what causes the hyperintense t2-weighting and increased short t2 signal in the corticospinal tract?

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Research articles What causes the hyperintense T 2 -weighting and increased short T 2 signal in the corticospinal tract?Bretta Russell-Schulz a, , Cornelia Laule b, c , David K.B. Li c, d , Alex L. MacKay a, c a Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1 b Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5 c Department of Radiology, University of British Columbia, Vancouver, BC, Canada V5Z 4E3 d Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 abstract article info Article history: Received 24 January 2012 Revised 30 June 2012 Accepted 8 July 2012 Keywords: T 2 relaxation Myelin water Corticospinal tract Geometric mean T 2 White matter Normal brain The corticospinal tract (CST) appears hyperintense on both T 2 -weighted images and myelin water maps. Here, an extended multiecho T 2 relaxation sequence with echoes out to 1120 ms was used to characterize the longer T 2 times present in the CST. The T 2 distribution from the CST was compared to other white matter structures in 14 healthy subjects. The intra-/extracellular T 2 peak of the CST was broadened relative to other white matter structures and often split into two distinct peaks. In the CST, it appeared that the intracellular and extracellular water environments had unique T 2 times, causing the intracellular water peak to be pushed down into the myelin water T 2 regime and the extracellular peak to be pushed up to longer T 2 times. The conventional myelin water T 2 limits of 5-40 ms resulted in an articial increase in myelin water fraction (MWF), causing the CST to be bright on myelin water images. When the upper limit for MWF was decreased to 25 ms, the CST regions exhibited MWF values similar to those found for adjacent anterior and posterior regions. The CST has unique magnetic resonance characteristics, which should be taken into consideration when being examined, especially when compared to pathological tissue. © 2013 Elsevier Inc. All rights reserved. 1. Introduction The corticospinal tract (CST) is an important descending nerve ber tract responsible for distinct, voluntary motor movements [1]. It originates in the cerebral cortex, travels through the posterior limb (PL) of the internal capsule (IC) [2,3] and nally into the spinal cord [1,4]. In most normal healthy adults, the CST can be identied on heavily T 2 -weighted magnetic resonance (MR) images as a bright focal region and on T 1 -weighted images as a hypointense area, relative to surrounding white matter [2]. As T 2 hyperintensities and T 1 hypointensities can also be an indicator of pathology, it is worthwhile to properly characterize and identify what gives rise to the unusual signal of the CST in healthy normal tissue. The CST has over 1 million bers in each tract; the majority of these bers are small (14 μm) in size (~90%), but 3.5% of the bers have very large axons (N 20 μm) up to 22 μm [1,5,6]. The ber morphology of the CST at the level of the IC was found to be composed mostly of large diameter axons (implying large myelin sheaths [7]), present in low density, when compared to areas directly anterior and posterior [2]. These morphological properties of the CST presumably give rise to its unique appearance on conventional MRI. A variety of advanced MRI methods, including diffusion tensor imaging (DTI), magnetization transfer (MT), T 1 and T 2 relaxation, have been used to characterize the CST in the brain [8,9]. Reich et al. [8] examined the CST in healthy controls and presented a summary of various MRI parameters within the CST including T 1 ,T 2 , magnetization transfer ratio (MTR), fractional anisotropy, mean diffusivity, trans- verse diffusivity, and the three diffusion tensor eigenvalues. From whole brain DTI, they used tractography to segment the tracts of the CST from the medulla to the cortex. They found all parameters to be roughly constant from the medulla to the IC, but beyond, the diffusion eigenvalues changed. In general, there was no signicant difference in parameters between the left and right branches of the CST. Data from a single scan of an individual with relapsingremitting multiple sclerosis (MS) highlighted abnormalities in many of these parameters within the CST. Hervé et al. [9] found that the MTR from the CST was lower when compared to an area directly anterior in the PLIC. Decreases in MTR may be a reection of a decrease in the nonaqueous proton pool, an increase in the water proton pool or both. Magnetic Resonance Imaging 31 (2013) 329335 Funding was provided by a Vancouver Hospital and Health Sciences Centre Interdisciplinary Grant. Cornelia Laule is the recipient of the Women Against MS (WAMS) endMS Research and Training Network Transitional Career Development Award from the MS Society of Canada. Corresponding author. E-mail address: [email protected] (B. Russell-Schulz). 0730-725X/$ see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.mri.2012.07.003 Contents lists available at SciVerse ScienceDirect Magnetic Resonance Imaging journal homepage: www.mrijournal.com

