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Motor training is a widely used therapy in many pain conditions. The brain’s capacity to undergo functional and structural changes i.e., neuroplasticity is fundamental to training-induced motor improvement and can be assessed by transcranial magnetic stimulation (TMS). The aim was to investigate the impact of pain on training-induced motor performance and neuroplasticity assessed by TMS. The review was carried out in accordance with the PRISMA-guidelines and a Prospero protocol (CRD42020168487). An electronic search in PubMed, Web of Science and Cochrane until December 13, 2019, identified studies focused on training-induced neuroplasticity in the presence of experimentally-induced pain, 'acute pain' or in a chronic pain condition, 'chronic pain'. Included studies were assessed by two authors for methodological quality using the TMS Quality checklist, and for risk of bias using the Newcastle–Ottawa Scale. The literature search identified 231 studies. After removal of 71 duplicates, 160 abstracts were screened, and 24 articles were reviewed in full text. Of these, 17 studies on acute pain (n = 7) or chronic pain (n = 10), including a total of 258 patients with different pain conditions and 248 healthy participants met the inclusion criteria. The most common types of motor training were different finger tasks (n = 6). Motor training was associated with motor cortex functional neuroplasticity and six of seven acute pain studies and five of ten chronic pain studies showed that, compared to controls, pain can impede such trainings-induced neuroplasticity. These findings may have implications for motor learning and performance and with putative impact on rehabilitative procedures such as physiotherapy.
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Brain Imaging and Behavior
https://doi.org/10.1007/s11682-021-00621-6
REVIEW ARTICLE
Pain’s Adverse Impact onTraining‑Induced Performance
andNeuroplasticity: ASystematic Review
NikolaStanisic1 · BirgittaHäggman‑Henrikson1,2 · MohitKothari3,4 · YuriMartinsCosta5 ·
LimorAvivi‑Arber6 · PeterSvensson1,2,7
Accepted: 9 December 2021
© The Author(s) 2022
Abstract
Motor training is a widely used therapy in many pain conditions. The brain’s capacity to undergo functional and structural
changes i.e., neuroplasticity is fundamental to training-induced motor improvement and can be assessed by transcranial
magnetic stimulation (TMS). The aim was to investigate the impact of pain on training-induced motor performance and
neuroplasticity assessed by TMS. The review was carried out in accordance with the PRISMA-guidelines and a Prospero
protocol (CRD42020168487). An electronic search in PubMed, Web of Science and Cochrane until December 13, 2019,
identified studies focused on training-induced neuroplasticity in the presence of experimentally-induced pain, 'acute pain'
or in a chronic pain condition, 'chronic pain'. Included studies were assessed by two authors for methodological quality
using the TMS Quality checklist, and for risk of bias using the Newcastle–Ottawa Scale. The literature search identified 231
studies. After removal of 71 duplicates, 160 abstracts were screened, and 24 articles were reviewed in full text. Of these, 17
studies on acute pain (n = 7) or chronic pain (n = 10), including a total of 258 patients with different pain conditions and 248
healthy participants met the inclusion criteria. The most common types of motor training were different finger tasks (n = 6).
Motor training was associated with motor cortex functional neuroplasticity and six of seven acute pain studies and five of
ten chronic pain studies showed that, compared to controls, pain can impede such trainings-induced neuroplasticity. These
findings may have implications for motor learning and performance and with putative impact on rehabilitative procedures
such as physiotherapy.
Keywords Exercise· Neuronal plasticity· Nociception· Transcranial magnetic stimulation· Motor function
Introduction
Neuroplasticity can be defined as the brain’s ability to reor-
ganize or undergo functional and structural changes. It was
long postulated that neuroplasticity was limited only to the
critical period during brain development (Michelini & Stern,
2009). However, during the past decades, it has been widely
recognized that neuroplasticity is the normal ongoing state
of the human brain throughout the life span (Pascual-Leone
etal., 2005). This feature of the brain is considered as one of
the foundations for acquisition of new motor skills. In every-
day life, we use different motor skills that we have acquired
gradually through training and changes in our environment,
e.g., walking, driving a car, riding a bicycle or chewing food
(Chang, 2014; Lohse etal., 2014).
The neuroplastic changes associated with the training
of a skill, i.e., motor training-induced neuroplasticity, are
thought to play an important role in the performance of the
* Nikola Stanisic
nikola.stanisic@mau.se
1 Department ofOrofacial Pain andJaw Function, Malmö
University, Malmö, Sweden
2 Scandinavian Center forOrofacial Neurosciences (SCON),
Aarhus, Denmark
3 Department ofClinical Medicine, Hammel
Neurorehabilitation Center andUniversity Research Clinic,
Aarhus University, Aarhus, Denmark
4 JSS Dental College andHospital, JSS Academy ofHigher
Education andResearch, Mysore, India
5 Department ofBiosciences, Piracicaba Dental School,
University ofCampinas, SaoPaulo, Brazil
6 Prosthodontics andOral Physiology, Faculty ofDentistry,
University ofToronto, Toronto, ON, Canada
7 Section forOrofacial Pain andJaw Function, Institute
forOdontology andOral Health, Aarhus University, Aarhus,
Denmark
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Brain Imaging and Behavior
1 3
skill being trained and can be reflected in measures such as
accuracy, precision and speed. It has been suggested that
training-induced neuroplasticity may be dependent on a
number of factors, including the complexity of the skills
being trained, training time, motivational conditions, age and
the muscle groups activated during skill training to name a
few (Duchateau etal., 2006; Hellmann etal., 2011; Wulf
etal., 2010).
There are also reports that the presence of pain can have
an impact on training-induced neuroplasticity and on the
motor performance when executing a motor skill (Bank
etal., 2013; Hodges & Tucker, 2011). The effect pain has on
motor performance can both be subtle, e.g., redistribution of
activity within/between muscles, increased variability, and
more salient, e.g., avoidance of the motor behaviour caus-
ing or increasing the pain (Akhter etal., 2014; Hodges &
Smeets, 2015; Hodges & Tucker, 2011).
Chronic pain conditions, as for example chronic lower
back pain, which often result in limitations in motor perfor-
mance, are common conditions and conventional treatments
often involve different types of skill training to reduce dis-
ability and pain. Movements engaged during skill training
will activate different corticomotor pathways in the brain to
achieve appropriate, precise, and effective motor control and
facilitate rehabilitation of the motor performance (Gurev-
ich etal., 1994; Kosek etal., 2013). However, conventional
rehabilitation and skill training programs may not optimally
restore impaired motor performance in patients with chronic
pain, compared to pain-free patients, due to a negative effect
on training-induced neuroplasticity. Despite the importance
of this topic in rehabilitation medicine, the effect of pain
on training-induced neuroplasticity and the subsequential
impact this has on motor skill acquisition and improvement,
is not well understood.
Transcranial magnetic stimulation (TMS), a non-invasive
brain imaging technique, can be used to assess training-
induced neuroplasticity in corticomotor pathways following
motor skill training (Rothwell, 2018). There is some evi-
dence that both acute and chronic pain can affect the plas-
ticity of the motor cortex—as assessed by TMS—follow-
ing motor skill training, although reported findings are not
conclusive. Thus, a reduction in corticomotor excitability
has been reported for patients with both chronic and acute
pain (Dettmers etal., 2001; Krause etal., 2006). In contrast,
both chronic pain (e.g., phantom limb pain) (Dettmers etal.,
2001) and acute pain have also been shown to increase motor
cortex excitability under certain circumstances (Romaniello
etal., 2000).
The aim of this systematic review was to investigate the
impact of pain (acute or chronic) on training-induced motor
performance and neuroplasticity as assessed by TMS.
Materials andmethods
Protocol
This study followed a protocol that was registered in Pros-
pero (CRD42020168487) and was carried out in accordance
with the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) Statement (Moher etal.,
2009).
Inclusion andexclusion criteria
Eligibility criteria were formulated using PICO (population,
intervention, comparison and outcome) to identify clinical
studies published in English and focused on pain and train-
ing-induced neuroplasticity assessed with TMS in humans.
Populations: Healthy humans with experimentally
induced acute pain or humans with a chronic pain condi-
tion.
Intervention: Short-term motor task training in the pres-
ence of pain (acute or chronic).
Comparison: Healthy humans with no pain.
Primary outcome: Neuroplasticity assessed with TMS
targeting motor cortex areas of the corresponding mus-
cles involved in the training task performed in the pres-
ence of pain.
Secondary outcome: Behavioral and functional out-
comes.
Articles were excluded if a) the population had psychiat-
ric or neurological disorders, b) participants did not perform
an active form of training, c) participantsperformed long
term training (e.g., sport athletes) and d) the training was
combined with other interventions (e.g., paired associative
stimulation).
Literature search
An electronic search was carried out in PubMed, Cochrane
and Web of Science until December 13, 2019. The search
strategy was developed for PubMed with a combination of
MeSH terms and free text terms in cooperation with an expe-
rienced research librarian (Martina Vall) and then adapted to
both Cochrane and Web of Science. The search was designed
to identify studies that assessed the possible effect of acute
or chronic pain on training-induced neuroplasticity assessed
with TMS. Table1 provides the full search strategy for Pub-
Med. There was no limitation on study design or language
in the search. The electronic search was combined with a
hand search of the reference lists of the included articles
to identify additional studies. Grey literature, letters to the
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Brain Imaging and Behavior
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editor and editorials were not included, and authors were not
contacted for additional information.
Article selection
Two authors (BHH, NS) independently screened all titles
and abstracts for potential eligibility. If at least one author
deemed an article to be of potential interest, it was retained
for the full text assessment. The full text assessment was
carried out independently by the same authors to determine
if articles met the inclusion criteria. Any disagreements
were resolved by discussion between the investigators and
if needed by a third author (MK).
Data extraction
Data extraction was carried out by two authors (NS, MK)
and checked by a third author (BHH). The data extracted
from the individual studies were: first author, publication
year, aim, study population, study setting, study design,
methods, outcomes, and study summary. All data support-
ing the findings of this study are available within the article
and its 19. A record of the database searches is available on
Prospero (CRD42020168487). If results allowed, primarily
with regard to reported TMS outcome measures for neuro-
plasticity and elapsed time between training and assessment,
a meta-analysis was planned using a random effects model
and using the I2 statistic for assessing heterogeneity among
studies.
