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Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits


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Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.
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Shape shifting pain: chronification of back pain
shifts brain representation from nociceptive
to emotional circuits
Javeria A. Hashmi,
Marwan N. Baliki,
Lejian Huang,
Alex T. Baria,
Souraya Torbey,
Kristina M. Hermann,
Thomas J. Schnitzer
and A. Vania Apkarian
1 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA
2 Department of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA
3 Departments of Anaesthesia and Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA
Correspondence to: A. Vania Apkarian, PhD,
Department of Physiology,
303 E. Chicago,
Tarry Bldg. 5-703,
Chicago, IL 60611
Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that
brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter
are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain
has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain mag-
nitude. First we compared back pain-related brain activity between subjects who have had the condition for 2 months with no
prior history of back pain for 1 year (early, acute/subacute back pain group,
94), to subjects who have lived with back pain
for 410 years (chronic back pain group,
59). In a subset of subacute back pain patients, we followed brain activity for back
pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute
back pain group,
= 19) and those in which the back pain persists (persistent acute/sub-acute back pain group,
= 20; based on
a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to
the terms pain, emotion, and reward (each map is based on 4200 brain imaging studies, derived from We
observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute
pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally
represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the
persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and
remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can
undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing
theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions
and mechanisms of chronic pain.
Keywords: chronic back pain; fMRI; longitudinal; emotion; reward
Abbreviations: CBP = chronic back pain; SBP = subacute back pain
doi:10.1093/brain/awt211 Brain 2013: 136; 2751–2768 | 2751
Received March 19, 2013. Revised May 16, 2013. Accepted June 14, 2013
Published by Oxford University Press on behalf of the Guarantors of Brain 2013. This work is written by US Government employees and is in the public domain in the US.
at Harvard University on September 4, 2013 from
Chronic pain imparts a large socioeconomic burden [Institute of
Medicine of the National Academies ( states that
chronic pain affects at least 100 million American adults, costing
up to $635 billion each year]. Extensive human and animal evi-
dence shows that it is associated with PNS and CNS reorganization
(Apkarian et al., 2009, 2011; Costigan et al., 2009; Tracey and
Bushnell, 2009). Human brain imaging studies indicate that differ-
ent chronic pain syndromes exhibit distinct brain activity and func-
tional/morphological alterations (Geha et al., 2008a; May, 2008;
Staud et al., 2008; Apkarian et al., 2009, 2011, Baliki et al.,
2011a; Weissman-Fogel et al., 2011; Farmer et al., 2012) and
that chronic pain also alters brain dynamics by changing brain
resting state interactions between networks implicated in default
states, attention, salience and reward (Baliki et al., 2008a, 2011b;
Cauda et al., 2009; Malinen et al., 2010; Napadow et al., 2010;
Tagliazucchi et al., 2010). Thus, it is evident that changes in brain
function and structure correlate with chronic pain. Yet, these stu-
dies are cross-sectional or retrospective, and as a result the rela-
tionship between brain reorganization and the onset and
maintenance of chronic pain has remained unknown.
The core clinical issue is that only a fraction of subjects who
experience an acute painful injury develop chronic pain, and
although many clinical studies have searched for parameters
predicting pain chronification, no consistent behavioural, psycho-
logical or neurobiological factors have emerged (Chou and
Shekelle, 2010). Human brain imaging studies have identified po-
tential anatomical and functional biomarkers that differentiate
chronic pain from healthy subjects (Apkarian et al., 2009, 2011;
Farmer et al., 2012), yet definitive evidence required to inter-
relate brain states and chronic pain requires repeated longitudinal
observations of individuals throughout the period of transition
from acute to chronic pain.
Cross-sectional functional MRI studies indicate preferential
involvement of brain emotional and limbic circuitry in encoding
fluctuations of ongoing pain for various chronic pain conditions
(Baliki et al., 2006, 2010; Geha et al ., 2007, 2008b; Farmer
et al., 2011; Parks et al., 2011; Hashmi et al., 2012).
Specifically in chronic back pain (CBP, back pain persisting 46
months) we have shown that rating of spontaneous pain primarily
activates the medial prefrontal cortex (Baliki et al., 2006, 2010;
Hashmi et al., 2012). In contrast, acute painful stimuli (mechanical
or thermal) applied in healthy subjects gives rise to a consistent
pattern of activity that engages, at least, multiple sensorimotor
regions, bilateral insula, thalamus, basal ganglia, and dorsal anter-
ior cingulate cortex (Apkarian et al., 2005). Moreover, in CBP we
have shown a double-dissociation between brain regions activated
for acute thermal painful stimuli and areas activated for rating
spontaneous fluctuations of ongoing pain (Baliki et al., 2006,
Given these observations, we expected that when back pain is
acute or subacute (SBP, back pain persisting for 53 months) the
experienced pain is preferentially driven by acute/nociceptive
mechanisms and related brain activity should be more similar to
brain activity seen for acute pain in healthy subjects; in contrast,
this activity should be dissimilar from brain activity for back pain in
CBP. Additionally, we hypothesized that a spatiotemporal dynam-
ical reorganization of brain activity accompanies the transition to
chronic pain, during which the representation of back pain in time
shifts away from sensory regions and gradually engages emotional
and limbic structures.
To test these hypotheses, we conducted a combined cross-
sectional and longitudinal anatomical and functional brain imaging
study in a cohort of subjects with an episode of SBP (back pain
persisting for at least 4 weeks, with no prior back pain experience
for at least 1 year). SBP participants were followed over a period
of 1 year as they either recovered or transitioned into chronic pain.
We followed brain properties of back pain for 1 year, as (i) it is
one of the most prevalent clinical conditions that becomes chronic;
and (ii) functional and anatomical reorganization, as well as their
partial reversal with adequate therapy, are best characterized in
this condition (Apkarian et al., 2004; Baliki et al., 2006, 2011
Seminowicz et
al., 2011). Recently we reported on the anatomical
and related functional connectivity changes with chronification
from this longitudinal study (Baliki et al., 2012). Here, we compare
brain activity for back pain between SBP with participants who
have been suffering with CBP for 410 years. We also assessed
longitudinal changes in back pain-related brain activity in SBP
as participants either recovered or persisted to transition to
chronic pain.
To directly test the assumption that early and later, or chronic,
stages of back pain may be preferentially associated with acute
pain versus emotion or reward/aversion circuitry, we used the
Neurosynth framework (, which combines text-
mining, meta-analysis, and machine learning techniques to gener-
ate probabilistic maps for cognitive constructs (Yarkoni et al.,
2011) based on forward or reverse inference statistics. We used
maps derived from Neurosynth for the terms pain, emotion and
reward, and we examined the overlap between these meta-ana-
lytic maps and back pain-related maps across the different groups,
and at different times from inception of back pain.
Materials and methods
Data presented in this manuscript are part of an ongoing study in
which we examine longitudinal changes in brain structure and function
in patients with SBP as they transition into persistence or recovery.
One hundred and twenty patients with SBP were recruited into the
study where subjects were scanned over a period of 1 year, at four
separate visits. At visit 1, 94 patients with SBP participated in the
functional MRI scans (48 females; age: mean = 42.09, SEM = 1.15
years). At the time of this report, 47 patients with SBP had complete
data for the four brain scans. Out of the 47 subjects, eight subjects
were excluded due to missing data points or excessive head motion
artefacts. Two subjects did not have functional scans for visit 2, one
subject did not have functional scan for visit 3, two subjects did not
have spontaneous pain ratings and three subjects had excessive head
motion artefacts (head motion 410 mm). It is important to note that
out of the 39 patients used in this study, 30 patients were from the
same data set that were recently used to track anatomical and
2752 | Brain 2013: 136; 2751–2768 J. A. Hashmi et al.
at Harvard University on September 4, 2013 from
functional brain properties in pain chronification (Baliki et al., 2012). In
addition, 31 patients with CBP were recruited for this study, and their
data were combined with additional functional MRI data collected in
patients with CBP (n=38) from two of our earlier studies (Baliki et al.,
2010; Hashmi et al., 2012). Healthy subjects were also recruited into
the longitudinal study, but these data were not used in the current
analysis. Overall, scans collected in patients with SBP at visit 1 (desig-
nated as early or early SBP; n=94) were compared with scans col-
lected in patients with CBP (back pain for 410 years, n=59) in a
cross-sectional analysis. In addition, scans from 39 patients with SBP
who had completed all four scans were analysed for longitudinal
The definition of chronic pain remains arbitrary and operational. For
back pain, 0–7 days of pain is considered acute, 7 days to 3 months is
classified as subacute, and 43 months is categorized as chronic pain
(Frank, 1993). We recruited subjects with SBP who reported a single
intense episode of back pain lasting 4–16 weeks and no prior back
pain for at least 1 year, performed brain scans as soon as possible
(mean SEM pain duration from injury at visit 1 = 9.14 0.48
weeks) and followed their pain and mood parameters, as well as
brain activity, over three additional visits for the next year (visit
2: 7.15 0.26 weeks; visit 3: 29.20 0.63 weeks; visit
4: 54.36 2.14 weeks; from visit 1).
