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Chronic cervical spinal cord injury: DTMRI correlates with
clinical and electrophysiological measures
Jens A. Petersen, MDa,d; Bertram J. Wilm, PhDb,c; Jan von Meyenburg, MDb; Martin
Schubert, MDd; Burkhardt Seifert, PhDe; Yousef Najafi, MDb; Volker Dietz, MDd;
Spyridon Kollias, MDb
a Dept. of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
b Institute of Neuroradiology, University Hospital Zurich, Raemistrasse 100, 8091 Zürich, Switzerland
c Institute for Biomedical Engineering, University & ETH Zurich, Gloriastrasse 35, 8092 Zurich, Switzerland
d Spinal cord Injury Center, University Hospital Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland
e Division of Biostatistics, Institute of Social and Preventive Medicine, University of Zurich, Hirschengraben 84,
8001 Zurich, Switzerland
Running title: SCI: Correl dtMRI clin neurophys
Corresponding author:
Jens A. Petersen, MD
Dept. of Neurology
University Hospital Zurich
Frauenklinikstrasse 26
8091 Zurich
Switzerland
+41 44 255 1111
jens.petersen@usz.ch
Page 1 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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Bertram J. Wilm, PhD
Institute for Biomedical Engineering
University & ETH Zurich
Gloriastrasse 35
8092 Zurich
Switzerland
+41 44 632 53 25
wilm@biomed.ee.ethz.ch
Jan von Meyenburg, MD
Institute of Neuroradiology
University Hospital Zurich
Raemistrasse 100
8091 Zürich
Switzerland
+41 44 255 1111
janvonmeyenburg@bluewin.ch
Martin Schubert, MD
Spinal cord Injury Center
University Hospital Balgrist
Forchstrasse 340
8008 Zurich
Switzerland
+41 44 386 1111
martin.schubert@balgrist.ch
Burkhardt Seifert, PhD
Division of Biostatistics
Institute of Social and Preventive Medicine
Hirschengraben 84
8001 Zurich
Switzerland
+41 44 634 46 44
seifert@ifspm.uzh.ch
Yousef Najafi, MD
Institute of Neuroradiology
University Hospital Zurich
Raemistrasse 100
8091 Zurich
Switzerland
+41 44 255 1111
yousef.najafi@usz.ch
Volker Dietz, MD
Spinal cord Injury Center
University Hospital Balgrist
Forchstrasse 340
8008 Zurich
Switzerland
+41 44 286 1111
vdietz@paralab.balgrist.ch
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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Spyros Kollias, MD
Institute of Neuroradiology
University Hospital Zurich
Raemistrasse 100
8091 Zurich
Switzerland
+41 44 255 1111
kollias@dmr.usz.ch
Page 3 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Abstract
Diffusion tensor MR imaging (DTI) is rarely applied in spinal cord injury (SCI). The
aim of this study was to correlate diffusion properties after SCI with
electrophysiological and neurological measures. 19 traumatic cervical SCI subjects
and 28 age-matched healthy subjects participated in this study. DTI data of the spinal
cord were acquired on a Philips Achieva 3 T MR scanner using an outer volume
suppressed, reduced field of view (FOV) acquisition with oblique slice excitation and
a single-shot EPI readout. Neurological and electrophysiological measures (ASIA
impairment scale, motor (MEP) and somatosensory evoked potentials (SSEP)) were
assessed in SCI subjects. Fractional Anisotropy (FA) values decreased in the SCI
subjects compared to the healthy subjects. In upper cervical segments, the decrease
in FA was significant for the evaluation of the entire cross sectional area of the spinal
cord and for corticospinal and sensory tracts. A decreasing trend was also found at
the thoracic level for the corticospinal tracts. The decrease of DTI values correlated
with the clinical completeness of SCI and with SSEP amplitudes. The reduced DTI
values in the SCI subjects are likely to be due to demyelination and axonal
degeneration of spinal tracts, which are related to clinical and electrophysiological
measures. A reduction of DTI values in regions remote from the injury site suggests
their involvement with Wallerian axonal degeneration. DTI can be used for a
quantitative evaluation of the extent of spinal cord damage and, eventually, to
monitor the effects of future regeneration inducing treatments.
Keywords: Assessment Tools, in vivo studies, MRI, Traumatic spinal cord injury
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Introduction
Conventional MRI is a clinical modality routinely used in the diagnosis of spinal cord
injury (SCI). However, since axonal integrity cannot be displayed there is no
quantitative correlation with the neurological deficit. Diffusion tensor imaging (DTI)
provides a 3-dimensional model of water diffusion (Hagmann, Jonasson et al. 2006).
