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Longitudinal Alterations of the Cisternal Segment of
Trigeminal Nerve and Brain Pain-matrix Regions in
Patients with Trigeminal Neuralgia Before and After
Treatment
Tai-Yuan Chen
Chi-Mei Medical Center
Ching-Chung Ko
Chi-Mei Medical Center
Te-Chang Wu
Chi-Mei Medical Center
Li-Ching Lin
Chi-Mei Medical Center
Yun-Ju Shih
Chi-Mei Medical Center
Yi-Chieh Hung
Chi-Mei Medical Center
Ming-Chung Chou ( mcchou@kmu.edu.tw )
Kaohsiung Medical University
Research Article
Keywords: Trigeminal Neuralgia, Trigeminal Nerve, Pain-matrix regions, RESOLVE DTI, T2-SPACE VBM
DOI: https://doi.org/10.21203/rs.3.rs-289655/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Background: Trigeminal neuralgia (TN) is the most common type of chronic neuropathic facial pain, but
the etiology and pathophysiological mechanisms after treatment are still not well understood. The
purpose of this study was to investigate the longitudinal changes of the cisternal segment of the
trigeminal nerve and brain pain-related regions in patients with TN before and after treatment using
readout segmentation of long variable echo-train (RESOLVE) diffusion tensor imaging (DTI) and
transverse relaxation (T2)-weighted sampling perfection with application-optimized contrast at different
ip angle evolutions (T2-SPACE).
Methods: Twelve patients with TN and four healthy controls were enrolled in this study. All patients
underwent assessment of the visual analog scale (VAS), and acquisition of RESOLVE DTI and T2-SPACE
images before and at 1, 6, and 12months after treatments. Regions-of-interest were placed on the
bilateral anterior, middle, and posterior parts of the cisternal segment of the trigeminal nerve, the bilateral
root entry zone (REZ), bilateral nuclear zone, and the center of pontocerebellar tracts, respectively. Voxel-
based morphometry (VBM) analysis was conducted with T2-SPACE images, and gray matter volumes
(GMV) were measured from brain pain-matrix regions.
Results: The results demonstrated that the axial diffusivity of the middle part of the cisternal trigeminal
nerve, the fractional anisotropy of the bilateral nuclear zones, and the mean diffusivity of the center of
pontocerebellar tract signicantly changed over time before and after treatment. The changes of GMV in
the pain-matrix regions exhibited similar trends to the VAS before and after treatment.
Conclusion: We conclude that magnetic resonance imaging with RESOLVE DTI and VBM with T2-SPACE
images were helpful in the understanding of the pathophysiological mechanisms in patients with TN
before and after treatment.
Introduction
Trigeminal neuralgia (TN) is the most common type of chronic neuropathic facial pain [1] and is
characterized by intermittent attacks of severe, electric shock-like unilateral pain along the distribution of
the trigeminal nerve branches [2]. Although not essential to TN pathophysiology, a well-established
etiological factor is the neurovascular compression (NVC) of the trigeminal nerve at the root entry zone
(REZ) [3–5], where focal demyelination is believed to occur at the point of contact [6, 7]. The surgical
treatments performed, including Gamma/Cyber Knife radiosurgery (CKRS), microvascular decompression
surgery, and percutaneous trigeminal rhizotomy, have been previously described [8, 9].
Advances in neuroimaging techniques have identied key neuroanatomical signatures. It is well known
that magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) is capable of depicting
microstructural changes of the trigeminal nerve [10]. With the application of readout segmentation of
long variable echo-train (RESOLVE) DTI and parallel imaging [11, 12], susceptibility distortions could be
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reduced substantially to analyze more accurately subtle changes involving the symptomatic cisternal
segment of trigeminal nerve, REZ, and the nuclear zone.
In addition, high-resolution longitudinal relaxation (T1)-weighted images were previously utilized to detect
whole-brain gray matter (GM) changes using voxel-based morphometric (VBM) analysis. Given that the
evaluation of the brain's GM could provide insights into disease mechanisms, it is helpful to use VBM
analysis in the detection of GM abnormalities in patients with neuralgia. Previously, brain GM
abnormalities have been identied in patients with chronic pain [13]. The most common locations of GM
abnormalities include regions implicated in the multidimensional experience of pain, such as the
prefrontal cortex (PFC), insula, anterior cingulate cortex (ACC) and mid-cingulate cortex), thalamus,
primary and secondary somatosensory cortices (S1, S2), basal ganglia, amygdala, and brainstem [13].
