ORIGINAL ARTICLE

Analgesic effects of navigated motor cortex rTMS in patients

with chronic neuropathic pain
S.S. Ayache1,2,3, R. Ahdab1,2,3, M.A. Chalah1,2, W.H. Farhat1,2, V. Mylius1,2,4, C. Goujon1,5, M. Sorel1,6,
J.-P. Lefaucheur1,2
1 EA 4391, Excitabilit

e Nerveuse et The
rapeutique, Universite

Paris-Est-Cre

teil, France
2 ^pital Henri Mondor, Assistance Publique – Ho
Service de Physiologie – Explorations Fonctionnelles, Ho ^pitaux de Paris, Cre

teil, France
3 Division of neurology, UMCRH, Beirut, Lebanon
4 Department of Neurology, Philipps University Marburg, Germany
5 Service de Neurochirurgie, Ho^pital Henri Mondor, Assistance Publique – Ho ^pitaux de Paris, Cre

teil, France
6 Centre d’Evaluation et de Traitement de la Douleur, Centre Hospitalier de Nemours, France

Correspondence Abstract
Samar S. Ayache
E-mail: samarayache@gmail.com Background: Repetitive transcranial magnetic stimulation (rTMS) can
relieve neuropathic pain when applied at high frequency (HF: 5–20 Hz)
Funding sources over the primary motor cortex (M1), contralateral to pain side. In most
None. studies, rTMS is delivered over the hand motor hot spot (hMHS),
whatever pain location. Navigation systems have been developed to
Conflicts of Interest
guide rTMS targeting, but their value to improve rTMS efficacy remains
None declared.
to be demonstrated.
Objective: To compare the analgesic efficacy of HF-rTMS targeting the
Accepted for publication hMHS (non-navigated procedure) or the M1 representation of the pain
11 February 2016 region (navigated procedure).
Methods: The analgesic effect of a single session of 10 Hz-rTMS of M1
doi:10.1002/ejp.864
was assessed in 66 patients with neuropathic pain of various causes and
locations, according to three conditions: sham or active non-navigated
rTMS of the hMHS and active navigated rTMS of the pain region.
Results: Pain was relieved by both active rTMS conditions, and not by
sham. Pain location influenced the results: upper or lower limb pain was
significantly relieved, but not facial or hemibody pain. Pain relief lasted
1 week only after navigated rTMS, compared to sham.
Conclusion: Navigation may improve HF-rTMS efficacy in patients with
limb pain, whereas targeting remains to be optimized for more diffuse or
facial pain.
What does this study add?: To produce analgesic effects, HF-rTMS
should be applied over the precentral cortex contralaterally to the
painful side. Although the hMHS is the target normally chosen for
stimulation, the optimal target has not been defined yet.
Neuronavigational methods have been recently developed; they allow
the integration of MRI data and are thought to improve rTMS efficacy.

1. Introduction
Neuropathic pain originates from a lesion or disease
of central or peripheral somatosensory system
(Treede et al., 2008), affecting up to 6–7% of the
general population (Torrance et al., 2006; Bouhassira
et al., 2008). Pharmacological interventions showed
limited efficacy in this domain, since only 30–40%
of patients with neuropathic pain report being
relieved satisfactorily (Attal et al., 2006). Developed

