A pilot study of pre-operative motor dysfunction from gliomas in the region of corticospinal tract: Evaluation with diffusion tensor imaging
A pilot study of pre-operative motor dysfunction from gliomas in the region of corticospinal tract: Evaluation with diffusion tensor imaging
Bo Gao 1 2
Xudong Shen 0 2
Mark S. Shiroishi 2
Mingfan Pang 2
Zhiqian Li 2
Benxia Yu 1 2
Guiquan Shen 2
0 Department of Radiology, Enshi Central Hospital , Enshi, Hubei , People's Republic of China, 3 Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America, 4 Chinese Center for Disease Control and Prevention , Beijing , People's Republic of China, 5 Department of Radiology, Affiliated Hospital of Guizhou Medical University , Guiyang, Guizhou , People's Republic of China
1 Department of Radiology, Yantai Yuhuangding Hospital , Yantai, Shandong , People's Republic of China
2 Editor: Steve Huntz Fung, Houston Methodist Hospital , UNITED STATES
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: B.G. is supported by Natural Science
Foundation of Shandong Province (ZR2014HL084)
and Shandong Provincial Key Research &
Development Project (2015GSF118185). M.S.S. is
partially supported by SC CTSI (NIH/NCRR/NCATS)
Grant KL2TR000131 and NIH Loan Repayment
Program 1 L30 CA209248-01. The funders had no
role in study design, data collection and analysis,
Background and purpose
Brain tumors in the corticospinal tract (CST) region are more likely to cause motor
dysfunction. The aim of this study is to evaluate the effect of gliomas located in the CST region on
motor function with diffusion tensor imaging (DTI) preoperatively.
Materials and methods
Forty-five patients with histopathologically confirmed gliomas were included in this pilot
study, in all cases (low-grade n = 13, high-grade n = 32) CST but not the motor cortex were
involved by the tumor. DTI image were acquired and the posterior limb of the internal
capsule fractional anisotropy (FA) and relative FA (rFA = affected FA/contralateral FA) were
measured. Injury of the CST from tumor was divided into three grades (grade 1:
displacement, grade 2: displacement and infiltration, grade 3: displacement and disruption). The
fiber density index (FDi) and relative FDi (rFDi = affected FDi/contralateral FDi) of the injured
and contralateral CST were measured. The correlations between muscle strength and the
CST injury grade and the rFA, affected FDi, rFDi values were calculated using Spearman
rank correlation analysis. rFA and rFDi values of muscle strength groups (MMT2-5) were
compared with one-way analysis of variance (ANOVA). The difference of muscle strength
between low- and high-grade glioma groups were analysed with the Mann-Whitney U-test.
Muscle strength was negatively correlated with the injury grade of the CST (r = -0.840,
P<0.001). Muscle strength was positively correlated with rFA, FDi and rFDi (correlation
decision to publish, or preparation of the
manuscript. There was no additional external
funding received for this study.
Competing interests: The authors have declared
that no competing interests exist.
Abbreviations: CST, corticospinal tract; DTI,
diffusion tensor imaging; DTT, diffusion tensor
tractography; FA, fractional anisotropy; FDi, fiber
coefficients (r) were 0.615, 0.643 and 0.567 for rFA, FDi and rFDi, respectively). The rFA
values between grades (2&3, 2&4, 2&5, 3&5, 4&5) of muscle strength were significantly
different (P<0.05), the rFDi values between grades (2&4, 2&5, 3&4, 3&5) of muscle strength
were significantly different (P<0.05), while the rFA and rFDi values in the remaining groups
of muscle strength grades showed no significant differences(P>0.05).
Preoperative DTI and diffusion tensor tractography may quantify the injury degrees of CST
and the extent of motor dysfunction in patients with brain glioma.
Gliomas are the most common malignant tumors of the central nervous system. Brain tumors
occurring in the motor cortex may cause reorganization of the motor function area[
Voluntary movement is mainly controlled by the primary motor cortex, premotor cortex, and
supplementary motor area. Therefore, tumors in these regions may not necessarily cause severe
limb dysfunction. The corticospinal tract (CST) passes through the spinal interneuron (Rexed
gray matter lamina IV layer), then to the proximal anterior horn motoneuron (control of
trunk and limb muscles), or terminate in the spinal cord anterior horn motor cell to dominate
free movement of skeletal muscle (control of fine movements of hand, foot and small muscles).
