The Journal of Pain, Vol 14, No 8 (August), 2013: pp 865-872

Available online at www.jpain.org and www.sciencedirect.com

Trigeminal Nerve Anatomy in Neuropathic and Non-neuropathic

Orofacial Pain Patients
Sophie L. Wilcox,* Sylvia M. Gustin,* Elizabeth N. Eykman,* Gordon Fowler,*
Christopher C. Peck,y Greg M. Murray,y and Luke A. Henderson*
*Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales, Australia.
y
Jaw Function and Orofacial Pain Research Unit, Faculty of Dentistry, Westmead Hospital, University of Sydney, Sydney,
New South Wales, Australia.

Abstract: Trigeminal neuralgia, painful trigeminal neuropathy, and painful temporomandibular

disorders (TMDs) are chronic orofacial pain conditions that are thought to have fundamentally
different etiologies. Trigeminal neuralgia and neuropathy are thought to arise from damage to or
pressure on the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor
activation. This study sought to assess the volume and microstructure of the trigeminal nerve in these
3 conditions. In 9 neuralgia, 18 neuropathy, 20 TMD, and 26 healthy controls, the trigeminal root
entry zone was selected on high-resolution T1-weighted magnetic resonance images and the volume
(mm3) calculated. Additionally, using diffusion-tensor images (DTIs), the mean diffusivity and frac-
tional anisotropy values of the trigeminal nerve root were calculated. Trigeminal neuralgia patients
displayed a significant (47%) decrease in nerve volume but no change in DTI values. Conversely, tri-
geminal neuropathy subjects displayed a significant (40%) increase in nerve volume but again no
change in DTI values. In contrast, TMD subjects displayed no change in volume or DTI values. The
data suggest that the changes occurring within the trigeminal nerve are not uniform in all orofacial
pain conditions. These structural and volume changes may have implications in diagnosis and man-
agement of different forms of chronic orofacial pain.
Perspective: This study reveals that neuropathic orofacial pain conditions are associated with
changes in trigeminal nerve volume, whereas non-neuropathic orofacial pain is not associated
with any change in nerve volume.
Crown Copyright ª 2013 Published by Elsevier Inc. on behalf of the American Pain Society
Key words: Volumetric MRI, trigeminal neuralgia, neuropathic pain, peripheral nerve, trigeminal
nerve.

T
he orofacial region represents one of the most
common sites of pain in the body.23 In general,
chronic orofacial pain arises either from trigeminal
and/or central nervous system damage (neuropathic
pain) or from nociceptor activation (nociceptive pain).
Received October 3, 2012; Revised December 13, 2012; Accepted February
28, 2013.
This research was supported by the National Health and Medical
Research Council of Australia (Grant 1032072) and the Australian Dental
Research Foundation, Inc.
The authors have no conflicts of interest, financial or otherwise, related
to this study.
Supplementary data accompanying this article are available online at
www.jpain.org and www.sciencedirect.com.
Address reprint requests to Luke A. Henderson, PhD, Department of
Anatomy and Histology, F13, University of Sydney, Sydney, New South
Wales, Australia. E-mail: lukeh@anatomy.usyd.edu.au
1526-5900/$36.00
Crown Copyright ª 2013 Published by Elsevier Inc. on behalf of the
American Pain Society
http://dx.doi.org/10.1016/j.jpain.2013.02.014
These different orofacial pain conditions also
present differently. For example, trigeminal neuralgia
(an example of a neuropathic pain condition) is
characterized by sharp, shooting paroxysms of pain
that last seconds to minutes, whereas trigeminal neurop-
athy (neuropathic) is characterized by a lower intensity
and a more prolonged or continuous burning pain.