These abnormalities are commonly found for many types of chronic pain, including those that affect the
trigeminal system, such as migraines [14], trigeminal neuropathic pain [15, 16], and temporomandibular
disorders [17]. Given that some abnormalities are common across most chronic pains (e.g., cortical
thinning in the anterior insula, cingulate cortex, and dorsolateral PFC) [13], the changes of these areas
likely reect pain chronicity in general and may be associated with negative effect and changes in pain
modulation [18]. In a previous TN study, the reductions of the volumes of the ACC and the superior
temporal gyrus (STG)/middle temporal gyrus were documented [19]. It was also considered that the GM
volume (GMV) of the STG decreased as the duration of disease increased. Such MR-detectable brain
structural alterations may reect changes in the neuronal size or number, synaptogenesis, dendritic
branching, axon sprouting, synaptic pruning, neuronal cell death, alterations in vasculature, and the sizes
or numbers of glial cells [20, 21].
Moreover, transverse relaxation (T2)-weighted sampling with application-optimized contrast with different
ip angle evolution (T2-SPACE) images were used to evaluate cortical/subcortical brain GM based on
VBM analyses [22]. However, T2-SPACE images have not been previously utilized to investigate
longitudinal brain changes in TN subjects after surgeries. As the surgical treatments could relieve pain
symptoms in patients, it is of importance to understand how the cisternal segment of the trigeminal nerve
and brain GM structures were changed after the treatments. Therefore, the purposes of this study were to
evaluate longitudinal diffusion changes of the cisternal segment of trigeminal nerves using RESOLVE DTI
technique and to assess longitudinal brain GM differences using T2-SPACE VBM analysis in TN patients
after CKRS or radiofrequency ablation (RFA).
Materials And Methods
Patients
The study received institutional approval from the Human Research Ethics Committee of our hospital
(Institutional Review Board 10603-003), and written informed consents were obtained from all
participants.
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We enrolled 12 patients with refractory TN that lasted for more than 2 years, who received CKRS or RFA
treatments from January 2016 to December 2018. In addition, four age- and sex-matched healthy
controls (2M/2F, age = 63.3 ± 4.4 years) were enrolled for comparisons.
Data Acquisition
After providing informed consent, all subjects underwent pain intensity assessments of the pain intensity
and the severity of neuralgia using the visual analog scale (VAS). MRI scans were also conducted to
exclude the possibility of occupying lesions. In this study, MRI was conducted on a 1.5-T scanner
equipped with a 24-channel phased-array head coil. The standard MRI protocol included the following:
axial T1-weighted imaging, T2-weighted imaging, uid attenuated inversion recovery, T2-weighted
gradient-recalled echo imaging, MR angiography, and single-shot spin-echo echo-planar diffusion-
weighted imaging. In addition, during the same imaging session and follow-up sessions at 1, 6, and 12
months after treatment, all subjects underwent three-dimensional (3D), whole-brain, high-resolution T2-
SPACE imaging (TR/TE = 2200/276 ms, echo train length = 150, number of slice = 192, matrix size =
256×256, voxel size = 1×1×1 mm3), in which an imaging plane parallel to cisternal segments of trigeminal
nerves was placed to acquire both single-shot DTI (TR/TE = 6000/87 ms, number of slice = 21, slice
thickness = 2 mm, no gap, FOV = 22 cm, matrix size = 128×128, number of excitation = 1, acceleration
factor = 2, b-values = 0 and 1000 s/mm2) and RESOLVE DTI (TR/TE = 3330/75 ms, number of slice = 21,
slice thickness = 2 mm, no gap, FOV = 22 cm, matrix size = 128×128, number of excitation = 1, number of
segment = 4, acceleration factor = 2, b-values = 0 and 1000 s/mm2) with 30 diffusion directions.
Image Processing and Analysis
All imaging data were transferred to a stand-alone workstation and post-processed with FSL (FMRIB
Software Library, Oxford, UK) and MATLAB (MathWorks Inc., Natick, MA, USA). First, the DTI data were
motion-corrected using rigid-body registration, and the diffusion directions were compensated by the
rotation matrix. Second, eddy-current distortions were minimized using 12-parameter ane image
registration. Third, the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean
diffusivity (MD) values in each voxel were calculated with the DTIFIT tool. Fourth, the DTI metrics were
analyzed in the trigeminal nerve cisternal segment on the affected and contralateral sides based on the
selection of a region-of-interest (ROI) with custom-made software that ran on a MATLAB platform that
automatically divided the trigeminal nerve cisternal segment into anterior, middle, and posterior parts, as
shown in Fig.1.
Moreover, individual FA maps were spatially transformed to a representative FA map—which used the
minimal transformation distance among all patients—using linear ane and nonlinear demon
registrations. Subsequently, ROIs were placed on the REZ, nuclear zone, and the center of pontocerebellar
tracts (PCT) in the pons, as shown in Fig.1. Finally, the mean FA, AD, RD, and MD values in these regions
were calculated for statistical analysis.
