Cerebral Cortex, May 2016;26: 1878–1890
doi: 10.1093/cercor/bhu319
Advance Access Publication Date: 21 January 2015
Original Article
ORIGINAL ARTICLE
Motor Cortex Reorganization and Impaired Function in
the Transition to Sustained Muscle Pain
S. M. Schabrun1, S. W. Christensen2, N. Mrachacz-Kersting2,
and T. Graven-Nielsen2
1
School of Science and Health, University of Western Sydney, Penrith, NSW 2751, Australia, and 2Laboratory for
Musculoskeletal Pain and Motor Control, Center for Sensory-Motor Interaction (SMI), Department of Health
Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
Address correspondence to Prof. Thomas Graven-Nielsen, Laboratory for Musculoskeletal Pain and Motor Control, Center for Sensory-Motor Interaction (SMI),
Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7D-3, 9220 Aalborg, Denmark. Email: [email protected]
Abstract
Primary motor cortical (M1) adaptation has not been investigated in the transition to sustained muscle pain. Daily injection of
nerve growth factor (NGF) induces hyperalgesia reminiscent of musculoskeletal pain and provides a novel model to study M1 in
response to progressively developing muscle soreness. Twelve healthy individuals were injected with NGF into right extensor
carpi radialis brevis (ECRB) on Days 0 and 2 and with hypertonic saline on Day 4. Quantitative sensory and motor testing
and assessment of M1 organization and function using transcranial magnetic stimulation were performed prior to injection on
Days 0, 2, and 4 and again on Day 14. Pain and disability increased at Day 2 and increased further at Day 4. Reorganization of M1
was evident at Day 4 and was characterized by increased map excitability. These changes were accompanied by reduced
intracortical inhibition and increased intracortical facilitation. Interhemispheric inhibition was reduced from the “affected” to
the “unaffected” hemisphere on Day 4, and this was associated with increased pressure sensitivity in left ECRB. These data
provide the first evidence of M1 adaptation in the transition to sustained muscle pain and have relevance for the development of
therapies that seek to target M1 in musculoskeletal pain.
Key words: elbow pain, interhemispheric inhibition, nerve growth factor, primary motor cortex, transcranial magnetic
stimulation
Introduction
Motor dysfunction is a prominent feature of chronic musculoskeletal pain. Yet, the neural mechanisms that mediate this effect are poorly understood. Although cross-sectional studies
reveal altered organization and function of the primary motor
cortex (M1) in the chronic stage of pain, and these changes are associated with pain severity and motor dysfunction, there has
been no longitudinal investigation of M1 in the transition from
acute to sustained pain.
Multiple aspects of M1 organization and function are distorted when musculoskeletal pain persists. Motor cortical representations show greater overlap and a reduced number of
discrete peaks in chronic elbow (Schabrun, Hodges et al. 2014)
and low back pain (Tsao et al. 2008; Tsao et al. 2011; Schabrun,
Elgueta-Cancino et al. 2014), whereas activity in inhibitory
networks (ϒ-aminobutyric acid [GABA] mediated) is reduced
(Masse-Alarie et al. 2012; Schwenkreis et al. 2003). These adaptations are associated with pain severity (Schwenkreis et al. 2003;
Schabrun, Elgueta-Cancino et al. 2014; Schabrun, Hodges et al.
2014) and/or motor dysfunction (Tsao et al. 2008). In addition, a
release of inhibition from the “affected” (corresponding to the
painful region) to the “unaffected” M1, known as interhemispheric inhibition (IHI), may underpin observations of bilateral
motor dysfunction in unilateral pain conditions (Pienimaki
et al. 1997; Bisset et al. 2006; Alizadehkhaiyat et al. 2007). Despite
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected]
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Schabrun et al.
| 1879
these findings, M1 adaptation in the transition to sustained muscle pain has not been characterized. It is unknown how M1 is
altered during the transition to sustained pain and at what
time-point changes develop. In particular, the amount of pain
(severity and/or duration) required to trigger M1 adaptation has
not been examined.
Repeated injection of nerve growth factor (NGF) has been
shown to sensitize peripheral and central neuronal mechanisms
and is a novel model capable of inducing progressive muscle
soreness, mechanical hyperalgesia, and temporal summation
of pressure pain that can last up to 14 days (Hayashi et al. 2013).
NGF-induced muscle pain mimics the time-course (slowly developing muscle soreness) and processes involved in the transition
to chronic musculoskeletal pain (Hayashi et al. 2013) and thus
provides a realistic model to investigate M1 adaptation in the
transition to sustained pain. Moreover, acute muscle pain induced by injecting hypertonic saline in a system already sensitized by NGF provides a unique opportunity to evaluate M1 in
response to a clinically relevant, acute exacerbation of muscle
pain.
In the present study, the NGF model was used to 1) investigate
the nature and time-course of M1 organization (representational
maps) and function (intracortical networks and interhemispheric networks) in response to progressively developing muscle soreness, 2) determine the relationship between altered M1
activity and pain and disability, and 3) examine the M1 response
to an acute exacerbation of muscle pain in an already sensitized
system. It was hypothesized that progressively developing muscle soreness would result in M1 reorganization, reduced intracortical inhibition, and reduced IHI from the “affected” to the
“unaffected” hemisphere, and these changes would be dependent
on the magnitude and duration of muscle soreness. Consistent
with previous studies (Le Pera et al. 2001; Schabrun and Hodges
2012; Schabrun et al. 2013), it was further hypothesized that an
acute exacerbation of muscle pain in a sensitized system would
reduce corticomotor output and increase intracortical inhibition.
Figure 1. Clinical (McGill Pain Questionnaire, PRTEE, muscle soreness, pressure
Materials and Methods
Participants
Twelve, healthy, right-handed individuals (8 female, 26 ± 4 years,
mean ± standard deviation [SD]) participated. Participants had no
history of neurological or upper-limb conditions and completed a
transcranial magnetic stimulation (TMS) safety screen (Keel et al.
2001) prior to commencement. All subjects received written and
verbal description of experimental procedures and provided written informed consent consistent with the Declaration of Helsinki. Experimental procedures were approved by the local
ethics committee (N-20130055).
Experimental Protocol
Each participant attended the laboratory on 4 occasions—Days 0,
2, 4, and 14 (Fig. 1). NGF was injected into the belly of the right extensor carpi radialis brevis (ECRB) muscle immediately following
administration of quantitative sensory and motor testing ( pressure pain thresholds (PPTs), muscle soreness, grip force,
patient-rated tennis elbow evaluation (PRTEE), and short-form
McGill Pain Questionnaire), and neurophysiological testing
(motor cortical maps, corticomotor excitability, intracortical inhibition and facilitation, and IHI) on Days 0 and 2. To assess the
immediate effect of the NGF injection on corticomotor output,
corticomotor excitability was measured directly following the
algometry, and grip force) and neurophysiological (resting and active motor
threshold, motor cortical maps, intracortical inhibition and facilitation, and IHI)
outcome measures were assessed at the beginning of each experimental
session on Days 0, 2, 4, and 14. On Days 0 and 2, these measures were followed
by injection of NGF to right extensor carpi radialis brevis (m. ECRB) and
corticomotor excitability immediately evaluated. On Day 4, hypertonic saline
was injected to m. ECRB to induce acute pain lasting approximately 10 min.
During acute pain, corticomotor excitability in the form of 15 MEPs and
intracortical inhibition and facilitation were assessed. Once pain had returned
to baseline, corticomotor excitability (15 MEPs) was re-evaluated.
injection on Days 0 and 2. All outcome measures were repeated
on Day 14, but no injection given.