Quality assessment
Assessment of risk of bias in the included studies was
carried out by two authors (NS, LAA) using the Newcas-
tle–Ottawa Scale (NOS) for case–control studies (Stang,
2010). In addition, the included studies were assessed by
two authors (NS, YC) with the TMS Quality checklist (Chip-
chase etal., 2012). For both of these instruments, any disa-
greement between the authors were resolved by discussion,
and if needed by a third author (BHH). The NOS evaluates
the risk of bias by looking at eight items categorized in three
different domains: selection, comparability and exposure.
NOS uses a star system where the studies with the highest
quality are awarded a maximum of one star for each item
with exception for the item related to comparability where
the assignment of two stars are allowed providing a total
score between 0 and 9. The TMS Quality checklist includes
eight items on participant characteristics, 20 items on TMS
methodology, of which three items specifically concern
paired pulse only, and two items on analysis. In total, the
checklist includes 26 factors that can be reported and/or
controlled for in studies using single pulse TMS, and 29
factors that can be reported and/or controlled for in studies
using paired pulse TMS. The checklist items were assessed
as: “Yes”, “No”, or “Not applicable”, and the number of
these respective answers was reported together with the total
percentage of “Yes” answers with the number of attainable
criteria as denominator.
Results
Literature search
The electronic literature search in PubMed, Cochrane and
Web of Science, identified a total of 231 articles (Fig.1).
After removal of 71 duplicates, 160 unique abstracts were
screened, and 24 articles were reviewed in full text. Of
the 24 articles, 7 articles were excluded (Bradnam etal.,
2016;Daligaduet al., 2013; MasséAlarie et al., 2015;
Massé-Alarie etal., 2017a; McCambridge etal.,2018; Rit-
tig-Rasmussen etal., 2013; Volz etal., 2012)(Table2) and
17 articles published between 2007 and 2018 met the inclu-
sion criteria, i.e., reported the impact of pain on training-
induced neuroplasticity assessed by TMS (Table3). The
electronic search was complemented with a hand search of
the reference lists of included articles.
Table 1 PubMed Search strategy
Search Search String
1. Plasticity ("Sensorimotor Cortex"[Mesh] OR corticomotor plasticity[tiab] OR corticomotor control[tiab] OR
corticomotor pathway*[tiab] OR sensorimotor cortex[tiab] OR neuroplasticity[tiab] OR "Neuronal
Plasticity"[Mesh] OR cortical plasticity[tiab] OR cortical neuroplasticity[tiab] OR brain plasticity[tiab]
OR Neuronal Plasticity[tiab])
2. TMS (TMS[tiab] OR Transcranial Magnetic Stimulation[tiab] OR "Transcranial Magnetic Stimulation"[Mesh])
3. Exercise (exercise[Mesh] OR rehabilitation[Mesh] OR rehabilitat*[tiab] OR exercis*[tiab] OR train*[tiab] OR
physical therapy modalities[Mesh] OR physical therapists[Mesh] OR physiotherap*[tiab] OR physical
therapy specialty[Mesh] OR kinesio*[tiab]OR learning[tiab] OR (physical[tiab] AND therap*[tiab]))
4. Pain Pain OR nociception
5. Result #1 AND #2 AND #3 AND #4
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Brain Imaging and Behavior
1 3
The majority of the included articles focused on chronic
pain conditions (n = 10) (Baarbe etal., 2018; Hoeger Bement
etal., 2014; Masse-Alarie etal., 2016, 2017b; Mendonca
etal., 2016; Parker etal., 2017; Rittig-Rasmussen etal.,
2014a; Schwenkreis etal., 2011; Tsao etal., 2010; Vallence
etal., 2013), and the remaining articles focused on acute
pain in healthy individuals (n = 7) (Boudreau etal., 2007;
Dancey etal., 2019; De Martino, Petrini, etal., 2018; De
Martino, Zandalasini, etal., 2018; Ingham etal., 2011; Mav-
romatis etal., 2017; Rittig-Rasmussen etal., 2014b). The
chronic pain conditions included headache (n = 1), pain in
the neck region (n = 2), lower back pain (n = 3), painful hand
arthritis (n = 1) and fibromyalgia (n = 3).
Acute pain was induced by either: i) applying capsaicin
cream (n = 3) intraorally (Boudreau etal., 2007), on the
right thumb (Mavromatis etal., 2017), or on the dominant
elbow (Dancey etal., 2019); ii) by injecting hypertonic
saline (n = 2) into the right first dorsal interosseous muscle
(Ingham etal., 2011) or the right side of the neck (Rittig-
Rasmussen etal., 2014b); or iii) eccentric exercise to induce
delayed onset muscle soreness (n = 2): in wrist extensor mus-
cles (De Martino, Petrini, etal., 2018; De Martino, Zanda-
lasini, etal., 2018).
Regarding the training paradigms, only one study focused
on the trigeminally-innervated region and involved train-
ing in a tongue-protrusion task (Boudreau etal., 2007). The
Fig. 1 PRISMA flow chart
showing numbers of included
and excluded studies
Table 2 Articles excluded from the study during full-text assessment
and the main reasons for exclusion (n = 7)
Main reason for exclusion First author Year
No pain population Rittig-Rasmussen 2013, Volz 2012
Neurological disorder Bradnam 2016
No training performed Massé-Alarie 2017
Cross-sectional data Daligadu 2013
Conference abstract Massé-Alarie 2015, McCambridge 2018
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Brain Imaging and Behavior
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Table 3 Data extracted from the included papers (n = 17)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Baarbe 2018 To determine if
cerebellar inhibi-
tion would reduce
to the same extent
in patients with
mild recurrent
neck pain as in
healthy individuals
following the same
MA task
Neck pain
n: 27
F/M: 16/11
Age: 21.1 (1.9) yrs
Healthy controls
n: 12
F/M: 2/10
Age: 22.4 (2.2) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1) Short test block (baseline)
2) TMS (baseline)
3) Manipulation:—Neck pain spinal manipulation (SM)
(n = 14) sham manipulation (n = 13)
- Healthy no intervention (n = 12)
4) Task training
5) TMS (post-training)
Task
Typing 8-letter sequence of 4 letters as quickly and accurately
as possible
Short test block 1–2min, MA 10min, short test block 1–2min.
Total training time: 15min
Outcome measures
TMS
Single pulse left FDI M1 (target muscle): Stimulator output
adjusted to elicit test MEP ≈ 0.5mV in peak-to-peak ampli-
tude. rMT and test MEP before + after manipulation/sham
and typing task
Functional
Response time and accuracy in test block before and after MA
TMS:
MEP amplitude before 0.67 ± 0.12mV and
after intervention: 0.64 ± 0.16mV. MEP
amplitudes: no interaction effects of
group vs. time (p = 0.3) or effects of time
(p = 0.3). rMT: no effects of group vs. time
(p = 0.7) of effects of time (p = 0.6)
Functional:
Neck pain + SM: reduced response time,
marginal increase accuracy
Neck pain + sham: moderate reduction
response time, improved accuracy
Healthy: marginally reduced response time,
no change accuracy
MEP amplitudes and rMT
did not change in any
group pre- to post-inter-
vention. The stimulator
output for the test MEP
was also the same pre- and
post-motor training
Neck pain group had subclinical
recurrent neck pain
Boudreau 2007 To determine if
i) short-term novel
tongue-protrusion
training in humans
is associated with
rapid neuroplasti-
city of the tongue
MI
ii) intra-oral tonic
pain affects
the tongue MI
neuroplasticity and
tongue-protrusion
training perfor-
mance
Healthy individuals
n:9
F/M: 2/7
Age: 24 (1.1) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1) TMS (baseline)
2) Experimental pain (capsaicin/ inert lotion)
3) Task training
4) TMS (post-training)
Experimental pain
Application area: tongue musculature
Capsaicin (cream) (n = 9)
Placebo (inert lotion) (n = 9)
Task
TPT: maintain cursor within moving target box displayed on
computer screen. Total training time: 15min
Outcome measures
TMS
Single pulse tongue M1 (target muscle) and FDI M1 (control
muscle): MT determined for relaxed muscles and defined as
lowest % TMS output that produced 5 out of 10 discernable
MEP for each muscle (i.e., 10uV for the tongue and ≥ 50uV
for the FDI). TMS-MEP stimulus–response curves con-
structed in increments of 10% threshold up to a maximum
of 85% TMS output. 10 stimuli delivered at each TMS
increment, ISI 8-10s. M1 excitability defined as relationship
between % TMS output required to elicit an MEP in both
muscles. TMS-MEPs were rectified and evaluated in terms
of the AUC. TMS-MEP stimulus–response curves before and
immediately after each task training session
Functional
Performance score (%) for maintaining cursor within target
box in TPT
TMS-MEP S-R curve:
Capsaicin: NS difference (p = 0.311)
Placebo: significant enhanced MEPs at 1.4
and 1.5 TMS intensity (p = 0.007 and
p = 0.005, respectively)
rMT: Capsaicin: 46.7 ± 3.3% vs 46.6 ± 3.7%
(p = 0.871)
Placebo: decrease 48.3 ± 4.1% vs 45.1 ± 3.4%
(p < 0.001)
NS difference pre-training TMS-MEP stimu-
lus response curves vehicle vs capsaicin
(p = 0.501)
Functional:
Significant increase with time for placebo
(p < 0.0001) and capsaicin (p < 0.012).
