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Fibromyalgia Pain and Depression: An Update on the Role of Repetitive

Transcranial Magnetic Stimulation

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DOI: 10.1021/acschemneuro.0c00785

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Fibromyalgia Pain and Depression: An Update on the Role of

Repetitive Transcranial Magnetic Stimulation
Abdul Haque Ansari,# Ajay Pal,# Aditya Ramamurthy, Maciej Kabat, Suman Jain,* and Suneel Kumar*,#

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ABSTRACT: Fibromyalgia is a musculoskeletal pain of different

parts of the body, which is also associated with fatigue, lack of
sleep, cognition deficits, family history, gender bias, and other
Downloaded via RUTGERS UNIV on January 5, 2021 at 15:36:43 (UTC).

disorders such as osteoarthritis and rheumatoid arthritis. It is

generally initiated after trauma, surgery, infection, or stress.
Fibromyalgia often coexists with several other conditions or
disorders such as temporomandibular joint disorders, bowel and
bladder syndrome, anxiety, depression, headaches, and interstitial
cystitis. While there is no permanent cure for fibromyalgia, some
interventions are available with multiple side effects. rTMS
(repetitive transcranial magnetic stimulation), a noninvasive management strategy is used widely for various pain-related etiologies
including fibromyalgia in both the laboratory and clinical settings. In this Review, we discuss the role and mechanism of action of
rTMS in fibromyalgia patients and on associated comorbidities including anxiety, pain, depression, neurotransmitter alterations,
sleep disorders, and overall quality of life of the patients suffering from this chronic problem. We also provide an update on the
rTMS application in the clinical trials of fibromyalgia patients and prospective management therapy for multiple problems that these
patients suffer.
KEYWORDS: Fibromyalgia, rTMS, musculoskeletal pain, cognition, genetic polymorphism, depression and anxiety, neurotransmitter,
sleep, quality of life

■ INTRODUCTION
Repetitive transcranial magnetic stimulation (rTMS) is a
noninvasive brain stimulation technique that has emerged as an
effective therapeutic intervention with proven efficacy in
conditions such as pain and depression. rTMS can modulate
functions of cortical and deep brain areas through an
electromagnetic field generated over the scalp, by either
decreasing (via low-frequency stimulation) or increasing (via
high-frequency stimulation) cortical excitability. Fibromyalgia
is a multifarious chronic neurological disorder with limited
effective treatments available currently. rTMS can be used as a
potential treatment for fibromyalgia (FM) as it has shown
great promise in treating central nervous system (CNS)
disorders. Recent scientific studies have indicated that rTMS
may act on the modulatory pain pathways such as the
descending inhibitory pathways and the social-affective regions
of the brain, namely, the right temporal region of the brain.
The objective of this Review is to present the current state of
the art in the management of fibromyalgia pain using rTMS as
a treatment strategy. We have thus briefly discussed
fibromyalgia and rTMS and provide in-depth insights by
summarizing the existing preclinical and clinical studies that
have evaluated the effects of rTMS on FM and another CNS
pathologies. We also discuss ongoing and published clinical
trials using rTMS in the management of pain and depression
and thereby propose rTMS as an effective therapeutic strategy
for the management of fibromyalgia pain.
Characteristics of Fibromyalgia. Fibromyalgia is a
widespread musculoskeletal chronic pain disorder associated
with chronic fatigue and emotional and sleep disturbances.1,2
The symptoms commonly associated with it are chronic and
diffuse pain, morning stiffness, fatigue, sleep disorders, anxiety,
depression, cognitive problems, and tenderness of muscles.2,3
FM is also associated with several other additional
comorbidities such as rheumatic disorders, neurological or
psychological disorders, diabetes, and frequent infections. In
addition, central sensitization, genetic, immunological, and
hormonal factors are considered to be the contributing
factors.4 FM symptoms can also be triggered by Lyme disease,
Q fever, viral hepatitis, Epstein−Barr virus,5,6 trauma,7 and
stressful war situations.8 In FM patients, there are more
Received: December 9, 2020
Accepted: December 21, 2020

