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Normalization of aberrant resting state functional connectivity in fibromyalgia patients following a three month physical exercise therapy

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  • University of Gothenburg, Sahlgrenska Academy, Institute of Neuroscience and Physiology

Abstract and Figures

Physical exercise is one of the most efficient interventions to mitigate chronic pain symptoms in fibromyalgia (FM). However, little is known about the neurophysiological mechanisms mediating these effects. In this study we investigated resting-state connectivity using functional magnetic resonance imaging (fMRI) before and after a 15 week standardized exercise program supervised by physical therapists. Our aim was to gain an understanding of how physical exercise influences previously shown aberrant patterns of intrinsic brain activity in FM. Fourteen FM patients and eleven healthy controls successfully completed the physical exercise treatment. We investigated post- versus pre-treatment changes of brain connectivity, as well as changes in clinical symptoms in the patient group. FM patients reported improvements in symptom severity. Although several brain regions showed a treatment-related change in connectivity, only the connectivity between the right anterior insula and the left primary sensorimotor area was significantly more affected by the physical exercise among the fibromyalgia patients compared to healthy controls. Our results suggest that previously observed aberrant intrinsic brain connectivity patterns in FM are partly normalized by the physical exercise therapy. However, none of the observed normalizations in intrinsic brain connectivity were significantly correlated with symptom changes. Further studies conducted in larger cohorts are warranted to investigate the precise relationship between improvements in fibromyalgia symptoms and changes in intrinsic brain activity.
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Normalization of aberrant resting state functional connectivity in
bromyalgia patients following a three month physical exercise therapy
P. Flodin
a,
*
,S.Martinsen
a
,K.Mannerkorpi
b
, M. Löfgren
c
, I. Bileviciute-Ljungar
c
,E.Kosek
a
, P. Fransson
a
a
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
b
Department of Rheumatology and Inammation Research, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
c
Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
abstractarticle info
Article history:
Received 1 June 2015
Received in revised form 29 July 2015
Accepted 6 August 2015
Available online 18 August 2015
Keywords:
Fibromyalgia
Physical exercise
Resting state fMRI
Functional connectivity
Physical exercise is one of the most efcient interventions to mitigate chronic pain symptoms in bromyalgia
(FM). However, little is known about the neurophysiological mechanisms mediating these effects. In this study
we investigated resting-state connectivity using functional magne tic resonance imaging (fMRI) before and
after a 15 week standardized exercise program supervised by physical therapists. Our aim was to gain an under-
standing of how physical exercise inuences previously shown aberrant patterns of intrinsic brain activity in FM.
Fourteen FM patients and eleven healthy controls successfully completed the physical exercise treatment. We
investigated post- versus pre-treatment changes of brain connectivity, as well as changes in clinical symptoms
in the patient group. FM patients reported improvements in symptom severity. Although several brain regions
showed a treatment-related change in connectivity, only the connectivity between the right anterior insula
and the left primary sensorimotor area was signicantly more affected by the physical exercise among the bro-
myalgia patients compared to healthy controls. Our results suggest that previously observed aberrant intrinsic
brain connectivity patterns in FM are partly normalized by the physical exercise therapy. However, none of the
observed normalizations in intrinsic brain connectivity were signicantly correlated with symptom changes. Fur-
ther studies conducted in larger cohorts are warranted to investigate the precise relationship between improve-
ments in bromyalgia symptoms and changes in intrinsic brain activity.
© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Introduction
Fibromyalgia (FM) is a condi tion characterized by widespread
chronic pain and is often accompanied by cognitive dysfunction and fa-
tigue. The pathogenesis is still largely unknown, but there is evidence of
both peripheral and central pathophysiology (for a review, see Clauw,
2014). The diagnosis is currently based on self-reported pain, and as of
yet, no laboratory test can directly test for FM. Intriguingly however,
several brain imaging studies of FM patients indicate an altered func-
tional brain structure which is related to aberrant pain evoked brain
activation , particularly in the anterior cingulate cortex and thalamus
(Jensen et al., 2013). Resting state brain connectivity constitutes
a promising complement to the traditional task-based fMRI studies
employing subtraction designs that disregard the brain activity reecting
sustained pain states. Resting state fMRI studies have reported altered
intrinsic brain activity in FM patients including: decreased connectivity
between insula and prefrontal areas (Ichesco et al., 2014) and the
periaqueductal grey (PAG) (Pujol et al., 2014), increased connectivity
between insula and medial regions of the default mode network (DMN)
(Napad ow et al., 2010), and decreased connectivity between somatosen-
sory regions and visual and auditory cortices (Pujol et al., 2014). Using a
comprehensive set of analytical approaches to characterize intrinsic
brain activity in FM, we recently showed a decreased connectivity
between pain-related and sensorimotor brain areas during rest (Flodin
et al., 2014).
