Dynamic contrast-enhanced magnetic resonance imaging in denervated skeletal muscle: Experimental study in rabbits
Dynamic contrast-enhanced magnetic resonance imaging in denervated skeletal muscle: Experimental study in rabbits
Liang Qi 0 2 3
Lei Xu 0 2 3
Wen-Tao Wang 0 2 3
Yu-Dong Zhang 0 2 3
Rui Zhang 1 2 3
Yue-Fen Zou 0 2 3
Hai-Bin ShiID 0 2 3
0 Department of Radiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing , PR China
1 Department of Neurosurgery, Nanjing Children's Hospital , Nanjing , PR China
2 Editor: Xi Chen, McLean Hospital , UNITED STATES
3 a Current address: Department of Radiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, PR , China ?b Current address: Department of Neurosurgery, Nanjing Children's Hospital , Nanjing , PR China
To investigate the value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for evaluating denervated skeletal muscle in rabbits.
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: This study was funded by the National
Natural Science Foundation of China (grant number
81701652), which was received by Liang Qi. The
URL is https://isisn.nsfc.gov.cn. The funders had
no role in study design, data collection and
analysis, decision to publish, or preparation of the
Competing interests: The authors have declared
that no competing interests exist.
Materials and methods
24 male rabbits were randomly divided into an irreversible neurotmesis group and a control
group. In the experimental group, the sciatic nerves of rabbits were transected for
irreversible neurotmesis model. A sham operation was performed in the control group. MRI of rabbit
lower legs was performed before nerve surgery and 1 day, 3 days, 5 days, 1 week, 2 weeks,
3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks after surgery.
Signal intensity changes were seen in the left gastrocnemius muscle on the T2-weighted
images. DCE-MRI derived parameters (Ktrans, Kep, and Vp) were measured in vivo. In the
irreversible neurotmesis group, T2-weighted images showed increased signal intensity in
the left gastrocnemius muscle. Ktrans, Vp values changes occur as early as 1 day after
denervation, and increased gradually until 4 weeks after surgery. There are significant increases
in both Ktrans and Vp values compared with those in the control group after surgery (P <
0.05). Kep values show no significant difference between the irreversible neurotmesis group
and the control group.
DCE-MRI hold the promise of an early and sensitive diagnosis of denervated skeletal
Peripheral nerve injury leads to morphologic and metabolic changes in the target denervated
skeletal muscles. Electromyography (EMG) is useful for the diagnosis of denervated muscles
]. However, EMG sometimes presents some difficulties in the detection of denervated
skeletal muscle because it is both invasive and dependent on the skill of the examiner, and it is
difficult to obtain information that is useful, objective, and reproducible with EMG in the deep
muscles or small intramuscular areas.
Conventional magnetic resonance imaging (MRI) has proved to be useful in the diagnosis
of denervated skeletal muscle after peripheral nerve injury [
]. Denervated skeletal muscle
usually show high signal intensity on T2-weighted MR images and normal signal intensity on
T1-weighted MR images. Numerous previous articles have corroborated these findings [
Recently, there have been a few of investigations of functional MR imaging in the evaluation
of denervated skeletal muscle [
]. Some previous studies found that acute and subacute
denervated skeletal muscles showed increased T2, apparent diffusion coefficient (ADC) and
decreased fractional anisotropy on T2 mapping, diffusion-weighted imaging (DWI), and
diffusion tensor imaging (DTI), respectively [
]. Another functional MR imaging, dynamic
contrast-enhanced (DCE) T1-weighted MR perfusion imaging, is also available. With the
recent improvements in functional MR imaging, tissue perfusion assessment with DCE-MRI
is routinely performed in neurology, oncology and cardiology as well as, more recently, in the
imaging of ischemic skeletal muscle [
]. To our knowledge, few articles have used this
technique to assess the denervated skeletal muscle after peripheral nerve injury. Therefore, the
purpose of our study was to determine the value of DCE-MRI for evaluating the early state of
denervated skeletal muscle in nerve injury models in rabbits.