© XXXX American Chemical Society https://dx.doi.org/10.1021/acschemneuro.0c00785

A ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
somatic symptoms than pain.9 A nationwide cohort study
showed that FM patients have 2.77 times more risk of
developing dementia than normal control groups.10 FM is
strongly associated with sleep disorders, headaches, depression,
and illness behavior.11 It is assumed that chronic inflammation
can play a significant role in the pathogenesis of FM. The
increase of some inflammatory proteins in the cerebrospinal
fluid and plasma of FM patients has been reported by Bäckryd
and colleagues suggesting systemic and neuroinflammation.12
Hyperalgesia and allodynia in FM patients have been shown to
result from an increased sensitivity of central nervous
mechanisms referred to as central sensitization.13,14 A recent
study showed that the threshold for the detection of
sensorimotor conflicts was lowered by persistent pain in FM
patients, which eventually results in chronic pain maintenance
in clinical populations. The pain of FM is usually subjective
and can also be present without any obvious tissue damage.15
History. The history of FM dates back to 1904 when it was
termed as “fibrositis” by Gowers owing to its etiology in
muscles. It was believed that the painful condition was due to
peripheral inflammation of muscles. The first introduction of
the modern concept of FM was given by Graham in 1950 as
pain syndrome with an absence of any specific organic
disease.16 Later, in mid-1970, it was renamed as fibromyalgia
by Smythe and Moldofsky who postulated the concept of FM
based on widespread pain and tenderness at highly localized
points as mentioned in Table 1.17 The pain of FM is usually
Table 1. Tender Points and Anatomical Locations
tender points anatomical locations
1−2 occipital
3−4 supraspinatus muscle
5−6 upper quadrant of gluteal muscle
7−8 greater trochanter
9−10 low cervical
11−12 trapezius
13−14 second rib lateral to costochondral junction
15−16 lateral epicondyle
17−18 knee: medial fat pad proximal to the joint line
subjective and may not be associated with actual tissue injury.
However, unlike other well-localized painful conditions, FM is
associated with many distressing symptoms besides pain, such
as musculoskeletal symptoms (pain at several points, stiffness,
the sensation of hurting all over and puffiness of soft tissues),
nonmusculoskeletal symptoms (morning stiffness, fatigue,
sleep alterations, and paresthesia), and other associated
symptoms (migraine, dysmenorrhea, tension-type headaches,
anxiety, irritable bowel syndrome, depression, female urethral
syndrome).18 Due to the presence of a variety of symptoms
besides pain, this disorder has been now described as FM
syndrome. Chronic pain such as FM is usually associated with
many complications such as depression and anxiety, which lead
to poor quality of life. Patients with FM and neuropathic pain
are more susceptible to mental sufferings such as anxiety and
depression in comparison to healthy individuals. FM patients
are more sensitive which makes them more vulnerable to
various somatic and mental problems. Due to widespread
distribution, a range of nonspecific symptoms, and multiple
causative factors, the pathogenesis of pain in FM is not fully
understood.
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The American College of Rheumatology (ACR) in 1990 set
well-established criteria for the diagnosis of FM, according to
which the patient should have a history of widespread pain in
all four quadrants of the body, with a minimum duration of 3
months and in at least 11 of the 18 designated tender points
when a specified amount of pressure is applied. ACR criteria
1990 were modified in 2010 and 2016. Although the history of
diagnosing FM is more than 100 years old, still subjective
methods are used for its diagnosis and are debatable. The
recent criteria for the diagnosis are having good sensitivity and
specificity.19,20 It eliminates the earlier confusing recommen-
dations used for diagnosing FM and combines physician as
well as questionnaire criteria, minimizing misclassification of
regional pain disorders.20
Incidence and Prevalence. The worldwide review of
literature related to FM categorized the FM population into
four categories based on the prevalence of FM in (a) rural and
urban areas; (b) women; (c) general population; (d) special
populations.21 FM prevalence as shown by the literature in the
general population is 0.2−6.6%, in women 2.4−6.8%, in urban
areas 0.7−11.4%, and in rural areas 0.1−5.2%; and in special
populations it ranges from 0.6 to 15%. A study in Finland
populations highlighted the relationship between childhood
adversities with FM.22 The worldwide occurrence of FM in 26
studies is 2.7% more prevalent in women, mostly in patients
over 50 years of age, with low education level, with low
socioeconomic status, and living in rural areas, and probably in
obese women.24 FM has been reported to consume social and
economic resources remarkably, in terms of loss of mobility,
disability, and reduced productivity of individuals.25 Risk
factors for the development of FM encompasses various
childhood issues, female sex (except with pre-existing medical
disorders), older/middle age, smoking, high body mass index,
alcohol abstinence, and pre-existing medical disorders in
adulthood.11 There are various theories given to explain the
prevalence of FM more in females in comparison to males. The
female population is more vulnerable to abuse due to
childhood and social events. Studies indicate the onset of
FM in adults is more common in subjects having traumatic
events.11,26 Other risk factors are headache, somatic symptoms,
and unsatisfactory sleep.11,20 The autoimmune diseases are also
linked with FM. Physical and/or mental stress could constitute
a triggering factor or a consequence rather than a cause, akin to
the condition in autoimmune diseases.27 The immune system
might be weakened by chronic stress and allow the recurrence
of a latent (viral) infection, leading to neuropathy or
neuroinflammation facilitating autoimmune disorders. Immu-
nological sex differences can also explain a sex bias in FM
prevalence.27 Recently, a proteomics study done in FM
patients indicated the differential expression of 33 plasma
proteins, most of which were related to inflammation, among
which haptoglobin and fibrinogen showed the highest FM/
control ratio.23
Most FM patients seek medical advice or alternative
treatment at least once a month and take nonsteroidal anti-
inflammatory drugs frequently as self-medication. The
incidence of FM has been reported to be 7% in the general
population,28 2.1−5.7% in general medical hospitals and
primary care practice, and 10−20% in a rheumatology clinic.29
The geographic prevalence of FM is worldwide. In Europe, the
prevalence is 1−2%,30 whereas in North America it is 2%.31
The majority of the afflicted patients are women ranging in the
age group of 30−60 years. The prevalence increases from 50
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years to 80 years of age, after which prevalence declines.32
When compared to a prevalence of 3.4% in women, only 0.5%
of men reported symptoms of FM.33 It is interesting to note
that men have less fatigue, morning stiffness, and irritable
bowel syndrome when compared to women.34 From a disorder
that was generally reported in female patients only, now it has
been widely reported in males, children, adolescents, and the
elderly as well. Higher prevalence rates are reported in relatives
of patients suffering from FM, suggesting that, besides
environmental factors, genetic factors are also important in
the pathogenesis of the disorder.35 Symptoms of FM have also
been reported in juveniles, and clinical presentation is quite
similar to that of adult patients.36
Genetics and Genetic Polymorphism in FM. The
enzyme catechol-O-methyltransferase (COMT) inactivates the
neurotransmitters norepinephrine, epinephrine, and dopamine
which are coded by the COMT gene.37 There is a 3−4-fold
rise in COMT enzymatic activity in individuals with a
homozygous val158 allele of the val158met polymorphism in
comparison to those with homozygous met158 alleles of the
val158met polymorphism due to variation in thermostability of
the COMT enzyme.38 The heterozygous allele val/met shows
intermediate enzymatic activities signifying codominance of
the alleles. This evidence confirms the role of the met158 allele
as a risk factor for chronic pain. The occurrence of FM has
been associated with the presence of the met158 allele,39,40 as
it leads to greater sensory as well as affective perceptions of
experimental pain.41 FM symptom severity across pain,
tiredness, sleep disturbances, and psychological disturbances
is reported more in patients with the met/met genotype.39 The
use of COMT inhibitors, like Nitecapone, in animal studies
helped to explain the mechanism of these studies. In pain
models of rodents, COMT inhibitors are mostly pronocicep-
tive, but in neuropathic pain models they are antinociceptive;
nitecapone was also found to be antiallodynic. The complex
interactions between enhanced dopaminergic and adrenergic
activity in various parts of the pain modulatory system possibly
elucidate the complex actions of low COMT activity.42
Indication for familial aggregation in FM patients indicates
the contribution of genetic risk factors to the etiology of FM43
and suggests that genetic factors may account for around 50%
of the total variance in chronic widespread pain of FM.44 Many
researchers have employed a candidate gene approach to study
genes associated with FM. Most of these reports indicate the
role of altered serotonergic or cholinergic neurotransmission,
along with serotonin, dopamine, epinephrine, and norepi-
nephrine transporters and receptors. A study found that FM
has been associated with genetic polymorphisms in dopami-
nergic, serotoninergic, and catecholaminergic systems.45 These
genetic variations may determine the susceptibility of specific
CNS structures and neurotransmitter systems triggered by the
harmful effect of stress. The exact degree and combination of
impaired CNS systems might eventually lead to a variety of
symptoms in FM patients. Significantly, the spectrum of
endophenotypes might clarify why some FM patients respond
to dopamine agonists, whereas another group of FM patients
feels better with serotoninergic agents.45 Serotonin receptor
(5-HT2A) and COMT gene polymorphisms were charac-
terized in Brazilian FM patients to assess the contribution of
these polymorphisms in the etiology of FM. Analysis of the
polymorphism in the COMT gene in FM patients showed a
greater frequency the of L/L genotype among patients in
comparison to normal healthy individuals, while there was no
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significant difference in the frequency of H/H and L/H of the
COMT gene and C/C, C/T, and T/T of the 5HT2A genetic
polymorphism. When environmental factors and polygenic
situations are taken into account, single nucleotide poly-
morphism studies of the COMT gene at the molecular level
may play an important role to identify vulnerable individuals.46
Fernández-de-Las-Peñas et al. found that the Val158Met
COMT polymorphism modulated only higher disabilities,
depression, and anxiety, leaving pressure pain sensitivity in FM
patients, as is obvious in FM women carrying the Met/Met
genotype which exhibit severe disability, anxiety, and
depression but similar pressure pain thresholds to those with
Val/Met and Val/Val genotypes.47 As FM is more prevalent in
women than in men, these studies highlight the role of genetic
variants along with inheritance mechanisms on pain-related
genes in FM. These studies provide additional evidence of
potential genetic factors that influence women with FM to
display more severe symptoms.
Neurochemicals and Pain Sensitivity in FM. Neuro-
transmitter studies show that FM patients have abnormalities
in opioidergic, dopaminergic, and serotoninergic systems. FM
patients’ brain structures are also different than healthy
individuals.48 About serotonergic systems, there are contra-
dictory reports, wherein, in some studies, the serum or
cerebrospinal fluid concentration of 5-HT was low in FM as
compared to control, while in other studies, no statistical
difference has been observed.28,49 Since 5-HT play important
role in the regulation of pain as well as mood and sleep pattern,
its altered concentration may disturb both and hence explain
the altered mood and sleep in many of the FM patients.50
Magnetic resonance spectroscopic studies found an increased
concentration of glutamate in the pain-related brain areas of
FM patients.51 Abnormal NE,52 dopamine,53 substance P,54,55
endorphins, and met-enkephalins56,57 have been reported as
the contributing factors in the etiology of fibromyalgia. The
paradoxical hyperactivity of the endogenous opioid system
with a significant reduction in the μ opioid receptor was shown
in FM patients.57 The left and right nucleus accumbens and
left amygdala were more significantly involved, while there was
a tendency for reduced activity in the right dorsal anterior
cingulate cortex. This evidence supports an abnormal
endogenous opioid system and a receptor down-regulation in
FM patients. Though the peptides of the endogenous opioid
system involved have been hypothesized to be hyperactive,
they are unable to modulate pain in FM, indicating the
reduction in the efficacy of exogenous opiates in FM.58
Anomalies in central pain processing mechanisms can be
classified into either abnormality in the descending inhibitory
and facilitatory pain pathways or central sensitization. The
descending facilitatory and inhibitory pain pathways project
from the brainstem, hypothalamus, and cortical structures and
control sensory inputs in the dorsal horn of the spinal cord
from projection neurons and primary afferent fibers.59 The
widely studied descending pain inhibitory pathways are the
serotonergic−noradrenergic pathways leading to the release of
norepinephrine, serotonin, and endogenous opioids that
inhibit the release of excitatory neurotransmitters like
glutamate at the spinal cord level. These analgesic pathways
are stimulated in response to painful stimuli, leading to a
widespread decrease in pain sensitivity following exposure to
an acutely noxious stimulus. In chronic pain conditions, often
there is an impairment of descending analgesic activity, termed
as a loss of descending analgesia or loss of diffuse noxious
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inhibitory controls. Descending analgesic pathways are
generally tonically active and inhibit upward transmission of
pain signals, but there may be abnormal descending pain
processing mechanisms involving enhanced activities in the
descending facilitatory pain pathways which eventually results
in overall increases in sensory sensitivity. Along with
descending facilitatory and inhibitory pathways, central
sensitization also results in enhanced pain signaling. Central
sensitization includes either general anomalies in central pain
processing (central augmentation) or specific defects in central
pain processing associated with activation of N-methyl-D-
aspartate receptor channels.60 Hyperalgesia and allodynia in
FM have been shown to result from central sensitization.13,14
The perception of chronic pain is linked with genotypic and
phenotypic changes that are expressed at all levels of the
nervous system (primary afferent pathways to cortex) leading
the pain modulation system toward hyperalgesic states.61 Many
studies provided psychophysical evidence that there is
abnormal pain processing in FM patients and that perceived
pain from various experimental stimuli, such as heat,
mechanical, electrical, or cold, was intensified for FM patients
compared to normal healthy subjects as shown by quantitative
sensory studies.62,63 Temporal summation of pain or wind up
of repeated heat stimuli which assess C-fiber dependent central
sensitization were used in the human patients. These studies
found that the wind up threshold after repeated stimuli was
greater in magnitude, lasted longer, and was more frequently
painful in FM subjects, suggesting both augmentations as well
as prolonged decay of nociceptive information, indicative of
central sensitization.62,63 Recent studies specify that FM also
has an immunological context. Cytokines/chemokines, neuro-
transmitters, and several plasma-derived factors cause the
inflammatory state in FM leading to allodynia and hyper-
algesia.
■
MECHANISM OF rTMS: BIOLOGY OF PAIN AND
DEPRESSION
Magnetic field (MF) therapy is a noninvasive, simple, cost-
effective, and safe technique, often administered over the site