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The whole-brain T2-SPACE images were used in VBM analysis to estimate the brain GMV with the
Computational Anatomical Toolbox version 12, (CAT12) and Statistical Parametric Mapping version 12
(SPM12) in MATLAB. First, T2-SPACE images were segmented into GM, white matter, and cerebrospinal
uid, spatially normalized with diffeomorphic anatomical registration through exponentiated Lie algebra
(DARTEL) to the subject-specic template. The segmented images were then smoothed with an isotropic
Gaussian kernel with a full-width-at-half-maximum equal to 8 mm. Subsequently, an automated
anatomical labeling brain template was used to separate the brain cortex into 116 regions, and mean
GMVs were calculated in the pain-related regions, including the periaqueductal GM (PAG), PFC, posterior
cingulate cortex (PCC), ACC, insula, amygdala, thalamus, posterior parietal cortex (PPC), S1, S2,
supplementary motor area (SMA), and cerebellum [23].
Statistical Analysis
A Wilcoxon signed-rank test was performed to understand the difference of DTI indices in the cisternal
segments of the trigeminal nerve, REZ, nuclear zone, and the center of PCT, and the difference of GMV in
pain-related brain regions in healthy controls and patients between the two hemispheres, respectively. The
results were considered signicant if P < 0.05.
In addition, one-way analysis of variation (ANOVA) was performed to show whether the DTI indices
changed along the three parts of the cisternal segments of the trigeminal nerve and whether the DTI
indices of the trigeminal nerve, REZ, nuclear zone, center of PCT, the GMV of pain-related brain regions,
and the VAS, signicantly changed over time before and after treatment, respectively. The results were
considered signicant if P < 0.05.
Moreover, Pearson's correlational analysis was performed to reveal the relationship between DTI indices
of trigeminal nerve, REZ, nuclear zone, the center of PCT, and the GMV of pain-related brain regions. The
correlations were considered signicant if P < 0.005.
Results
The mean age of the 12 enrolled patients was 68.9 years, including four men and eight women. All of
them had TN unilaterally, with 11 on the right side and 1 on the left side. None of them had denite space-
occupying lesions. All patients successfully underwent VAS assessments before and at 1, 6, and 12
months after treatment. However, in the imaging study, although all patients underwent MRI prior to the
treatment, six patients did not undergo a follow-up MRI at 1 and 6 months, and eight patients did not
undergo a follow-up MRI at 12 months after treatment owing to refusals or dropout. The demographic
and clinical characteristics of the enrolled patients are listed in Table1.
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Table 1
Demographic characteristics of patients with trigeminal neuralgia (TN) enrolled in this study.
Patient NVC VAS score Procedure
Before Tx 1
month 6 months 12 months
1 NO 7 0 0 0 CKRS
2 Rt. REZ 8 0 0 0 CKRS
3 Lt. REZ 9 1 0 0 RFA
4 Rt. REZ 9 0 9 2 RFA, CKRS
5 Rt. REZ 10 0 0 0 RFA, CKRS
6 Rt. REZ 9 0 0 0 RFA
7 Rt. REZ 9 0 2 4 CKRS, RFA
8 NO 10 0 0 0 CKRS
9 Rt. REZ 10 0 0 0 CKRS
10 Rt. REZ 10 0 0 0 RFA
11 Lt. middle part 10 0 0 0 RFA
12 NO 10 0 0 0 CKRS
Abbreviations: NVC = neurovascular compression, Tx = treatment, REZ = root entry zone, VAS = visual
analog scale, CKRS = cyber knife radiosurgery, RFA = radiofrequency ablation.
The diagnostic MRI demonstrated that among the 12 patients, eight had NVC on the trigeminal nerve
REZ, one had NVC at the middle part of the cisternal segment of trigeminal nerve, and three had no NVC
signs. In addition, six patients received RFA, and others received CKRS treatment. However, after
treatment, two patients experienced TN relapse at 6 months and received an additional treatment using
CKRS or RFA. In the VAS analysis, the results showed that the initial VAS was as high as 9.25 ± 0.97 (10
was the highest score). After 1 month of treatment, the VAS was signicantly reduced to 0.08 ± 0.29.
However, the VAS was slightly increased to 0.92 ± 2.61 at 6 months but was decreased to 0.50 ± 1.24 at
12 months after treatment. The ANOVA analysis revealed that the VAS signicantly changed over time
before and after treatment.
Diffusion changes using RESOLVE DTI technique
In patients with TN, the entire cisternal segment of the trigeminal nerve exhibited no signicant difference
in DTI indices between the affected and contralateral sides before and at 1, 6, and 12 months after
treatment. In the anterior part of the cisternal trigeminal nerve, no signicant difference of FA, AD, RD, and
MD values was noted between the two sides before treatment, but signicant AD differences were noted
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between the two sides at 1 month after treatment. Additionally, AD was signicantly increased from 1 to 6
months after treatment in the affected side (Fig.2). However, in healthy controls, no signicant
differences in the DTI indices were noted between the two sides.