Compared to placebo, capsaicin had
significantly lower performance score with
less improvement
Additional outcomes:
Mean performance score for capsaicin TPT
session not significantly correlated to AUC
pain intensity (p = 0.91)
Short-term TPT is associated
with rapid neuroplasti-
city of tongue MI and
significant increases in
TPT performance, but the
presence of experimental
pain interferes with these
neuroplastic and perfor-
mance changes
The study also showed
that the perceived pain
intensity was not cor-
related to the overall mean
performance scores for the
capsaicin TPT session
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Brain Imaging and Behavior
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Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Dancey 2019 To determine the
interactive effect
of acute tonic
pain and early
motor learning on
corticospinal excit-
ability as measured
by TMS
Healthy individuals
n:24
F/M: 18/6
Age: 20.2 (1.3) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1) TMS, NPRS (baseline)
2) Experimental pain (capsaicin/ Inert lotion)
3) TMS, NPRS (post application)
4) Task training
5) TMS, NPRS (post-training)
6) Task training (24-48h from baseline (w/o capsaicin)
Retention
Experimental pain
Application area: Lateral aspect dominant elbow
Capsaicin (cream) (n = 12)
Placebo (inert lotion) (n = 12)
Task
Tracing sequences sinusoidal waves (varying amplitude and
frequency) on touchpad with dominant thumb. Training: pre-
test 4min, post-test 4min, retention 4min, MA 15min. Total
training time: 27min
Outcome measures
TMS
Single pulse dominant APB M1 (target muscle): rMT utilizing
lowest stimulatory intensity that in 5 of 10 sessions evoked
MEP of at least 0.05mV, while muscle was at rest. TMS-IO
curve intensity established using each participants rMT to
stimulate 90–140% of rMT in 10% increments. 12 stimuli
at each stimulus intensity with ISI 5s (72 stimuli / IO curve
session) TMS IO curves at baseline, post-application, and
following MA
Functional
Mean error (%) on motor task
TMS:
No effect of time on IO slopes following
capsaicin or placebo, or post MA
Significant increase in IO slope after motor
acquisition for control group. NS change
for capsaicin group
Functional:
Relative to the pre-test: both groups
decreased error post-MA and following
retention (all p < 0.001)
Placebo: 48.7% decrease in mean error post
MA, further 21.9% decrease at retention
Capsaicin: 35.2% decrease in mean motor
error following MA and a subsequent
10.7% decrease at retention
The acute tonic pain in this
study was shown to negate
the increase in IO slope
observed for the control
group despite the fact
that motor performance
improved similarly to the
control group following
acquisition and retention
Clearly there is a link
between motor and
sensory systems and the
effects of pain on motor
learning may be due to
cortico-thalamic, cortico-
cerebellar, or cortico–cor-
tico loops
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Brain Imaging and Behavior
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Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
De Martino
2018a
To investigate if
i) combined injec-
tion of NGF and
DOMS provokes
greater muscle
soreness and dis-
ability, increased
hyperalgesia,
and reduction
of maximal grip
force compared
with intramuscular
injections of NGF
alone,
ii) the sensorimotor
cortical neuroplas-
tic consequences
of muscle soreness
induced by DOMS
in a muscle pre-
sensitized by intra-
muscular injection
of NGF
Healthy individuals
NGF
n:12
F/M: 7/5
Age: 25.1 (1.6) yrs
NGF + DOMS
n:12
F/M: 7/5
Age: 26.7 (1.2) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
4 experimental sessions over 6days. Day-0, 2, 4 and 6:
1) Pain related questionnaires
2) TMS (Not Day 2)
3) Sensory and motor assessment: grip force, wrist extensor
force, and PPTs
Experimental pain
Both groups: NGF injection right ECRB muscle at end of ses-
sion Day-0, 2 + 4
NGF + DOMS group Day-4: eccentric exercise before receiving
NGF injection to provoke DOMS
Task
Right hand eccentric contractions from maximally extended
wrist position to maximally flexed wrist position, duration of
at least 4s while holding a weight (max 25kg). Sets of 5 rep-
etitions. First set, 90% of MVC repeated until participant was
not able to control the eccentric contraction over 4s. Load
then progressively reduced in steps of 10% MVC ending at
load of 50% MVC in final set
Outcome measures
TMS
Single pulse ECRB M1 (target muscle): rMT threshold defined
as intensity at which 5 of 10 stimuli evoked MEP with ampli-
tude of at least 50 uV while muscle was in rest. Stimulus
intensity set at 120% rMT. Motor cortical map representing
the ECRB activation recorded based on MEPs evoked every
6s with a total of 5 stimuli at each site on the stimulation
grid. All grid sites randomly stimulated from the hotspot
until no MEP was recorded (defined as < 50uV) in all five
stimuli at all border sites. If average peak-to-peak amplitude
of 5 MEPs evoked at site was greater than 50 uV, site was
considered active. Map volume calculated as sum of MEPs
from active sites. CoG defined as the amplitude-weighted
center of the map
TMS:
Map volume: Progressive increase Day-0 to
4 in both groups (p < 0.01). Day-6, NGF
group increase compared with Day-0,
(p < 0.01), NGF + DOMS g roup reduction
compared with Day-4 (p = 0.01)
MEP: Compared with Day-0, number of
active sites and MEP amplitudes on hot
spot increased Day-4 (p < 0.01) and Day-6
(p < 0.02)
No difference in rMT (p = 0.5), longitude or
latitude center of gravity (CoG) (p = 0.55)
and p = 0.07, respectively) between groups
and days
NGF induced soreness
extended the ECRB motor
map which subsequently
was depressed by DOMS
De Martino
2018b
To assess changes
in sensorimotor
cortical excitability
during experimen-
tal muscle soreness
across several days
provoked by eccen-
tric exercise of
wrist extensors
Healthy individuals
n:12
F/M: 6/6
Age: 24 (3.2) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
5 experimental sessions over 6days. Training session (day
before baseline) not analyzed
Day 0 (baseline):
1) Pain related questionnaires and TMS
2) Max grip force and max wrist extension force, PPT as
baseline
3) Eccentric exercise right wrist extensor muscles to induce
DOMS
4) 2h after eccentric exercise: postexercise session on the same
day and TMS measures performed after
Day 2 and 6: Data collection repeated
Experimental pain and task
See De Martino 2018a (same task but no NGF injections)
Outcomes measures
TMS
See De Martino 2018a
TMS:
Number of active sites and map volume
significantly reduced at 2-h and day 2
compared with baseline (p < 0.001 and
p < 0.0026, respectively). The map area
still reduced at Day 6 compared with
Baseline (p = 0.026)
NS effects for: rMT (p = 0.16), MEPs
(p = 0.3), number of discrete peaks
(p = 0.33), and position of CoG (long
p = 0.41 lat p = 0.27)
DOMS is associated with
decreased number of MEP
active sites and motor map
area of the affected muscle
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Hoeger Bement
2014
To assess corticomo-
tor excitability
in fibromyalgia
during a noxious
stimulus before
and after fatiguing
exercise and exam-
ine associations
with pain percep-
tion
Fibromyalgia
n:15
F/M: 15/0
Age: 53.7 (9.9) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
3 sessions: 1 familiarization, and 2 experimental
Familiarization session: subjects introduced to pressure pain
device and TMS
Randomized experimental sessions (S1, S2)
NRS and TMS before and after: (S1) 30min rest or (S2) Task
training
Experimental pain
Noxious stimuli with pressure pain device on right index finger
Task
Submaximal isometric contraction left elbow flexor muscles
until task failure or patient required to stop
Outcome measures
TMS
Single pulse left brachioradialis muscle M1 (target muscle):
MEP determined by stimulating the motor cortex at intensity
40–70% of MSO that produced MEP in the muscle at least
3 of 6 trials. Stimulation intensity 120% of the MEP. TMS
delivered in sets of 4 pulses (3s apart) at 6 separate time
points before and after task training or rest. TMS before and
after rest/contraction at 6 time points: before, start of pain
test, midpoint of pain test, before end of pain test, immedi-
ately after pain test and 30s after pain test
TMS:
MEP amplitude:
No changes during pain test in rest or task
sessions (p = 0.45)
After training, significant decrease during
and immediately after pain test compared
with baseline: 0s (p = 0.03), 50s
(p = 0.006), 110s (p = 0.01) and immedi-
ately after pain (p = 0.05)
No differences for other time points or for
rest sessions
Decrease in mean MEP
amplitude but an interac-
tion between pain response
after exercise and pain
induced changes in MEPs
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Ingham 2011 To investigate if pain
interferes with
plasticity, affecting
acceleration of
finger movement
when the training
task is painful,
despite control
of training task
performance
Study population:
Healthy individuals
n: 9
F/M: 6/3
Age: 21.4 (2.3) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
3 separate experimental sessions:
1) Injection of saline
2) TMS (baseline)
3) Task training (block 1–3) 1 block: 8 sets × 50s, 10s rest
between sets for NRS
4) TMS after each task training block
5) TMS 5, 10 and 15-min post-training
Experimental pain model
Local pain: HS injection in trained FDI
Remote pain: HS injection in infrapatellar fat pad on knee
Control: IS injection FDI
Task
Brisk movements right index finger in opposite direction to
TMS evoked movement. Each training set 50s, followed by
10s rest to minimize risk for fatigue. Total training time:
8min including 80s rest
Outcome measures
TMS
Single pulse right FDI M1 (target muscle) and finger extensor
M1 (control muscle): Stimulation intensity required to elicit
MEPs in FDI with observed finger movement towards the
thumb in 5 consecutive stimuli determined. Stimulation
intensity set at 120% of this value, as this intensity provides
consistent MEPs in the test muscle. 10 stimulations admin-
istered at baseline and after each of the 3 training sessions.
Three additional blocks of stimuli delivered after training
(5, 10 and 15min). Peak amplitude of TMS-induced finger
acceleration compared between conditions and between times
Functional
Number of finger movements and peak acceleration
TMS:
TMS evoked peak acceleration after training
was reduced in FDI pain and control
following 3rd training and 1st recovery
session (both p < 0.001) with no difference
between FDI pain and control (p > 0.189)
No difference in latency to onset of MEP
amplitude between conditions (p = 0.94) or
following training (p = 0.80)
No difference MEP amplitude between
conditions (p = 0.94) or following training
(p = 0.16)
Functional:
Number of finger movements similar
between sessions (p = 0.1). Peak accel-
eration increased during training and
improvement rate was similar in all condi-
tions (p = 0.65)
There was no change in FDI
MEPs in any conditions.