All participants were right-handed and gave informed consent to
procedures approved by the Northwestern University Insistutional
Review Board committee. Subjects were recruited by newspaper or
internet advertisements in the Chicago city area. All patients were
diagnosed by a clinician and fulfilled the International Association for
the Study of Pain criteria for back pain. An additional list of criteria
was imposed, including the following: for SBP, back pain intensity
440/100 on the Visual Analogue Scale and duration 5 16 weeks;
and for CBP, back pain intensity 4 40/100 on the Visual Analogue
Scale and duration 4 6 months. Subjects were excluded if they re-
ported other chronic painful conditions, systemic disease, history of
head injury or coma, psychiatric diseases, or more than mild to mod-
erate depression (Beck Depression Inventory score 4 19). For demo-
graphics see Tables 1 and 3.
Pain and mood parameters
For all visits, patients with SBP completed the short-form of the McGill
Pain Questionnaire. The main components of the McGill Pain
Questionnaire are 12 sensory and four affective descriptors, which
are used to compute the sensory and affective scores, respectively.
Radiculopathy scores were quantified from pain locations based on
the body regions that patients had shaded in with pencil on the
McGill Pain Questionnaire form. The McGill Pain Questionnaire form
also includes a visual analogue scale (0 = no pain, 100 = maximum
imaginable pain) and pain duration. In addition, patients with SBP
completed the Positive Affect Negative Affect Score (PANAS), which
includes 60 items and measures the two original higher order scales for
positive and negative affect. Depression scores for all subjects were
assessed using the Beck Depression Inventory. All questionnaires were
given 1 h before brain scanning.
Thirty-four patients primarily used acetaminophen and non-steroidal
anti-inflammatory drugs (ibuprofen, Motrin, Aleve, Naproxen,
Tylenol). Six patients also used opiates (Vicodin or Precocet). One
subject used epidural steroid shots (Tramadol), serotonin–
norepinephrine reuptake inhibitors (Effexor and pregabalin) and
muscle relaxants (cyclobenzaprine). Five patients received no treat-
ment. Patients were subdivided into early (treatment commencement
before visit 1) or late drug (treatment commencement post visit 1)
groups. Drug consumption at each visit was quantified using the
Medication Quantification Scale, which computes a scalar value rep-
resentation of dosage and duration of drug use.
Experimental tasks
Participants were trained to perform two tasks using a finger-span
device with which they provided continuous ratings. The device was
composed of a potentiometer, the voltage of which was digitized and
time-stamped in reference to functional MRI image acquisition and
connected to a computer providing visual feedback of the ratings
(Apkarian et al., 2001). For the first task, patients provided continuous
ratings of fluctuations in spontaneously occurring back pain from 0–
100 visual analogue scale for a period of 10 min during a functional
MRI scan. The second functional MRI scan was acquired while subjects
conducted a visual rating control task (Baliki et al., 2006), during
which subjects rated the changes in the length of a visual analogue
scale bar (0–100) projected on a screen for a 10 min period. The
length of the bar varied over time to match the pain ratings obtained
from the subject in the preceding scan. Thus this task serves as a
control for task-related activations, such as visual inputs, motor per-
formance, magnitude estimation, attention and anticipation.
Image preprocessing
Image analysis to reveal significant brain activity based on changes in
blood oxygen level-dependent signal was performed on each patient’s
data using Functional Magnetic Resonance Imaging of the Brain
(FMRIB) Expert Analysis Tool [(FEAT; Smith et al., 2004; http://]. Preprocessing was conducted using the
FSL 4.1 and MATLAB 7.9. The first four volumes were removed to
compensate for scanner drifts, and slice-time correction, spatial
smoothing with 5 mm kernel, intensity normalization, and high-pass
filtering (150 s) were applied. Mean blood oxygen level-dependent
signal from white matter, CSF, whole brain (after skull removal),
six motion components, and motion outlier vectors were regarded as
covariates of no interest and regressed out from the blood oxygen
level-dependent signal. In addition, probabilistic Independent
Component Analysis was then implemented in MELODIC
(Multivariate Exploratory Linear Decomposition into Independent
Components) to select artefact components, using an automated pro-
cedure that identified and removed edge components and signal drop-
out components. The functional MRI signal was then linearly modelled
on a voxel-by-voxel basis using FMRIB’s Improved Linear Model
(FILM) with local autocorrelation correction (Woolrich et al., 2001,
Scan parameters
For all participants and visits, MPRAGE type T
-anatomical brain
images were acquired with a 3 T Siemens Trio whole-body scanner
with echo-planar imaging (EPI) capability using the standard radio-
frequency head coil with the following parameters: voxel size
1 1 1 mm; repetition time = 2500 ms; echo time = 3.36 ms; flip
angle = 9
; in-plane matrix resolution, 256 256; slices, 160; field of
view, 256 mm. Functional MRI images were acquired on the same day
and scanner with the following parameters: multi-slice T
echo-planar images with repetition time repetition time = 2.5 s, echo
time = 30 ms, flip angle = 90
, number of volumes = 244, slice thick-
ness = 3 mm, in-plane resolution = 64 64. The 36 slices covered the
whole brain from the cerebellum to the vertex.
Shape shifting pain Brain 2013: 136; 2751–2768 | 2753
at Harvard University on September 4, 2013 from
General linear model analysis
The patients with SBP with functional MRI scans at visit 1 were desig-
nated as the early SBP group and the relationship between their back
pain-related brain activity was compared with patients with CBP in a
cross-sectional analysis.
Brain functional activity in the early SBP and CBP groups was
assessed for ratings of spontaneous pain and for visual control rat-
ings. Ratings (Baliki et al., 2006) were convolved with a canonical
haemodynamic response function [gamma function: lag, 6 s; standard
deviation (SD), 3 s]. The significance of the model fit to each voxel
time series was calculated, yielding statistical parametric maps for
each subject and condition using the general linear modelling
(GLM) procedure in FSL. After the co-registration of individual
scans to standard space [152 subject average Montreal
Neurological Institute (MNI) space,
cgi/icbm_view/], group level analyses were carried out using
Randomise in FSL. This technique uses permutation-based inference
to allow for rigorous comparisons of significance within the frame-
work of the general linear model with P 5 0.05. Group differences
were tested against 5000 random permutations, which exactly ac-
counts for multiple comparisons. Significant clusters were identified
using the threshold-free cluster enhancement method, and activity
maps were corrected for multiple comparisons using family-wise
error correction (P 5 0.05).
Average group activity maps associated with the pain task were
generated for the early SBP patients and for CBP patients.
Furthermore, brain activation was contrasted between the early
SBP and the CBP group using an unpaired t-test. All activity
comparisons were corrected for confounds due to age, sex and pain
Perception-triggered regional activity
The objective of this analysis was to identify the relationship between
pain ratings and regional brain activity for regions identified in the
general linear model analyses. Functional regions of interest were
determined from the spontaneous pain-related activation maps in pa-
tients with early SBP and those with CBP, and the contrast between
these maps. The region of interest analysis should be considered post
hoc and designed to identify changes in time course of regional activ-
ity. The regions were fixed size (5 5 5 voxel) masks centred at
activation peak coordinates in standard MNI space. For each subject,
individual brain space functional MRI was normalized to standard
space, and then the blood oxygen level-dependent signal averaged
for all voxels in the region was extracted and converted into per
cent blood oxygen level-dependent change. These events were aver-
aged for a fixed time window relative to a trigger, defined as pain
perception crossing an arbitrary threshold (set to 1 SD). These re-
sponses were calculated in all patients (early SBP and CBP) for the
spontaneous pain rating task. The list of regions of interest used for
this analysis included the left medial prefrontal cortex (x = 4, y = 48,
z = 0) and right amygdala (x=24, y=2, z=18) that represented
CBP-related regions, as well as the left insula (x=38, y=20,
z= 4) and left thalamus (x= 14, y= 2, z=18) that repre-
sented early SBP-related regions. Regional differences in peak blood
oxygen level-dependent responses to spontaneous pain rating in CBP
and early SBP were compared using an unpaired t-test at a single time
point (15 s from the trigger), which corresponded to the mean peak
pain rating for both groups. Similar region of interest analyses were
performed for the visual rating task.
Back pain-related brain activity in
relation to meta-analytic maps
We used the web tool Neurosynth to create (reverse inference) meta-
analytic maps for the terms: pain, emotion and reward (Yarkoni et al.,
2011) and generated masks to compare brain activity for different
back pain groupings in relation to these signatures. It is of note that
for the term ‘pain’, the obtained map is based on all identified papers
in which the term is used, and thus the map does not distinguish
between acute and chronic pain conditions. However, the large
majority of publications used to generate the map were from studies
for acute pain conditions (only 6 of 224 studies used included chronic
pain data).