In the middle part of the cisternal trigeminal nerve, the results yielded no signicant differences for FA, AD,
RD, and MD values between the two sides before, and at 1, 6, and 12 months after treatment, whereas RD
and MD values were signicantly decreased from 1 to 6 months after treatment in the affected side in
patients with TN, as shown in Fig.3. However, in healthy controls, no signicant differences were noted in
the DTI indices between the two sides.
In the posterior part of the cisternal trigeminal nerve, no signicant difference was noted in FA, AD, RD,
and MD values between the two sides in patients with TN before and at 1, 6, and 12 months after
treatment. However, the FA value was signicantly increased from 1 to 6 months after treatment in the
affected side, as shown in Fig.4. In healthy controls, no signicant differences were noted in the DTI
indices between the two sides. The ANOVA analysis further revealed that only the AD values signicantly
changed over time (P = 0.034) in the middle part of the cisternal trigeminal nerve of the affected side
before and after treatment.
In the REZ, the results yielded signicant differences for the FA values between the two sides in the
patients with TN before and 6 months after treatment and signicant differences for the AD, RD, and MD
values before and at 1 and 6 months after treatment. In the affected side, the FA was signicantly
increased 1 month after treatment but was signicantly decreased from 1 to 6 months after treatment. In
the contralateral side, however, the FA value was signicantly reduced 1 month after treatment, as shown
in Fig.5. In healthy controls, no signicant differences in the DTI indices were noted between the two
sides. The ANOVA analysis showed no signicant changes in the DTI indices over time in both sides
before and after treatment.
In the nuclear zone, the results yielded signicant differences in the cases of the FA, AD, and MD values
between the two sides in patients with TN before treatment and signicant FA value differences 6 months
after treatment. However, in both sides, the FA value was signicantly reduced 1 month after treatment
but was signicantly increased from 1 to 6 months after treatment, as shown in Fig.6. In healthy
controls, no signicant differences in the DTI indices were noted between the two sides. Additionally, the
ANOVA analysis revealed that the FA value signicantly changed over time in the nuclear zones of both
sides (P = 0.0002 in the normal side, P = 0.0389 in the lesion side) before and after treatment.
In the center of PCT, the FA and AD values were slightly decreased, whereas the RD and MD values were
slightly increased in patients with TN 1 month after treatment. No signicant difference was noted
between two time points, as shown in Fig.7. However, the ANOVA analysis revealed that the MD value
signicantly increased over time (P = 0.00069) in the center of PCT before and after treatment.
T2-SPACE VBM analysis
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In the VBM analysis, the results revealed that GMV was signicantly lower in the affected side compared
with the contralateral side in the PCC, ACC, insula, amygdala, and S1 in the patients before treatment.
After 1 month of treatment, no signicant GMV difference was noted in the pain-related regions between
the two hemispheres. However, the GMV was signicantly lower in the affected side compared with the
contralateral side in the PCC, insula, amygdala, and S2 at 6 months after treatment, but the difference no
longer existed in the pain-related regions between the two hemispheres at 12 months after treatment, as
shown in Fig.8. In healthy controls, no signicant differences in the GMVs were noted between the two
hemispheres. The ANOVA analysis showed that the GMVs did not signicantly change over time in the
pain-matrix regions of the affected and contralateral sides before and after treatment.
In correlational analysis, the results revealed that before treatment, the FA of the anterior part of the
cisternal trigeminal nerve in the affected side was signicantly correlated with the GMV of PAG, bilateral
PFC, bilateral amygdala, bilateral SMA, bilateral cerebellum, left S1, left PCC, left insula, right PPC, and
right ACC. Moreover, the AD of the middle part of the cisternal trigeminal nerve in the affected side was
signicantly correlated with the GMV of the bilateral PFC, bilateral PPC, and left S2, and the RD and MD
values of the middle part of the cisternal trigeminal nerve in the affected side were also signicantly
correlated with the GMV of the right S2, as shown in Table2.
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Table 2
Signicant correlation coecients between DTI indices of cisternal trigeminal nerve and gray matter
volume (GMV) of pain-matrix regions in patients with TN before treatment.
