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Spatial Profiling of the Corticospinal
Tract in Amyotrophic Lateral
Sclerosis Using Diffusion Tensor
Imaging
John C.T. Wong, BSc
Luis Concha, MD
Christian Beaulieu, PhD
Wendy Johnston, MD
Peter S. Allen, PhD
Sanjay Kalra, MD
ABSTRACT
Background and Purpose: Diffusion tensor imaging (DTI) was
used as a noninvasive method to evaluate the anatomy of the
corticospinal tract (CST) and the pattern of its degeneration
in amyotrophic lateral sclerosis (ALS). Methods. Fourteen pa-
tients with ALS and 15 healthy controls underwent DTI. Pa-
rameters reflecting coherence of diffusion (fractional anisotropy,
FA), bulk diffusion (apparent diffusion coefficient, ADC), and di-
rectionality of diffusion (eigenvalues) parallel to (λ) or perpen-
dicular to (λ⊥) fiber tracts were measured along the intracra-
nial course of the CST. Results: FA and λincreased, and ADC
and λ⊥decreased progressively from the corona radiata to the
cerebral peduncle in all subjects. The most abnormal finding
in patients with ALS was reduced FA in the cerebral pedun-
cle contralateral to the side of the body with the most severe
upper motor neuron signs. λwas increased in the corona ra-
diata. Internal capsule FA correlated positively with symptom
duration, and cerebral peduncle ADC positively with the Ash-
worth spasticity score. Conclusion: There is a spatial depen-
dency of diffusion parameters along the CST in healthy indi-
viduals. Evidence of intracranial CST degeneration in ALS was
found with distinct diffusion changes in the rostral and caudal
regions.
Received August 18, 2006, and in revised form November
13, 2006. Accepted for publication November 17, 2006.
From the Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Alberta, Canada (JCTW); Divi-
sion of Neurology, Department of Medicine, University
of Alberta, Edmonton, Alberta, Canada (WJ, SK); and
Department of Biomedical Engineering, University of Al-
berta, Edmonton, Alberta, Canada (LC, CB, PSA).
Address correspondence to Sanjay Kalra, MD, 2E3.18
Walter C Mackenzie Health Sciences Centre, 8440-112
Street, Edmonton, Alberta, T6G 2B7, Canada. E-mail:
sanjay.kalra@ualberta.ca.
Key words: Amyotrophic lateral sclerosis, diffusion tensor
imaging.
Wong JCT, Concha L, Beaulieu C, Johnston W, Allen PS,
Kalra S.
Spatial profiling of the corticospinal tract in amyotrophic lateral
sclerosis using diffusion tensor imaging
J Neuroimaging 2007;17:234-240.
DOI: 10.1111/j.1552-6569.2007.00100.x
Introduction
The hallmark of amyotrophic lateral sclerosis (ALS),
a progressive neurodegenerative condition of unknown
etiology, is the combination of physical exam findings
reflecting lower motor neuron (LMN) and upper mo-
tor neuron (UMN) degeneration. LMN dysfunction can
be evaluated by electrodiagnostic techniques, including
electromyography and motor unit number estimation.
However, the extent and nature of UMN involvement
is difficult to characterize clinically due to limitations of
the neurological examination or the presence of severe si-
multaneous LMN signs. Indeed, pathological evidence of
corticospinal tract (CST) degeneration has been demon-
strated in patients who are lacking UMN signs.1A sensi-
tive marker of UMN damage is required to gain further
insight into the pathogenesis of the disease, to allow for
improved disease detection and monitoring, and to aid
in the evaluation of therapeutic agents. Magnetic reso-
nance imaging (MRI) unfortunately affords poor sensi-
tivity and specificity for degeneration2and thus remains
a tool to rule out other disorders. Studies continue to
explore the potential of other promising techniques to
provide a biomarker of cerebral degeneration. Abnor-
malities in cerebral neurochemistry and electrophysio-
logical properties have consistently been demonstrated
using magnetic resonance spectroscopy and transcranial
magnetic stimulation, respectively.3-5
234 Copyright ◦
C2007 by the American Society of Neuroimaging
Diffusion tensor imaging (DTI) is an MRI technique
that has emerged as a tool to visualize the organization
and integrity of white matter bundles. This is made possi-
ble by collecting images with diffusion sensitizing gradi-
ents such that the diffusion properties of water molecules
can be characterized in vivo. The pattern of diffusion is
dependent on water’s anatomical localization. In nerve
fibers, the net motion of water is greater parallel to the lon-
gitudinal axis of the axons than perpendicular to them.6
This preferential directionality of diffusion is attributed
to physical restrictions imposed by axonal membranes
and their myelin sheaths.7The degree of this directional-
ity in three spatial dimensions can be quantified in each
voxel by the index of fractional anisotropy (FA). The min-
imum FA of zero corresponds to no directional depen-
dence of diffusion (ie, isotropic diffusion, water displace-
ment is random in all directions), whereas the maximum
FA of one indicates diffusion is anisotropic (ie, diffusion is
highly biased in one direction compared to the other two).