To examine the effect of an acute exacerbation of muscle
pain in the m. ECRB already sensitized by repeated NGF injection, an identical procedure to that described for Days 0 and 2
was followed on Day 4, except the NGF injection was replaced
with an injection of hypertonic saline to induce immediate experimental muscle pain. Measures of corticomotor excitability
(motor-evoked potentials [MEPs]) and intracortical inhibition
and facilitation were made during saline-induced muscle pain
that lasted ∼10 min. Corticomotor excitability was reassessed
once pain had returned to baseline levels. These data were compared with measures of corticomotor excitability and intracortical networks made in the NGF sensitized system immediately
prior to saline-induced pain (i.e., data from the main protocol
at Day 4).
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NGF-Induced Muscle Soreness
Sterile solutions of recombinant human NGF were prepared by
the pharmacy at Aalborg hospital. After cleaning the skin with alcohol, a dose of 5 μg (0.2 mL) was given as a bolus injection into
the muscle belly of m. ECRB at Days 0 and 2 using a 1-mL syringe
with a disposable needle (27G). The site of injection of m. ECRB
was determined using real-time ultrasound guidance.
The PRTEE was used to assess average pain and disability of
the injected arm at the start of each testing session (Days 0, 2,
4, and 14) (Macdermid 2005). Scores for pain (sum of 5 items out
of a maximum score of 50) and disability (sum of 10 items, divided by 2, out of a maximum score of 50) were combined to
give a total score ranging from 0 (no pain and no functional impairment) to 100 (worst pain imaginable with significant functional impairment).
Muscle soreness was assessed at the start of testing on Days 2,
4, and 14 using a modified 7-point Likert scale; 0 = “a complete absence of soreness,” 1 = “a light soreness in the muscle felt only
when touched/vague ache,” 2 = “a moderate soreness felt only
when touched/a slight persistent ache,” “3 = “a light muscle soreness when lifting or carrying objects,” 4 = “a light muscle soreness, stiffness or weakness when moving the wrist without
gripping an object,” 5 = “a moderate muscle soreness, stiffness
or weakness when moving the wrist,” and 6 = “a severe muscle
soreness, stiffness or weakness that limits the ability to move”
(Hayashi et al. 2013).
The short-form McGill Pain Questionnaire (Melzack 1987) was
administered at the start of testing on Days 2, 4, and 14 to
investigate the characteristics and distribution of NGF-induced
pain. Subjects scored the 15 pain descriptors on the McGill
Pain Questionnaire as “None,” “Mild,” “Moderate,” or “Severe”.
Words chosen by at least one-third of participants were used in
data analyses.
Saline-Induced Muscle Pain
Saline-induced pain was induced on Day 4 by a bolus injection of
0.5 mL of hypertonic saline (5.8%) into the muscle belly of
m. ECRB after the skin had been cleaned with alcohol. Injections
were performed using a 1-mL syringe with a disposable needle
(27G). The site of injection of m. ECRB was determined using
real-time ultrasound guidance. Pain was recorded every 30 s
using an 11-point numerical rating scale (NRS: anchored with
“no pain” at zero and “worst pain imaginable” at 10) immediately
following hypertonic saline injection until pain returned to baseline. To capture the characteristics and distribution of pain
induced specifically by hypertonic saline, the McGill Pain
Questionnaire was administered once pain had returned to
baseline.
Pressure Algometry
Pressure was applied at a rate of 30 kPa/s perpendicular to the
surface of the skin using a handheld algometer (1-cm2 probe,
Somedic) covered by a disposable latex sheath. Three readings
at the PPT were made at 1-min intervals, at 4 sites: 1) right
m. ECRB (injection site), 2) left m. ECRB, 3) right m. Tibialis Anterior, and 4) left m. Tibialis Anterior. For each site, the muscle belly
was located and marked. The PPT was defined as the point at
which a sensation of pressure changed to a sensation of pain.
Participants were requested to push a button when the pressure
sensation first became painful. The average PPT of the 3 measures was used for statistical analysis. A tape measure was
used to measure the position of each site (m. ECRB—distance
(cm) distal to the lateral epicondyle and medial distance (cm);
m. Tibialis Anterior—distance (cm) distal from the base of the patellar tendon), and these values were recorded to ensure consistent positioning across measurement sessions.
Grip Force
Maximal voluntary grip force was recorded using an electronic
digital dynamometer (MIE Medical Research Ltd.). Participants
positioned their forearm in pronation and 90 degrees elbow flexion. Peak values determined maximal grip force and were found
following a single maximal voluntary effort lasting 10 s on each
side. The force signal was sampled at 500 Hz.
Corticomotor Excitability
Electromyographic (EMG) activity was recorded from right
and left m. ECRB using silver/silver chloride surface electrodes
(Medicotest 720-01-K, Ambu A/S) positioned over the muscle
belly. EMG signals were sampled at 4 kHz and bandpass filtered
at 10 Hz–2 kHz. Data were digitized by a 16-bit data-acquisition
card (National Instruments, NI6122) and saved by custom-made
Labview software (Mr. Kick, Knud Larsen, SMI, Aalborg University).
Single-pulse transcranial magnetic stimuli (TMS) were delivered using a Magstim 200 stimulator (Magstim Co. LtD) and a
figure-of-eight coil. The coil was positioned over the left hemisphere at a 45-degree angle to the sagittal plane to preferentially
induce current in a posterior-to-anterior direction. The optimal
cortical site (“hotspot”) to evoke responses in right m. ECRB was
determined as the coil position that evoked a maximal peakto-peak MEP for a given stimulation intensity. All TMS procedures adhered to the TMS checklist for methodological quality
(Chipchase et al. 2012). With the participant seated, 3 measures
were made:
1. Resting motor threshold (rMT), defined as the minimum
stimulator intensity at which 5 out of 10 stimuli applied at
the optimal scalp site evoked a response with a peak-topeak amplitude of at least 50 μV.
2. Active motor threshold (aMT), defined as the minimum
stimulator intensity at which 5 out of 10 stimuli evoked a response amplitude of 200 μV while m. ECRB was contracted at
10% of maximum voluntary contraction force. The arm was
positioned with the elbow in 90 degrees flexion and the
wrist pronated. Force feedback was provided via an oscilloscope positioned in front of the participant, with the target
force of 10% marked. Participants were asked to maintain
their force on the marked line at all times.
3. Fifteen MEPs were recorded at 120% of rMT over the optimal
cortical site with m. ECRB at rest to evaluate corticomotor excitability. MEP responses were measured as peak-to-peak amplitudes and averaged for analysis.
Motor Cortical Maps
The procedure for cortical mapping has been described in detail
previously (Schabrun and Ridding 2007; Schabrun et al. 2009).
Participants were fitted with a cap, marked with a 1 × 1 cm grid
and orientated to the vertex ( point 0,0). The stimulus intensity
for mapping was 120% rMT. TMS was applied every 6 s with a
total of 5 stimuli at each site. The number of scalp sites was
pseudorandomly increased until no MEP was recorded (defined
as <50-µV peak-to-peak amplitude in all 5 trials in all border
sites (Schabrun and Ridding 2007; Schabrun et al. 2009).
Motor Cortical Organization of Sustained Muscle Pain
Participants were seated and instructed to maintain their hand and
forearm relaxed with the wrist pronated throughout the experiment. Trials containing background EMG activity were discarded.