These data do not support
direct effects of pain on
training-induced plasticity
of corticomotor pathways
Remote pain may com-
promise learning due to
distraction from the train-
ing task or other complex
central pain processes
Small group (n = 9)
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Massé-Alaire
2017b
To determine
whether combining
RPMS and motor
training of the
superficial MF
better improved
the corticomotor
control of spine
than training alone
in chronic low
back pain
Study population:
Back Pain
n:21
F/M: 10/11
Allocated to:
RPMS
Age: 33.2 (10.8) yrs
n = 11 (2 dropouts)
Sham
Age: 42.1 (17.2) yrs
n = 10 (1 dropout)
Study setting:
Neurostimulation labora-
tory
Study design:
Experimental study
Experimental protocol
Task performed twice a day at home and 3 lab sessions (S1, S2,
S3) over 1week with intervention (RPMS) or sham before
performing task supervised
S1 and S3: 1) TMS, APA, muscle activation, VAS (baseline)
2) Task training and RPMS (n = 11) or Sham (n = 10)
3) TMS, APA, muscle activation, VAS (post-training)
S2: 1) Task training and RPMS (n = 11) or Sham (n = 10)
Task
Isometric contraction lumbar MF (attention contraction deep
MF, minimal activation of superficial MF and adjacent
erector spinae)
Outcome measures
TMS
Single pulse MF M1 (target muscle): AMT defined as TMS
intensity eliciting at least 5 measurable MEP in the pre-
activated MF, out of 10 trials
Paired pulse MF M1 (target muscle): SICI probed by condition-
ing TMS (70% AMT) and test TMS at 120%. AMT; two ISI
were tested with the conditioning TMS delivered 2ms and
then 3ms before the test. SICF probed by conditioning TMS
(90% AMT) delivered 1ms after a test TMS at 100% AMT.
In each paradigm, 8–10 unconditioned (test) MEP and 8–10
conditioned MEP were elicited
For each participant, amplitudes of test MEP matched between
pre-intervention at S1 and other time points (adjustment test
TMS intensity) to ensure valid comparisons of conditioned
MEP amplitudes
Functional
Onset of activation for each muscle and onset of APAs
TMS:
Sham: No effects were detected in TMS
outcomes
Functional:
Sham: Earlier APA at S3 compared to S1
(0.008)
Task training in the presence
of chronic low back pain
had no effect on any TMS
measure
Small group (n = 9) with chronic
low back pain
Only results from the sham group
eligible in the present review
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Massé-Alaire
2016
To compare the
effects of isometric
activation (ISOM)
of deep multifidi
muscles (MF) and
global activation
of paravertebral
muscles (GLOB)
on MF postural
activation and
M1 function in a
chronic low back
pain population
Study population:
Back Pain
n:22
F/M: 8/ 14
Allocated to:
GLOB
Age 45.4 (18.1) yrs
n = 11 (1 dropout)
ISOM
Age: 35.1 (11.4) yrs
n = 11
Study setting:
Neurostimulation labora-
tory
Study design:
Experimental study
Experimental protocol
Task performed twice a day at home and 4 experimental ses-
sions (S1-4) over 3weeks (W1-W3)
S1 (W1): 1) TMS, APA, VAS (baseline S1)
2) Supervised task training: ISOM/GLOB
S2-S3 (W2): 1) Supervised task training: ISOM/GLOB
S4 (W3): 1) TMS (baseline S4)
2) Supervised task training: ISOM/GLOB
3) TMS, APA, VAS (post task)
Task
GLOB: global activation of paravertebral muscles (hip exten-
sion); ISOM: Isometric contraction lumbar MF (attention
contraction deep MF, minimal activation of superficial MF
and adjacent erector spinae)
Outcome measures
TMS
AMT, SICI, SICF (same as Massé-Alaire 2014)
Paired pulse MF M1 (target muscle): LICI: conditioning TMS
120% AMT; 100ms later test TMS 120% AMT. LICF:
conditioning TMS (80% AMT); 15ms later test MEP 120%
AMT. In each paradigm, 8–10 unconditioned (test) MEP and
8–10 conditioned MEP were elicited
For each participant, amplitudes of test MEP were matched
between pre-intervention at first session (S1) and other time
points (adjustment of test TMS intensity) to ensure valid
comparisons of conditioned MEP amplitudes
Functional
Two rapid limb movements: bilateral shoulder flexion and
unilateral hip extensions to study APA latency of MF, TrA/
IO and EO muscles. Onset of activation determined by visual
inspection and onset of APAs
TMS:
AMT significant decrease for post-
S4 (48.6 ± 11.7% MSO) vs. pre S4
(51.1 ± 11.4% MSO). No p-values
reported, no between-group difference
Ln-transform MEP amplitude, based on
analysis n = 10 GLOB and n = 9 ISOM
due to TMS artefacts: ISOM: significantly
decreased S1 vs post S4 (p = 0.006) and
pre-S4 vs post-S4 (p = 0.015). GLOB: no
change (p > 0.05)
Normalized SP duration: based on analysis
n = 7 GLOB (not presented) and n = 9
ISOM due to EMG problems: ISOM: sig-
nificant effect of time (p = 0.03), but not in
pairwise comparisons between individual
time points (S1 vs. pre-S4: p = 0.08; pre-
vs. post-S4: p = 0.14)
Functional:
Bilateral shoulder flexion task:
ISOM: significant effect of Time (p = 0.006);
earlier MF-S onset at post-S4 than at
S1 (p = 0.02), not changed in GLOB:
(p = 0.73)
Prone hip extension task: Group vs. Time
interaction for MF onset. GLOB: NS
difference
ISOM: main effect of Time (p = 0.04) with
MF-S onset earlier at post-S4 than at S1
Exercise decreased AMT in
back pain patients. Iso-
metric exercise modulated
cortical inhibition and
corticospinal excitability
with
decrease in MEP amplitude
Small groups analysed (n = 7 to
n = 10)
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Mavromatis
2017
To assess the
effect of pain on
changes in motor
performance and
corticospinal
excitability during
training of a novel
motor task
Study population:
Healthy population
Allocated to:
Capsaicin
n:15
F/M: 6/9
Age: 26 (6) yrs
Control
n:15
F/M: 9/6
Age:27 (6) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1) TMS (baseline 1)
2) Experimental pain (Capsaicin/ placebo cream)
3) TMS (baseline 2)
4) Task training (10 blocks)
5) TMS assessed after each training block; SICI assessed at
halfway point and at end of training
Experimental pain
Application area: lateral border of the first metacarpal
Capsaicin (cream) (n = 15)
Placebo (inert lotion) (n = 15)
Task
Pinching force transducer between right thumb and index
finger. Single session of 10 training blocks, measures early
(1–2), mid (5–6) and late (9–10) training block. Each block
with 15 continuous sequences
Outcome measures
TMS
Single pulse FDI M1(target muscle): Intensity set to evoke
average MEP of approximatively 1mV with muscle fully
relaxed (mean of 15 MEPs). AMT assessed with contraction
of 5% of MVC, defined as the intensity that produced at least
5/10 MEPs with amplitude greater than 10% of the mean
background EMG
Paired pulse TMS for right FDI M1 (target muscle): SICI
assessed with conditioned stimulus at 90% of AMT, intensity
similar to the one used for single pulse measurements and
kept throughout the entire experiment
Task performed after second baseline measurements and after
each training block, 15 single-pulse MEPs were recorded.
SICI recorded halfway (block 5) and at end of the motor
learning (block 10)
Functional
Movement time, accuracy and skill measure
TMS:
MEP amplitudes
Placebo: Increase between early- and mid-
training periods (p = 0.005), followed by
return to baseline in late training period
(p = 0.995)
Capsaicin: No increase from early- to mid-
training (p = 0.713). No significant differ-
ences between any time periods
SICI over time during motor training
revealed NS effect of group (p = 0.319),
time (p = 0.717) or group x time interac-
tion (p = 0.983)
Functional:
Both groups performed the task faster with
training (p < 0.001), showed a significant
improvement over time (p < 0.001), and
with
similar rate of improvement (p = 0.573)
Subjects in the capsaicin group performed
better throughout the training period
(p = 0.029)
Pain did not negatively
impact the acquisition
of a novel motor task,
however, it did have a
negative effect on the
training-related increase in
corticospinal excitability
observed in the control
group
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Mendonca 2016 To determine the
clinical and
neurophysiologi-
cal effects of the
combination of
tDCS and AE on
a treadmill over
1month to gener-
ate results of a new
intervention and
to understand how
modulation of the
M1 circuit leads to
pain control
Study population:
Fibromyalgia
n: 45
F/M: 44/1
Age: 47.8 (12.1) yrs
Allocated to:
tDCS + AE n:15
AE n:15
tDSC n:15
Study setting:
University laboratory
Study design:
Clinical, randomized,
double-blind study
Experimental protocol
4-week task period: 5days of training week 1, and 3days of
training week 2–4
1) NRS (pain and anxiety levels), PPT, QOL, mood, TMS
(baseline 1week before training task)
2) Task training
3) All variables after the fifth day of intervention
4) Task training
5) After task (T2)
6) Follow ups (1-month + 2-months post-training)
Task
AE treadmill: Intensity 60% of max heartrate week 1 and if
possible 70% of max heartrate week 2
AE sham treadmill: 5% of resting heartrate maintained at
minimum speed
Total training time: 30min per session
tDCS + AE: active intervention of aerobic exercise train-
ing + tDCS
AE: active intervention of aerobic exercise + placebo tDCS
tDCS: placebo AE + active intervention for tDCS
Outcome measures
TMS
Single pulse right adductor muscle of the thumb M1 (target
muscle): MT lowest intensity for TMS pulse to generate
peripheral response of at least 50mV of amplitude. Same
method used to determine MEP at 120% of the intensity
found for the MT. 10 MEPs measured at each stage
Paired pulse right adductor muscle of the thumb M1 (target
muscle): ICF conditional pulse with intensity of 80% of the
MT and test pulse with the MEP intensity. ISI 10ms. ICI:
same parameters but 2ms ISI. 15 measures of ICF and ICI
each, randomized between inhibition, facilitation and ME,
totaling 45 pulses
TMS:
NS effects found for any TMS outcomes for
any group
Task training in the pres-
ence of fibromyalgia had
no effect on any TMS
measure
Only results from AE group eligi-
ble in the present review
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Parker 2017 To i) provide a
thorough analysis
of corticomotor
and intracortical
excitability in peo-
ple with chronic
arthritic hand
pain ii) examine
the relationship
between these
measures and
performance on a
motor skill learn-
ing task
Study population:
Arthritic hand pain
n: 23
F/M: 17/5
Age: 72 (6) yrs
Healthy controls
n: 20
F/M: 14/6
Age: 71 (7) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1)TMS (baseline)
2)Task training
3) TMS (0- and 10-min post-training)
Task
30-min voluntary finger twitches with auditory cue to target
direction (opposite direction to baseline TMS induced finger
twitches). Total training time: 30min
Outcome measures
TMS
Single pulse FDI M1 (targeted muscles): rMT defined as mini-
mum stimulus intensity that elicited MEP with peak-to-peak
amplitude of at least 50uV in a minimum of 4 out of a train
of 8 stimuli, established by increasing stimulus intensity in
5% increments until MEPs were elicited, and then adjusted
intensity in 1% intervals until rMT was determined. S-R-
curve obtained by delivering 80 stimuli at 10% increments
from 90 to 160% rMT, with 10 stimuli at each intensity
Paired pulse TMS FDI M1 (target muscle): A block of 60 test
stimuli delivered over the hot spot. 10 stimuli delivered for
each condition. Two SICI assessed at 70% and 80% rMT
and the test stimulus was 1mV with an ISI of 2ms. Two
SICF assessed with conditioning stimuli being 1mV and
test stimulus 90% rMT with an ISI of 1.4ms and 2.8ms.