Materials and methods
This study was carried out in strict accordance with the recommendations in the Guide for the
Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was
approved by the Committee on the Ethics of Animal Experiments of The First Affiliated
Hospital of Nanjing Medical university (Protocol Number: 25783). All surgery was performed
under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering. The
animals were held in separate cages in a clean environment with proper temperature and
humidity. The rabbits were subjected to 12h light /dark cycle and allowed to have food and
water ad libitum. Viability and behavior were recorded every day, and body weight was
recorded twice weekly. If the rabbits presented with signs of suffering (pain, weakening) or
loss of more than 15% of baseline weight, the animals were humanely killed considered. We
used a total of 24 male New White rabbits, each of which weighted approximately 3kg. The
rabbits was numbered from 1 to 24 according to the body weight, using the random number
table, the animals were divided into an irreversible neurotmesis group (group A) and a control
group (group B), there were 12 rabbits in each group. The rabbits were anesthetized with 30
mgkg?1of pentobarbital sodium (Nembutal; Bayer, Leverkusen, Germany) injected into the
external ear vein. In the group A, a 3cm incision of the skin was made on the left proximal
hind limb at the level of the hip bone. The sciatic nerve was exposed at the sciatic notch, we
transected and removed 1cm length of sciatic nerve for a complete irreversible neurotmesis
model. In the group B, we performed sham operations (incision and exploration of the sciatic
nerve only) at the same time. To avoid infection, 800000 units of penicillin (HenRui Co,
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China) were administered via intramuscular injection over the 7 days following operation.
Ketoprofen (1.0mg/kg, once daily, (Xinan Pharmaceutical Factory, China) were
subcutaneously injected for three days. All surgical procedures were performed by an author who had 10
years of experience with microsurgical procedures.
MRI acquisition technique
MR studies was performed before nerve surgery and was repeated 1 day, 3 days, 5 days, 1week,
2 weeks, 3weeks 4 weeks, 6 weeks, 8 weeks, 10 weeks and 12 weeks after surgery. A venous
indwelling needle (24 Gauge) was inserted into a lateral ear vein and secured for intravenous
administration of anesthetics and MR contrast agent. All examinations were conducted on a 3
Tesla MR unit (Magnetom Trio Tim; Siemens, Erlangen, Germany). The measurements were
performed with the rabbits under anesthesia and in a prone position with both hind limbs
positioned in a dedicated eight-channel knee coil (Invivo, Gainesville, FL, USA). The MRI
protocol included the following sequences: (1) Axial T1-weighted by turbo spin-echo (TSE)
sequence images were obtained by using the following parameters: repetition time (TR),
824ms; echo time (TE), 22ms; matrix size, 320 ? 320; field of view (FOV), 120 ? 120mm; slice
thickness, 3mm. (2) Axial T2-weighted images by TSE with fat suppression was obtained with
the following parameters: TR, 4000; TE, 52; matrix size 320 ? 320; FOV, 120 ? 120mm; slice
thickness, 3mm; (3) In the term of DCE imaging, for the baseline T1 mapping, unenhanced
T1-weighted volume interpolated gradient echo (VIBE) images were acquired at each of the 3
flip angles using the following parameters: TR, 4.6ms; TE, 1.6ms; flip angle (FA), 2?, 8?, and
15?; FOV, 120? 120mm; matrix, 192 ? 192; slice thickness, 3 mm. Then, DCE MR imaging
using a radial three-dimensional VIBE with k-space-weighted image contrast reconstruction
was performed. After 3 acquisitions, a bolus injection of 0.1 mmol/kg Gd-DTPA
(gadopentetate dimeglumine, Magnevist, Bayer Schering, Berlin, Germany) was injected at a rate of 1 mL/
s through the venous indwelling needle. Bolus injection was performed with a MR-compatible
power injector (Spectris; Medrad, Pittsburgh, PA) followed by a 2-mL saline flush. The
parameters were as follows: TR, 4.6ms; TE,1.6ms; FA, 11?; FOV, 120? 120mm; matrix, 192 ? 192;
slice thickness, 3mm; time resolution per measurement, 6 seconds; total scan duration, 10min.
We subjectively classified signal intensity changes in the denervated gastrocnemius muscle
into the following four grades: grade 0 (iso-signal intensity compared with that in the control
group); grade 1 (slightly hyperintense); grade 2 (intermediate to high signal intensity); grade 3
(high signal intensity). Two authors (more than 10 years of experience with musculoskeletal
MR imaging) evaluated the images in consensus.
