diffusion tensor mri of early upper motor neuron involvement in amyotrophic lateral sclerosis

Diffusion tensor MRI of early upper motor neuroninvolvement in amyotrophic lateral sclerosis

Miriam Sach, Gerhard Winkler, Volkmar Glauche, Joachim Liepert, Bernhard Heimbach,Martin A. Koch, Christian BuÈchel and Cornelius Weiller

Department of Neurology, Neuroimage Nord, University

Hospital Hamburg, Eppendorf, Germany

Correspondence to: Miriam Sach, MD, Klinik und

Poliklinik fuÈr Neurologie, UKE, Martinistrasse 52,

20246 Hamburg, Germany

E-mail: [email protected]

SummaryAmyotrophic lateral sclerosis (ALS) is a progressiveneurodegenerative system disorder affecting both upperand lower motor neurons. Despite supportive electro-physiological investigations, the involvement of theupper motor neuron is often dif®cult to assess at anearly stage of disease. Diffusion tensor MRI provides anestimate of the orientation of ®bre bundles in whitematter on the basis of the diffusion characteristics ofwater. Diffusivity is generally higher in directions along®bre tracts than perpendicular to them. This degree ofdirectionality of diffusion can be measured as fractionalanisotropy. Changes in tissue structure due to degener-ation of the corticospinal ®bres can lead to a modi®ca-tion of the degree of directionality which can bedetected by diffusion tensor MRI. We investigated 15patients with ALS, six of whom had no clinical signs ofupper motor neuron involvement at the time of MRIinvestigation, but developed pyramidal tract symptoms

later in the course of their disease. These patients met

the El Escorial criteria as their disease progressed. We

found a decrease in fractional anisotropy in the corti-

cospinal tract, corpus callosum and thalamus in all 15

ALS patients, including the patients without clinical

signs of upper motor neuron lesion, compared with

healthy controls. Regression analysis showed a negative

correlation between fractional anisotropy and central

motor conduction time obtained by transcranial mag-

netic stimulation, allowing spatial differentiation

between the degenerated corticospinal tract ®bres that

supply the upper and lower extremities. Thus, diffusion

tensor MRI can be used to assess upper motor neuron

involvement in ALS patients before clinical symptoms

of corticospinal tract lesion become apparent, and it

may therefore contribute to earlier diagnosis of motor

neuron disease.

Keywords: diffusion tensor MRI; amyotrophic lateral sclerosis; upper motor neuron; corticospinal tract; transcranial

magnetic stimulation

Abbreviations: ALS = amyotrophic lateral sclerosis; CMCT = central motor conduction time; DTI = diffusion tensor

imaging; EPI = echoplanar imaging; LMN = lower motor neuron; MEP = motor evoked potential; MNI = Montreal

Neurological Institute; ROI = region of interest; STEAM = stimulated echo acquisition mode; TMS = transcranial

magnetic stimulation; SNR = signal-to-noise ratio; UMN = upper motor neuron

Received March 22, 2003. Revised August 18, 2003. Accepted September 23, 2003. Advanced Access publication November 7, 2003

IntroductionThe diagnosis of amyotrophic lateral sclerosis (ALS), a

progressive neurodegenerative system disorder affecting both

upper and lower motor neurons (LMN), is mainly based on

clinical criteria with possible symptoms such as progressive

weakness of voluntary muscles, muscular atrophy, spasticity,

tendon jerks and Babinski signs. Upper motor neuron (UMN)

pathology often starts in the primary motor and premotor

cortex, with secondary degeneration of motor ®bres and

gliosis along the corticospinal tract (Davidoff, 1990). The

lesions of the LMN include the brainstem and spinal cord.

Diagnosis at an early stage of the disease is desirable because

of the poor prognosis of ALS, with an average life expectancy

of 25 months after onset of symptoms, and the necessity of

excluding other curable diseases. It is often dif®cult to decide

whether the UMN is involved. This is because of only

discrete UMN signs in clinical investigation or severe

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DOI: 10.1093/brain/awh041 Brain (2004), 127, 340±350

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simultaneous lesions of the LMN. In contrast, LMN

involvement can be detected subclinically using supportive

techniques, such as needle electromyography. Both neuro-

physiological and neuroimaging techniques have been used to

evaluate UMN pathology, but there are currently no sensitive

techniques available in clinical practice for objectively

assessing UMN damage at an early stage of the disease.

Transcranial magnetic stimulation (TMS) measurements

may contribute to the diagnosis of ALS by revealing a

clinically undetectable UMN dysfunction. However, the

diagnostic sensitivity in unravelling UMN lesions, in par-

ticular those of limb muscles compared with cranial muscles,

is rather low (Urban et al., 2001), and published results are

inconsistent (Eisen et al., 1990; Berardelli et al., 1991; Claus

et al., 1995). The triple stimulation technique can increase the

sensitivity to UMN lesions but it is not yet being used

routinely as it is dif®cult to apply (Buhler et al., 2001).