Physical exercise is a potent treatment for FM, on par with the ef-
ciency of cognitive behavioural therapy, education in coping strategies
and phar macological in terve ntions (Clauw, 2014). In th is study, we
aimed to investigate if physical exercise could normalize the previously
described aberrant patterns of intrinsic brain connectivity in FM and if
this was related to symptom improvement. To our knowledge, this is
the rst study to investigate the longitudinal effects of physical exercise
NeuroImage: Clinical 9 (2015) 134139
Abbreviations: FM, bromyalgia; PAG, periaqueductal grey; FIQ, Fibromyalgia Impact
Questionnaire; SF36BP, bodily pain subscale of the Short Form Health Survey.
* Corresponding author at: Department of Clinical Neuroscience, Karolinska Institutet,
Nobels väg 9, Stockholm SE-171 77, Sweden. Tel.: +46 709 243172.
E-mail address: parodin@gmail.com (P. Flodin).
http://dx.doi.org/10.1016/j.nicl.2015.08.004
2213-1582/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Contents lists available at ScienceDirect
NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl
on intrinsic brain activity in FM. Our hypothesis was that the physical
training program would inuence the previously detected deviant con-
nectivity patterns in six pairs of brain ROI-to-ROI (Region-of-Interest)
connectivity in FM patients (Flodin et al., 2014). We further aimed to in-
vestigate the extent to which longitudinal changes in connectivity cor-
related with changes in symptoms.
2. Methods
2.1. Subjects
Subject recruitment and inclusion criteria were identical to our base-
line study (Flodin et al., 2014). All FM patients satised the American
College of Rheumatology (ACR) 1990 disease criteria for FM. Of the 16
female subjects included in the baseline study, two subjects failed to
comply with the longitudinal study protocol. The mean age of the re-
maining fourteen subjects was 48.4 (range 2564) years (all female).
The mean symptom gravity (assessed with the Fibromyalgia Impact
Questionnaire (FIQ), see Bennett, 2005 for reference) was 60.8 (SD =
11.8), and the mean FM duration was 7.3 years ( SD = 4.0). Among
the 22 female subjects originally inc luded a s healthy controls in the
baseline study, nine subjects were only scanned once, fMRI data from
one subject was discarded due to excessi ve head-motion, and fMRI
data from one sub ject was rejected due to technical failures in the
image acquisition process. Thus, fMRI res ting-state data from eleven
healthy controls were included (mean age 41.8 years, range 2063).
2.2. Training intervention
A 15-week exercise program with two sessions each week was carried
out under supervis ion from a physio therapi st (PT). Before the part icipants
started the intervention, they had individual meetings with a PT who test-
ed their one repetition maximum (1 RM) and tolerance before deciding
the initial load of each exercise. At the same time the participants received
individual instructions for each exercise. Each session lasted for about 1 h
and included 10 min of warming up by ergometer cycling, isometric exer-
cises for the deep muscles in the back and stomach, and concentric and
non-concentric exercises for the legs, back, stomach, arms and hands.
The program ended with stretching exercises.
The participants3 individual 1 RM for the different exercises were
tested before starting and at three time points during the program. For
the legs and arms the initial loads were set at approximately 40% of
one 1 RM and the participants were instructed to repeat each exercise
1520 times in one to three sets within symptom tolerance. In between
each set, the participants rested for at least 45 s. After 5 weeks the load
was raised up to about 50% of 1 RM with 2 sets of 1215 repetitions,
after 8 weeks up to about 60% of 1 RM with 2 sets of 1012 repetitions
and after 12 weeks up to about 70% of 1 RM with 2 sets of 810 repeti-
tions. Leg exercises for explosive strength were also included at weeks
ve and eight.
The participants reported pain and other adverse effects of the exer-
cise program to the PT during every session. In the case that the level of
pain increased without returning back to normal within a few days, the
participants were instructed to lower the load, but continue to do the
exercise. The same instructions were given if the participants had a
bad day or an increase of symptoms. If any special exercise was causing
problems the participants were instructed to refrain from doing it. The
PT followed up on program compliance; if participants did not partici-
pate in a session they were instructed to give notice with the reason
of absence, on which the physiotherapist made a follow-up phone call.
