Neurobiology of Pain 13 (2023) 100129

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Neurobiology of Pain
journal homepage: www.sciencedirect.com/journal/neurobiology-of-pain

Review

Exercise training augments brain function and reduces pain perception in

adults with chronic pain: A systematic review of intervention studies
Kierstyn L. Palmer a, Madeline E. Shivgulam b, Anne Sophie Champod c, Brian C. Wilson d,
Myles W. O’Brien e, Nick W. Bray f, g, *
a
School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, V1V 1V7, Canada
b
Division of Kinesiology, Dalhousie University, Halifax, Nova Scotia, B3H 3J5, Canada
c
Dept. of Psychology, Acadia University, Wolfville, Nova Scotia, B4P 2R6, Canada
d
Department of Biology, Acadia University, Wolfville, Nova Scotia, B4P 2R6, Canada
e
School of Physiotherapy (Faculty of Health) and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 3J5, Canada
f
Cumming School of Medicine, Dept. of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
g
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, T2N 1N4, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Chronic pain (CP) is a leading cause of disability worldwide. Pain may be measured using subjective
Physical activity questionnaires, but understanding the underlying physiology, such as brain function, could improve prognosis.
Pain inhibition Further, there has been a shift towards cost-effective lifestyle modification for the management of CP.
Functional neuroimaging
Methods: We conducted a systematic review (Registration: #CRD42022331870) using articles retrieved from four
Subjective pain measurement
databases (Pubmed, EMBASE, AMED, and CINAHL) to assess the effect of exercise on brain function and pain
perception/quality of life in adults with CP.
Results: Our search yielded 1879 articles; after exclusion, ten were included in the final review. Study participants
were diagnosed with either osteoarthritis or fibromyalgia. However, two studies included “fibromyalgia and low
back pain” or “fibromyalgia, back, and complex regional pain.” Exercise interventions that were 12 weeks or
longer (n = 8/10) altered brain function and improved pain and/or quality of life outcomes. The cortico-limbic
pathway, default-mode network, and dorsolateral prefrontal cortex were key regions that experienced alterations
post-intervention. All studies that reported an improvement in brain function also demonstrated an improvement
in pain perception and/or quality of life.
Discussion: Our review suggests that alterations in brain function, notably the cortico-limbic, default-mode and
dorsolateral prefrontal cortex, may be responsible for the downstream improvements in the subjective experience
of CP. Through appropriate programming (i.e., length of intervention), exercise may represent a viable option to
manage CP via its positive influence on brain health.

1. Introduction leading to altered pain processing (Staud et al., 2008). Further,

Pain is an unpleasant sensory and emotional experience associated
with potential or actual tissue damage (Raja et al., 2020). If pain is
experienced for three months or more, regardless of location, it is
considered chronic pain (CP), a leading cause of disability worldwide
(QuickStats, 2016). Although the mechanisms governing CP are com­
plex and not yet fully understood, it is thought that some types of CP
result from disruption of pain inhibitory pathways (Julien et al., 2005),
perceived pain levels can be intensified through increased responsive­
ness of the nervous system to harm, otherwise known as central sensi­
tization (Bingel and Tracey, 2008; Yang and Chang, 2019). Several
variables also influence pain perception, including but not limited to
environment, emotions, genetics, age, and sex (Bingel and Tracey, 2008;
Yang and Chang, 2019). Understanding the underlying physiology and
factors that contribute to CP could improve its prognosis and
management.

* Corresponding author at: Lab of Human Cerebrovascular Physiology, MR Neuroimaging Lab, Heritage Medical Research Building, Room HMRB 128, Calgary, AB
N6C 0A7, Canada.
E-mail addresses: kierstyn.palmer@ubc.ca (K.L. Palmer), madeline.shivgulam@dal.ca (M.E. Shivgulam), anne.champod@acadiau.ca (A.S. Champod), brian.
wilson@acadiau.ca (B.C. Wilson), myles.obrien@dal.ca (M.W. O’Brien), nicholas.bray@ucalgary.ca (N.W. Bray).

