Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up

Abstract

Objectives:
Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.

Methods:
Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1 Hz/1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).

Results:
In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant change in pain ratings was observed.

Conclusion:
Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through targeting spinal pain circuits and top-down pain modulation .

Trial registration:
Ref No: CTRI/2013/12/004228.

Full text

R E S E A R C H Open Access
Repetitive transcranial magnetic stimulation
of the prefrontal cortex for fibromyalgia
syndrome: a randomised controlled trial
with 6-months follow up
Suman Tanwar
1,2
, Bhawna Mattoo
1
, Uma Kumar
3
and Renu Bhatia
1*
Abstract
Objectives: Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In
recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various
chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over
the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.
Methods: Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1Hz/
1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week
for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were
followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).
Results: In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post
rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant
change in pain ratings was observed.
Conclusion: Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through
targeting spinal pain circuits and top-down pain modulation .
Trial registration: Ref No: CTRI/2013/12/004228.
Keywords: Neuromodulation, Chronic pain, Dorsolateral prefrontal cortex, Non-invasive therapy, Nociceptive flexion
reflex, Oxidative stress
Introduction
Fibromyalgia affects nearly 2.10% of the world’s popula-
tion [1]. The etiopathogenesis of FMS is largely un-
known, although tender points all over the body suggest
a peripheral pathology, but a considerable amount of
data also points towards the sensitization of central pain
processing pathways [2], dysfunctional pain inhibition
[3] and abnormal cortical excitability [4]. Keeping in
view the variable pathophysiology, the management
strategies recommended for FMS include; pharmaceuti-
cals, behavioral interventions, physical therapy, exercises
along with other complementary and alternativemedic-
inal approaches [5]. However, no single treatment mo-
dality has been able to alleviate the full range of FMS
symptoms. Hence, it is pertinent to search for effective
alternative methods of therapy.
Transcranial magnetic stimulation is a non-invasive
brain stimulation technique which is being used to man-
age psychiatric cases, several movement disorders and
chronic pain conditions including fibromyalgia [6–8].
Recent study has shown that rTMS of the DLPFC in-
duces changes in the activity of a network of structures
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* Correspondence: renuaiims28@gmail.com
1
Department of Physiology, AIIMS, New Delhi 110029, India
Full list of author information is available at the end of the article
Advances in Rheumatolo
gy
Tanwar et al. Advances in Rheumatology (2020) 60:34
https://doi.org/10.1186/s42358-020-00135-7