The application of DTI to the human spinal cord is technically challenging due to the
small cross-sectional area of the spinal cord, cardiac and respiratory motion and
strongly varying magnetic susceptibility (Agosta, Benedetti et al. 2005; Demir, Ries et
al. 2003; Elshafiey, Bilgen et al. 2002). Recent developments in MR pulse sequence
design have greatly reduced these problems (Thurnher and Law 2009; Wilm,
Gamper et al. 2009; Wilm, Svensson et al. 2007). Clinical findings correlate with DTI
metrics of the injured spinal cord (Budzik, Balbi et al. 2011; Chang, Jung et al. 2010;
Kim, Loy et al. 2010; Qian, Chan et al. 2011). Few studies have explored the
relationship between structural integrity, evaluated using DTI, and physiological
function of the human spinal cord (Ellingson, Kurpad et al. 2008; Kerkovsky,
Bednarik et al. 2011; Qian, Chan et al. 2011). However, to prove the validity of a
technique that may be used to monitor the effects of new therapeutic interventions it
is crucial to firstly prove its potential to reflect the functionality of the evaluated
structures. The aim of our study was to characterize diffusion properties across the
spinal cord and to correlate the data with clinical and electrophysiological measures.
Our hypotheses were that: 1.) atrophy and a drop in DTI measures will be found
remote and particularly distal from the spinal lesion level with respect to axon
localization; 2.) the regional local and remote loss of directional structure correlates
with clinical and neurophysiological parameters and allows a linkage between
Page 5 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
function and structure for the application of DTI in spinal lesions, even those remote
from the site of injury; 3.) the distribution of DTI changes remote from the lesion site
will follow the neuroanatomical distribution of severity of the damaged tracts as can
be assessed by clinical / neurophysiological parameters.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
METHODS
Subjects
All procedures complied with the principles of the Declaration of Helsinki and were
approved by the Institutional Review Boards of Zurich University. 19 traumatic SCI
subjects (level of lesion C3 to C8, mean age 59.7 years, time since injury 2 months to
8 years, mean 32 months) and 28 healthy subjects (mean age 58 years) participated
in this study. Control subjects had no history of neurological illness. 14 SCI subjects
had vertebral fixation, which substantially deteriorated image quality. Therefore, only
DTI measurements above and below the level of lesion were used. Subjects with SCI
and healthy subjects were age- and sex-matched. Table 1 shows the characteristics
of chronic SCI subjects.
MR imaging
MRI of the spinal cord was performed on a 3-T Philips Achieva (Philips Healthcare,
Best, the Netherlands) system. No upgrade of the MR system or other changes in the
software and hardware of the MR system were undertaken during the study. For
image acquisition, a dedicate spine coil array with 6 coil elements along the spinal
cord was used. The standardized imaging protocol included: a) sagittal T2-weighted
images (TR = 3352 ms, TE = 120 ms, flip angle = 90°, field-of-view (FOV) = 270
x 259 mm2, slice thickness = 3 mm, number of slices = 11) along the entire spinal
cord (Fig. 1); b) DTI data was obtained at the cervical (~C2, ~C5) and thoracic (~T5)
levels, as well as at the Lumbar enlargement (LE) of the spinal cord (Fig. 1). To
account for the relatively large slice thickness, the imaging stack was carefully
aligned perpendicular to the spinal cord to avoid sub-voxel effects. The scan time
Page 7 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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for each level was approximately 10 minutes. In each region six transverse slices
were acquired using a DW single-shot spin-echo EPI sequence on a reduced FOV
(Wilm, Gamper et al. 2009; Wilm, Svensson et al. 2007) (NEX = 6/12 for b = 0/b =
750 s/mm2, acquisition matrix = 176 x 44, FOV = 120 x 30 mm2, TR = 4000 ms, TE =
49 ms, 60% partial-Fourier acquisition, slice thickness = 5 mm, in-plane resolution =
0.7 mm2). After image co-registration FA and mean apparent diffusion coefficients
were calculated (Fig. 2); c) thereafter sagittal T1-weighted gadolinium enhanced
images (TR/TE = 414/8 ms, flip angle = 90°, FOV = 260 x 260 mm2 , slice
thickness = 3 mm, number of slices = 11) were performed.
Image analysis
The investigator was blinded to the clinical and electrophysiological status of the SCI
subjects before analysis. To correct for bulk motion and eddy-current distortions, the
data was co-registered using the scanner systems standard co-registration method.
Signal-to-noise-ratio (SNR) was calculated and used as a threshold. Images with
SNR (Signal to noise ratio) <20 were excluded, as were those in which grey and
white matter of the spinal cord were indistinguishable owing to poor image quality.