The number of active map sites and map volume was calculated. A site was considered “active” if the mean peak-to-peak
amplitude of the 5 MEPs evoked at that site was greater than
50 µV. The mean peak-to-peak MEP amplitudes at all active
sites were summed to calculate the map volume. The center of
gravity (CoG) was defined as the amplitude-weighted center of
the map (Wassermann et al. 1992; Uy et al. 2002) and was calculated for each muscle using the formula:
CoG ¼
ΣVi Xi ΣVi Yi
;
ΣVi
ΣVi
where Vi represents mean MEP amplitude at each site with the
coordinates Xi, Yi. The reliability of these procedures for calculating the number of active sites, volume and center of gravity, and
the stability of map measures over time has been previously demonstrated (Uy et al. 2002; Malcolm et al. 2006; Ngomo et al.
2012).
Finally, the number of discrete map peaks, defined as the
number of scalp sites over which TMS evoked a discrete “peak”
in the motor cortex representation, was determined. Motor cortical maps were normalized to the maximum MEP amplitude at
Day 0 for each participant. Using an established procedure
(Schabrun, Hodges et al. 2014; Schabrun, Jones et al. 2014), discrete peaks were identified if the MEP amplitude at a grid site
was greater than 50% of maximum, was separated by a reduction
in amplitude of at least 5% of peak MEP amplitude in 7 out of 8 of
the surrounding grid sites, and was separated by at least 1 grid
site from another peak that satisfied the first 2 criteria.
Intracortical Inhibition and Facilitation
Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were measured for right m. ECRB using a standard
paired-pulse TMS protocol (Kujirai et al. 1993). Twelve trials were
recorded at each of 2 interstimulus intervals—2 ms for SICI and
13 ms for ICF. The test stimulus was set to produce a MEP of between 0.3 and 0.4 mV peak-to-peak amplitude in relaxed
m. ECRB, and the conditioning stimulus was set at 90% aMT
(Ortu et al. 2008; Perez and Cohen 2008). As previous studies
have shown a reduction in MEP amplitude in response to muscle
pain (Le Pera et al. 2001; Schabrun and Hodges 2012) and the size
of the test response is known to influence the magnitude of SICI
(Chen et al. 1998), we selected a test response of 0.3–0.4 mV to ensure that the test response could be kept constant across measurement sessions should corticomotor excitability reduce in
response to pain. Twelve unconditioned (test) trials were also recorded (36 trials in total). Trials were recorded in pseudorandom
order. MEP responses were measured as peak-to-peak amplitudes and conditioned responses (SICI/ICF) expressed as a proportion of the unconditioned test response.
Interhemispheric Inhibition
IHI was measured using a standard paired-pulse TMS protocol
(Ferbert et al. 1992), 2 Magstim stimulators and 2 figure-of-eight
coils. The conditioning stimulus and the test stimulus were delivered over the optimal cortical site to evoke a MEP in right and left
m. ECRB. The protocol was completed in both directions
(i.e., with the test stimulus in the left hemisphere and then repeated with the test stimulus in the right hemisphere). Both
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the conditioning and test stimuli were set to produce a MEP of
between 0.3 and 0.4 mV (Harris-Love et al. 2007; Perez and
Cohen 2008). To investigate short- and long-latency interhemispheric inhibition (SIHI and LIHI), 10- and 40-ms interstimulus
intervals were selected (Nelson et al. 2009; Sattler et al. 2012). In
pseudorandom order, 10 trials were recorded at each interstimulus interval and a further 10 trials using the test stimulus alone
(30 trials in total). MEP responses were measured as peak-topeak amplitudes and conditioned responses (SIHI/LIHI) expressed as a proportion of the unconditioned test response.
Statistical Analyses
Muscle soreness scores, PRTEE, McGill Pain Questionnaire, and
neurophysiological data (rMT, aMT, MEP amplitude at the hotspot, active sites, map volume, discrete map peaks, CoG, SICI,
ICF and IHI) were compared between Days (0, 2, 4, and 14) using
one-way repeated-measures analysis of variance (ANOVA). PPTs
and maximal grip force were compared between Days (0, 2, 4, and
14) and sides (right, left) using two-way repeated-measures
ANOVA. Data that did not meet assumptions of normality were
log-transformed. Linear regression lines were used to assess
the relationship between neurophysiological mechanisms of
aMT, SICI/ICF, and IHI and quantitative variables of pain, disability (PRTEE), grip force, and pressure pain sensitivity.
The immediate effect of the NGF injection on corticomotor
output was examined using two-way repeated-measures
ANOVA that compared corticomotor excitability data before and
after NGF injection (factor “time”) on Days 0 and 2 (factor “day”).
To assess the effect of saline-induced muscle pain on corticomotor excitability and intracortical networks (SICI/ICF), these
measures were compared before, during, and after hypertonic saline infusion on Day 4 using one-way repeated-measures ANOVA.
Where appropriate, post hoc analyses were performed using
Holm–Sidak multiple comparison tests. Statistical significance
was set at P < 0.05. All data in text are presented as mean ± SD.
Results
Sensory and Functional Measures in Response to
Repeated NGF Injections
Pain and Disability
NGF-induced muscle soreness was local to the injection site in
the majority of participants at Days 2 and 4 (Fig. 2). Two participants reported an ache that radiated to the upper arm and 2 to
the lower forearm (radiating symptoms showed a similar distribution for these participants at Days 2 and 4 and were not present
at Day 14). On the McGill Pain Questionnaire, NGF-induced muscle soreness was commonly described as a mild-to-moderate
ache (33% of participants), heavy (33%), and/or tender (33%) at
Day 2 and a mild-to-severe ache (58%), heavy (42%), tender
(33%), stabbing (42%), and/or tiring (58%) at Day 4.
NRS scores corresponding to NGF-induced muscle pain
(ANOVA: F3,33 = 30.3; P < 0.001) increased 2 days after the first injection compared with Day 0 (P < 0.001), increased further after
the second injection from Day 2 to Day 4 (P < 0.02), and returned
toward baseline scores at Day 14 (Fig. 3A).
PRTEE scores followed a profile similar to that of pain (ANOVA:
F3,33 = 23.9; P < 0.001). PRTEE scores were increased at Day 2 compared with Day 0 (P < 0.001), elevated further at Day 4 compared
with Day 2 (P < 0.014), and returned to baseline at Day 14 (Fig. 3B).
Likert scores of muscle soreness (ANOVA: F3,33 = 27.9; P < 0.001)
were increased at Day 2 compared with Day 0 (P < 0.001) and
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Figure 2. Body chart pain drawings showing distribution of pain in response to NGF administration at Days 2, 4, and 14 and in response to hypertonic saline injection at Day 4.
Figure 3. Group data (mean ± SD, N = 12) for pain (A), PRTEE (B), muscle soreness (C), and grip force (D) at each time-point (Days 0, 2, 4, and 14). Each asterisk denotes a
significant (P < 0.05) difference from baseline (Day 0). Pain, PRTEE, and muscle soreness were increased at Day 2 and further elevated at Day 4. Grip force was reduced
at Day 4 on the right (injected) side and remained reduced at Day 14.
remained elevated at Day 4 compared with Day 0 (P < 0.001) with a
trend toward an increase from Day 2 scores (P < 0.065). Muscle
soreness returned to baseline at Day 14 (Fig. 3C).
Grip Force
Grip force in the right (injected) arm was reduced at Day 4
(ANOVA interaction: F3,33 = 3.20; P < 0.04) compared with Day 0
Motor Cortical Organization of Sustained Muscle Pain
(P < 0.03; Fig. 3D). Reduced grip force persisted at Day 14 (P < 0.038).
A greater reduction in grip force in the right arm was associated
with a greater increase in active motor threshold at all timepoints (R = 0.42, P < 0.014, Fig. 7A). Grip force was lower in the
left arm when compared with the right arm at Day 0 (P < 0.012)
and Day 2 (P < 0.002), but there was no difference between the 2
sides at Day 4 or Day 14. Grip force in the left arm was unaltered
over time.