involved in the integration and modulation of pain sig-
nals, including the thalamus, brainstem, insular and cin-
gulate cortices [9]. A previous study by our group
observed beneficial effects of low frequency rTMS and
established the role of DLPFC modulation in chronic
tension type headache [10]. However, the substrates of
the analgesia and its longevity remains to be unravelled.
We hypothesized that TMS of the right DLPFC using
low-frequency rTMS could relieve pain and associated
symptoms of fibromyalgia. The objectives (primary and
secondary) of the study were to investigate the effect of
rTMS on FMS pain and related symptoms and explore
the mechanism of analgesia by recording the nocicep-
tive flexion reflex (NFR); an objective marker of pain.
Further, in order to understand the effect of right-
DLPFC rTMS on descending pain inhibitory pathways,
we assessed the diffuse noxious inhibitory controls
(DNIC) system. To further substantiate the literature
suggesting the role of oxidative stress markers in FMS
[11,12], we assessed the levels of thiobarbituric acid re-
active substances (TBARS) and F2-isoprostane in our
FMS patients before and after rTMS therapy.
Materials and methods
Ethical considerations and trial design
The study was conducted at the Pain Research and TMS
Laboratory, Department of Physiology, All India Institute
of Medical Sciences (AIIMS) New Delhi, India. Human
Ethics committee of the AIIMS, New Delhi (Ref No:
IESC/T-251/15.06.2013) approved the research protocol
in 2013. The study was also registered in ICMR-CTRI;
India (Ref No: CTRI/2013/12/004228). The study was a
randomized, parallel group, placebo controlled trial.
Randomization was performed through a computer gen-
erated random number table and concealment was done
with sequentially numbered, sealed, opaque envelopes.
Block randomization design used was to ensure equal
sample size between two groups over time. The patients
were blinded to the block size as well as to the treatment
allocations. Participants were free to withdraw from the
study at any stage. All the participants were enrolled
only after obtaining the ethical approval and a duly
signed informed consent form.
Study protocol
Participants were randomly assigned to either the Sham
or Real rTMS group. Subjective, objective assessment of
pain and estimation of oxidative stress markers were
done at baseline and post-Sham/Real rTMS. Immedi-
ately post-rTMS, the patients were followed up to a
period of 6 months, at the three time points; 15 days
Post-rTMS, 3-months and 6-months after the therapy.
During follow-up, subjective evaluation using specific
questionnaires was done for a period of 6 months while
NFR and DNIC were performed at post-rTMS and 15th-
day post-rTMS (Fig. S1).
Sample size calculation
According to a preliminary study on fibromyalgia [13],
NPRS ratings were 5·60 (1·85) at baseline which were re-
duced to 3·99 (1·90) after Real rTMS, while in Sham
group, baseline and post treatment values were 5·34 (1.82)
and 5·07 (1·89) respectively. Using this data, we required
41 cases per group to detect a significant difference
between sham and real rTMS treatment in a 5% two sided
t-test with 90% power. Assuming a 10% loss to the follow
up, we required 45 patients of FMS per group. Accord-
ingly a sample size of 90 patients (45 on sham treatment
and 45 on real rTMS treatment) was decided.
Recruitment of FMS patients
Female patients with FMS (age, 18–50 years) having
regular menstrual cycle were recruited from the
Rheumatology Clinic, Department of Rheumatology,
AIIMS, New Delhi; after establishing the diagnosis by a
Rheumatologist. The diagnosis was based on the Ameri-
can College of Rheumatology criteria, 2010 for the clas-
sification of FMS [14]. Only those patients, who gave
written informed consent, were enrolled for the study.
The record of rescue analgesics was also maintained.
The details of medication used by patients (NSAIDs, an-
tidepressants and opioids, etc) before and after the treat-
ment with rTMS have been given Table 1. FMS patients
were excluded from the study, if they had following
conditions: i) unable to give written informed consent
form ii) History of seizures iii) History of seizures in
first-degree relatives iv) History of any illness involving
the brain v) Consumption of medications (like tramadol,
acetylcholinesterase inhibitors, anticholinergics, anti-
emetics, antihistamines, baclofen, ß-blockers, cephalo-
sporins, cyclosporine etc) known to lower the seizure
threshold vi) History of tinnitus vii) History of bipolar
disorder viii) having implants of defibrillators or neuro-
stimulators or cardiac pacemakers ix) pregnant or lactat-
ing x) having chronic systemic disease, inflammatory
joint diseases, secondary FM, history of trauma xi) with
a concomitant diagnosis of chronic fatigue syndrome
and/or any psychiatric disorder xii) currently undergoing
psychotherapy.
Protocol for real/sham rTMS
MagPro R100 (MagVenture, USA) transcranial magnetic
stimulator was used for repetitive magnetic stimulation
of the brain. Real rTMS was administered using a
butterfly coil (MCF-B70, MagVenture, USA). For selec-
tion of the optimal scalp area on the right motor cortex;
resting motor threshold (RMT) was determined using
single-pulse stimulation over the right primary motor
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 2 of 11

