Download Reciprocal influences of physical function and cognitive inhibition in

Reciprocal influences of physical function and cognitive inhibition
in chronic pain states
Boessenkool, L.S.J. BSc
3268519
Abstract
Chronic pain is associated with deficits in cognitive function and decreased physical
functioning, both significantly impacting daily life of chronic pain patients. Evidence for
cognitive inhibitory deficits in chronic pain patients is mixed; research in this area is
complicated by the heterogeneity of chronic pain disorders and the variety of tasks used to
measure cognitive inhibition. Although the exact mechanisms underlying cognitive deficits in
chronic pain are currently not known, processing of pain and cognition occurs in overlapping
brain areas and significant changes in grey matter density and functional changes in these
areas have been observed in chronic pain patients. Because physical fitness has been
associated with neuroprotective effects and improved cognition in healthy adults, it has been
suggested that improving physical fitness in chronic pain patients might benefit cognitive
inhibitory ability. However, some evidence is available that cognitive inhibitory capacity
mediates the relationship between pain and physical function, in which case development of
clinical interventions should focus on improving cognitive inhibitory ability. Future research
on the mechanisms underlying cognitive inhibitory deficits and decreased physical function in
chronic pain patients should aim to clarify the direction of the relationship between these
factors.
Examiner: D.S. Veldhuijzen, PhD
Second examiner: C.H. Dijkerman, PhD
Introduction
Chronic pain is widespread in Western society and interferes with normal functioning
(Breivik et al., 2006). Deficits in both physical (Lichtenstein et al., 1998, Edwards, 2006) and
cognitive (Moriarty et al., 2011) domains have been reported, but few studies have focused on
the interactions between these domains (Solberg Nes, 2009). It is difficult to treat chronic pain
effectively due to incomplete knowledge of the heterogeneous mechanisms underlying
different syndromes (Breivik et al., 2006). Potential shared mechanisms related to decreases
of physical function and cognitive inhibitory deficits in chronic pain syndromes are discussed
in this review with the aim to create new insights in chronic pain states, inspire new research
and improve treatment options.
Disambiguating cognitive inhibition
While cognitive inhibition is a prominent concept in cognitive research (MacLeod, 2007),
performances on accepted cognitive inhibitory measures do not correlate strongly (.15-.23; Miyake et
al., 2000, Friedman & Miyake, 2004). Tasks like the Stroop task, antisaccade task, Go-NoGo task,
Trail Making Task (TMT) and Flanker task all appear to require the ability to override an
automatic or dominant response (MacLeod, 2007), but theoretical and statistical approaches
suggest that this ability does not reflect one generalizable cognitive inhibitory trait, but multiple
interlaced functions (Nigg, 2000, Miyake et al., 2000, Friedman & Miyake, 2004). Three
distinctions are suggested by one dominant taxonomy: whether a behavioral or cognitive
process should be suppressed, the conscious effort needed to suppress the process and
whether one is suppressing a voluntary or involuntary process (Nigg, 2000). Another
prominent approach suggests that the origin of the interference being suppressed, internal or
external, might be the dividing feature (Friedman & Miyake, 2004). To prevent excluding
important studies, cognitive inhibition was broadly defined in this review as the conscious or
unconscious stopping or overriding of any mental or behavioral process, in whole or in part,
with or without intention (MacLeod, 2007).
The acute noxious stimulation and cognitive inhibitory performance in healthy
participants
Mixed results have been reported on the relationship between cognitive inhibitory capacity
and acute noxious stimulation in healthy subjects. Recently, Stroop task performance was
reported to be positively correlated to the duration of immersion on a cold pressor test (CPT;
Oosterman et al., 2010). Additionally, performance on the antisaccade task was associated
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with better performance on a tone-discrimination task during CPT (Verhoeven et al., 2011),
suggesting that there is a relationship between cognitive inhibitory ability and pain.
Speculatively, better cognitive inhibitory capacity enables participants to maintain attention
away from pain, resulting in longer immersion times in Oosterman et al.’s (2010) study and
better distractor task performance in Verhoeven et al.’s (2011) study. A paradigm where the
intensity of the noxious stimulation is varied, and participants are instructed to either focus on
the pain or to distract themselves from it would be useful to determine the role of cognitive
inhibitory capacity in pain perception.