The overall compliance rate was high, with an average of 29.12 (SD =
3.2) training sessions taken for the 25 participants (for FM: M = 29.4,
SD =1.6;HC:M = 28.7, SD = 4.5). There was no signicant group dif-
ference with regard to compliance (t(23) = 0.52, p
=.60).
2.
3. Behavioural measures
We used two behavioural measures to estimate pain and bromyalgia
symptomatology. We used the bodily pain subscale of the Short Form
Health Survey (SF36BP) for pain assessment, since this assesses pain dur-
ing a 4 week period and thus reects long-term changes, disregarding
temporary uctuations in pain intensity (Contopoulos-Ionannidis et al.,
2009). In addition, we used the Fibromyalgia Impact Questionnaire
(FIQ), which is a general questionnaire regarding the impact of bromy-
algia on everyday life (Bennett, 2005).
2.4. MRI data acquisition
Anatomical and functional MR imaging were performed on a 3 T
General Electric 750 MR scanner. For each subject we performed one
resting state scan consisting of 200 volumes, using an echo-planar imag-
ing sequence with TR/TE = 2500/30 ms, ip = 90°, 49 slices, 96 × 96
matrix size, FOV = 288×288 mm, slice thickness = 3 mm using inter-
leaved slice acquisition. In the resting state condition, subjects were
instructed to lie still and rest, and keep their eyes closed and try not to
fall asleep. Prior to the resting state fMRI data acquisition, subjects
underwent two fMRI sessions of a task-evoked pain fMRI paradigm
(approx. 7 min each), and two sessions of an fMRI adopted version of
the Stroop task (approx. 7 min each). Data from the task-evoked fMRI
sessions will be reported elsewhere.
2.5. Resting state fMRI data analysis
In this study we investigated longitudinal changes (post- versus pre-
physical exercise treatment) of functional connectivity of six seed re-
gions located in pain regions as dema rked by a metaanalysis on 314
pain studies carried out in the framework of neurosynth (Yarkoni
et al., 2011), that we previously found to be affected by FM in our base-
line study (FM: n = 16, HC: n = 22, see Flodin et al., 2014). Specically,
the spherical Region-of-Interest (ROI, with a radius of 4 mm) were lo-
cated in the insula, sensorimotor cortex and thalamus. A detailed list
of the anatomical location of the ve seed ROIs and the corresponding
six target clusters is given in Table 1. Supplementary Fig. S1 illustrates
the whole brain connectivity maps pertaining to eac h of the seed
regions shown at baseline for both the FM and the HC cohort.
Image preprocessing, seed-based correlation analysis (SCA) and
group-level analyses were carried out in Matlab (Mathworks Inc., Na-
tick, MA, USA). Prior to SCA, imaging data were preprocessed using
the Matlab toolbox SPM12 (Wellcome Trust Centre of Neuroimaging,
University College London, UK). Image preprocessing included slice
time correction to the middle slice, realignment to the mean im age
using the 4th degree of B-spline interpolation, co-registration of func-
tional and structural images, tissue segmentation of structural images,
normalization of structural and functional scans to the MNI template
using the deformation eld obtained from the segmentation (4th de-
gree B-spline function, resampling to 2 mm isotropic voxels). Finally,
functional volumes were spatially smoothed using an 8 mm FWHM
Gaussian kernel. Subject level SCA analyses were carried out using
the Conn toolbox (
http ://www.nitrc.org/p rojects/conn)(Whitel d-
Gabrieli & Nieto-Castanon, 2012). Functional volumes were band pass
ltered at 0.0080.09 Hz (default values). Subject specicnuisancere-
gressors included 6 movement and their time derivatives, and 5 regres-
sors pertaining to white matter and CSF signals respe ctively, using a
component based noise correction (CompCor) approach (Behzadi
et al., 2007). Additionally, images that were regarded as movement out-
liers were regressed out. Outliers were detected using the ART toolbox
(
http://nitrc.org/projects/ar tifact_detect/) and dened as volumes
with frame wise displacement (FD) larger than 0.5 mm or signal inten-
sity changes greater than 3 standard deviations (default thresholds). For
both pre- and post-treatment fMRI data, estimates for the strength of
135P. Flodin et al. / NeuroImage: Clinical 9 (2015) 134139
resting-state functional connectivity were obtained from each subject
and for each of the six ROI-to-ROI connectivity pairs.