LICI assessed with conditioning stimuli being 120% rMT
and test stimulus was 1mV with ISI of 99ms. CSP assessed
with 10% MVC of FDI. 10 stimuli delivered at 120% rMT.
Duration of silent period measured from MEP onset, when
EMG exceeded baseline level, until EMG activity reached/
exceeded prestimulus baseline level for at least 50ms
Functional
Difference in % accurate twitches between the first and last 10%
of twitches
TMS:
Arthritis: less SICI (0.98 ± 0.86 vs
0.57 ± 0.36) and greater SICF (5.4 ± 7.0
vs 2.1 ± 1.3) compared with healthy (both
p = 0.03)
No other significant differences in stimulus
response, paired pulse, or cortical silent
period
Functional:
No difference number of performed training
twitches (arthritis: 755 ± 24; control:
749 ± 14; p = 0.3), magnitude of twitches
(p = 0.6), or overall accuracy of training
twitches (arthritis: 71% ± 21; control:
75% ± 21; P = 0.6)
Arthritis: significantly lower number of
accurate voluntary twitches (54% ± 30) in
first 10% of trials compared with healthy
(72% ± 42; p = 0.05)
No difference in accuracy in last 10% of tri-
als (arthritis: 72% ± 26; control: 72% ± 42;
p = 0.98); however, change in accuracy
from first to last 10%, reflecting skill
learning, significantly greater for arthritis
(18% ± 25) compared with Healthy
(0% ± 43; p = 0.02)
Greater training-induced
motor cortex reorganiza-
tion was observed in
people with hand pain due
to arthritis compared to
controls
There was no evidence that
these changes in cortical
excitability are
related to impaired motor
function or skill learning
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Rittig-Rasmus-
sen 2014a
To investigate
i) neuroplastic
changes of corti-
comotor pathways
induced by neck
training in patients
with chronic neck
or knee pain and
in pain-free partici-
pants performing
no training
ii) the effect of pain
and training on
motor strength
performance,
motor learning
capabilities,
muscle fatigue,
pain experience
and pain
catastrophizing
Study population:
Neck pain
n:20
F/M:6/14
Age: 29 (7) yrs
Knee pain
n:15
F/M: 5/10
Age: 27 (6) yrs
Healthy controls
n: 15
F/M: 3/12
Age: 25 (3.5) yrs
Study setting:
University laboratory
Study design:
Randomized study
Experimental protocol
2 experimental session (S1 and S2)
S1: 1) TMS (baseline)
2) Task training
3) TMS (30min and 1h post-training)
S2: 1) TMS (1-week post -training)
Task
Pain groups: 20min upper trapezius training: elevating and
lowering right shoulder 70 times in an ascending /descending
movement path (moving a line displayed on the screen of
a feedback system) with a load of 10% of maximal lifting
capacity. Total training time: 20min
Healthy: no training
Outcomes measures
TMS
Single pulse right trapezius muscle M1(target muscle) and right
APB M1 (control muscle): MT set as minimum stimulus
intensity that produced 5 discrete MEPs (> 50 uV). MT and
TMS intensity were determined and stimuli were equivalent
to 120–140% of the individual MT. Stimuli repeated approxi-
mately 4–6 times with increasing intensity until no further
increase in amplitude was obtained and then 10 stimuli were
delivered with 5-to 10-s ISI and averaged. Amplitudes and
latencies of MEPs recorded at baseline and post task (30min,
1h, 7days) from trapezius muscle and APB as control
Functional
Deviation from feedback curve between the first 5 and last 5
repetitions (of the total 70) only for the pain group
TMS:
MEP amplitudes compared with baseline:
Neck pain: significantly decreased at 30min
(p < 0.05), NS difference at 1h and 1week
Knee pain: significantly increased at 30min
and 1h (p < 0.01) but not after 1week
Healthy: NS at any time point
Comparison between groups:
Neck pain NS compared with other two
groups (mean 1.57mV ± 0.66)
Healthy Higher mean amplitudes (mean
1.95mV; 95%) compared to Knee pain
(mean 1.31mV; 95%) (p < 0.05)
No difference for APB in any group. No
difference in MEP latencies for trapezius
or APB in any group over time
Between baseline and 30min, MEP ampli-
tudes reduced: 18% in neck pain group,
28% in pain-free group; increased 36% in
knee pain group
Functional:
Motor learning improved significantly in
both pain groups. Neck pain + training
8.5% (p < 0.001) and knee pain + training
6.2%(p < 0.001)
Neck training reduced neu-
roplastic responsiveness
of corticomotor pathways
in neck pain patients in
contrast to knee pain
patients and pain-free
participants
Rittig-Rasmus-
sen 2014b
To investigate the
interaction between
experimental neck
pain and training
and the effect on
corticomotor excit-
ability
Study population:
Healthy population
n: 52
F/M: 31/21
Age: 23 (2) yrs
20—32
Study setting:
University laboratory
Study design:
Randomized study
Experimental protocol
2 experimental sessions (S1 and S2) (see Rittig-Rasmussen
2016a)
Experimental pain model
HS injection neck + training (n = 20)
IS injection neck + trapezius training (n = 20)
Control: HS injection neck, no training (n = 12)
Task
See training task Rittig-Rasmussen 2014a
Outcomes measures
TMS/ functional
See Rittig-Rasmussen 2014a
Functional
See Rittig-Rasmussen 2014a
Both training groups
TMS:
Trapezius MEP amplitudes compared with
baseline:
HS + training: significantly decreased
30min, 1h, and 1week (p < 0.0001)
IS + training: significantly increased 30min,
1h, and 1week (p < 0.0001)
HS: significantly decreased 30min and 1h
(p < 0.001)
No difference for APB in any group
MEP latencies compared with baseline:
trapezius NS for any group (p = 0.075)
APB: HS + training: significantly increased
(0.19ms) at 1h (p < 0.01)
IS + training: NS difference (p = 1.71)
HS: significantly increased 1h (p < 0.01)
Functional:
Motor learning improved significantly
in both groups HS + training: 4.5%
(p < 0.001) IS + training: 6.2% (p < 0.001).
NS between groups
The results infer that pain
and concomitant training
induce an enhanced and
sustained inhibition of
MEP amplitudes lasting
for one week. Suggesting
that motor training should
be conducted in a pain-
free manner as pain is an
important factor in deter-
mining training-induced
corticomotor excitability
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Schwenkreis
2011
To assess ICI during
fatiguing muscle
exercise in healthy
humans and
patients with Mus-
cular dystrophy
and Fibromyalgia
syndrome to
obtain insight into
differential central
mechanisms
Study population:
Healthy population
n: 23
F/M: 16/7
Age: 37.7 (11.5) yrs
Muscular dystrophy
n:23
F/M: 2/21
Age: 41 (10.4) yrs
Fibromyalgia
n:16
F/M: 14/2
Age: 48.7 (8.4) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
1) TMS (baseline)
2) Task training
3) TMS (0- and 40-min post-training)
Task
Fatiguing muscle exercise by repeating right hand grip, 50%
of maximum voluntary strength at a frequency of 1–2/s until
they could no longer attain this force level
Outcome measures
TMS
Single pulse right superficial flexor muscle of the forearm M1
(target muscle): Stimulus intensity adjusted to evoke a MEP
of approximately 0.5 mv
Paired pulse stimulation TMS for right superficial flexor muscle
of the forearm M1 (target muscle): Test stimulus adjusted
to evoke a MEP of approximately 0.5mV; conditioning
stimulus set at 80% of the individual MT. ISI at 2, 4, 10,
and 15ms. ICI at 2ms and 4ms, and ICF at 10ms and
15ms tested in resting muscle. CSP: to measure activity of
subpopulation of intracortical inhibitory interneurons. CSP
duration measured from the end of the MEP (onset of EMG
suppression) until first re-occurrence of voluntary EMG
activity
TMS:
Healthy: significant difference MEP
amplitudes between measures (p = 0.016).