The aim of the study was to assess normal appearing white matter representing
alterations that cannot be demonstrated on conventional T2-weighted imaging. The
sagittal T2-weighted images were screened for presence of focal T2 hyperintense
lesions, diffuse signal abnormality, atrophy and spinal cord or nerve root
compression. From the DTI data sets the transverse T2 (b = 0) maps were screened
for lesions. Subsequently, diffusion tensor maps were calculated. ADC and FA maps
were calculated using the standard DTI software of the scanner system. The cross
sectional area (mm2) was evaluated using the ADC images, where the contrast
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
between CSF and spinal cord is best. Measurements of FA- and ADC values
(transverse ADC) were performed in several regions of interest (ROI’s) in the cross-
sectional area of the spinal cord (corticospinal tracts [CSTs] including the crossed
pyramidal tract and dorsal tracts including fasciculus cuneatus and gracilis ) as
shown in Fig 3. The size of the ROI’s was identical at the cervical level and the
lumbar enlargement (LE). Smaller ROIs were chosen at the thoracic level to take the
reduced cross sectional area of the thoracic spinal cord into account.
Neurological scoring
The neurological level of injury was determined by standard neurological
classification of spinal injury according to American Spinal Injury Association (ASIA),
which was then used to define the lesion site and completeness of injury according to
ASIA impairment scale (AIS A= motor and sensory complete; AIS B = motor
complete and sensory incomplete; AIS C and D = motor and sensory incomplete)
(Marino, Barros et al. 2003). Five key leg and arm muscles were manually tested
(0=total paralysis, 1=palpable or visible contraction, 2=active movement with gravity
eliminated, 3=active movement, against gravity, 4=active movement, against some
resistance, 5=active movement, against full resistance). Each of these muscles
represents a spinal segment (elbow flexors, C5; wrist extensors, C6; Elbow
extensors, C7; Finger flexors, C8; Finger abductors, T1; hip flexors, L2; knee
extensors, L3; ankle dorsiflexors, L4; long toe extensors, L5; ankle plantar flexors,
S1). Light touch and pin prick examinations of dermatomes C2 and below were
performed down to the sacral segments (S4/5).
Page 9 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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Electrophysiologcal measures
In the 18 SCI subjects (Table 1), sensory evoked potentials (SSEP) were recorded
by electrical stimulation of the posterior tibial nerve at the medial malleolus and of the
ulnar nerve at the wrist (square wave of 0.2 msec duration applied at 3 Hz; cathode
placed 2–3 cm proximal to the anode). The stimulus intensity was adjusted to
produce a visible muscle response or up to a maximal intensity of 40 mA. Electrodes
were attached to the skin over the popliteal fossa, the ERB point and the nape (level
C2) to test transmission of the stimulus along the peripheral nerve and spinal cord.
Scalp electrodes were positioned at Cz_-Fz according to the international 10/20
electrode system. The electrode impedance was maintained below 5 k ohms. The
peaks of N8, N10, N20, P25, P40 and N50 were used to determine the latency and
amplitude of the response. Two sets of 300 responses were averaged and
superimposed to ensure consistency.
In 12 of the SCI subjects (Table 2), Motor evoked potentials (MEP) were recorded
after applying single pulse transcranial magnetic stimulation (TMS) with a double
cone coil at the vertex using a MagStim 2002 magnetic stimulator. The hot spot
(defined as the point from which stimuli triggered MEPs of maximal amplitude and
minimal latency) for stimulation of the anterior tibial muscle (TA) was determined
starting at the vertex and gradually by moving the coil rostral and contralateral to
optimize coil position for best size of the MEP amplitude. The same procedure was
used for the abductor digiti minimi muscle of the hand (ADM), but with a different
starting point, 4 cm rostral and 3cm contralateral to Cz. The duration of the biphasic
transcranial single pulse stimuli was 50 µsec. The sample frequency was 2000 Hz,
and a band-pass filter was set at 30 Hz to 1 kHz. TMS threshold to evoke a MEP was
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
determined during slight and steady voluntary muscle pre-activation at approximately
10% of maximal voluntary muscle contraction. MEP onset latencies and the baseline
to peak amplitudes were determined with the same steady preactivation of 10%
maximum voluntary muscle contraction.
Statistics
ROIs from the patients were compared with corresponding ROIs from the healthy
subjects to assess differences in DTI parameters. Groups were compared using the
Mann-Whitney-test based on independent subject-based observations. P-values ≤
0.05 were considered as statistically significant. Nonparametric Spearman rank
correlations were calculated between ROI-based age-FA/ADC, clinical and
electrophysiological parameters-FA/ADC. To quantify the proportion of inter-group
variability (SCI / healthy subjects) in diffusivity measures, variance components were
estimated in a random three-way analysis of variance with factors, subject, ROI and
group at each level.
Page 11 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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RESULTS
Table 2 summarizes ADC and FA values of four spinal levels (C2, C5, T5 and LE)
among the control and SCI subjects. Due to small subject numbers, left and right-
side diffusion measures, as well as electrophysiological and clinical data were
accumulated.
Image quality.
Some images were excluded due to low SNR or because grey and white matter of
the spinal cord were indistinguishable (Table 1). At level C5, this was the case for all
SCI subjects with vertebral fixation. For level C2, the 4 youngest SCI subjects were
excluded, so that the SCI group was sex- and age-matched with the control group. In
the control group, the number of subjects included per level was 12 (level C2 / C5),
16 (T5) and 14 (LE). In the SCI group, the number of subjects included was 12 (C2),
4 (C5), 14 (T5) and 13 (LE) (Table 2).