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Page 1: What causes the hyperintense T2-weighting and increased short T2 signal in the corticospinal tract?

Magnetic Resonance Imaging 31 (2013) 329–335

Contents lists available at SciVerse ScienceDirect

Magnetic Resonance Imaging

j ourna l homepage: www.mr i journa l .com

Research articles

What causes the hyperintense T2-weighting and increased short T2 signal in thecorticospinal tract?☆

Bretta Russell-Schulz a,⁎, Cornelia Laule b,c, David K.B. Li c,d, Alex L. MacKay a,c

a Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1b Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5c Department of Radiology, University of British Columbia, Vancouver, BC, Canada V5Z 4E3d Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3

☆ Funding was provided by a Vancouver HospitalInterdisciplinary Grant. Cornelia Laule is the recipient(WAMS) endMS Research and Training Network TranAward from the MS Society of Canada.⁎ Corresponding author.

E-mail address: [email protected] (B. Russell-Sch

0730-725X/$ – see front matter © 2013 Elsevier Inc. Alhttp://dx.doi.org/10.1016/j.mri.2012.07.003

a b s t r a c t

a r t i c l e i n f o

Article history:Received 24 January 2012Revised 30 June 2012Accepted 8 July 2012

Keywords:T2 relaxationMyelin waterCorticospinal tractGeometric mean T2White matterNormal brain

The corticospinal tract (CST) appears hyperintense on both T2-weighted images and myelin water maps.Here, an extended multiecho T2 relaxation sequence with echoes out to 1120 ms was used to characterizethe longer T2 times present in the CST. The T2 distribution from the CST was compared to other whitematter structures in 14 healthy subjects. The intra-/extracellular T2 peak of the CST was broadened relativeto other white matter structures and often split into two distinct peaks. In the CST, it appeared that theintracellular and extracellular water environments had unique T2 times, causing the intracellular waterpeak to be pushed down into the myelin water T2 regime and the extracellular peak to be pushed up tolonger T2 times. The conventional myelin water T2 limits of 5-40 ms resulted in an artificial increase inmyelin water fraction (MWF), causing the CST to be bright on myelin water images. When the upper limitfor MWFwas decreased to 25ms, the CST regions exhibitedMWF values similar to those found for adjacentanterior and posterior regions. The CST has unique magnetic resonance characteristics, which should betaken into consideration when being examined, especially when compared to pathological tissue.

and Health Sciences Centreof the Women Against MS

sitional Career Development

ulz).

l rights reserved.

© 2013 Elsevier Inc. All rights reserved.

1. Introduction

The corticospinal tract (CST) is an important descending nervefiber tract responsible for distinct, voluntarymotormovements [1]. Itoriginates in the cerebral cortex, travels through the posterior limb(PL) of the internal capsule (IC) [2,3] and finally into the spinal cord[1,4]. In most normal healthy adults, the CST can be identified onheavily T2-weighted magnetic resonance (MR) images as a brightfocal region and on T1-weighted images as a hypointense area,relative to surrounding white matter [2]. As T2 hyperintensities andT1 hypointensities can also be an indicator of pathology, it isworthwhile to properly characterize and identify what gives rise tothe unusual signal of the CST in healthy normal tissue.

