S0730-725X(01)00392-7

whole-body research system operated with a S.M.I.S. con-sole (Guildford, Surrey, England). For the studies at 1.5 T aGE head coil was employed with single-shot gradient-echoand spin-echo EPI. Excitation pulses were 90o pulses inboth cases. Studies carried out at 3 T employed a birdcagehead coil and images were acquired with 8-shot segmentedEPI for both gradient-echo and spin-echo imaging. Forgradient-echo imaging a 20o flip angle was used and therepetition time between segments was 240 msec (60 msecbetween slices3 4 slices). Spin-echo EPI was carried outwith a repetition time of 500 msec between segments.

In all experiments, regardless of the MR system used,images of 4 contiguous slices (5 mm thick) parallel to thecalcarine fissure were obtained. The image matrix wasmaintained at 643 64 with a 22 cm field of view, a 100 kHzreceiver bandwidth and the time between repeated imagingof the 4 slices was 6 s. Visual stimulation was applied toboth eyes via goggles (Grass Medical Instruments, QuincyMass., USA) fitted with light emitting diodes flashing at 8Hz. The stimulation paradigm consisted of 48 s at rest, 48 sof stimulation, 36 s rest, 60 s of stimulation, followed by36 s at rest.

Functional MRI time course data were analyzed bymeans of a straightforward correlation with a boxcar modelof the stimulation paradigm [7]. A 3-point median filter wasapplied in the time domain prior to analysis and the corre-lation threshold was set atR 5 0.32 (p 5 0.05). Finally,regions of interest were drawn to select only those activatedpixels within the visual cortex. The intensity change uponneuronal activation for each time course was determined byaveraging the fractional signal changes during stimulationwhere the response appeared to have reached a relativelysteady state.

3. Results

FMRI data were obtained from 12 volunteers (6 at 1.5 Tand 6 at 3 T) over a range of echo times for each subject.Fractional signal changes (DS/S) measured in the visualcortex with spin-echo and gradient-echo EPI consistentlyfollowed a linear function of the echo time (TE). Plots ofDS/S as a function of TE are shown in Fig. 1a and 1b fordata obtained at 1.5 T and at 3 T, respectively. Linear fits tothe data obtained at 1.5 T yielded the following functions(TE expressed in units of seconds, uncertainties expressedas standard errors):

GE-EPI:DS/S5 (0.436 0.05) TE1 (0.00176 0.0020)R2 5 0.81 (n 5 19 pts from 6 subjects)

SE-EPI:DS/S5 (0.126 0.02) TE1 (0.00726 0.0012)R2 5 0.55 (n 5 20 pts from 6 subjects)

The data obtained at 3 Tesla demonstrated the corre-sponding linear functions:

GE-EPI:DS/S5 (1.046 0.11) TE1 (0.00356 0.0022)R2 5 0.84 (n 5 19 pts from 6 subjects)

SE-EPI:DS/S5 (0.276 0.06) TE1 (0.01036 0.0019)R2 5 0.59 (n 5 18 pts from 6 subjects)

4. Discussion

The relaxation rate changes observed at 1.5 T are20.43sec21 for D(1/T2*) and 20.12 sec21 for D(1/T2). The cor-responding values observed at 3 Tesla are21.04 sec21 and20.27 sec21, respectively. These values are in good agree-ment with published values observed by others, as summa-rized in Table 1. As expected, the relaxation rate changesare larger at 3 T than at 1.5 T with a ratio of 2.3 for thespin-echo data and 2.4 for the gradient echo data. Moreover,

Fig. 1. a: BOLD signal enhancement dependence on echo time with gradient-echo (open symbols) and spin-echo (filled symbols) EPI at 1.5 T. Data obtainedfrom each of the 3 subjects are shown with the same symbol. Fig. 1b: BOLD signal enhancement dependence on echo time with gradient-echo (open symbols)and spin-echo (filled symbols) EPI at 3 T. Again, as in Fig. 1a, the data obtained from each of the 3 subjects studied at this field strength are shown withthe same symbol.