cortex (M1) and systematically moving and adjusting
until each pulse resulted in an isolated movement of the
right thumb at rest (abductor pollicis brevis muscle).
The machine output was adjusted to the lowest intensity
that reliably induced thumb movement [15]. The RMT
was defined as the lowest stimulus intensity could elicit
at least five twitches in abductor pollicis brevis muscle
(Motor Evoked Potentials) out of ten consecutive stimuli
given over the “motor hot spot”at M1.
During real and sham stimulations, the TMS coil
was aligned in a parasagittal line (stimulation coil was
held at a 45° angle off the midline, with the handle
pointing in the posterior direction) 5 cm (right
DLPFC)fromtheareathatproducedrightabductor
pollicis brevis muscle movement for resting motor
threshold testing [8](Fig. S2). Stimulation was given
at a pulse frequency of 1.0 Hz over the right DLPFC
at 90% of resting motor threshold. rTMS was given
in 8 trains of 150 pulses/train at inter train interval
of 1 min. Total of 1200 stimuli were given during
each session which lasted for 27 min. There were 5
sessions (Monday through Friday) per week and
rTMS therapy was given over 4 consecutive weeks
(20 sessions). During Sham (placebo/inactive) stimula-
tion, an inactive rTMS coil (MC-B70, MagVenture,
MagPro, Denmark) was used and placed over the
same area as the active coil. The sham coil produced
similar sound as the real coil but without active
stimulation of the brain.
Primary outcome
The primary outcome was defined as a reduction in pain
intensity. This was assessed with the help of Numerical
Pain Rating Scale (NPRS), an 11-point numerical scale
ranging from ‘0’representing “No pain”to ‘10’repre-
senting “Pain as bad as you can imagine”or “Worst pain
imaginable”[16].
Secondary outcomes
We assessed Pain related depression, anxiety, impact of
pain and quality of life, as secondary outcomes using
McGill Pain Questionnaire (MPQ) [17]; Hamilton De-
pression Rating Scale (HDRS) [18]; Hamilton Anxiety
Rating Scale (HARS) [19] and WHOQOL-Quality of
Life-BREF (WHOQOL-BREF) questionnaire [20]. The
other secondary outcomes assessed were, the NFR, pain
modulation (effect of cold pressor test; CPT on NFR)
and estimation of oxidative stress markers.
In the present study, NFR was recorded according the
method described by Willer and colleagues [21]. Further
details of the NFR are mentioned in our research article
[22](Fig. S3). Pain modulation was assessed by observ-
ing the effect of cold pressor test (CPT) on NFR parame-
ters according to methods shown by Sandrini et al. [23]
(Fig. S4). For biochemical estimation, blood samples
were collected in heparinzed BD21q vacutainer collec-
tion tubes. The samples were centrifuged at 1500 rpm
for 15 min at 4°C. The plasma was separated and trans-
ferred to the microcentrifuge tube and stored at −80 °C
till further analysis. Urine samples were also collected
and stored at −80 °C until further analysis. Both, blood
and urine samples were collected at two time points i.e.
pre rTMS and immediately post rTMS. To assess the
oxidative stress, plasma levels of TBARS (Quanti-
ChromTM TBARS Assay Kit (DTBA-100), USA) and
urinary levels of F
2
-isoprostane (Elabscience Biotechnol-
ogy Co. Ltd. (Elabscience®, China) were estimated with
commercial kits.
Statistical analysis
All the analyses were performed using IBM SPSS Statis-
tics version 22.0 (IBM Statistics for Windows, Chicago,
IL, USA) and graphs were created using Graph Pad
Prism 5.01 for Windows, (GraphPad Software, San
Diego, California, USA). Baseline scores of the parame-
ters between FMS Sham-rTMS and FMS Real-rTMS
groups were compared using paired t test/ Wilcoxon
Signed Rank test. The difference between FMS-Sham
and FMS-rTMS was analyzed using unpaired t test/
Mann-Whitney U test. p< 0.05 was considered statisti-
cally significant. Analysis of follow- up data was done by
Table 1 General characteristics and medication details of FMS
Sham-rTMS and Real-rTMS group
Parameters FMS Sham-
rTMS
(n= 41)
FMS Real-
rTMS
(n= 45)
*p
Age (year) 39.05 ± 7.12 41.54 ±
8.58
0.14
Height (cm) 158.13 ±
6.34
157.17 ±
4.70
0.30
Weight (kg) 61.80 ± 7.54 62.73 ±
8.01
0.92
Pain duration (Yrs) 7.63 ± 4.65 8.0 ± 5.11 0.73
Medication used
Analgesics % 7 9 –
Opiates % 4 5 –
Antidepressants % 3 4 –
Nonsteroidal anti-inflammatory
drugs (NSAIDs) %
24 22 –
Anxiolytic % 8 9 –
Sedatives % 4 4 –
Gastrointestinal % 12 21 –
Thyroid % 3 0 –
Multivitamins % 34 26 –
Data is expressed as Mean ± SD
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 3 of 11

paired t tests/ Wilcoxon Signed Rank test examining
follow-up scores relative to post-rTMS (immediate after
completion of therapy). Repeated Measures ANOVA
was applied to assess the statistical significance within
the group between two subsequent time points after
Bonferroni correction.
Results
After Real/Sham rTMS, Follow-up (FU) was done at
three time points i.e. 15 days post-rTMS (FU-1), 3
months post-rTMS (FU-2) and 6 months post-rTMS
(FU-3). At the end of follow-up, 41 subjects in Sham-
rTMS while 45 subjects in Real-rTMS group were ana-
lysed (Fig. S5). The data is presented as Mean ± SD and/
or Median (25Q-75Q). Age, height, body weight and
other general body parameters were comparable be-
tween Sham and Real-rTMS group (Table 1).
Primary outcome
A decrease in NPRS ratings due to rTMS treatment was
observed in the Real-rTMS group immediately post-
rTMS (p= 0·001) which was sustained through 6 months
(Fig. 1). In the Sham-rTMS group no significant change
in pain ratings was observed.
Secondary outcomes
The ratings of affective-motivational components of pain
were reduced post-rTMS (p= 0·001) and were main-
tained even at 6 months when compared to its baseline
value (Table 2). The results of other components of
MPQ ratings have been presented in Table 2. The HDRS
and HARS ratings of Real-rTMS group decreased, post-
rTMS and the changes were maintained through 6
months of therapy (Figs. 2and 3). WHOQOL-BREF rat-
ings were significantly increased post-rTMS when
compared to baseline in Real-rTMS and through 6
months of therapy (Table 2).
In Real-rTMS group, the threshold (volts, V) of NFR
post-rTMS and 15 days post-rTMS was higher, com-
pared to the baseline (p= 0·001) as well as from the
Sham-rTMS group (Fig. 4). No significant change was
observed in other parameters of NFR (latency, duration
and amplitude) between Sham-rTMS and Real-rTMS
group (Table 3).
A sustained improvement in NFR thresholds (V) in re-
sponse to cold noxious stimulus (4-5 ºC) during DNIC
paradigm was observed in Real-rTMS group post-rTMS
which was maintained 15 days post-rTMS also compared
to the baseline (Table 3). NFR latency (ms), amplitude
(μV) and duration (ms) did not change significantly in
response to CPT (DNIC paradigm) in Real-rTMS or
Sham-rTMS group during post-rTMS and 15 days post-
rTMS. Plasma levels of TBARS were comparable in
Real-rTMS group at baseline and post-rTMS (Real) (p=
0·12). Urinary levels of F2-isoprostane levels, did not
vary significantly between groups at baseline and post-
rTMS (Table 3).
Side effects due to sham/real rTMS
During the entire study period no serious side effects of
rTMS were observed. However, two Real-rTMS allo-
cated patients complained of headache; two Sham-rTMS
allocated patients complained of neck pain while another
patient reported mild dizziness.
Discussion
Selection of low frequency right DLPFC rTMS
In the present study, low-frequency rTMS (1 Hz) of right
dorsolateral prefrontal cortex was selected as low fre-
quency is safer and, previous studies targeting DLPFC
have shown its beneficial effects in relieving chronic pain
Fig. 1 :Effect of rTMS on subjective pain rating scores in FMS. Subjective pain assessed by numerical pain rating scale (NPRS) in Sham (n= 41)
and Real-rTMS (n= 45) group at each time points;pre, post and follow up (FU-1 = 15 days, FU-2 = 3 months and FU-3 = 6 months post-rTMS). Hash
(#) symbol indicates within group pvalue. Asterisk (*) symbol indicates pvalue between Sham-rTMS and Real-rTMSgroup. *por #p< 0.05; **por
##p< 0.01; ***por ###p< 0.001
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 4 of 11