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Effects of navigated motor cortex rTMS on neuropathic pain
in the early nineties (Tsubokawa et al., 1991a,b),
epidural motor cortex stimulation (EMCS) using sur-
gically implanted electrodes was shown capable of
producing long-term analgesia in about half of
patients with chronic neuropathic pain resistant to
medication (Cruccu et al., 2007; Fontaine et al.,
2009; Nguyen et al., 2009). Ten years later (Lefau-
cheur et al., 2001a), non-invasive stimulation of the
primary motor cortex (M1) using repetitive transcra-
nial magnetic stimulation (rTMS) was successfully
applied in the same clinical context (Lefaucheur,
2006; Lefaucheur et al., 2008a; Leung et al., 2009).
This technique could have particular interest to
select candidates for subsequent surgical implanta-
tion (Lefaucheur et al., 2011b; Andr
e-Obadia et al.,
2014). Recently, a group of international experts
concluded to a level A of evidence for the efficacy of
rTMS on neuropathic pain when applied at high fre-
quency (HF), i.e. 5–20 Hz, over M1 contralaterally
to the painful side (Lefaucheur et al., 2014). How-
ever, in this consensus, some practical issues have
not been addressed, including how to define the
optimal location of the cortical target. In many rTMS
studies, analgesic effects have been obtained by tar-
geting the motor hot spot of the hand (hMHS),
which is the scalp site whose stimulation produces
the greatest motor-evoked potentials (MEPs) in con-
tralateral hand muscles (Lefaucheur et al., 2004,
2008b; Khedr et al., 2005; Andr
e-Obadia et al.,
2006, 2011; Kang et al., 2009; Matsumura et al.,
2013). Conversely, in this context, very few rTMS
studies have used image-guided navigation system to
specifically target the M1 representation of the pain-
ful body area (Hirayama et al., 2006; Hodaj et al.,
2015), while one study even used navigation to tar-
get the hand motor cortical region, regardless of pain
location (Lefaucheur et al., 2012). In the present
work, we compared for the first time the analgesic
effects produced in patients with chronic neuro-
pathic pain by stimulating either the hMHS regard-
less of pain location or the anatomical M1
representation of the pain area using image-guided
navigation.
2. Materials and methods
2.1 Patients
The study protocol was included within the frame-
work of a research programme on EMCS for pain
treatment, approved by the local ethical committee
and performed in compliance to the declaration of
Helsinki. Sixty-six patients (32 men, 34 women,
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mean age 51.2  11.5 years, age range 18–76 years)
with various types of chronic refractory neuropathic
pain from peripheral or central origin were enrolled
consecutively in this study without any dropout. The
pain was unilateral or frankly asymmetrical and
located at the face (n = 16), hemibody (n = 16),
upper limb (n = 20) or lower limb (n = 14). The
causes of pain were persistent idiopathic (atypical)
facial pain secondary to dental surgery (n = 7),
trigeminal neuralgia with nerve lesion secondary to
previous surgical treatment (n = 9), nerve trunk,
plexus or root lesion (n = 22), myelopathy (n = 11)
and cortical, thalamic or brainstem stroke (n = 17).
Detailed patients’ demographic and clinical data are
shown in Table S1 (Supporting Information). These
patients had no contraindications to magnetic stimu-
lation, including no history of epilepsy and/or ferro-
magnetic implant. They were asked to keep their
pharmacological treatment at a constant level
throughout the entire stimulation protocol. All of
them voluntarily gave their informed consent prior
to sessions.
2.2 Neuronavigation
Navigation was performed using the eXimia NBS sys-
tem (Nexstim Oy, Helsinki, Finland) that relies on
frameless stereotaxy. Each patient underwent a T1-
weighted magnetic resonance imaging (MRI), free of
motion and artifacts. MRI data were integrated in
the NBS system, which automatically generates a
3D-reconstruction of the brain. By means of an
infrared camera system which detects standardized
cranial landmarks, the patients’ head and the rTMS
stimulation coil were coregistered in the MRI coordi-
nate system. This allows a real-time visualization of
the location and orientation of the coil over the
head, the resulting electric field density and the cor-
tical targets, with an imprecision of less than
5.7 mm (Ruohonen and Karhu, 2010).
2.3 rTMS procedures
We assessed the analgesic effects produced by single
rTMS sessions. Three different rTMS conditions were