Evidence suggests that the most common cause of
trigeminal neuralgia is mechanical compression of the
trigeminal nerve at its root entry zone, commonly by
a blood vessel.22 In contrast, although a small percentage
(20%) of trigeminal neuropathy patients also display
neurovascular compression,16 it is suggested that the
majority of cases result from direct trauma to or inflam-
mation of the trigeminal nerve.14
Whereas trigeminal nerve root neurosurgery is a highly
effective treatment for patients with trigeminal neural-
gia, it is less successful and can even be detrimental

865
866 The Journal of Pain
when attempted in patients with trigeminal neuropathy.
Because trigeminal nerve resection is often performed in
patients with trigeminal neuralgia, a number of studies
have investigated the anatomy of the trigeminal nerve
in these patients. For the main part, it has been revealed
that trigeminal neuralgia is associated with smaller
trigeminal nerves and decreased nerve fiber numbers,5
a situation that is thought to result in short episodes of
sharp, shooting pain. In contrast, the anatomy of the
trigeminal nerve in patients with trigeminal neuropathy
or temporomandibular disorder (TMD) has not been
explored. It is possible that changes also occur in the
trigeminal nerve in these patients and that targeting
the trigeminal nerve may provide a potential treatment
option. The aim of this case-controlled study is to use
structural magnetic resonance imaging (MRI) to deter-
mine the volume and diffusion tensor imaging (DTI) to
assess the microstructure of the trigeminal nerve in
patients with trigeminal neuralgia, trigeminal neuropa-
thy, and nociceptive TMD and compare these results to
healthy pain-free controls. We hypothesized that the
trigeminal nerve volumes would be reduced in both
neuropathic pain conditions and remain unchanged in
non-neuropathic orofacial pain.
Methods
Subjects
Nine patients with painful trigeminal neuralgia
(2 males, mean [6SEM] age: 64.9 6 2.6), 18 patients with
painful trigeminal neuropathy (3 males, mean [6SEM]
age: 48.0 6 1.7), 20 patients with painful TMD (4 males,
mean [6SEM] age: 45.7 6 2.9), and 26 healthy controls
without facial pain (mean [6SEM] age: 52.3 6 2.95, 5
males [ages: 55, 56, 60, 78, 87], 21 females [ages: 32, 32,
36, 37, 41, 41, 41, 42, 44, 48, 50, 53, 53, 56, 57, 58, 59, 64,
64, 68, 73]) were recruited at the Faculty of Dentistry,
University of Sydney, during a period from August 2006
to November 2012. Individual pain patient demographics
are shown in Supplementary Table 1. Trigeminal neurop-
athy and trigeminal neuralgia patients were diagnosed
according to the Liverpool criteria.22 TMD patients were
diagnosed using the research diagnostic criteria for
TMD.6 No chronic pain subject was diagnosed as having
more than 1 of these 3 pain conditions. Furthermore,
healthy controls were excluded only if they gave self-
report of chronic pain (pain lasting for more than
3 months, including migraine and headache), were
currently taking any form of analgesic medication, or
had any neurologic disorder. Informed written consent
was obtained for all procedures, and the study was
approved by the Institutional Human Research Ethics
Committees.
Pain Measures
To assess the intensity of facial pain, each pain subject in-
dicated, with a vertical pencil stroke on a 10-cm horizontal
line, the intensity of their pain (0 cm = ‘‘no pain’’ to
10 cm = ‘‘maximum imaginable pain’’) in the morning,
noon, and at night. These 21 individual pain rating values
Trigeminal Nerve Anatomy in Orofacial Pain
were averaged to provide an indication of each subject’s
chronic pain rating (‘‘diary pain’’). Each subject also drew
a distribution map of their ongoing pain onto a standard
drawing of the face and completed a McGill Pain Question-
naire20 in order to assess the nature of their pain. The
McGill questionnaire includes a series of graded adjectives
in categories related to the sensory component of pain.