Pressure Pain Sensitivity
PPTs measured over the right (injected) m. ECRB were reduced
(ANOVA interaction: F3,33 = 20.6; P < 0.001) at Day 2 (P < 0.001) and
Day 4 (P < 0.001) compared with Day 0. There was a trend for PPTs
to remain reduced at Day 14 (P = 0.076; Fig. 4). Interestingly, PPTs
over the left m. ECRB were also reduced, although to a lesser extent than those for right m. ECRB (P < 0.001), at Day 4 compared
with Day 0 (P < 0.025), returning to baseline at Day 14. PPTs over
m. Tibialis Anterior were unaltered over time.
Neurophysiological Measures in Response to Repeated
NGF Injection
P-values for significant post hoc tests are shown in the text below.
P-values, F-values, and degrees of freedom (DF) from the primary
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ANOVA performed for each neurophysiological measure are provided in Tables 1–3.
Motor Threshold and Motor Cortical Maps
Active, but not resting, motor threshold was increased at Day 4
compared with Day 0 (P < 0.021) but returned to baseline at Day
14 (Table 1).
Motor cortical maps at each time-point are provided in
Figure 5. Compared with Day 0, map volume was increased at
Day 4 (P < 0.005), and this was accompanied by an increase in
the number of discrete map peaks at Day 4 (P < 0.038, Table 1).
Neither parameter differed when compared with baseline at
Day 14. There was no alteration in the amplitude of the MEP at
the hotspot, the number of active sites, or the position of the CoG.
Intracortical Networks
Consistent with the direction (increased excitability) and timing
of changes in motor threshold and motor cortical maps, SICI was
reduced, and ICF increased, at Day 4 (SICI, P < 0.033; ICF, P < 0.004;
Table 1). These changes were not maintained at Day 14. The amplitude of the test response remained stable over time. Representative traces from 1 individual are provided in Figure 6. Greater
Figure 4. Group data (mean ± SD, N = 12) for PPTs at m. ECRB and m. Tibialis Anterior at each time-point (Days 0, 2, 4, and 14). Each asterisk denotes a significant (P < 0.05)
difference from baseline (Day 0). PPTs were reduced at Days 2 and 4 in the right (injected) m. ECRB and at Day 4 in left m. ECRB. No changes were observed in m. Tibialis
Anterior at any time-point.
Table 1 Neurophysiological measures (mean ± SD, N = 12)
rMT (%)
aMT (%)
MEP amplitude (mV)
Map active sites (number)
Map volume (mV)
Map discrete peaks (number)
CoG latitude (cm)
CoG longitude (cm)
SICI/ICF test response (mV)
SICI ( proportion of test)
ICF ( proportion of test)
Day 0
Day 2
Day 4
Day 14
P-value
F-value
DF effect:error
43.2 ± 8.0
32.8 ± 8.4
0.28 ± 0.17
23.4 ± 8.9
2.6 ± 0.89
4.2 ± 1.6
6.0 ± 0.69
4.6 ± 1.1
0.31 ± 0.20
0.59 ± 0.25
1.18 ± 0.32
43.7 ± 7.7
34.3 ± 8.6
0.18 ± 0.12
19.8 ± 8.8
3.1 ± 2.0
4.1 ± 1.6
5.5 ± 0.75
4.6 ± 0.97
0.37 ± 0.22
0.64 ± 0.28
1.14 ± 0.23
45.7 ± 8.1
36.0 ± 8.8*
0.21 ± 0.09
21.0 ± 8.9
4.6 ± 2.1*
6.2 ± 2.6*
5.6 ± 0.80
4.9 ± 1.4
0.38 ± 0.18
0.89 ± 0.29*
1.44 ± 0.40*
44.1 ± 8.1
33.6 ± 8.5
0.28 ± 0.33
23.5 ± 11.9
3.3 ± 2.4
3.8 ± 1.5
5.6 ± 0.92
4.7 ± 1.30
0.33 ± 0.20
0.82 ± 0.25
1.24 ± 0.34
0.19
0.024
0.29
0.29
0.005
0.009
0.16
0.71
0.62
0.012
0.001
1.67
3.60
1.31
1.31
5.10
4.57
1.87
0.46
0.60
4.37
6.81
3:33
3:33
3:33
3:33
3:33
3:33
3:33
3:33
3:33
3:33
3:33
Note: P-values, F-values, and DF are from the primary ANOVA for each variable; *P < 0.05 post hoc tests relative to baseline; rMT, resting motor threshold; aMT, active motor
threshold; CoG, center of gravity in maps, SICI, short-interval intracortical inhibition; ICF, intracortical facilitation.
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Table 2 IHI measures (mean ± SD, N = 12)
Left hemisphere (right ECRB)
Test response (mV)
IHI 10 ms ( proportion of test)
IHI 40 ms ( proportion of test)
Right hemisphere (left ECRB)
Test response (mV)
IHI 10 ms ( proportion of test)
IHI 40 ms ( proportion of test)
Day 0
Day 2
Day 4
Day 14
P-value
F-value
DF effect:error
0.37 ± 0.15
0.59 ± 0.63
0.63 ± 0.51
0.45 ± 0.29
0.57 ± 0.36
0.68 ± 0.46
0.46 ± 0.23
0.51 ± 0.29
0.57 ± 0.29
0.42 ± 0.20
0.62 ± 0.35
0.71 ± 0.37
0.98
0.90
0.76
0.06
0.19
0.39
3:33
3:33
3:33
0.27 ± 0.14
0.69 ± 0.36
0.73 ± 0.41
0.33 ± 0.18
1.30 ± 0.56
1.3 ± 0.46
0.31 ± 0.15
1.60 ± 0.92*
1.4 ± 0.64*
0.32 ± 0.16
1.30 ± 0.54
1.2 ± 0.44
0.94
0.022
0.029
0.13
3.78
3.47
3:33
3:33
3:33
Note: P-values, F-values, and DF are from the primary ANOVA for each variable; *P < 0.05 post hoc tests relative to baseline; IHI, interhemispheric inhibition.
Table 3 Influence of hypertonic saline-induced pain at Day 4 on MEP amplitude and SICI/ICF (mean ± SD, N = 12)
MEP amplitude (mV)
Test response (mV)
SICI ( proportion of test)
ICF ( proportion of test)
Before pain
During pain
After pain
P-value
F-value
DF effect : error
0.21 ± 0.09
0.38 ± 0.18
0.89 ± 0.29
1.44 ± 0.40
0.34 ± 0.18*
0.36 ± 0.27
0.80 ± 0.19
1.20 ± 0.27*
0.37 ± 0.19*
—
—
—
0.015
0.17
0.31
0.019
5.10
2.17
1.14
7.49
2:22
1:11
1:11
1:11
Note: P-values, F–values, and DF are from the primary ANOVA for each variable; *P < 0.05 post hoc tests relative to baseline; MEP, motor-evoked potential; SICI, shortinterval intracortical inhibition; ICF, intracortical facilitation.
Figure 5. Averaged (N = 12) motor cortex maps normalized to the maximum MEP for each participant. Maps for Days 2, 4, and 14 are normalized to Day 0 for each
participant. The colored scale represents the proportion of the maximum MEP amplitude of Day 0. The vertex is located at coordinate (0, 0). Note the increased map
excitability (map volume) and larger number of discrete peaks following repeated NGF injection at Day 4.