Region FA (anterior portion
of the affected side) AD (middle part of
the affected side) RD (middle part of
the affected side) MD (middle part of
the affected side)
PAG 0.8319 -- -- --
Lt. PFC 0.8454 0.7779 -- --
Rt. PFC 0.8632 0.7916 -- --
Lt. PCC 0.7500 -- -- --
Rt. ACC 0.7560 -- -- --
Lt.
amygdala 0.7807 -- -- --
Rt.
amygdala 0.8418 -- -- --
Lt. PPC -- 0.8114 -- --
Rt. PPC 0.7889 0.7818 -- --
Lt. SMA 0.8503 -- -- --
Rt. SMA 0.8859 -- -- --
Lt. S1 0.7611 -- -- --
Lt. S2 -- 0.8397 -- --
Rt. S2 -- -- 0.7658 0.8137
Lt.
cerebellum 0.8215 -- -- --
Rt.
cerebellum 0.7898 -- -- --
Abbreviations: FA = fractional anisotropy, AD = axial diffusivity, RD = radial diffusivity, MD = mean
diffusivity, PAG = periaqueductal gray, PFC = prefrontal cortex, PCC = posterior cingulate cortex, ACC =
anterior cingulate cortex, SMA = supplementary motor area, S1 = primary somatosensory cortex, S2 =
secondary somatosensory cortex.
However, after 1 month of treatment, only the FA of the middle part of the cisternal trigeminal nerve in the
affected side yielded a signicant correlation with the GMV of PAG (cc = 0.9759). After 6 months of
treatment, only the RD of the nuclear zone in the affected side yielded a signicant correlation with the
GMV in the right S1 (cc = 0.9537). After 12 months of treatment, only the MD of the nuclear zone in the
affected side yielded a signicant correlation with the GMV in the left thalamus (cc = 0.9957).
Discussion
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To the best of our knowledge, this is the rst study that conducted both RESOLVE DTI and 3D T2-SPACE
imaging to investigate the longitudinal changes of the cisternal segment of the trigeminal nerve, REZ,
nuclear zone, the center of PCT, and brain pain-matrix regions in the patients with TN before and after
treatment. Several ndings presented herein may help understand the etiology and pathophysiology of
TN. First, the trigeminal nerve REZ and nuclear zone exhibited more changes than the cisternal segment
of the trigeminal nerve and the GMVs of brain pain-matrix regions before and after treatment. Second, the
contralateral REZ and nuclear zone were signicantly altered after treatment most likely owing to
Wallerian degeneration. Third, the AD of the middle part of the cisternal trigeminal nerve, the FA of
bilateral nuclear zones, and the MD of the center of PCT signicantly changed over time before and after
treatment. Fourth, the difference of GMV in the pain-matrix regions between the two hemispheres
exhibited similar trends to the VAS before and after treatment. Finally, the DTI indices in the cisternal
trigeminal nerve (FA) and nuclear zone (RD and MD) of the affected side were signicantly correlated
with the GMVs in specic pain-matrix regions (PAG, right S1, and left thalamus) before and after
treatment. These ndings are further discussed in the following parts of the document.
In the DTI analysis, the results showed that patients with TN exhibited slightly lower AD and FA values
with no statistical signicance in the affected side of the cisternal segment of the trigeminal nerve before
treatment. The signicant changes in the AD, RD, MD, and FA values in the affected side after treatment
suggested that the treatments signicantly altered the microstructural diffusion in the trigeminal nerve. In
contrast, the REZ and nuclear zones yielded signicant differences in the values of the DTI indices
between the two sides before and after treatment, thus indicating that TN led to more tissue alterations in
the REZ and nuclear zones than the cisternal trigeminal nerve, most likely owing to the fact that 67%
(8/12) of studied patients exhibited NVC at REZ.
Our study also demonstrated that patients with TN not only had lower FA but also had higher AD, RD, and
MD values at the affected REZ. Consistent with a prior study [24], our ndings suggested that the
increased MD and RD may be linked to NVC-induced focal demyelination in the trigeminal nerve REZ [25],
neuroinammatory processes, and/or edema [26] that affected the trigeminal system. Therefore, DTI can
detect subtle pathological features at the trigeminal nerve REZ supporting a role for this regional
involvement in TN pathophysiology. Moreover, the present study performed the treatments with a focus
on the middle part of the cisternal trigeminal nerve in the affected side. Thus, the signicant changes of
the FA values in the distal and contralateral REZ and nuclear zone suggested that the Wallerian
degeneration occurred through the PCT [27, 28], wherein minor changes of the DTI indices were observed
after treatment.
The present study employed 3D T2-SPACE images to examine cortical/subcortical brain GMVs based on
VBM analysis. A previous study reported that patients with TN had greater GMVs in the thalamus,
contralateral S1, amygdala, frontal pole, PAG, primary motor cortex, and basal ganglia and cortical
thinning in the orbitofrontal cortex, pregenual ACC, and insula [29], whereas anther study reported that
patients with TN showed GMV reductions including the frontal, temporal, and parietal areas, as well as in
the left thalamus and right cerebellum [30]. Our study found that patients with TN had signicantly lower
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GMVs in PCC, ACC, insula, amygdala, and S1 in the affected side compared with the contralateral side
before treatment. These ndings may reect unique symptoms because TN is characterized by
paroxysmal pain triggered by innocuous stimuli or movements and does not involve major sensory
losses. However, the differences between the previous ndings and ours may be attributed to the mixed
trigeminal pain patient groups and the different methodology (T1-VBM versus T2-VBM) used to assess
GM changes.