Another study reported that both painful and non-painful heat stimulation lowered
performance on the Go-NoGo task, Flanker task and Posner cueing task compared to a nostimulation condition, but no significant difference was reported between painful and nonpainful stimulation conditions (Moore et al., 2012). However, non-painful stimulation was
performed at 1˚C above the detection threshold determined for the participant, and painful
heat at the temperature determined as the pain threshold. Because more intense pain is
associated with greater deficits in cognitive performance (Eccleston & Crombez, 1999),
painful stimulation at the pain threshold might be too weak a noxious stimulus to influence
task performance disproportionately. Possibly, this study measured distraction by the
stimulation, rather than the effect of pain on cognitive inhibitory performance.
In summary, although cognitive inhibitory capacity appears to be related to pain
perception, current studies does not provide sufficient evidence to determine the mechanisms
underlying this interaction. For a better understanding of the relationship between pain and
cognitive inhibitory processes it is necessary to examine cognitive inhibitory performance in
chronic pain patients.
Cognitive inhibitory performance in chronic pain patients
Mixed results have also been reported regarding cognitive inhibitory function in chronic pain
patients. No deficits were found in Stroop task performance in a sample of irritable bowel
syndrome patients as compared to controls (Atree et al., 2003), or in a group of heterogeneous
chronic pain patients as compared to controls (Oosterhuis et al., 2012). Fibromyalgia (FM)
patients did show significantly slower reaction times on a Stroop task compared to controls,
but neither significantly more slowing on trials where a prepotent response should be
inhibited, nor significantly more false positives than controls (Veldhuijzen et al., 2012). These
results were found to be better explained by psychomotor slowing as opposed to deficits in
cognitive inhibitory function.
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Psychomotor slowing has been reliably reported in chronic pain patients (Hart et al.,
2000, Moriarty et al., 2011, Oosterhuis et al., 2012). To reduce the influence of psychomotor
slowing, a Go-NoGo task was adapted for a sample of FM patients by including longer
latencies (Glass et al., 2011). Indeed, FM patients did not show decreased reaction time or
accuracy scores compare to controls, but functional magnetic resonance imaging data
gathered during response inhibition in both groups showed that FM patients had significantly
decreased activation in areas associated with inhibition, motor preparation and attention
(bilateral MCC/SMA, right premotor/precentral cortex, right inferior parietal lobule, left
dorsolateral prefrontal cortex and left lentiform cortex), compared to controls. Additionally,
hyperactivation was observed in areas not normally active during cognitive inhibition (inferior
temporal/fusiform gyrus). Speculatively, additional brain areas were recruited to compensate
for the decreased activation in the areas regularly associated with cognitive inhibitory tasks,
enabling patients to attain similar reaction time scores and accuracy scores as controls (Glass
et al., 2011).
Several other studies observe effects of both cognitive inhibitory deficits and
psychomotor slowing in chronic pain patients. A sample of chronic pancreatitis pain patients
showed significant decreases in performance on the Go-NoGo task and TMT part a (but not
part b or errors) as well as significantly more intrusions on the Verbal Word Learning Task,
and a significant decrease in correctly answered trials on the Stroop task (Jongsma et al.,
2011). While the first two tasks use reaction time measures and decreased scores might thus
reflect reduced psychomotor speed, the last two measures rely less on psychomotor slowing,
suggesting suboptimal cognitive inhibitory function in this patient sample. Similarly, a sample
of FM patients showed significantly more false positives compared to controls on a Go-NoGo
task (Correa et al., 2011). Additionally, controls showed the usual faster reaction times to
valid trials compared to invalid trials, but patients did not show this pattern, suggesting
psychomotor slowing as well as cognitive inhibitory deficits in this patient sample.
Besides the interfering effect of psychomotor slowing, another possible cause of the
influence of chronic pain on cognitive inhibitory function is the variation in clinical pain
levels. It has been observed that chronic pain sufferers with high intensity pain show
decreases in task performance, while low intensity pain sufferers do not score significantly
different than controls (Eccleston, 1995, Grisart & Plaghki, 1999).