The trace apparent diffusion coefficient (ADC) provides
no directional information on water’s diffusion, rather is
simply a measure of the magnitude of bulk diffusion. The
principal eigenvalues 1,2, and 3reflect the magnitude
of diffusion (directional apparent diffusion coefficient)
along the fiber tracts (1) or perpendicular to them (2,
3).
Applying region of interest (ROI) analysis, Ellis et al
first demonstrated a significant reduction of FA and an
increase in mean diffusivity in the internal capsule of
patients with ALS.8Subsequent studies have expanded
to study FA and ADC in the CST at the motor cor-
tex, corona radiata, cerebral peduncles, pons, and pyra-
mids, sometimes with inconsistent results. Discrepancies
reported between studies may in part be attributed to the
high variability of CNS architecture along the CST9,10
and the variable selection between studies of the regions
studied within the anatomical structure of interest. To cir-
cumvent this, groups have encompassed the CST with
ROIs drawn on contiguous axial slices; in effect, ana-
lyzing the CST in a three-dimensional manner.10,11 A
downfall of this technique is that depending on slice thick-
ness and the extent of the CST one wishes to study, this
method can be laborious, time consuming, and prone to
user-dependent errors.
The objective of this study was to evaluate the integrity
of the CST in ALS using a reproducible ROI-based DTI
approach. We used an alternative method of studying the
CST in three dimensions by encompassing it in a coronal
plane. This would permit capturing a large portion of the
tract in a more convenient manner than drawing ROIs on
multiple axial slices. In contrast to most previous studies,
we also measured eigenvalues to better understand diffu-
sion characteristics. Our hypothesis was that patients with
ALS would show water diffusion abnormalities along the
CST, providing an indirect marker of degeneration.
Methods
Subjects and Clinical Evaluation
Patients (n=14) were recruited from the ALS Clinic at
the University of Alberta and were required to have less
than 5 years of symptoms and meet El Escorial criteria
for “probable” or “definite” ALS.12 According to these
criteria, all subjects would have examination findings
reflecting both LMN and UMN dysfunction. Healthy
age-matched controls (n=15) were free of neurological
or psychiatric disease. All subjects gave informed con-
sent and the study was approved by the Human Research
Ethics Board. Subject details are given in Table 1.
Patients were administered the ALS Functional Rating
Scale (ALSFRS) to assess general disability. Clinical signs
of UMN involvement were quantified on each side with
the modified Ashworth spasticity scale for the upper and
lower limb, and finger and foot tapping speeds (number
of taps in 10 seconds averaged over two attempts).13
Image Acquisition
MR imaging was performed on a Siemens Sonata 1.5
Tesla scanner. T2-weighted images 5-mm thick were
acquired in sagittal (26 contiguous slices, repetition time
[TR] 6860 msec, echo time [TE] 112 msec, matrix 256
×216, field of view [FOV] 260 ×220 mm), axial (25
contiguous slices, TR 6950 msec, TE 113 msec) and coro-
nal (25 contiguous slices, TR 7480 msec, TE 113 msec)
planes. Diffusion tensor images were acquired using spin-
echo echo planar imaging in coronal orientation (20 con-
tiguous slices, 5-mm thick, TR 3200 msec, TE 88 msec,
matrix 128 ×128 zero-filled to 256 ×256, 75% phase
Table 1. Clinical Characteristics of Patients and Healthy Con-
trol Subjects
ALS Control
N1415
M:F 5:9 8:7
Age (years) 53 ±14 54 ±12
Symptom duration 22 ±12
(months) (18, 10-43)
Limb:Bulbar Onset 12:2
ALS functional rating 30 ±6
scale (range 0-40) (31, 15-37)
Values are mean ±standard deviation (median, range).