and depression in fibromyalgia [8,25]. According to an
earlier research, chronic pain is known to be closely as-
sociated with depression and anxiety, in fact the disabil-
ity felt by the patient due to chronicity of pain and the
existing poor quality of life, could be a contributory cause
of depressive symptoms [26]. A reduction in both pain
and depression/anxiety has been observed by targeting
(reducing the activity) of DLPFC via transcranial direct
current stimulation [27]. Low frequency TMS causes
long-lasting inhibition of cell–cell communications
or long term depression; whereas high-frequency TMS
can produce long term potentiation [28,29]. Neuro-
imaging studies have also affirmed that the DLPFC may
have a role in top–down mode of inhibition through de-
scending fibres from the prefrontal cortex (PFCx) which
may modulate pain perception [30,31]. The findings of
an fMRI research suggested that interhemispheric
DLPFC connectivity can affect pain tolerance by altering
interhemispheric inhibition [26]. Low frequency rTMS
stimulation of right DLPFC possibly causes the removal
of transcallosal inhibition, allowing an enhanced de-
scending inhibition from the left hemisphere [10].
Effect of rTMS on subjective pain assessment
We observed a significant decrease in the pain ratings
(NPRS) in Real-rTMS group compared to Sham-
rTMS group which was sustained till 6 months of fol-
low up period. Our findings are consistent with previ-
ous studies which reported reduced pain ratings after
rTMS therapy and showed that rTMS performed sub-
stantially better than placebo, in management of FMS
[25]. Pain related depression and anxiety ratings were
also reduced in Real-rTMS group, this is consistent
with the previous reports of right DLPFC TMS stud-
ies in chronic pain [8,25]. We also recorded an im-
provement in pain scores in the Sham-rTMS though
not statistically significant suggesting some placebo
effect may exist for such therapies. Similar results
have been reported with placebo type sham manoeu-
vres [32]. Our findings are supported by recent study
from our group which has assessed the effect of low
frequency rTMS on the right DLPFC in chronic ten-
sion type headache and reported a beneficial effect on
pain and related symptoms [10].
Effect of rTMS on objective pain measures and pain
modulation
Ours is amongst the first few studies to report the effect
of rTMS on threshold of NFR. NFR is a spinally medi-
ated withdrawal response that has been used to assess
pain objectively. NFR was recorded at baseline and post
rTMS to assess the pain objectively. In our FMS patients
NFR thresholds were significantly lower indicating an
exaggerated response to painful stimuli or hyperalgesia
[22]. However, at the end of real-rTMS treatment, there
was an increase in NFR threshold which was maintained
during follow-up i.e. 15 days post-rTMS. Considering
the intricacy of the procedure and time involved, NFR
was not recorded at the 3 and 6 months follow-up time
points. In contrast, a previous study which administered
a single rTMS session, observed no significant effect of
rTMS on threshold or recruitment curve of NFR in
healthy subjects [33]. The contrasting results may be
due to difference in study population and the rTMS
protocol (single session of rTMS). The mechanisms that
are thought to contribute to the pain-relieving effects of
rTMS in experimentally induced and chronic pain lie
within the medial or the lateral pain pathways and the
descending pain inhibitory systems, modulating the pain
perception [34].
In our study, descending pain inhibitory pathways
were assessed by recording the effect of CPT on NFR.
Fig. 2 : Effect of rTMS on pain related depression in FMS. Depression assessed by Hamilton depression rating scale (HRDS) in Sham (n= 41) and
Real-rTMS (n= 45) group at each time points;pre, post and follow up (FU-1 = 15 days, FU-2 = 3 months and FU-3 = 6 months post-rTMS). Hash (#)
symbol indicates within group pvalue. Asterisk (*) symbol indicates pvalue between Sham-rTMS and Real-rTMS group. *por #p< 0.05; **por
##p< 0.01; ***por ###p< 0.001
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 5 of 11