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the ratios of relaxation rate changesD(1/T2*)/D(1/T2) are3.7 and 3.8 at 1.5 T and 3 T, respectively. These values arein excellent agreement with the ratio of 3.526 0.56 re-ported by Bandettini et al. [2] and roughly correspond toa vessel radius of 8mm according to the model of Ogawaet al. [3].

The data we have obtained comparing the apparentBOLD signal changes in spin-echo and gradient-echo EPI at1.5 T and 3 T are in excellent agreement with the currentBOLD model. However, consistent with our previous ob-servations [4,5], the value ofDS/S obtained with SE-EPI isnot a factor of 3 smaller than that observed with GE-EPI atthe same echo time. This results from the intercept of thelinear relation betweenDS/S and TE being greater than zeroin every case, and consistently larger with SE-EPI than withGE-EPI.

The most obvious source of an unwanted increase insignal in our data are possible in-flow effects. However,in-flow has been shown to cause paradigmatic increases insignal intensity only at short repetition times (200 msec) andno in-flow effect has been demonstrated in data obtainedwith repetition times of 3 s orlonger [8,9]. To minimize thiseffect the time between repeated imaging of the volume wasmaintained at 6 s in ourstudy. Except for the segmentedspin-echo EPI, the multi-slice image acquisition was com-pleted in 2 s and 4 s were allowed for the magnetization torelax fully between repeated acquisitions. Segmented SE-EPI at 3 Tesla was acquired with 500 msec between seg-ments for each slice resulting in an acquisition time of 4 s.This was followed by a 2 sdelay before repeated imaging ofthe volume, allowing sufficient time for the blood within thevolume to be refreshed. It is possible, however, that fullyrelaxed blood flowed into a slice in the interval betweenacquisition of two segments in this case, thereby enhancingthe signal within the vessels. If the in-flow rate also in-creased upon neuronal stimulation then this enhancementwould have contributed to the fractional signal change weobserved. However, the consistency between our observa-tions and those reported by others (see Table 1), and be-tween our observations with single-shot SE-EPI at 1.5 T andsegmented SE-EPI at 3 T leads us to conclude that in-flowenhancement did not have a significant effect on our data.

Other possible explanations for the positive interceptinclude the possibility that we are fitting a linear function toa non-linear relationship. Specifically, this relationshipwould have to be less than linear as has been shown only forsignal arising from within large vessels [1]. The magnitude

and field strength dependence of our data are consistent withBOLD signal arising from tissues and not from within largevessels [1]. Therefore, if the BOLD signal from tissues doesindeed follow a non-linear relationship that reaches zero atan echo time of zero, then the nonlinearity must becomevisible only below the echo times we have sampled (i.e.,,18 msec). One could argue that a small contribution fromwithin large vessels could become more significant atshorter echo times, thereby making the relationship non-linear. In this case, the gradient-echo data would be ex-pected to be as sensitive to the effect as the spin-echo data,which is not supported by our observations. A non-lineardependence on TE in T2*-weighted signals has been de-scribed as a result of dephasing in the static inhomogenousfield around vessels in cases where diffusion can be ignored[10]. These authors show that at echo times below a certainthreshold (roughly 28 msec at 1.5 T or 14 msec at 3 T) therelaxation rate, 1/T2*, is not constant but depends linearlyon TE. The effect of this form of non-linear dependencewould be to reduce the fractional signal change and makethe intercept value smaller or even negative. Moreover, thiseffect has not been demonstrated with T2-weighted signalsand so does not account for our observations. The magneticfield gradients around blood vessels could cause a non-linear loss of signal if diffusion is not ignored though. In thiscase the signal loss due to diffusion would be similar forgradient-echo and spin-echo data and would be greater atlonger echo times. The linear BOLD model demonstratesthat either this diffusion-weighting effect is small or iscanceled out in the ratioDS/S, and so can also be ruled outas the cause of the non-zero intercept we observe.