T2 findings
Focal T2 hyperintense lesions, diffuse signal abnormality, atrophy and spinal cord or
nerve root compression were not found in any of the SCI subjects on T2 MRI images
at levels C2, T5 or L5 (Table 1). All SCI subjects without vertebral fixation showed
signs of myelomalacia at level C5 (Table 1).
DTI metrics of the control group.
Significant differences were observed in the FA values of corticospinal, the dorsal
tracts and the whole cross section of the spinal cord between C2 and C5
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
(corticospinal tracts: p=0.001; dorsal tracts: p=0.02; whole cross section: p=0.028),
between C2 and T5 (p<0.001; p<0.001; p<0.001), between C2 and LE (p<0.001),
between C5 and T5 (p=0.005; p=0.006; p<0.001), C5 and LE (p<0.001; p<0.001;
p<0.001) and between T5 and LE (p=0.005; p=0.01; p<0.001). FA values were
highest in the upper cervical segments and lowest in the conus medullaris (table 2)
for the whole cross section (C2 0.66 ± 0.03; LE 0.57 ± 0.05) and for the CSTs (C2
0.75 ± 0.04; LE 0.63 ± 0.05). FA values were highest in the upper cervical segments
and lowest at T5 for the dorsal tracts (C2 0.76 ± 0.02; T5 0.69 ± 0.06; LE 0.7 ± 0.06).
There was no difference between the left-side and right-side FA values of
corticospinal and dorsal tracts.
ADC values differed between levels C2 and C5 (dorsal tracts, p=0.045), between C2
and LE (whole cross section, p=0.001) and between T5 and LE (p=0.012). ADC was
highest in the upper cervical segments (0.87 ± 0.04 x 10-3 mm2/s) and lowest at C5
(0.82 ± 0.07 x 10-3 mm2/s) for the dorsal tracts (Table 2), highest at the LE (0.92 ±
0.07 x 10-3 mm2/s) and lowest at C5 (0.85 ± 0.07 x 10-3 mm2/s) for the whole cross
section, and highest at the LE (0.88 ± 0.10 x 10-3 mm2/s) and lowest at C5 (0.82 ±
0.09 x 10-3 mm2/s) for the CSTs.
In the non-accumulated data, ADC values of the left and right dorsal tracts differed at
levels C2 (p=0.005). ADC values of left-side and right-side CSTs differed at level C5
(p<0.005).
Spearman rank correlation revealed a significant impact of age on FA (whole cross
section, r=0.309, p=0.003; CSTs right, r=0.323, p=0.002; CSTs left, r=0.272, p=0.011;
dorsal tracts right, r=0.464, p<0.001; dorsal tracts left, r=0.489, p<0.001). There was
no significant impact on ADC values.
Page 13 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
DTI metrics of the SCI subjects group
In SCI subjects, FA of all four spinal levels was lower than in the control group at the
whole cross section (p=0.008) and at the CSTs (p=0.019). Compared to age- and
sex-matched control subjects, FA decreases or a decreasing FA tendency were also
found when all four spinal levels were analyzed separately (Table 2, Fig. 5). At level
C2, the decrease was statistically significant for the cross sectional area (p=0.001),
as well as for corticospinal (p=0.002) and sensory tracts (p=0.004). At level C5, the
decrease was statistically significant for the whole cross section (p=0.05). At level T5,
there was a decreasing trend at the CSTs (p=0.058). Similar to control subjects, FA
was highest in the upper cervical segments and lowest at the LE (table 2).
In the CSTs of SCI subjects, the tendency was towards lower ADC values at level C2
(p=0.052) and higher ADC values at level T5 (p=0.088, Table 2).
At level C2, the inter-group-differences (SCI subjects / control subjects) account for
44% of the variability of the FA measures compared to other factors. At level C5, it
was is only 4% while at level T5 and at the LE, other factors, such as inter-subject-
differences, account for most of the variability.
The surface area of the injured spinal cord was significantly decreased at all spinal
levels (Table 3).
Diffusion measures and evoked potentials
In SCI subjects, mean ulnar SSEP N20 was 23.05 ± 2.09 ms with a mean amplitude
of 1.35 ± 0.95 µV. Mean tibial SSEP P40 was 46.85 ± 5.05 ms with a mean
amplitude of 0.79 ± 0.83 µV (see also Tab. 4). Mean abductor digiti minimi MEP
latency was 24.23 ± 6.97 ms with an amplitude of 1.31 ± 1.29 mV. Mean tibialis
anterior MEP latency was 34.21 ms with an amplitude of 0.63 ± 0.81 mV.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Amplitudes (P40) of the tibial SSEP (Table 4) correlated with FA measures of the
dorsal tracts of all levels taken together (Spearman rank correlation r=0.46, p<0.001,
Fig. 4) and inversely with ADC measures of the dorsal tracts of all levels taken
together (r=-0.26, p<0.034), while ulnar SSEP (Table 4) did not correlate.