The CST has over 1 million fibers in each tract; the majority ofthese fibers are small (1–4 μm) in size (~90%), but 3.5% of the fibershave very large axons (N20 μm) up to 22 μm [1,5,6]. The fiber

morphology of the CST at the level of the IC was found to becomposed mostly of large diameter axons (implying large myelinsheaths [7]), present in low density, when compared to areas directlyanterior and posterior [2]. These morphological properties of the CSTpresumably give rise to its unique appearance on conventional MRI.

A variety of advanced MRI methods, including diffusion tensorimaging (DTI),magnetization transfer (MT), T1 and T2 relaxation, havebeen used to characterize the CST in the brain [8,9]. Reich et al. [8]examined the CST in healthy controls and presented a summary ofvariousMRI parameterswithin the CST including T1, T2, magnetizationtransfer ratio (MTR), fractional anisotropy, mean diffusivity, trans-verse diffusivity, and the three diffusion tensor eigenvalues. Fromwhole brain DTI, they used tractography to segment the tracts of theCST from the medulla to the cortex. They found all parameters to beroughly constant from the medulla to the IC, but beyond, the diffusioneigenvalues changed. In general, there was no significant difference inparameters between the left and right branches of the CST. Data froma single scan of an individual with relapsing–remitting multiplesclerosis (MS) highlighted abnormalities in many of these parameterswithin the CST. Hervé et al. [9] found that the MTR from the CST waslower when compared to an area directly anterior in the PLIC.Decreases inMTRmay be a reflection of a decrease in the nonaqueousproton pool, an increase in the water proton pool or both.

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330 B. Russell-Schulz et al. / Magnetic Resonance Imaging 31 (2013) 329–335

Quantitative assessment of T2 relaxation has also demonstratedthat the CST has unique characteristics relative to other white matterareas. T2 relaxation is influenced by the interactions of water protonswith protons on other molecules (nonaqueous) in its vicinity and isalso affected by water diffusion on the timescale of the experiment[10,11]. In healthy white matter, T2 decay curves are multiexponen-tial and can be separated into at least two components which arisefrom different water environments [10,12,13]. The shortest compo-nent (~20 ms) is from myelin water (MW), which is water trappedbetween the myelin sheaths and an intermediate T2 signal (~80 ms)arises from intra-/extracellular (IE) water [12,14–16]. The myelinwater fraction (MWF), which is defined as the fraction of the T2distribution in the shorter T2 component range, was found tocorrelate with myelin content in histological studies [17–22]. T2times from the IE water environment are sensitive to differencesbetween healthy and pathological tissue [23–25].

Since Yagishita et al. [2] proposed the CST had longer T2 and T1times in the IC, when compared to areas directly anterior andposterior, a number of studies have gone on to quantitativelyexamine the relaxation properties of the IC and CST. In a 32-echostudy of normal healthy brain structures, Whittall et al. [10] foundthat, compared to other cerebral white matter structures, the PLIChad a higher MWF than surrounding tissue and thus appeared brighton MWF maps. As well, Whittall et al. [10] noted that the PLIC hadthe longest IE geometricmean T2 (gmT2) compared to all other whitematter structures examined and the largest IE peak distributionwidth of all structures. The widening of the IE peak could be areflection of morphological differences [10,16]. Furthermore, the IEpeak in the PLIC and the splenium of corpus callosum (CC) werefound to often split into two peaks, while other white matterstructures rarely exhibited this behavior [10]. Using a 48-echo T2relaxation experiment to more accurately characterize all portions ofthe T2 distribution, Laule et al. [24] found that the PLIC had signalwith longer T2 times (signal arising in the range of 200 msbT2b800ms) in 10/15 healthy subjects. This long T2 component was not seenin any other healthy white matter structures examined but wasfound in pathological white matter in phenylketonuria and MSlesions. Finally, in a more recent study using a gradient-echosampling of a spin-echo sequence and monoexponential analysisfor T2, the CST itself was reported to have, on average, longer T2 andT1 times, when compared to regions directly anterior [9]. However,

Fig. 1. Axial (A) proton density-weighted (TE=10ms) and (B) heavily T2-weighted (TE=23corpus callosum (CC), (2)minor forceps, (3) anterior limb of the internal capsule (ALIC), (4)and (8) posterior to CST.