compared in the following order: (i) non-navigated
sham rTMS over the hMHS of the painful side (re-
gardless of pain location); (ii) non-navigated active
rTMS over the same target; and (iii) navigated active
rTMS over the anatomical representation of the
painful zone. These three sessions were performed
3 weeks apart to avoid any carry-over effect, the
analgesia induced by a single rTMS session being
maximal 2–3 days after the session and lasting less
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S.S. Ayache et al.
than 2 weeks (Lefaucheur et al., 2001b). A MagPro
X100 stimulator [MagVenture (Mag2Health), Farum,
Denmark] was used for all the sessions. Active rTMS
was performed with a 2 9 75 mm winding-diameter
figure-of-eight coil (Cool-B65, MagVenture). The
sham procedure was performed with a sham coil
(MCF-P-B65, MagVenture), replicating the appear-
ance and operation of the active coil, but without
stimulating cortical tissue, as already used in a simi-
lar type of study (e.g., Andr
e-Obadia et al., 2014).
As in our previous studies (Lefaucheur et al., 2006a,
2008b), the patients were not informed about the
existence of a sham condition. They only knew that
three sessions of rTMS using different parameters of
stimulation were tested for their respective efficacy
to relieve pain, including one with an image-guided
navigation control. It was mentioned to the patients
that this condition was not performed to improve
stimulation accuracy, but just to retrieve anatomical
targeting data. The sham condition was performed
first, according to a previous study which demon-
strated the importance of this placebo timing in
rTMS protocols for pain relief (Andr
e-Obadia et al.,
2011).
During the whole sessions, the patients were
seated in a comfortable reclining chair. In the first
session, the location of the hMHS was determined.
Pre-gelled disposable surface electrodes (Ref
9013S0242, Natus-Dantec, Skovlunde, Danemark)
were placed with a belly tendon montage over the
first dorsal interosseous muscle (FDI) of the hand of
the painful side to record MEPs. The location of the
hMHS was defined as the scalp site whose stimula-
tion produced the largest FDI-MEPs. The procedure
of hMHS location was as follows: (i) we placed the
centre of the TMS coil at C3/C4 location according
to the 10–20 international system of EEG electrode
positioning, the coil being maintained tangential to
the scalp with the handle pointing backwards at 45°
away from the interhemispheric midline; (ii) we
delivered TMS at gradually increasing intensities
until evoking reproducible FDI-MEPs of 0.5–1 mV in
amplitude; (iii) using the same intensity of stimula-
tion and coil orientation, we stimulated the cortex
by moving the TMS coil by steps of 0.5 cm in the
four directions (anterior, posterior, medial and lat-
eral), while recording FDI-MEPs. The site of stimula-
tion giving the largest FDI-MEPs was considered the
hMHS. Then, the rest motor threshold (RMT) was
determined at this point, as the minimum stimula-
tion intensity required for eliciting MEPs greater
than 50 lV peak-to-peak amplitude on five out of
10 trials performed with complete muscle relaxation
© 2016 European Pain Federation – EFICâ
Effects of navigated motor cortex rTMS on neuropathic pain
(Rossini et al., 2015). This procedure was repeated
in the second session, prior to non-navigated active
stimulation of the hMHS. Conversely, in the third
session performed with a navigation system, we did
not determine the location of the hMHS and we did
not measure the RMT.
To perform rTMS, in all the sessions, the coil was
oriented in an anteroposterior direction, parallel to
the interhemispheric midline, which is the optimal
orientation to produce analgesia (Andr
e-Obadia
et al., 2008; Lefaucheur et al., 2010a). Pulses of
biphasic waveform were delivered at a frequency of
10 Hz and an intensity of 90% of the RMT measured
at the hMHS. Since this measurement was not per-
formed in the third session (navigated active rTMS),
for this session, we performed the stimulation at the
same intensity as for the second session (non-navi-
gated active rTMS of the hMHS). Each session lasted
15 min and consisted of 3000 pulses (30 trains of
10 s each with intertrain intervals of 20 s). Short
intertrain intervals have already been used in HF-
rTMS protocols for analgesia (Lefaucheur et al.,
2012; Hodaj et al., 2015) and remain in the safety
limits of rTMS guidelines (Rossi et al., 2009; Lefau-
cheur et al., 2011a).
It is known that M1 occupies the anterior wall of
the central sulcus and only a limited part of the