The computed estimate of the strength of connectivity (β values) be-
tween the seed ROIs and target clusters was subsequently used at a sec-
ond level group model of differences in intrinsic connectivity (Δβ
FM
and
Δβ
HC
) (after controlling for age and inter-individual differences in mean
frame-wise displacement, see Flodin et al., 2014). Additionally, we test-
ed for the relationship between changes in functional connectivity and
changes in behaviour (post-minus pre-physical exercise treatment),
using the Pearson correlation coefcient. Since we were interested in
connectivity change s that were specic to the FM condition (rather
than general training effects independent of group), we compared the
post- versus pre-change in intrinsic brain connectivity in the FM pa-
tients versus the HC cohort (Δβ specicity = |Δβ
FM
Δβ
HC
|). Due to
relatively unequal group sizes (14 FM and 11 HC), we conducted per-
mutation tests that are less sensitive to unbalanced designs compared
to parametric t-tests. Thus, for each of the six seed-target connectivity
pairs, we estimated the likelihood of the observed group difference,
given the null hypothesis that there would be no difference in longitudi-
nal change in connectivity, by randomly shufin g the group membershi p
of the subjects (1000 permutations, p-value threshold b0.05, Bonferroni
corrected).
3. Results
3.1. Behaviour
Pre-treatment, the mean SF36BP score for the FM cohort was
37.00 ± 9.70, (highest subjective health, i.e. no pain = 100) whereas
the post-treatment score was 37.07 ± 11.40 (t(14) = 0.026, p =
0.98). Furthe r, in the FM cohort, the pre-treatment mean FIQ was
60.8 ± 11.8 (maximally severe FM impact = 100), and for post-
training 53.3 ± 29.5 (t(13) = 2.282, p = 0.040, effect size r = 0.53).
The FIQ and SF36BP were negatively correlated both pre- (r = 0.78,
p = 0.00080) and post-treatment (r = 0.79, p = 0.00089) (Fig. 1).
3.2. Intrinsic brain connectivity
Out of the six seed connectivity pairs tested, four showed a signi-
cant normalization among the FM patients (see Table 1). The observed
changes included an increased connectivity between the right anterior
insula and left primary sensory motor areas, the right supramarginal
gyrus and primary sensorimotor areas, and the right supramarginal
gyrus and left inferior prefrontal cortex. The aberrantly high baseline
connectivity in FM between supramarginal gyrus and cerebellum was
normalized. Noteworthy, also healthy controls showed signicant lon-
gitudinal connectivity changes. Hence, in order to investigate the extent
to which the change in intrinsic connectivity was selective to the FM
group, we performed permutation tests by which the absolute differ-
ence in magnitude of the connectivity change between the two groups
was compared. In the permutation test, only the change in connectivity
between the insula and primary sensorimotor regions showed a selec-
tive normalization in the FM group (see Table 1 an d Fig. 2). None of
the treatment-related changes in intrinsic connectivity correla ted
signicantly with the FIQ or SF36BP scores (Table 1).
4. Discussion and conclusion
In this study we have shown that the previously reported abnormal
patterns of resting state connectivity in FM patients are partly normal-
ized after a 3 month schedule of regular physical exercise. Although
several intrinsic brain connectivity patterns underwent longitudinal
change, only the c onnectivity between the right insula and primary
sensorimotor cortex displayed a selectively greater change for FM com-
pared to HC. It should be noted that all the seed regions used in the cur-
rent study belongs to a set of brain areas that commonly are activated in
Table 1
Functional connectivity
(seed) (target)
Δβ
FM
t (p)
Δβ
HC
t (p)
Δβ specicity
|Δβ
FM
Δβ
HC
| t (p)
β
HC
N β
FM
baseline t (p)
Correlation of Δβ
FM
and FIQ
r (p)
Insula (40, 24, 8) S1/M1 (30, 22, 68) 3.95
(.0017)*
0.133
(.90)
0.12
(.0050)*
3.064
(.0055)*
0.019
(.95)
Supr. gyr. (60, 36, 28) S1/M1 (10, 24, 80) 3.12
(.0081)*
0.98
(.35)
0.023
(0.48)
3.12
(.0048)*
0.14
(.63)
Supr. gyr. (50, 26, 28) inferior PFC (32, 30, 8) 3.34
(.0053)*
2.23
(.050)
0.0041
(.86)
4.063
(.00048)*
0.49
(.076)
Mid cing (0, 36, 28) occipital (42, 72, 12) 1.94
(.074)
0.41
(.69)
0.089
(.030)
2.58
(.016)
0.16
(.59)
Thalamus (10, 16, 8) premotor (0, 6, 56) 1.44
(.17)
0.20
(.85)
0.049
(.21)
2.30
(.031)
0.28
(.32)
Supr. gyr. (60, 36, 28) cerebellum (42, 74, 34) 3.60
(.0033)*
3.45
(.0062)*
0.03
(.38)
6.1
(.0000035)*
0.21
(.47)
Su
mmary of changes in intrinsic brain connectivity related to physical exercise training and correlations between intrinsic connectivity and the only pain-related parameter that displayed
signicant longitudinal changes (FIQ) among FM patients.