The extent of back pain activity relative to a given meta-analytic
map was computed as the percentage of non-zero voxels activated in
the mean general linear model-based contrast of parameter estimates
for early SBP or CBP conditions encompassed within the meta-analytic
maps. For instance, the amount of overlap between the early SBP map
and the meta-analytic pain map is represented by the percentage of
voxels activated in the early SBP mean map within the meta-analytic
pain map, divided by the total number of voxels in the meta-analytic
pain map. Identical procedures were used for computing per cent
overlap with the emotion and reward maps.
The meta-analytic maps for pain, emotion and reward are not com-
pletely segregated from each other, and the extent of their overlap
varied with threshold. Therefore, we calculated overlap with meta-
analytic maps at two different thresholds, including the top 5% and
1% of voxels from the reverse inference meta-analytic statistical maps,
which generated the 95th percentile and 99th percentile maps,
Longitudinal changes in back pain
representation relative to meta-analytic
The 39 patients with SBP who completed the study (visits 1 to 4) were
subdivided into recovering (recovering SBP, n=19) and persisting
(persisting SBP, n = 20), based on a self-reported 20% change in
back pain intensity from first assessment to 1 year later (e.g. difference
in pain between visits 1 and 4). To assess changes in pain represen-
tation between the persisting and the recovering SBP groups within
the selected meta-analytic maps over time, first, the statistical para-
metric maps were generated using convolved spontaneous pain ratings
using a general linear model procedure for all four visits. Next, we
assessed the mean activation for each subject within the three, reverse
inference, meta-analytic maps for pain, emotion and reward, thresh-
olded at the 95th and 99th percentiles. To assess group (persisting SBP
versus recovering SBP) by time (visits 1–4) interactions, we used a
two-way repeated-measures ANOVA. Post hoc comparisons between
groups were performed using repeated measures one-way ANOVA
and Tukey’s test for pair-wise comparisons.
To test the hypothesis that brain representation for back pain may
be distinct in subjects who have lived with the condition for dif-
ferent durations of time, we examined brain activity for back pain
in CBP and in early SBP (early SBP, first functional MRI scan in SBP
subjects). In early SBP (n=94), the back pain intensity was
2754 | Brain 2013: 136; 2751–2768 J. A. Hashmi et al.
at Harvard University on September 4, 2013 from
58.25 1.95 (mean SEM) and present for a duration of
9.14 0.48 weeks. In contrast, in CBP (n=59) back pain intensity
was slightly, but significantly, higher 69.58 2.61 and was pre-
sent for a far longer duration of 13.5 1.3 years, compared with
early SBP.
Recent evidence shows that increasing the number of subjects in
functional MRI can lead to the identification of more extensive
brain activity (Gonzalez-Castillo et al., 2012). This may be espe-
cially true for the task used in the present study, because it entails
rating subjective fluctuations of an ongoing perception, wherein
the fidelity of ratings may differ between participants, and because
the temporal variability of the perception can also differ between
subjects. Thus, the brain activity we have reported in CBP in the
past (Baliki et al., 2006, 2008b; Hashmi et al., 2012) may have
underestimated the breadth of brain regions related to back pain.
Therefore, the CBP data were pooled from multiple studies to
make the number of subjects more similar to that of early SBP,
and also to increase confidence (by improving detection power) in
the brain areas activated for back pain. With these two groups
(CBP and early SBP), we examined brain activity for back pain of
approximately comparable intensity, between a large group of
subjects who have lived with the condition either for a few
months or for many years. Pain properties and demographics are
presented in Table 1.
Cross-sectional analysis: differences
between early subacute back pain
and chronic back pain
Pain, mood and demographics
Important pain and mood parameters were matched between CBP
and early SBP, yet there were some demographic and pain-related
parameters that differed. The CBP and early SBP groups were not
significantly different in levels of neuropathic pain (Neuropathic
Pain Scale) or depression and had equivalent numbers of males
and females. However, age, self-reported back pain intensity
(based on Visual Analogue Scale), and the sensory and affective
McGill Pain Questionnaire scores were significantly higher in the
CBP group compared to early SBP (Table 1).
Task variability
Given that the brain activity for back pain was based on subjective
ratings of spontaneous fluctuations, the extent of variability of
these ratings is a critical parameter that can control functional
MRI signal size. Two spontaneous pain properties were contrasted
between the two groups: variance and number of trigger events
(i.e. number of times in one scan a subject rates an increase in their
pain larger than 1 SD compared with the mean pain rating, Fig. 1A
and B). The ratings of spontaneous pain exhibited a mean variance
of 14.7 4.3 (on a 0–100 visual analogue scale) in patients with
CBP (n=59) and 12.2 2.35 in patients with early SBP patients
(n=94), with no differences found between the two groups
(t = 0.55, P=0.58). Furthermore, both groups showed similar
numbers of trigger events per scan (CBP: 3.07 1.56 versus
early SBP: 3.03 1.55, t = 0.14, P=0.88). These results indicated
that CBP and early SBP exhibited similar spontaneous pain proper-
ties, and thus any differences observed in brain activation in rela-
tionship to spontaneous pain are independent from the dynamical
properties of fluctuations of spontaneous pain.
Brain activity
Within and across group comparisons
The spontaneous pain ratings activated a different set of brain
regions in early SBP and CBP groups. The mean activation map
in early SBP showed activity extending from the anterior to mid
insula bilaterally with contiguous activations in the thalamus, stri-
atum, and lateral aspects of the orbitofrontal and inferior cortex,
as well as the dorsal parts of the anterior cingulate cortex. In
contrast, CBP patients’ mean brain activity was localized bilaterally
in the perigenual anterior cingulate cortex (Brodmann area 32)
extending into the medial prefrontal cortex (Brodmann area 10)
and parts of the amygdala. Contrasts between the two groups
(CBP 4 early SBP and early SBP 4 CBP) essentially reproduced
the corresponding group activity maps, indicating that early SBP
and CBP back pain engage separate brain regions (Fig. 1C,
Table 2). Note that all activity maps and contrasts were corrected
for age, pain (visual analogue scale) and sex. Although depression
(Beck Depression Inventory) was not different between the groups
Table 1 Demographics, pain and mood parameters for patients with CBP and early SBP
CBP Early SBP CBP 4 early SBP, t-score (P-value)
Number of subjects 59 94
Age 48.8 1.2 42.1 1.15 3.81 (P 5 0.01)
Gender 25 females (42.4%) 48 females (51.1%)
Duration 13.5 1.3 years 9.14 0.48 weeks 14.91 (P 5 0.01)
VAS 69.58 2.61 58.25 1.95 3.67 (P 5 0.01)
MPQ sensory 15.9 0.78 11.2 0.62 4.36 (P 5 0.01)
MPQ affective 5.29 0.46 3.04 0.41 3.4 (P 5 0.01)
MPQ radiculopathy 4.61 0.31 4.90 0.21 0.82 (P=0.41)
BDI 7.30 0.61 6.53 0.61 0.87 (P=0.38)
NPS 52.81 2.22 40.32 1.81 3.91 (P 5 0.01)
BDI = Beck Depression Index; MPQ = McGill Pain Questionnaire; NPS = Neuropathic Pain Scale; PANAS = Positive Affect Negative Affect Scale; VAS = Visual Analogue
*P 5 0.05 **P 5 0.01, unpaired t-test. Data presented as mean SEM.
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Figure 1 Brain activity for rating back pain is distinct in early sub-acute back pain (SBPe) in comparison to CBP. (A) Individual subject
examples of the trigger pulses generated from ratings of back pain, after convolving the rating with a canonical haemodynamic response in
a subject with early sub-acute back pain. Arrows and green curve represent pain onset triggers and green curve represents example of
durations for which subjects reported a greater than 1 SD increase in pain. (B) Shows the number of pain triggers in each subject within the
scan in SBP and CBP patients. (C) Group-averaged brain activity for rating fluctuations of back pain in 94 subjects with early SBP (right),
and in 59 subjects with CBP (middle). The contrast between the two groups (early SBP 4 CBP is shown in blue, and CBP 4 early SBP
in red) (left). The contrasts largely reproduce corresponding group activity maps, indicating that early SBP and CBP engage separate brain
regions. Results are thresholded at P 5 0.05 (FWE corrected). (D) Trigger evoked blood oxygen level-dependent response in regions of
interest. Pain ratings (left) and blood oxygen level-dependent signal (right) were extracted over a 30 s time window that spanned the pain
onset (10 s before and 20 s after onset) for every event and averaged in each subject to construct a group early SBP and CBP average.