Motor Cortical Organization of Sustained Muscle Pain
Schabrun et al.
| 1885
Figure 6. Raw traces of MEP amplitudes from 1 representative individual for SICI, ICF, and the associated test response (top panels) and for short (SIHI) and long (LIHI)
latency interhemispheric inhibition and the associated test response (bottom panels) at Day 0 (solid black line), Day 2 (solid gray line), Day 4 (dotted line), and Day 14
(dashed line). Note the reduction in SICI, increase in ICF, and reduction in SIHI/LIHI at Day 4.
ICF was associated with higher pain and disability on the PRTEE
(R = 0.37, P < 0.018; Fig. 7B).
The Influence of an Acute Exacerbation of Muscle Pain on
Corticomotor Excitability and Intracortical Networks in a
NGF Sensitized System
Interhemispheric Networks
The amount of IHI from the left (“affected”) to the right (“unaffected”) hemisphere (left, uninjected m. ECRB) was reduced
at both short and long latencies at Day 4 (SIHI, P < 0.016; LIHI
P < 0.026, Fig. 6). Lower IHI from the affected to the unaffected
hemisphere at short- (R = 0.30, P < 0.049; Fig. 7C) and long-latency
(R = 0.91, P < 0.001; Fig. 7D) was associated with reduced PPTs in
left m. ECRB across all time-points. The amount of IHI from the
unaffected to the affected hemisphere (right, injected m. ECRB)
was unaltered across time at either latency. The amplitude of
the test response in each muscle was stable over time (Table 2).
Injection of hypertonic saline induced an average muscle pain intensity of 7.6 ± 1.8 on the NRS and an average pain duration of 7.5
± 2.6 min (range 5.0–12.5 min). The most frequent words used to
describe the pain on the McGill Pain Questionnaire were stabbing
(42%), sharp (58%), aching (42%), and heavy (50%). The majority of
participants reported symptoms localized to the region of the injection. Three participants reported symptoms that radiated to the
upper arm and 2 to the lower forearm. The injection of hypertonic
saline at Day 4 into m. ECRB already sensitized by repeated NGF injection produced an increase in MEP amplitude during acute pain
(P < 0.049), and this increase persisted after acute pain had returned to baseline (P < 0.019; Table 3). A reduction in ICF was present during acute pain (ANOVA: P < 0.019). There was no change in
SICI or in the amplitude of the test response during pain.
The Immediate Effect of NGF Injection on Corticomotor
Excitability
Corticomotor excitability (ANOVA: P < 0.044) was unaltered immediately following the NGF injection on Day 0 ( pre 0.28 ± 0.17
mV to 0.24 ± 0.15 mV post). However, once the system was sensitized on Day 2, the NGF injection produced an immediate
increase ( pre-NGF injection 0.18 ± 0.12 mV to 0.28 ± 0.21 mV
post-NGF injection) in corticomotor excitability (P < 0.034).
Discussion
This study is the first to examine M1 in the transition to sustained
muscle soreness. A novel feature is the use of a clinically realistic
model that incorporates development of progressive muscle
soreness with an acute exacerbation of muscle pain. The data
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| Cerebral Cortex, 2016, Vol. 26, No. 5
Figure 7. Relationship between grip force in right m. ECRB and active motor threshold (both expressed as percent change from baseline). A greater reduction in grip force was
associated with a greater increase in active motor threshold at all time-points (P < 0.014, A). Association between ICF and PRTEE score. Increased ICF was associated with higher
(worse) PRTEE score across participants (P < 0.018, B). Association between short (SIHI; C) and long (LIHI; D) latency interhemispheric inhibition and PPTs (left m. ECRB) for all
participants at all time-points. Lower interhemispheric inhibition at both latencies was associated with reduced PPTs in left m. ECRB (SIHI, P < 0.049; LIHI, P < 0.001).
demonstrate altered M1 organization and impaired function
characterized by increased corticomotor excitability (increased
map volume, increased map peaks, reduced intracortical inhibition, and increased intracortical facilitation), that is present
at Day 4 following progressively developing muscle soreness
and is further potentiated by acute muscle pain. A unique, and
previously unreported finding, was a reduction in IHI from the
left (“affected”) to the right (“unaffected”) hemisphere, also present at Day 4, associated with greater pressure pain sensitivity
in the unaffected arm. These findings provide original insight
into the nature and temporal profile of M1 adaptation during
the transition to sustained muscle pain.
Temporal Profile of NGF-Induced Muscle Soreness and
Disability
A single injection of NGF at Day 0 induced muscle soreness,
hyperalgesia to pressure, and reduced function of m. ECRB by
Day 2. Repeated NGF injection resulted in a progressive increase
in pain and disability, along with a reduction in grip force, at Day
4. All measures of pain, hyperalgesia, and disability, with the exception of grip force, returned toward baseline at Day 14. This
temporal profile is usual following single (Bergin et al. 2014)
and repeated NGF injection (Hayashi et al. 2013) with some studies reporting maintenance of symptoms up to 21 days (Dyck et al.
1997). These data confirm the suitability of repeated NGF injection as an experimental model to investigate the transition to
sustained elbow pain.
A vehicle control was not included in the current study for several reasons. First, numerous studies demonstrate that measures
of M1 organization and function are stable and reliable over time
(Uy et al. 2002; Malcolm et al. 2006; Ngomo et al. 2012). Second,
the use of such a control is common in both animal and human
studies of experimental pain and rarely, if ever, shows an effect
(Adachi et al. 2008; Nash et al. 2010). For instance, previous studies
that have examined SICI/ICF in response to pain demonstrated no
change in MEP amplitudes, SICI or ICF following a vehicle control
(Fierro et al. 2010). Finally, in the present study, differential effects
on M1 were observed over time (effects were not present at Day 2
and returned to baseline at Day 14). Taken together, these observations indicate that standard measures of M1 organization and
function are not sensitive to time effects, and our findings are unlikely to be replicated in a no pain control condition.
The Influence of Progressively Developing Muscle
Soreness on M1 Organization
Pain and disability evoked by repeated NGF injection-induced reorganization of M1 that was evident at Day 4. This temporal profile implies progressively developing muscle soreness is an
Motor Cortical Organization of Sustained Muscle Pain
important driver of M1 reorganization. However, although pain
and disability were greater at Day 4 than Day 2, no association between M1 organization and pain severity/disability was found,
suggesting sustained muscle soreness may be more important
in driving reorganization than pain severity. Altered M1 organization was characterized by increased map volume and an increased number of discrete peaks in M1 activity. These findings
provide evidence of an increase in corticomotor excitability that
may reflect the search for a new motor strategy during the transition to sustained muscle pain.
The organizational structure of human M1 relies on a balance
between discrete and distributed (overlapping) muscle representations (Devanne et al. 2006; Strother et al. 2012; Cunningham
et al. 2013). This structure supports integrated, multi-joint, and
synergistic movements while maintaining fine, individuated
motor control (Dechent and Frahm 2003; Plow et al. 2010). Previous studies have shown that this structure is based on variation
in the threshold of excitability such that each muscle has a lower
threshold for excitation of key movements (observed as discrete
peaks of excitability) whereas adjoining muscles not required for
movement completion have a higher threshold (Humphrey and
Freund 1991; Plow et al. 2010). The presence of multiple discrete
peaks in the cortical representation of wrist muscles in the present study can therefore be interpreted to reflect intermuscle coordination required for different functions (Humphrey and
Freund 1991; Scott and Kalaska 1997; Passingham et al. 2002),
such as coordination between wrist extensor and finger flexor
muscles. Consistent with recent theories on pain adaptation
(Hodges and Tucker 2011), an increase in the number of discrete
peaks may reflect the search for a new motor strategy that utilizes synergies with surrounding muscles to redistribute muscle
activity and reduce loading on a painful structure.