T2 measurements with limited echo time (TE) coverage [9] areknown to produce inaccurate results [26] and multiecho sequencesfor which the longest TE time is 320 ms [10] are suboptimal foraccurate detection of the longer T2 times of IE peak in the CST [27].

In certain cases of the motor neuron disease amyotrophic lateralsclerosis (ALS), the CST appears qualitatively more hyperintensethan in healthy CST [2] and this hyperintensity has been taken to be asign of pathology [28,29]. However, two studies which carried out T2measurements using a 2-echo sequence [30] and a 32-echo pulsesequence with a monoexponential fit [31] found no significantdifference in CST T2's between ALS subjects and normal controls. Thequalitative differences supposedly seen in CST and pathological CSTcould not be explained using these T2 techniques.

Given that the MR properties of the CST are still not understood,the goal of our study was to reexamine the T2 behavior of the CSTusing a pulse sequence especially designed to provide more accurateT2 distributions for the IE T2 peak [27]. Our T2 sequence made use of48 echoes, extending to a final echo at 1120 ms. We focused on thearea under the MW peak, location of the IE peak and shape of the T2distributions of white matter structures in the vicinity of the CSTwith the aim of understanding why the CST appears bright onheavily T2-weighted sequences and MWF maps.

2. Methods

2.1. Subject information

Fourteen normal healthy subjects were examined; mean age±S.D.=27±4 years (range=19–34); 6 males and 8 females. Theresearch protocol was granted ethical approval by the ClinicalResearch Ethics Board at our institution.

2.2. MR Studies

MR experiments were carried out on a 1.5-T MR scanner (EchoSpeed; GE Medical Systems, Milwaukee, WI, USA) operating atsoftware and hardware level version 5.7. After a localizer, protondensity and T2-weighted sequences (TR=2500 ms, TE=30/80 ms), a48-echo modified Carr-Purcell-Meiboom-Gill (CPMG) sequencewith variable repetition time (TR) [32] was collected. The multiechoT2 sequence excited a single transverse slice (5 mm thick; 128×128

0ms) images from one subject with representative white matter ROIs: (1) genu of thesplenium of the CC, (5)major forceps, (6) anterior to corticospinal tract (CST), (7) CST

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331B. Russell-Schulz et al. / Magnetic Resonance Imaging 31 (2013) 329–335

matrix, four averages) through the base of the genu and splenium ofthe CC. The echo spacing for the CPMG sequence was 10 ms for thefirst 32 echoes and 50 ms for the last 16 echoes [27]. To decrease theacquisition time, a variable TR was used; the TR was 3800 ms for the20 central lines of k-space and TR linearly decreased from 3800 to2120 ms for the k-space extremities. The effect of this variable TRstrategy on T2 distributions is negligible [32].

2.3. Data analysis

Using the 10 ms echo of the multiecho train, regions of interest(ROIs) were drawn in the genu and splenium of the CC and anteriorlimb of the IC (ALIC) and major and minor forceps. If the slicelocation and angulation was such that it was not possible to draw anROI around the entire genu, the right (four ROIs) or left side (oneROI) of the genu was used. Representative locations of the ROIs canbe seen in Fig. 1. The location of the CST was taken as the bright focalregionwithin the PLIC on a heavily T2-weighted image (TE=230ms)(Fig. 1B). As well, areas anterior and posterior to the CST were drawnbilaterally on the TE=230 ms image and were sufficiently separatedthat they would not overlap with CST. These areas anterior andposterior to the CST were also examined on the TE=10 ms image toensure that the ROIs did not overlap non-white matter areas. Anexample of the ROIs anterior and posterior to the CST can be seen inFig. 1B. T2 analysis was completed using AnalyzeNNLS [33] whichemploys regularized nonnegative least squares (NNLS) fitting [34] ofthe multiexponential decay curve [35]. For each structure, arepresentative T2 distribution was made by summing the T2distributions from all subjects. For display, the T2 distributionfor each white matter region was divided by its maximum peakheight. For each ROI, the MWF was defined as the area under theMW peak divided by the total area under the T2 distribution peaks,given in Eq. (1):