Wong et al: Spatial Profiling Using DTI in ALS 235
partial Fourier, FOV 220 ×220 mm, six diffusion gra-
dient directions, b=1000 sec/mm2, eight averages, scan
time 3:04 minutes). Coronal images were angulated to
lie parallel to the CST as identified on sagittal images.
Angulation was refined by intersection of a slice through
the cerebral peduncles and the hyperintense signal of the
CST in the posterior limb of the internal capsule as visu-
alized on axial images.
Diffusion Tensor Image Data Processing
DTI images were processed on a PC running DTIstu-
dio (Johns Hopkins University, Baltimore, MD). Quan-
titative diffusion parameter maps were created, includ-
ing fractional anisotropy (FA), mean apparent diffusion
coefficient (ADC), parallel diffusivity (=1), and per-
pendicular diffusivity (⊥=[2+3]/2), as well as a color
map encoding the principal diffusivity of the tracts (ie, the
eigenvector associated with ).
Diffusion Tensor Imaging Analysis
The coronal slice containing the greatest volume of the
CST as viewed on both the color-coded and FA maps
was selected for ROI placement. The right and left CST
of each subject were individually traced by a single oper-
ator (JCTW) blinded to diagnosis. The rostral and caudal
borders of this ROI were set at the superior margin of
the superior longitudinal fascicle and at the transition of
the cerebral peduncles to the pons, respectively. The lat-
eral borders were defined by the extent of the CST itself.
Each CST was further segmented into three subregions:
corona radiata (rostral margin to inferior border of lateral
ventricle), posterior limb of the internal capsule (inferior
border of lateral ventricle to superior edge of red nucleus),
and cerebral peduncles (superior edge of red nucleus to
caudal margin) (Fig 1).
Two different analyses were performed. First, FA,
ADC, , and ⊥were plotted at 1-mm intervals along
the course of the entire CST within the ROI. To do this,
the distance between the rostral and caudal borders of the
ROI was normalized amongst all subjects. The mean and
standard deviation of a diffusion parameter was then cal-
culated at discrete contiguous cross sections of the CST
along this distance. Second, mean FA, ADC, , and ⊥
were calculated for each of the three anatomical subre-
gions and for the entire CST.
Statistical Analysis
Diffusion findings were averaged between left and right
hemispheres in controls. This was compared to the CST
of ALS patients ipsilateral and contralateral to the most
severe UMN findings on examination. To determine if a
diffusion parameter was different between these groups,
Fig 1. A region of interest (ROI) encompasses the right
CST from the corona radiata to the cerebral peduncle on a
coronal DTI-derived color-coded map. DTI indices were ex-
amined along the rostro-caudal course of the CST at 1-mm
intervals (Fig 2) and within the labeled anatomical subregions.
The colors red, green, and blue represent fibers running in
left–right, anterior–posterior, and superior–inferior directions,
respectively.
a multivariate analysis of variance with age as a covariate
(MANCOVA) was used for each diffusion parameter with
dependent variables representing each region (corona
radiata, posterior limb of internal capsule, cerebral pe-
duncle, and entire CST). Significant results indicating an
abnormal parameter within a region were followed by
ANCOVA and post-hoc analyses with the Tukey test to
ascertain group effect. Pearson (r) and Spearman rank (R)
correlation coefficients were computed to evaluate rela-
tionships with clinical measures. Correlations with age,
symptom duration, and ALSFRS were performed with a
diffusion parameter averaged between sides, since these
clinical measures do not have lateral bias. Unilateral cor-
relations were done with diffusion parameters and the
contralateral Ashworth score and tapping speeds. Statis-
tical significance was accepted for a two-tailed P<.05.