A second and more plausible explanation for the positiveintercept is an increase in the baseline signal intensity uponneuronal activation. Support for this idea comes from Hen-nig et al. [11] who also observed an apparent baselinechange and termed it the “amplitude effect.” Such a baselinechange could come about as a result of an increased bloodvolume, or an increase in the extravascular water content inactivated voxels. The difference in sensitivity to the baselineshift between spin-echo and gradient-echo data provides aclue to its source. If an increase in proton density occurs inthe same fluid component where the BOLD effect occurs,then both spin-echo and gradient-echo fMRI data should besensitive to it. In order to test the possibility that there is achange in the baseline signal only in areas where spin-echofMRI is more sensitive, the GE-EPI signal changes wereexamined in the common areas where both SE-EPI and

Table 1Comparison of relaxation rate changes observed in the present study and values found in the literature. Units are in sec21

D(1/T2*) at 1.5 T D(1/T2) at 1.5 T D(1/T2*) at 3 T D(1/T2) at 3 T

Present Study 20.436 0.05 20.126 0.02 21.046 0.11 20.276 0.06Bandettini et al. (13) 20.556 0.08 20.166 0.02Bandettini et al. (2) 20.846 0.05 21.766 0.05Zong et al. (14) 20.11

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GE-EPI showed signal changes for one subject. The frac-tional signal changes were increased marginally at eachecho time with these selected voxels, but these changes didnot affect the intercept extrapolated to an echo time of zero.This suggests that the baseline signal intensity change doesnot occur in the same fluid component where the BOLDeffect occurs.

The gradient-echo data can be insensitive to the baselinesignal increase if it occurs in an extravascular water com-ponent with a relatively short T2* value. In this model theextravascular water component would undergo considerablerelaxation by the time the gradient echo is formed and so itseffect would be reduced. This would require a value of T2*which is shorter than that of arterial blood and no larger thanthe shortest echo times sampled (9 msec). The T2 value ofthis component, on the other hand, could be as long as thatof blood because it appears to persist for at least as long asthe echo times we have sampled. Support for the idea thatthere are changes in the extravascular fluid compartmentupon neuronal activation comes from Darquie´ et al. [12].This group has demonstrated small but significant changesin the apparent water self-diffusion coefficient (ADC) thatthey have attributed to increases in the intracellular watercontent upon neuronal activation.

If we do not assume that the baseline signal intensity isthe same during the rest condition and during activation,then the signal intensity during each of these periods can bespecified as:

SR 5 SoR exp (2TE/T2R) (2)

SA 5 SoA exp (2TE/T2A) (3)

In these expressions the subscript R is used to refer to therest condition and A represents the active condition, and S0R

and S0A are the baseline intensities in each condition, re-spectively. The fractional change in signal intensity uponneuronal activation is then given by equation 4:

DS

S5

SA 2 SR

SR5

SoA exp~ 2 TE/T2A!

SoR exp ~ 2 TE/T2R!2 1 (4)

By combining the two exponential terms into a single one,expanding this term with a first order approximation, andexpressing the change in relaxation rate upon neuronal stim-ulation asD(1/T2), the expression is reduced to:

DS

S5 2 TE D S 1

T2D SSoA

SoRD 1 SSoA

SoR2 1D (5)

As the ratio of baseline signal intensities, (SoA/SoR), isexpected to have a value close to 1, this equation is only aminor departure from equation 1, except for the inclusion ofthe intercept term.

While the data presented demonstrate that a linear fit tothe fractional signal change as a function of echo time hasa consistently positive intercept in spin-echo fMRI data, itdoes not reveal the cause of the non-zero intercept. We have

ruled out in-flow enhancement as the cause, and so it ap-pears that we are detecting a baseline signal intensity shift inaddition to the BOLD signal changes. By definition such abaseline shift cannot be due to the BOLD effect. Nonethe-less, the expression we have derived in Eq. 5 serves toapproximate the fractional signal changes observed in spin-echo and gradient-echo fMRI, over a range of commonlyused echo times. These data also serve to demonstrate thatupon neuronal activation, although the change in relaxationrates,D(1/T2*) and D(1/T2), are in a ratio of approximately3.5:1, the fractional signal changes observed with T2* andT2-weighted fMRI data can be very similar at sufficientlyshort echo times.