The DCE-MRI data was post-processed by in-house software (OmniKinetics Version 2.0,
GE Healthcare, China). The current tracer-kinetic modeling for quantitation of DCE images
are based on a modified tofts model [
]. The model describes the tissue as a combination of a
vascular compartment and an extracellular extravascular compartment, the following
concentration-time equation was used:
C?t? ? Ktrans t
0 Cp?t?ekep?t t?dt ? vpCp?t?
Where Ktrans is the volume transfer constant between blood plasma and the extracellular
extravascular space (EES); Kep is the rate constant between the EES and blood plasma; Vp is
blood plasma volume fraction; Cp(?) is the concentration-time curve in the arterial blood
plasma. For quantitation of DCE images, the contrast concentration was semi-quantitated by
using relative signal intensity enhancement ratio. For the purpose of the vascular input
function (VIF), a region of interest (ROI) was placed in the popliteal artery, the mean size of
ROIs was 4 mm2 (range, 3?5 mm2). Then the pixel-by-pixel plots of Ktrans, Kep and Vp maps
were automatically constructed by a Levenberg-Marquardt nonlinear least squares algorithm.
ROIs were manually drawn on all imaging sections to acquire a volume of interest (VOI) of
gastrocnemius muscle, and an effort was made to exclude fatty septa and vessels. Then, the
mean Ktrans, Kep, and Vp values derived from Color-coded parametric maps were obtained.
The mean VOIs of the gastrocnemius muscle were 4.54 ? 2.18 cm3. The above DCE
parameters were measured by two independent observers (more than 10 years of experience with
musculoskeletal MR imaging, respectively) who were blinded to the group allocations. The
results acquired from two observers were averaged and used for analysis.
A Cadwell Sierra (Neuropack Four Mini; Nihon Kohden, Tokyo, Japan) computer-based
EMG unit was used for electrodiagnostic studies, two rabbits randomly selected from each
group were again anesthetized, and a conventional concentric needle electrode was placed in
the left gastrocnemius muscle. We looked for abnormal spontaneous activity (positive sharp
waves or fibrillation). The measurements were performed before nerve surgery and were
repeated at 1 day, 3 days, 5 days, 1week, 2 weeks, 3weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks
and 12 weeks after surgery by an author who had 10 years of experience with EMG.
All statistical analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, IL,USA).
Continuous variables were expressed as mean ? standard deviation (SD). Interobserver reliability of
the measurements was assessed by using the intraclass correlation coefficient (ICC). The ICC
was interpreted as follows: poor agreement (ICC = 0); minor agreement (ICC = 0?0.2); fair
agreement (ICC = 0.21?0.40); moderate agreement (ICC = 0.41?0.60); good agreement
(ICC = 0.61?0.8), perfect agreement (ICC = 0.81?1.00). Ktrans, Kep, and Vp values of specific
acquisition points within groups were compared by using repeated-measures analysis of
variance. Comparisons between the two groups at each acquisition point were performed by using
one-way analysis of variance (ANOVA) test, statistical significances was considered when P
value of less than 0.05.
Changes in signal intensity
In the irreversible neurotmesis group (Group A), T2-weighted images with fat suppression
showed slightly hyperintense in the target gastrocnemius muscle beginning 5 days after
surgery, at 3 weeks, high signal intensity were observed. For all rabbits in this group, signal
intensity remained high until 12-week follow up (Table 1).
Quantitative DCE MR imaging parameters
Kappa values (?) of 0.823, 0.852, and 0.792 for Ktrans, Kep, and Vp, respectively, show good
In the irreversible neurotmesis group (group A), Ktrans, Vp values increased gradually until
4 weeks after surgery and remained high (mean, approximately 15.391 ? 2.829 ? 10?2 min-1
and 3.893 ? 0.890 ? 10?1, respectively,) throughout the remainder of the study period (Tables
2 and 3, Figs 1, 2 and 3). In this group, we observed significant increases in both Ktrans and Vp
values compared with those in the control group during the period from1 day after surgery to
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12 weeks after surgery (Tables 2 and 3, Figs 1, 2 and 3). Ktrans values increased significantly
during the periods from pre-operation to1 day after surgery (P = 0.029), from 1 day after
surgery to 3 days after surgery (P < 0.001), from 3 days after surgery to 5 days after surgery
(P < 0.001), from 5 days after surgery to 1 week after surgery (P < 0.001), from 1 week after
surgery to 2 weeks after surgery (P < 0.001), from 2 weeks after surgery to 4 weeks after
surgery (P < 0.001). Vp values increased significantly during the periods from pre-operation to 1
day after surgery (P < 0.001), from 1 day after surgery to 3 days after surgery (P = 0.001), from
3 days after surgery to 1 week after surgery (P < 0.001), from 1 week after surgery to 2 weeks
after surgery (P = 0.007). From 2 weeks after surgery to 4 weeks after surgery (P = 0.001)
However, Kep values show no significant difference between the irreversible neurotmesis group and
the control group.
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W = week. P-value represents the comparison results between group A and B by the one-way analysis of variance analyzation.