The finding of increased map peaks in the transition from
acute to maintained pain is in contrast to a reduced number of
peaks observed in chronic elbow pain (lateral epicondylalgia)
in cross-sectional studies (Schabrun, Hodges et al. 2014). This
discrepancy may be explained by the long duration of pain
(>6 weeks) used to classify individuals with chronic lateral epicondylalgia. Increased excitability and reorganization of motor
cortical maps is known to occur in the early stages of motor
learning (Pascual-Leone et al. 1994, 1995). However, once a new
motor strategy is acquired and becomes more automatic, motor
representations contract (Pascual-Leone et al. 1994). A similar
pattern may exist in the early versus late stages of sustained
muscle soreness as a new motor strategy is first sought and
then adopted. Indeed, studies have shown increased variability
in trunk muscle activation in acute experimentally induced
back pain (Hodges et al. 2013) but decreased variability in individuals with chronic back pain (Falla et al. 2014).
The Influence of Progressively Developing Muscle
Soreness on Intracortical Networks
This study is the first to examine cortical organization and inhibitory networks in tandem in response to progressively developing
muscle soreness. Sustained muscle soreness reduced intracortical inhibition and increased intracortical facilitation. The direction (increased corticomotor excitability) and time-course
(changes evident at Day 4) was similar to that observed for cortical reorganization. As cortical representations are known to
be maintained and adjusted by GABAergic intracortical inhibitory networks (Liepert et al. 1998), altered intracortical activity
is a plausible mechanism to explain M1 reorganization in the
current study.
Schabrun et al.
| 1887
Previous studies have reported a reduction in intracortical inhibition (GABAA mediated) and facilitation (glutamate mediated)
in chronic pain conditions such as low back pain (Masse-Alarie
et al. 2012), fibromyalgia (Mhalla et al. 2010), and complex regional pain syndrome (Schwenkreis et al. 2003; Eisenberg et al. 2005).
Yet, intracortical inhibition is increased (facilitation remains reduced) in response to acute muscle pain (Schabrun and Hodges
2012). This finding, coupled with data from the present study,
suggests a reversal of inhibitory activity that develops early in
the transition to sustained muscle soreness (Day 4) and persists
when pain becomes chronic. Although this temporal profile requires further investigation, differences in inhibitory networks
between acute and chronic pain may reflect the type of motor
strategy employed at each stage. For instance, the goal of the
motor system immediately following the onset of acute pain
may be to restrict motor output to the painful part in order to prevent further injury (Schabrun and Hodges 2012). Conversely, pain
that persists may require a release of intracortical inhibition in
order to support cortical reorganization and redistribution of
muscle activity during the search for alternate motor strategies
(Hodges and Tucker 2011). Although the effect of sustained
elbow pain on SICI and ICF in the present study is complementary, several authors have suggested that inhibitory and facilitatory networks act independently (Ziemann et al. 1996; Liepert
et al. 1998). This may explain why ICF, but not SICI, was associated with greater pain and disability in the current study.
In contrast to data for cortical organization and intracortical
networks, active motor threshold was increased at Day 4. This
finding could be explained by decreased spinal motoneuron excitability, reduced corticospinal excitability, or a combination of
both, during active contraction. As spinal motoneuron excitability was not measured in the present study, it is not possible to determine the relative contribution of cortical versus spinal
mechanisms, and this limitation should be addressed in future
work. Regardless of the precise mechanism, increased active
motor threshold could explain the reduction in grip force on
the affected side. In support of this hypothesis, the increase in active motor threshold in the current study was associated with reduced grip force on the affected side. This finding is consistent
with previous studies of chronic low back pain where higher active motor threshold has been shown to be correlated with poorer
synchronization between transversus abdominus and internal
oblique muscle onset (Masse-Alarie et al. 2012) and with higher
disability (Strutton et al. 2005). One consideration is whether
the increase in active motor threshold contaminated the measurement of SICI and ICF. Although this possibility cannot be
ruled out, an increase in active motor threshold would be expected to produce an underestimation of the effects observed
in the present study (i.e., increased active motor threshold
would be expected to reduce excitability).
The Influence of Progressively Developing Muscle
Soreness on IHI
Bilateral sensorimotor dysfunction is observed in chronic unilateral pain conditions. For instance, individuals with unilateral lateral epicondylalgia display flexed wrist postures, increased
upper-limb reaction times, reduced speed of movement, and increased pressure and thermal pain thresholds in the unaffected
limb (Pienimaki et al. 1997; Bisset et al. 2006; Heales et al. 2014),
indicating a role for supraspinal mechanisms. This study is the
first to examine IHI in the transition to sustained muscle pain.
IHI was reduced from the left (“affected”) to the right (“unaffected”) hemisphere at both short and long latencies at Day
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| Cerebral Cortex, 2016, Vol. 26, No. 5
4. There was no change in IHI from the right (“unaffected”) to the
left (“affected”) hemisphere. There is good evidence that IHI is
mediated via transcallosal pathways and is of cortical origin
(Meyer et al. 1995; Di Lazzaro et al. 1999; Reis et al. 2008). Consistent with data from chronic lateral epicondylalgia, a reduction in
PPTs was found in the unaffected left m. ECRB at Day 4. As PPTs
are reliable when recorded over multiple days (Nussbaum and
Downes 1998), this effect is unlikely to be due to the repeatedmeasures design.
A particularly novel finding was the association between a
greater reduction in IHI at both short and long latency and
the reduction in PPTs in left m. ECRB. These data provide the
first evidence of a release of inhibition from the affected to
the unaffected hemisphere during the transition to sustained
muscle pain that could underpin bilateral changes in sensorimotor dysfunction observed in chronic pain states. Although
the precise mechanism is unknown, it is possible that a release
of IHI influenced PPTs on the unaffected side through reduced
inhibition of thalamic neurons. It is well documented that M1
stimulation relieves pain, an effect likely mediated via corticothalamic projections that induce suppression of sensory information relayed in the spinothalamic tract (Lefaucheur
et al. 2006; Lucas et al. 2011). In addition, imaging studies reveal
effects of M1 stimulation on other pain-processing regions including the anterior cingulate cortex, orbitofrontal cortex, insula, secondary sensory cortex, and periaqueductal gray
matter (PAG) (Garcia-Larrea et al. 1999; Garcia-Larrea and Peyron 2007; Peyron et al. 2007). One possibility is that release of IHI
in the unaffected hemisphere reduces downstream inhibition
of thalamic neurons, the PAG, and/or other pain-processing regions, increasing sensitivity to pressure stimuli. However, the
relationship between altered M1 excitability and pain sensitivity has not yet been characterized. This hypothesis requires
further investigation before the specific mechanistic pathways
can be disentangled.
The Effect of an Acute Exacerbation of Muscle Pain
in a NGF Sensitized System
The induction of an acute exacerbation of muscle pain in a system already sensitized by NGF produced opposite effects on
corticomotor excitability, but similar effects on intracortical
networks, to those seen when acute muscle pain is induced in
healthy individuals (Le Pera et al. 2001; Svensson et al. 2003;
Martin et al. 2008; Schabrun and Hodges 2012). Increased corticomotor excitability was observed during and after acute muscle pain, and this effect was accompanied by a reduction in
ICF, but no change in SICI, during pain. The reduction in ICF,
and no change in SICI, during pain is consistent with previous
studies of hypertonic saline injection in healthy individuals
(Schabrun and Hodges 2012). Why corticomotor excitability
was increased in the NGF sensitized system is unclear. However,
as individually recorded MEPs provide a measure of excitability
of the entire pathway from cortex to muscle, 1 possibility is that
excitation observed in the NGF sensitized system reflects
changes occurring at the level of the spinal motoneuron.