Brain tumors located in the CST region are more likely to cause motor system dysfunction.
Limb muscle strength is an important index to predict clinical prognosis and to evaluate quality of life in such patients.
Compared to conventional MRI, diffusion tensor imaging (DTI) can infer the extent of gli
oma invasion by evaluating changes of water molecule diffusion in white matter fiber tracts[3±
5]. The surgical treatment of intracranial tumors near the CST remains a challenge because of
the uncertainty in predicting postoperative limb function assessment is usually more difficult.
Using DTI for the quantitative analysis the infiltration degree of the CST has been proven to
be critical in the evaluation of motor dysfunction and surgical guidance[
In this pilot study, we utilize preoperative DTI to study the effect of gliomas located in the region of the CST region on motor function.
Materials and methods
The study was approved by the institutional review board (IRB) of Hubei Enshi Central Hospi
tal, China. All patients provided written informed consent. For minors, this study was carried
out following the written informed consent of the parents or guardian.
Fifty-two patients with suspected primary supratentorial gliomas at Hubei Enshi Central
Hospital were enrolled in this study from February 2013 to April 2016. Tumors were diag
nosed with pre-operative conventional and contrast-enhanced MRI and were classified by two
neuroradiologists with more than five years interpretation experience, according to World
Health Organization 2007 criteria as confirmed by surgery and biopsy. All histopathological data were provided and reviewed by department of pathology of Hubei Enshi Central Hospital and Guizhou Medical University.
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The inclusion criteria were the followings: 1) histopathologically confirmed glioma; 2) MR
imaging examination prior to surgery; 3) no radiation or chemo-therapy before the MR
imaging examination; 4) tumors located in the cerebral hemispheres in the region of the ipsilateral
CST; 5) contralateral CST demonstrating normal appearance or only mild displacement on FA
color-coded map. The exclusion criteria were the followings: 1) evidence of tumor located in
the primary motor cortex or centered in this region demonstrated on contrast-enhanced MR
images or abnormal T2-hyperintensity; 2) CST regions affected by other diseases such as
leukodystrophy, vascular diseases, etc; 3) lesions in the motor cortex may lead to limb motor
dysfunction such as cerebral infarction, infection,etc; 4) obvious motion artifacts; 5) muscle
motor dysfunction caused by other diseases such as limb disuse, arthrogenous, osteoporotic or
joint soft tissue injury.
Contralateral knee muscle strength of all patients was measured by manual muscle testing
(MMT). The knee muscle strength was divided into 0±5 grade (0: no evidence of muscle
contraction, 1: contraction but no movement, 2: movement with without gravity, 3: movement
against gravity but not against resistance, 4: movement against resistance but less than normal,
and 5: normal strength). The test was repeated three times and the muscle strength grade was
determined by a neurologist with more than five-year experience and who are blinded to
MRI scans were performed on a Philips Achieva X-Series 3.0T system with a 16-channel
SENSE head coil. All patients underwent conventional contrast-enhanced brain MRI and DTI
scans. Routine MRI scanning protocols include axial T1-weighted imaging (T1WI), axial and
sagittal T2-weighted imaging (T2WI), and axial T2-weighted fluid-attenuated inversion
recovery (FLAIR). T1WI: inversion time, 800 ms; repetition time/echo time, 2278/20 ms; section
thickness, 6 mm; matrix size, 288×190; field of view, 196×196 mm. Axial and sagittal T2WI:
repetition time/echo time, 2500/90 ms; section thickness, 6 mm; matrix size, 420×306; field of
view, 230×230 mm. Axial FLAIR: repetition time/echo time, 8000/120 ms; section thickness, 6
mm; matrix size, 304×216; field of view, 230×230 mm. Axial contrast-enhanced SE T1WI scan:
repetition time /echo time 400/8.6 ms; section thickness, 6 mm; matrix size, 288×192; field of
view, 230×230 mm. For contrast-enhanced T1WI, 0.1mmol/kg dose of gadolinium-DTPA
contrast agent (Bayer Schering Pharma, Magnevist) was administered intravenously. Spoiled
gradient echo (FFE) T1WI: repetition time/echo time, 200/2 ms; section thickness, 1 mm;
interval 1 mm; flip angle 75Ê; matrix 256×256; field of view, 230×230 mm. For DTI,
diffusionweighted respiratory-triggered single-shot echo-planar imaging (SS-EPI) was used with the
following parameters: repetition time /echo time, 7103.62/60 ms; matrix size, 92×92; field of
view, 222×222 mm; 60 sections, 2 mm slices no gap; NEX 2. Diffusion-gradient encoding in 15
directions with b value of 800 sec/mm2 and an additional measurement without
diffusion-gradient encoding (b = 0 sec/mm2) were performed. The total scanning time was about 50
minutes for each patient.