of a painful injury or inflammation. Repetitive magnetic
stimulation of the central and peripheral nervous system has
gained relevance as a noninvasive approach for neuro-
modulation and pain relief. As per Faraday’s principle, an
electric current passed through a primary coil creates a
changing magnetic field, which in turn induces a secondary
current in conductors located in the vicinity. Transcranial
magnetic stimulation (TMS) was thus devised as a new
neuromodulatory technique in neuroscience.64,65 Short mag-
netic pulses are applied over the scalp to induce an electric
current in the motor cortex to modulate cell membrane
properties and thereby affect neuronal function. Initially, TMS
was used in motor conductivity studies to stimulate the motor
cortex, record motor evoked potentials, and analyze the
amplitude. Extremely low-frequency currents can alter ion
binding capabilities and ligand−receptor interactions of
membrane macromolecules and thereby influence ion trans-
port across the membrane. These altered membrane properties
affect the movement of Ca2+ and cyclic nucleotides thereby
regulating cell physiology and cell growth.66−68 A magnetically
induced electric field of 0.1 V/m in the extracellular fluid
significantly increases Ca2+ uptake in mitogen-activated
thymocytes.69
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The magnetic pulses can be administered individually
(single) or in pairs a few milliseconds apart (paired-pulse
stimulation) or repetitively lasting seconds to minutes
(repetitive TMS; rTMS). The advent of rTMS introduced a
possibility to deliver multiple pulses and induce physiological
changes in the neural tissue that outlast the duration of the
stimulation.70 The rTMS pulses can be delivered in trains
separated by specific time intervals called intertrain intervals.71
This finding increased the applicability of rTMS to treat
psychological disorders including depression. The U.S. Food
and Drug Administration (FDA) approved the rTMS device in
late 2008. Since then rTMS has being used to study the
pathophysiology of diseases and to understand the coordina-
tion between the regions of the brain during cognition. The
effect of rTMS is dependent on the history of synaptic activity
in the stimulated region; that is, a prior history of enhanced
activity increases the effectiveness of rTMS protocols that
decrease excitability, whereas a prior history of decreased
activity increases the effect of facilitatory rTMS. For example, if
6 Hz rTMS is applied for a very short period (below the
threshold for any lasting after-effects), then the suppressive
effect of a subsequent period of 1 Hz rTMS is increased.72
Experiments in animals proved that a similar rule governs
synaptic plasticity within the cortex, which is referred to as
“homeostatic plasticity.”73 Owing to its self-reinforcing nature,
this is believed to prevent processes such as long-term
potentiation (LTP) from destabilizing neuronal activity.
The effect of rTMS on neural functions depends on how it is
delivered. The behavioral effects of rTMS depend on the
frequency, stimulus intensity, and duration of stimulation.74,75
By convention, if the stimulation frequency is equal to or lower
than 1 Hz, it is referred to as low-frequency stimulation,
whereas, when more than 5 Hz, it is called high-frequency
stimulation. Slow rTMS decreases the excitability76 while fast
TMS increases the excitability77 of the motor cortex. For
rTMS to be effective, the intensity of magnetic fields
administered should be able to induce currents in the neurons
of the motor cortex, referred to as the stimulation intensity. It
is usually expressed as a percentage of motor threshold, i.e., the
intensity that yields a motor response in at least half of the
applied trials and is determined before each session with the
TMS coil. rTMS is usually applied at intensities that range
between 80 and 110% of the motor threshold. In most of the
studies, localizing dorsolateral prefrontal cortex (DLPFC) has
been performed by means of the “5 cm rule.” According to this
rule, the hand area of the primary motor cortex is taken as the
detectable reference point. From this point, the coil is moved 5
cm anteriorly, in a sagittal direction, and positioning the coil at
this location during treatment is assumed to target the
DLPFC.74,78,79 TMS allows the study of the neural basis of
cognitive functions in neurologically intact subjects80 and
exhibits therapeutic potential in several neurological and
psychiatric conditions.71,81 Extremely low frequency (ELF)
MF interacts with living systems by two well-established
mechanisms: induced electric fields produced by Faraday’s law
of electromagnetic induction and direct MF effects on
magnetic particles such as magnetite crystals (Fe3O4) that
have been found in several organisms. A large number of other
interaction mechanisms, including resonance effects, have been
proposed but the proof of existence for these interactions is not
well established in living systems.
rTMS is a technique that allows an active, reversible
modulation of brain function, and a transient disruption or
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ACS Chemical Neuroscience
enhancement in task performance may be produced.70,82
Magnetic stimulation has an established role in inhibiting pain
in various animals including land snails, mice, and pigeons. 0.5
Hz rotating MF and 60 Hz extremely low MF exposure
reduced analgesia and the effect lasted for a significant duration
postexposure.83 There is also evidence of the use of the pulsed
electromagnetic field (PEMF) for the treatment of knee
osteoarthritis. In both rheumatoid arthritis and FM patients,
there was a significant correlation between the pre and
postexposure pain ratings, with a significant reduction of pain
in the PEMF exposed group in comparison to sham.84,85 The
first study of rTMS in chronic pain was a placebo-controlled
study in which 18 FM patients with intractable neurogenic
pain were recruited and rTMS stimulation of the motor cortex
in these patients significantly reduced pain as assessed by
VAS.86 It is inferred that rTMS reduces fibromyalgia pain by
enhancing intracortical modulation. Preliminary studies have
indicated the therapeutic efficacy of TMS because of its safety
and is relatively painless (Table 3). TMS has many other
therapeutic applications and may be beneficial in treating
psychiatric disorders that have not yet been fully explored. If
proven useful for the treatment of neuropsychiatric disorders
as well as chronic pain conditions, TMS may well become a
standard therapeutic tool (Table 2).
Table 2. Effects of rTMS on Pain and Depression
study model key outcomes
thymocytes 60 Hz MF enhances Ca2+ uptake in mitogen-
from rats activated thymocyte cells
human low frequency rTMS increases the amount of cortical
depression
human rTMS and motor cortex long-term depression is
induced with the same parameters
human rTMS reduces fibromyalgia pain
human rTMS has antidepressant effects and improves mood
human rTMS is independent of serotonin to exert an
antidepressant effect and its patients are resistant
to mood perturbations
snails ELF-MF exposure reduces analgesia
snails, human, PEMF exposure reduces pain in RA and FM patients
rodents
human low static MF was used to reduce pain in FM
patients
human rTMS reduces pain in Fibromyalgia patients.
The mechanism of action of rTMS in FM is not clear and
there are no biomarkers available to support in clinical practice
to forecast the response of FM patients to rTMS. As stated
above, the biological effects of rTMS depends on the
stimulation parameters, duration of intervention, and the
brain area stimulated. Possible mechanisms of action of rTMS
in fibromyalgia patients are top-down modulation of the
antinociceptive pathways, alteration in the release of neuro-
transmitters and endorphins, inducing LTP or LTD, and
modifying ionic channels permeability (Figure 1). Activation of
an endogenous opioid analgesic system for the treatment of
chronic pain is the main target of noninvasive rTMS treatment.
de Andrade et al. first showed the role of the endogenous
opioid system in mediating the analgesic effects of rTMS on
the primary motor cortex in healthy subjects.87 Later on, these
observations were substantiated by PET and MRI/MRS
studies, which clearly showed modulatory effects of rTMS on
cortical as well as subcortical brain areas like cingulate,
prefrontal, striatum, insula, etc. involved in affective-emotional
pubs.acs.org/chemneuro Review
components of pain and rich in opioid receptors.88−91
Recently, to observe the effect of rTMS on other neuro-
transmitters involved in pain modulation, Gröhn et al. used
magnetic resonance spectroscopy and resting-state functional
MRI.92 They observed a significant increase in the inhibitory
neurotransmitters GABA in the ipsilateral motor cortex and a
decrease on the contralateral side. Akin to these results, in
depressed adult patients, rTMS of the DLPFC Hz increased
GABA in the MPFC.93 Dopamine and serotonin have also
been postulated to mediate the analgesic effects of rTMS.94,95
N-Methyl-D-aspartate (NMDA) glutamate receptors are
suggested to mediate LTP or LTD like mechanisms in rTMS
induced analgesia.96,97 Lee et al. observed a decrease in the
transcription of mGluR1 as well as the synthesis of mGluR,
GluR2, and PKC after rTMS in the cerebellar cortex of the rats
after a single session of high-frequency rTMS.98 Whole-cell
patch-clamp recordings and calcium imaging of cortical
neurons in acute rat brain slices showed direct and transient
activation of voltage-gated sodium channels, induction of
action potential, a significant increase in steady-state currents,
and an increase in intracellular calcium following rTMS
stimulation, indicating the role of rTMS in modulating neural
plasticity.99 Akin to these changes, in fibromyalgia and chronic
pain patients, a reversal of the reduction in the cortical silent
period, short intracortical inhibition, and facilitation of
intracortical facilitation and motor evoked potentials by
rTMS have been shown, suggesting modulation of cortical
ref excitability.100,101 Further, these analgesic responses induced
69 by repetitive TMS seem to persist for weeks, indicative of long-
term plastic changes at the level of the synapse.102,103
72
Fibromyalgia and rTMS: Laboratory Investigations
76 on Pain and Depression. In the last few decades,
electromagnetic radiations have been widely used as a
79 therapeutic measure to reduce pain, depression, and anxiety,
78 especially in drug-resistant cases (Table 2). Thomas et al.
74 observed an analgesic effect in land snails when they were
exposed to PEMF that increased the response latency to a
83
warm surface.103 This analgesia was in part opioid-mediated,
85
being significantly attenuated but not eliminated by the opiate
antagonist, naloxone, and other μ and δ opioid receptor
84 directed antagonists. However, PEMF induced analgesia was
not affected by the k opioid receptor antagonist. A study
107 showed that SMF exposure for 6 h daily for 7 days in
carrageenan-injected rat models decreased inflammation in the
ankle and thenar muscles, serum, and articular lixivium IL-6
and TNF-α when compared to the control group.104 Some
studies also reported the beneficial effects of long and short-
term EMF exposure on cognitive function and dopaminergic
pathways.105,106
Mice exposed to EMF 1 h daily for a month resulted in a 5−
10-fold increase in Aβ (1−40) solubility and also altered Aβ
disaggregation.108 Using intracerebral microdialysis in con-
scious and anesthetized adult male Wistar rats, the effects of
acute rTMS (20 Hz) was studied on the intrahippocampal,
intra-accumbal, and intrastriatal release patterns of dopamine
and its metabolites such as homovanillic acid and 3, 4-
dihydroxyphenylacetic acid. In the dorsal hippocampus,
nucleus accumbens, and dorsal striatum, the extracellular
concentration of dopamine was found to be significantly
elevated in response to rTMS.106 PEMF has been reported to
alter the biomechanical properties of tissues and has been used
in the treatment of fractures, spinal fusions, and chronic
wounds.109−111 A study reported that the PEMF stimulation
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ACS Chemical Neuroscience
Figure 1. Schematic diagram showing a possible mechanism of action of rTMS in chronic pain. M1, primary motor cortex; DLFC, dorsolateral
prefrontal cortex; GABA, γ-aminobutyric acid; PAG, periaqueductal gray; MT, motor threshold; CSP, cortical silent period; SICI, short interval
intracortical inhibition; ICF, intracortical facilitation; LTP, long-term potentiation; LTD, long-term depression.
twice daily for 30 min for 3 weeks increased the tensile
strength by 69% as compared to nonstimulated control in the
transection rat model. They inferred that PEMF enhances Ca2+
binding to the growth factors involved in tissue healing,
thereby increasing tensile strength at the repair site.112
A recent study investigated the effects of varying frequencies
of rTMS on chronic neuropathic pain in rats.113 It was
observed that high-frequency rTMS may relieve neuropathic
pain as it downregulates nNOS and inhibits astrocyte activity
in the ipsilateral DRG and the L4−6 spinal dorsal horn. Zhao
et al. investigated the effect of rTMS on depression in
Sprague−Dawley rats with vascular dementia, using a chronic
unpredictable mild stress paradigm. Two days after injury, they
administered 30 pulses of rTMS to each of the hemispheres at
a frequency of 0.5 Hz and MF intensity of 1.33 T for 30
days.114 The study concluded that rTMS can abrogate the loss
of hippocampal neurons and restore the balance of the HPA
axis, significantly improve the learning and memory deficits,
and increase levels of acetylcholinesterase, choline acetyl-
transferase, cholinergic neuron density, and also the number of
brain-derived neurotrophic factor (BDNF)-immunoreactive
cells. These results indicate that rTMS can ameliorate
depression and learning and memory function in rats with
vascular dementia. The mechanism through which this occurs
seems to be related to the promotion of BDNF expression and
subsequent restoration of cholinergic system activity in the
hippocampal CA1 region.114 Moreover, the intermediate-
frequency of rTMS (2 Hz) stimulation has also been shown
to improve the behavioral and histological parameters
following traumatic brain injury in rats.115 A 10 Hz rTMS
study conducted in SCI-rats concluded that rTMS upregulates
the expression of the potassium chloride cotransporter-2
protein and thereby alleviates spasticity. It also inferred that
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high-frequency rTMS treatment at an early stage of the injury
can be more effective.116
Multiple studies have studied the antidepressive effects of
rTMS along with their molecular mechanisms. Peng et al., in
chronic unpredictable stress-treated rats, assessed the effects of
1/5/10 Hz, 0.84/1.26 T rTMS on 5HT, 5-HIAA, DA, and NE
levels and monoamine oxidase A (MAO-A) activity, along with
the expression of sirtuin 1 (Sirt1) and MAO-A in the
prefrontal cortex (PFC) and cortex-derived astrocytes. The
study inferred that rTMS treatment (5/10 Hz, 0.84/1.26 T)
attenuated depressive-like behaviors, increased 5-HT, DA, and
NE levels, decreased the 5-HIAA level, Sirt1, and MAO-A
astrocytic expression, and reduced MAO-A activity in the PFC.
These results suggest that inhibition of Sirt1/MAO-A
expression in the astrocytes of the prefrontal cortex contributes
to the antidepressive effects of rTMS.117 Luo et al. found that
conventional 20 Hz rTMS enhanced neurogenesis by
activating the BDNF/tropomyosin-related kinase B (TrkB)
pathway in ischemic rats.118 El Arfani et al. observed that the
accelerated HF-rTMS increased motor activity in rats with
treatment-resistant depression by altering the striatal neuro-
chemical mileu.119 Hesselberg et al. observed that both the
high and low-frequency rTMS can cause a significant
antidepressant effect.120 In a spontaneously hypertensive rat
(SHRs), an animal model of attention deficit hyperactivity
disorder (ADHD), they observed that the SHRs treated with
rTMS exhibited less locomotor activity in the open field test
throughout treatment and showed an increase in levels of
BDNF and decrease in noradrenaline concentrations. The
results of this preclinical study indicate that rTMS may
constitute a new modality of treatment for patients with
ADHD.121 Gersner and colleagues aimed to study the
antiepileptic potential of high-frequency rTMS in status
epilepticus. They found that rTMS alone acutely decreased
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Table 3. Preclinical Investigation of Pain and Depression