In addition, our results demonstrated that TN led to signicant GMV differences between the two
hemispheres in some pain-related brain regions (PCC, ACC, insula, amygdala, and S1) and that the
therapy helped reduce the GMV difference at 1 month after treatment. However, the GMV differences in
some pain-related regions (PCC, insula, amygdala, and S2) became signicant again at 6 months after
treatment but returned to insignicant outcomes at 12 months after treatment. The sequential changes of
GMV in the pain-matrix regions were generally consistent with the VAS in patients with TN. Initially, the
pain intensity was measured to e as high as 9.25 ± 0.97 before treatment and was signicantly reduced
to 0.08 ± 0.29 after 1 month of treatment. However, at 6 months after treatment, two patients who
exhibited degraded pain intensity, which resulted in a slight increase in VAS (0.92 ± 2.61), received a
second treatment. After the second treatment, one patient had improved symptoms with the VAS reduced
from 9 to 2, but the other had deteriorated symptoms with a VAS increased from 2 to 4. As a result, the
overall VAS was slightly decreased after 12 months of treatment. Moreover, the correlation analysis
revealed signicant correlations between the DTI indices of the cisternal trigeminal nerve and nuclear
zone and the GMVs of the pain-matrix regions in the affected side before and after treatment. These
ndings suggested that the changes of GMV in the pain-matrix regions were likely associated with the
changes of VAS and that VBM analysis of T2-SPACE was helpful in the noninvasive monitoring and
reection of the pain intensity in patients with TN before and after treatment.
The etiology and pathophysiological mechanisms of TN are still not well understood, and the central
contributions in TN are still debated. The most common theory of the classical TN etiology is a peripheral
theory that involves the compression of the trigeminal nerve's REZ by blood vessels owing to the surgical
experience [5]. Moreover, several studies demonstrated pathological changes and most notably the
demyelination of the trigeminal nerves in patients with TN [6, 31–35]. In the present study, despite the
fact that minor changes were observed in the DTI indices in the cisternal segment of the trigeminal nerve,
no statistical signicance was revealed between the affected and contralateral sides before treatment.
Nevertheless, the REZ and nuclear zone yielded signicant changes in the DTI indices before treatment
and more signicant changes than the cisternal segment of trigeminal nerve after treatment. This
suggested that the REZ and nuclear zone were more sensitive to TN before treatment and had more
demyelination after treatment compared with the cisternal segment of the trigeminal nerve.
However, the NVC theory of TN cannot suciently explain the disorder because some individuals can
develop TN in the absence of NVC, and some individuals with NVC never develop TN. In the present study,
25% (3/12) of the studied patients developed TN without NVC. This suggests that the TN symptoms were
not fully attributable to the presence of NVC. It is known that peripheral nerve injury can lead to central
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nervous system (CNS) plasticity [36, 37] most likely owing to the sustained or repetitive activation of
primary afferent bers and central sensitization [38]. In the present study, our results demonstrated that
the changes of DTI indices in the trigeminal nerve were associated with the alterations of GMVs in brain
pain-matrix regions before and after treatment. Furthermore, the longitudinal changes of GMV in the pain-
matrix regions were generally consistent with the sequential changes of VAS, thus suggesting that the
CNS changes in conjunction with trigeminal nerve injury contribute to TN symptoms.
The study is associated with some limitations. First, the small sample size of this study may lead to a
low statistical power. Thus, the results ought to be interpreted with care. Second, some patients did not
undergo a follow-up MRI scan owing to refusal or dropout. Thus, the incomplete dataset may affect the
statistical results. Third, comparisons were not conducted between patients with TN and healthy controls
in DTI and VBM analysis because only four age- and sex-matched healthy controls were enrolled in this
study. Further investigations with larger groups will be needed to comprehensively compare the
differences of cisternal trigeminal nerve and brain pain-matrix regions among healthy subjects and
patients with TN before and after treatment.
Conclusions
MRI with RESOLVE DTI was capable of detecting microstructural changes in patients with refractory TN
before and after treatment, as demonstrated by the longitudinal changes of the FA, AD, RD, and MD
values on the symptomatic side of the trigeminal nerve cisternal segment, REZ, nuclear zone, and PCT.
The VBM analysis of T2-SPACE data was helpful in detecting longitudinal changes of GMV in the pain-
matrix regions on the symptomatic cerebral hemisphere in the studied patients before and after
treatment. In this study, we discussed theories of TN pathophysiology, assessed how advanced
neuroimaging methods contribute to our current understanding of TN, and outlined future directions for
clinical trials that may use these methods to allow treatment selection and response for patients with TN
based on brain and/or nerve biomarkers.