In neuroimaging, MRI-FLAIR (¯uid-attenuated inversion

recovery) images and T2- and proton density-weighted MRIs

may show increased signal intensity in the white matter

(Hecht et al., 2001). However, these ®ndings are rather

unspeci®c and are not yet quanti®able (Karitzky and Ludolph,

2001). Proton magnetic resonance spectroscopy is useful for

assessing UMN involvement in ALS (Ellis et al., 2001), but it

is not sensitive enough to reveal early changes in the

subcortical white matter in the motor region. This is due to

considerable overlap between the ranges of metabolic peak

area ratios from patients in an early stage of the disease and

those from healthy control subjects (Ellis et al., 1998).

Functional MRI and magnetization transfer are also promis-

ing methods. Further investigations are needed to elucidate

their signi®cance as diagnostic and prognostic tools in

patients with ALS (Tanabe et al., 1998; Brooks et al., 2000a).

Diffusion tensor imaging (DTI) is a relatively new method

in structural neuroimaging. It allows the estimation of the

orientation of ®bre bundles in white matter on the basis of the

diffusion characteristics of water. Diffusivity is generally

higher in directions along ®bre tracts than perpendicular to

them (Chenevert et al., 1990). This can be described

mathematically by a tensor, which is characterized by its

three eigenvectors and the corresponding eigenvalues. The

eigenvector associated with the largest eigenvalue (the ®rst

eigenvector) indicates the predominant orientation of ®bres in

the given voxel. The directionality of diffusion can be

quanti®ed by the fractional anisotropy index, which is a

rotationally invariant property of the diffusion tensor (Basser

and Pierpaoli, 1996). Fractional anisotropy values range from

0 (no directional dependence of diffusion coef®cients) to 1

(diffusion along a single direction). Changes in tissue

structure (in this case degeneration of the corticospinal ®bres)

can lead to a modi®cation of the degree of directionality,

which can be detected by diffusion tensor MRI. Therefore, in

degenerated white matter tracts of patients with ALS one

would expect to ®nd changes in the anisotropy of diffusion in

comparison with healthy subjects. DTI has already produced

promising results in assessing UMN pathology in patients

with ALS (Ellis et al., 1999). The authors demonstrated that

fractional anisotropy correlates with UMN involvement in

ALS patients. For the analysis of diffusion characteristics,

Ellis and colleagues used six prede®ned regions of interest

(ROIs) along white matter tracts descending through the

posterior limb of the internal capsule.

In our study, we were interested in white matter changes in

the motor system at different levels of the brain caused by

ALS. Thus, we calculated the fractional anisotropy voxelwise

in a larger area not con®ned to the internal capsule. This area

covered ®bre bundles descending from the motor and

premotor cortex to the brainstem. We calculated voxel-

based statistics on the fractional anisotropy maps to demon-

strate fractional anisotropy differences in patients with ALS

compared with healthy controls, using SPM99 (Friston et al.,

1995). As the fractional anisotropy correlates with UMN

lesions, we additionally investigated the correlation between

fractional anisotropy and central motor conduction time

(CMCT), which was derived from TMS. To explore the

usefulness of DTI for assessing early UMN lesions, we

studied a subgroup of six patients without clinical signs of

UMN involvement at the time of MRI investigation. These

patients developed clinical evidence of corticospinal tract

degeneration in the course of their disease. In accordance

with our anatomical a priori hypothesis regarding white

matter changes in ALS along the corticospinal tract, we

corrected for multiple comparisons using the small volume

correction method implemented in SPM99.

MethodsSubjectsWe studied a total of 15 patients with TMS, conventional MRI and

DTI. Among these, nine had de®nite, probable or possible ALS and

six displayed no clinical signs of UMN involvement according to the

revised El Escorial criteria (Brooks et al., 2000b) at the time of

investigation, but developed clinical pyramidal tract symptoms later

in the course of their disease. Patients were compared with 12

healthy, age-matched controls. Clinical details of the patients are

provided in Table 1. As suggested by the World Federation of

Neurology (Brooks et al., 2000b), we identi®ed signs of UMN

degeneration as any of the following: hyper-re¯exia with patho-

logical spread of re¯exes; clonic tendon re¯exes; preserved re¯exes

in weak wasted limbs; spasticity; emotional lability; loss of

super®cial abdominal re¯exes; and Babinski sign. Although brisk

deep tendon re¯exes in the absence of muscle weakness and wasting

are not considered as a UMN sign according to the El Escorial

criteria, this clinical feature is also listed in Table 1. LMN signs

included muscular weakness, wasting and fasciculation. Time after

onset of symptoms ranged from 6 to 24 months (mean 11.9 months,

SD 5.6). Age ranged from 27 to 63 years (mean 52.2 years, SD 11.8).