In summary, although part of the results described above might be explained by
psychomotor slowing, decreases in accuracy suggest deficits in cognitive inhibitory function
in chronic pain patients. Additionally, brain activation patterns in chronic pain patients during
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cognitive inhibition suggest altered inhibition functionality. Lastly, it appears that higher pain
levels are associated with reduced task performance.
Cognitive inhibition and physical function in healthy participants
Recently, it has been demonstrated that physical function and cognitive abilities are closely
interrelated (Vaynman & Gomez-Pinilla, 2006, Hillman et al., 2008, Gomez-Pinilla &
Hillman, 2013). Research in healthy older adults indicates that physical fitness correlates
negatively with age-related brain tissue loss and resultant cognitive decline (Gomez-Pinilla &
Hillman, 2013). Specifically, physically fit participants were found to have larger grey matter
volumes correlated to better Stroop task performance compared to participants with lower
physical fitness scores (Weinstein et al, 2012).
Additionally, the mediating role of physical fitness in the regulation of autonomic
nervous system (ANS) arousal is proposed to influence cognitive inhibitory performance
(Solberg Nes et al., 2009). Research suggests that moderate increases of autonomic nervous
system (ANS) arousal facilitate cognitive inhibitory performance (Magnié et al., 2000), while
large increases in ANS arousal hinder performance (Yerkes & Dodson, 1908). Indeed,
accuracy scores and reaction times on a Stroop task performed during high intensity physical
exercise were significantly lower than scores during moderate intensity exercise (Labelle et
al., 2013). Additionally, compared to pre-exercise performance, accuracy and reaction times
on a Flanker task significantly improved on a second task, performed after heart rate had
returned within 10% of baseline following intense physical exercise (Hillman et al., 2003).
Shorter latencies and higher peaks of the P300 event-related potential were also observed
during the second Flanker task (Hillman et al., 2003), which have been associated with
improved cognitive inhibitory ability (Huster et al., 2013). Because physical fitness is
associated with smaller increases in ANS arousal after physical exercise (Hautala et al.,
2009), and stressful cognitive tasks (Heydari et al., 2013), it might mediate the beneficial
effect of physical exercise on cognitive inhibitory performance in healthy adults. Indeed,
physically fit participants improved accuracy scores on a Flanker task after moderate physical
exercise, while the unfit participants did not show significant differences between scores
(Hogan et al., 2013). The unfit group also showed higher levels of alpha wave coherence
measured with electroencephalography during the Flanker task, which was speculatively
interpreted as reflecting increased effort to inhibit incorrect responses. Additionally,
variability in reaction times in response to a Stroop task increased significantly more in unfit
participants in response to increased exercise intensity compared to fit participants, indicating
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proportionally more difficulty to maintain performance during increasing ANS arousal
(Labelle et al., 2013).
In summary, physical fitness might mediate cognitive performance in healthy adults
through its associations with neuroprotective effects and efficient ANS arousal regulation.
Cognitive inhibition, physical function and chronic pain
Recent studies have attempted to integrate the reduced physical function (Andrews et al.,
2012) and cognitive deficits (Moriarty et al., 2011) associated with chronic pain. In a sample
of heterogeneous chronic pain patients, physical function, cognitive performance and pain
intensity were all found to correlate significantly with one another (Pulles & Oosterman,
2011). Results indicated that psychomotor speed, but not cognitive inhibitory capacity,
mediated the relationship between pain intensity and physical performance. Additionally, pain
intensity in older CLBP patients was associated with decreased physical function, a
relationship mediated by TMT part b scores (Weiner et al., 2006). However, because the TMT
part b is a reaction time measure, these results might similarly reflect a mediating effect of
psychomotor slowing, as well as cognitive inhibitory capacity.