Level C2
Amplitudes (P40) of the tibial SSEP correlated with FA measures of the whole cross
section (r=0.7, p<0.001) and with the dorsal tracts (r=0.53, p<0.007, Fig. 4), while
ulnar SSEP did not correlate. Tibial SSEP latencies did not correlate with FA
measures. ADC measures did not correlate with ulnar or tibial SSEP measures.
Neither MEP latencies nor amplitudes correlated with FA measures.
Level C5
No significant correlations were found for diffusion measures with evoked potential
amplitudes or latencies.
Level T5
No significant correlations were found for diffusion measures with evoked potentials.
Lumbar enlargement (LE)
Amplitudes (P40) of the tibial SSEP correlated with FA (r=0.99, p<0.001) and ADC
(r=-0.7, p=0.003) measures of the dorsal tracts. SSEP latencies and MEP did not
correlate with diffusion measures.
Diffusion measures and clinical outcome
FA measures correlated with the AIS impairment scale scores along the whole cross
section of the spinal cord (r=0.27, p=0.006), the CSTs (r=0.32, p<0.001, Fig. 4) and
at all levels of the dorsal tracts (r=0.29, p=0.001). ADC values did not correlate with
the AIS. At level C2, FA measures correlated with the AIS score regarding the whole
Page 15 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
cross section (r=0.64, p=0.001, Fig. 4), corticospinal (r=0.5, p=0.002, Fig. 4) and
dorsal tracts (r=0.41, p=0.013). ADC values did not correlate with the AIS. At level C5,
FA measures correlated with the AIS score along the whole cross section (r=0.57,
p=0.012) and the CSTs (r=0.45, p=0.046). T5, FA measures significantly correlated
with the AIS score regarding the CSTs (r=0.44, p=0.003, Fig. 4) and the dorsal tracts
(r=0.448, p=0.002); ADC values did not correlate with the AIS. At the LE, FA and
ADC measures did not correlate with the AIS.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
DISCUSSION
Tissue characteristics
Diffusion characteristics in SCI subjects and healthy controls differed in spinal cord
regions remote from the injury site. This is in line with earlier SCI observations (Deo,
Grill et al. 2006; Ellingson, Ulmer et al. 2008; Ford, Hackney et al. 1994; Fraidakis,
Klason et al. 1998; Nevo, Hauben et al. 2001; Shanmuganathan, Gullapalli et al.
2008). Decreased FA values at the cervical level of the SCI subjects were within the
range of previous publications (Chang, Jung et al. 2010; Kerkovsky, Bednarik et al.
2011). The FA loss in SCI subjects might be linked to a reduced number of fibers
linked to increased diffusivity in the extracellular space (Facon, Ozanne et al. 2005)
and is likely to reflect anterograde and retrograde Wallerian degeneration.
Retrograde Wallerian degeneration has been described only rarely in the human
CNS (Bronson, Gilles et al. 1978; Yamamoto, Yamasaki et al. 1989). It results in a
loss of diffusion anisotropy (Batchelor, Atkinson et al. 2003) and is reported in the
cranial CST after cervical SCI (Guleria, Gupta et al. 2008).
The probability of direct tissue injury induced by SCI at level C2 cannot be excluded
but does not seem probable because there were no signs of pathological changes at
C2 level on T2 MRI images in our subjects and no clinical indication of a C2 deficit
(Table 1).
In SCI subjects, at level C5, a significant difference was only found in FA for the
whole cross section and a trend in the sensory tracts. The fact that no significant
difference was found in the CSTs might be because this group consisted of only four
Page 17 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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SCI subjects, three of whom had minor trauma (AIS D) with signs of central and / or
dorsal myelomalacia on T2 MRI images not necessarily affecting the CSTs (Table 1).
Previous studies have shown that FA values are of higher sensitivity and specificity
than ADC values in patients with spinal cord compression (Facon, Ozanne et al.
2005) and spinal cord injury (Chang, Jung et al. 2010). Accordingly, in degenerated
sciatic frog nerve and in human brain, a loss of anisotropy is noted but average
diffusivity may remain unchanged owing to an accumulation of cellular debris from a
breakdown of the longitudinal axonal structure, while glial proliferation may hinder
water movement in a parallel direction (Beaulieu, Does et al. 1996; Werring, Toosy et
al. 2000). ADC maps may not, therefore, be able to distinguish between normal and
degenerated cord in cases of severe neuropathology (Aota, Niwa et al. 2008).