5. Conclusions

Functional MRI data were obtained in the visual cortexat 1.5 T and 3 T with spin-echo and gradient-echo EPI thatare entirely consistent with the currently accepted BOLDmodel and with published fMRI data. Linear fits to thefractional signal changes as a function of echo time, how-ever, extrapolate to positive values at an echo time of zeroand is significantly greater than zero with spin-echo data,but not with gradient-echo data. As a result, the fractionalsignal changes are similar in magnitude with spin-echo andgradient-echo data at relatively short echo times. We havederived a slightly modified equation to describe the frac-tional signal changes observed over the range of commonlyused echo times that takes into account the non-zerointercept. Our data do not reveal the cause of the non-zero intercept, however, we hypothesize that it is theresult of signal enhancement by extravascular water pro-tons.

References

[1] Menon RS, Ogawa S, Tank DW, Ugurbil K. 4 Tesla gradient recalledecho characteristics of photic stimulation-induced signal changes inthe human primary visual cortex. Magn Reson Med 1993;30:380–6.

[2] Bandettini PA, Wong EC, Jesmanowicz A, Hinks RS, Hyde JS.Spin-echo and gradient-echo EPI of human brain activation usingBOLD contrast: A comparative study at 1.5 T. NMR in Biomed1994;7:12–20.

[3] Ogawa S, Menon RS, Tank DW, Kim S-G, Merkle H, Ellerman JH,Ugurbil K. Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. Biophys J 1993;64:803–12.

[4] Stroman PW, Ryner LN. Spinal fMRI. Proceedings of ISMRM, 7th

Annual meeting. Philadelphia, 1999. p. 445.[5] Stroman PW, Ryner LN. Functional MRI of motor, and sensory

activation in the human spinal cord. Magn Reson Imaging (acceptedfor publication).

[6] Stroman PW, Ryner LN. Investigating BOLD signal intensitychanges in fMRI of the human spinal cord. Proceedings of ISMRM,8th Annual meeting, Denver, 2000, p. 941.

[7] Bandettini PA, Jesmanowicz A, Wong EC, Hyde JS. Processingstrategies for time-course data sets in functional MRI of the humanbrain. Magn Reson Med 1993;30:161–73.

830 P.W. Stroman et al. / Magnetic Resonance Imaging 19 (2001) 827–831

[8] Speck O, Hennig J, Functional imaging by Io-, and T2*-parametermapping using multi-image EPI. Magn Reson Med 1998;40:243–8.

[9] Wiggins CJ, Norris DG. Investigation of inflow effects on fMRI at3T. Proceedings of ISMRM, 8th Annual meeting, Denver, 2000, p.942.

[10] Yablonskiy DA, Haacke EM. Theory of NMR signal behavior inmagnetically inhomogeneous tissues: The static dephasing regime.Magn Reson Med 1994;32:749–63.

[11] Hennig J, Janz C, Speck O, Ernst T. Functional spectroscopy of brainactivation following a single light pulse: Examinations of the mech-anism of the fast initial response. Int J Imag Syst Technol 1995;6:203–8.

[12] Darquie A, Poline JB, Saint-Jalmes H, Le Bihan D. Transient de-creases in water diffusion observed in occipital cortex during visualstimulation. MAGMA 2000;11(suppl. 1):76–7.

[13] Bandettini PA, Wong EC, Jesmanowicz A, Prost R. Cox RW, HinksRS, Hyde JSMRI of human brain activation at 0.5 T, 1.5 T, and 3.0T: Comparisons ofDR2*, and functional contrast to noise ratio.Proceedings of SMR, San Francisco 1995. p. 434.

[14] Zhong J, Kennan RP, Fulbright RK, Gore JC. Quantification ofintravascular and extravascular contributions to BOLD effects in-duced by alteration in oxygenation or intravascular contrast agents.Magn Reson Med 1998;40:526–36.

831P.W. Stroman et al. / Magnetic Resonance Imaging 19 (2001) 827–831