The healthy controls were free of neurological or other diseases and

were age-matched, with an age range from 28 to 63 years (mean 52.8

years, SD 10.9). Only subjects without contraindications for MRI

were included. Written informed consent to participation in the study

was obtained from all patients and healthy controls. The study was

approved by the ethics committee of the University Hospital

Eppendorf.

DTI of early upper motor neuron lesion in ALS 341



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Tab

le1

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nic

al

det

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01

,F

59

11

(Pro

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lab

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ed)

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risk

DT

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all

lim

bs)

B,

dysp

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loss

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mas

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sp.

insu

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C,

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esis

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gen

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tion

02

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62

6D

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ite

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oti

on

alla

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,B

abin

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ted

lim

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B,

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loss

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mas

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rre

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gen

eral

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03

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arm

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tion

06

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sig

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gen

eral

fasc

icula

tion

07

,M

56

6P

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able

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ulb

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yp

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iab

oth

arm

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fab

do

min

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,dysp

hag

ia,

par

esis

of

arm

san

dri

ght

leg,

gen

eral

fasc

icula

tion

08

,M

58

14

Pro

bab

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bL

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asti

city

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abin

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atte

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ated

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risk

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all

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kw

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par

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C,

gen

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DT

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M5

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Bab

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trunk,

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gen

eral

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11

,M

31

24

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342 M. Sach et al.



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Transcranial magnetic stimulationTMS was delivered by a Magstim magnetic stimulator 200 HP

(Magstim Company, Dyfed, UK) using a 90-mm circular coil.

Initially, we determined the optimal coil position. This was de®ned

as the position in which the largest motor evoked potential (MEP)

was produced in the target muscle. We recorded EMG signals from

the contralateral ®rst dorsal interosseus and anterior tibial muscle via

surface electrodes (Viking IV; Nicolet, Kleinostheim, Germany) and

analysed them off-line. Threshold was de®ned as the lowest stimulus

intensity capable of inducing an MEP with an amplitude of at least

0.05 mV in ®ve of 10 trials, the muscle being tested in the resting

state. Then the stimulus intensity was increased to 20% above

threshold, and stimuli were applied during slight voluntary

contraction. We also obtained MEPs by stimulating the cervical

and lumbar spinal roots to calculate the CMCT. F-waves of the ulnar

and peroneal nerve were measured to calculate peripheral motor

conduction times. MEP amplitudes were expressed as percentages of

the maximal M response amplitude (MEP amplitude ratio) and

compared with values of healthy, age-matched subjects (Kloten

et al., 1992).

MRI protocol and data analysisMRIs were acquired on a 1.5 Tesla MR system (Magnetom Vision,

Siemens, Erlangen, Germany) with 25 mT/m maximum gradient

strength. Head movement was limited by a vacuum ®xation cushion.

Structural T1-weighted images with a resolution of 1 3 1 3 1 mm3

were acquired using three-dimensional fast low angle shot (FLASH)

imaging [¯ip angle 30°, repetition time (TR) 15 ms, echo time (TE)

5 ms, matrix 256 3 256 3 196]. For DTI, we used a single-shot

stimulated echo acquisition mode (STEAM) sequence (¯ip angle

15°, TR 8872 ms, TE 65 ms) (Nolte et al., 2000). The STEAM

sequence is an MRI sequence which yields single-shot images within

a measuring time of ~600 ms. We chose STEAM rather than

echoplanar imaging (EPI) sequences, which are widely used for

diffusion-weighted imaging, because of the crucial advantages of

STEAM for our study. EPI sequences characteristically display

signal loss and geometric distortions caused by susceptibility

gradients in orbitofrontal and inferior temporal brain areas

(Johnson and Hutchison, 1985). In particular, in the vicinity of

air±tissue interfaces (e.g. brainstem), signal alteration and distor-

tions become a problem when using EPI in whole-brain studies to

cover regions from the cortex to the brainstem, as in our study (Nolte

et al., 2000). At the level of the internal capsule, the ferrous basal

ganglia also lead to signal loss, resulting in a decreased signal-to-

noise ratio (SNR) when using EPI sequences. The susceptibility

artefacts of EPI may be reduced by using segmented instead of

single-shot EPI, although the susceptibility to motion due to

segmentation cannot be removed completely by correction methods

(Atkinson et al., 2000). Additionally, eddy current effects arising

from switching strong diffusion gradients (Nolte et al., 2000)

contribute to image artefacts in EPI. These eddy currents depend on

the direction and amplitude of the diffusion gradients and can be

reduced only to a limited degree (Koch and Norris, 2000).