The MR Workspace (Extended V184.108.40.206, Philips Medical System) software package was used
for post-processing of DTI and DTT. Data acquisition noise was eliminated with Gaussian
smoothing filter. A region of interest (ROI) area measuring about 50 mm2 was placed in the
posterior three quarters of the posterior limb of the internal capsule of the affected side by two
experienced neuroradiologists who had at least five years of work experience and were familiar
with the utility of the post-processing methods. FA values were measured by the same two
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independent readers on the axial FA color-coded map of the healthy and injured side. ROI
measurement of the healthy and the injured side were repeated three times and an average
value was recorded. This value was used to calculate relative FA values (rFA = injured
Seed regions were selected using the axial color encoding direction map for CST fiber track
ing. The CST originates in the motor cortex (Broadman 4 and Broadman 6), and then extends
into the corona radiata, posterior limb of internal capsule, cerebral peduncle, and pyramids of
medulla oblongata. Therefore, the ROIs of the CST were placed in the following three areas:
pyramids of medulla oblongata, cerebral peduncle, subcortical white matter of precentral
gyrus and premotor cortex.
A line propagation technique was used to track fibers and the logic algorithm "AND" was
used to include the three ROIs through the fiber tracts, as well as "NOT" to exclude fiber tracts
deviating from normal anatomy, using the contralateral corresponding region as a reference.
The FA threshold was set to 0.2, the angle of fiber tracing was 27 degrees, and step size was 0.2.
FDi is the number of white matter fibers per unit volume that is calculated after the fiber trac
ing is completed (rFDi = injured FDi/contralateral FDi). Ipsilateral and contralateral CST FDi
and rFDi were obtained.
Witwer et al.[
] and Field et al.'s[
] classification method was employed to quantify the
status of the CST relative to tumors. Because nearly all patients in this study had displacement
of the CST to a certain extent, infiltration and disruption were defined as follows: 1) grade 1:
displacementÐwhite matter tracts display normal signal normal on the FA map or FA
colorcoded map; 2) grade 2: displacement and infiltrationÐdisplacement and abnormal signal on
the FA map or FA color-coded map with decreased FA values; white matter fiber tracts
surrounded by tissue edema but remained intact without significant disruption (Fig 1); 3) grade
3: displacement and disruptionÐcoexistence of white matter fiber tract displacement and disruption; the direction of white matter tracts cannot be identified on the FA map or FA colorcoded map, and interruption of white matter tracts can be found on DTT (Fig 2).
All statistical analysis was performed using SPSS 13.0 (SPSS, Inc., Chicago, IL, USA). The
relationship between the injury degrees of the CST, rFA, FDi, rFDi values and muscle strength
were analyzed with Spearman rank correlation analysis. The rFA and rFDi values of each
muscle strength group were tested for normality as well as equality of variances. If the data met the
assumption of normal distribution and homogeneity of variance, an independent sample-t test
was applied. If the data followed a normal distribution and heterogeneity of variance, the
approximated independent sample-t test was used for analysis. The differences between the
mean rFA and rFDi values of different muscle strength groups were analyzed with analysis of
variance (ANOVA). The difference of muscle strength between low- and high- grade gliomas
groups were analysed with the Mann-Whitney U-test. Statistical significance was designated as
P < 0.05.