exposed surface of the precentral gyrus (Rademacher
et al., 2001). Therefore, in the navigated condition,
rTMS was delivered over the anterior lip of the cen-
tral sulcus to be more certain to target M1 and not
the premotor cortex in the rostrocaudal axis (Fig. 1)
(Mylius et al., 2013; Ahdab et al., 2014). In the
mediolateral axis, the stimulation was performed on
the segment of the central sulcus facing the upper
frontal gyrus (F1) for lower limb pain, the middle
frontal gyrus (F2) for upper limb or hemibody pain
and the lower frontal gyrus (F3) for facial pain
(Fig. 1), according to the classical homunculus anat-
omy (Penfield and Boldrey, 1937; Nguyen et al.,
1999). For hemibody pain, which was mainly due to
stroke lesion, we chose to target the hand area,
because pain was most critical at this level.
2.4 Clinical evaluation
The primary objective of the study was to assess
rTMS-induced analgesia on a 0–10 Visual Analogue
Scale (VAS). The VAS scores recorded during the
week before and the week after each stimulation
session were averaged (VASweek). A special attention
was paid on the VAS pain scores recorded on days 2
and 3 of each week of assessment (VASd2d3), a per-
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Effects of navigated motor cortex rTMS on neuropathic pain
Figure 1 Location of the navigated targets based on a three-dimen-
sional reconstruction of the brain. F1, F2 and F3 correspond to the
superior, middle and inferior frontal gyri, respectively, separated by
the superior frontal sulcus (sFS, in green) and the inferior frontal sul-
cus (iFS, in red). The sFS and iFS were projected (black dotted lines)
onto the central sulcus (CS, in yellow) to divide it into three segments.
The stimulation was performed over the segment of the CS that faced
F1 in case of lower limb pain (target ○;1), F2 in case of upper limb or
hemibody pain (target ○;2, corresponding to the hand knob) and F3
in case of facial pain (target ○;3). In the sagittal plane, we carefully
checked that the target was located within the grey matter on the
anterior lip of the CS (top of the posterior border of the precentral
gyrus, detailed view in the bottom right corner).
iod at which the maximum analgesic effect occurs
after a motor cortex rTMS session (Lefaucheur et al.,
2001b). In addition, the percentage of pain reduction
(PPR) was calculated from the VAS scores measured
before and after each rTMS session according to the
following equation:
PPR ¼ ðVAS postrTMSÞðVAS prerTMSÞ
ðVAS prerTMSÞ  100. The PPRs
were determined for the entire week of assessment
(PPRweek) and for the days 2 and 3 of each week of
assessment (PPRd2d3).
2.5 Statistical analysis
Statistics were performed using StatView software
(Abacus Concepts, Berkeley, CA, USA). In the entire
series of patients, the VASweek and VASd2d3 scores
recorded before and after each rTMS session were
compared using repeated measures ANOVA under
six conditions that resulted from the combination of
two nominal variables as within-subject factors:
‘Time’, with two group levels (before and after) and
‘Treatment’, with three group levels (sham, non-
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S.S. Ayache et al.
navigated and navigated rTMS). Second, the PPRweek
and PPRd2d3 calculated for each rTMS condition
(sham, hMHS-targeted, navigated) were compared
using a repeated measure one-way ANOVA. If
repeated measures ANOVA yielded significant results
(p < 0.05), Bonferroni post-hoc tests were performed
for further interpretation. In addition, the same anal-
yses were performed in four groups of patients
defined by pain location (face, hemibody, upper limb
and lower limb).
Finally, the influence of various other factors on
the PPRweek and PPRd2d3 calculated for each rTMS
condition (sham, hMHS-targeted, navigated) was
studied. We used nonparametric test for these analy-
ses, because assumption tests performed with the
methods of Kolmogorov–Smirnov and Bartlett
showed that the data of the groups did not follow
Gaussian distributions with equal standard devia-
tions. Comparisons between the five groups of
patients defined by pain cause (atypical facial pain,
trigeminal neuralgia, nerve/plexus/root lesion,
myelopathy and stroke) were performed using non-
parametric ANOVA (Kruskal–Wallis test). Dunn’s
post-hoc tests were performed for further interpreta-
tion if ANOVA yielded significant results (p < 0.05).
The influence of gender (woman vs. man), pain side
(right vs. left) and intake of anticonvulsant, antide-
pressant or opioid medication (yes or no for each