Out of the six pairs of brain regions tested, four displayed a signicant longitudinal renormalization in the bromyalgia cohort. The degree of connectivity was signicantly changed for the
healthy control between the supramarginal gyrus and cerebellum. Of note, only the change of connectivity between the insula and S1/M1 was relatively signicantly larger for FM than
that for HC (no change in connectivity was signicantly larger for the healthy compared to bromyalgia). The level of statistical signicance (p = 0.05) was corrected for multiple com-
parisons with regard to the six tested seed regions using Bonferroni correction (p b 0.0083). Statistical signicant changes are marked with *. Abbreviations: Supr. gyr. = supramarginal
gyrus; S1/M1 = primary sensorimotor areas; ΔB = changes in connectivity; t = t-value; p = p-value; r = Pearson correlation coefcient. All coordinates (x, y, z) are in MNI space.
Fig. 1. Average FIQ and SF36BP ratings in 14 FM patients before (solid bars) and following
(striped bars) the exercise intervention. The reduction in FIQ ratings indicates reduced FM
symptoms. No cha nge was observed in pain ratings (SF36BP). The asterisk sign (*)
signies a signicant difference at p b 0.01 between post- versus pre-treatment condi-
tions. Error bars denote standard deviations. FIQ = Fibromyalgia Impact Questionnaire,
SF36BP = short form bodily pain subscale.
136 P. Flodin et al. / NeuroImage: Clinical 9 (2015) 134139
pain studies, as delineated by an automated meta-analysis (described in
Flodin et al., 2014). The insula plays a pivotal role in pain processin g
(Duerden et al., 2013) and activity in its anterior part has been associat-
ed with interoceptive accuracy and subjective feeling (Critchley et al.,
2004). Interestingly, a re cent study in FM patients reported a hypo-
connectivity between the bilateral anterior insula and PAG (peri-
aqueductal grey nucleus), that correlated with symptom severity (Pujol
et al., 2014). Speculatively, the shift towards increased insula connectivity
following physical exercise therapy observed here could reect an in-
creased interaction between brain regions responsible for interoceptive
valiance and bodily representations. The restoration of functional con-
nectivity between the right SMG and primary sensorimotor areas, as
well as between the right SMG and inferior prefrontal cortex, consisted
in reduction of anticorrelations for FM patients.
Whereas functional connectivit y is commonly interpre ted as (at least
partly) reecting a history of co-activation of brain regions interacting in
order to accomplish a specic (cognitive or housekeeping) function at
a given time, the functional signicance of anticorrelation is less well
understood. It has previously been shown that anticorrelations can be
articially induced during preprocessing of the data, such as by global
mean regression of the fMRI signal intensity time-series (Murphy et al.,
2009). However, using electrophysiological techniques, a neurobiological
origin of anticorrelations has been conrmed (Keller et al., 2013). Further-
more, preprocessing strategies that omit global signal regression, in-
cluding the CompCor strategy that is employed here, commonly render
anticorrel atio ns (Chai et al., 2012). The general functional signicance of
anticorrelations, especially outside the well studied relationship between
the default mode network and task positive networks (Fox et al., 2005;
Fransson, 2005), remains tentative. One interpretation of the normaliza-
tion (i.e. decreases in anticorrelation) observed here, is that pain- and so-
matosensory regions interact in a more coherent fashion, implying a
reduced mismatch between sensorimotor signals and activity in brain
regions involved for pain processing. Our nding complement results
from previous FM intervention studies that primarily reported decreased
insular connectivity following FM interventions. For instance, Schmidt-
Wilcke et al. (2014) found that improvements in clinical pain correlated
with decreased functional connectivity between the anterior insula and
ACC following a 6 week long milnacipran treatment. Likewise, the same
research group observed a decreased connectivity between insula
and the default mode network following an acupuncture treatment
(Napadow et al., 2012). These results were interpreted as a restoration
of FM-associated hyperconnectivity between the brain regions involved
in pain perception (anterior insula) and self-referential thought (DMN).