MRI Acquisition
Subjects lay supine on the bed of a 3-T MRI scanner
(Achieva; Philips Medical Systems, Amsterdam, The
Netherlands) with their head immobilized in a tight-
fitting head coil. In each subject, 3 high-resolution
3-dimensional T1-weighted anatomic image sets
covering the entire brain were collected (turbo field
echo; echo time = 2.5 ms, repetition time = 5,600 ms,
flip angle = 8 , voxel size = .8  .8  .8 mm). Three
acquisitions were acquired to improve signal-to-noise
ratios. In addition, using a single-shot multisection
spin-echo echo-planar pulse sequence (repetition
time = 8,788 ms; flip angle = 90 , matrix
size = 112  112, field of view = 224  224 mm, slice
thickness = 2.5 mm, 55 axial slices), 4 high-resolution
DTI image sets covering the entire brain were collected.
For each slice, diffusion gradients were applied along
32 independent orientations with b = 1,000 s/mm2 after
the acquisition of b = 0 s/mm2 (b0) images. Four acquisi-
tions were acquired to improve signal-to-noise ratios.
MRI Analysis
Trigeminal Nerve Volume Analysis. Using SPM8,9 the
3 T1-weighted images from each subject were coregis-
tered, averaged, and resampled at .3  .3  .3 mm. Using
the resampled images, the left and right trigeminal
nerves within the root entry zone were isolated in all
subjects (Fig 1). All resampled images were coded with
a numerical identifier and the assessor (S.L.W.) was blind
to patient group. The root entry zone encompasses the
trigeminal nerve within the pontine cistern, that is, from
the point at which the nerve emerges from the pons to
the point at which it exits the pontine cistern anteriorly.
All 3 orthogonal planes were used in defining the nerve,
with the axial plane being the first plane used, followed
by coronal and sagittal views. The volume (mm3) within
the isolated nerve was then calculated. In addition, the
cross-sectional volume of the nerve in each coronal slice
was selected and from this the maximal coronal
cross-section value (mm2) was calculated. Additionally,
a second blinded assessor (G.F.) also isolated the nerve in
a subsample (n = 9) of control subjects in order to asses
interrater reliability; the total nerve volume of the
2 assessors was positively correlated (r = .66, P = .003).
Trigeminal Nerve Diffusion Analysis. Using SPM8 and
custom software, the 4 diffusion tensor image sets were
realigned and averaged. Using diffusion-weighted
images collected from 32 directions and b0 images, the
diffusion tensor was calculated from the averaged
images using a linear model. Once the elements of
diffusion tensor were calculated, fractional anisotropy
(FA) and mean diffusivity (MD) maps were derived. The
Wilcox et al
Figure 1. Axial, sagittal, and coronal T1-weighted anatomic images and corresponding DTIs showing the trigeminal nerve root entry
zone in a single subject. The DTI image is color coded for direction of greatest water movement. The outline of the trigeminal nerve
region used for total nerve analysis is also shown in red shading on the T1-weighted anatomic image and outlined in white on DTI
images. To the right is an example of the regions selected for the rostral (red), middle (yellow), and caudal (green) third of the nerve
at the maximal cross-sectional area.
images were then resampled at .3  .3  .3 mm. Using the
resampled images, the left and right trigeminal nerves
within the root entry zone were isolated as
aforementioned. Because of technical difficulties, DTI
image sets were not obtained or could not be used for 2
of the control subjects. The FA and MD values within the
entire isolated nerve were then calculated. Furthermore,
using the coronal slice at which there was the maximum
cross-sectional area, the FA and MD values were calcu-
lated. In addition, because it has been previously sug-
gested that c-fibers lie within the caudal portion of the
trigeminal root,4 we divided this coronal section into
caudal, middle, and rostral thirds, and mean FA and MD
values were calculated and compared (Fig 1).
Statistical Analysis
In control subjects, the left and right trigeminal nerve
values were averaged. Within-group ipsilateral and
contralateral comparisons were determined using
dependent-samples t-tests. Between-group comparisons
were determined using independent-samples t-tests.
Volume and DTI values and pain characteristics were
correlated using 2-tailed Pearson correlations. Signifi-
cance was set at P < .05.
Results
Pain Characteristics
Individual patient characteristics and analgesic
medication usage are shown in Supplementary Table 1.