medication class) was studied using the Mann–Whit-
ney test. Finally, the influence of numerical vari-
ables, i.e. the age of the patients, the intensity of
pain at baseline and the duration of the pain condi-
tion on rTMS efficacy was studied using the Spear-
man correlation test.
3. Results
3.1 Entire series of patients
No adverse effects were reported, which is consistent
with what is currently reported following single ses-
sions of rTMS delivered to the motor cortex at a sub-
threshold intensity in patients with chronic pain
(Muller et al., 2012). Repeated measure ANOVA
showed a significant Time 9 Treatment interaction
for the VASweek and VASd2d3 scores (p = 0.0002 and
0.0006, respectively) (Figs. 2 and 3). Similarly, both
PPRweek and PPRd2d3 significantly differed according
to the rTMS condition (p = 0.0002 and 0.0005,
respectively) (Figs. 2 and 3).
Post-hoc tests showed that both VASweek and
VASd2d3 scores were significantly reduced after
hMHS-targeted rTMS (p = 0.003 and 0.0002, respec-
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Figure 2 Mean values + SEM of the pain scores (upper graph) and
the percentages of pain score reduction (lower graph) recorded for
the week before and the week after each stimulation session (sham,
hotspot-targeted and navigated procedures) in the entire series of
patients. The p-values of ANOVA and post-hoc tests are presented.
Figure 3 Mean values + SEM of the pain scores (upper graph) and
the percentages of pain score reduction (lower graph) recorded on
days 2 and 3 of each week of assessment before and after each stim-
ulation session (sham, hotspot-targeted and navigated procedures) in
the entire series of patients. The p-values of ANOVA and post-hoc
tests are presented.
tively) and navigated rTMS (p < 0.0001 and
p < 0.0001, respectively), but not after sham rTMS
(p = 0.842 and 0.357, respectively). Regarding
PPRweek and PPRd2d3, a significant difference was
observed during the hMHS-targeted and the navi-
© 2016 European Pain Federation – EFICâ
Effects of navigated motor cortex rTMS on neuropathic pain
gated procedure compared to the sham procedure
(p < 0.05 and p < 0.001, respectively). However, no
significant differences were found by comparing the
hMHS-targeted to the navigated procedure.
3.2 Influence of pain location
Repeated measures ANOVA did not show any signif-
icant variations among the rTMS conditions regard-
ing the four following parameters: VASweek and
VASd2d3 scores, PPRweek and PPRd2d3 in patients with
facial pain (p = 0.40, 0.33, 0.60, and 0.30, respec-
tively) or hemibody pain (p = 0.21, 0.19, 0.22, and
0.17, respectively).
Conversely, there was a significant Time 9 Treat-
ment interaction for the VASweek and VASd2d3 scores
in patients with upper limb pain (p = 0.01 and
0.0003, respectively) or lower limb pain (p = 0.04
and 0.009, respectively) (Figs. 4 and 5). Similarly,
both PPRweek and PPRd2d3 significantly differed
according to the rTMS condition in patients with
upper limb pain (p = 0.009 and 0.0005, respectively)
or lower limb pain (p = 0.03 and 0.006, respectively)
(Figs. 4 and 5).
Post-hoc tests showed that the VASweek scores
were significantly reduced after hMHS-targeted and
navigated rTMS, but not after sham rTMS in patients
with upper limb pain (p = 0.03, 0.0006, and 0.95,
respectively) or lower limb pain (p = 0.02, 0.01, and
0.65, respectively). Similar results were observed for
the VASd2d3 scores in patients with upper limb pain
(p = 0.003, 0.0004, and 0.99, respectively) or lower
limb pain (p = 0.003, 0.0004, and 0.61, respectively).
Compared to the sham procedure, the PPRweek
reached significance only following navigated active
rTMS in patients with upper limb pain (p < 0.005)
or lower limb pain (p < 0.05), whereas the PPRd2d3
reached significance following both hMHS-targeted
and navigated active rTMS in patients with upper
limb pain (p < 0.005 and p < 0.001, respectively) or
lower limb pain (p < 0.05 and p < 0.05, respec-
tively).
3.3 Influence of pain cause
The PPRweek and PPRd2d3 did not vary with the cause
of pain (p > 0.05, Kruskal–Wallis test), except for the
PPRd2d3 in the navigated condition (p = 0.004). Post-
hoc tests showed higher PPRd2d3 in patients with
nerve/plexus/root lesion than with stroke following
navigated rTMS (28.9%  5.9 vs. 5.8%  3.9)
(Fig. 6). Patients with atypical facial pain or trigemi-
nal neuralgia had also low PPRd2d3 but the difference
with patients with peripheral nerve lesion did not
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Effects of navigated motor cortex rTMS on neuropathic pain S.S. Ayache et al.