MWF ¼

XT2MWmax

T2MWmin

S T2ð Þ

XT2max

T2min

S T2ð Þð1Þ

where T2MWmin=5 ms and T2MWmax had two different values of 40and 25 ms, and T2min=5 ms and T2max=2000 ms.

10 125 400

0.5

1

Inte

nsity

10 125 400

0.5

1

T2 Tim

Inte

nsity

A

B

Fig. 2. Average T2 distributions of white matter structures with vertical lines drawn at 25peak is centered at higher T2 times and broadened in comparison to other white matter s

The position of the IE peak was examined using the gmT2, whichis the mean T2 on a logarithmic scale given by Eq. (2):

gmT2 ¼

XT2max

T2min

S T2ð ÞlogT2

XT2max

T2min

S T2ð Þð2Þ

for a given peak defined from T2min to T2max [33,35] where T2min wasthe designated boundary between MW and IE water (25 or 40 ms)and T2max=600 ms. The upper limit of 600 ms was chosen to avoidoverlap with cerebrospinal fluid (CSF), but to include IE signal fromthe CST in the 400 to 600 ms range.

A Student's t-test was used to test significance between the entiregenu (nine ROIs) and the right or left genu (five ROIs) for MWF andIE gmT2. Pb .05 was considered to be significant for each test; an f-testwas used to test for differences in variance.

The average MWF and percent change between the two upperlimits were determined for each structure. All errors are reported asstandard deviations unless otherwise stated. A Student's t-test wasused to test for significant differences between the MWF of the CSTand the areas anterior and posterior to the CST. The right and leftsides of bilateral structures were examined separately. P values wereBonferroni corrected; there were 15 t-tests each for the 25 and 40mslimit; therefore Pb .0033 was considered to be significant. Signifi-cance differences were also tested between the two MW/IEboundary limits of 25 and 40 ms for MWF and IE gmT2 for eachstructure and Bonferroni corrected; there were eight t-tests (for theeight structures) for each limit; therefore Pb .00625 was consideredto be significant.

3. Results

3.1. T2 Distributions

The average T2 distributions for each structure are shown inFig. 2. Fig. 2A demonstrates that the CST T2 distribution had adistinctly different shape from other white matter structures, eventhose within close anatomical proximity to the CST such as regionsimmediately anterior and posterior (Fig. 2B). The CST IE peak wasbroadened to encompass shorter and longer T2 times, causing it to bedistributed over a wider range of T2 times. The CST had an atypical T2distribution shape; the IE peak was split into two subsidiary peaks in

00 1000

00 1000e (ms)

CST

Splenium of CC

ALIC

Major Forceps

Genu of CC

Minor Forceps

CST

Anterior to CST

Posterior to CST

ms (solid black line) and 40 ms (dashed black line) to show MW/IE limits. The CST IEtructures.

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10 100 100040250

0.2

0.4

0.6

0.8

1

T2 Time (ms)

Inte

nsity

CST Split

CST No Split

Splenium of CC

Fig. 3. Average T2 distribution of CST demonstrating splitting (solid black line) and no splitting (dashed black line) of the IE peak compared to the splenium of the CC (solid grayline) with vertical lines drawn at 25 ms (solid black line) and 40 ms (dashed black line) to show MW/IE limits. The CST splits into two peaks in 50% of the ROIs.