In all 9 patients with trigeminal neuralgia, 9 of the
18 patients with trigeminal neuropathy, and 3 of the 20
TMD patients, ongoing pain was confined to one side
of the face. The remaining patients had pain on both
sides of the face. In 16 of the trigeminal neuropathy
and 17 of the TMD patients, their orofacial pain was
confined to areas of the face innervated by the maxillary
The Journal of Pain 867
and mandibular divisions of the trigeminal nerve. The
average pain intensity during the week prior to the
scanning session was similar in all 3 pain groups
(P > .05, mean 6 SEM visual analog scale pain score;
trigeminal neuralgia: 3.2 6 .8; trigeminal neuropathy:
3.9 6 .4; TMD: 3.7 6 .5). In contrast, the average pain du-
ration was different between the 3 groups (mean 6 SEM
years; trigeminal neuralgia: 14.6 6 4.3; trigeminal
neuropathy: 4.8 6 .8; TMD: 9.1 6 2.0).
Trigeminal neuralgia patients described their pain as
shooting (67%), stabbing (56%), and sharp (67%);
trigeminal neuropathy patients described their pain as
radiating (39%), shooting (33%), and sharp (33%);
whereas TMD patients described their pain as throbbing
(70%), tender (60%), and shooting (40%).
Trigeminal Nerve Root Volumes
Nerve volumes and maximum cross-sectional areas for
all subjects are shown in Table 1. The left and right
trigeminal nerve root volumes and maximal cross-
sectional areas in control subjects were not significantly
different (P > .05). Because these values were not
significantly different, they were averaged for the
remainder of the analysis (mean 6 SEM; total nerve:
58.70 6 3.2, maximal cross-sectional area: 2.53 6 .1).
Age was not significantly correlated with nerve volume
(r = .14, P > .05) or maximal cross-sectional area
(r = .27, P > .05) in control subjects. Furthermore, there
was no effect of gender on nerve volume (total nerve:
males: 60.26 6 9.22, females: 58.33 6 2.94, P > .05) or
maximal cross-sectional area (males: 2.57 6 .26, females:
2.52 6 .12, P > .05).
In trigeminal neuralgia patients, comparison of the
ipsilateral (to side of pain) and contralateral nerves
revealed no significant difference in volume or maximal
cross-sectional area. However, comparison of the nerve
ipsilateral to the pain to controls revealed a significant
868 The Journal of Pain Trigeminal Nerve Anatomy in Orofacial Pain
Table 1.Overall Volume and Maximal Cross-Sectional Area of the Trigeminal Root Entry Zone in
Pain-Free Controls, Trigeminal Neuralgia Patients, Painful Trigeminal Neuropathy Patients, and
Painful TMD Patients
CONTROLS TRIGEMINAL NEURALGIA TRIGEMINAL NEUROPATHY TMD
(BILATERAL AND (BILATERAL AND
UNILATERAL UNILATERAL
(N = 26) (UNILATERAL N = 9) (UNILATERAL N = 9) N = 18) N = 20)

PAIN NONPAIN PAIN NONPAIN MAXIMUM MAXIMUM

LEFT RIGHT SIDE SIDE SIDE SIDE PAIN SIDE PAIN SIDE
Total nerve volume (mm3)
Mean (6SEM) 61.1 (3.6) 56.3 (2.8) 31.4 (5.7) 31.4 (4.5) 75.4 (11.7) 64.3 (4.9) 81.9 (7.2) 62.3 (7.4)
Maximal cross-sectional area (mm2)
Mean (6SEM) 2.6 (.1) 2.5 (.1) 1.7 (.2) 1.5 (.2) 3.1 (.2) 2.9 (.3) 3.2 (.2) 2.5 (.2)

(P < .05), 47% decrease in total nerve volume and
a 32% decrease in the maximal cross-sectional area
(Table 1, Fig 2). In striking contrast to trigeminal
neuralgia patients, trigeminal neuropathy patients
displayed significant nerve volume increases. Although
there were no significant differences between the
ipsilateral and contralateral nerves in trigeminal
neuropathy patients with unilateral pain (n = 9), the
ipsilateral nerve volume of all trigeminal neuropathy
patients (n = 18) displayed a significant (P < .05), 40%
increase in total nerve volume and a significant
(P < .05), 26% increase in the maximal cross-sectional
area, compared with controls. Finally, total nerve
volume and maximal cross-sectional area of the
ipsilateral trigeminal nerve in patients with TMD
were not significantly different from those of controls
(P > .05, Table 1, Fig 2).