Thus, an emerging picture is that improvements in symptom severity in
FM could be associated either with reduced interaction between regions
sub-serving pain processing and self-related cognition, or by a decreased
asynchr ony betw een the pain and senso rimo tor regio ns. Sinc e the current
study investigated the effects of physical exercise, it is plausible that the
mechanism mediating these symptom improvements to a larger degree
involves the sensorimotor brain areas.
Few studies have directly investigated longitudinal changes of in-
trinsic brain conn ectivity following physical exercise interventions.
Becerra et al. (2014) investigated the effects of a three week physical
and psychological training program in a group of children and adoles-
cents with paediatric complex regional pain syndrome. They reported
treatment effects in several networks (e.g. DMN, salience networks
and cer ebellum). However, signicance levels were not adjusted for
testing of multiple networks, and their relatively small cohort (12 pa-
tients and an equal number of controls), prevents any strong conclu-
sions on the effect of the intervention. There are severa l studies on
effects of motoric skill training, such as sequential motor training para-
digms with durations of a couple of weeks. A general ndi
ng among
these studies is that an initially increased task evoked responses in
both the primary sensory and primary motor cortices (Floyer-Lea &
Matthews, 2005; Hlustík et al., 2004). Interestingly, also resting state re-
gional cerebral blood ow (rCBF, measured with positron emission to-
mography) in the primary motor cortex is increased following motor
training (Xiong et al., 2009). Focusing on resting state connectivity,
Krafft et al. (2014) studied the effects of an 8 month exercise interven-
tion in a cohort of overweight children. They report increased network
synchronicity within the motor network, and decreased synchronicity
within th e DMN and cogn itive cont rol n etworks in the intervention
group relative to controls. Another study reports on the acute effect of
a 20 minute aerobic exercise intervention on restin g state activity
(Rajab et al., 2014). Their primary nding was an increased co-
activation within the primary and sensorimotor areas.
Although the current study is the rst to investigate the resting state
changes follow ing an exercise intervention among bromyalgia pa-
tients, there are several studies coherent with our nding that physical
exercise primarily inuences functional connectivity within cardinal
sensorimotor regions.
The benecial health effects of physical exercise are well acknowl-
edged. Following the intervention, FM patients rated lower on the FIQ
scale, reecting increased healthiness and a decrease of symptom sever-
ity, physical disability and overall impact of bromyalgia. However, the
body pain levels (SF36BP) did not change. These ndings indicate that
the therapeutic effects of the 3 month exercise intervention rendered
improvements of symptom s that only indirectly pertained to pain.
Thus, the observed normalizations of functional connectivity involving
sensory areas could possibly reect subclinical therapeutic processes,
likely induced by increased levels of motor activity.
However, since neither SF36BP nor FIQ could be linearly correlated
with change in brain activity in the current study, the behavioural im-
plications of the obse rved normalization in intrinsic connectivity
warrants further investigation. A possible explanation for the absent
brainbehavioural coupling could be that treatment-induced chang-
es in brain connectivity follow an inverted u-shape temporal prole
as proposed by the expan sionpartial n orma liz ation hypoth esis of
Fig. 2. Physical exercise induced normalization of resting state connectivity between the
right insula and the left sensorimotor region in the FM cohort. (A) Intrinsic connectivity
between a spherical seed region (radius = 4 mm) located in the right anterior insula
and a cluster extending 1490 voxels i n the left sensorimotor cortex. (B) Post- versus
pre- treatment insular-sensorimotor connectivity (arbitrary units) for bromyalgia
(blue) and controls (red). Error bars denote standard deviations.
137P. Flodin et al. / NeuroImage: Clinical 9 (2015) 134139
neuroplastici ty (Brehmer et al., 2014). However, plotting change in
behavioural scores against change in connectivity did not indicate
any such relationship. Another possible scenario is t hat the behav-
ioural parameters monitored in the present investigation were
subserved by different neuronal processes other than the ones in-
vestigated here.