P values indicate statistical significance.
Group B (?10?1 ml/ml)
0.210 ? 0.031
0.217 ? 0.085
0.182 ? 0.055
0.217 ? 0.087
0.187 ? 0.064
0.201 ? 0.113
0.225 ? 0.100
0.188 ? 0.082
0.194 ? 0.050
0.195 ? 0.056
0.236 ? 0.057
0.216 ? 0.088
In the irreversible axonotmesis group (group A), spontaneous activity was observed at 2-week
follow-up; in the control group (group B). EMG was completely normal throughout the study
As in other studies, we demonstrate here that denervated skeletal muscle in the acute and
subacute phase characteristically show high signal intensity on T2-weighted MR images [
5, 6, 9
However, to our knowledge, few studies available to date have used DCE MR imaging to
evaluate denervated skeletal muscle. In this study, we evaluated the utility of DCE MR imaging for
assessing denervated skeletal muscles in rabbits. Among the three different DCE MR
imagingderived parameters (Ktrans, Kep, and Vp values) used in this study, we found that compared to
Fig 1. Graph shows the time course of Ktrans values for each injury group. There were significant differences
between irreversible neurotmesis group (group A, blue line) and control group (group B, orange line) after surgery
(P < 0.05). = P < 0.05.
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Fig 2. Graph shows the time course of Vp values for each injury group. There were significant differences between
irreversible neurotmesis group (group A, blue line) and control group (group B, orange line) after surgery (P < 0.05).
= P < 0.05.
the uninjured nerves group (group A) showed a significant increase in Ktrans and Vp values of
denervated skeletal muscle after surgery.
For DCE MR imaging parameters, we found Ktrans and Vp values increased significantly in
the irreversible axonotmesis groups compared those in the control group during the stage of
denervation. MR contrast agent Gd-DTPA does not enter the intracellular compartment and
passes freely through the endothelial barrier with a rapid equilibrium between the interstitial
and intravascular space . Therefore, the increased Ktrans and Vp values could be caused by
a dilatation of the vascular bed, an enlargement of the extracellular space, or both. A previous
study by Wessig et al found a significant increase of muscle capillaries at 2 days after
denervation, and peak capillary enlargement was reached at 4 weeks follow up . Another study by
Eisenberg et al using radiolabeled microspheres in rats found a ten-fold increase in blood flow
in denervated skeletal muscle. Several other experimental studies also have suggested that
injury of sympathetic vasoconstriction leads to increased blood volume in denervated skeletal
]. In the study by Yamabe et al and Holl et al, they demonstrated that
extracellular fluid space significantly increased in the denervated skeletal muscle. Denervation
causes increases in proteolysis , and the permeability muscle cell membrane [
decrease in protein synthesis and glycolysis [
]. Also, loss of neurotrophic factor [
atrophy caused by immobilization, and functional disability of Na,K-ATPase may occur[
All of these changes could increase the extracellular water volume. In the present study, we
found increase of Ktrans and Vp values in denervated skeletal muscle as early as 1 day after
surgery, i.e., about 2 weeks before the appearance of EMG abnormities. Compared with signal
intensity changes, the Ktrans and Vp values obtained from DCE MR imaging further narrowed
this diagnostic gap.
Kep values represents the flux rate constant between the EES and blood plasma, in the
present study, there was no significant differences in Kep values between the irreversible
axonotmesis group and the control group. In our opinion, it may be due to contrast enhanced pattern.
In our study, we found that both the denervated skeletal muscle and normal skeletal muscle in
the rabbits showed persistent pattern (type-I) time-intensity curve (TIC). During the scan
time, the contrast in the skeletal muscle constantly full-filled into the EES. Considered that Kep
is the flux rate constant from EES to blood plasma, it was not surprising to find that there was
no significant difference in Kep values between these two groups.
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Fig 3. Axial fat-suppressed T2-weighted MR images of the left gastrocnemius muscle (outlined muscle in image)
obtained with rabbits in the prone position. (a): At 5 days after surgery, image shows grade 1 signal intensity (ie,
signal intensity was isointense or slightly hyperintense compared with that in the control group). (b, c): Color-coded
parametric maps are derived from DCE MR imaging. Corresponding Ktrans and Vp values are 4.513 ?10?2 min-1,
0.152ml/ml, respectively. (d): At 2 weeks after surgery, image shows grade 2 signal intensity (ie, intermediate to high
signal intensity compared with that in the control group). (e, f): Color-coded parametric maps are derived from
DCE-MR imaging. Corresponding Ktrans and Vp values are 11.681 ?10?2 min-1, 0.272ml/ml, respectively. (g): At 4
weeks after surgery, image shows grade 3 signal intensity(ie, high signal intensity compared with that in the control
group). (h, i): Color-coded parametric maps are derived from DCE MR imaging. Corresponding Ktrans and Vp values
are 16.203 ?10?2 min-1, 0.422ml/ml, respectively.