Regions were selected based on peak activations in the General Linear Model based early SBP mean map [anterior cingulate cortex (ACC)
and insula] and CBP mean map (medial; prefrontal cortex, amygdala). *P 5 0.01, unpaired two-tailed t-test.
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(Table 1), we tested correcting for Beck Depression Inventory, as
well as for McGill Pain Questionnaire sensory and McGill Pain
Questionnaire affective scores, and observed no differences in ob-
tained contrast maps.
As activity maps for back pain were focal and distinct in early
SBP and CBP, we examined the time course of the blood oxygen
level-dependent signal for regions of interest identified from peak
activations of each map. The SBP group average (n=94) showed
greater peak responses (computed at 15 s post-trigger) than the
CBP group (n=59) in the thalamus (t = 4.00, P 5 0.001) and
insula (t = 4.32, P 5 0.001), whereas the CBP group showed
more pain-related activation in amygdala (t = 4.98, P 5 0.001)
and medial prefrontal cortex (t = 4.50, P 5 0.001) (Fig. 1D).
Given that all subjects also performed a rating task for a visual
task (a control for task performance), we also extracted blood
oxygen level-dependent signals for the corresponding regions
from this visual control task. The comparison of blood oxygen
level-dependent between the two conditions differentiates pain-
related activity from that of task demands. For this contrast, we
statistically compared trigger-evoked blood oxygen level-depend-
ent responses in regions of interest between the spontaneous
pain task and the matched visual task in the early SBP and
CBP groups (Supplementary Fig. 1). Left insula showed greater
blood oxygen level-dependent responses for pain but not for
visual ratings in early SBP (t = 4.77, P 5 0.01) but not in CBP
(t = 0.88, P=0.85). We observed the opposite pattern for medial
prefrontal cortex, which showed larger blood oxygen level-
dependent responses to the pain in CBP patients (t = 4.47,
P 5 0.001). These results indicate that the insula and medial pre-
frontal cortex reflect pain-specific responses in early SBP and
CBP, respectively.
Overlap with meta-analysis maps
Visual inspection of activity maps for early SBP and CBP hint that
the former includes brain regions commonly seen for acute pain,
whereas the latter engages more emotional regions (Fig. 1A
and B). To formally test this idea, we calculated the overlap of
each map with meta-analysis maps generated for the words: pain
(derived from 224 studies, identifying 14.5% voxels), emotion
(derived from 324 studies, identifying 8.6% voxels), and reward
(derived from 203 studies, identifying 5.7% voxels), generated
from Neurosynth (Yarkoni et al., 2011). The meta-analytic map
for pain showed peak activations in the insula, thalamus,
mid-brain, anterior cingulate cortex and somatosensory area 1.
In comparison, the emotion map showed greatest activations in
amygdala, hippocampus, orbitofrontal cortices, and operculum
and in dorsal, ventral and rostral regions of the medial prefrontal
cortex. The reward map overlapped with emotion maps in the
medial and orbitofrontal cortices, but showed high levels of acti-
vation in the basal ganglia and mid-brain, and showed relatively
less activation in the amygdala and hippocampus in comparison to
the emotion map (Fig. 2A).
The top 5% and 1% of voxels of meta-analysis z-score maps
were identified and used to generate two, threshold-dependent
(95th and 99th percentile) term-specific binarized maps
(Supplementary Fig. 2). The emotion and reward maps exhibited
the largest overlap with each other, and the overlap between any
two meta-analytic maps decreased with increasing the threshold
(Supplementary Fig. 2). The percentage overlap between the back
pain maps and the term-specific maps, for both thresholds, are
shown in Fig. 2B. The CBP map exhibited greater overlap with
emotion compared to early SBP for both the 95th percentile
threshold (CBP: 51.19 %; SBP: 11.12 %) and the 99th percentile
threshold (CBP: 44.49 %; SBP: 9.36%). In contrast to CBP,
the early SBP activation map showed the highest overlap with
the pain meta-analytic map, and this held true at the 95th per-
centile threshold (CBP: 35.27%; SBP: 62.18%) and 99th percentile
threshold (CBP: 5.09%; SBP: 24.71%). The reward map showed
slightly higher overlap with CBP map at the 95th percentile thresh-
old (CBP: 56.93%; SBP: 39.41%), but not at the 99th percentile
threshold (CBP: 33.19 %; SBP: 30.94%). Overall, the pain map
overlap was consistently higher for early SBP compared to CBP.
This was mainly due to the unique activation of bilateral insular
cortex in the early SBP. The emotion map overlap was consistently
Table 2 Coordinates of brain activity for rating spontaneous fluctuations of back pain in early SBP and CBP groups
Brain region Early SBP CBP Early SBP 4 CBP
-score Coordinates
-score Coordinates
Right INS 44, 16, 0 5.26 44, 14, 4 4.53
Left INS 36, 22, 2 5.13 38, 20, 4 5.09
Right caudate 10, 14, 6 5.34 12, 14, 4 5.01
Left caudate 12,18, 6 5.30 10, 14, 4 5.53
Left putamen 24, 0, 10 6.98 28, 4, 2 2.84 20, 12, 8 5.31
Right putamen 24, 10, 6 5.93 24, 10, 0 3.82 26, 6, 6 4.47
ACC 2, 30, 16 5.88 0, 30, 16 5.62
Right thalamus 14, 12, 12 6.32 14, 12, 12 4.36
Left thalamus 14, 14, 16 5.51 14, 14, 16 5.32
MPFC 4, 48, 0 6.46 4, 48, 0 4.28
OFC 2, 42, 12 7.30 2, 40, 12 4.19
Left amygdala 24, 2, 18 8.51 24, 2, 18 6.14
Right amygdala 28, 2, 16 8.73 28, 2, 16 5.14
INS = insula; OFC=orbitofrontal cortex; ACC=anterior cingulate cortex; MPFC=medial prefrontal cortex.
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Figure 2 Early SBP (SBPe) and CBP activation maps correspond to distinct meta-analytic circuits. (A) Brain meta-analytic maps for the
terms: pain, emotion and reward, from Neurosynth (Yarkoni et al., 2011). (B) Brain images represent masks derived from maps above at
different thresholds (top five and one percentile voxels) for pain (red), reward (green) and emotion (blue) meta-analytic maps. Bar graphs
represent the % overlap for CBP (black) and early SBP (grey) with the three meta-analytic maps at the 95th and 99th percentile thresholds.
Overall SBP activity is more similar to the pain term related mask, whereas CBP activity is similar to emotion term related mask. Activity in
both groups engage parts of the reward mask. (C) Brain images show the overlapping (yellow) and non-overlapping (blue) voxels for early
SBP (top row) and CBP (bottom row) with the 95th percentile thresholded meta-analytical masks. Early SBP overlaps with pain mainly in
bilateral insula, thalamus and anterior cingulate cortex (ACC), whereas CBP overlaps with emotion in bilateral amygdala and medial
prefrontal cortex (mPFC).
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higher for CBP compared with early SBP, primarily because of the
CBP-specific activation of the medial prefrontal cortex and bilateral
amygdala. CBP and early SBP both showed similar overlap with
the reward map, reflecting engagement of different parts of the
basal ganglia. Finally, early SBP shared more overlap with the
dorsal striatum, whereas CBP overlapped with the ventral striatum.
The spatial distribution of overlap for early SBP and CBP activity
across the pain, emotion and reward term maps are illustrated
in Fig. 1C.
Longitudinal analysis
Of the 94 patients with early SBP, 39 completed the longitudinal
part of the study and had complete functional MRI scans for back
pain at four sessions over a 1 year period. In this subgroup of
patients, we examined brain activity longitudinally as participants
either recovered (recovering SBP) from back pain or persisted into
chronification (persisting SBP).
Pain, mood and demographics
In the 39 patients with early SBP, brain scans for back pain were
performed as soon as possible upon recruitment (mean SEM
pain duration from injury at visit 1 = 12.28 4.80 weeks) and
we followed their pain and mood parameters, as well as brain
activity, over three additional visits for the next year (visit
2: 7.15 2.48 weeks; visit 3: 29.20 6.06 weeks; visit
4: 54.36 6.12 weeks; from visit 1) (Fig. 3A)
We subdivided the group into recovering (recovering SBP,
n=19) and persisting (persisting SBP, n = 20), based on a self-
reported 20% change in back pain intensity from first assessment
to 1 year later (i.e. difference in pain between visits 1 and 4).
These two groups diverged in back pain intensity at visits 2 and 3
(weeks 15 and 45 from onset of back pain, Fig. 3B) and exhibited
no significant difference in pain duration at visit 1 (persisting SBP:
12.4 1.12; recovering SBP: 12.16 1.06; two-sided unpaired
t-test: t = 0.16, P 4 0.05). At visit 1, both groups reported similar
pain and mood characteristics (Table 3). In addition, both groups
had similar variance in spontaneous pain ratings of back pain, in
the amount of head motion, and in medication use (Table 3,
Supplementary Fig. 3). At visit 4, the recovering SBP group
showed a decrease in mood impairment and pain parameters,
indicating recovery from back pain.