Table 2 Comparison of subjective pain measures in FMS Sham-rTMS and Real-rTMS group
Pre-rTMS Post-rTMS Follow-up
FU-1 (15-days) FU-2 (3-months) FU-3 (6-months)
MPQ: Sensory
Sham 23.0 (17.0–26.5) 20.0 (17.0–24.5) 22.0 (20.0–23.0) 22.0 (21.0–23.0) 22.0 (20.0–24.0)
Real 23.0 (21.0–26.0) 23.0 (18.3–26.8) 21.0 (18.0–26.0) 22.0 (18.0–25.5) 22.0 (18.0–28.0)
p* 0.40 0.29 0.89 0.72 0.74
MPQ: Affective-motivational
Sham 8.0 (4.5–9.0) 7.0 (4.0–8.0) 6.0 (4.0–8.0) 6.0 (4.0–8.0) 6.0 (5.0–7.5)
Real 7.0 (5.0–8.0) 3.0 (3.0–4.0)## 4.0 (3.0–4.5) 4.0 (3.0–5.0) 4.0 (3.0–5.0)
p* 0.10 0.001 0.001 0.001 0.001
MPQ: Evaluative
Sham 3.0 (3.0–3.5) 3.0 (2.0–3.5) 3.0 (2.0–3.5) 2.0 (1.0–3.5) 3.0 (2.0–4.0)
Real 3.0 (3.0–4.0) 2.0 (1.0–2.0)## 2.0 (1.0–2.0) 2.0 (1.0–2.0) 2.0 (1.0–2.0)
p* 0.33 0.001 0.001 0.004 0.001
MPQ: Miscellaneous
Sham 9.0 (4.25–10.75) 7.0 (5.0–8.0) 7.0 (4.0–9.0) 7.0 (5.0–9.0) 7.0 (5.0–9.0)
Real 7.0 (4.0–9.0) 6.0 (4.0–9.0) 5.0 (3.0–9.0) 6.0 (3.5–9.0) 7.0 (4.0–10.0)
p* 0.34 0.33 0.51 0.45 0.95
MPQ: Total score
Sham 39.0 (36.0–44.0) 39.0 (33.0–45.0) 38.0 (34.0–41.5) 39.0 (34.5–41.0) 38.0 (32.5–41.0)
Real 39.0 (36.0–44.5) 20.0 (16.0–29.5) ## 20.0 (17.0–30.0) 20.0 (17.0–30.0) 21.0 (18.0–29.0)
p* 0.87 0.001 0.001 0.001 0.001
MPQ: Present pain intensity
Sham 3.0 (2.0–3.0) 2.0 (1.0–2.0) 2.0 (2.0–3.0) 2.0 (2.0–3.0) 2.0 (2.0–3.0)
Real 3.0 (2.0–4.0) 1.0 (1.0–2.0)## 2.0 (1.0–2.0) 2.0 (1.0–2.0) 2.0 (1.0–2.0)
p* 0.60 0.001 0.001 0.001 0.001
WHOQOL-BREF: Physical
Sham 38.0 (38.0–44.0) 43.0 (38.0–50.0) 44.0 (38.0–47.0) 44.0 (38.0–50.0) 44.0 (38.0–47.0)
Real 38.0 (31.0–50.0) 44.0 (38.0–56.0) #47.0 (40.0–62.0) 44.0 (40.0–56.0) 44.0 (38.0–56.0)
p* 0.59 0.05 0.05 0.05 0.05
WHOQOL-BREF: Psychological
Sham 56.0 (38.0–69) 59.0 (38.0–75.0) 44.0 (44.0–69.0) 56.0 (38.0–69.0) 56.0 (44.0–75.0)
Real 56.0 (44.0–56.0) 69.0 (56.0–75.0) #69.0 (56.0–75.0) 58.0 (56.0–69.0) 69.0 (56.0–69.0)
p* 0.74 0.002 0.004 0.04 0.05
WHOQOL-BREF: Social
Sham 44.0 (44.0–56.0) 50.0 (44.0–56.0) 44.0 (44.0–56.0) 44.0 (43.0–56.0) 50.0 (44.0–56.0)
Real 50.0 (31.0–69.0) 56.0 (44.0–69.0) #56.0 (53.0–69.0) 56.0 (47.0–69.0) 56.0 (50.0–69.0)
p* 0.57 0.004 0.001 0.001 0.02
WHOQOL-BREF: Environmental
Sham 56.0 (44.0–69) 56.0 (47.0–69.0) 56.0 (44.0–72.0) 56.0 (44.0–69.0) 56.0 (44.0–69.0)
Real 69.0 (56.0–69.0) 56.0 (53.0–75.0) 56.0 (53.0–69.0) 49.0 (56.0–72.0) 56.0 (48.5–69.0)
p* 0.06 0.28 0.91 0.28 0.94
Sham (n= 41) and Real (n= 45); Data is presented as Median (25Q-75Q); MPQ: McGill Pain Questionnaire; WHOQOL-BREF: WHO-Quality of Life questionnaire.;
Asterisk (*) symbol indicates pvalue between Sham-rTMS and Real-rTMS group. Hash (#) symbol indicates pvalue within group. *por #p< 0.05; **por ##p< 0.01;
***por ###p< 0.001.
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 6 of 11