In contrast, both chronic lower back pain (CLBP) patients and controls showed
decreases in gait stability and upper body mobility while performing cognitive tasks during
self-paced walking, but the CLBP group showed significantly larger decreases during a
simultaneous Stroop task compared to controls. Decreases observed in patients during a
control colour naming task not requiring the inhibition of a prepotent response did not differ
significantly from decreases in controls (Lamoth et al., 2008), suggesting a role for cognitive
inhibitory capacity in gait maintenance for CLBP pain patients. It has been speculated that
movement is less automated in chronic pain patients, due to recruitment of additional
cognitive inhibitory resources in an effort to protect the painful area from noxious stimulation
during movement (Lamoth et al., 2008). Indeed, cognitive inhibition, as measured by
proportional scores on the Stroop task and TMT, also correlated significantly with gait
cadence, walking speed and aerobic endurance in a sample of FM patients (Cherry et al.,
2012). Additionally, attentional capacity was found to be significantly correlated with gait
cadence, walking speed and psychomotor speed (Cherry et al., 2012). These results suggest
that gait abnormalities in chronic pain patients are influenced by both cognitive inhibitory
ability and attentional capacity.
In summary, there appears to be a complex relationship between physical function and
cognitive inhibitory capacity in chronic pain. Physical function shows positive correlations
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with both cognitive inhibitory function and attentional capacity. Psychomotor slowing is
suggested as a mediator in the relationship between chronic pain and physical function, as
well as cognitive inhibitory capacity.
Discussion
To improve treatment outcomes for chronic pain patients, it is important to increase current
understanding of the mechanisms underlying chronic pain states. Interactions between pain,
cognitive inhibitory function, and physical function are discussed in this review and the
following main conclusions can be drawn: 1) cognitive inhibitory capacity might interact with
pain in healthy participants but more research is needed to determine the nature of this
interaction, 2) several studies provide evidence for cognitive inhibitory deficits in chronic
pain patients in addition to psychomotor slowing, and 3) while physical fitness might mediate
cognitive inhibitory function through neuroprotective effects and improved arousal regulation
in healthy adults, evidence suggests a more complicated interaction in chronic pain patients.
Below, the clinical implications of the mechanisms underlying the interactions between these
factors are discussed, particularly relating to physical fitness as a target for treatment.
Chronic pain states are associated with changes in brain anatomy and function, such as
decreased grey matter density (Tracey & Mantyh, 2007, Apkarian et al., 2009). One of the
most prominent explanations for cognitive inhibitory deficits in chronic pain patients is the
decreased cortical integrity observed in areas such as the prefrontal cortex (PFC) and anterior
cingulate cortex (ACC; Apkarian et al., 2004, Ruscheweyh et al., 2011, Absinta et al., 2012),
that are involved both in pain perception (Tracey & Mantyh, 2007, Apkarian et al., 2005) and
cognitive inhibitory tasks (Mortiarty et al., 2011, Solberg Nes et al., 2009). It has been observed
that the intensity and duration of pain are positively correlated to grey matter loss in chronic pain
patients (Weiner et al., 2006, Apkarian et al., 2009), although it is currently unclear whether
chronic pain causes these changes or individuals with certain predispositions are more likely
to develop chronic pain (Apkarian et al., 2009). Considering that grey matter loss is a normal
part of aging (Fjell & Walhovd, 2010), and that physical fitness appears to have a
neuroprotective function in this process (Vaynman & Gomez-Pinilla, 2006, Gomez-Pinilla &
Hillman, 2013), possibly the decrease in physical fitness observed in chronic pain states
modulates grey matter loss in chronic pain patients.
The neuroprotective effect of physical fitness observed in healthy individuals is
proposed to partly depend on increased synaptic plasticity due to heightened concentrations of
neurotrophins released after physical exercise, most notably Brain-Derived Neurotrophic
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Factor (BDNF; Vaynman & Gomez-Pinilla, 2006, Gomez-Pinilla & Hillman, 2013). However,
the role of BDNF in chronic pain disorders appears to be more complicated. BDNF has been
reported to have anti-inflammatory effects and can help reduce pain in chronic inflammation
pain disorders (Gomes et al., 2013). In contrast, it has also been suggested that observed
increased levels of BDNF in FM patients are partly responsible for the etiology of the disorder
(Nugraha et al., 2012). Indeed, animal models suggest that increased excitability of the central
and peripheral nervous system following initial noxious stimulation might be part of the
initiation and maintenance of the morphological and functional changes associated with
chronic pain (Masino & Ruskin, 2013, Apkarian et al., 2009), and this process might partly
depend on BDNF signaling in the spinal cord (Biggs et al., 2010). More research is required
to determine whether influence of BDNF in different chronic pain disorders might be
neuroprotective before conclusions can be drawn about the possible usefulness of clinical
interventions aiming to improve physical fitness in chronic pain patients.