https://doi.org/10.1016/j.ynpai.2023.100129
Received 31 January 2023; Received in revised form 11 April 2023; Accepted 11 April 2023
Available online 20 April 2023
2452-073X/© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
K.L. Palmer et al.
Pain intensity may be measured using questionnaires. Such ques­
tionnaires can be specific to the type of CP, measure the impact of CP on
quality of life, and/or measure general pain intensity (Dworkin et al.,
2005; Camann, 1999; von Baeyer et al., 2009; Larsson et al., 2015; Kong
et al., 2019; Tüzün et al., 2005; Price et al., 1983). These questionnaires
are inherently prone to bias caused by patients’ attitudes (including
thoughts and emotions) and interviewer predisposition (Xu and Huang,
2020). Due to the subjective nature of pain, a truly objective measure of
CP is not currently possible. However, utilizing a physiological mea­
surement may provide greater insight while avoiding the inherent biases
of questionnaires (Xu and Huang, 2020). Functional magnetic resonance
imaging (fMRI) and functional near-infrared spectroscopy (fNIRS) are
two neuroimaging tools that can be used to objectively measure “brain
function” via cerebral oxygenation (Xu and Huang, 2020; Karim et al.,
2012); for the purpose of this review, brain function refers to both brain
activity and connectivity. Indeed, people with CP demonstrate altered
brain function when compared to healthy controls (Baliki and Apkarian,
2015; Heitmann et al., 2022); this reflects the plastic nature of the brain
or its ability to functionally and structurally change with repeated
exposure to (pain-inducing) stimuli (Mateos-Aparicio and Rodríguez-
Moreno, 2019). In addition to providing greater insight into the mech­
anisms of pain processes, fMRI and fNIRS can be used to evaluate the
efficacy of and understand the underlying physiological changes
induced by CP interventions.
Opioid medications are a widely used CP treatment (Wang et al.,
2019). However, they are highly addictive and, as a result, have led to an
epidemic of opioid addiction and overdoses (Wang et al., 2019); since
the 1990s, the number of deaths due to opioid-induced overdoses has
quadrupled (US Department of Health and Human Services, 2021).
Conversely, physical exercise (e.g., aerobic, resistance training, Tai Chi,
etc.) has demonstrated many benefits in those suffering from CP,
including: increasing mood-enhancing chemicals, promoting pleasure/
reward circuitry in the brain, improving quality of life, and reducing
perceived levels of pain, disability, and pain-induced anxiety (Polaski
et al., 2021). Such changes are in addition to a multitude of other ben­
efits that extend beyond pain, and is exactly why exercise has been
described as having a sledgehammer effect on human health (Erickson
et al., 2022). Ultimately, exercise may be a viable intervention strategy
to promote pain management in those suffering from CP.
To our knowledge, only one systematic review has been conducted
on the effects of exercise on fMRI-determined brain function in in­
dividuals with CP (de Zoete et al., 2020). While exercise promoted
functional brain changes, there was heterogeneity within brain regions
studied and exercise strategies used across studies (de Zoete et al.,
2020). Further, this review focused specifically on (chronic) musculo­
skeletal pain and, as a result, included only four studies (de Zoete et al.,
2020). Therefore, the purpose of our systematic review was to investi­
gate the effect of exercise on brain function (as assessed by fMRI and
fNIRS) and measures of pain perception and quality of life in adults
living with CP. We hypothesized that exercise would improve: 1) brain
function; and 2) pain perception and quality of life in those suffering
from CP.
2. Methods
2.1. Study design and search strategy
This systematic review was registered with PROSPERO (Registration
number: CRD42022331870) (Supplemental Material A) and followed
the Preferred Reporting Items for Systematic Review and meta-Analysis
(PRISMA) statement (Moher et al., 2009). Similar to previous systematic
reviews conducted by our group (Bray et al., 2021; Champod et al.,
2018; O’Brien et al., 2022) and others in the field (de Zoete et al., 2020),
we included the following databases: PubMed, EMBASE, AMED, and
CINAHL. The search strategy was developed based on current guidelines
for the design of systematic reviews (Selcuk, 2019), our prior experience
2
Neurobiology of Pain 13 (2023) 100129
with systematic reviews, and input from content experts (Belavy et al.,
2021). The search strategy consisted of related terms for “exercise,”
“functional neuroimaging,” and “pain” (Supplemental Material B);
terms were searched in each database as title and abstract keywords, as
well as subject headings (Supplemental Material C). There were no re­
strictions on country, language, or publication period. The search
included articles from inception to March 4th, 2023.
2.2. Screening and inclusion criteria
Screening was completed in two steps using Covidence (Veritas
Innovation ltd, Australia): 1) title and abstract; and 2) full-text. Studies
were independently screened by two authors (KLP and MES). Following
each step, reviewers met to discuss any inconsistencies regarding their
inclusion decisions. If a resolution was not found, a senior reviewer
(NWB) was consulted to make a final decision.
Studies were included if they: 1) conducted a repetitive (i.e., greater