We note several limitations in the current study. First, the resting
state scans were acquired approximately 30 mi n after two task fMRI
sessions were admin istered in the MR scanner (Stroop and evoked
pain, data will be reported elsewhere). Thus, we cannot rule out the
possibility that putative spill-over effects from task-based fMRI para-
digms occur, which cou ld have had a differential inuence on the
group brain activity patterns. Second, since our study did not include a
placebo or no-treatment FM control group, the observed longitudinal
changes in brain connectivity might in part be driven by spontaneous
improvements in pain severity and accompanying changes in brain
connectivity that is not attributable to the physical intervention per se
(i.e. regression towards the mean, Stigler, 1997). Third, changes in in-
trinsic brain connectivity might be unrelated to the measured improve-
ments in pain (at least in relation to the pain measures used here).
Theoretically, the observed connectivity changes could be accompanied
by changes in other commonly reported FM symptoms such as mood
changes, insomnia, fatigue or impairments in cognitive function, al-
though the fact that the seed regions were placed in pain-related
brain areas supports the interpretation that there is a link between the
physical intervention and pain relevant brain processes. Finally, we sug-
gest that our ndings should be treated to some extent as preliminary in
nature, given the relatively small number of participants that completed
the post-therapy imaging session. Future studies using larger study
samples would likely enable a more detailed investigation of the rela-
tionship between changes at the neurophysiological versus the behav-
ioural level. Addition ally, it might be desirable for fut ure studies to
record brain connectivity and behaviour at multiple time-points and
thereby achieve a temporally more ne-gr ained characterization of
the longitudinal neurophysiological and behavioural changes related
to exercise therapy in FM patients.
In conclusion, we have shown that a therapeutic physical exercise-
training program increases the perceived degree of healthiness in patients
diagnosed with bromyalgia. Interestingly, we observed a restoration of
functional connectivity between several pain and sensorimotor regions.
In this context, it is important to note that longitudinal change of intrinsic
connectivity between the sensorimotor system and the insula was
observed exclusively in the FM cohort. This nding suggests that the
insula connectivity may play a key role for the observed physical
therapy-induced effects on FM symptomatology.
Supplementary data related to this article can be found online at
http://doi.dx.org/10.1016/j.nicl.2015.08.004.
Conicts of interest
None declared.
Funding
This study was supported b y grants f rom the Swedish Rheuma-
tism Association, Stockholm County Council - 2010, Swedish Foun-
dation for Strategic Research (2012-0179), Swedish Research
Council K2013-5 2X-22199-01-3, and Karolinska Institut e Founda-
tion (2012FoBi34779). The funders had no role in the study design,
data collection and analysis, decision to publish, or preparation of
the manuscript.
Acknowledgements
The authors would like to thank all the participants in this study.
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Fibromyalgia (FM) is a syndrome characterized by chronic pain without known peripheral causes. Previously we have reported dysfunctional pain inhibitory mechanisms for FM patients during pain administration. In the current study we employed a seed correlation analysis (SCA), independent component analysis (ICA), and an analysis of fractional amplitude of low frequency fluctuations (fALFF) to study differences between a cohort of female fibromyalgia patients and an age- and sex matched healthy control group during a resting state condition. FM patients showed decreased connectivity between thalamus and premotor areas, between the right insula and primary sensorimotor areas, as well as between supramarginal and prefrontal areas. Individual sensitivity to painful pressure was associated with increased connectivity between pain related regions (e.g. insula and thalamus) and midline regions of the default mode network (including posterior cingulate cortex and medial prefrontal cortex) among patients and controls. However, neither ICA nor fALFF revealed any group differences. Our findings suggest that abnormal connectivity patterns between pain related regions and the remaining brain during rest reflect an impaired central mechanism of pain modulation in FM. Weaker coupling between pain regions and prefrontal- and sensorimotor areas might indicate a less efficient system level control of pain circuits. Moreover, our results show that multiple, complementary analytical approaches are valuable for obtaining a more comprehensive characterization of deviant resting state activity. In conclusion, our findings show that FM primarily is associated with decreased connectivity, e.g. between several pain related areas and sensorimotor regions, which could reflect a deficiency in pain regulation.
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Aging is typically related to changes in brain and cognition, but the aging process is heterogeneous and differs between individuals. Recent research has started investigating the influence of cognitive and physical training on cognitive performance, functional brain activity, and brain structure in old age. The functional relevance of neural changes and the interactions among these changes following interventions is still a matter of debate. Here we selectively review research on structural and functional brain correlates of training-induced performance changes in healthy older adults and present exemplary longitudinal intervention studies sorted by the type of training applied (i.e., strategy-based training, process-specific training, and physical exercise). Although many training studies have been conducted recently, within each task domain, the number of studies that used comparable methods and techniques to assess behavioral and neural changes is limited. We suggest that future studies should include a multimodal approach to enhance the understanding of the relation between different levels of brain changes in aging and those changes that result from training. Investigating inter-individual differences in intervention-induced behavioral and neuronal changes would provide more information about who would benefit from a specific intervention and why. In addition, a more systematic examination of the time course of training-related structural and functional changes would improve the current level of knowledge about how learning is implemented in the brain and facilitate our understanding of contradictory results.