Significantly lower MEP amplitudes when
comparing post-exercise vs. baseline
(395.7 ± 303.8 uV vs. 534.8 ± 302.8 uV,
p = 0.017) and with post40 (506.3 ± 363
uV p = 0.020)
ICI differed significantly between measures
(p = 0.019). Significantly decreased ICI, as
indicated by an increased amplitude ratio
post-exercise vs. baseline (50.0 ± 24.8%
vs. 40.2 ± 15.4%, p = 0.029). ICF and CSP
showed NS difference between measures
Muscular dystrophy: NS between measures
Fibromyalgia: ICI differed significantly
between measurements (p = 0.032). Sig-
nificant increase in ICI at post40 vs. post-
exercise (49.2 ± 2 4.0% vs. 63.5 ± 36.0,
p = 0.041). MEP amplitudes, ICF, and CSP
were NS between measures
Fibromyalgia patients had
lower ICI at baseline com-
pared to healthy, but ICI
increased after training
Tsao 2010 To examine whether
motor training
can induce changes
in motor cortical
organization and
whether such
changes, if present,
are associated
with changes in
postural activation
of the trained
muscles
Study population:
Lower back pain
Allocated to:
Training
n:10
F/M: 6/4
Age: 24 (8) yrs
Control
n:10
F/M: 5/5
Age: 23 (3) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
Two experimental sessions: before and after 2weeks of task
training
1) TMS + single rapid arm movements (baseline)
2) Task training (n = 10) or Control (n = 10)
3) TMS + single rapid arm movements (post-training)
Task and training
Skilled training at home (isolated voluntary contractions of
transversus abdominis (TrA), control intervention of self-
paced walking exercise for 2weeks
Outcomes measures
TMS
Single pulse TrA M1(target muscle): 5 stimuli at 120% AMT
delivered over each scalp site during 10% MVC with an ISI
of at least 5s. If 120% AMT exceeded MSO, stimulation
intensity for mapping was set to the MSO
Functional
Motor coordination assessed pre- and post-training using a
rapid arm movement paradigm to induce postural challenges
to the body
TMS:
Motor cortical map:
Training: anterior/medial shift over both
hemispheres (p < 0.016)
Control: No change in motor cortex represen-
tation (p > 0.57)
No difference map volume between groups
(p = 0.25) or after training (p = 0.30)
MT not different between the left and right
TrA (Double-cone coil: muscle p = 0.86;
Figure-of-eight coil: muscle p = 0.85)
No differences in MTs between groups prior
to (p = 0.33), or pre- and post-training
(p = 0.052). NS correlation between
changes onset of TrA EMG and changes
MTs (all r2 < 0.026, p > 0.35)
Functional:
Training induced earlier postural activa-
tion of TrA (interaction Time/Training:
p < 0.001). No change in muscle activation
following walking exercise (p = 0.86)
Motor skill training induced
an anterior and medial
shift in motor cortical
representation of TrA in
patients with back pain.
This shift was associated
with earlier postural
activation of TrA
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Brain Imaging and Behavior
1 3
Table 3 (continued)
First author
Year Aim Study population
Number
Female/Male
Age: Mean (SD)
Study setting
Study design
Methods Results
Primary outcomes: TMS
Secondary outcomes: Functional
Study summary related to
training and pain Comments
Vallence 2013 To determine if
neuroplasticity
would be exag-
gerated in CTTH
patients compared
to healthy controls,
which might
explain (in part)
the development
of chronic pain in
these individuals
Study population:
CCTH:
n:11
F/M: 6/5
Age: 35 (13.2) yrs
Healthy controls:
n:18
F/M:11/7
Age: 23 (8) yrs
Study setting:
University laboratory
Study design:
Experimental study
Experimental protocol
Single experimental session
1) TMS (baseline)
2) Task training
3) TMS (0, 5-, 10-, 20- and 30-min post-training)
Task
2 blocks of 225 thumb abduction (9 sub-blocks each with 25
abductions), with 5min rest between the 2 blocks. Paced
metronome 0.25Hz
Total training time: 35min including 5min of break between
two blocks
Outcome measures
TMS
rMT: before and 2min after task training protocol
Single pulse APB M1: Blocks of 15 single-pulse TMS trials
with an inter-trial interval of 7s (10%), at baseline and at 0,
5, 10, 20 and 30min after the end of task training protocol
Functional
Peak acceleration of initial abduction movement after cue
calculated for each trial (m/s2). Changes in mean peak accel-
eration with motor training
TMS:
MEP amplitude after training:
No significant change in rMT for CTTH or
controls (both p > 0.05). Significant effect
of time for controls (p < 0.05) but not
CTTH (p > 0.05); significant increase in
MEP amplitude after motor training for
controls
Controls: MEP amplitude was significantly
increased 10- and 20-min post-training
(p < 0.05). 30min after training, MEP
amplitude had returned to baseline levels
(p > 0 0.5)
Functional:
Greater increase in acceleration with motor
training in healthy controls than CTTH;
controls significantly greater mean peak
acceleration in sub-blocks 3–9 and 12–18
(both p < 0.05)
Individuals with CTTH
showed significantly less
motor learning on the
training task than healthy
controls, suggesting a
deficit in use-dependent
neuroplasticity within net-
works responsible for task
performance in patients
with CTTH
CBI, cerebellar inhibition; MA, motor acquisition task; TMS, transcranial magnetic stimulation; FDI, First dorsal interosseus; MEP, Motor Evoked potential; rMT, Resting motor threshold;
RCT, Randomized clinical control trial; TPT, Tongue-protrusion task; AUC, Area under the curve; NRS, Numeric pain rating scale; IO, input–output; APB, abductor pollicis brevis; NGF,
Nerve growth factor; DOMS, Delayed onset muscle soreness; PPT, Pressure pain thresholds; CoG, Center of gravity; ECERB, extensor carpi radialis brevis; MSO, maximum stimulator output;
HS, Hypertonic saline; IS, Isotonic saline; APA, Anticipatory postural activation; RPMS, Repetitive peripheral magnetic stimulation; MF, multifidus muscle; VAS, Visual analog scale; AMT,
Active motor threshold; MSO, Maximal stimulation output; ICI, Intracortical inhibition; ICF, intracortical facilitation; tDCS, transcranial direct current stimulation; QOL, Quality of Life, AE,
Aerobic exercise ICI: intracortical inhibition; ISI, interstimulus intervals; CSP, Cortical silent period; APB, Abductor pollicis brevis; CTTH, Chronic tension-type headache; PB, abductor pol-
licis brevis; MT, Motor threshold; SICI, Short interval intracortical inhibition; SICF, Short interval intracortical facilitation; LICI, Long interval intracortical inhibition; LICF, Long-interval
intracortical inhibition facilitation
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Brain Imaging and Behavior
1 3
remaining studies focused mainly on the spinally-innervated
upper extremities (hands/arms) and most often involved
training in different finger tasks (n = 6). These finger tasks
included: typing letter sequences on a keyboard (Baarbe
etal., 2018), tracing sinusoidal waves on a touchpad with
dominant thumb (Dancey etal., 2019), brisk movements
with the index finger in the opposite direction to the twitches
evoked by TMS (Ingham etal., 2011), pinching a force trans-
ducer (Mavromatis etal., 2017), voluntary finger twitching
(Parker etal., 2017) and thumb abduction in response to an
auditory cue (Vallence etal., 2013).
Six of the seven acute pain studies (Boudreau etal.,
2007; Dancey etal., 2019; De Martino, Petrini, etal.,
2018; De Martino, Zandalasini, etal., 2018; Mavroma-
tis etal., 2017; Rittig-Rasmussen etal., 2014b) and five
of the ten chronic pain studies (Hoeger Bement etal.,
2014; Masse-Alarie etal., 2016; Rittig-Rasmussen etal.,
2014a; Schwenkreis etal., 2011; Vallence etal., 2013)
showed that acute and chronic pain impede trainings-
induced functional neuroplasticity otherwise observed in
the primary motor cortex (e.g., increased corticomotor
excitability).
In terms of motor performance, only five of the seven
studies that induced acute pain evaluated subsequent
changes in motor performance (Boudreau etal., 2007;
Dancey etal., 2019; Ingham etal., 2011; Mavromatis etal.,
2017; Rittig-Rasmussen etal., 2014b). Two of these five
studies (Boudreau etal., 2007; Ingham etal., 2011) showed
that pain in the region being trained (i.e., tongue and finger,
respectively) had a negative effect on the training-induced
motor performance gain (i.e., tongue protrusion and fin-
ger abduction, respectively). The remaining three studies
(Dancey etal., 2019; Mavromatis etal., 2017; Rittig-Ras-
mussen etal., 2014b) did not demonstrate any differences
between pain and control groups.
For the chronic pain studies, only five of the ten studies
(De Martino, Petrini, etal., 2018; De Martino, Zandalasini,
etal., 2018; Hoeger Bement etal., 2014; Mendonca etal.,
2016; Schwenkreis etal., 2011) evaluated motor perfor-
mance in comparison to pain-free control groups. Four of
these studies did not show any conclusive findings whereas
one study on chronic headache showed greater improvement
in a thumb abduction motor task in the pain-free control
group (Vallence etal., 2013).
Table 4 Risk of bias in included
studies (n = 17) assessed with
a modified Newcastle–Ottawa
Scale for case–control studies
S – Selection of case and control; C – Comparability of cases vs control; E – Exposure
S1: Case Definition; S2: Case Representativeness; S3: Control Selection; S4: Control Definition. C1a: Age;
C1b: Other factors. E1: Assessment; E2: Same method cases and controls; E3: Nonresponse rate
* Please note that per the definitions of the criteria in the Newcastle–Ottawa scale studies without a control
group cannot achieve scores for items S3, S4, C1a, C1b, E2 and E3. We have therefore modified the scale
by adding a score (in brackets) for internal control groups
First author Year Selection Comparability Exposure Total
Assessment Category S1 S2 S3 S4 C1a C1b E1 E2 E3
Experimental pain in healthy (n = 7)
Boudreau 2007* - - (★) (★) (★) (★) 3 (4)
Dancey 2019 -★ ★ ★ ★ ★ 8
De Martino 2018a* - - (★) (★) (★) (★) -2 (4)
De Martino 2018b* - - (★) (★) (★) (★) -2 (4)
Ingham 2011* - - (★) (★) (★) (★) -2 (4)
Mavromatis 2017 - - ★ ★ ★ ★ 7
Rittig-Rasmussen 2014b* -(★) (★) (★) (★) (★) (★) 2 (6)
Chronic pain population (n = 10)
Baarbe 2018 - - ★ ★ -6
Hoeger Bement 2014* - - (★) (★) (★) (★) 2 (4)
Massé-Alaire 2017b* -(★) (★) 6 (2)
Massé-Alaire 2016* -(★) (★) ★ -5 (2)
Mendonca 2016 -★ ★ ★ -7
Parker 2017 9
Rittig-Rasmussen 2014a -★ ★ ★ -7
Schwenkreis 2011 - - ★ ★ - ★ ★ 6
Tsao 2010 - - ★ ★ -6
Vallence 2013 - - ★ ★ -6
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Brain Imaging and Behavior
1 3
Risk ofbias assessment
The risk of bias as assessed with the use of NOS is pre-
sented in Table4. Lower scores were generally associated
with study design and often with lack of inadequate control
groups. Therefore, we added a modified score for internal
control groups. For the assessment with the TMS checklist
the average quality score was 72% (range 54—90%), for
reported factors and 65% (range 38 – 83%) for controlled
factors (Table5). All studies scored over 50% for factors
that should be reported and only three studies scored less
than 50% (Baarbe etal., 2018; Hoeger Bement etal., 2014;
Mendonca etal., 2016) for factors that should be controlled.