than one session) intervention study with experimental manipulation of
physical exercise (Caspersen et al., 1985); 2) measured brain function
via fMRI and/or fNIRS under any conditions (i.e., rest, task, etc.); 3)
measured pain perception and/or quality of life via questionnaires or
other subjective measures, such as sensitivity tests (e.g., Visual Analogue
Scale, Numerical Rating Scale, pressure algometer); and 4) included
human participants ≥18 years of age who were experiencing CP, but
otherwise healthy. Finally, back-searching was conducted on included
studies to ensure that no additional studies satisfied the inclusion
criteria.
2.3. Bias assessment
The quality of individual studies was independently assessed by two
reviewers (KLP and MES), and any inconsistencies were resolved by a
third (NWB). We utilized the National Institutes of Health bias assess­
ments for 1) controlled intervention studies; and 2) before-after (pre-
post) studies with no control group (National Institutes of Health, 2021).
As per the tool creators, specific quality assessment scores were not
calculated. As a result, no studies were excluded based on quality
assessment scores.
2.4. Outcome measures
The primary outcome measures were: 1) brain function, as measured
by fMRI and/or fNIRS; and 2) pain perception and/or quality of life
scores. Notably, brain function was separated into two categories: 1)
brain activity, which subsequently permits the measurement of 2)
functional brain connectivity or regions of the brain that are anatomi­
cally separate but temporally synchronized in their activation (Dam­
oiseaux et al., 2008). Reporting of these outcomes varied between
individual studies, as many focused on widespread regions of interest.
2.5. Data extraction
We extracted the following data from all included studies: 1) authors
and publication date; 2) participant characteristics (age, sex, CP diag­
nosis); 3) details of the physical exercise intervention (frequency, in­
tensity, type, time, volume, and progression); 4) change in outcome
measurements (e.g., brain activity or functional brain connectivity, pain
perception and/or quality of life) and 5) method of collection (i.e., im­
aging and questionnaire type). No studies were excluded from this re­
view based on quality assessment, although quality assessment was used
to provide context when interpreting the study findings.
K.L. Palmer et al.
3. Results
3.1. Search results
1879 articles were identified via our electronic search. 1511 studies
remained after duplicates were removed (n = 368), and 29 articles were
retained for full-text screening. No additional articles were identified via
back searching, leaving ten articles to be included in the present review
(Fig. 1) (Flodin et al., 2015; Kong et al., 2021; Liu et al., 2019; Liu et al.,
2019; Martinsen et al., 2018; Micalos et al., 2014; Shen et al., 2021;
Ozturk et al., 2021; Lofgren et al., 2023; de Winckel et al., 2022).
3.2. Quality assessment
“No” and “not reported” were the most frequent answers for two
studies (Flodin et al., 2015; Micalos et al., 2014), suggesting poor or low
quality; the remaining studies were of relatively higher quality (Liu
et al., 2019; Liu et al., 2019; Martinsen et al., 2018; Shen et al., 2021;
Ozturk et al., 2021; Lofgren et al., 2023; de Winckel et al., 2022) (Figs. 2
& 3). Broadly, studies with a control group poorly reported or did not
report the blinding of participants and providers, adherence to inter­
vention protocols, and if the sample size was large enough to detect
differences between groups (Flodin et al., 2015; Kong et al., 2021;
Martinsen et al., 2018; Micalos et al., 2014). Conversely, they
Fig. 1. PRISMA flow diagram of study selection and quality analysis.
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Neurobiology of Pain 13 (2023) 100129
implemented valid and reliable outcome measurements across study
participants (Flodin et al., 2015; Kong et al., 2021; Martinsen et al.,
2018; Micalos et al., 2014). Broadly, studies without a control group
poorly reported or did not report if the sample size was large enough to
detect differences between groups and what participants were lost to
follow-up (Liu et al., 2019; Liu et al., 2019; Shen et al., 2021; Ozturk
et al., 2021). Conversely, they did well in all other quality assessment
questions, including a clear statement of study objective(s), eligibility
criteria, reliable outcome measurements, and the use of statistical
methods to examine pre- and post-intervention changes (Liu et al., 2019;
Liu et al., 2019; Shen et al., 2021; Ozturk et al., 2021; Lofgren et al.,
2023; de Winckel et al., 2022). The detailed quality assessment is
available in Supplementary Materials D & E. Importantly, two studies
were produced from the same trial, which means the results include
identical participants, despite focusing on different brain regions of in­
terest (Liu et al., 2019; Liu et al., 2019).
3.3. Population demographics and study design characteristics
The ten included studies focused on patients diagnosed with osteo­
arthritis (n = 4) (Liu et al., 2019; Liu et al., 2019; Shen et al., 2021;
Ozturk et al., 2021), fibromyalgia (n = 4) (Flodin et al., 2015; Kong
et al., 2021; Martinsen et al., 2018; Lofgren et al., 2023), or multiple
types of CP, including “fibromyalgia and back pain” (n = 1) (de Winckel
K.L. Palmer et al. Neurobiology of Pain 13 (2023) 100129