In our patients, pain tolerance time to noxious cold water
was lower indicating diffuse hyper-excitability and
sensitization of the nociceptive system which is also
shown by earlier reports on fibromyalgia [35]. After rTMS
therapy, we found an increase in threshold of NFR during
CPT and pain tolerance for CPT suggesting that rTMS
has alleviated the diffuse hyper-excitability and
sensitization of the nociceptive system associated with
FMS. Findings of this study are consistent with previous
research suggesting that low-frequency (1 Hz) rTMS of
the right DLPFC could increase cold pain tolerance [36].
Our results of pain modulation paradigm are also in ac-
cordance with a recent study on chronic myofascial pain
syndrome which found that rTMS enhanced the cortico-
spinal inhibitory system (41.74% reduction in quantitative
sensory testing and conditioned pain modulationand a de-
crease of 23.94% in the intracortical facilitation) [37].
rTMS and oxidative stress markers
Recently, oxidative stress has been implicated as an im-
portant factor in the pathogenesis of FMS [11]. Al-
though, we did not find any difference between levels of
oxidative stress markers (TBARS and F2-isoprostane)
before and after rTMS. To the best of our knowledge,
no published report is available on effect of rTMS on
TBARS and F2-isoprostane in FMS. The literature offers
limited information about oxidative stress in FMS. It has
been reported that malondialdehyde (MDA), which is an
indicator of lipid peroxidation, increased [11,12] and
vitamin E, which prevents lipid peroxidation, is de-
creased in FMS patients [11].
Proposed mechanism of action rTMS in fibromyalgia
The possible mechanism of relief in pain and associated
depression and anxiety after DLPFC stimulation could be
Fig. 3 :Effect of rTMS on pain related anxiety in FMS. Anxiety assessed by Hamilton anxiety rating scale (HARS) in Sham (n= 41) and Real-rTMS
(n= 45) group at each time points;pre, post and follow up (FU-1 = 15 days, FU-2 = 3 months and FU-3 = 6 months post-rTMS). Hash (#) symbol
indicates within group p value. Asterisk (*) symbol indicates pvalue between Sham-rTMS and Real-rTMSgroup. *por #p< 0.05; **por ##p< 0.01;
***por ###p< 0.001
Fig. 4 : Effect of rTMS on spinal nociception (NFR) in FMS. Central nociception assessed by nociceptive flexion reflex (NFR) thresholds in Sham
(n= 41) and Real-rTMS (n= 45) group at each time points;pre, post and follow up (FU-1 = 15 days, FU-2 = 3 months and FU-3 = 6months post-
rTMS). Hash (#) symbol indicates within group pvalue. Asterisk (*) symbol indicates pvalue between Sham-rTMS and Real-rTMS group. *por #p<
0.05; **por ##p< 0.01; ***por ###p< 0.001
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 7 of 11