In comparison with EPI, the STEAM sequence exhibits a lower

SNR. To increase the SNR in the tensor maps, data acquisition was

repeated 20 times (scan time of 25 min for DTI). The number of

averages was not increased further, so as not to impair patient

compliance and comfort. We measured the SNR on the averaged

images obtained with a b value of 0 s/mm2 (where b = g2G2d2

(D ± d/3), g = gyromagnetic ratio; G = gradient amplitude; d =

gradient pulse duration; D = delay between the leading edges of the

gradient pulses) in an ROI in the posterior limb of the internal

capsule at the expected location of the pyramidal tract ®bres. The

SNR was de®ned as the ratio of the mean signal intensity in the

internal capsule to the standard deviation of the signal in a

background ROI outside the brain (Hunsche et al., 2001). This

calculation provided an SNR of 96.5. Previous studies recommended

Fig. 1 Voxels with a signi®cant decrease in fractional anisotropy the pyramidal tract, corpus callosum and right thalamus (shown in green)in 15 ALS patients compared with healthy controls. Coordinates are in MNI space (mm). (A) Pyramidal tract (21, ±15, ±6; globalmaximum with P < 0.05, corrected for entire volume; ±24 ±12, 12), corpus callosum (1, ±12, 24) and right thalamus (9, ±12, 4) in thiscoronal section. (B) Transverse view of pyramidal tract in the posterior half of the posterior limb of the internal capsule (21, ±15, ±6; ±24,±12, 12). Statistical fractional anisotropy results (thresholded at P < 0.01, uncorrected) of ALS patients versus controls are superimposedon a spatially normalized T1-weighted MRI. Corrected P values (small volume correction) are given in Table 2.




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an SNR of 20 in images obtained with a b value of 0 s/mm2 for a

reliable estimate of parameters derived from DTI (Basser et al.,

1996; Hunsche et al., 2001).

Because of our interest in imaging the corticospinal tract from the

primary motor and premotor cortex to the internal capsule and the

brainstem, we chose STEAM rather than EPI because of its

insensitivity to eddy currents and susceptibility gradients, especially

in the vicinity of air±tissue interfaces, such as the brainstem (Nolte

et al., 2000), to guarantee anatomically reliable diffusion tensor maps.

For diffusion-weighted imaging, the matrix size was 56 3 64 and

the ®eld of view was 168 3 192 mm2. The imaging volume of 20

coronal slices comprised pyramidal tract ®bres descending from the

primary motor and premotor cortex to the brainstem [y = 32 mm to

y = ±49 mm; coordinates in the Montreal Neurological Institute

(MNI) space], slice thickness 3 mm without a gap between slices, 20

coronal slices (maximum of possible number of slices with the

software) and voxel size 3 3 3 3 3 mm. Diffusion weighting was

obtained with a Stejskal±Tanner spin echo preparation (Stejskal and

Tanner, 1965) with b = 750 s/mm2 and six gradient directions

(gradient coordinate system, x, y, z): (0, 1, 1); (0, 1, ±1); (1, 0, 1); (1,

0, ±1); (1, 1, 0); and (1, ±1, 0). In addition, we acquired a reference

image without diffusion weighting.

Data processing was performed in Matlab 5.3 (MathWorks,

Natick, MA, USA). As the STEAM sequence is insensitive to eddy

currents, correction of geometrical distortion (shift, shear and scale

artefacts) was not necessary. The images of each subject were

realigned and the T1-weighted data set was spatially normalized to

the template using the software package SPM99 (Friston et al.,

1995). Individual brain masks were used to exclude the scalp from

normalization. The resulting af®ne and non-linear transformations

were applied to the diffusion-weighted data. The diffusion gradient

directions were rotated according to every rigid rotation in the

process of normalization. The normalization allows a voxelwise

group comparison based on the common stereotactic MNI space

(Friston et al., 1995). To ensure correct normalization of the MRIs,

we used voxel-based morphometry on the white matter segment of

the structural T1-weighted images. Diffusion tensor maps were

computed voxelwise on the normalized data with multivariate linear

regression (Basser et al., 1994) using SPM99. Fractional anisotropy

was derived from the diffusion tensor and the fractional anisotropy

maps were smoothed with a Gaussian ®lter of 6 mm FWHM (full-

width half-maximum) to validate the statistical inference for

calculation of the corrected P values. The residuals were tested for

normal distribution, an assumption for valid statistical inference

through the probabilistic behaviour of Gaussian random ®elds

(Worsley, 1994) as implemented in SPM99. We performed two

voxel-based statistics on the fractional anisotropy maps using

SPM99. First, fractional anisotropy in patients was compared with

that in healthy controls in a two-sample t-test. Secondly, a linear

regression was calculated to determine the correlation between

fractional anisotropy and CMCT in ALS patients separately for arms

and legs. Patients with absent MEPs due to paresis and muscular

atrophy or prolongation of peripheral motor conduction time were

excluded from the regression analysis. Because of our a priori

hypothesis regarding the pyramidal tract, we also performed small

volume correction for multiple comparisons. Ellis et al. (1999)

previously reported reduced fractional anisotropy in the posterior

limb of the internal capsule in ALS patients compared with healthy

controls. We centred the correction volume (sphere of 8 mm) at

voxels with local fractional anisotropy maxima within the pyramidal

tract from the primary motor and premotor cortex to the brainstem

(P < 0.05, corrected). The images presented are thresholded at

P < 0.01, uncorrected. To visualize the eigenvector, we show the

projection of the ®rst eigenvector onto the image planes.