Fig. 2. Quality assessment summary of studies with a control group. See Supplemental Material D for more details.

Fig. 3. Quality assessment summary of studies with no control group. See Supplemental Material E for more details.

et al., 2022) and “fibromyalgia, back, and complex regional pain” (n =
1) (Micalos et al., 2014) (Table 1). The mean age of participants ranged
from 42 to 65 years, although two studies simply reported a range
(40–70 years) (Liu et al., 2019; Liu et al., 2019), and one study had an
average median of 53.5 (Lofgren et al., 2023). Altogether, there were
more female than male participants (398/488 total participants). Most
studies’ sample size was less than 50 (Liu et al., 2019; Liu et al., 2019;
Shen et al., 2021; Ozturk et al., 2021; Lofgren et al., 2023; de Winckel
et al., 2022), but the two studies from the same trial had the largest
sample size (n = 140) (Liu et al., 2019; Liu et al., 2019).
Most studies focused on one exercise modality (n = 7), including
resistance training (n = 4), Tai Chi (n = 2), and aerobic training (n = 1).
Three studies incorporated multi-domain intervention strategies,
including multiple exercise modalities (Tai Chi, Buandjin, aerobic
training or qigong and resistance training) and health education (Liu
et al., 2019; Liu et al., 2019; de Winckel et al., 2022) (Table 2). Across all
studies (multimodal and non-multimodal), Tai Chi (n = 4) and resis­
tance training (n = 4) were the most reported exercise modality, fol­
lowed by aerobic training (n = 3). Interventions ranged from 6 to 15
weeks in duration, however, eight studies had interventions of 12 weeks
or more (Lofgren et al., 2023; de Winckel et al., 2022; Flodin et al., 2015;
Kong et al., 2021; Liu et al., 2019; Liu et al., 2019; Martinsen et al., 2018;
Micalos et al., 2014). Healthy (non-CP) individuals were included as
controls in six studies (n = 4) (Flodin et al., 2015; Kong et al., 2021;
Martinsen et al., 2018; Micalos et al., 2014; Lofgren et al., 2023; de
Winckel et al., 2022). Alternatively, the other four studies did not
include a control group (Liu et al., 2019; Liu et al., 2019; Shen et al.,
2021; Ozturk et al., 2021).

4
K.L. Palmer et al. Neurobiology of Pain 13 (2023) 100129

Table 1
Characteristics of included studies.
Study ID Sample size Average age (mean Diagnosis Exercise Modality Connectivity/ Pain QL
(Author, Year) (male) ± SD) Activity

Flodin et al. (2015) 38 (0) I: 48.4 Fibromyalgia Resistance training ↑ NC Improved

C: 41.8
Kong et al. (2021) 48 (NR) I: 51.6 ± 11.6 Fibromyalgia Tai Chi ↑ Improved Improved
C: 52.3 ± 10.4
Liu et al. (2019a, 140 (25) 40–70 Osteoarthritis Baduanjin, Tai Chi, Aerobic ↑↓ Improved Improved
2019b) training
Lofgren et al. (2023) 122 (0) I: 51 (median) Fibromyalgia Resistance Training ↑ Improved Improved
C: 56 (median)
Shen et al. (2021) 17 (0) 64.5 ± 6.7 Osteoarthritis Tai Chi NC Improved Improved
Lofgren et al. (2023) 122 (0) I: 51 (median) Fibromyalgia Resistance Training ↑ Improved Improved
C: 56 (median)
Martinsen et al. (2018) 31 (0) 49.6 Fibromyalgia Resistance training ↑ Improved Improved
Micalos et al. (2014) 19 (3) I: 50 ± 12 Fibromyalgia Back Aerobic training NC§ NC§ NR§
C: 49.6 ± 10 Regional
Ozturk et al. (2021) 15 (1) 59.2 ± 6.28 Osteoarthritis Resistance and Flexibility ↓§ Improved§ Improved§
training
Van de Winckel et al. 58 (13) I1: 46.43 ± 14.28 Chronic Low Back Qiqong and Resistance ↑ Improved Improved
(2022) I2: 44.88 ± 15.68 Pain Training
C: 39 ± 16.45

Note: Lofgren is reported twice because it measured activity and connectivity. SD = standard deviation, QL = quality of life, I = intervention, C = control, NC = no
significant change, NR = not reported, § = outcome was measured in conjunction with pain stimulus.