These data indicate that an acute exacerbation of muscle pain
in a sensitized system may increase spinal excitability without
concomitant changes in motor cortical excitability. This finding
may have relevance for clinical pain states that display acute exacerbation of muscle pain in the presence of ongoing muscle
soreness. Future studies should seek to clarify the contribution
of spinal motoneuron excitability to the findings outlined in this
study.
Conclusions
Primary motor cortical organization and function are altered in
the transition to sustained muscle soreness and are further potentiated by an acute exacerbation of muscle pain. Changes become evident after 4 days of progressing intensity of muscle
soreness. Altered organization is characterized by increased
map volume and an increased number of map peaks and is accompanied by altered function of intracortical networks (reduced
intracortical inhibition and increased ICF). A release of IHI from
the “affected” to the “unaffected” hemisphere occurs at Day 4
and is associated with a reduction in PPTs in the asymptomatic
m. ECRB. These findings provide the first insight into the nature
and temporal profile of M1 adaptation in the transition to sustained muscle pain. This information may have relevance for
the development of therapeutic interventions that seek to M1
in the transition period.
Funding
S.M.S. is supported by a Clinical Research Fellowship (ID631612)
from the National Health and Medical Research Council of
Australia.
Notes
Conflict of Interest: None declared.
References
Adachi K, Murray GM, Lee JC, Sessle BJ. 2008. Noxious lingual
stimulation influences the excitability of the face primary
motor cerebral cortex (face MI) in the rat. J Neurophysiol.
100:1234–1244.
Alizadehkhaiyat O, Fisher AC, Kemp GJ, Vishwanathan K,
Frostick SP. 2007. Upper limb muscle imbalance in tennis
elbow: a functional and electromyographic assessment.
J Orthop Res. 25:1651–1657.
Bergin M, Hirate R, Mista C, Christensen SW, Tucker KT,
Vicenzino B, Hodges PW, Graven-Nielsen T. 2014. Sustained
mechanical hyperalgesia and pain during movement after
intramuscular injection of nerve growth factor into a forearm
muscle. In: International Association for the Study of Pain:
World Congress on Pain. Rio de janeiro, Argentina.
Bisset LM, Russell T, Bradley S, Ha B, Vicenzino BT. 2006. Bilateral
sensorimotor abnormalities in unilateral lateral epicondylalgia. Arch Phys Med Rehabil. 87:490–495.
Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC,
Cohen LG. 1998. Intracortical inhibition and facilitation
in different representations of the human motor cortex.
J Neurophysiol. 80:2870–2881.
Chipchase L, Schabrun S, Cohen L, Hodges P, Ridding M,
Rothwell J, Taylor J, Ziemann U. 2012. A checklist for assessing
the methodological quality of studies using transcranial magnetic stimulation to study the motor system: An international
consensus study. Clin Neurophysiol. 123:1698–1704.
Cunningham DA, Machado A, Yue GH, Carey JR, Plow EB. 2013.
Functional somatotopy revealed across multiple cortical regions using a model of complex motor task. Brain Res.
1531:25–36.
Dechent P, Frahm J. 2003. Functional somatotopy of finger representations in human primary motor cortex. Hum Brain Mapp.
18:272–283.
Motor Cortical Organization of Sustained Muscle Pain
Devanne H, Cassim F, Ethier C, Brizzi L, Thevenon A, Capaday C.
2006. The comparable size and overlapping nature of upper
limb distal and proximal muscle representations in the
human motor cortex. Eur J Neurosci. 23:2467–2476.
Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P,
Rothwell JC. 1999. Direct demonstration of interhemispheric
inhibition of the human motor cortex produced by transcranial magnetic stimulation. Exp Brain Res. 124:520–524.
Dyck PJ, Peroutka S, Rask C, Burton E, Baker MK, Lehman KA,
Gillen DA, Hokanson JL, O’Brien PC. 1997. Intradermal recombinant human nerve growth factor induces pressure allodynia
and lowered heat-pain threshold in humans. Neurology.
48:501–505.
Eisenberg E, Chistyakov AV, Yudashkin M, Kaplan B, Hafner H,
Feinsod M. 2005. Evidence for cortical hyperexcitability of
the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study. Pain.
113:99–105.
Falla D, Gizzi L, Tschapek M, Erlenwein J, Petzke F. 2014. Reduced
task-induced variations in the distribution of activity across
back muscle regions in individuals with low back pain. Pain.
155:944–953.
Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD.
1992. Interhemispheric inhibition of the human motor cortex.
J Physiol. Lond. 453:525–546.
Fierro B, De Tommaso M, Giglia F, Giglia G, Palermo A, Brighina F.
2010. Repetitive transcranial magnetic stimulation (rTMS) of
the dorsolateral prefrontal cortex (DLPFC) during capsaicininduced pain: modulatory effects on motor cortex excitability.
Exp Brain Res. 203:31–38.
Garcia-Larrea L, Peyron R. 2007. Motor cortex stimulation for
neuropathic pain: From phenomenology to mechanisms.
Neuroimage. 37(Suppl 1):S71–S79.
Garcia-Larrea L, Peyron R, Mertens P, Gregoire MC, Lavenne F, Le
Bars D, Convers P, Mauguiere F, Sindou M, Laurent B. 1999.
Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study. Pain.
83:259–273.
Harris-Love ML, Perez MA, Chen R, Cohen LG. 2007. Interhemispheric inhibition in distal and proximal arm representations
in the primary motor cortex. J Neurophysiol. 97:2511–2515.
Hayashi K, Shiozawa S, Ozaki N, Mizumura K, Graven-Nielsen T.
2013. Repeated intramuscular injections of nerve growth
factor induced progressive muscle hyperalgesia, facilitated
temporal summation, and expanded pain areas. Pain. 154:
2344–2352.
Heales LJ, Lim EC, Hodges PW, Vicenzino B. 2014. Sensory and
motor deficits exist on the non-injured side of patients with
unilateral tendon pain and disability—implications for central nervous system involvement: a systematic review with
meta-analysis. Br J Sports Med. 48:1400–1406.
Hodges PW, Coppieters MW, MacDonald D, Cholewicki J. 2013.
New insight into motor adaptation to pain revealed by a combination of modelling and empirical approaches. Eur J Pain.
17:1138–1146.
Hodges PW, Tucker K. 2011. Moving differently in pain: A new theory to explain the adaptation to pain. Pain. 152:S90–S98.
Humphrey DR, Freund HJ, editors. 1991. Motor Control: Concepts
and Issues. City: Wiley.
Keel JC, Smith MJ, Wassermann EM. 2001. A safety screening
questionnaire for transcranial magnetic stimulation. Clin
Neurophysiol. 112:720.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD,
Ferbert A, Wroe S, Asselman P, Marsden CD. 1993.
Schabrun et al.
| 1889
Corticocortical inhibition in human motor cortex. J Physiol
Lond. 471:501–519.
Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Keravel Y,
Nguyen JP. 2006. Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain. Neurology.
67:1568–1574.
Le Pera D, Graven-Nielsen T, Valeriani M, Oliviero A, Di Lazzaro V,
Tonali PA, Arendt-Nielsen L. 2001. Inhibition of motor system
excitability at cortical and spinal level by tonic muscle pain.
Clin Neurophysiol. 112:1633–1641.
Liepert J, Classen J, Cohen LG, Hallett M. 1998. Task-dependent
changes of intracortical inhibition. Exp Brain Res. 118:421–426.
Lucas JM, Ji Y, Masri R. 2011. Motor cortex stimulation reduces
hyperalgesia in an animal model of central pain. Pain.