ResultsThe voxel-based morphometry on the white matter segments

of the structural T1-weighted images did not show any

differences between patient and control groups, elucidating

the accurate normalization of the images. Thus, any differ-

ences in fractional anisotropy can be attributed to differences

in the diffusion-weighted images.

Fig. 2 Voxels with signi®cantly decreased fractional anisotropy underneath the motor and premotor cortex (shown in green) in 15 ALSpatients compared with controls. Coordinates are in MNI space (mm). (A) Coronal section at y = ±18. Pyramidal tract descending fromthe motor cortex (24, ±18, 39; ±21, ±21, 42) and premotor cortex (±18, ±18, 60). (B) Coronal section at y = ±3. Pyramidal tract bilaterallyunderneath the premotor cortex (21, ±3, 42; ±42, ±3, 33). Statistical fractional anisotropy results (thresholded at P < 0.01, uncorrected) aresuperimposed on a spatially normalized T1-weighted MRI. Main ®bre direction is shown by the dashed yellow lines. For corrected Pvalues after small volume correction, see Table 2.

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We found a bilateral decrease in fractional anisotropy in

the posterior half of the posterior limb of the internal capsule

(right, P < 0.00001; left, P < 0.012, corrected) and in the

corona radiata underneath the motor cortex (right, P < 0.03;

left, P < 0.006, corrected) and premotor cortex (right,

P < 0.018; left, P < 0.001, corrected) in the 15 patients

with ALS compared with healthy controls (Figs 1 and 2,

Table 2). The global maximum was located in the internal

capsule (21, ±15, ±6) with P < 0.046, corrected for entire

volume. The decrease in fractional anisotropy in the

pyramidal tract extended to the brainstem (right, P < 0.022;

left, P < 0.042, corrected) (Fig. 3, Table 2). Fractional

anisotropy was also reduced in the corpus callosum (1, ±12,

24) and right thalamus (9, ±12, 4) in ALS patients compared

with healthy subjects (P < 0.01, uncorrected) (Figs 1 and 3A).

Seven out of 15 patients had a pathological CMCT

obtained by TMS to at least one extremity (Table 3). Two

patients without any signs of UMN involvement on clinical

investigation displayed pathological prolongation of the

CMCT (Table 3).

The regression analysis revealed a negative correlation

between fractional anisotropy and CMCT to the upper and

lower extremities. Figure 4 shows regions with negative

correlation between fractional anisotropy and CMCT separ-

ately for the arms and legs. They were located in the internal

capsule (right arm, P < 0.033; left arm, P < 0.020, corrected;

left leg, P < 0.053, corrected) and in the corona radiata

underneath the motor and premotor cortex (right arm,

P < 0.034; right leg, P < 0.035, corrected) (Fig. 4, Table 4).

The diagrams in Fig. 4 show the regression lines for each

extremity with the corresponding correlation coef®cient r and

the statistical P value.

The six patients without any clinical signs of UMN lesion

at the time of MRI investigation also showed a bilateral

Fig. 3 Voxels with a signi®cant decrease in fractional anisotropy in the caudal pyramidal tract ®bres to the brainstem (shown in red) in 15ALS patients compared with healthy subjects. Coordinates are in MNI space (mm). (A) Coronal view of pyramidal tract ®bres in thebrainstem (9, ±18, ±21; ±6, ±15, ±21). (B) Transverse view of pyramidal tract ®bres descending through the brainstem (9, ±18, ±21; ±6, ±15, ±21). Statistical fractional anisotropy results (thresholded at P < 0.01, uncorrected) are superimposed on a spatially normalized T1-weighted MRI. The dashed yellow lines show the projection of the ®rst eigenvector, which corresponds to the main ®bre direction.Corrected P values (small volume correction) are listed in Table 2.

Table 2 Regions of decreased fractional anisotropy in 15 ALS patients versus healthy controls within the pyramidal tractat the small volume correction level (sphere of 8 mm) centred at voxels with local maxima (Figs 1±3)

Region 15 ALS patients compared with healthy controls

x, y, z Z score P corrected

Pyramidal tract in the internal capsule (Fig. 1A, B) 21, ±15, ±6, 4.54 0.000±24, ±12, 12 3.61 0.012

Pyramidal tract in the brainstem (Fig. 3A, B) 9, ±18, ±21 3.45 0.022±6, ±15, ±21 3.27 0.042

Pyramidal tract underneath motor cortex, BA 4 (Fig. 2A, B) 24, ±18, 39 3.37 0.030±21, ±21, 42 3.79 0.006

Pyramidal tract underneath premotor cortex, BA 6 (Fig. 2B) 21, ±3, 42 3.51 0.018±42, ±3, 33 4.29 0.001±18, ±18, 60 3.31 0.037

Coordinates (x, y, z) are in MNI space. BA = Brodmann area; P corrected = P value corrected for multiple comparisons.