However, none of the included studies were rated as having
an overall high risk of bias and all studies were retained for
the qualitative synthesis.
Meta‑analysis
When all included papers were assessed for the possibility of
a quantitative analysis, there was a lack of studies reporting
central and dispersion measures for comparable outcomes.
Two studies from the same research group (Masse-Alarie
etal., 2016, 2017b) in chronic back pain patients reported
short intracortical inhibition (SICI) and facilitation (SICF)
(before and after intervention). The same studies, together
with one study on acute pain in healthy individuals (De
Martino, Zandalasini, etal., 2018), presented data on MEP
amplitudes and silent periods. Based on this, it was not
deemed suitable to carry out a meta-analysis but instead a
qualitative synthesis of main findings is presented (Table6).
Discussion
Pain, training, andneuroplasticity
This systematic review included 7 studies investigating the
impact of experimental acute pain in pain-free participants,
and 10 studies investigating the effects of chronic pain on
corticomotor excitability of the muscle in pain and the
associated training-induced motor performance gain. The
main findings suggest that both acute and chronic pain may
impede training-induced neuroplasticity.
The studies included in the present review were heteroge-
neous with regard to several aspects of study designs. One
aspect to consider is that the selected cases included in the
studies represented a wide range of chronic pain conditions
and different acute pain protocols, manifested at different
regions of the body. The chronic pain conditions included
either widespread pain in multiple anatomical locations (i.e.,
fibromyalgia), regional pain in the cervical, spinal, or lum-
bar regions, or localized pain in the hand, head and facial
regions. The acute pain protocols ranged from application
of a topical capsaicin cream or hypertonic saline injec-
tion to the target muscle or nearby area, to injections of a
Table 5 Quality assessment of
included articles (n = 17) with
the TMS checklist
* Paired pulse.otal number of possible reported/controlled items are 26 for single pulse TMS, and29 for
paired pulse TMS
First author Year Reported Controlled
Yes No N/A % Yes Yes No N/A % Yes
Baarbe 2018 15 9 6 63 11 12 7 48
Boudreau 2007 19 6 5 76 16 9 5 64
Dancey 2019 19 5 6 79 17 7 6 71
De Martino 2018a 17 8 5 68 14 11 5 56
De Martino 2018b 18 7 5 72 18 7 5 72
Hoeger Bement 2014 13 11 6 54 9 15 6 38
Ingham 2011 19 7 5 72 18 7 5 72
Masse Alaire 2017b * 23 6 1 79 23 6 1 79
Masse Alaire 2016 * 22 7 1 76 22 7 1 76
Mavromatis 2017 * 20 8 2 71 19 9 2 68
Mendonca 2016 * 15 13 2 54 13 15 2 46
Parker 2017 * 26 3 1 90 24 5 1 83
Rittig-Rasmussen 2014a 20 5 5 80 17 8 5 68
Rittig-Rasmussen 2014b 19 6 5 76 16 9 5 64
Schwenkreis 2011* 18 10 2 64 18 10 3 64
Tsao 2010 17 7 6 71 16 8 6 67
Vallence 2013 18 6 6 75 17 7 6 71
Mean 19 7 4 72 17 9 4 65
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Brain Imaging and Behavior
1 3
Table 6 Results reported for pain groups (black arrows) and control groups (white arrows) as no changes (), increase () and decrease () for
the included studies (n = 17)
First author Year Single pulse TM
SP
aired pulse TMS
rMTAMT MEP
ampl
MEP
active
sites
MEP
latency
MT Map
volume
SICI SICF CoGLICILICFICF ICI
Experimental acute pain studies (n=7)
Boudreau 2007
Dancey 2019
De Martino 2018a
De Martino 2018b
Ingham 2011
Mavromatis 2017
Rittig-Rasmussen 2014b
Chronic pain studies (n=10)
Baarbe 2018
Hoeger Bement 2014
Massé-Alaire 2017b
Massé-Alaire 2016
Mendonca 2016
Parker 2017
Rittig-Rasmussen 2014a*
Schwenkreis 2011
Tsao 2010
Vallence 2013
rMT, Resting motor threshold; AMT, Active motor threshold; MEP, Motor evoked potential; MT, Motor threshold; SICI, Short interval intracor-
tical inhibition; SICF, Short interval intracortical facilitation; CoG, Center of gravity; LICI, Long interval intracortical inhibition; LICF, Long-
interval intracortical inhibition facilitation ICF, Intracortical facilitation; ICI, intracortical inhibition
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Brain Imaging and Behavior
1 3
nerve growth factor, eccentric exercises to provoke delayed
onset muscle soreness, or a combination of the last two.
Furthermore, the training tasks differed between studies.
Some studies were simpler and involved only one (i.e., one-
dimensional) or a few muscles, whereas other studies were
more complex with tasks involving coordinated activation of
multiple muscles and muscle groups as well as being more
cognitively demanding. The range of training tasks included
some that can be presumed, at least in part, to utilize already
existing motor pattern skills such as typing (Baarbe etal.,
2018), whereas other motor tasks can be viewed as more
novel motor patterns, e.g., tracing an external target utilizing
shoulder muscles (Rittig-Rasmussen etal., 2014a, 2014b).
Other studies incorporated more fatiguing or strength-
demanding tasks (De Martino, Petrini, et al., 2018; De
Martino, Zandalasini, etal., 2018; Hoeger Bement etal.,
2014; Mavromatis etal., 2017), thereby putting additional
functional demands on muscles, muscle groups and the cor-
ticospinal tract.
The large variation in the duration, repetition, intensity
and type of training performed, each of which can impact
the neuroplastic changes occurring in the brain, is consistent
with the time, intensity, repetition and specificity principles
of neuroplasticity (Avivi-Arber & Sessle, 2018; Kleim &
Jones, 2008). This relates to the question “when is enough
enough?” or maybe a ceiling effect for pain conditions. It has
been shown that neuroplastic changes are more pronounced
in skills training (Pascual-Leone etal., 1995), as opposed
to fatiguing and strength training exercises (Remple etal.,
2001) and that exercise-induced fatigue may even reduce
neuroplasticity (Wang etal., 2020). In the present review,
several of the primary studies included training protocols
either designed to induce fatigue (De Martino, Petrini,
etal., 2018; De Martino, Zandalasini, etal., 2018; Hoeger
Bement etal., 2014; Mendonca etal., 2016; Schwenkreis
etal., 2011), or protocols that may have induced fatigue
due to the length of training sessions or the load applied
(Boudreau etal., 2007; Parker etal., 2017; Rittig-Rasmussen
etal., 2014a, 2014b; Vallence etal., 2013). In addition to the
duration of individual sessions, the number of sessions may
also affect the overall effects from training, consistent with
the ‘repetition’ principle of neuroplasticity.
Consistent with the ‘timing’ principle of neuroplasticity
(Avivi-Arber & Sessle, 2018; Kleim & Jones, 2008), the
time between training and TMS measurements should be
considered in relation to immediate versus more long-lasting
neuroplastic changes. Time is an important factor since dif-
ferent forms and different directions of neuroplastic changes
occur at different points of time after motor training (Avivi-
Arber & Sessle, 2018; Kleim & Jones, 2008). Whereas most
studies performed TMS measurement to assess neuroplas-
tic changes immediately after training (i.e., within one-hour
timeframe), several studies also explored training-induced
neuroplastic changes more thoroughly by performing mul-
tiple TMS measurements within the first 15-min (Ingham
etal., 2011; Parker etal., 2017; Vallence etal., 2013) or first
hour (Rittig-Rasmussen etal., 2014a, 2014b; Schwenkreis
etal., 2011; Vallence etal., 2013) following training. Two
studies also investigated possible long term effects after one
week of training (Rittig-Rasmussen etal., 2014a, 2014b)
and found a long lasting inhibition of corticomotor excit-
ability in healthy subjects who performed neck exercises
in the presence of acute neck pain (Rittig-Rasmussen etal.,
2014b). Therefore, it is noteworthy in the context of train-
ing, that pain can induce fast-onset and long-lasting neuro-
plastic changes manifested as decreased corticomotor excit-
ability. Clearly, there are several important training-related
parameters that need to be taken into consideration before a
more comprehensive understanding of the effects of pain on
training-induced corticomotor excitability can be obtained.
The wide range of pain conditions discussed above can
explain variations across the studies in the expression of pain
sensations in terms of intensity and quality of pain, as well
as temporal aspects of pain such as timing of peak intensity
and duration. Consistent with the ‘specificity’ principle of
neuroplasticity (Avivi-Arber & Sessle, 2018; Kleim & Jones,
2008), these variations in pain characteristics may explain
differences in neuroplastic changes between selected cases
and controls within and across studies.
Additionally, age is a factor that should be considered as
aging is associated with different processes, e.g., physiologi-
cal degradation and neuronal atrophy, resulting in declines
in sensorimotor control and performance. There was a large
mean age range from 21.1years (Baarbe etal., 2018) to
72.0years (Parker etal., 2017) for the studies evaluating the
effect of chronic pain on corticomotor excitability, whereas
for the studies that induced acute pain in pain-free partici-
pants the mean age ranged only from 20.2years (Dancey
etal., 2019) to 26.5years (Mavromatis etal., 2017). How-
ever, no significant effects attributed to age were found for
any of the included studies. Another subject related factor
worth taking into consideration is that of gender. All stud-
ies reported varying ratios of male and female participants.
According to the TMS checklist gender is a factor that only
should be reported and not controlled, which was the case
for all included studies.