Results
Patients and healthy controls did not differ with respect
to age or sex (Table 1). The overall pattern of variation
in DTI parameters along the rostro-caudal extent of the
CST from the corona radiata to the cerebral peduncles
was similar between patients and controls (Fig 2). Sig-
nificant deviations were, however, present at specific re-
gions within the CST (Table 2).
236 Journal of Neuroimaging Vol 17 No 3 July 2007
Fig 2. Spatial variation of diffusion indices along the corticospinal tract. The mean and one standard deviation is plotted along
the course of the corticospinal tract from the corona radiata to the cerebral peduncles (see Fig 1). “ALS, Most affected”and
“ALS, Least affected”refer to the CST contralateral and ipsilateral to the side with the most severe UMN signs, respectively.
Fractional Anisotropy
FA increased progressively from the corona radiata to
the cerebral peduncles in patients and controls. It was
increased in ALS for most of the extent of the corona
radiata on the least-affected side (Fig 2). The plots cross
over rostral to the mid-PLIC with FA in patients lower
in the remaining extent of the CST to the cerebral pe-
duncles. Quantitative regional analysis (Table 2) revealed
significantly reduced FA at the cerebral peduncle con-
tralateral to the most severe UMN signs and a statistical
trend to a reduction ipsilateral to the most severe UMN
signs.
Apparent Diffusion Coefficient
In both patients and controls, ADC decreased from the
corona radiata to the midcerebral peduncles before ex-
hibiting a small rise at the caudal cerebral peduncles. El-
evations of ADC at the corona radiata and PLIC of the
patients did not reach statistical significance (Table 2).
Parallel and Perpendicular Diffusivity
Parallel diffusivity () for both patient and control groups
exhibited a continuous rise from the corona radiata to the
cerebral peduncles. It was significantly increased in the
corona radiata of patients (Table 2). Perpendicular diffu-
sivity (⊥) decreased from the rostral to caudal region of
the CST in patients and controls. It appeared to be ele-
vated on the most-affected side in ALS patients; however,
this failed to reach statistical significance.
Clinical Correlations
Of the diffusion parameters averaged over the left and
right side, FA in the internal capsule correlated with
symptom duration (r=0.56, P=.036). Diffusion pa-
rameters did not correlate with age or ALSFRS.
Wong et al: Spatial Profiling Using DTI in ALS 237
Table 2. Quantitative DTI Analysis by Regions of the Corticospinal Tract in Healthy Controls (n=15) and ALS Patients (n=14)
ALS (n=14)
Control (n=15) Contralateral to Most Severe UMN Signs Ipsilateral to Most Severe UMN Signs
Region FA ADC ⊥FA ADC ⊥FA ADC ⊥
Corona 0.46 ±0.04 0.78 ±0.04 1.20 ±0.07 0.57 ±0.04 0.47 ±0.06 0.81 ±0.05 1.27 ±0.06∗0.59 ±0.06 0.48 ±0.05 0.81 ±0.04 1.27 ±0.05∗0.58 ±0.06
radiata
Internal 0.65 ±0.03 0.75 ±0.04 1.40 ±0.07 0.42 ±0.04 0.64 ±0.04 0.77 ±0.05 1.42 ±0.06 0.44 ±0.06 0.66 ±0.04 0.75 ±0.04 1.42 ±0.04 0.42 ±0.05
capsule
Cerebral 0.75 ±0.03 0.74 ±0.03 1.55 ±0.08 0.33 ±0.03 0.72 ±0.04∗0.74 ±0.05 1.51 ±0.09 0.36 ±0.05 0.72 ±0.03 0.75 ±0.04 1.51 ±0.07 0.36 ±0.05
peduncle
Entire CST 0.61 ±0.03 0.76 ±0.04 1.38 ±0.06 0.44 ±0.04 0.59 ±0.04 0.78 ±0.04 1.40 ±0.06 0.46 ±0.05 0.60 ±0.04 0.77 ±0.04 1.40 ±0.04 0.45 ±0.05
FA: fractional anisotropy; ADC: apparent diffusion coefficient (×10−3mm2/sec); : parallel diffusivity (×10−3mm2/sec); ⊥=perpendicular diffusivity (×10−3mm2/sec).