study
models intervention key outcomes disadvantages ref
snails PMF Induces analgesia Analgesia was partially opioid mediated 103
rats ELF-MF Analgesic effect of ELF magnetic field The role of other nociceptive systems was also suspected 125
mice EMF (1) Protects mice from later cognitive impairments; (2) Reverses Animals received full-body exposure instead of head only 105
(long/ impairment and AD-like brain pathology in older Tg mice; (3) exposure; AD-Tg mice are partial disease models
short- Increases cognitive performance of normal mice
term)
No effect on DNA repair enzymes, antioxidant enzymes, or extent
of protein damage
mice HF-EMF Enhances brain mitochondrial function; Aβ disaggregation EMF treatment is not localized; mitochondrial function 108
different in Tg mice and WT mice
rats rTMS Increases the activity of dopaminergic systems It only proves the primary mechanism of action, does not 106
prove downstream effects
hamsters SMF Iit inhibits tumor growth and angiogenesis; sensitizes Treatment parameters are undetermined; a combination of 126
chemotherapy SMF and chemotherapy is only tested; antitumoral
effects might be due to different mechanisms.
rats PEMF Pulsed EMF increased tensile strength Effects not understood in tendons with synovial fluid 112
rats rTMS High-frequency rTMS relieves neurotrophic pain. Other studies have proved that the effectiveness of rTMS 113
is more when applied to adjacent areas
rats rTMS rTMS abrogates the loss of hippocampal neurons and restores the Evidence is empirical 114
balance of the HPA axis in the treatment of depression.
rats rTMS Intermediate rTMS can be used for TBI recovery in rats Memory and hippocampus disorganization remain 115
unexplored
rats rTMS rTMS can alleviate spasticity Findings predicted rTMS at an early stage is more 116
influential, but not confirmed
neonatal rTMS rTMS can be used for treating MDD and depression-like behavior Lack of suitable models to confirm antidepressive effects; 117
rats effects of other neurotransmitters not considered
rats rTMS Reduces subacute ischemic brain damage 118
rats rTMS Suppresses seizures Can work only in combination with lorazepam 122
rats rTMS Immediate activation of voltage-gated ion channels Works along with activity 99
rats rTMS Increases BDNF mRNA levels Only biphasic pulse was used, stimulation is not focal 123
enough to support the conclusion
rats rTMS Effect of iTBS and cTBS on redox state parameters on the Evidence given does not explain why GSH concentration 124
cerebellar cortex is unchanged; lack of focal stimulation
rats rTMS rTMS improves key biochemical deficits related to dyskinesia Conclusion based on GNDF levels only and does not 127
assay other molecules involved in dyskinesia