As mentioned earlier, most studies incorporated train-
ing that targeted painful areas, either through acute pain or
by the presence of localised chronic pain conditions. There
was however a number of studies that examined the more
global effects, from chronic tension type headaches (Val-
lence etal., 2013), neck pain (Baarbe etal., 2018), back pain
(Tsao etal., 2010) or fibromyalgia (Schwenkreis etal., 2011)
in hand or arm training or from knee pain in neck training
(Rittig-Rasmussen etal., 2014a). The last of these studies
investigated neck training in three groups; neck pain, knee
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Brain Imaging and Behavior
1 3
pain and controls, and demonstrated significantly reduced
corticomotor excitability of neck muscles as assessed by
MEP amplitudes in the neck pain, but not in the knee pain
or control groups (Rittig-Rasmussen etal., 2014a). This
finding is in accordance with a lack of difference in MEP
amplitudes between healthy controls and a neck pain group
following a typing task (Baarbe etal., 2018), and between
healthy controls and a fibromyalgia group following a hand
grip task (Schwenkreis etal., 2011). This finding strongly
indicates that it may not be pain in general but pain in a rel-
evant region for the motor task that determines the impact on
training-induced neuroplasticity. In contrast, reduced motor
learning in a thumb abduction task was reported for head-
ache patients compared to healthy controls (Vallence etal.,
2013), indicating that the relationship between pain location
and trained regions may be dependent not only on the loca-
tion but also on the type of pain condition.
There are several factors to consider when comparing the
chronic pain and acute pain groups of the studies included
in the present review. One aspect is that in the chronic pain
conditions, and in most of the acute pain conditions, motor
skill acquisition training and motor skill acquisition occurred
in the presence of pain. In contrast, in two studies of acute
pain, motor training occurred in the absence of pain but the
motor skill acquisition was evaluated in the presence of pain
(De Martino, Petrini, etal., 2018; De Martino, Zandalasini,
etal., 2018). In a systematic review based on 43 studies that
evaluated motor cortex excitability in chronic pain condi-
tions, Parker etal. found that chronic pain conditions can
induce a range of motor cortex neuroplastic changes that
vary across studies there was inconsistency for most out-
come measures. Among the changes were reduced dura-
tion of silent period and SICI together with enhanced SICF.
There were also indications that these effects were more
pronounced in populations with neuropathic pain (Parker
etal., 2016). Most of the included studies were however
based on migraine populations, thereby representing a pain
condition with complex pathophysiology specifically related
to the trigeminal region.
Functional aspects
Another factor to consider when comparing exercise in the
presence of chronic pain versus acute pain is the “salience
principle” (Kleim & Jones, 2008). The salience principle
describes the brain's attention to any input, and in the con-
text of exercise can be seen as increased attention to a task
being practiced. Patients with chronic pain may have such
a cognitive incentive when exercising, due to perceived or
expected healing or analgesic effects. In acute pain, however,
exercise probably has no cognitive incentive, but rather may
have an “interference” effect, e.g., worsening the acute pain,
thereby resulting in non-salient exercise. This is supported
by the increased representation in the motor cortex from sali-
ent exercise compared to non-salient exercise (Stefan etal.,
2004). It has been suggested that this may be explained in
part by the increase of acetylcholine in the cortex in salient
exercises compared to non-salient exercises (Meintzschel &
Ziemann, 2006).
With regard to the functional outcomes, there was a large
variety also here with regard to reported outcomes, and five
of the ten chronic pain studied (De Martino, Petrini, etal.,
2018; De Martino, Zandalasini, etal., 2018; Hoeger Bement
etal., 2014; Mendonca etal., 2016; Schwenkreis etal.,
2011) and six of the seven acute pain studies (Boudreau
etal., 2007; Dancey etal., 2019;De Martino etal., 2018a;
De Martino etal., 2018b; Mavromatis etal., 2017; Rittig-
Rasmussen etal., 2014b), did not report specific functional
outcomes. Different types of percentage performance score
were reported in relation to tracking tasks (Boudreau etal.,
2007; Rittig-Rasmussen etal., 2014a, 2014b) and accuracy
(Baarbe etal., 2018; Mavromatis etal., 2017; Parker etal.,
2017) sometimes combined with response time or speed of
movement (Baarbe etal., 2018; Mavromatis etal., 2017).
In general, performance improved with training regardless
of presence of pain, although some performance scores
were affected in pain groups compared to pain-free controls
(Boudreau etal., 2007; Vallence etal., 2013).
Quality assessment
As per our Prospero protocol we carried out a risk of bias
assessment utilizing two instruments. The first instrument,
NOS, covers domains for selection of participants, compa-
rability between groups, and exposure, and is the recom-
mended instrument for case–control studies. A general
finding across all studies was that the study populations
were often convenience samples and therefore not truly
representative of the populations under study. Furthermore,
our assessment was based on the specific aim to evaluate
neuroplasticity after training in the presence of pain. With
regard to study design, studies without a control group can
by definition only be scored on three items in the NOS and
we therefore added a modified score for studies with internal
control groups. Furthermore, the quality scores for some
of the included studies could be higher if they had been
assessed in relation to the specific aim of the respective stud-
ies. We therefore regard the results from the assessment with
NOS to be of limited value in the present review, given that
many studies were based on intraindividual comparisons,
before and after training, and not on comparisons between
groups. We also carried out an assessment with the TMS
checklist which was introduced in 2012 (Chipchase etal.,
2012). This instrument was developed based on a 2-round
international Delphi process with 42 participants result-
ing in a 30-item checklist covering domains of participant
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Brain Imaging and Behavior
1 3
characteristics, TMS protocol and analysis. The overall
mean scores for the primary studies in the present review
of 72 and 68% for reported and controlled factors, respec-
tively, indicate a moderate methodological quality and are
in line with other reviews utilizing this checklist. Items in
the checklist that were reported to a less degree included
prescribed medication and history of repetitive motor activ-
ity for participants, participants’ attention during testing,
and size of unconditioned MEP in the target muscles. These
findings are also in accordance with other reviews (Parker
etal., 2016; Rosso & Lamy, 2018) indicating that the pri-
mary studies in the present review have a methodological
quality similar to other recent systematic reviews.
Neurophysiological aspects
The main goal of many neurorehabilitation regimes is to
promote neuroplasticity at the subcortical and cortical lev-
els, such that long-lasting and beneficial alterations in motor
control strategies can be achieved (Gabriel etal., 2006).
Novel motor skill training, in contrast to passive assistance
or repetitions of general exercise (strength training), has
been associated with improvements in task performance and
increased representation of the trained muscle in the motor
cortex (Kothari etal., 2013; Svensson etal., 2003). At this
point in time, in terms of evaluating the combined effect of
pain and motor training on neuroplasticity, there was not
sufficient data available that could be extracted from the pri-
mary studies and grouped according to outcome measures
to carry out a meta-analysis. However, from the qualitative
synthesis we can conclude that both acute pain and chronic
pain may impede training-induced neuroplasticity which
may have implications for motor learning and performance
during rehabilitation following injury or disease. Training-
induced neuroplasticity has been shown to occur rapidly and
to continually evolve with more training (Koeneke etal.,
2006; Svensson etal., 2003). It is therefore reasonable to
assume that presence of pain may impede plasticity induced
by long-term training in a similar manner to short-term train-
ing, as reported in the present review.
The results from the present review are in line with the
principle that pain, both acute and chronic, is not purely a
sensory process but that pain networks interact with other
complex networks in cerebral structures including, but not
limited to, the primary motor cortex (M1), thalamus and
prefrontal cortices. Such interactions are used for example
to initiate and modulate actions to avoid or reduce pain. The
possible interaction between pain and the M1 can influence
training-induced neuroplasticity and some of the findings in
the present review may to some extent indicate the neuro-
physiological processes involved. Single pulse TMS meas-
ure outcomes, such as a decrease in rMT, were reported in
control conditions but negated by pain. This may indicate
increased excitability in a central core region of neurons
in M1. On the other hand, an increase in MEPs may imply
involvement of additional neurons in other regions (Hallett
etal., 1999). Variations in paired pulse TMS outcomes such
as ICI represent changes to the inhibitory cortical networks
primarily regulated by the chief inhibitory neurotransmit-
ter GABA (Hallett etal., 1999). Reduced activity in these
inhibitory cortical networks is an indication of enhanced
neuroplasticity but may be negated in the presence of pain.
Furthermore, pain may also affect performance due to
movement related pain or kinesiophobia directly resulting
in impaired motor output (Hodges & Smeets, 2015; Hodges
& Tucker, 2011). Consequently, the performed training of
a specific motor skill is hampered which indirectly impedes
the associated training-induced neuroplasticity.
Summary
The present study has shown that both acute pain and chronic
pain may impede training-induced functional neuroplasticity
manifested as decreased corticomotor excitability as defined
by TMS. Overall, the findings reflect the many aspects of
human neuroplasticity, that cannot be encapsulated by a sin-
gle outcome measure. It should be acknowledged that other
brain imaging techniques such as structural and functional
magnetic resonance imaging (sMRI, fMRI), electroencepha-
lography (EEG) and magnetoencephalography (MEG) can
provide complementary information that can help identify
neural correlates underlying a particular neuroplastic brain
change and associated motor behaviour. This information
is important for developing better rehabilitative training
approaches that adequately manage pain and facilitate adap-
tive neuroplasticity and improved motor performance.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s11682- 021- 00621-6.
Acknowledgements The assistance of Mrs Martina Vall ( information
specialist) is acknowledged for the electronic literature search.
Authors’ contribution NS, BHH, MK, PS: Study design; NS, BHH,
MK: Literature search, article selection; NS, MK: Data extraction
and analysis, NS, YMS: Quality assessment of included papers; NS,
LAA: risk of bias assessment of included articles; NS, BHH: Drafted
manuscript; All authors: critically reviewed manuscript and approved
final version.
Funding Open access funding provided by Malmö University. Yuri
Martins Costa acknowledges the Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior, Brasil – Capes [Finance Code 001, Capes/
Print 88887.468350/2019–00].
Data availability Not applicable it is a systematic review, but the data
can be made available by the authors if requested.
Code availability Not applicable.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Brain Imaging and Behavior
1 3
Declarations
Ethics approval, Consent to participate, Consent for publication. Not
applicable.
Conflict of Interest None of the authors have a conflict of interest to
declare.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
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