through top-down modulation by rTMS. As DLPFC is as-
sociated with other brain areas such as rostral anterior cin-
gulate cortex (which has been known to play an important
role in pain processing [3] and bilateral amygdala and
contralateral anterior insula (where an increased neuronal
activity is observed in association with depressive symp-
toms) [38], it can potentially modulate this nexus. Recent
studies have also observed decrease in regional cerebral
blood flow (rCBF) in the bilateral medial prefrontal cortex,
bilateral premotor area, bilateral anterior insula, right anter-
ior and posterior insula, left anterior cingulate, right sub-
genual cingulate and right frontal cortex after right DLPFC
rTMS. These studies have also reported a correlation be-
tween therapeutic efficacy of rTMS and decreased rCBF in
bilateral frontal white matter [39–42]. Another study re-
ported a significant decrease of activation in the bilateral
middle frontal gyrus with right DLPFC-rTMS in rTMS re-
sponders [43]. Therefore, improvement in depression and
anxiety after therapy suggests that rTMS of right DLPFC
positively influences the brain regions responsible for such
symptoms.
In our study, improvement in quality of life with rTMS
indicates that right DLPFC stimulation may also have
positive effect on the limbic system (right medial
temporal cortex, involved in modulation of the emo-
tional aspects of pain) [44] and superior temporal sulcus
(involved in the social cognition and perception under-
lying social functioning of quality of life) [45–47], as
neural connections have been reported between these
areas and the limbic system [48].
The mechanisms that are thought to contribute to the
pain relieving effects of rTMS of the motor cortex in ex-
perimentally induced pain and in chronic pain are the
modulation of pain perception within the medial or the
lateral pain pathway and the modulation of the descending
inhibitory systems [34,49]. In the present study, increased
NFR threshold during CPT and the enhanced pain toler-
ance (during CPT) suggest that rTMS of DLPFC indirectly
modulates nociception through its association with the
cingulate cortex and medial thalamus which are known to
be involved in nociceptive modulation [50–52]. The
DLPFC is a highly integrated area with the “affective cir-
cuit”[53] i.e. ventral and anterior division of the anterior
cingulate cortex including the hypothalamus, amyg-
dala, orbitofrontal cortex, nucleus accumbens, and
other limbic structures [54]. Therefore, the positive
effects of rTMS on pain and associated symptoms are
probably due to modulation of right DLPFC which
further modulates the brain areas related with this
‘affective circuit’(Fig. 5).
To sum up, decrease in ratings of pain and related
symptoms, increased NFR threshold and the enhanced
pain tolerance during CPT suggests that rTMS of
DLPFC modulates nociception, associated with the
cingulate cortex and medial thalamus which are
known to be involved in such type of nociceptive
modulation [50,51].
Strengths and limitations of the study
There are many strengths of our study. Based on the
published literature on the effect of rTMS in FMS symp-
toms, this is the first study which shows long term bene-
ficial effects of rTMS (6 months follow-up). Most of the
previous rTMS studies have reported 1–2 weeks of
follow-up, and some have also followed their patients till
1 month or 3 months. Moreover, in earlier studies num-
ber of rTMS sessions were less as compared to our
rTMS protocol and continuity of the sessions was also
lacking in these studies [25,45].
Table 3 Comparison of objective pain measures and oxidative
stress markers between FMS Sham-rTMS and Real-rTMS group
Pre-rTMS Post-rTMS Follow-up
FU-1 (15-days)
NFR: Latency (ms)
Sham 105.0 (95.0–124.4) 105.0 (90.0–120.0) 102.0 (87.6–104.0)
Real 110.0 (95.5–137.8) 106.5 (97.6–120.8) 105.0 (97.3–120.0)
p* 0.41 0.06 0.05
NFR: Duration (ms)
Sham 42.5 (40.0–47.5) 42.5 (40.0–45.5) 45.0 (40.0–50.0)
Real 40.5 (38.3–45.25) 40.0 (38.65–45.0) 42.3 (40.0–45.0)
p* 0.52 0.06 0.07
NFR: Amplitude ((μV)
Sham 294.0 (273.0–312.0) 287.0 (263.3–297.0) 284.5 (260.8–298.5)
Real 281.6 (260.5 ± 314.3) 276.0 (234.5–311.5) 276.0 (243.8–295.2)
p* 0.42 0.28 0.35
DNIC: Threshold (V)
Sham 21.0 (18.5–24.5) 21.0 (20.0–24.0) 22.0 (19.0–25.0)
Real 22.0 (18.0–25.5) 27.0 (25.0–34.0) ## 29.0 (25.0–39.0)
p* 0.75 0.001 0.001
Thiobarbituric acid reactive substances; TBARS (ng/ml)
Sham 0.88 (0.11–2.3) 0.90 (0.22–2.11) –
Real 0.97 (0.23–2.1) 0.78 (0.18–1.6) –
p* 0.71 0.07 –
F
2
-isoprostanes (pg/ml)
Sham 209.8 (135.8–317.4) 183.9 (123.6–251.4) –
Real 180.4 (78.35–243.8) 181.9 (89.4–315.3) –
p* 0.14 0.19 –
Sham (n= 41) and Real (n= 45); Data is presented as Median (25Q-75Q); NFR:
Nociceptive flexion reflex. Asterisk (*) symbol indicates pvalue between Sham-
rTMS and Real-rTMS group. Hash (#) symbol indicates pvalue within group.
Hyphen-minus (−) symbol indicates that the data not recorded. *por #p<
0.05; **por ##p< 0.01; ***por ###p< 0.001
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 8 of 11