The reduction in cross-sectional area in SCI compared with healthy subjects
suggests atrophy (Freund, Weiskopf et al. 2011) in regions remote from the injury
site owing to subsequent axonal degeneration and dieback (Potter and Saifuddin
2003). Spinal cord atrophy is seen in patients with a long history (more than 2 years)
of post-traumatic myelopathy (Curati, Kingsley et al. 1992) and is the most common
spinal cord abnormality (prevalence of 62%) seen in patients imaged more than 20
years after injury (Wang, Bodley et al. 1996).
Relationship to clinical and electrophysiological measures
SSEP and MEP are regarded as an objective measure of the functional integrity of
spinal pathways (Chabot, York et al. 1985; Curt, Keck et al. 1998; Steeves,
Lammertse et al. 2007). The morphometry and permeability of the axonal membrane
to water are intimately tied to both MR diffusion measurements (Ford, Hackney et al.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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1998; Schwartz, Cooper et al. 2005) and neuronal excitability (Clamann and
Henneman 1976; Clay 2005; Freeman 1978; Mirolli and Talbott 1972). It is
therefore reasonable to assume that quantitative changes in DTI measurements
following injury quantitatively reflect structural damage of the spinal tracts, which may
be expected to affect SSEP and MEP parameters accordingly. A loss of amplitude
would be expected for SEP and MEP measurements in cases of axonal damage
while demyelinating diseases would be more likely to entail a reduced conduction
velocity and thus increased SEP or MEP latencies. Our results demonstrate a
selective relationship between tibial SSEP amplitude and diffusion measures of the
dorsal tracts. The parallel alterations in both SSEP amplitudes and DTI measures
suggest significant axonal disruption in SCI. This is in line with a study that reveals a
high correlation of SSEP and DTI measures of the dorsal columns in rats (Ellingson,
Kurpad et al. 2008). Ulnar SSEP amplitudes did not correlate with diffusion measures:
this might be because the region-of-interest setting covers more the medial part of
the dorsal tracts, while fibers from cervical levels are located more laterally and were
therefore not perfectly matched by the respective ROI.
MEP did not correlate with diffusion measures. This is probably a consequence of the
well-known variability of MEP amplitudes. Theoretically, the size of a MEP should
reflect the number of conducting central motor neurons, but this relation is obscure.
MEPs are usually smaller than compound motor action potentials elicited by
peripheral nerve stimulation, and their size varies from one stimulus to the next as
well as between subjects owing to a varying degree of facilitation (Hess, Mills et al.
1987; Kiers, Cros et al. 1993). Furthermore, varying synchronization of the
descending action potentials causes MEP amplitude variation. The resulting phase
Page 19 of 38
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Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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cancellation phenomenon (Magistris, Rosler et al. 1998) impedes straightforward
conclusions on the number of activated motor neurons and is probably responsible
for a lack of correlation in the present comparison of DTI with MEP amplitudes.
Regarding clinical scores, the decrease of the FA correlated with the completeness
of injury reflected by the AIS scale (i.e., lowest FA values were found in sensori-
motor complete SCI patients). This has already been shown for cervical (Cohen-
Adad, El Mendili et al. 2011) but not for thoracic and lumbar FA metrics in cervical
SCI subjects. In previous studies, FA also correlated with clinical measures in
spondylotic myelopathy (Budzik, Balbi et al. 2011) and FA but not ADC metrics were
correlated with motor function in SCI subjects (Chang, Jung et al. 2010). In patients
with poor clinical scores, FA metrics are decreased in cases of spinal cord
arteriovenous but the ADC values are variable (Ozanne, Krings et al. 2007). FA also
correlates with disability scales in neuromyelitis optica (Qian, Chan et al. 2011). FA
DTI measures may be useful to quantify the degree of neural damage as a
prognostic factor and to monitor the effects of future regeneration inducing
treatments.
Clinical relevance
The structural changes underlying motor recovery in SCI are not yet fully understood.
A pure imaging approach would not be sufficient to prove functional significance of
preserved or re-establishing directional organization of tissue. By combining the
application of clinical, electrophysiological and imaging approaches the functional
and structural contributions to the recovery of function after an SCI can be
determined. However, before a quantitative evaluation of the combined methods can
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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be applied there must be proof of feasibility and validity. The ultimate goal would be
to relate changes over time in DTI and neurophysiology. This would be an approach
that allows us to assess and localize both spontaneous and induced regeneration
following SCI. This is important to evaluate the effects of new treatments that target
different pathophysiological mechanisms after injury, such as inflammation, scarring,
enhancing neuroplasticity or the disinhibition of regeneration. With such an
evaluation the effect of an optimal combination of treatments could also be reliably
assessed.
Study limitations
This study enrolled DTI examinations from 2 months to 8 years after SCI. As
Wallerian degeneration results in progressive decline of FA values along white
matter tracts, this variation of time points may affect the accuracy of the results. The
study would have benefited from a larger SCI population size and especially from
patients without a metal implant at the lesion site. In other SCI studies (Ellingson et
al., 2008; Shanmuganatham et al., 2008), subject groups were not age- and sex-
matched although diffusivity metrics are clearly age-dependent (Mamata et al., 2005).