∗indicates values different from controls with P<.05. There was a statistical trend for reduced FA in the cerebral peduncle in ALS patients ipsilateral to the most severe UMN
signs (P<.10) compared to controls. For statistical analysis, each diffusion parameter was tested using multivariate analysis of covariance with Tukey’s posthoc pairwise analysis
when required.
For unilateral analyses, the Ashworth score correlated
with the ADC of the contralateral cerebral peduncle (R=
0.46, P=.009) and whole CST (R=0.36, P=.039). A
correlation of the Ashworth score with ⊥approached
statistical significance in the internal capsule (R=0.41,
P=.065) and the cerebral peduncle (R=0.48, P=.053).
Correlations were not detected with unilateral FA or ,
nor with tapping speed.
Discussion
The observed trends of the various diffusion parameters
along the length of the corticospinal tract in all subjects
(controls and patients) can be explained with present
knowledge of the organization of the CST. Starting ros-
trally, the corona radiata is a region of converging fibers
with the corticofugally oriented fibers of the CST inter-
mingled with U-fibers and fibers of association tracts that
are directed in oblique planes to it in both left–right and
anterior–posterior directions. Thus, a net incoherence of
directionality of diffusion is reflected by a low FA accom-
panied by similar and ⊥. Descending caudally, the
CST becomes progressively more densely packed and
homogenous, free of alternately arranged bundles. This
is reflected by increasing FA and , and declining ⊥and
ADC. The increase of ADC in the cerebral peduncle is
perhaps due to inclusion of CST fibers that are beginning
to disperse as they enter the pons.
In the ALS patients, the most abnormal finding was
reduced FA at the cerebral peduncles, indicative of CST
degeneration at this level. The 8% increase in ⊥, al-
though not statistically significant, is likely responsible
for the reduced diffusion anisotropy given that was in-
tact. This pattern of reduced FA and increased ⊥is in
agreement with prior studies of the cerebral peduncle14
and internal capsule.15 Several histopathological findings
in ALS, including neuronal degeneration, inclusion bod-
ies, cytoskeletal structural abnormalities, and astrocytic
gliosis, may each serve as candidates responsible for such
observed changes in diffusion parameters. However, the
main determinants of anisotropic diffusion are the tight
packing of axons and axonal membranes,7structures
that are notably deranged in ALS. Axonal degeneration
would increase permeability transversely across the CST,
permitting water diffusion with greater ease and increas-
ing ⊥. Myelin has a modulating effect on anisotropy16,17
and thus demyelination, which is present to a variable ex-
tent in ALS,18 could contribute to some of the observed
loss of anisotropy.
The correlation of FA in the posterior limb of the in-
ternal capsule with symptom duration further supports
the potential of these indices as biomarkers, perhaps of
238 Journal of Neuroimaging Vol 17 No 3 July 2007
different pathologic processes. The lack of a correlation
with the ALSFRS is not unexpected given that many
of the functions surveyed with this disability scale are
significantly dependent on strength,19 which in turn is
dependent heavily on LMN integrity.13 A positive cor-
relation between FA and symptom duration would not
seem intuitive; however, this may be reflective of subjects
with more aggressive disease who seek medical attention
sooner because of rapidly progressing symptoms. Such
patients would have advanced disease with low FA and
shorter symptom duration. Indeed, shorter symptom du-
ration is predictive of reduced survival.20
Inspection of the high resolution plots (Fig 2) would
suggest that ADC may be abnormally increased in ALS,
as others have inconsistently found.8,10,11,21 ,22 That this
may have pathological relevance is supported by a cor-
relation of ADC at the cerebral peduncle with the Ash-
worth spasticity score. Parallel diffusivity and FA were
increased in the corona radiata. At areas where coher-
ence of fiber orientation is high, such as the cerebral
peduncles, alterations in diffusion indices are attributed
to changes in tissue structure. In contrast, at regions
where intersecting fibers coexist, such as the corona ra-
diata, structural and “architectural”features have com-
peting influences.9Subsequent to CST degeneration at
the corona radiata in ALS, which is supported by abnor-
mal axonal staining present subjacent to the motor cor-
tex23 and by myelin pallor that may be detected quite
rostrally in the CST,18 the superior longitudinal fasci-
culus and the corpus callosum would become the rem-
nant fiber tracts. This would result in greater congru-
ence in fiber orientation, which would be reflected by
an increase in FA. Although our study failed to show the
FA change as statistically significant, this may in part be
due to the low anisotropy of the subcortical white mat-
ter such that FA changes are less noticeable or detectable
than, for example, at the cerebral peduncles. This would
also suggest that at regions where multiple fiber tracts
coexist, the sensitivity of FA as a surrogate marker is
less compared to a region like the cerebral peduncles.