This is the first study which has tediously explored the
effect of low frequency right DLPFC rTMS on subjective
and objective pain parameters, descending pain modula-
tion and oxidative stress markers in FMS patients.
Although, we have extensively studied the role of rTMS
applied over DLPFC on pain status in FMS, yet there are
some limitations that need to be addressed. We identified
hotspot for rTMS therapy by using abductor muscle
twitch. This method of getting hotspot has limitations , as
far as targeting the actual area of stimulation is concerned.
Recent research has recommended MRI based neuro-
navigational techniques to localize the DLPFC thereby de-
creasing the inter-subject variability [55]. The exact mech-
anism of action of low frequency on pain modulation and
central neurotransmitters involved could not be ad-
dressed. This could be due to inter-subject variability. Our
study is a single blinded trial, although the participants’
blinding was meticulous, yet the rTMS administrator bias
cannot be disregarded.
Future directions
Further studies should investigate the consistency of
structural and functional DLPFC abnormalities in
chronic pain conditions utilizing neuroimaging tech-
niques; compare low frequency right DLPFC rTMS with
other administration protocols or other novel paradigms
in FMS patients. Future research should also assess the
effect of rTMS on the levels of central neurotransmitters
which play predominant role in endogenous pain facili-
tatory and inhibitory pathways. For oxidative stress
markers, more studies may be designed with assessment
at multiple time points during progression and post
therapy, including follow-up period in FMS patients.
Fig. 5 : Putative mechanism for the effect of low frequency right DLPFC in fibromyalgia syndrome. Proposed mechanism for effect of Rt DLPFC
rTMS on pain and related symptoms of FMS. (rDLPFC = right dorsolateral prefrontal cortex; rVMPFC = right ventromedial prefrontal cortex; ACC =
anterior cingulate cortex; OFC = orbitofrontal cortex; rCBF = regional cerebral blood flow). ‘Skull with TMS coil’image was adapted from Diana
et al., [24]
Tanwar et al. Advances in Rheumatology (2020) 60:34 Page 9 of 11

Conclusions
Findings of our 6-months follow-up study suggest that
right DLPFC rTMS can significantly reduce pain and as-
sociated symptoms of FMS and preferentially targets
spinal pain circuits and top-down pain modulation with
no effect on oxidative stress markers.
Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s42358-020-00135-7.
Additional file 1: Figure S1. Study protocol. Figure S2. Patient
receiving rTMS therapy. Figure S3. Nociceptive Flexion Reflex recording
set up. Figure S4. Set up for DNIC study (NFR recording during cold
pressor test; CPT). Figure S5. CONSORT flow diagram
Acknowledgements
Authors acknowledge FMS patients for participation and technical staff of
Pain Research and TMS laboratory, AIIMS, New Delhi, India.
Authors’contributions
Renu Bhatia takes responsibility for the integrity of the work as a whole, from
inception of idea to final manuscript. Suman Tanwar, Uma Kumar and Renu
Bhatia made primary contributions in study design, data acquisition, analysis
and interpretation of data and preparing of the final manuscript. Bhawna
Mattoo made notable contributions in data acquisition, analysis,
interpretation and preparing of the final manuscript along with its critical
revision. All authors have discussed the results and gave final approval of the
version to be submitted for publication.
Funding
Research work was supported by University Grant Commission (UGC), New
Delhi. SumanTanwar was awarded by UGC-Junior/Senior Research fellowship
grant for her doctoral research by UGC, New Delhi, India.
Availability of data and materials
The authors confirm that the data supporting the findings of this study are
available within the article and additional information can be provided if
requested.
Ethics approval and consent to participate
The study was conducted at the Pain Research and TMS Laboratory,
Department of Physiology, All India Institute of Medical Sciences (AIIMS) New
Delhi, India. Human Ethics committee of the AIIMS, New Delhi (Ref No: IESC/
T-251/15.06.2013) approved the research protocol in 2013. The study was
also registered in ICMR-CTRI; India (Ref No: CTRI/2013/12/004228). All proce-
dures performed during study involving human participants were in accord-
ance with the ethical standards of the Human Ethics committee of the
AIIMS, New Delhi. All the participants provided written informed consent. All
the participants were enrolled only after getting ethical approval.
Consent for publication
Consent to publish was also obtained from all the participants included in
the study.
Competing interests
Authors declare no competing interests concerning the work reported in
this manuscript.
Author details
1
Department of Physiology, AIIMS, New Delhi 110029, India.
2
Department of
Zoology, Govt. College for Girls, Sec-14, Gurugram, Haryana 122001, India.
3
Department of Rheumatology, All India Institute of Medical Sciences, AIIMS,
New Delhi 110029, India.
Received: 10 February 2020 Accepted: 28 May 2020
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