Figure 4 Mean values + SEM of the pain scores (upper graph) and the percentages of pain score reduction (lower graph) recorded for the week
before and the week after each stimulation session (sham, hotspot-targeted and navigated procedures) in the groups of patients with upper limb
pain (left panel) or lower limb pain (right panel). The p-values of ANOVA and post-hoc tests are presented.

Figure 5 Mean values + SEM of the pain scores (upper graph) and the percentages of pain score reduction (lower graph) recorded on days 2 and
3 of each week of assessment before and after each stimulation session (sham, hotspot-targeted and navigated procedures) in the groups of
patients with upper limb pain (left panel) or lower limb pain (right panel). The p-values of ANOVA and post-hoc tests are presented.

reach statistical significance, mostly because these
groups were characterized by small samples and
more variable individual results.
3.4 Influence of other factors
The PPRweek and PPRd2d3 did not vary with pain side
and anticonvulsant medication for the various rTMS

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S.S. Ayache et al.
Figure 6 Mean values + SEM of the percentages of pain score reduc-
tion recorded on days 2 and 3 of each week of assessment (PPRd2d3)
before and after the navigated stimulation procedure in the different
groups of patients defined by pain cause. *: p-value significance
(p < 0.05) of the post-hoc test.
conditions (p > 0.05, Mann–Whitney test). The
PPRweek and PPRd2d3 were also not influenced by the
other studied factors for the active hMHS- and navi-
gation-targeted rTMS conditions. Conversely, the
sham procedure was influenced by gender and the
intake of antidepressant or opioid medication: (i) the
PPRweek and PPRd2d3 were lower in women than in
men in the sham rTMS condition (9.7%  4.8 vs.
8.9%  4.5, p = 0.004 for the PPRweek; 6.1% 
5.6 vs. 11.9%  4.9, p = 0.049 for the PPRd2d3); and
(ii) the PPRd2d3 was higher in patients receiving
antidepressants and the reverse for opioids in the
sham rTMS condition (11.2%  6.3 vs. 4.9% 
4.7, p = 0.031 for antidepressants; 3.5%  5.6 vs.
6.8%  5.3, p = 0.031 for opioids).
Regarding correlation studies, the PPRweek and
PPRd2d3 were not influenced by patients’ age and
pain duration for the various rTMS conditions
(p > 0.05, Spearman test). Conversely, the intensity
of pain at baseline influenced the efficacy of the
sham procedure, but not of the active hMHS- and
navigation-targeted rTMS conditions. The PPRweek
and the PPRd2d3 were positively correlated with pain
intensity at baseline (p = 0.023, r = 0.28 and
p = 0.020, r = 0.29, respectively).
4. Discussion
First, this study confirms that, compared to sham
stimulation, a single session of HF-rTMS delivered
© 2016 European Pain Federation – EFICâ
Effects of navigated motor cortex rTMS on neuropathic pain
to M1 is able to produce significant, short-lasting
analgesic effects in patients with chronic neuro-
pathic pain, at least when pain is located at the
upper or lower limb. Analgesic effects were
obtained by targeting either the hMHS regardless of
pain location or the anatomical M1 representation
of the pain region, according to classical homuncu-
lus anatomy. Although pain reduction at D2–D3
after the rTMS session (PPRd2d3) was similar for the
two procedures, only the navigated procedure pro-
duced significant analgesia for the entire week after
the rTMS session (PPRweek). This result suggests an
additional value of using neuronavigation to guide
rTMS therapy in pain patients in terms of analgesic
efficacy.
The lack of efficacy in case of hemibody pain
could be related to a too focal effect of our rTMS
procedure, although hMHS stimulation was previ-
ously found to produce analgesia in widespread, but
non-neuropathic pain syndromes (Passard et al.,
2007; Mhalla et al., 2011; Lee et al., 2012; Boyer
et al., 2014; Dall’Agnol et al., 2014). Regarding facial
pain, our results are even more surprising, since
rTMS targeted to the hMHS (Lefaucheur et al., 2004,
2006b) or to the motor cortical representation of the
face (Hodaj et al., 2015) was previously found to