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The insular (IC) and cingulate cortices (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and Default Mode Network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. Here we more thoroughly evaluate the degree of resting state connectivity to multiple regions of the IC in individuals with FM and healthy controls (HC). We also investigated the relationship between connectivity, experimental pain and current clinical chronic pain. Functional connectivity was assessed using resting state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched HC using pre-defined seed regions in the anterior, middle and posterior IC. FM patients exhibited greater connectivity between: (1) right mid IC and right mid/posterior CC and right mid IC; (2) right posterior IC and the left CC; and (3) right anterior IC and left superior temporal gyrus. HCs displayed greater connectivity between: left anterior IC and the bilateral medial frontal gyrus/ACC; and left posterior IC and the right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation playing a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with fibromyalgia.
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The insular (IC) and cingulate cortices (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and Default Mode Network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. Here we more thoroughly evaluate the degree of resting state connectivity to multiple regions of the IC in individuals with FM and healthy controls (HC). We also investigated the relationship between connectivity, experimental pain and current clinical chronic pain. Functional connectivity was assessed using resting state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched HC using pre-defined seed regions in the anterior, middle and posterior IC. FM patients exhibited greater connectivity between: (1) right mid IC and right mid/posterior CC and right mid IC; (2) right posterior IC and the left CC; and (3) right anterior IC and left superior temporal gyrus. HCs displayed greater connectivity between: left anterior IC and the bilateral medial frontal gyrus/ACC; and left posterior IC and the right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. Perspective These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation playing a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with fibromyalgia.
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Fibromyalgia typically presents with spontaneous body pain with no apparent cause and is considered pathophysiologically to be a functional disorder of somatosensory processing. We have investigated potential associations between the degree of self-reported clinical pain and resting-state brain functional connectivity at different levels of putative somatosensory integration. Resting-state functional MRI was obtained in 40 women with fibromyalgia and 36 control subjects. A combination of functional connectivity-based measurements were used to assess (i) the basic pain signal modulation system at the level of the periaqueductal gray (PAG), (ii) the sensory cortex with an emphasis on the parietal operculum/secondary somatosensory cortex (SII) and (iii) the connectivity of these regions with the self-referential "default mode" network. Compared with control subjects, a reduction of functional connectivity was identified across the three levels of neural processing, each showing a significant and complementary correlation with the degree of clinical pain. Specifically, self-reported pain in fibromyalgia patients correlated with (i) reduced connectivity between PAG and anterior insula, (ii) reduced connectivity between SII and primary somatosensory, visual and auditory cortices, and (iii) increased connectivity between SII and the default mode network. The results confirm previous research demonstrating abnormal functional connectivity in fibromyalgia and show that alterations at different levels of sensory processing may contribute to account for clinical pain. Importantly, reduced functional connectivity extended beyond the somatosensory domain and implicated visual and auditory sensory modalities. Overall this study suggests that a general weakening of sensory integration underlies clinical pain in fibromyalgia.
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Importance Fibromyalgia is present in as much as 2% to 8% of the population, is characterized by widespread pain, and is often accompanied by fatigue, memory problems, and sleep disturbances.Objective To review the epidemiology, pathophysiology, diagnosis, and treatment of fibromyalgia.Evidence Review The medical literature on fibromyalgia was reviewed from 1955 to March 2014 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis on meta-analyses and contemporary evidence-based treatment guidelines. Treatment recommendations are based on the most recent evidence-based guidelines from the Canadian Pain Society and graded from 1 to 5 based on the level of available evidence.Findings Numerous treatments are available for managing fibromyalgia that are supported by high-quality evidence. These include nonpharmacological therapies (education, exercise, cognitive behavioral therapy) and pharmacological therapies (tricyclics, serotonin norepinephrine reuptake inhibitors, and gabapentinoids).Conclusions and Relevance Fibromyalgia and other “centralized” pain states are much better understood now than ever before. Fibromyalgia may be considered as a discrete diagnosis or as a constellation of symptoms characterized by central nervous system pain amplification with concomitant fatigue, memory problems, and sleep and mood disturbances. Effective treatment for fibromyalgia is now possible.
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