Table 2
Exercise parameters of included studies.
Study ID FITTVP
(Author, Year)
Frequency Intensity Time Type Volume Progression
(minutes) (minutes)

Flodin et al. (2015) 2x/week × 15 weeks 40 % of one 1 RM 15–20 60 Resistance Training 120 Week 5: 50 % x1RM
reps for 1–3 sets 2 sets of 12–15 reps.
Week 8: 60 % x 1RM
2 sets of 10–12 reps
Week 12: 70 % x 1RM
2 sets of 8–10 reps
Kong et al. (2021) 2x/week × 12 weeks + 30 min Not reported 60 Tai Chi 120 Not reported
practice × day
Liu et al. (2019a, 5x/week × 12 weeks Not reported 60 Tai Chi, Badjuanjin, 300 Not reported
2019b) Aerobic Training
Lofgren et al. (2023) 2x/week × 15 weeks 40 % of one 1 RM 50 Resistance Training 100 Up to 80 % of 1RM with
15–20 reps for 2 sets 5–8 reps
Shen et al. (2021) 3x/week × 8 weeks Not reported 60 Tai Chi 180 Not reported
Martinsen et al. 2x/week × 15 weeks Not reported 60 Resistance Training 120 Not reported
(2018)
Micalos et al. (2014) 2x/week × 12 weeks Not reported 20 Aerobic Training 40 Not reported
Ozturk et al. (2021) 3x/week × 6 weeks 30–60 % of 10 RM, for 10 45 Resistance and Flexibility 135 Week 3: + 1 set of 3 reps
reps Training
Van de Winckel 3x/week × 12 weeks Not reported 41 Qiqong and Resistance 123 Not reported
et al. (2022) Training

Note: RM = rep maximum, Volume = Frequency × days per week.

3.4. Brain function
Of the eight included studies, six measured functional brain con­
nectivity (Shen et al., 2021; Lofgren et al., 2023; Flodin et al., 2015;
Kong et al., 2021; Liu et al., 2019; Liu et al., 2019). Three recorded in­
creases (Flodin et al., 2015; Kong et al., 2021; Lofgren et al., 2023) and
two recorded bidirectional changes (Liu et al., 2019; Liu et al., 2019),
respectively; notably, the bidirectional changes were from studies that
used the same cohort. One study did not observe a significant change in
functional brain connectivity (Shen et al., 2021), but it contained the
lowest sample size (n = 17), included no control group, and was the only
intervention less than 12 weeks to measure connectivity (Shen et al.,
2021). Across the six studies, the anterior cingulate cortex (n = 4),
medial prefrontal cortex (n = 4), posterior cingulate cortex (n = 2),
thalamus (n = 2), and cerebellum (n = 2) increased connectivity with a
multitude of regions, but most commonly, the hypothalamus, dorsolat­
eral prefrontal cortex (DLPFC), periaqueductal gray, and ventral
tegmental area (Shen et al., 2021; Flodin et al., 2015; Kong et al., 2021;
Liu et al., 2019; Liu et al., 2019). For the two studies that demonstrated
bidirectional change, the DLPFC, as well as the ventral tegmental and
periaqueductal gray regions, decreased connectivity with several other
areas (Liu et al., 2019; Liu et al., 2019) (Supplemental Material F).
Four studies focused on changes in (whole brain) activity (Martinsen
et al., 2018; Micalos et al., 2014; Ozturk et al., 2021; de Winckel et al.,
2022) (Supplementary Material G). Importantly, three of these studies
measured brain function during the application of pressure (pain)
stimuli (Micalos et al., 2014; Ozturk et al., 2021) and one was also the
only study to utilize fNIRS in measuring brain function (Ozturk et al.,