epileptic spike frequency. However, combinatory treatment of
half-dose lorazepam with rTMS was as effective as a full
lorazepam dose. This report shows that high-frequency rTMS
has a moderate antiepileptic potential but complements
lorazepam to suppress seizures.122
To unravel the underlying cellular mechanisms activated by
rTMS, Banerjee et al. applied 20 Hz rTMS and assessed rat
brain activity with whole-cell patch-clamp and calcium
imaging. They observed that each TMS pulse caused transient
activation of voltage-gated sodium channels in neurons, while
the short 500 ms, 20 Hz rTMS stimulation-induced action
potentials only in a subpopulation of neurons, increased the
steady-state current of the neurons at near-threshold voltages,
and led to a delayed increase in intracellular calcium levels.
These results indicate that rTMS has an immediate and
cumulative effect on neuronal activity and intracellular calcium
levels and thus suggests that rTMS may enhance neuronal
responses when it is combined with an additional motor,
sensory, or cognitive stimulus.99 Beom et al. also reported that
rTMS increased mRNA levels of immediate early genes such as
Arc, Junb, and Egr2 and BDNF in the stimulated cortex, rather
than the contralateral side.123 rTMS altered the levels of
proteins involved in excitatory and inhibitory responses along
glial fibrillary acidic protein, and oxidative status in cerebellar
tissue and plasma.124 TMS stimulation significantly increased
thiol groups (SH) in the cerebellar tissue of the SS iTBS group
and decreased in iTBS RS. The activity of glucose-6-phosphate
dehydrogenase (G6PD) was increased in cTBS RS. Immunor-
eactivity of vGluT1 decreased in cTBS RS, whereas GLT-1
increased in cTBS SS and cTBS RS as compared to control.
This study gave insight into molecular and biochemical
mechanisms by which iTBS and cTBS exert their effects on
rat’s cerebellar cortex.124 In Parkinson’s disease, fluctuation in
the level of dopamine and upregulation of NR2B tyrosine
phosphorylation in the striatum has been associated with
levodopa (L-dopa)-induced dyskinesia (LID). Ba et al.
assessed the effect of rTMS on abnormal involuntary
movements (AIM) of LID in Parkinson’s disease rat model.
They observed that using TMS daily for 3 weeks reduced AIM
scores, loss of nigral dopaminergic neurons and stabilized
striatal dopamine levels. It also increased levels of GDNF
which may restore the damage in the dopaminergic neurons.127
Further, rTMS also reduced the levels of the NR2B tyrosine
phosphorylation and its interactions with Fyn in the lesioned
striatum of a LID rat model, thereby indicating that rTMS is
beneficial in LID therapy as it restores the biochemical deficits
related to dyskinesia (Table 3).