Functional changes, as well as anatomical changes, characterize chronic pain states.
Chronic pain patients show increased resting state activity in the medial PFC compared to
controls (Apkarian et al., 2009), and spontaneous pain is associated with sustained prefrontal
activation (Apkarian et al., 2005). Interestingly, practiced Zen meditators have significantly
higher pain tolerance scores than controls, which are positively correlated to decreased PFC
activity and increased ACC activity during acute painful stimulation (Grant et al., 2011). In
contrast, chronic pain patients show increased activation in both the PFC and ACC in
response to acute noxious stimulation (Apkarian et al., 2005) and cognitive inhibitory tasks
(Weissman-Fogel et al., 2011) compared to controls. Clearly, modulation of activation in both
areas plays a pivotal role in pain modulation. Interestingly, little evidence is available for
differences in ACC and PFC activation in response to different cognitive inhibitory tasks, or
different subdomains of cognitive inhibitory function using different brain areas (Barch et al.,
2001). Therefore, it remains unclear whether cognitive inhibition in chronic patients is
impaired in general, or if a subdomain of cognitive inhibitory ability is affected.
PFC activity levels might also influence cognitive inhibitory performance via the
regulation of ANS arousal through the central autonomic network (CAN). It has been
suggested that measures of ANS arousal might be a sensitive measure of PFC damage
(Solberg Nes et al., 2009). Chronic pain patients indeed show increased variability in the time
between heart beats compared to controls, indicating less efficient ANS arousal regulation by
the CAN (Solberg Nes et al., 2009). Because small increases in ANS arousal have been
reported to increase cognitive inhibitory performance, but large increases in ANS arousal are
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thought to decrease cognitive inhibitory performance (Magnié et al., 2000, Labelle et al.,
2013, Yerkes & Dodson, 1908), effectiveness of ANS arousal regulation might also predict
cognitive inhibitory performance (Solberg Nes et al., 2009). As physical fitness improves
ANS arousal regulation through smaller increases in arousal in response to both physical
exercise (Hautala et al., 2009) and cognitive tasks (Heydari et al., 2013) in healthy individuals
decreased physical fitness associated with chronic pain states might result in ANS arousal
dysregulation.
Another possible mechanism underlying the interaction between physical function and
cognitive inhibitory performance in chronic pain patients is glucose depletion. It was observed
that effortful cognitive inhibition on a Stroop task lowers blood glucose levels, that lowered
glucose levels corresponded to decreased performance on a subsequent Stroop task, and that
glucose intake before the second Stroop task restores performance (Gailliotet al., 2007).
Glucocorticoids excreted from the adrenal cortex are important for glucose production and
metabolism (Solberg Nes et al., 2009). Chronic pain disorders have been observed to be
associated with dysregulated hypothalamic-pituary-adrenal (HPA) axis function, leading to
significantly altered cortisol levels compared to healthy individuals (Crofford et al., 1996,
Jones et al., 1997, Korszun et al., 2002). Speculatively, HPA dysregulation might contribute
to glucose depletion in chronic pain patients, which might partly explain reduced cognitive
inhibitory performance (Solberg Nes et al., 2009). Interestingly, physical fitness has been
reported to correlate positively with reduced HPA response to physical and psychological
stressors (Traustadóttir et al, 2005, de Diego Acosta et al., 2001). Speculatively, decreases in
physical fitness in chronic pain patients might contribute to the increased cortisol levels
observed in some chronic pain disorders (Jones et al., 1997, Korszun et al., 2002). Clinical
interventions to increase physical fitness in these patients might be effective to restore
neurochemical balance.
Recent research in animal models for chronic pain suggests another approach that
might be helpful to remedy glucose depletion. High-fat, low-carbohydrate diets increase
ketone bodies in the blood, which can replace glucose as an energy source in the brain.