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Table 3 Central motor conduction time (ms) of patients with ALS

Patient, sex M. interosseus dorsalis DI M. tibialis anterior

Right Left Normal Right Left Normal

01, F 8.1 8.3 8.7 16.2 14.7 19.902, F 8.7 7.7 8.7 26.2 22.1 19.903, M 6.4 6.8 7.8 15.1 14.5 17.704, F 7.9 7.5 7.8 12.9 12.5 17.205, F 8.7 7.9 7.8 16.5 16.8 17.706, M 7.1 7.0 8.7 15.3 17.0 19.907, M 7.9 7.8 7.8 16.1 15.8 17.708, M 0M 0M 7.8 14.9 15.1 17.709, M 8.4 6.2 8.7 16.4 16.4 19.910, M 9.7 8.7 7.8 26.3 24.8 17.711, M 0M 9.2 7.8 19.7 14.4 17.712, M 0M 0M 7.8 0M 0M 17.713, M 5.8 exc. 8.7 19.5 0M 19.914, M 0M 9.0 7.8 19.3 16.9 17.715, F 0M 0M 7.8 0M 0M 17.7

F = female; M = male; 0M = absent MEP due to paresis and muscular atrophy; normal = upper limit of normal values for age of thepatient (Kloten et al., 1992); exc. = excluded due to prolongation of peripheral motor conduction time. Bold face indicates prolongedcentral motor conduction time.

Fig. 4 Voxels with negative correlation between fractional anisotropy and CMCT to the extremities are shown in green (hands) and red(legs) in patients with ALS. Overlapping voxels are shown in yellow. Coordinates are in MNI space (mm). (A) Coronal section at y = ±12.Negative correlation between fractional anisotropy and CMCT to hands (24, ±12, 12; ±27, ±12, 15) and to leg (±27, ±18, 15) in thepyramidal tract at level of the internal capsule. (B) Coronal section at y = ±18. Negative correlation between fractional anisotropy andCMCT to hand (21, ±18, 42) and leg (12, ±15, 57) in pyramidal tract ®bres descending from the motor and premotor cortex.(C) Transverse view of regions with negative correlation between fractional anisotropy and CMCT in the posterior half of the posteriorlimb of the internal capsule with pyramidal tract ®bres supplying the hands (24, ±12, 12; ±27, ±12, 15) and leg (±27, ±18, 15). A±C showstatistical fractional anisotropy results (thresholded at P < 0.01, uncorrected) superimposed on a spatially normalized T1-weighted MRI.Corrected P values (small volume correction) are given in Table 4. The surrounding diagrams display the regression line for eachextremity with the corresponding correlation coef®cient r and statistical P value.

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reduction in fractional anisotropy in the corona radiata

underneath the motor cortex (right, P < 0.021, corrected) and

premotor cortex (right, P < 0.016; left, P < 0.02, corrected)

and in the posterior half of the posterior limb of the internal

capsule (right, P < 0.001; left, P < 0.034, corrected) (Fig. 5,

Table 5). The decrease in fractional anisotropy in the

pyramidal tract involved ®bre bundles leading to the

brainstem (right, P < 0.019; left, P < 0.045, corrected)

(Fig. 6, Table 5). Additionally, fractional anisotropy was

reduced in the corpus callosum (not shown) and in the right

thalamus (10, ±12, 7, P < 0.01, uncorrected) (Fig. 5B) in

comparison with healthy subjects.

DiscussionWe investigated the ®bre integrity of the cerebral white

matter in ALS patients compared with healthy controls using

DTI and TMS. First, our voxel-based statistics showed

decreased ®bre integrity in the corticospinal tract ®bres

descending from the motor and premotor cortex to the

internal capsule and brainstem. Secondly, we found a

negative correlation between fractional anisotropy and

CMCT in the corticospinal tract ®bres. The correlation

analysis enables an anatomical subdivision of the corticosp-

inal tract between ®bres supplying the upper and lower

extremities. Thirdly, a subgroup of patients with no signs of

UMN lesion at the time of MRI investigation, who developed

pyramidal tract signs later in the course of their disease,

already showed reduced ®bre integrity in the corticospinal

tract underneath the premotor and motor cortex, in the

internal capsule and in the brainstem in DTI. Additionally, we

demonstrated reduced fractional anisotropy in the thalamus

and in the corpus callosum in all patients investigated.