■
with redox homeostasis. In the rat, Mancic et al. investigated
the effects of single (SS) as well as repeated sessions (RS) of
intermittent and continuous theta-burst stimulation (iTBS; FIBROMYALGIA MANAGEMENT
cTBS) on the expression of vesicular and plasma membrane Recommendations of the European League Against Rheuma-
glutamate transporters 1 (vGluT1 and GLT-1 respectively), tism and American Pain Society for FM management have
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been published,128,129 albeit a universally accepted treatment
algorithm or approach is lacking.130 Treatment targets of FM
are to alleviate pain, increase restorative sleep, and improve
physical functions through a reduction in associated symptoms
such as fatigue, sleep disturbances, cognitive impairment,
stiffness, and mood or anxiety disorders.131 The management
strategies contain four main stages in compliance with the
decision of patients. Patient education and emphasis on
nonpharmacological therapies should be an initial step. If
patients are not responding, further therapy should be tailored
to the precise needs of the patient and may include
psychological remedies (for coping strategies and mood
disorders), pharmacotherapy (for severe pain or sleep
disturbance), and/or a multimodal rehabilitation program
(for severe disability).132 Both pharmacologic and non-
pharmacologic treatments have been tried. Duloxetine,
Milnacipran (serotonin/norepinephrine reuptake inhibitors),
and Pregabalin (anticonvulsant) are approved by the FDA as
the drugs of choice.133−135 Pregabalin presents side effects of
abnormal thinking, euphoria, dry mouth, peripheral edema,
weight gain, nausea, blurred vision, abnormal thought,
constipation, headache, increased appetite, amnesia, ataxia,
asthenia, incoordination, nervousness, and peripheral
edema.136 Moreover, complementary and alternative medicines
are also very commonly prescribed, e.g., anthocyanidins,
capsaicin, soy, and S-adenosylmethionine.137 Local application
of 0.025% capsaicin for 4 weeks improved only tenderness.138
Transient stinging or burning at the application sites are
reported as adverse effects. Soy which is common dietary
supplements caused indigestion, nausea, and sinusitis.139
In the absence of any other alternative satisfactory
treatment, nonsteroidal anti-inflammatory drugs are commonly
prescribed. These initially provide temporary relief from the
symptoms for a few hours which is mediated by a decrease in
the sensitivity of peripheral nerve receptors due to a decrease
in peripheral prostaglandin synthesis.140 The use of cyclo-
benzaprine leads to an improvement in pain, sleep, and fatigue
in FM patients. TNX-102 SL is a sublingual formulation of
cyclobenzaprine (2.8 mg) designed for rapid absorption and
bedtime use. In comparison to the placebo, small dose
sublingual cyclobenzaprine for 12 weeks showed a significant
improvement in FM and sleep symptoms in a multicentered
Phase II trial.141 All the drugs used for FM patients give only
symptomatic relief and work in a small population of patients.
Among nonpharmacological treatments recommended are
patient education, cognitive and behavioral therapies, exercises,
and noninvasive therapies as described above.132 Non-
pharmacological noninvasive methods have also recently
been tried; e.g., low-frequency rTMS has shown significant
improvement in pain and associated symptoms.79 rTMS is a
novel, noninvasive method of brain stimulation using brief
magnetic pulses to modulate brain activity.142 Magnetic pulses
generated via the stimulating coil placed on the scalp pass
unimpeded through the skull bone and cortex. An electric field
is induced into the neural tissue which is sufficient to activate
cortical neurons and fibers and provide sustained changes in
neuronal excitability and regional brain activities.107 Thus, the
limbic areas involved in pain processing are modulated trans-
synaptically by TMS, suggesting a “top-down” model of
inhibition of neuronal activity coupled with ascending
midbrain-thalamic-cingulate pathway through the descending
fibers from the prefrontal cortex.143,144
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■
Review
BENEFITS AND DRAWBACKS: rTMS IN FM
MF therapy is a noninvasive, safe, and simple technique, often
administered over the site of a painful injury or inflammation.
MF has been used for decades, and robust evidence exists in
the literature of its analgesic efficacy.145 rTMS over different
areas of the scalp like the right and left DLPFC or right and left
motor cortex to alleviate pain has been more commonly used.
It is reported that 1 Hz rTMS for 15 min at 100% motor
threshold of the right DLPFC has a selective effect to increase
pain tolerance in comparison to the left DLPFC or right or left
motor cortex and vertex in normal healthy individuals. A
number of studies provide evidence for the selection of
DLPFC for pain relief over the other areas of the brain. A few
studies also have shown long-lasting relief in pain conditions
after chronic exposure to a magnetic field in FM.79,146−148 As
FM is an aberrant in the central pain processing system, rTMS
may reduce fibromyalgia pain by enhancing intracortical
modulation.
The available pharmacological and nonpharmacological
therapeutic options for FM are not able to relieve the
symptoms efficiently. Preliminary studies indicate the ther-
apeutic efficacy of TMS because of its safety and relative
painlessness. TMS has many possible applications as a
therapeutic device and may be beneficial for treating
psychiatric disorders that have not yet been explored. If it
ultimately proves useful for the treatment of neuropsychiatric
disorders and chronic pain conditions, rTMS may well become
a standard medical tool. Though a recent review (2013−2017)
on rTMS shows a 7% reduction in pain when rTMS applied for
less than 1 week, in several other studies no difference is
reported when stimulation is applied to the prefrontal cortex
compared to sham treatment for short-term follow-up.149
There is no evidence that rTMS improves disability, but there
is an improvement in the quality of life in FM patients after
rTMS in comparison to sham treatment groups.149 In addition,
Altas et al. showed that rTMS applied over either the right
DLPFC or primary motor significantly reduced pain as well as
depression, physical functions, and general health perceptions
in FM patients.150 The study highlights a significantly greater
reduction in pain in the group receiving rTMS at the motor
area, whereas rTMS stimulation at DLPFC improved more of
physical functioning. The review study showed beneficial
effects of rTMS not only in FM patients but also in other
chronic pain patients.151 Most of the RCTs showed significant
improvements not only in pain but also in physical functioning,
depression, and quality of life. Instead of the negative results of
a few RCTs, the promising analgesic effects of rTMS on FM as
reported indicate the importance of rTMS as a possible
therapeutic option, being noninvasive and cost-effective.
■ FM AND rTMS: CLINICAL TRIAL INVESTIGATIONS
Currently, rTMS is an FDA-cleared noninvasive management
strategy for major depression, which is currently studied for a
multitude of conditions including fibromyalgia. An analysis of
fibromyalgia clinical trials using rTMS as a management
strategy was done. Data were extracted on July 8, 2020 from
www.ClinicalTrials.gov using the term “fibromyalgia” and
“TMS” yielding 24 trials, 3 of which were removed due to
not being relevant. The data included the NCT number
(identifier for each trial), title of the trial, recruitment status,
clinical phase, and registration date. These trials were then
screened on PubMed for publications for outcomes and results.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
 Table 4. Clinical Trials Investigations in Pain and Depression
number study
NCT number study title phase enrolled start status results ref
NCT00374673 Efficacy of transcranial magnetic stimulation (TMS) in chronic idiopathic pain 3 60 10/06 completed not published
disorders
NCT00523302 A pilot study of TMS effects on pain and depression in patients with N/A 20 7/07 completed rTMS reduced pain symptoms in comparison to baseline but were 152
fibromyalgia not different in the sham group
NCT00524420 Transcranial magnetic stimulation for treating women with chronic widespread 2 68 2/08 completed rTMS group had a greater antidepressant response rate, greater 153
pain remission rate, and reduction in pain compared to sham
NCT00697398 Repetitive transcranial magnetic stimulation of the motor cortex in N/A 38 10/08 completed rTMS group had greater QoL improvement in the FIQ and metal 154
PMID: fibromyalgia: a study evaluating the clinical efficiency and the metabolic component of SF-36 than the sham stimulation group
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24670891 correlate in 18FDG-PET