relieve facial pain secondary to dental or trigeminal
neuralgia surgery, as in our patients. Our negative
result could be explained by underpowered statistics
due to a too small sample size or a bias in the
recruitment of a significant number of non-respon-
ders among our patients with facial pain.
Indeed, the variability in the individual results
observed in our patients with atypical facial pain or
trigeminal neuralgia prevents the difference in rTMS
efficacy to reach the level of significance compared
to the patients with peripheral nerve injury. Con-
versely, the difference between the patients with
peripheral nerve injury and stroke was significant,
showing a better rTMS efficacy in case of peripheral
neuropathic pain. However, the fact that 82% of our
stroke patients had hemibody pain probably explains
this result. Body pain diffusion was a confounding
factor, likely having a more significant impact on
rTMS outcome than the location of stroke in cortical,
thalamic or brainstem structures.
The sham procedure was influenced by gender,
medication and baseline pain intensity: the analgesia
experienced following sham rTMS was greater in
men, in patients receiving antidepressants, in
patients not receiving opioids and with respect to a
higher intensity of pain at baseline. Conversely,
none of these variables influenced the efficacy of
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Effects of navigated motor cortex rTMS on neuropathic pain
active rTMS procedures and therefore the impact of
these factors is probably limited to explain our
results or to be further considered in rTMS practice
for pain treatment.
Several methodological limitations of our study
should be discussed. First, our study was single-blind.
The patients were not informed of the nature of the
rTMS session and self-assessed their pain scores, but
the operator was aware of the type of stimulation.
Second, the order of the three rTMS sessions was
not randomized. On the one hand, the sham rTMS
condition was always performed first, according to a
previous study which demonstrated the importance
of placebo timing in rTMS protocols for pain relief
(Andr
e-Obadia et al., 2011). On the other hand, the
navigated rTMS condition was always performed
last, because we thought that this procedure could
be more impressive (use of camera, trackers, 3D-
reconstruction of the brain on NBS system screen)
for the patients and therefore they may underesti-
mate the effect of a non-navigated stimulation if per-
formed after a navigated one. Thus, the patients
could have overestimated the effect of navigated
rTMS, given its greater technical complexity, but, as
indicated above, they were informed that this condi-
tion was only performed to retrieve anatomical tar-
geting data. Despite this limitation of our study
design, we believe that our findings make sense,
especially considering the selectivity of rTMS efficacy
depending on pain location.
Third, the sensations caused by the different pro-
cedures were not objectively evaluated. Differences
in scalp sensation between the three conditions,
especially between the use of the active and sham
coils may have theoretically influenced the results.
This could have been prevented by the application of
a ‘realistic sham’ condition with concomitant electri-
cal stimulation of the scalp (Lefaucheur et al.,
2010b; Hosomi et al., 2013). However, the stimula-
tions were carried out at moderate stimulus intensi-
ties (below motor threshold), and caused no local
discomfort to the patients, in contrast to what is
reported following prefrontal stimulation for depres-
sion, for example (Anderson et al., 2009; Borckardt
et al., 2013). Therefore, it is unlikely that this factor
may have substantially threatened the blind and or
influenced the reported outcomes.
Fourth, when pain was not located at the hand,
targets had obviously very different locations
between the navigated and non-navigated proce-
dures. Conversely, they could have been very close
in case of hand pain, although the hMHS does not
systematically correspond to the anatomical hand
8 Eur J Pain