In all 3 pain groups, ongoing pain intensity (pain diary)
values were not significantly correlated to either nerve
volume or maximal cross-sectional area of the nerve on
the affected side: nerve volume—trigeminal neuralgia,
r = .551, P > .05; trigeminal neuropathy, r = .208,
P > .05; TMD, r = .130, P > .05; maximal cross-sectional
area—trigeminal neuralgia, r = .211, P > .05; trigeminal
neuropathy, r = .002, P > .05; TMD, r = .240, P > .05.
Similarly, in all 3 pain groups, pain durations were not
significantly correlated to either nerve volume or
maximal cross-sectional area of the nerve on the affected

Figure 2. Bar graphs showing mean (1SEM) total nerve volumes (upper panel) and maximal cross-sectional areas (lower panel) in
controls, trigeminal neuralgia, trigeminal neuropathy, and TMD patients. *P < .05.
Wilcox et al
side: nerve volume—trigeminal neuralgia, r = .205,
P > .05; trigeminal neuropathy, r = .047, P > .05; TMD,
r = .063, P > .05; maximal cross-sectional area—trigeminal
neuralgia, r = .109, P > .05; trigeminal neuropathy,
r = .084, P > .05; TMD, r = .091, P > .05.
Trigeminal Nerve Root Diffusion Values
MD and FA values for the entire nerve and for the
coronal sections at the maximum cross-sectional area
for all subjects are shown in Table 2. The left and right
trigeminal nerve root MD and FA values in control
subjects were not significantly different and were
averaged for the remainder of the analysis. Age was
not significantly correlated with overall MD (r = .01,
P > .05) or FA (r = .07, P > .05).
In trigeminal neuralgia patients, comparison of the
ipsilateral and contralateral nerves revealed no signif-
icant difference in overall MD or FA values or maximal
cross-sectional area MD or FA values (Table 2, Fig 3). In
trigeminal neuralgia patients, comparison of the
ipsilateral nerve to controls revealed no significant
difference in any MD or FA value (ie, overall, total at
maximum cross-sectional area, or dorsal, middle, or
caudal nerve sections). Similarly, in trigeminal neurop-
athy patients, comparison of the ipsilateral and
contralateral nerves in unilateral neuropathy subjects
(n = 9) revealed no significant differences in any MD
or FA value. Comparison of the ipsilateral nerve in all
trigeminal neuropathy patients compared to controls
also revealed no significant difference in any MD or
FA value. Finally, in patients with TMD, comparison
of the ipsilateral nerve to controls revealed no
significant difference in any MD or FA value (Table 2,
Fig 3).
The Journal of Pain 869
Discussion
This study suggests that neuropathic orofacial pain
conditions are associated with changes in trigeminal
nerve volume, with the direction of change differing
between different types. Whereas trigeminal neuralgia
patients displayed a decrease in volume compared to
controls, neuropathy patients conversely displayed an
increase in volume. Surprisingly, these changes in nerve
volume were not coupled with any apparent change in
microstructure as assessed by DTI. In contrast to
neuropathic conditions, TMD was not associated with
any change in volume.