Declarations
Ethics approval and consent to participate
The study was approved by local institution review board (10603-003) of Chi Mei Medical Center.
Consent for publication
Inform consent was obtained from all subjects. The study was carried out in accordance with Helsinki
Declaration.
Availability of data and materials
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The data presented in this study are available on request from the corresponding author. The data are not
publicly available due to the nature of this research, participants of this study did not agree for their data
to be shared publicly.
Competing interests
No conict of interest exists in this study.
Funding
This study was funded by Chi-Mei Medical Center (CMFHR10617).
Authors' contributions
Chen TY, Lin CL, Hung YC, and Chou MC designed the study. Chen TY, Ko CC, Wu TC, and Shih YJ
collected the patient data. Lin LC and Hung YC performed the treatment. Chen TY and Chou MC analyzed
and wrote the original draft. All authors reviewed and edited the manuscript.
Acknowledgements
This work was supported by a grant from the Chi-Mei Medical Center (CMFHR10617).
References
1. Koopman JSHA, Dieleman JP, Huygen FJ, de Mos M, Martin CGM, Sturkenboom MCJM: Incidence of
facial pain in the general population.
Pain
2009, 147(1-3):122-127.
2. Eller JL, Raslan AM, Burchiel KJ: Trigeminal neuralgia: denition and classication.
Neurosurg Focus
2005, 18(5):E3.
3. Antonini G, Di Pasquale A, Cruccu G, Truini A, Morino S, Saltelli G, Romano A, Trasimeni G, Vanacore
N, Bozzao A: Magnetic resonance imaging contribution for diagnosing symptomatic neurovascular
contact in classical trigeminal neuralgia: a blinded case-control study and meta-analysis.
Pain
2014,
155(8):1464-1471.
4. Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L: Signicance of neurovascular contact in
classical trigeminal neuralgia.
Brain
2015, 138(Pt 2):311-319.
5. Nurmikko TJ, Eldridge PR: Trigeminal neuralgia--pathophysiology, diagnosis and current treatment.
Br
J Anaesth
2001, 87(1):117-132.
6. Devor M, Govrin-Lippmann R, Rappaport ZH: Mechanism of trigeminal neuralgia: an ultrastructural
analysis of trigeminal root specimens obtained during microvascular decompression surgery.
J
Neurosurg
2002, 96(3):532-543.
Page 14/15
7. Love S, Coakham HB: Trigeminal neuralgia: pathology and pathogenesis.
Brain
2001, 124(Pt
12):2347-2360.
8. Hodaie M, Coello AF: Advances in the management of trigeminal neuralgia.
J Neurosurg Sci
2013,
57(1):13-21.
9. Tohyama S, Hung PS, Zhong J, Hodaie M: Early postsurgical diffusivity metrics for prognostication
of long-term pain relief after Gamma Knife radiosurgery for trigeminal neuralgia.
J Neurosurg
2018,
131(2):539-548.
10. Basser PJ, Mattiello J, LeBihan D: MR diffusion tensor spectroscopy and imaging.
Biophys J
1994,
66(1):259-267.
11. Holdsworth SJ, Skare S, Newbould RD, Guzmann R, Blevins NH, Bammer R: Readout-segmented EPI
for rapid high resolution diffusion imaging at 3T.
Eur J Radiol
2008, 65(1):36-46.
12. Porter DA, Heidemann RM: High resolution diffusion-weighted imaging using readout-segmented
echo-planar imaging, parallel imaging and a two-dimensional navigator-based reacquisition.
Magn
Reson Med
2009, 62(2):468-475.
13. Davis KD, Moayedi M: Central Mechanisms of Pain Revealed Through Functional and Structural MRI.
J Neuroimmune Pharm
2013, 8(3):518-534.
14. Rocca MA, Ceccarelli A, Falini A, Colombo B, Tortorella P, Bernasconi L, Comi G, Scotti G, Filippi M:
Brain gray matter changes in migraine patients with T2-visible lesions - A 3-T MRI study.
Stroke
2006,
37(7):1765-1770.
15. DaSilva AF, Becerra L, Pendse G, Chizh B, Tully S, Borsook D: Colocalized Structural and Functional
Changes in the Cortex of Patients with Trigeminal Neuropathic Pain.
Plos One
2008, 3(10).
16. Gustin SM, Peck CC, Wilcox SL, Nash PG, Murray GM, Henderson LA: Different Pain, Different Brain:
Thalamic Anatomy in Neuropathic and Non-Neuropathic Chronic Pain Syndromes.
J Neurosci
2011,
31(16):5956-5964.