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S.S. Ayache et al.
knob (Ahdab et al., 2010). However, the distance
between the hMHS and the navigated target was
unfortunately not measured in our patients with
upper limb or hand pain.
Fifth, regarding the intensity of stimulation, the
second and third sessions were performed at the
same intensity, determined as 90% of the RMT cor-
responding to the hMHS, i.e. at a site of stimulation
producing the largest hand MEPs. The RMT was not
measured at the site of stimulation in the navigated
session, but it was likely higher than the RMT corre-
sponding to the hMHS. Therefore, it is probable that
the intensity of stimulation used in the third session
corresponded to a lower percentage of the RMT rela-
tive to the site of stimulation. Thus, maybe the stim-
ulation was underpowered in the navigated
condition, reducing its potential efficacy and there-
fore the possibly additional interest of navigation. In
addition, our study design could have further
reduced the relative intensity of stimulation in case
of facial and lower limb pain, since the RMT is likely
higher for these muscles than for hand muscles.
However, this cannot explain the lack of rTMS effi-
cacy in case of facial pain, since lower limb pain was
significantly relieved. Therefore, the impact of a pos-
sibly too low intensity of stimulation was probably
limited.
In conclusion, our study confirms that high-fre-
quency rTMS delivered to the motor cortex con-
tralateral to pain side can produce analgesic effects
in patients with chronic neuropathic pain. Concern-
ing the targeting procedure, our study compared the
analgesia induced by stimulating the hMHS regard-
less of pain location versus the M1 representation of
the pain region using image-guided navigation. Both
procedures appeared to be efficacious, although the
navigated approach produced more prolonged
effects, at least in patients with focal neuropathic
pain at the upper or lower limb. In addition, image-
guided navigation is thought to improve the reliabil-
ity of coil placement within individuals in repeated
rTMS session protocols (Lefaucheur, 2010) and also
between individuals compared to a hMHS-based tar-
geting method, because of the anatomical variability
in hMHS location (Ahdab et al., 2010). Our results
also show that rTMS can produce analgesia only in
selected responders (according to pain location in
this study) and this leaves room to improve the pro-
cedure of rTMS, including targeting, in a more per-
sonalized approach tailored to the individual patient.
This is an important issue, among other factors
recently listed by Klein et al. (2015), before consid-
ering rTMS therapy in clinical practice.
© 2016 European Pain Federation – EFICâ
S.S. Ayache et al.
Authors contribution
S.S.A., R.A., M.A.C., W.H.F, V.M. and J.-P.L. contributed
to rTMS manipulations or data collection; C.G. and M.S.
contributed to the recruitment and clinical assessment of
the patients; S.S.A. and J.-P.L. contributed to data analy-
ses; S.S.A., M.A.C. and J.-P.L. contributed to the redaction
of the manuscript.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article at the publisher’s web-site:
Table S1. Demographic and clinical data
© 2016 European Pain Federation – EFICâ