This aspect was taken into account in this study.
Further studies are needed to discover whether the lesion extent displayed by DTI
correlates with histopathological findings. The fine in-plane resolution makes it
possible to measure alterations of ultrastructural tissue such as the motor and
sensory tracts. Despite careful planning of the scan geometry and ROI placement,
sub-voxel effects may degrade the achievable accuracy of the quantification. A
further increase in image resolution is expected to improve the correlation with
functional data. Detailed regional histological analysis at different time points after
Page 21 of 38
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Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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SCI to determine the state of myelin and neurofilaments is required but unfeasible in
humans.
Owing to the short single-shot readout duration the employed DTI sequence is
inherently robust against motion artefacts (motion ghosting). Thus, imaging proved to
be robust against distortions and SNR-dropout in most patients. However, we cannot
exclude that movement artefacts may have contributed to within- and between-
subject variations during MRI scanning.
In this study motion related effects were addressed by using a short acquisition
duration and bulk motion correction. Moreover, the high number of image averages
may also help to avoid systematic motion errors. In future studies, the use of cardiac
gating (Kharbanda, Alsop et al. 2006) might help to further improve the accuracy of
the obtained diffusitivity values.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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Author Disclosure Statement
Jens A. Petersen: No competing financial interests exist.
Bertram J. Wilm, PhD: No competing financial interests exist.
Jan von Meyenburg: No competing financial interests exist.
Martin Schubert, MD: No competing financial interests exist.
Burkhardt Seifert, PhD: No competing financial interests exist.
Yousef Najafi, MD: No competing financial interests exist.
Volker Dietz, MD: No competing financial interests exist.
Spyridon Kollias, MD: No competing financial interests exist.
Page 23 of 38
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Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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No.
Age
Sex
Level
AIS
Score
Metal
implant
Cause
Time
since injury
Minor image
quality (dropout)
MRI findings
(T2)
SSEP
MEP
1
76
m
C4
D
yes
Traumatic discal hernias C2/3 and C3/4
2 m
C5, LE
-
+
+
2
72
f
C6
C
no
Periradicular infiltration
12 m
-
diffuse myelomalacy C5
+
-
3
68
m
C4
D
yes
Traumatic discoligamentary luxation C4/5
3 m
C5, LE
-
+
+
4
68
m
C6
C
yes
Traumatic discoligamentary luxation C6/7
72 m
C5, T5
-
+
+
5
66
m
C6
B
yes
Traumatic fractures C5 and C6
7m
C5. LE
-
+
+
6
65
f
C6
A
yes
Traumatic discoligamentary luxation C7/T1
36 m
C5
-
+
+
7
61
m
C4
D
yes
Traumatic spinal contusion
72 m
C2, C5
-
+
-
8
61
m
C3
D
yes
Compressive myelopathy due to spinal stenosis
60 m
C5, T5, LE
-
+
-
9
59
f
C5
D
no
Compressive myelopathy due to spinal stenosis
24 m
C2, C5
-
-
-
10
55
m
C3
D
yes
Traumatic spinal contusion
48 m
C5, T5, LE
-
+
-
11
42
m
C8
D
yes
Traumatic fracture C6 and C7
96 m
C5
-
+
-
12
36
m
C6
D
no
Traumatic fractures C4, C5 and C7
72 m
-
central myelomalacy C5
+
+
13
32
m
C7
C
yes
Traumatic fracture C7/T1
18 m
C5
-
+
+
14
31
m
C5
D
yes
Traumatic fracture C6
12 m
C5
-
+
+
15
31
m
C5
D
no
Traumatic spinal contusion
2 m
T5, LE
central myelomalacy C5
+
+
16
51
m
C5
D
no
Compressive myelopathy due to spinal stenosis
4 m
-
dorsal myelomalacy C5
+
-
17
27
m
C7
A
yes
Traumatic fracture C7
60 m
C5
-
+
+
18
25
m
C5
B
yes
Traumatic fracture C4 and C5
4 m
C2, C5, T5
-
+
+
19
20
m
C7
D
yes
Traumatic fracture C6
5 m
C5
-
+
+
Page 27 of 38
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Table 1. SCI subjects. m = male, f = female; AIS = ASIA Impairment Scale; m = months. AIS A (motor-sensory complete), AIS B (motor complete, sensory
incomplete), AIS C (motor-sensory incomplete) and AIS D (motor-sensory incomplete). MRI= Magnetic resonance imaging, SSEP=somatosensory
evoked potentials, MEP=motor evoked potentials.