Brain activity
The results of the cross-sectional analysis suggest that, with chron-
ification of pain, the brain activity for back pain is spatially trans-
formed from the pattern observed for the term ‘pain’ to that
identified for the term ‘emotion.’ However, the latter does not
provide information regarding the time-span within which such
reorganization may occur. We directly tested this notion in the
longitudinal group, expecting that, in time, the recovering group
(recovering SBP) would show decreases in back pain-related brain
activity, whereas those persisting to pain chronification (persisting
SBP) would exhibit a shift of pattern towards the emotion term
related map, as we observed for CBP cross-sectionally. Therefore,
we tracked brain activity for persisting SBP and recovering SBP
for rating fluctuations of back pain over time, in relation to the
meta-analytic maps, and compared with masks generated from
early SBP and CBP activity.
First, as observed in the scanning schedule in Fig. 3A, the per-
sisting SBP and recovering SBP groups were scanned within the
same time window and with a distribution of times, at all four
visits, that were random across groups, thereby eliminating the
potential bias of scan order as a factor in group differences in
brain activity. As expected the patients with recovering SBP, in
contrast to those with persisting SBP, exhibited decreased pain
in time (Fig. 3B). Changes in pain intensity across groups and
time were computed using a two-way repeated-measures
ANOVA. Persisting SBP and recovering SBP showed significant
group differences [F(1,37) = 16.09, P 5 0.001], time effect
[F(3,111) = 7.09, P 5 0.001], and group time interaction
[F(3,111) = 6.92, P 5 0.001]. Post hoc comparisons between
pain scores were performed using Tukey’s test and indicated
that patients with recovering SBP reported an immediate decrease
in pain ratings at visit 2 as compared to baseline (visit 1), and in
persisting SBP, the pain intensity was maintained for the duration
of the study.
Pain-related brain activity for persisting SBP and recovering SBP
for the four visits are shown in Fig. 3C. At visits 1 and 2, recover-
ing SBP and persisting SBP exhibited similar brain activation pat-
terns that included bilateral thalamus, insula, mid anterior
cingulate cortex and basal ganglia. At visit 3, persisting SBP
showed activity in the thalamus, basal ganglia and brainstem re-
gions, whereas recovering SBP exhibited no significant activation
in response to pain, which is consistent with the significant de-
creases in pain intensity reported by recovering SBP at visit 3
compared with visit 1. At visit 4, persisting SBP showed activity
within the amygdala and medial prefrontal cortex, in addition to
the basal ganglia. On the other hand, the recovering SBP did not
show any significant activity. Therefore recovering SBP showed
overall activity confined to pain-specific regions (mainly insula,
anterior cingulate cortex and thalamus) for visits 1 and 2, which
significantly decreased at visits 3 and 4. Persisting SBP showed
similar activation patterns for the two visits, which shifted to a
more emotion term-related representation 1 year later (visit 4),
(Tables 4 and 5).
Longitudinal changes in back pain-related brain activity were
determined using a region of interest analysis with the 99th
percentile map masks for the terms pain, emotion and reward,
and by calculating the extent of activity observed within these
masks in the persisting SBP and recovering SBP groups, as a
function of the time of brain scan. For any given subject, the
fit for spontaneous pain with each mask was computed as the
mean contrast of parametric estimate value of all voxels within
each mask. These values were compared using two-way re-
peated-measures ANOVA to evaluate the variability of parametric
estimate values across meta-analytic map types and time, separ-
ately for persisting SBP and recovering SBP. Persisting SBP ex-
hibited decreased representation of back pain-related brain
activity within the meta-analytic pain map (Fig. 3D). There was
no significant effect of meta-analytic map type [F(2,56) = 0.43,
P = 0.65], yet both time [F(3,111) = 3.99, P 5 0.01] and mask
type-by-time interaction [F(6,168) = 9.76, P 5 0.001] were sig-
nificant. Tukey’s post hoc indicated that the persisting SBP
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Figure 3 Longitudinal changes in brain activity underlying spontaneous pain when patients transition from acute to chronic back pain
state. (A) Plots show the scanning calendar dates of subjects with recovering SBP (SBPr) and persistent SBP (SBPp) for all four visits.
Vertical marks represent individual persistent SBP (black) and recovering SBP (grey) subjects. Groups were scanned within the same time
window (major ticks are years; minor ticks are months). (B) Recovering SBP in contrast to persistent SBP patients exhibited decreased pain
in time. (C) Group average activation maps (P 5 0.01 uncorrected) for recovering and persistent SBP groups at the four visits. Recovering
and persistent SBP groups show activation within acute pain regions for visits 1 and 2 encompassing bilateral insula, thalamus and anterior
cingulate cortex (ACC). Recovering SBP patients show no significant activity for visits 3 and 4, whereas persistent SBP shows increased
activation in the medial prefrontal cortex and amygdala at visit 4. (D) Plots show the group average cope (normalized) for pain, emotion
and reward masks, for each group (persistent SBP, CBP, recovering SBP), across all visits. Persistent SBP exhibited decreased presentation
of their spontaneous pain within the pain mask. This decrease was coupled with an increased activity within the emotion mask. The middle
panel shows CBP activity for all three masks. These values correspond to those we observe in persistent SBP at 1-year scans. In contrast to
persistent SBP, the recovering SBP group exhibited decreased activity within all masks in time. (E) Classifier performance applied to
individual persistent SBP activation maps for either pain/emotion or CBP/early SBP, at visits 1 and 4. Persistent SBP activity mainly
classified as pain or early SBP at visit 1, and as emotion or CBP at visit 4.
P 5 0.05,
P 5 0.01, within group comparison to visit 1;
**P 5 0.01 comparison between groups at a corresponding time.
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activity decreased in the pain mask at visits 3 and 4, compared
with visit 1. This decrease was coupled with an increased activity
within the emotion mask at visit 4 compared to visit 1. The
persisting SBP activity within the reward mask did not show
any changes in activity across all time points. Values for overlap
for the three masks with CBP (shown for comparison in Fig. 3D)
were similar to the persisting SBP values for overlap at visit 4. In
contrast, recovering SBP exhibited decreased activity across all
three meta-analytic masks with time (Fig. 3C). This finding is
consistent with their pain reports, which also significantly
decreased in time. Thus, there was a significant group effect
[F(2,54) = 4.85, P 5 0.05], time effect [F(6,162) = 11.83,
P 5 0.001] and group time interaction [F(6,162) = 2.71,
P 5 0.05). Post hoc analyses showed that activity within both
the reward and pain masks showed significant decreases at
visits 3 and 4, as compared to visit 1.
Table 4 Coordinates of brain activity for rating spontaneous fluctuations of back pain in persistent SBP across visits
Brain region Visit 1 Visit 2 Visit 3 Visit 4
-score Coordinates
-score Coordinates
-score Coordinates
Right INS 40, 12, 6 6.71 44, 14, 4 2.97
Left INS 34, 12, 8 6.32 44, 24, 4 2.73
Right caudate 16, 16, 10 6.25 12, 20, 4 3.05 16, 18, 8 2.94
Left caudate 14, 14, 10 6.20 16, 18, 6 4.74 18, 18, 6 3.41 16, 14, 18 2.47
Right putamen 26, 10, 4 5.63 24, 6, 2 3.42 26, 6, 4 2.99
Left putamen 24, 6, 8 5.89 28, 8, 2 4.07
ACC 4, 28, 16 6.25
Right thalamus 8, 16, 10 4.05 10, 14, 6 2.80 8, 6, 6 5.12
Left thalamus 10, 10, 10 3.12 6, 8, 6 2.53 10, 12, 6 3.97
Right S2 58, 24, 26 5.10 2, 34, 24 3.47
MPFC 0, 50, 2 4.51
Right amygdala 24, 4, 16 2.69 24, 2, 16 4.02
Left amygdala 28, 0, 18 3.01
Right ITG 50, 36, 16 3.35
Left ITG 62, 30, 20 3.49
Precuneus 12, 70, 36 3.32
ACC = anterior cingulate cortex; INS = insula; ITG = inferior temporal gyrus; MPFC = medial prefrontal cortex; PCC = posterior cingulate cortex; S2 = secondary somato-
sensory cortex.