Corticospinal tract changes in ALS patientsversus controlsOur voxel-based statistic showed a signi®cant bilateral

decrease in fractional anisotropy in the posterior half of the

posterior limb of the internal capsule of patients with ALS

compared with healthy controls. This result agrees well with

the known pathology of the combined motor neuron disease

and the localization of the corticospinal tract ®bres in the

internal capsule (Hanaway and Young, 1977). A recent study

using prede®ned ROIs for analysis of diffusion characteristics

along white matter tracts descending through the internal

Fig. 5 Voxels with signi®cantly decreased fractional anisotropy in the pyramidal tract underneath the motor and premotor cortex, in theinternal capsule and in the right thalamus (shown in green) in a subgroup of ALS patients without upper motor neuron signs at the time ofMRI investigation, in comparison with healthy controls. Coordinates are in MNI space (mm). (A) Coronal view at y = ±3: pyramidal tractunderneath the premotor cortex (39, ±3, ±39; ±42, ±3, 33). (B) Coronal view at y = ±12: pyramidal tract underneath the motor cortex (30,±9, 39); pyramidal tract in the internal capsule (21, ±15, ±6; ±24, 12, 12); right thalamus (10, ±12, 7; P < 0.01, uncorrected). (C)Transverse view of pyramidal tract ®bres in the posterior limb of the internal capsule (21, ±15, ±6; ±24, ±12, 12). Statistical fractionalanisotropy results (thresholded at P < 0.01, uncorrected) are superimposed on a spatially normalized T1-weighted MRI. Corrected P-values (small volume correction) are provided in Table 5.

Table 4 Regions of decreased fractional anisotropy (FA) correlated with central motor conduction time (CMCT)separately for arms and legs in patients with ALS within the pyramidal tract at the small volume correction level (sphereof 8 mm), centred at voxels with local maxima (Fig. 4)

Region Correlation FA and CMCT to arms Correlation FA and CMCT to legs

x, y, z Z score P corrected x, y, z Z score P corrected

Pyramidal tract in internal capsule (Fig. 4A, C) 24, ±12, 12 3.34 0.033±27, ±12, 15 3.48 0.020 ±27, ±18, 15 3.21 0.053

Pyramidal tract underneath motor cortex,BA 4/premotor cortex, BA 6 (Fig. 4B)

21, ±18, 42 3.33 0.034 12, ±15, 57 3.32 0.035

Coordinates (x, y, z) are in MNI space. BA = Brodmann area; P corrected = P value corrected for multiple comparisons.




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capsule also demonstrated a reduction in the fractional

anisotropy in the posterior limb of the internal capsule (Ellis

et al., 1999). Because our ®eld of view was not con®ned to the

internal capsule but also included the primary motor and

premotor cortex and parts of the brainstem, we were able to

assess ®bre disintegration at different levels of the motor

system. Thus, we also detected a decrease in fractional

anisotropy in more caudal parts of the corticospinal tract,

comprising the mesencephalon and pons. Additionally, we

found a decrease in fractional anisotropy underneath the

motor and premotor cortex in ALS patients compared with

controls.

The decrease in fractional anisotropy underneath the motor

cortex corresponds to degeneration of motor ®bres emerging

from the primary motor cortex (Davidoff, 1990). About 60%

of pyramidal tract axons originate from the primary motor

cortex (Brodmann area 4) while the remaining ®bres arise

from the premotor cortex (Brodmann area 6) and the parietal

lobe (Davidoff, 1990). Thus, the reduced fractional aniso-

tropy underneath the premotor cortex can be explained by

disintegration of pyramidal tract ®bres emerging from the

premotor cortex. Anatomical connections between the

premotor and motor cortex could also contribute to the

decrease in fractional anisotropy. Clinically, ALS patients

may display degenerative changes in the premotor cortex

(Lawyer and Netsky 1953; Pioro et al., 1994). This can result

in degeneration of the ®bres emerging from the premotor

cortex, resulting in a decrease in fractional anisotropy

underneath it. Hence, we demonstrated white matter disinte-

gration along the corticospinal tract.

Extramotor involvement in ALS and whitematter changes beyond the corticospinal tractThe decrease in fractional anisotropy in the corpus callosum

re¯ects the neuropathological ®ndings of degenerated pyr-

Fig. 6 Voxels with a signi®cant decrease in fractional anisotropy in the caudal pyramidal tract ®bres (shown in red) in ALS patientswithout signs of upper motor neuron lesion, compared with healthy controls. Coordinates are in MNI space (mm). (A) Coronal view ofpyramidal tract ®bres descending to the brainstem (12, ±18, ±18; ±9, ±18, ±21). (B) Transverse view of pyramidal tract ®bres in themesencephalon (12, ±18, ±18; ±9, ±18, ±21). Statistical fractional anisotropy results (thresholded at P < 0.01, uncorrected) superimposedon a spatially normalized T1-weighted MRI. Main ®bre orientation is shown by the dashed yellow lines. Corrected P values (smallvolume correction) are given in Table 5.