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Controls
SCI subjects
C2 (n=12)
C5 (n=12)
T5 (n=16)
LE (n=14)
C2 (n=12)
C5 (n=4)
T5 (n=14)
LE (n=13)
Cross section
ADC (*10-3 mm2/s)
0.89 ± 0.04
0.85 ± 0.07
0.88 ± 0.07
0.92 ± 0.07
0.89 ± 0.07
0.89 ± 0.24
0.92 ± 0.07
0.81 ± 0.13
P value
0.8
0.1
0.1
0.28
FA
0.66 ± 0.03
0.62 ± 0.06
0.60 ± 0.04
0.57 ± 0.05
0.61 ± 0.03
0.53 ± 0.06
0.57 ± 0.05
0.50 ± 0.04
P value
0.001
0.05
0.1
0.50
CSTs
ADC (*10-3 mm2/s)
0.88 ± 0.06
0.82 ± 0.09
0.83 ± 0.09
0.88 ± 0.10
0.82 ± 0.08
0.81 ± 0.23
0.88 ± 0.10
0.81 ± 0.13
P value
0.052
0.8
0.088
0.25
FA
0.75 ± 0.04
0.67 ± 0.08
0.67 ± 0.06
0.63 ± 0.05
0.7 ± 0.04
0.63 ± 0.08
0.63 ± 0.05
0.59 ± 0.06
P value
0.002
0.4
0.058
0.2
Dorsal tracts
ADC (*10-3 mm2/s)
0.87 ± 0.04
0.82 ± 0.07
0.83 ± 0.08
0.82 ± 0.08
0.85 ± 0.1
0.84 ± 0.2
0.82 ± 0.08
0.78 ± 0.11
P value
0.5
0.5
0.8
0.17
FA
0.76 ± 0.02
0.71 ± 0.06
0.69 ± 0.06
0.70 ± 0.06
0.72 ± 0.05
0.67 ± 0.04
0.70 ± 0.06
0.67 ± 0.05
P value
0.004
0.3
0.6
0.6
Table 2. DTI parameters in SCI and healthy subjects (mean values ± standard deviation across all voxels in the selected regions across
all participants). Significant differences between SCI and the healthy are indicated in bold. FA = Fractional Anisotropy; ADC = Apparent
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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Diffusion Coefficient. CSTs = corticospinal tracts.
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Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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Control
SCI subjects
C2
C5
T5
LE
C2
C5
T5
LE
Surface area (mm2)
754.2 ± 27.8
722.4 ± 59
412.5 ± 21
518.6 ± 19
586.1 ± 31.2
535.2 ± 78
318.5 ± 24
446.2 ± 25
P value
0.002
0.025
0.004
0.024
Table 3. Spinal cord surface area in SCI and healthy subjects. Significant differences between SCI and the healthy are indicated in bold.
Page 33 of 38
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Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
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ulnar
tibial
Latencies (ms)
AIS A+B
24.1 ± 2.6
-
AIS C+D
22.3 ± 2.1
46.85 ± 5.05
Amplitudes (µV)
AIS A+B
0.56 ± 0.89
0 ± 0
AIS C+D
2.38 ± 0.85
1.01 ± 0.81
Table 4. Somatosensory evoked potentials (SSEP).
Left (n=18) and right (n=18) side data pooled (Mean
± standard deviation). In AIS A+B subjects, no SSEP
could be derived from the legs.
Fig. 1 Sagittal T2 weighted image of the entire myelon. Fields of view on upper cervical, lower cervical,
thoracic and at the lumbar segments are marked by boxes.
Fig. 2 Cervical spinal cord of a healthy control centered at level C5 in the transversal plane, showing 6
consecutive slices (top to bottom), displayed in the different contrasts. Left: FA (fractional anisotropy),
middle: ADC (apparent diffusion coefficient), right: colour-coded FA
Fig. 3 FA image in axial plane at cervical level. Regions of interest are shown as circles.
Anatomical region (Voxels on cervical level and at the lumbar enlargement / voxels at thoracic level /
spinal tract(s).
Cross sectional area (a)
Corticospinal tracts (b: right lateral funiculus [7/6/crossed pyramidal tract] / c: left lateral funiculus
[7/6/crossed pyramidal tract])
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Dorsal tracts (d right dorsal funiculus [7/4/fasciculus cuneatus and gracilis] / e: left dorsal funiculus
[7/4/fasciculus cuneatus and gracilis])
Fig. 4 Correlations of diffusivity measures with tibial nerve sensory evoked potentials (Tib SEP) and
clinical scores. FA (Fractional anisotropy) given in mean values across all voxels across all slices in
the selected regions of interest across all participants. Linear regression lines added. 1= AIS A (motor
and sensory complete); 2= AIS B (motor complete and sensory incomplete); 3= AIS C and 4 = AIS D
(motor and sensory incomplete)
Fig. 5 Fractional anisotropy in healthy controls and SCI subjects.
Page 35 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 37 of 38
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Journal of Neurotrauma
Chronic cervical spinal cord injury: DTMRI correlates with clinical and electrophysiological measures (doi: 10.1089/neu.2011.2027)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