5
K.L. Palmer et al.
2021). One did not demonstrate a change in activity (Micalos et al.,
2014), while the other demonstrated a decrease in activity of the DLPFC
(Ozturk et al., 2021). The other two studies measured brain activity
without the application of pain stimuli and demonstrated increased
activation in the amygdala, cerebellum, and putamen (Martinsen et al.,
2018), as well as the parietal operculum, angular gyrus, precentral
gyrus, and supramarginal gyrus (de Winckel et al., 2022).
3.5. Pain perception and quality of life
Studies measured pain perception and/or quality of life outcomes
utilizing the Short-Form Health Survey (n = 3), Visual Analogue Scale
(n = 4), McGill Pain Questionnaire (n = 1), Fibromyalgia Impact
Questionnaire (n = 4), Knee Osteoarthritis Outcome Scale (n = 2),
Western Ontario and McMaster Universities Osteoarthritis Index (n = 2),
Beck Depression Inventory (n = 2), and the Hospital Anxiety and
Depression Score (n = 2). All but one study (Micalos et al., 2014) re­
ported improvements post-exercise in the measure of pain perception
and/or quality of life; however, this particular study was the only one to
include multiple types of CP, including fibromyalgia, back pain, and
complex regional pain, and recorded brain function during the appli­
cation of pressure (pain) stimulation (Micalos et al., 2014) (Supple­
mentary Material H). Importantly, people with CP experienced an
improvement in pain perception and/or quality of life in all studies that
recorded a change in brain function and conducted their exercise
intervention for 12 weeks or longer (n = 8/10) (Flodin et al., 2015; Kong
et al., 2021; Liu et al., 2019; Liu et al., 2019; Martinsen et al., 2018;
Ozturk et al., 2021; Lofgren et al., 2023; de Winckel et al., 2022).
4. Discussion
We conducted a systematic review to assess the effect of exercise
interventions on brain function (connectivity and activity) and pain
perception/quality of life in adults with CP. In partial support of our
hypothesis, exercise improved brain function in all studies that con­
ducted a 12+ week intervention and measured brain function in the
absence of pain stimulation. Also in partial support of our hypothesis, all
studies that reported an improvement in brain function after 12 weeks or
more of exercise also demonstrated an improvement in pain perception
and/or quality of life. Such findings suggest that exercise-induced im­
provements in CP may be mediated through changes in brain function
but that the parameters (i.e., frequency, intensity, etc.) of the inter­
vention are critical.
4.1. Brain function measures and implications
Cotico-limbic: The anterior cingulate cortex, amygdala, thalamus, and
medial prefrontal cortex reported increased connectivity with various
regions of interest across multiple studies (Micalos et al., 2014; Dam­
oiseaux et al., 2008; Flodin et al., 2015; Kong et al., 2021; Liu et al.,
2019); although conflicting research exists, increases in connectivity
between regions linked or part of an identified network are believed to
reflect improved brain health. The amygdala and thalamus were also
regions of interest in studies focused on whole-brain activity (Martinsen
et al., 2018; Micalos et al., 2014). Together, the anterior cingulate cor­
tex, amygdala, thalamus, and medial prefrontal cortex play key roles in
the cortico-limbic system, a pathway of regions that have been impli­
cated during pain processing (Rusbridge, 2020). More specifically, the
cortico-limbic system encompasses the flow of information from higher
cortical brain areas to the spinal level, which dictates emotional and
behavioural responses to pain (Yang and Chang, 2019). Therefore, this
system plays a critical function in pain regulation, as it has the ability to
inhibit pain by exerting top-down pain control on the descending pain
modulation system (Yang and Chang, 2019; Rusbridge, 2020).
It is hypothesized that the maladaptive functioning of the cortico-
limbic system, that is, neural reorganization as a result of prolonged
6
Neurobiology of Pain 13 (2023) 100129
exposure (i.e., chronic) to pain (Yang and Chang, 2019; Rusbridge,
2020), may maintain CP. The persistence of pain in people with CP is
likely attributable to impaired functioning or reduced connectivity be­
tween regions of the cortico-limbic pathway that are responsible for pain
inhibition/control. Other research supports this hypothesis, demon­
strating reduced connectivity between several parts of the cortico-limbic
system, including the hypothalamus, thalamus, amygdala, and the
medial prefrontal cortex in people with CP (Kong et al., 2021; Ayoub
et al., 2019). Relative to the present review, the observed increases in
connectivity between cortico-limbic brain regions suggest how exercise
may help to normalize or restore the functioning of the cortico-limbic
pathway. Such findings are supported further by the consistent down­
stream improvements in subjective pain perception and/or quality of life
measures.
Default Mode Network: Despite being a part of the cortico-limbic
pathway, the medial prefrontal cortex and posterior cingulate cortex
are also regions belonging to a functional network known as the default-
mode (Raichle et al., 2001); this highlights a key point, that is, a single
region can belong to multiple networks or pathways and our under­
standing of functional brain connectivity is still developing. The default
mode network is upregulated when a person is engaged in mind-
wandering or passive tasks, such as thinking about the past or
dreaming about the future (Anticevic et al., 2012). For this reason, it also
plays a role in memory and is known to compete with attention-
requiring processes (Raichle et al., 2001; Anticevic et al., 2012).
Downregulation of the default mode network suggests that attention-
requiring processes, such as those involved in the frontoparietal or ex­