Table 3 Pain and mood parameters and differences between and within persisting SBP and recovering SBP over 1 year
Visit 1 Visit 4
Persisting SBP
(mean SEM)
Recovering SBP
(mean SEM)
Persisting SBP 4
Persisting SBP
(mean SEM)
Recovering SBP
(mean SEM)
Persisting SBP 4
recovering SBP
VAS (0–100) 57.61 4.12 52.93 4.33 0.78 53.61 6.13 27.77 5.10 # 5.94**
MPQ sensory 12.42 1.59 9.66 1.05 1.43 11.50 1.42 5.65 1.37 # 2.96**
MPQ affective 3.05 0.61 1.43 0.51 1.44 3.20 0.69 0.89 0.42 # 3.43**
MPQ radiulopathy 5.6 0.49 4.30 0.50 1.80 5.30 0.90 3.50 0.73 # 2.48*
NPS 47.71 4.25 34.4 3.44 2.55* 42.00 4.78 16.53 2.98 # 5.14**
BDI 6.45 1.01 6.55 1.32 0.05 6.06 1.46 3.54 1.17 # 1.25
PANAS positive 33.05 8.05 32.97 1.89 0.03 29.73 6.69 34.42 1.90 1.9*
PANAS negative 19.4 1.80 16.63 1.44 1.32 20.07 1.54 15.26 2.39 # 2.40*
Duration (weeks) 12.4
12.15 1.08 0.15 65.93 1.22 68.80 1.10 0.70
Mean pain variance 10.8 3.29 10.8 4.57 0.01 6.2 1.89 1.52 0.49 # 2.30*
MQS 1.91 0.60 2.62 0.68 0.71 3.71 0.99 4.10 0.99 0.25
MAD 0.53 0.41 0.51 0.58 0.10 0.67 0.53 0.41 0.42 1.7
Clinical pain and mood parameters for persisting SBP (n=21) and recovering SBP (n=18) at visit 1 (within weeks from entry into study) and visit 4 (1 year after entry into
study). Significant changes between visit 1 and visit 4 (paired t-test, P 5 0.01) are displayed as increases ("), or decreases (#).
BDI = Beck Depression Index; MAD = mean absolute displacement (motion); MPQ = McGill Pain Questionnaire; MQS = Medication Quantification Scale;
NPS = Neuropathic Pain Scale; PANAS = Positive Affect Negative Affect Scale; VAS = Visual Analogue Scale.
*P 5 0.05 **P 5 0.01, unpaired t-test. Data presented as mean SEM.
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In a second alternative approach, we used a classification
technique to investigate the similarity of individual persisting SBP
activation maps (for visits 1 and 4) to pain and emotion meta-ana-
lysis maps, and to early SBP and CBP maps (generated from the
cross-sectional analysis). Individual persisting SBP brain activity was
classified as either pain or emotion using a conjunction analysis. For
each subject, the top 1% of activated voxels were identified and the
ratio of overlap between the pain or emotion maps, or either early
SBP or CBP maps, was determined. Subjects were then classified
dependent on higher overlap with either map. Results are shown in
Fig. 3E. Brain activity for patients with persisting SBP were more
often classified as pain at visit 1 (n=16 of 20), and as emotion at
visit 4 (n = 13 of 20) (Fisher’s exact test, P 5 0.004). Similar results
were obtained when subjects were classified as either CBP or early
SBP. At visit 1 the majority of patients with persisting SBP were
classified as early SBP (n=18 of 20), whereas at visit 4 they were
classified as CBP (n=12 of 20) (Fisher’s exact test, P 5 0.001).
Thus, with two separate approaches we show that persisting SBP
brain activity shifts in time to become more similar to the emotion
map, as well as to the CBP map.
Figure 4 Medial prefrontal cortex–nucleus accumbens (mPFC-NAc) functional connectivity strength predicts extent of shift in brain
activity underlying spontaneous pain in patients with persistent SBP from pain-related to emotion-related regions. (A) Brain image shows
the location and coordinates of the medial prefrontal cortex and nucleus accumbens seeds used. (B) Bar graph shows the mean SEM for
medial prefrontal cortex–nucleus accumbens functional connectivity in persistent SBP (black) and recovering SBP (grey) at visit 1.
Persistent SBP exhibited higher medial prefrontal cortex–nucleus accumbens connectivity compared with recovering SBP. (C) Scatter plots
show the relationship between medial prefrontal cortex–nucleus accumbens connectivity at visit 1 and change in brain activity (
Parametric estimate = average cope at visit 4 average cope at visit 1) for pain (left) and emotion (right) term related masks. High medial
prefrontal cortex–nucleus accumbens connectivity showed a strong relationship with decreased activation in pain regions and increased
activiations in emotional regions in patients with persistent SBP over a 1-year period (visit 4 versus visit 1).
Table 5 Coordinates of brain activity for rating spontaneous fluctuations of back pain in recovering SBP across visits
Brain region Visit 1 Visit 2
-score Coordinates
Right INS 42, 12, 6 6.90 36, 10, 2 5.40
Left INS 38, 12, 4 6.77 38, 14, 0 5.12
Right caudate 14, 16, 12 6.44 14, 14, 12 3.78
Left caudate 16, 14, 10 6.05 16, 12, 10 4.21
Right putamen 24, 10, 4 5.93 24, 10, 4 4.90
Left putamen 26, 6, 6 5.75 24, 6, 8 4.95
ACC 2, 32, 14 5.05 2, 32, 16 3.55
Right thalamus 8, 18, 14 5.62 12, 20, 10 4.47
Left thalamus 14, 10, 12 5.50 8, 10, 12 3.75
Right IPS 50, 52, 46 3.93 56, 52, 48 2.41
Left IPS 46, 52, 52 3.54
Right DLPFC 44, 26, 32 3.21
Left DLPFC 48, 30, 32 4.05 46, 40, 16 2.31
Right S2 50, 42, 32 2.66
ACC = anterior cingulated cortex; DLPFC = dorsal prefrontal cortex; INS = insula; IPS = intraparietal sulcus; S2 = secondary somatosensory cortex. There were no significant
activations for visits 3 and 4.
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We have recently shown that early increased functional con-
nectivity between nucleus accumbens and medial prefrontal
cortex can highly predict whether back pain persists in patients
with persisting SBP 1 year after the onset of pain (Baliki et al.,
2012). Here we investigate the relationship between medial pre-
frontal cortex–nucleus accumbens connectivity and the observed
change in brain activity underlying spontaneous pain in patients
with persisting SBP. Similar to our previous report, medial pre-
frontal cortex–nucleus accumbens functional connectivity strength
was significantly higher in persisting SBP (0.38 0.03) compared
with recovering SBP (0.17 0.05) at visit 1 (t-score = 4.48,
P 5 0.01). More importantly, medial prefrontal cortex-nucleus
accumbens connectivity at visit 1 was significantly correlated to
change in brain activity underlying spontaneous pain (average
cope at visit 4 average cope at visit 1), for both pain
(R = 0.44, P = 0.051) and emotion (R = 0.52, P=0.021) term
defined regions (Fig. 4).
To our knowledge this is the first study that examines a highly
prevalent clinical pain condition, back pain, as its brain signature
evolves in time, by following reorganization of underlying brain
representation for the percept. Our main findings are:
(i) Perception of back pain, as determined by continuous rating
of spontaneous pain fluctuations, activates two separate
non-overlapping brain circuits in patients in which the pain
is present for only 2 months (early SBP), in comparison to
those who have lived with the same condition for 410
years (CBP).
(ii) This cross-sectional result was closely replicated in the lon-
gitudinal analysis in a sub-group of early SBP for which pain
and brain activity were followed over a 1-year time span.
When the SBP group was subdivided into recovering and
persisting SBP groups, we observed that in recovering SBP
brain activity for rating back pain decreases over this 1-year
period. In contrast in persisting SBP, the brain regions ini-
tially encoding back pain diminish in response as the back
pain continues to persist, whereas activity in another set
of brain regions emerges to encode the ongoing pain
(iii) We adopted a novel approach of identifying brain functional
circuits associated with specific terms, including pain, emo-
tion and reward, to identify related brain activity derived
from an automated meta-analysis of brain imaging literature
(Yarkoni et al., 2011). We then used these maps to quantify
the relationship between these term-related circuits and the
reorganization of brain activity encoding back pain over time
(in early SBP and CBP, as well as in persisting SBP and re-
covering SBP). This analysis indicates that acute/subacute
back pain primarily engages pain and reward circuitry; in
contrast, CBP and late persisting SBP (after 6–12 months
of back pain persistence) show a shift away from the
acute pain circuit and the gradual engagement of the emo-
tion and reward circuits. Moreover, we could demonstrate
that the extent of shift of activity in persisting SBP from pain
to emotion related maps (over the 1-year period) was
related to the strength of functional connectivity between
medial prefrontal cortex and nucleus accumbens determined
at the time of entry into the study. These results were ob-
tained after correcting for pain intensity, sex, and age dif-
ferences between groups. Therefore, we conclude that the
representation of the percept of back pain is not a unitary
construct; rather it engages distinct brain circuitry as a func-
tion of the persistence of back pain. As a result, we have
identified the brain signature underlying back pain chronifi-
cation. Furthermore, the demonstration that a unitary per-
cept, back pain, can correspond to different brain circuitry
configurations poses a fundamental challenge to the local-
ization theory that posits a one-to-one correspondence be-
tween brain regional activity and the mind.