The distal DTI changes are in keeping with the histo-
logical observations that support the presence of a “dy-
ing back”axonopathy,24 wherein the usual DTI findings
due to chronic degeneration are decreased FA and
increased ⊥.9,25,26
The magnitude of diffusion abnormalities was rela-
tively small in these patients. This may reflect the clin-
ical and pathological heterogeneity of ALS patients as a
group; however, it questions the ability of DTI to function
as a diagnostic tool.
In contrast to DTI studies of ALS to date, we chose
to encompass the entire segment of the CST from the
corona radiata to the cerebral peduncles as one ROI po-
sitioned in coronal orientation, thus allowing analysis of
DTI parameters with high rostro-caudal spatial resolu-
tion using a scan with short acquisition time. This method
is practically advantageous compared to positioning and
analyzing multiple axial or coronal ROIs, which can be
time-consuming during both acquisition and analysis.
Studying the entire CST would also conceptually address
the discrepancies between studies that are at least in part
due to the use of different landmarks to define the extent
of small anatomical regions of interest. Also different from
most previous studies was our analysis of the left and right
CSTs separately, as opposed to averaging them to yield
single value for each individual. This would be a more
sensitive method since patients can present with asym-
metric findings. These factors, in addition to differences
in patient characteristics, may account for discrepancies
in results at the various levels of the CST studied among
various groups.8,10,11,21 ,22
Our study has limitations in common with all ROI-
based techniques, namely the potential of user-dependent
errors and the inherent challenge of complete inclusion
of the anatomical structure of interest with exclusion of
extraneous fibers. We addressed the latter by careful an-
gulation of the coronal acquisition and selection of the
coronal image where the majority of the CST existed, as
reflected by the strongest intensity (and homogeneity) on
color-coded and FA maps. Use of a single coronal slice
limited our study to the CST between the corona radiata
and the cerebral peduncles; rostral to this it is dispersed
widely and caudal to the peduncles it deflects posteriorly
in the pons. ROI analysis on multiple coronal or axial im-
ages would be required to study these regions. Relatively
thick (5 mm) images were acquired to minimize MR ac-
quisition time and be inclusive of as much of the CST
within a single image plane. This could have resulted in
partial volume averaging of non-CST tissue. The use of
tractography to segment out the CST specifically may be
beneficial in this regard,27 though it too is associated with
technical challenges.
In summary, intracranial CST degeneration was
demonstrated noninvasively using DTI.
Although the small magnitude of change in ALS pa-
tients questions the ability of DTI to be a diagnostic tool, it
has significant potential to shed light on pathophysiology.
Further work is required to determine the reproducibil-
ity of DTI measures and to what extent biological vs.
methodological issues are responsible for the variability
in results between DTI studies to date. A better under-
standing of the in vivo pathogenesis of ALS may be possi-
ble by correlative studies with complementary imaging23
and neurophysiological8,28 modalities.
Wong et al: Spatial Profiling Using DTI in ALS 239
Funding: This study was supported by the University Hospital Foun-
dation and the MSI Foundation of Alberta. Dr. Beaulieu is supported
by a salary award from the Alberta Heritage Foundation for Medical
Research and L. Concha by PROMEP. MRI infrastructure provided by
the Canada Foundation for Innovation, Alberta Science and Research
Authority, and the University Hospital Foundation. Fiber tracking soft-
ware kindly provided by Drs. Hangyi Jiang and Susumu Mori (National
Institutes of Health grant P41 RR15241–01).
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