ecutive function network are in use (Beaty et al., 2015). While a healthy
individual may be “daydreaming” at rest, a patient with CP is more
likely to be thinking or reminded about the pain they are experiencing
and, therefore, less likely to be in a default state (Čeko et al., 2020;
Alshelh et al., 2018). Alterations of the default mode network have been
recorded in people with CP, specifically, decreased connectivity be­
tween known regions or hubs (Baliki and Apkarian, 2015; Čeko et al.,
2020). The present review demonstrated that exercise increased con­
nectivity between regions within and beyond the default mode network,
including two of its key hubs, the medial prefrontal and posterior
cingulate cortex. Increasing connectivity and, by extension, upregula­
tion of the default mode network suggests a downregulation of
attention-requiring processes; this may mean the CP patient is no longer
focused or attentive to their pain and, instead, free to daydream like a
pain-free individual. Again, such findings are supported by the consis­
tent improvements in pain and quality of life outcomes for the included
studies.
DLPFC: The DLPFC experienced bidirectional changes in connectiv­
ity with multiple brain regions. More specifically, the DLPFC increased
connectivity with regions belonging to the cortico-limbic system (ante­
rior cingulate cortex and medial prefrontal cortex) (Liu et al., 2019) and
decreased connectivity with regions beyond the cortico-limbic system,
such as the supplemental motor areas and the temporoparietal junction
(Liu et al., 2019). At a minimum, such changes suggest that exercise can
alter DLPFC connectivity in people with CP. Admittedly, it is difficult to
draw more meaningful interpretations of the bidirectional changes
observed in DLPFC connectivity. In considering the simultaneous
changes in clinical outcomes, we theorize that increased connections
between the DLPFC and the cortico-limbic pathway are good, while
connections to other regions, which were decreased or downregulated
within the present review, are bad.
Within the present review, the DLPFC was the only region to also
report bidirectional changes in activity, specifically an increase (Lofgren
et al., 2023) and decrease (Ozturk et al., 2021) during the application of
pain stimuli. Other researchers have suggested that upregulated DLPFC
activation is related to the production and continuation of CP (Liu et al.,
2019). Past research has also demonstrated abnormally high DLPFC
activity in people with CP (Weissman-Fogel et al., 2008), as well as in­
creases in DLPFC activation during the application of noxious pressure
K.L. Palmer et al.
stimuli (Ozturk et al., 2021). Further research supports the potential of
treating CP via targeted regulation of DLPFC activity (Seminowicz and
Moayedi, 2017). Taken together, such findings may suggest that
downregulation of the DLPFC in CP may be associated with restoration
or normalization of brain function and subsequent improvements in pain
perception/quality of life in people with CP post-exercise.
4.2. Mechanisms
The mechanistic model suggests exercise induces behavioral or
clinical change by acting on multiple physiological levels, including
molecular, cellular, and structural/functional (El-Sayes et al., 2019). In
summary, exercise induces upregulation of molecules that cause positive
changes at the cellular level, including the formation of new neurons (i.
e., neurogenesis and gliogenesis), connections between neurons (i.e.,
synaptogenesis), and blood cells (i.e., angiogenesis) (El-Sayes et al.,
2019). Developing new cells with more synapses increases gray and
white matter volume, which influences receptor activity and blood flow
(El-Sayes et al., 2019). Exercise may also improve brain function and
perceived pain scores in those suffering from CP via its anti-
inflammatory effect (da Scheffer and Latini, 2020). The inflammatory
response is designed to protect and heal the body from injury; however,
increased or consistently high levels of inflammatory markers are pre­
sent in people with prolonged pain, such as adults with CP (Morris et al.,
2020). Exercise has been shown to decrease/increase levels of pro-/anti-
inflammatory molecules within the nervous system (da Scheffer and
Latini, 2020). Finally, exercise, particularly resistance training and Tai
Chi, can exert a direct effect on the area or sources of pain by
strengthening the bones, muscles, tendons, and ligaments (United
Kingdom National Health Service, 2022). Future CP research is inves­
tigating the relationship between exercise, inflammation, and pain to
understand what governs the relationship and, therefore, shape future
CP treatments (Martin Ginis et al., 2020).
4.3. Previous research
A 2020 systematic review examined the effect of exercise on brain
function in patients with strictly chronic musculoskeletal pain and re­
ported changes post-intervention (de Zoete et al., 2020). However, the
authors of the 2020 review did not report specific regions of interest. As
such, it is difficult to draw more specific comparisons (de Zoete et al.,
2020). An umbrella review encompassing 21 Cochrane Reviews with a
total of 381 studies concluded that there was evidence of improved
physical function but a variable effect on both psychological function
and quality of life outcomes in people with CP post-exercise (Geneen
et al., 2017). Another systematic review observed increased cerebral
blood flow to the thalamus and anterior cingulate cortex, along with a
reduction in pain intensity following other interventional strategies
(Kim et al., 2021). Taken together, the present review and previous
research suggest that 12 weeks or more of exercise alters brain health in
people with CP and that the cortico-limbic, default-mode, and DLPFC
are central players; such alterations are responsible for the (down­
stream) improvements in pain perception and life quality (Kim et al.,