Although our sample size of trigeminal neuralgia
patients was relatively limited, thus restricting the
certainty of our results, there is mounting evidence
that this condition is associated with structural changes
in the trigeminal nerve. Similar to our findings, it
has been shown that the volume, diameter, and cross-
sectional area of the nerve is smaller on the symptom-
atic side.7,17 This overall nerve atrophy likely
corresponds to structural abnormalities reported in
pathologic findings of nerve sampled from neuralgia
patients, which show evidence of axonal loss,
axonopathy, demyelination, and dysmyelination.5,24
Furthermore, we found a significant decrease in nerve
volume on the asymptomatic side, raising the
possibility of additional mechanisms. Trigeminal
neuralgia is thought to result from neurovascular
compression because neurovascular contact by an
artery or a vein at the trigeminal root entry zone is
typically seen in neuralgia patients.27 However, innocu-
ous contact of the trigeminal nerve and vessels has also
been shown in cadaver and MRI such that the observa-
tion of contact is unreliable for diagnostic purposes.12

Table 2.Fractional Anisotropy and Mean Diffusivity Values of the Trigeminal Root Entry Zone in
Pain-Free Controls, Trigeminal Neuralgia Patients, Painful Trigeminal Neuropathy Patients, and
Painful TMD Patients
CONTROLS TRIGEMINAL NEURALGIA TRIGEMINAL NEUROPATHY TMD
(BILATERAL AND (BILATERAL AND
UNILATERAL UNILATERAL
(N = 26) (UNILATERAL N = 9) (UNILATERAL N = 9) N = 18) N = 20)

AVERAGE PAIN NONPAIN PAIN NONPAIN MAXIMUM MAXIMUM

LEFT RIGHT LEFT/RIGHT SIDE SIDE SIDE SIDE PAIN SIDE PAIN SIDE
Fractional anisotropy (mean [6SEM])
Total nerve .28 (.01) .27 (.01) .28 (.01) .26 (.02) .28 (.02) .26 (.02) .27 (.02) .26 (.01) .26 (.01)
Maximal cross-sectional area
Total .29 (.01) .27 (.01) .28 (.01) .27 (.02) .28 (.02) .26 (.02) .25 (.02) .25 (.01) .28 (.03)
Rostral third .35 (.01) .30 (.01) .33 (.01) .29 (.02) .30 (.03) .20 (.02) .28 (.02) .19 (.01) .30 (.03)
Middle third .22 (.01) .26 (.01) .24 (.01) .26 (.02) .23 (.03) .31 (.02) .27 (.02) .30 (.02) .25 (.03)
Caudal third .30 (.01) .25 (.01) .28 (.01) .28 (.01) .31 (.02) .27 (.02) .21 (.02) .26 (.01) .29 (.02)
Mean diffusivity (mean [6SEM]  103)
Total nerve 2.49 (.07) 2.38 (.06) 2.44 (.07) 2.37 (.15) 2.43 (.06) 2.45 (.14) 2.33 (.10) 2.46 (.08) 2.50 (.08)
Maximal cross-sectional area
Total 2.52 (.09) 2.47 (.07) 2.50 (.08) 2.28 (.13) 2.51 (.11) 3.10 (.20) 2.90 (.30) 2.54 (.08) 2.43 (.12)
Rostral third 2.49 (.06) 2.51 (.08) 2.50 (.07) 2.23 (.12) 2.55 (.09) 3.06 (.15) 2.87 (.23) 2.46 (.10) 2.51 (.17)
Middle third 2.50 (.11) 2.40 (.09) 2.45 (.11) 2.41 (.21) 2.52 (.15) 3.21 (.22) 2.99 (.33) 2.60 (.06) 2.37 (.13)
Caudal third 2.54 (.07) 2.44 (.06) 2.49 (.06) 2.16 (.14) 2.41 (.11) 3.18 (.26) 2.85 (.36) 2.56 (.12) 2.44 (.12)
870 The Journal of Pain
Figure 3. Bar graphs showing mean (1SEM) mean diffusivity and fractional anisotropy of the entire trigeminal root (upper panel)
and at the maximal cross-sectional area (lower panel) in controls, trigeminal neuralgia, trigeminal neuropathy, and TMD patients. No
significant differences (P < .05) were observed.