332 B. Russell-Schulz et al. / Magnetic Resonance Imaging 31 (2013) 329–335

14 of 28 ROIs. The average T2 distributions of the CST split and no-split distributions are shown in Fig. 3 compared to a more typicalwhite matter T2 distribution from the splenium of the CC.

3.2. Myelin water fraction

A MWF map for one subject demonstrates the qualitativedifference between the myelin water T2 ranges of 5–40 and 5–25 ms (Fig. 4A and B, respectively). In Fig. 4A (5–40 ms), the CST isbright compared to other white matter areas, implying higher MWF.Fig. 4B (5–25ms) shows a dramatic reduction in CSTMWF but only aslight decrease in other white matter areas, suggesting the CST ispreferentially affected when the upper MWF T2 boundary is loweredfrom 40 to 25 ms.

The MWF values for the entire genu and for the right genu or theleft genu were not significantly different, except for the IE gmT2for the 25 ms limit, where the IE gmT2 for the entire genu was 6%lower (P=.035).

Fig. 4. MWF maps from one subject: (A) MWF T2b40 ms, (B) MWF T2b25 ms. The map o

A quantitative comparison between the MW windows 5–40 and5–25 ms for various white matter structures is given in Table 1.Comparing the CST to white matter regions in close anatomicalproximity found that, for the MW T2 upper boundary of 40 ms, theCST had a significantly higherMWF than areas anterior and posteriorto the CST (Pb .002). When the MW T2 upper boundary was set to 25ms, no significant differences were found between the MWF in theCST and the areas anterior and posterior to the CST (PN .08). All ROIsshowed a smaller MWF when the MW T2 upper limit was 25 ms,compared to 40 ms. The largest reduction in MWF was observed inthe CST, which decreased by 44.3%, more than twice than observedon average in all other white matter structures (mean: −15.6%;range: −0.007% to −29.4%).

3.3. Intra-/extracellular water

The IE gmT2 of the entire genu and that of the right or left genuwere not significantly different, except for the IE gmT2 for the 25 mslimit, where the IE gmT2 for the entire genu was 6% lower (P=.035).

n the left shows increased MWF in the CST in comparison to surrounding structures.

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Table 1Changes in MWF between the two different MWF T2 ranges

Structure MWF Range %Change

P value

T2=5–40 ms T2=5–25 ms

CST 0.19 (0.05) 0.11 (0.04) 44.3 1.87×10−6

Splenium of CC 0.14 (0.04) 0.11 (0.04) 26.3 .042Major forceps 0.11 (0.04) 0.086 (0.02) 22.3 .0021Anterior to CST 0.11 (0.03) 0.095 (0.03) 15.1 .010Posterior to CST 0.098 (0.02) 0.098 (0.02) 0.007 .33Minor forceps 0.074 (0.02) 0.069 (0.02) 7.4 .039ALIC 0.066 (0.02) 0.060 (0.03) 8.6 .12Genu of CC 0.085 (0.04) 0.060 (0.03) 29.4 .041

A Bonferroni-corrected t-test was used to test significance. Pb .00625 was consideredto be significant; significance is represented by italicized values.

333B. Russell-Schulz et al. / Magnetic Resonance Imaging 31 (2013) 329–335

A quantitative comparison of the IE gmT2 for IE ranges of 40–600and 25–600 ms is summarized in Table 2. With the exception of theCST, the majority of structures showed little signal in the 25–40-msrange and thus very little change in IE gmT2 when the IE water lowerlimit was reduced to 25 ms. The largest reduction in IE gmT2 wasobserved in the CST, which decreased by 10.7%, approximately sixtimes the reduction observed on average in all other white matterstructures (mean: −1.7%; range: −0.001% to −4.5%).