Brain activity for acute/subacute
and chronic back pain is
One of the most notable findings of this study is the observation
that the perception of back pain engages distinct brain activations
across different groups of patients who suffer from back pain of
comparable intensities. The observed CBP brain activity pattern
replicates and further extends earlier observations. In the first
study examining brain activity for rating spontaneous perception
of back pain, we predominantly identified medial prefrontal cortex
activity as a unique marker for CBP (Baliki et al., 2006). This
result was replicated in two separate CBP cohorts, with functional
MRI conducted on 1.5 and 3.0 T magnets. Compared with the
current study, these earlier results were obtained in a smaller
number of participants (Baliki et al., 2006, 2008b; Hashmi
et al., 2012). After quadrupling the number of subjects, the
only additional brain regions identified here included the bilateral
amygdala and parts of the basal ganglia. Given that the meta-
analytic map for emotion is mainly comprised of medial prefrontal
cortex and amygdala, whereas the reward map encompasses
these regions as well as large portions of the basal ganglia, we
can conclude that perception of back pain in subjects living with
the condition for 410 years mainly engages the emotion and
reward circuitry.
For early SBP, in contrast to CBP, back pain was experienced for
2 months with no prior back pain history for at least a year, and
brain regions that encode back pain perception are regions that
have been repeatedly observed to be activated for acute pain
(Price, 2000; Apkarian et al., 2005), as identified by the meta-
analytic map for the term pain. When we contrasted brain activity
between CBP and early SBP, we observed group-specific patterns
of activity, with no brain regions showing activity of comparable
magnitude in both groups. Given the large number of subjects we
studied, it is highly unlikely that critical brain areas involved in back
pain perception were missed. Furthermore, because the group
contrasts were conducted with corrections for pain intensity, the
SBP and CBP maps illustrate distinct brain circuits for perceiving
back pain in the two groups.
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Brain activity within the same group of
subjects, and for a constant percept,
undergoes large-scale spatial shift with
chronification of back pain
In patients with SBP whose pain persisted over the observation
period, persisting SBP, we observed that the same percept of
back pain, characterized by stable intensity and no discernable
changes in anxiety or depression, is associated with a brain activity
pattern that, in time, continuously shifts away from the meta-
analytic acute pain circuit and progressively activates the emotion
(as well as reward) circuit. Therefore, these longitudinal results
replicate the cross-sectional between-subjects comparisons and
reinforce that, even within the same individual, brain activity for
back pain can activate different brain circuits.
It is remarkable that the brain signature for CBP, once
developed within the first year (as shown in persisting SBP), is
then stabilized and seems to remain constant over 10 years
(brain activity for persisting SBP at 1 year closely matches that
for CBP). Thus within the first year, the brain carves a chronic
pain state, implying that this first year can be viewed as a critical
period for back pain chronification. Importantly, this time period
closely matches the clinical definition of the transition to chronic
pain (commonly assumed to be between 3–12 months; Frank,
1993), and as such, our results provide the first objective marker
for the clinical transition to chronic pain. It is likely that the time
required to reach a stable representation of chronic pain is variable
across clinical pain conditions, given that the anatomical reorgan-
ization of cortical grey matter shows diverse time constants for
different chronic pain conditions (Baliki et al., 2011a). Similarly,
the brain activity signature for different chronic pain conditions
may also be distinct, although in post-herpetic neuropathy and
in knee osteoarthritis, but not in pelvic pain, the brain activity
for rating spontaneous pain shows close similarities to CBP
(Geha et al., 2007, 2008b; Farmer et al., 2011; Parks et al.,
2011). In the past, we have interpreted the dissociation between
acute and chronic pain as reflecting cognitive and attentional dis-
engagement from sensory properties of the pain and the enhance-
ment of self-referential emotional relevance of the condition
(Apkarian et al., 2008, 2009). Given the common clinical obser-
vation that chronic pain conditions are comorbid with depression
and anxiety (Rubin, 2007; Tunks et al., 2008), we had expected
the shift in brain activity to be accompanied by, and dependent
on, increases in depression and/or anxiety. Here, we see that
the transitional shift in brain activity is, in fact, independent of
the latter factors in persisting SBP, indicating that the early SBP
reorganization is not necessarily predicated on psychological
comorbidities. Rather, the properties that capture the qualitative
subjective salience of the pain seem sufficient to shift its represen-
tation from acute pain to emotion circuitry.
Mechanistic considerations
In the 1-year period marking the transition to chronic pain in
persisting SBP, but not in recovering SBP, the brain undergoes
regional morphological changes, including decreased grey matter
density in insula, S1/M1 and nucleus accumbens, and related al-
terations in functional connectivity, which collectively correlate
with back pain intensity (Baliki et al., 2012). Within this same
time frame, brain activity related to back pain shifts from the
insula, anterior cingulate cortex, thalamus, and basal ganglia to
medial prefrontal cortex, amygdala and basal ganglia. We surmise
that all these processes are inter-related and define the transition
to chronic pain. The specific mechanistic relationships remain to be
identified. Yet, the baseline medial prefrontal cortex-nucleus
accumbens functional connectivity strength, which is stable over
time and predicts the development of CBP with 80% accuracy,
suggests that enhanced mesolimbic circuitry drives brain reorgan-
ization. Here we tested this hypothesis directly in persisting SBP
and demonstrated a direct relationship between extent of shift of
back pain-related brain activity (from pain to emotion related re-
gions) reorganization over 1 year and medial prefrontal cortex–
nucleus accumbens functional connectivity strength at time
of entry into the study. Therefore, we postulate that the predis-
posing characteristics of mesolimbic circuitry at time of pain incep-
tion initiates a cascade of emotionally-driven learning events that
effectually reorganize the brain into a chronic pain state with dis-
tinct functional, anatomical and resting state properties (Fields,
2006; Apkarian, 2008). The precise details of underlying mechan-
isms remain to be unravelled, as well as the inter-relationship
between cortico-mesolimbic reorganization with the peripheral
and spinal cord reorganization that has been extensively docu-
mented in animal models (Julius and Basbaum, 2001; Costigan
et al., 2009).
Theoretical implications: localization
versus construction of the mind
from the brain
Our results show that the perception of back pain is associated
with two grossly distinct spatial patterns of brain activity, de-
pending on the time lapsed from inception of the pain. We
demonstrate this principle both within and across patient
groups, for matching pain intensities and for matching levels of
anxiety and depression (as specifically observed in persisting SBP).
Therefore, we show for the first time that two distinct and stable
cortical activity patterns, macroscopically located in distinct parts
of the cortex, can encode a unitary perception of pain derived
from verbal reports. The latter observation poses the challenge
that either the reported pain is a poor verbal descriptor of sub-
jectively subtly distinct states (the Wittgenstein position); or al-
ternatively, the brain localization (or specificity) theory—defined
as discrete perceptual categories consistently and specifically cor-
responding to distinct brain circuits [(Lindquist et al., 2012), per-
haps first conceptualized by Descartes (Finger, 2001), later
expounded into phrenology by Gall and Spurzheim 1835 (Gall,
1835), and in modern neuroscience commonly referred as ‘par-
ticular circuits’ (Kandel, 1992)]—is not tenable. The notion of
subjectivity, and thus the verbal incommunicability, of personal
pain was seminal in Wittgenstein’s abandonment of logic and his
subsequent emphasis on language-based philosophical inquiry
(Wittgenstein, 1953). To overcome these difficulties, modern
2764 | Brain 2013: 136; 2751–2768 J. A. Hashmi et al.