NCT01229852 Treatment of fibromyalgia using deep shaped-field transcranial magnetic N/A 35 8/10 completed rTMS sessions with 10 Hz produced a pain inhibition in NRS which 155
stimulation a clinical feasibility study was maintained for at least 4 weeks
NCT01308801 Repetitive transcranial magnetic stimulation in fibromyalgia N/A 42 4/11 completed not published
NCT02381171 Transcranial magnetic stimulation and/or neurofunctional electrical N/A 80 2/12 completed rTMS showed a reduction in pain intensity assessed by a Visual 156
acupuncture in myofascial chronic pain patients Analogue Scale
NCT01608321 rTMS for the treatment of chronic pain in GW1 veterans 3 17 9/12 terminated N/A
NCT01942538 The efficiency of rTMS sessions after a successful 3 week-treatment in N/A 78 9/13 completed not published
fibromyalgia
NCT01992822 Pain sensitivity of subjects with fibromyalgia before and after repetitive N/A 72 11/13 completed not published
transcranial magnetic stimulation treatment
NCT02083588 A prospective trial to explore the efficacy of dTMS in subjects with fibromyalgia 2 30 3/14 completed not published
NCT02572726 An exploration of the neuroplasticity of endogenous analgesia in health and N/A 100 10/15 recruiting N/A