152:1398–1407.
Macdermid J. 2005. Update: the patient-rated forearm evaluation
questionnaire is now the patient-rated tennis elbow evaluation. J Hand Ther. 18:407–410.
Malcolm MP, Triggs WJ, Light KE, Shechtman O, Khandekar G,
Gonzalez Rothi LJ. 2006. Reliability of motor cortex transcranial magnetic stimulation in four muscle representations.
Clin Neurophysiol. 117:1037–1046.
Martin PG, Weerakkody N, Gandevia SC, Taylor JL. 2008. Group III
and IV muscle afferents differentially affect the motor cortex
and motoneurones in humans. J Physiol Lond. 586:1277–1289.
Masse-Alarie H, Flamand VH, Moffet H, Schneider C. 2012. Corticomotor control of deep abdominal muscles in chronic low
back pain and anticipatory postural adjustments. Exp Brain
Res. 218:99–109.
Melzack R. 1987. The short-form Mcgill pain questionnaire. Pain.
30:191–197.
Meyer BU, Roricht S, Grafin von Einsiedel H, Kruggel F, Weindl A.
1995. Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients
with abnormalities of the corpus callosum. Brain. 118(Pt
2):429–440.
Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. 2010.
Alteration of cortical excitability in patients with fibromyalgia. Pain. 149:495–500.
Nash PG, Macefield VG, Klineberg IJ, Gustin SM, Murray GM,
Henderson LA. 2010. Changes in human primary motor cortex
activity during acute cutaneous and muscle orofacial pain. J
Orofac Pain. 24:379–390.
Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R. 2009. Bi-directional
interhemispheric inhibition during unimanual sustained
contractions. BMC Neurosci. 10:31.
Ngomo S, Leonard G, Moffet H, Mercier C. 2012. Comparison of
transcranial magnetic stimulation measures obtained at rest
and under active conditions and their reliability. J Neurosci
Methods. 205:65–71.
Nussbaum EL, Downes L. 1998. Reliability of clinical pressurepain algometric measurements obtained on consecutive
days. Phys Ther. 78:160–169.
Ortu E, Deriu F, Suppa A, Tolu E, Rothwell JC. 2008. Effects of volitional contraction on intracortical inhibition and facilitation
in the human motor cortex. J Physiol. 586:5147–5159.
Pascual-Leone A, Grafman J, Hallett M. 1994. Modulation of cortical motor output maps during development of implicit and
explicit knowledge. Science. 263:1287–1289.
Pascual-Leone A, Nguyet D, Cohen LG, Brasil-Neto JP,
Cammarota A, Hallett M. 1995. Modulation of muscle responses evoked by transcranial magnetic stimulation during
the acquisition of new fine motor skills. J Neurophysiol.
74:1037–1045.
1890
| Cerebral Cortex, 2016, Vol. 26, No. 5
Passingham RE, Stephan KE, Kotter R. 2002. The anatomical basis
of functional localization in the cortex. Nat Rev Neurosci.
3:606–616.
Perez MA, Cohen LG. 2008. Mechanisms underlying functional
changes in the primary motor cortex ipsilateral to an active
hand. J Neurosci. 28:5631–5640.
Peyron R, Faillenot I, Mertens P, Laurent B, Garcia-Larrea L. 2007.
Motor cortex stimulation in neuropathic pain. Correlations
between analgesic effect and hemodynamic changes in the
brain. A PET study. Neuroimage. 34:310–321.
Pienimaki TT, Kauranen K, Vanharanta H. 1997. Bilaterally decreased motor performance of arms in patients with chronic
tennis elbow. Arch Phys Med Rehabil. 78:1092–1095.
Plow EB, Arora P, Pline MA, Binenstock MT, Carey JR. 2010. Withinlimb somatotopy in primary motor cortex—revealed using
fMRI. Cortex. 46:310–321.
Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA,
Harris-Love M, Perez MA, Ragert P, Rothwell JC, Cohen LG.
2008. Contribution of transcranial magnetic stimulation to
the understanding of cortical mechanisms involved in
motor control. J Physiol. 586:325–351.
Sattler V, Dickler M, Michaud M, Simonetta-Moreau M. 2012. Interhemispheric inhibition in human wrist muscles. Exp
Brain Res. 221:449–458.
Schabrun SM, Elgueta-Cancino E, Hodges PW. 2014. Smudging of
the motor cortex is related to the severity of low back pain
Spine. In press.
Schabrun SM, Hodges PW. 2012. Muscle pain differentially modulates short interval intracortical inhibition and intracortical
facilitation in primary motor cortex. J Pain. 13:187–194.
Schabrun SM, Hodges PW, Vicenzino B, Jones E, Chipchase LS.
2014. Novel Adaptations in Motor Cortical Maps: The Relationship to Persistent Elbow Pain. Med Sci Sports Exerc. Epub
ahead of print, PMID 25102290.
Schabrun SM, Jones E, Elgueta Cancino EL, Hodges PW. 2014. Targeting Chronic Recurrent Low Back Pain From the Top-down
and the Bottom-up: A Combined Transcranial Direct Current
Stimulation and Peripheral Electrical Stimulation Intervention. Brain Stimul. 7:451–459.
Schabrun SM, Jones E, Kloster J, Hodges PW. 2013. Temporal
association between changes in primary sensory cortex and
corticomotor output during muscle pain. Neuroscience.
235:159–164.
Schabrun SM, Ridding MC. 2007. The influence of correlated afferent input on motor cortical representations in humans.
Experimental Brain Research. 183:41–49.
Schabrun SM, Stinear CM, Byblow WD, Ridding MC. 2009. Normalizing Motor Cortex Representations in Focal Hand Dystonia. Cerebral Cortex. 19:1968–1977.
Schwenkreis P, Janssen F, Rommel O, Pleger B, Volker B,
Hosbach I, Dertwinkel R, Maier C, Tegenthoff M. 2003. Bilateral
motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand. Neurology. 61:515–519.
Scott SH, Kalaska JF. 1997. Reaching movements with similar
hand paths but different arm orientations .1. Activity of individual cells in motor cortex. J Neurophysiol. 77:826–852.
Strother L, Medendorp WP, Coros AM, Vilis T. 2012. Double representation of the wrist and elbow in human motor cortex.
Eur J Neurosci. 36:3291–3298.
Strutton PH, Theodorou S, Catley M, McGregor AH, Davey NJ.
2005. Corticospinal excitability in patients with chronic low
back pain. Journal of Spinal Disorders & Techniques. 18:
420–424.
Svensson P, Miles TS, McKay D, Ridding MC. 2003. Suppression of
motor evoked potentials in a hand muscle following prolonged painful stimulation. European Journal of PainLondon. 7:55–62.
Tsao H, Danneels LA, Hodges PW. 2011. ISSLS Prize Winner:
Smudging the Motor Brain in Young Adults With Recurrent
Low Back Pain. Spine. 36:1721–1727.
Tsao H, Galea MP, Hodges PW. 2008. Reorganization of the motor
cortex is associated with postural control deficits in recurrent
low back pain. Brain. 131:2161–2171.
Uy J, Ridding M, Miles T. 2002. Stability of Maps of Human Motor
Cortex Made with Transcranial Magnetic Stimulation. Brain
Topography. 14:293–297.
Wassermann EM, McShane LM, Hallett M, Cohen LG. 1992. Noninvasive mapping of muscle representations in human
motor cortex. Electroencephalogr Clin Neurophysiol. 85:1–8.
Ziemann U, Rothwell JC, Ridding MC. 1996. Interaction between
intracortical inhibition and facilitation in human motor cortex. Journal of Physiology-London. 496:873–881.