17. Moayedi M, Weissman-Fogel I, Crawley AP, Goldberg MB, Freeman BV, Tenenbaum HC, Davis KD:
Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with
temporomandibular disorder.
Neuroimage
2011, 55(1):277-286.
18. Wiech K, Tracey I: The inuence of negative emotions on pain: Behavioral effects and neural
mechanisms.
Neuroimage
2009, 47(3):987-994.
19. Li M, Yan J, Li S, Wang T, Zhan W, Wen H, Ma X, Zhang Y, Tian J, Jiang G: Reduced volume of gray
matter in patients with trigeminal neuralgia.
Brain Imaging Behav
2017, 11(2):486-492.
20. Blumenfeld-Katzir T, Pasternak O, Dagan M, Assaf Y: Diffusion MRI of Structural Brain Plasticity
Induced by a Learning and Memory Task.
Plos One
2011, 6(6).
21. Zatorre RJ, Fields RD, Johansen-Berg H: Plasticity in gray and white: neuroimaging changes in brain
structure during learning.
Nat Neurosci
2012, 15(4):528-536.
22. Diaz-de-Grenu LZ, Acosta-Cabronero J, Pereira JMS, Pengas G, Williams GB, Nestor PJ: MRI detection
of tissue pathology beyond atrophy in Alzheimer's disease: Introducing T2-VBM.
Neuroimage
2011,
Page 15/15
56(4):1946-1953.
23. Price DD: Neuroscience - Psychological and neural mechanisms of the affective dimension of pain.
Science
2000, 288(5472):1769-1772.
24. DeSouza DD, Hodaie M, Davis KD: Abnormal trigeminal nerve microstructure and brain white matter
in idiopathic trigeminal neuralgia.
Pain
2014, 155(1):37-44.
25. Marinkovic S, Cetkovic M, Gibo H, Todorovic V, Jancic J, Milisavljevic M: Immunohistochemistry of
Displaced Sensory Neurons in the Trigeminal Nerve Root.
Cells Tissues Organs
2010, 191(4):326-
335.
26. Beaulieu C: The basis of anisotropic water diffusion in the nervous system - a technical review.
Nmr
Biomed
2002, 15(7-8):435-455.
27. Silva G, Vieira D, Costa D, Fonseca J: Wallerian degeneration of the pontocerebellar bres secondary
to pontine infarction.
Acta Neurol Belg
2016, 116(4):615-617.
28. De Simone T, Regna-Gladin C, Carriero MR, Farina L, Savoiardo M: Wallerian degeneration of the
pontocerebellar bers.
Am J Neuroradiol
2005, 26(5):1062-1065.
29. DeSouza DD, Moayedi M, Chen DQ, Davis KD, Hodaie M: Sensorimotor and Pain Modulation Brain
Abnormalities in Trigeminal Neuralgia: A Paroxysmal, Sensory-Triggered Neuropathic Pain.
Plos One
2013, 8(6).
30. Wu M, Jiang XF, Qiu J, Fu XM, Niu CS: Gray and white matter abnormalities in primary trigeminal
neuralgia with and without neurovascular compression.
J Headache Pain
2020, 21(1).
31. Kerr FW, Miller RH: The pathology of trigeminal neuralgia. Electron microscopic studies.
Arch Neurol
1966, 15(3):308-319.
32. Hilton DA, Love S, Gradidge T, Coakham HB: Pathological ndings associated with trigeminal
neuralgia caused by vascular compression.
Neurosurgery
1994, 35(2):299-303; discussion 303.
33. Rappaport ZH, Govrin-Lippmann R, Devor M: An electron-microscopic analysis of biopsy samples of
the trigeminal root taken during microvascular decompressive surgery.
Stereotact Funct Neurosurg
1997, 68(1-4 Pt 1):182-186.
34. Love S, Hilton DA, Coakham HB: Central demyelination of the Vth nerve root in trigeminal neuralgia
associated with vascular compression.
Brain Pathol
1998, 8(1):1-11; discussion 11-12.
35. Marinkovic S, Gibo H, Todorovic V, Antic B, Kovacevic D, Milisavljevic M, Cetkovic M: Ultrastructure
and immunohistochemistry of the trigeminal peripheral myelinated axons in patients with neuralgia.
Clin Neurol Neurosurg
2009, 111(10):795-800.
36. Taylor KS, Anastakis DJ, Davis KD: Cutting your nerve changes your brain.
Brain
2009, 132(Pt
11):3122-3133.
37. Davis KD, Taylor KS, Anastakis DJ: Nerve injury triggers changes in the brain.
Neuroscientist
2011,
17(4):407-422.
38. DeSouza DD, Hodaie M, Davis KD: Structural Magnetic Resonance Imaging Can Identify Trigeminal
System Abnormalities in Classical Trigeminal Neuralgia.
Front Neuroanat
2016, 10.