MRI changes in denervated skeletal muscles were first described by Polak et al in 1988[
Fifteen days after transection of the sciatic nerves in rats, prolongation of T2 TR was observed
in the denervated skeletal muscles of the lower legs. Thereafter, some other studies also
demonstrated that the denervated skeletal muscles presented with high signal intensity on
T2-weighted MR images. This phenomenon of high signal intensity on T2-weighted image in
denervated skeletal muscles might correlate with an increase in extracellular fluid [
6, 7, 9
In the present study, denervated skeletal muscles showed increased signal intensity that
started 5 days after surgery, and presented continuously high signal intensity from 3 weeks
after surgery. The time course of signal intensity changes seen on T2-weighted MR images of
denervated skeletal muscle in our study was inconsistent with those in previous reports. The
study by Holl et al demonstrated that increased signal intensity in denervated skeletal muscle
occurred as early as 1 day after sciatic nerve axotomy [
], whereas in another study by Ku?llmer
et al, increased signal intensity on T2-weighted images in denervated skeletal muscle has been
shown to occur as early as 3 weeks after suprascapular nerve transection [
]. This discrepant
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results might be due to different nerve injury pattern [
], denervation develops earlier when
the nerve was cut near the muscle. Long peripheral nerve stump allows a longer release of
neurotrophic and protective factors than short stump [
In our study, the EMG findings after experimental denervation were consistent with those
in the literature [
], about 2?3 weeks after denervation, the first changes (spontaneous
activity) were found. When compared with EMG findings, the observed MR signal changes were
an early phenomenon occurred about one week before the earliest EMG abnormalities after
experimental denervation in rabbits.
Our study had some limitations. First, the results of kinetic parameters may vary when
using different post-processing model, and it may also be influenced by following factors: MR
scanning parameters, vascular input function, methods for T1 measurement, and injection
rate of contrast agent. However, this is common issue which was reported by many previous
researches, and we will not address it in this study. Second, in our study, we used a 6-second
temporal resolution, relatively lower than those of established articles [
]. The low
temporal resolution may result in an underestimate of the VIF, thus leading to overestimate Vp and
Ktrans values of skeletal muscle. This was a technical limitation because our current MR
sequences did not support faster scanning for so large imaging coverage. Afterall, the
quantitative results here reflect significant differences between injured and control groups, which
demonstrate that DCE is a reliable tool to determine early and time-course hemodynamic changes
in denervated skeletal muscles in a rabbit model. Third, the present study focused only on
complete nerve transection. Less severe nerve damage and regeneration was not considered in
this study. However, an article by Yamable et al. demonstrated that T2 ratios depended on the
degree of nerve injury, the more severe the nerve damage, the higher signal intensity on
T2-weighted images . Forth, we consider the results to be consistent with changes at MR
imaging in human muscle. Further clinical study will be needed in human subject.
In summary, Ktrans and Vp values obtained from DCE MR imaging parameters changes occur
as early as 1 day after denervation. Increased Ktrans and Vp values is an early phenomenon
markedly preceding not only EMG abnormalities but also signal intensity changes after nerve
transection. DCE MR imaging hold the promise of an early and sensitive diagnosis of
denervated skeletal muscle.
S1 Tables. Data of the dynamic contrast-enhanced magnetic resonance imaging in
denervated skeletal muscle: experimental study in rabbits.
S1 Appendix. The ARRIVE guidelines checklist (Animal research: Reporting in vivo
Conceptualization: Hai-Bin Shi.
Data curation: Lei Xu, Rui Zhang.
Formal analysis: Wen-Tao Wang, Yue-Fen Zou.
Funding acquisition: Liang Qi.
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Investigation: Liang Qi, Yu-Dong Zhang.
Methodology: Lei Xu, Yu-Dong Zhang, Rui Zhang.
Project administration: Liang Qi, Yue-Fen Zou.
Resources: Liang Qi, Yu-Dong Zhang.
Software: Lei Xu.
Supervision: Hai-Bin Shi.
Visualization: Wen-Tao Wang, Rui Zhang.
Writing ? original draft: Liang Qi.
Writing ? review & editing: Hai-Bin Shi.
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