2021).
4.4. Limitations and future directions
We conducted the first systematic review on the effect of physical
exercise on global CP, but it is not without limitations. Most notably, our
review included just ten studies, and only two were randomized
controlled trials. Admittedly, this was surprising given that CP is a
leading cause of disability worldwide. The limited literature forced us to
modify the original criteria of our PROSPERO document to include all
types of intervention studies (randomized and non-randomized).
Further, none of the included studies had a non-exercise control group
to compare results, and only half had a non-pain control group. Not
7
Neurobiology of Pain 13 (2023) 100129
including a non-exercise control group fails to account for the social
interaction of exercise and including a non-pain control group helps
clarify whether the observed changes in brain function simply reflect the
uptake of a new lifestyle behaviour or have implications for CP.
Sex differences were not analyzed in any studies included in the
present review. Among studies, there was an uneven distribution of
participant sex, as five included only female participants, and the other
five included both sexes but with a greater percentage of females. Future
research on exercise and CP should aim to achieve sample sizes large
enough to assess sex differences. As previously stated, one group of
authors used the same participants/dataset to produce two manuscripts.
Previous fMRI research has completed multiple analyses of the same
participants. Such an approach likely reflects a desire to maximize the
dataset, given the cost associated with fMRI collection. However,
including both manuscripts means that one cohort is reported twice
within our review of 10 studies. Our review may have included more
studies if we expanded our inclusion criteria to those experiencing CP as
a secondary diagnosis; that is, individuals who experience pain as a
result of being diagnosed with spinal cord injury, multiple sclerosis,
traumatic brain injury, or some other chronic condition. The included 10
studies demonstrated varying degrees of quality, as per our bias
assessment, and focused on various regions of interest. We included
studies that measured brain activity and connectivity and grouped them
under “brain function.” Had studies been more numerous, activity and
connectivity could have been assessed in independent reviews; this
further supports the need for more research exploring brain physiology
in CP.
The authors of the original studies used their own preferred methods
of collecting, processing, and analyzing functional imaging data.
Recently, there has been a movement towards standardizing image
collection (Duchesne et al., 2019), folder organization (Gorgolewski
et al., 2016), and pre-processing (Esteban et al., 2019), but these are
simply suggestions. Additionally, there is no agreed-upon method for
analyzing imaging results, and as previously demonstrated, researchers
can take very different approaches to answer the exact same question
(Botvinik-Nezer et al., 2019). Taken together, this prevented us from
conducting a meta-analysis. Correlation analysis between changes in
brain function and clinical outcomes post-intervention was not con­
ducted in any studies in this review. As a result, we reframed from
exploring such outcomes.
Despite such shortcomings, our findings are encouraging given the
consistency of regions altered post-exercise, regions that previous
research, beyond the field of exercise, has demonstrated to be implicated
in pain (Yang and Chang, 2019; Rusbridge, 2020; Ayoub et al., 2019;
Čeko et al., 2020; Alshelh et al., 2018; Seminowicz and Moayedi, 2017).
Further, included studies demonstrated an improvement in pain
perception and/or quality of life post-intervention. Although the effec­
tiveness of different exercise modalities in treating people with CP was
not a focus of this review, Tai Chi and resistance training were common
modalities. Future exercise interventions should aim to determine the
mechanism(s) governing changes in brain function of people with CP, if
it differs by exercise modality, and which exercise modality and pa­
rameters are most efficacious for a specific type of CP (El-Sayes et al.,
2019); this is particularly relevant given that the present review iden­
tified 12 weeks as a threshold for altering brain function.
5. Conclusion
This systematic review investigated the effects of exercise on brain
function (connectivity and activity) and pain perception/quality of life
in people with CP. We observed that exercise (Tai Chi, resistance, and/or
aerobic training) promoted upregulation between regions of the cortico-
limbic pathway, as well as the default-mode network. We also observed
downregulation of the DLPFC post-exercise. These changes occurred
simultaneously with improvements in pain perception/quality of life.
Such findings suggest that exercise may help restore or normalize brain
K.L. Palmer et al.
function in key cortical regions of CP, with downstream implications for
behavioural outcomes (i.e., pain experience and quality of life), after an
exercise intervention ≥ 12 weeks.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
Systematic Review: therefore, secondary data
Acknowledgements
MES is supported by a Heart & Stroke BrightRed Scholarship. MWO
is supported by a CIHR Post-Doctoral Fellowship Award (#181747) and
a Dalhousie University Department of Medicine University Internal
Medicine Research Foundation Research Fellowship Award. NWB is
supported by a University of Calgary Eyes High Postdoctoral Fellowship.
This research did not receive any specific grant from funding agencies in
the public, commercial, or not-for-profit sectors.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ynpai.2023.100129.
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