Table 5 Regions of decreased fractional anisotropy in ALS patients without upper motor neuron (UMN) involvement at thetime of investigation within the pyramidal tract at the small volume correction level (sphere of 8 mm), centred at voxelswith local maxima (Figs 5 and 6)

Region ALS patients with no UMN signs versus controls

x, y, z Z±score P corrected

Pyramidal tract underneath premotor cortex, BA 6 (Fig. 5A) 39, ±3, 39 3.49 0.016±42, ±3, 33 3.42 0.020

Pyramidal tract underneath motor cortex, BA 4 (Fig. 5B) 30, ±9, 39 3.41 0.021Pyramidal tract in the internal capsule (Fig. 5B, C) 21, ±15, ±6 4.32 0.001

±24, ±12, 12 3.22 0.034Pyramidal tract in the brainstem (Fig. 6A, B) 12, ±18, ±18 3.44 0.019

±9, ±18, ±21 2.85 0.045

Coordinates (x, y, z) are in MNI space; BA = Brodmann area; P corrected = P value corrected for multiple comparisons.

348 M. Sach et al.



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amidal tract bundles running across the middle of the corpus

callosum in patients with ALS (Brownell et al., 1970). It also

corresponds to the atrophy of the corpus callosum that is often

found in ALS and to other pyramidal tract degeneration

processes (e.g. in familiar spastic paralysis), which are often

observed in conventional MRI (Yamauchi et al., 1995;

Krabbe et al., 1997). Severe atrophy in the anterior fourth of

the corpus callosum is also associated with cognitive decline

and psychiatric symptoms in ALS (Yamauchi et al., 1995).

Many pyramidal tract axons terminate in, or send collateral

branches to, a number of supraspinal structures (e.g. the

striatum, sensory and motor nuclei of the thalamus, red

nucleus, pontine nuclei, midbrain and bulbar reticular

formation, inferior olive, dorsal column nuclei, trigeminal

nuclei) (Davidoff, 1990). Regarding the thalamus, necropsy

studies have shown degeneration in the thalamus in patients

with ALS (Iwanaga et al., 1997). The decrease in fractional

anisotropy in the thalamus in this study agrees well with this

result. In addition, ALS patients with impaired verbal ¯uency

showed signi®cantly attenuated rCBF responses in the

anterior thalamic nuclear complex in PET studies (Kew

et al., 1993). Patients with familiar ALS also revealed

bilateral thalamic hypoperfusion as well as parietal and

frontal hypoperfusion in single photon emission computed

tomography (SPECT) (Kumar and Abdel-Dayem, 1999).

In addition to the areas reported above, we found decreased

fractional anisotropy in extramotor regions in the frontal lobe

[underneath the left inferior frontal gyrus (Brodmann areas

44, 45 and 47) and underneath the medial frontal gyrus

(Brodmann areas 8 and 9)]. Similar areas have been reported

in previous ALS studies (Lloyd et al., 2000; Ellis et al., 2001).

Correlation between fractional anisotropy andCMCTA regression analysis was calculated to determine the

correlation between fractional anisotropy and CMCT ob-

tained by TMS. The displayed regions exhibited a negative

correlation between fractional anisotropy and CMCT to all

extremities in patients with ALS. In these voxels, an increase

in CMCT was associated with a decrease in fractional

anisotropy. The separation of the CMCTs to all extremities

into four groups (one extremity per group) and the correlation

with fractional anisotropy for each extremity allows the

anatomical differentiation of the corticospinal tract between

®bres to the arms and legs. The observed topology of the

corticospinal tract ®bres to the arms and legs in the internal

capsule corresponds to the known anatomical topology. In the

internal capsule the motor ®bres to the legs run posterior and

lateral to the ®bres to the arm. In contrast, the white matter

®bres to the legs directly underneath the premotor and motor

cortex are located medial to the ®bres supplying the upper

extremity, as we showed in the coronal section. These results

suggest an in¯uence of white matter disintegration in the

corticospinal tract on the prolongation of the CMCT in ALS

patients.

Patients without signs of UMN involvement atthe time of MRI investigationThis study demonstrated that ALS patients without any

clinical evidence of UMN lesion at the time of MRI

investigation also showed a bilateral reduction in fractional

anisotropy in the posterior limb of the internal capsule,

underneath the motor and premotor cortex and in the

brainstem, in comparison with healthy controls.

Additionally, the fractional anisotropy of the corpus callo-

sum, right thalamus and frontal lobe in these patients was

reduced when compared with that in normal subjects. Hence,

DTI can be used to detect early lesions of the corticospinal

tract in patients with ALS and may therefore contribute to

earlier diagnosis of the disease in the future. This result

matches ®ndings from post-mortem cytochemistry analyses

in patients with the progressive muscular atrophy variant of

ALS, who frequently have undetected corticospinal tract

pathology (Ince et al., 2003). We are planning single-subject

analyses of ALS patients without clinical signs of UMN

involvement in order to explore the clinical impact of DTI on

the assessment of UMN lesions. This may help to differen-

tiate between upper and LMN involvement at an early stage

of the disease.

AcknowledgementsWe wish to thank all the patients and test subjects for their

cooperation in the study. This work was supported by a grant

from the Karberg Stiftung.

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diffusion tensor mri of early upper motor neuron involvement in amyotrophic lateral sclerosis

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