I
chronic pain
NCT02969707 Use of repetitive transcranial magnetic stimulation to augment hypnotic N/A 100 4/17 completed not published
analgesia
NCT03460340 dTMS as a treatment for patients with fibromyalgia N/A 40 4/18 completed not published
NCT03843203 Long-term home based tDCS in fibromyalgia N/A 84 6/18 recruiting N/A
NCT03801109 Transcranial magnetic stimulation and hyperbaric chamber for women N/A 69 2/19 active N/A
fibromyalgia
NCT03658694 Repetitive transcranial magnetic stimulation of relief of fibromyalgia pain N/A 40 4/19 recruiting N/A
NCT03909009 Repetitive transcranial magnetic stimulation (rTMS) in fibromyalgia N/A 20 4/19 completed rTMS did not show any significant beneficial effect on pain, stiffness, 157
pubs.acs.org/chemneuro

fatigue, quality of life, mood, and cognitive state over sham

stimulation
NCT03371225 Optimized tDCS for fibromyalgia: targeting the endogenous pain control N/A 148 4/19 recruiting N/A
system
Review

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The total number of clinical trials increased with each year
from 2006 until 2019, with 2018 and 2019 alone having six
new registered clinical trials. These clinical trials assessed the
role of rTMS on fibromyalgia and the associated change in
related symptoms including pain, anxiety, depression, and
overall quality of life of patients (Table 4). Some trials have
also shown beneficial effects of rTMS on multiple symptom
domains as compared to sham. However, additional trials are
necessary to determine the optimal treatment protocols for
rTMS therapy to treat FM patients.
■ CONCLUSION
Fibromyalgia is characterized by diffuse and chronic pain,
along with other related symptoms like fatigue, anxiety, sleep
disorders, morning stiffness, depression, memory loss,
dizziness, irritable bowel syndrome, and generalized muscle
tenderness. It is difficult to imagine the agony of a person
suffering from pain for several years. It affects the personal life
of the patient and the economic status of the patient’s family
and can lead to poor management of the home front. Such is
the plight of a FM patient, who is usually a middle-aged
woman. FM patients elaborate on all the components of pain,
namely, sensory-discriminative, affective-motivational, and
cognitive- evaluative. The condition is globally identified and
lacks any treatment except for nonsteroidal anti-inflammatory
drugs, inhibitors of serotonin/norepinephrine reuptake, and
anticonvulsants or local application of analgesics. All these
formulations have temporary effects that are associated with
more disturbing side effects, besides being expensive. FM has
now begun to be identified as a disease process by scientists.
Evidence is accumulating regarding an association with
aberrant processing of sensory information, at both peripheral
and central levels. Therefore, there is an urgent need to search
for a better, safe management strategy. Recently, magnetic
stimulation has emerged as a corrective adjunct or principle
management strategy in several neurological disorders, namely,
Parkinson’s disease, stroke, and neuropathic pain, besides, of
course, FM syndrome. FM patients have been reported to
benefit from it, although there are only a few clinical trials
available. It is important to note that both the stimulation
parameters and site of stimulation bear a strong relationship
with the outcome of the study. Both high-frequency rTMS (10
Hz) and low-frequency rTMS (1 Hz) administered over the
right dorsolateral prefrontal cortex have elicited analgesic and
antidepressant effects. Several protocols have been published
for providing rTMS to FM patients. The effect of rTMS is
primarily because of the induction of an electrical field in the
brain which is sufficient to activate cortical neurons and
provide enduring changes in cortical excitability and regional
brain activities. The activity also spreads to underlying
subcortical limbic and other related structures, which are
crucial in the processing of sensory stimuli because of bilateral
connections. The sustained effect of rTMS is because of its
restorative/corrective influence on the concentration of
neurotransmitters like dopamine, serotonin, and opioids. All
these underlying electrophysiological-neurochemical changes
reflect in the long-term potentiation/long-term depression.
Once the restorative effects occur at the cellular level, it is
bound to reflect in the behavior. Therefore, rTMS is
recommended as an ideal management strategy for FM
syndrome with more and more clinical studies needed for a
FM patient’s welfare and better quality of life.
J https://dx.doi.org/10.1021/acschemneuro.0c00785
■
Review
AUTHOR INFORMATION
Corresponding Authors
Suneel Kumar − Department of Biomedical Engineering,
Rutgers, The State University of New Jersey, Piscataway, New
Jersey 08854, United States; orcid.org/0000-0003-4829-
8654; Phone: 848-445-6581; Email: sk1350@
soe.rutgers.edu; Fax: 732-445-3753
Suman Jain − Department of Physiology, All India Institute of
Medical Sciences, New Delhi 110029, India; Phone: +91-11-
26593229; Email: sumanjain10@gmail.com
Authors
Abdul Haque Ansari − Department of Physiology, College of
Medicine, Texila American University, East Bank, Demerara,
Guyana, South America
Ajay Pal − Department of Orthopedic Surgery, Movement
Recovery Laboratory, Columbia University Medical Center,
New York 10032, United States
Aditya Ramamurthy − Department of Orthopedic Surgery,
Movement Recovery Laboratory, Columbia University
Medical Center, New York 10032, United States;
orcid.org/0000-0002-1642-3855
Maciej Kabat − Hackensack Meridian School of Medicine,
Seton Hall University Interprofessional Health Sciences
Campus, Nutley, New Jersey 07110, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acschemneuro.0c00785
Author Contributions
#
A.H.A., A.P., and S.K. contributed equally. The manuscript
was written through the contributions of all authors. All
authors approved the final version of the manuscript.
Notes
The authors declare no competing financial interest.
■
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