Of our 52 patients, 4 cases with partial infiltration of the primary motor cortex and 3 cases
with very large tumors that precluded fiber tracking were excluded. Therefore, we ultimately
enrolled 45 cases that satisfied our inclusion criteria. The average age was 45 (range 6±78)
years. Twenty-six were male and 19 were female. Thirty-eight cases demonstrated motor
dysfunction. Seven cases exhibited headache, dizziness, convulsions and slight movement
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Fig 1. A 40-year-old female with right frontotemporal astrocytoma (WHO grade II) and left lower limb
muscle strength was MMT 5. ADC map (A) show the solid part of tumor was slightly lower signal, FA map
(B) and color encoding pattern map (C) and DTT map (D, E) on the right side of the corticospinal tract showed
mild displacement, DTT-FLAIR show around of the CST without edema.
Patient demographics and the results of CST injury grade are listed in S1 Table. CST injury
grade: Twenty-one cases demonstrated grade 1, 6 cases showed grade 2, 18 cases had grade 3.
Muscle strength: Six cases had grade 2, 12 cases demonstrated grade 3, 21 cases showed grade
4, and 6 cases had grade 5.A negative correlation was found between muscle strength and CST
injury grade (r = -0.840, P< 0.05) while a positive correlation was found between muscle
strength and rFA value of the posterior limb of internal capsule between the injured and
contralateral side (r = 0.615, P< 0.05). Positive correlations were also noted between muscle
strength and rFDi (r = 0.567, P< 0.05) and FDi of the injured side (r = 0.643, P< 0.05). There
were 13 cases with low-grade gliomas and 32 cases with high-grade gliomas, a statistically
significant difference in muscle strength was found between these 2 groups of tumors (Z =
The values of rFA and rFDi between different muscle strength groups were compared. The
rFA values between grade (2 & 3, 2 & 4, 2 & 5, 3 & 5, 4 & 5) groups of muscle strength were
significant difference (P<0.05), the rFDi values between grade (2& 4, 2 & 5, 3 & 4, 3 & 5)groups
of muscle strength were significantly difference (P<0.05), the rFA and rFDi values in the
remaining groups of muscle strength grades had no significant difference(P>0.05) in S2 Table.
Tumors in the motor cortex may not result in serious limb dysfunction because of motor function remodeling[11,12]. The purpose of this study was to quantitatively analyze the degree of
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Fig 2. A 48-year-old female with left thalamic glioblastoma multiforme (WHO grade IV), the right knee
muscle strength was MMT 3. ADC map (A), FA map (B),T1WI(C), contrast-enhanced T1WI (D) show the
tumor infiltrated normal tissues. DTT map (E, F) show the left corticospinal tract was displaced and infiltrated,
and the number of left corticospinal fibers decreased.
damage to the conductive fibers and resulting muscle strength. Therefore, we exclude lesions
in the motor cortex and lower limb lesions. The statistical results showed that muscle strength
was negatively correlated with the degree of CST injury, while a positive correlation was seen
with rFA, FDi and rFDi values. Tumor cell proliferation and invasion would result in
disruption of CST myelin and axonal membranes, the degree of which may reflect its biological
]. DTI characterizes the movement of water molecules, which can be used to
evaluate the proliferation and invasion, as well as Na+-K+ pump damage of the cell membrane
. Nerve fiber tract damage results in the inability of nerve impulses to spread sequentially,
thus resulting in reduce of limb resistive exercise. Damage to nerve fiber tracts can lead to a
reduction of anisotropic diffusion of water molecules and an increase in isotropic diffusion,
with resulting decrease of FA and rFA values[
]. Fiber disruption and tumor infiltration may
lead to decreasing units within the fiber voxel with consequent reduction of FDi and rFDi[
Consequently tumor infiltrating the CST can lead to CST damage and subsequent motor dysfunction.