4. Discussion

Our study focused on the T2 distributions of white matterstructures in the vicinity of the corticospinal tract with the aim ofunderstanding why the CST appears bright on heavily T2-weightedsequences and MWF maps. The key finding of our study is that thelargest signal peak in the CST T2 distribution was substantiallybroadened compared to other white matter structures, which maybe the result of separation between intracellular and extracellularwater. We found the IE peak in the T2 distribution shifted to bothlonger T2 times, causing the CST to appear bright on T2-weightedimages, and to shorter T2 times, causing an increase in MWF that isnot related to increased myelin density.

4.1. Origin of the bright CST signal on T2-weighted images

Decreased proximity to nonaqueous protons, such as those onphospholipid headgroups, will cause less dephasing of the transversemagnetization and lead to an increase in T2 [36]. Using a 48-echosequence extending to 1120 ms allowed us to detect an increased IEgmT2 in the CST relative to other whitematter structures. At the levelof signal-to-noise ratio in this study, accurate characterization oflong T2 times up to 600 ms required the longest TE time to beapproximately twice the expected T2 times being examined. This in

Table 2Changes in IE gmT2 between the two different IE gmT2 T2 ranges

Structure IE gmT2 Range %Change

P value

T2=40–600 ms T2=25–600 ms

CST 105 (8) 94 (6) 10.7 5.40×10−6

Splenium of CC 85 (8) 82 (6) 4.5 .049Major forceps 84 (4) 82 (3) 2.7 .0028Anterior to CST 81 (4) 80 (3) 1.9 .015Posterior to CST 80 (3) 80 (3) 0.0010 .33Minor forceps 75 (3) 74 (2) 0.42 .042ALIC 72 (4) 72 (3) 0.60 .14Genu of CC 72 (3) 71 (3) 2.0 .029

A Bonferroni-corrected t-test was used to test significance. Pb .00625 was consideredto be significant; significance is represented by italicized values.

turn also provides for more accurate measurement of the short T2components. In particular, the CST had an approximately 30% longerIE gmT2 (40 msbT2b600 ms) than white matter regions anterior andposterior, causing the CST to appear bright on T2-weighted images.Our findings are in agreement with the previous literature [2,8,9]and support the work by Laule et al. [24] which reported bright areasin the IC of healthy controls on some long-T2 maps (fraction of T2signal from 200 to 800 ms).

4.2. Origin of the bright CST signal on myelin water images

Using the conventional myelinwater upper T2 boundary of 40ms,we observed the CST to have the highest MWF of all white matterstructures examined. In particular, the CST had an approximately83% higher MWF (5 msbT2b40 ms) than white matter regionsanterior and posterior. Our observation is in agreement withprevious work by Whittall et al. [10], but in contradiction to earlierhistology studies from Yagishita et al. [2] who reported a loweraxonal density in the CST, thereby implying the CST also had lowermyelin density compared to surrounding areas. However, Figs. 2 and3 demonstrate that, for the CST, part of the IE peak extends into theregion designated for MW, consequently leading to an artificialincrease in MWF. Table 1 shows the result of decreasing the myelinwater upper T2 boundary to 25 ms and clearly highlights that a non-negligible amount of signal in the CST arose fromwater with T2 timesin the range of 25–40 ms. While the MWF in all white matter wasreduced at the 25-ms limit compared to the 40-ms limit, the mostdramatic effect was observed in the CST, which showed a decreasemore than twofold greater than any other region. This suggests thatit was not increased myelin density that caused the bright focalregions of the CST on MWF images but rather the extension of theCST IE peak into the MW T2 region.