Despite this, structural disarray and electrical instability
are thought to be caused by abnormal contact on
the trigeminal root, resulting in characteristic pain
paroxysms.
In striking contrast to the decreased volume in
neuralgia patients, trigeminal neuropathy was associ-
ated with a significant increase in nerve volume. This
difference between nerve volumes in neuralgia and
neuropathy suggests that these 2 types of neuropathic
pain have different underlying pathomechanisms.
Although neuralgia patients present with intermittent
episodes of sharp, shooting pain, trigeminal neuropathy
is typically characterized by episodic sharp, shooting pain
combined with constant or long episodes of background
pain. Only 1 other study has examined trigeminal nerve
volumetry in neuropathy patients. Kress and
colleagues15 examined nerve volume in trigeminal
neuropathy patients—defined as having a burning pain
condition with a duration of pain >10 minutes. Their
study found no significant volume difference when
comparing the symptomatic to the asymptomatic
trigeminal nerve, nor when they compared the
symptomatic nerve with healthy controls. A possible
explanation for the discrepancy between these and our
results may be in the patient population used. Kress
and colleagues noted that a high percentage (84%) of
their neuropathy patients displayed a neurovascular
conflict, possibly reflecting a significant influence of
atypical (type 2) trigeminal neuralgia. In contrast, our
neuropathy patient population was almost exclusively
Trigeminal Nerve Anatomy in Orofacial Pain
composed of individuals with posttraumatic neuropathy.
It remains unknown if, despite sharing a longer duration
of pain complaint, the pathogeneses of posttraumatic/
inflammatory neuropathy is similar to atypical trigemi-
nal neuralgia.
Surprisingly, the changes in nerve volumes associ-
ated with trigeminal neuralgia and neuropathy
were not coupled with any changes in free water
movement, suggesting that the volumetric changes
are not coupled to changes in microstructure of the
nervous tissue itself. Diffusion-weighted parameters
are sensitive to microstructural changes because
processes including demyelination and axonal injury
can affect water anisotropy.1 On the basis of the
volumetric changes and the previously reported path-
ologic findings, it was hypothesized that these
structural abnormalities would be reflected in
changes in the diffusion values. Previous studies
employing diffusion imaging to study the trigeminal
nerve in neuralgia patients have produced mixed
results varying from no apparent changes,10 to
significantly decreased FA with no change in MD,19
to significantly decreased FA coupled with an
increased MD.17 Recently, Hodaie and colleagues13
utilized DTI to study microstructural changes in the
trigeminal nerve after focal radiosurgery. Interest-
ingly, they reported that pain relief following
treatment was associated with a decrease in FA
values, possibly resulting from localized myelin
degeneration. In subjects with long-term follow-up,
Wilcox et al
recovery of FA values—suggesting myelin regenera-
tion—was coupled with pain recurrence. Although
Hodaie’s study demonstrates the potential applica-
tion of diffusion imaging in assessing treatment and
longitudinal changes, the mixed results in baseline
studies remain at odds. Part of the discrepancy may
stem from variations in techniques, including the
location of data sampling. In order to potentially
alleviate this issue, we measured diffusion parameters
in a variety of positions; however, all measures
suggest that the nerve microstructure appears
unaltered in our neuralgia and neuropathy patients.
To our knowledge, only 1 case report has investi-
gated nerve histology in an individual with trigeminal
neuropathy. Watson and colleagues26 reported, in
the case of a 14-year-old boy with severe posttrau-
matic trigeminal neuropathic pain, that although
the unmyelinated fiber density remained normal
there was an increase in small, thinly myelinated
fibers that they suggest represents regenerating
axons.26 It is possible our observed increase in nerve
volume in neuropathy subjects reflects an increase in
small, thinly myelinated fibers. Although human
histologic evidence is limited, many investigators
have explored peripheral nerve anatomy in animal
models of neuropathic pain such as chronic constric-
tion injury model. Histologic studies indicate that
chronic constriction injury results in degeneration of
myelinated and unmyelinated axons distal to the
ligation; however, proximal to the ligation site
only minor or no pathologic changes occur.3,18
Interestingly, Stanisz and colleagues25 have shown
that although nerve transection results in long-term
pathologic changes, nerve crushing results in regener-
ation over time. Given that our neuropathy patients
developed pain following traumatic injuries that
did not result in nerve transaction, our results may
in fact reflect adaptive changes in the nerve
in response to altered activity peripheral to the
trigeminal root.