Ketogenic diets have been shown to induce hypoalgesia by altering brain energy metabolism
in response to acute noxious stimulation in healthy rats, and in rat models of chronic pain
(Ruskin et al., 2013, Masino & Ruskin, 2013). Interestingly, while the hypoalgesic effect of
the diet persisted, blood glucose levels recovered during the diet (Ruskin et al., 2013). It has
been suggested that a ketonic diet boosts adenosine signaling, a neuromodulator with
analgesic properties (Masino & Ruskin, 2013). Indeed, adosine agonist treatment increases
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the analgesic effect of physical exercise in a mouse model of chronic pain (Martins et al.,
2013). Research on the effects on the cognitive inhibitory capacity of chronic pain patients on
a ketogene diet, where both ketogene levels and glucose levels in the blood are monitored,
might result in helpful new treatment strategies. Additionally, a personalized physical exercise
program might be helpful to determine whether such a diet might have similar analgesic
effects in human chronic pain patients as were found in mice models.
A more psychological explanation for cognitive inhibitory deficits in chronic pain
patients centers on limited available resources which have to be shared by pain and attentional
processes. This hypothesis is in line with the idea that pain and cognitive inhibition partly
depend on the same brain networks. Indeed, attentional processes are also associated with
PFC activation, and attention to pain specifically with the anterior mid cingulate cortex and
insula (Weissman-Fogel et al., 2011). With pain demanding attention, less attention is
available for the cognitive inhibitory task, resulting in decreased performance (Eccleston &
Crombez, 1999). Speculatively, cognitive inhibitory capacity might be important for the
ability to disengage attention from pain or prevent pain from capturing attention, improving
performance (Verhoeven et al., 2011). Indeed, a dual tasking study showed disproportionate
increases in gait instability in CLBP patients compared to controls during a cognitive
inhibitory performance, but not during a control task (Lamoth et al., 2008). Acute noxious
stimulation in CLBP patients resulted in faster and stronger contraction of stabilizing trunk
muscles during arm movements, proportional to subjective pain ratings, while performing a
cognitive task slowed trunk muscle contraction (Larivière et al., 2013). These results suggest
that chronic pain patients reduce mobility to protect the painful area by recruiting additional
attentional or cognitive inhibitory resources for motor planning, but fail to maintain these
strategies when these resources are also required for cognitive tasks.
In conclusion, the evidence for the neuroprotective effects of physical fitness,
improved ANS arousal regulation, and reduced stress responses in healthy adults, as well as
possible interactions with a ketone diet in mice suggest that improving physical fitness in
chronic pain patients through clinical interventions might be helpful, however several factors
should be taken into consideration. First, positive and negative effects of increased BDNF
levels have been reported in different chronic pain disorders, and the role of BDNF should be
clarified for specific disorders before clinical interventions targeting BDNF levels are piloted.
Additionally, while reducing cortisol secretion in chronic pain patients with heightened levels
might aid in restoring glucose levels, the effects of increased physical fitness on chronic pain
patients with reduced cortisol levels are unclear, and might possibly further decrease available
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glucose. Furthermore, the analgesic effect of the ketogenic diet is speculated to depend on
adenosine’s effects on opioid signaling (Masino & Ruskin, 2013) As patients with some
chronic pain disorders show increased pain, rather than opioid mediated analgesia after
physical exercise (Nijs et al., 2012), such a paradigm might not be effective for all chronic
pain conditions. Lastly, and most importantly, while increasing physical function through
clinical intervention appears promising, one study shows that cognitive inhibitory capacity
might mediate the relationship between pain and physical function (Wiener et al., 2006),
rather than physical function mediating the relationship between cognitive inhibitory capacity
and pain. Decreases in physical performance during simultaneous physical and cognitive
inhibitory performance in chronic pain patients appear to support this idea. If this is the case,
improving physical fitness in chronic pain patients will probably not improve cognitive
inhibitory capacity, and clinicians should focus on developing interventions to increase
cognitive inhibitory ability. To guide the development of clinical interventions, future studies
should aim to provide more conclusive evidence for the direction of the relationships between
cognitive inhibitory capacity and physical function in chronic pain states. Because physical
exercise interventions in chronic pain patients are already being conducted to improve other
factors, longitudinal measurement of cognitive inhibition, physical fitness, pain and
morphological changes in the brain of the patients participating in such interventions would
be useful.
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