4.3. CST peak splitting: increased extracellular water ordecreased exchange?

The CST had an atypical T2 distribution shape compared to otherwhite matter structures; the IE peak often split into two subsidiarypeaks. Depending upon the signal-to-noise ratio of the T2 decaycurve, NNLS analysis may produce two separated peaks or as a singlebroad T2 peak. The frequent appearance of split peaks in the CSTmost likely reflects the presence of two distinguishable waterenvironments, one with T2 of approximately 40 ms and the otherwith T2 of approximately 120 ms. The most likely candidates forthese two environments are intracellular water and extracellularwater. Nerve studies involving garfish and optic nerve [37] andcrayfish abdominal nerve [14] and rat peripheral nervous system(PNS) [19] have found T2 relaxation involving three componentsattributing them to myelin water, axoplasm (intracellular) waterand interaxonal/extra-axonal (extracellular) water. Studies in frogsciatic nerve have also demonstrated three components [38–42]including a longer component, which has been assigned to beextracellular water based on a diffusion study [41]; an intermediateT2 component, which has been attributed to interaxonal water basedupon a contrast agent study [42]; and myelin water. Two possibleexplanations for the anomalous behavior of the CST IE T2 peak in thisstudy are increased extracellular water or decreased exchange.

We believe that themost likely explanation for the unique shapeof the CST T2 distribution is increased CST extracellular water incomparison to the other structures. Fig. 2B demonstrates that theareas immediately anterior and posterior to the CST exhibited muchnarrower IE peaks at shorter gmT2 times when compared to theCST. From histology studies, the CST is known to have largerextracellular spaces compared to areas directly adjacent [2]. In thepresence of large extracellular water spaces, water protons will

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334 B. Russell-Schulz et al. / Magnetic Resonance Imaging 31 (2013) 329–335

have limited interactions with nonaqueous protons, such asmembrane surfaces, and should have longer T2 times. These uniqueCST T2 distribution characteristics appear to also be responsible forthe appearance of the CST on MWF maps; separation of the peakscould push the intracellular water to shorter T2 times therebycausing the intracellular water peak to overlap with the T2 timesfrom the MW pool.

Alternatively, the separation of the two water environments inthe CST could arise from a decrease in exchange betweenintracellular and extracellular water due to the presence of thickermyelin sheaths in the CST compared to adjacent white matter. Otherstructures having smaller axons compared to the CST, such as thesplenium and genu of the CC (axonal diameter of 4–5 and 3–4 μm,respectively) [43], may experience greater exchange between theintracellular and extracellular water pools [44,45]. Increasedexchange should cause not only a decreased gmT2 but also anarrowing of the IE peak [46,47]. This could explain why the splittingof the IE peak observed in the CST is not often seen in other whitematter structures, such as regions immediately anterior andposterior to the CST, which are known to have smaller, closelypacked axons [2].

Whether water exchange between the intracellular and extra-cellular regions occurs rapidly on the timescale of the T2 experiment,and therefore has a large influence on the T2 measurements, is still inquestion. Two bovine studies found that exchange was too slow toaffect the measurements dramatically on the timescale of T2experiments [47,48] and a recent in vivo human brain study foundthat exchange had little effect on MWFs in several brain struc-tures [49]. However, other studies in rat spine determined thatexchange did affect the T2 values appreciably [44,45] and determin-ing the role of exchange on MWF measurements is still a very activearea of research.

5. Conclusion

By using a T2 relaxation measurement designed to better explorethe shape of the T2 distribution at times in the vicinity of 100ms, thisstudy found that the T2 distribution from the corticospinal tract hadan IE peak which was not only shifted to longer times but alsoexhibited a second IE peak with a shorter T2 time. The shift of the IEpeak to longer T2 times is responsible for the bright focal regionsobserved on heavily T2-weighted images of the CST. The additional IEcomponent with shorter T2 times caused bright regions of MWFmaps due to the extension of the IE peak into the myelin waterwindow. It is postulated that the mechanism for this broadening ofthe IE peak is due to the presence of significantly more extracellularwater in the corticospinal tract. Magnetization exchange on thetimescale of the experiment may also play a role in creating the CST'sanomalous T2 distribution. The corticospinal tract is a uniquestructure that has unique MR characteristics; hence special consid-erations are required when interpreting MR results from it.

Acknowledgments

We wish to thank the volunteers and MRI technologists atUBC Hospital.

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