The striking finding of the differing direction of
volumetric change between different types of neuro-
pathic orofacial pain is particularly interesting in light
of a potential new addition in the differential diagnosis
of trigeminal neuralgia versus neuropathy. Although
the current criteria distinguish the 2 primarily based
on sensory components (ie, pain quality and duration),
it has been noted that there is phenotypic overlap
between the 2 conditions.2 Additionally, although MRI
has been used to optimally image the relationship of
the root entry zone of the nerve with blood vessels in
the vicinity, the accuracy of these findings in differenti-
ating neuralgia from neuropathy remains uncertain.22
The potential remains for this technique to be supple-
mented with the addition of volumetric assessment of
the nerve itself.
In comparison to both trigeminal neuralgia and
neuropathy, TMD patients were not associated with
any change in nerve volume or diffusion. Although
the etiology and pathology of TMD remains debated,
there is evidence for the role of peripheral nociceptive
The Journal of Pain 871
afferent input combined with a more generalized
hyperexcitability in the central nervous system and/or
impairments of endogenous pain inhibitory systems.8
The lack of trigeminal nerve anatomic change
suggests that the locus of aberrant input and/or
generalized hyperexcitability does not lie in the root
entry zone of the trigeminal nerve. Furthermore, we
have previously shown that in contrast to trigeminal
neuropathy, which is associated with significant gray
matter volume changes in regions such as the
thalamus, TMD is not associated with any changes in
regional gray matter volume.11 Younger and col-
leagues28 did report volume increases in some brain
regions in TMD patients. However, given the differ-
ences in pain duration between studies (4.4 vs
11.5 years), the lack of change reported here may
reflect adaptive changes that have subsided over
time. In contrast to our results, Moayedi et al21 have
recently reported findings of lower FA and higher
MD and radial diffusion in TMD subjects, in conjunc-
tion with alterations in cortical white mater tracts.
The authors suggest that these microstructural
changes may be caused by increased nociceptive
activity. This discrepancy in results may be due to
technique differences, as aforementioned. Equally,
the difference in findings may be due to differing
patient populations, with Moayedi’s study focusing
on idiopathic TMD patients whereas ours included all
patients fulfilling the TMD research criteria.6
The limitations of this study include that our diagnos-
tic criteria encompassed the broader populations of
TMD and trigeminal neuropathy as defined by the
TMD research diagnostic criteria and the Liverpool crite-
ria, respectively. Our sample numbers do not allow for
subgroup analysis and thus we cannot rule out that
these nerve changes are specific to certain subtypes.
Furthermore, although we assessed pain intensity and
duration and controlled for age and gender ratios,
there are further potential confounding variables that
may influence nerve anatomy, such as the presence of
allodynia and hyperalgesia, tender points, previous
dental procedures, and others.
In conclusion, the present study has contributed to the
characterization of the root entry zone of the trigeminal
nerve in 3 distinct orofacial pain conditions. The data
suggest that the changes occurring within the trigemi-
nal nerve are not uniform in all orofacial neuro-
pathic pain conditions; rather, trigeminal neuralgia is
associated with decreased volume whereas trigeminal
neuropathy is associated with increased volume. In
contrast, TMD may not be associated with any nerve
changes.
Acknowledgments
We wish to thank the many volunteers in this study.
Supplementary Data
Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.jpain.2013.02.014.
872 The Journal of Pain
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