DTI parameters may potentially quantify the degree of CST injury, assess the damage to
motor conduction fibers preoperatively, and predict therapeutic effect and outcome[
Our statistical results showed that the values of rFA between different muscle strength groups have significant differences. Beppu et al. measured FA values in glioblastoma and normal brain tissue and found that FA may reflect glioma cell density and proliferative activity. Some studies have suggested that FA value is closely related to the integrity of white matter fiber
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]. Stadlbauer et al. studied 10 glioma patients with preoperative DTI positron
emission tomography (PET) and found that the pyramidal tract rFA value in the sensorimotor
deficits group was significantly reduced while 18F-FDG uptake was significantly increased, the
increase of 18F-FDG uptake may be associated with tumor cell proliferation and infiltration.
Therefore, changes of muscle strength due to CST injury may be the result of tumor cell prolif
eration and infiltration degree.
The comparison between different grades of gliomas showed that muscle strength was
significantly different between high- and low-grade groups. FA values may reflect the degree of
]. Prior studies have found that FA values were reduced in the CST which
may be associated with decrease muscle strength in the contralateral limb[23±26]. Different
degrees of glioma infiltration may have resulted in inconsistencies in the nerve fiber axon gap
and the number of axons in each voxel. The fiber density and anisotropy had no significant
changes or just mild changes in our low-grade glioma patients (S1 Table), possibly because the
myelin membrane has no obvious or only mild injury in low-grade gliomas. High-grade
glioma grow aggressively and so the necrotic microcapsules within the tumor may lead to
damage of the surrounding glial cells and neurons with reduction of fiber density[
decrease of the fibers density may then lead to a reduction of brain nerve impulse conduction
from the motor cortex resulting in involuntary limb movements. Stadlbauer et al.[
that the FDi value of the affected side was significantly lower than that of contralateral side and
also that there was a difference of FDi values between high-grade and low-grade groups. They
found that both the N-acetyl-aspartate (NAA) peak from MR spectroscopy (MRS) and FDi
decrease in high-grade glioma indicated the damage to the integrity of the nerve structure and
fibers. Their results suggest that the FDi value can reflect the degree of tumor infiltration better
than the FA. FDi was significantly linearly correlated with the number of tumor cells[
Muscle dysfunction and the degree of CST injury from glioma were linearly correlated with fiber
density suggesting that DTI can reflect different degrees of injury from glioma in CST area.
The action potential conduction in the motor area is influenced by the myelin sheath
integrity and diameter of fibers [
]. Theoretically, the closer a brain tumor is to the CST, the
greater the potential for decreases of muscle strength. Furthermore, larger tumors may result
in higher degree of injury on CST. This may result in smaller axonal diameter and thinner
myelin which may cause decreased transmission of nerve impulses[
]. Although prior studies
have shown that the size of benign brain tumors was not significantly different between
hemiplegia versus non-hemiplegic groups[
], these results may be due to tumor location, duration
of diseases, pathological type and sample size among other factors.
Several limitations of our work should be considered. Linear extension technology tracing
of fiber tracts is defined based on the diffusion property of water molecules in each voxel, not
true fiber tracts[
]. Although a large number of studies have shown a high degree of
consistency using fiber tracing techniques with classical anatomy, our results were not confirmed by
histopathology. Therefore, our finding of abnormal white matter fibers need to be further
confirmed in subsequent studies using histopathological confirmation. Although ROI-based
measurement is the most common DTI analysis method, our use of this technique did not
adequately consider tumor heterogeneity[
]. With the growth of tumor, microvascular necrosis
within the tumor may lead to damage to the surrounding glial cells and neurons; therefore, the
pathological concept of "tumor invasion margin" should be introduced into a future study[
Placement of the borders of the ROI along the edge of the tumor outline is the most commonly
]. It has been noted that the junction of tumor and normal tissue are rich in
cancer stem cells, which might represent tumor invasion, within the range of three to five
layers of cells[
]. Our study also found that tumor infiltrating margin was associated with the
CST injure grades. Based on the above, we chose the corticospinal tract ROI area to avoid the
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outline of tumor edge. Our study used only DTI for preoperative assessment of the degree of
CST injury. Changes in the dispersion of the fibers caused by tumor infiltration or edema can
also potentially be identified by MRS analysis[
]. Blood oxygen level-dependent (BOLD)
functional MRI (fMRI) can also localize brain functional areas and display its activation level
]. Combining MRS, fMRI with DTI may provide more information on the assessment
brain tumors and motor function changes[
]. Furthermore, our study provided only
preoperative muscle strength grading for patients. Intraoperative cortical or subcortical stimulation
were not combined to obtain EEG and postoperative motor function and life quality were not
evaluated either. Only the pre-operative motor function of patients was assessed in this study.
In addition, language dysfunction was also not assessed here. In our study, only contralateral
knee muscle strength was tested. Tumor involving any portion of the CST may lead to lower
limb muscles and trunk muscles weakness and so it may be more meaningful to incorporate
these muscle strength changes into study in the future. The change of muscle strength is not
likely to be the result of one single factor, actually which is affected by primary motor cortex,
degree of CST injury and joint muscle disease. Therefore, the clinical evaluation of muscle
strength must take these factors into consideration.
In summary, our study suggests that pre-operative DTI quantitative parameters can assess the
degree of CST injury by glioma and show abnormal brain tumor infiltration area. The degree
of muscle strength dysfunction is correlated well with the injury degree of the CST. DTI may
provide critical information for the greatest degree of tumor resection and protection of
S1 Fig. A 40-year-old female with right frontotemporal astrocytoma (WHO grade II) and
left lower limb muscle strength was MMT 5. ADC map (A) show the solid part of tumor was
slightly lower signal, FA map (B) and color encoding pattern map (C) and DTT map (D, E) on
the right side of the corticospinal tract showed mild displacement, DTT-FLAIR show around
of the CST without edema.
S2 Fig. A 48-year-old female with left thalamic glioblastoma multiforme (WHO grade IV),
the right knee muscle strength was MMT 3. ADC map (A), FA map (B),T1WI(C),
contrastenhanced T1WI (D) show the tumor infiltrated normal tissues. DTT map (E,F) show the left
corticospinal tract was displaced and infiltrated, and the number of left corticospinal fibers
S1 Table. Clinical characteristics of 45 patients with glioma.
S2 Table. The comparison of rFDi and rFA among different muscle groups. Note: rFA was
the injuryed/contralateral FA value of injured and contralateral side in posterior limb of
internal capsule, rFDi was the injuryed/contralateral FDi value of injured and contralateral CST,
test level to P <0.05 was considered statistically significant, indicated statistically significant
8 / 11
S1 File. STROBE_checklist_v4_combined_PlosMedicine.
S2 File. ICMJE conflicts of interest-Bo Gao.
Conceptualization: Bo Gao, Mark S. Shiroishi, Zhiqian Li, Guiquan Shen.
Data curation: Bo Gao, Xudong Shen, Mark S. Shiroishi, Mingfan Pang, Zhiqian Li, Benxia
Yu, Guiquan Shen.
Formal analysis: Bo Gao, Xudong Shen, Mark S. Shiroishi, Zhiqian Li, Benxia Yu, Guiquan
Funding acquisition: Bo Gao, Zhiqian Li, Guiquan Shen.
Investigation: Bo Gao, Xudong Shen, Mingfan Pang, Zhiqian Li, Benxia Yu, Guiquan Shen.
Methodology: Bo Gao, Xudong Shen, Mark S. Shiroishi, Mingfan Pang, Zhiqian Li, Benxia
Yu, Guiquan Shen.
Project administration: Bo Gao, Xudong Shen, Mingfan Pang, Benxia Yu, Guiquan Shen.
Resources: Bo Gao, Mark S. Shiroishi, Zhiqian Li, Guiquan Shen.
Software: Bo Gao, Xudong Shen, Mark S. Shiroishi, Mingfan Pang, Zhiqian Li, Guiquan Shen.
Supervision: Zhiqian Li, Guiquan Shen.
Validation: Xudong Shen, Mark S. Shiroishi, Zhiqian Li, Benxia Yu, Guiquan Shen.
Visualization: Mingfan Pang, Zhiqian Li, Guiquan Shen.
Writing ± original draft: Xudong Shen.
Writing ± review & editing: Bo Gao, Xudong Shen, Mark S. Shiroishi, Guiquan Shen.
9 / 11
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