at Harvard University on September 4, 2013 from
pain researchers use long lists of questionnaires to interrogate the
patient about the cognitive and emotional disturbances that may
distinguish between pain states. However in the current study,
the back pain, whether it lasts a few months or a year, is
described with equivalent descriptive characteristics, and thus
limitations inherent in verbal communication cannot explain
dual brain representations of back pain. Instead, the results chal-
lenge localization theory by demonstrating large-scale changes in
brain anatomical and functional connectivity with sustained back
pain (Baliki et al., 2012), some of which may be reversed with
successful therapy (Seminowicz et al., 2011). Therefore, the spa-
tial shift in brain areas encoding back pain are accompanied by,
and thus reflect, reorganized brain network properties. This is
consistent with evidence that the acute pain circuit itself may
not be specific for pain perception (Iannetti and Mouraux,
2010; Mouraux et al., 2011) [note, however, the recent strong
evidence for a brain activity signature for acute pain (Wager
et al., 2013)], with neurobiological theories (McIntosh, 2000;
Sporns et al., 2004) that emphasize the importance of the inter-
action between brain regions in explaining brain function, and
with accumulating evidence that distinct emotions cannot be spa-
tially mapped to specific brain regions, and instead they must be
emergent properties of interactive networks (Lindquist et al.,
From a localization viewpoint of emotions, the shift of back
pain-related activity from the acute pain circuit to medial pre-
frontal cortex/amygdala suggests that the perception is trans-
formed from pain-oriented to a focus on the specific emotions
of fear, anger and sadness (Murphy et al., 2003; Johansen
et al., 2011). Yet, this seems to be a highly artificial conclusion,
as it suggests that these patients are conflating fear and sadness
with back pain. Instead, we interpret our results as complimen-
tary to and consistent with recent ideas regarding the relation-
ship between the brain and emotions (Kober et al., 2008;
Hamann, 2012; Lindquist et al., 2012). Meta-analyses of brain
imaging studies for emotions find little evidence that discrete
emotion categories can be consistently localized to distinct
brain regions. Rather, they hypothesize a psychological construc-
tionist theory that posits that emotions of a certain type are
constructed from more general brain modules whose function
is not specific to that emotion, or to emotions at all, thereby
emphasizing context and prior learning in shaping an emotional
experience. Within this framework, the amygdala is implicated in
the more general functions of orienting to motivationally rele-
vant, or novel, or uncertain stimuli (Wilson and Rolls, 1993;
Breiter et al., 1996; Holland and Gallagher, 1999; Herry et al.,
2007; Blackford et al., 2010; Moriguchi et al., 2011), and that it
preferentially responds to salient sensations (Lindquist et al.,
2012). On the other hand, the medial prefrontal cortex is asso-
ciated with the process of assigning meaning to sensory cues,
based on stored memories of prior experiences (Vincent et al.,
2006; Bar, 2009; Mitchell, 2009), and in linking episodic
memory with affective qualities of sensory events, and as such
playing a unique role in transducing concepts into affective
behavioural and physiological responses (Roy et al., 2012).
Given that the definition of pain is ‘an unpleasant sensory and
emotional experience associated with actual or potential tissue
damage, or described in terms of such damage’ (Merskey and
Bogduk, 1994), we interpret the observed spatial shift in back
pain representation as evidence for the pain percept reflecting
less its sensory properties and instead becoming a heightened
and more complex emotional state, constructed from learning
and resultant memory traces of the presence and persistence
of the condition, which orient the motivational preferences of
the subject toward ‘suffering’ with the condition.
Technical considerations
One can always argue that the functional MRI technique is not
sensitive enough to detect the nociceptive-specific neurons that, in
a fixed location in the cortex, encode back pain. Given that a
single functional MRI voxel reflects average activity of 20 million
neurons (Logothetis, 2008) and only a handful of nociceptive
neurons have been described in the cortex (Kenshalo and
Isensee, 1983; Peyron et al., 2002; Chen et al., 2009; Benison
et al., 2011; Vierck et al., 2013), their presence may in fact not
be detected with functional MRI. Yet, those neurons would still be
correlated to the large-scale circuits we identify for back pain, and
thus their identification would not resolve the issues we have dis-
cussed regarding the interface between brain representation and
The meta-analytic maps provide a powerful tool for testing
hypotheses related to brain structure and function relationships,
as illustrated with the present results. Yet, the term-to-circuit cor-
respondence should not be interpreted as a unique relationship.
For example, the pain circuit, although observed in more than 200
studies, reflects activity related to acute pain, and is likely not
specific to nociception (Baliki et al., 2009; Iannetti and
Mouraux, 2010; Mouraux et al., 2011; Yarkoni et al., 2011).
Similarly, the reward circuit, although best characterized for posi-
tive rewards (Kalivas et al., 2005; Taha and Fields, 2006), also
encodes value for negative reinforcement for aversive conditions
(Maeda and Mogenson, 1982; Schultz and Romo, 1987; Bassareo
et al., 2002; Ungless et al., 2004; Badrinarayan et al., 2012), as
well as for pain (Becerra et al., 2001; Seymour et al., 2005; Scott
et al., 2006; Baliki et al., 2010; Navratilova et al., 2012), and is
more generally involved in emotionally learned motivated behav-
iour (Reynolds and Berridge, 2002; Fields, 2006; Berridge, 2007;
Fields et al., 2007). The emotion circuit is intimately linked with
the reward circuit, as it modulates the properties of the latter and,
as expounded above, should more generally be viewed as part of
the salience and value-based circuitry controlling motivated behav-
iour. Note also that there are significant overlaps between these
circuits, especially between reward and emotion. Thus, classifica-
tion of brain circuitry using such meta-analytic maps should be
interpreted with caution. We used the reverse inference maps of
Neurosynth as they are the more stringent and specific brain
activity-to-term relationships (Yarkoni et al., 2011). Regarding
formal Bayesian inference, our results demonstrate a mismatch
between forward and reverse inference for back pain and thus
provide an example that, at least under some specific conditions,
reverse inference can be incorrect, thereby adding to the list of
pitfalls associated with the use of brain imaging data to identify
mental states or processes (Poldrack, 2011).
Shape shifting pain Brain 2013: 136; 2751–2768 | 2765
at Harvard University on September 4, 2013 from
Brain activity related to the perception of back pain shifts in loca-
tion from regions involved in acute pain to engage emotion cir-
cuitry as the condition persists, thereby providing a percept-linked
brain signature for the transition to chronic pain. We provide a
spatial template and time window (6–12 months) for the stabil-
ization of this signature, which identifies a specific functional bio-
marker for back pain chronification. Thus, these results have
important clinical implications regarding the definition of chronic
pain, its aetiology, and the optimal time window for treatments
targeting its prevention. Additionally, these results challenge long
standing theoretical constructs of brain-mind relationships.
We thank all participants and the Apkarian lab personnel for help
in various aspects of the study and insightful discussions, especially
Dr. M. Farmer for help in editing the manuscript. We also ac-
knowledge Dr. Todd Parrish and personnel at the Northwestern
University brain imaging core facility (Center for Translational
Imaging) for help in data collection.
The study was funded by NIH NINDS R01 NS035115 and NIDCR
R01 DE022746 (A.V.A.), and by an anonymous foundation
Supplementary material
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at Harvard University on September 4, 2013 from
... Chronic pain is thought to alter brain reward circuitry (23, 24) to include effects on shifting emotional states associated with pain chronification (25). Understanding this relationship between TC and reducing pain measurements of eCB and OxL can help advance knowledge to treat knee OA. ...
... The self-reported pain reduction and its impact on physical functioning results of WOMAC and BPI in OA subjects is evidence that 8 weeks of TC intervention diminishes pain, stiffness, and functional limitations that are linked to some extent with pro-inflammatory OxL biomarkers. The changes in lipid-derived eCB and OxL after TC are associated with improved well-being (11), which is important to pain perception, brain emotional circuits (25), and loss of gray matter density (35). Interestingly TC also resulted in lower LEA compared to baseline and may seem to lower activation of Transient Receptor Potential Vanilloid 1 (TRPV1) and pain sensation (36). ...
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Background Tai Chi (TC) controls pain through mind–body exercise and appears to alter inflammatory mediators. TC actions on lipid biomarkers associated with inflammation and brain neural networks in women with knee osteoarthritic pain were investigated. Methods A single-center, pre- and post-TC group (baseline and 8 wk) exercise pilot study in postmenopausal women with knee osteoarthritic pain was performed. 12 eligible women participated in TC group exercise. The primary outcome was liquid chromatography tandem mass spectrometry determination of circulating endocannabinoids (eCB) and oxylipins (OxL). Secondary outcomes were correlations between eCB and OxL levels and clinical pain/limitation assessments, and brain resting-state function magnetic resonance imaging (rs-fMRI). Results Differences in circulating quantitative levels (nM) of pro-inflammatory OxL after TC were found in women. TC exercise resulted in lower OxL PGE 1 and PGE 2 and higher 12-HETE, LTB 4 , and 12-HEPE compared to baseline. Pain assessment and eCB and OxL levels suggest crucial relationships between TC exercise, inflammatory markers, and pain. Higher plasma levels of eCB AEA, and 1, 2-AG were found in subjects with increased pain. Several eCB and OxL levels were positively correlated with left and right brain amygdala-medial prefrontal cortex functional connectivity. Conclusion TC exercise lowers pro-inflammatory OxL in women with knee osteoarthritic pain. Correlations between subject pain, functional limitations, and brain connectivity with levels of OxL and eCB showed significance. Findings indicate potential mechanisms for OxL and eCB and their biosynthetic endogenous PUFA precursors that alter brain connectivity, neuroinflammation, and pain. Clinical Trial Registration , identifier: NCT04046003.
... For functional connectivity, we used known seeds in the DMN 8,18 , however, did not see any differences. The sample sizes across these studies 8,18 and reviews in the area 7,19 , are small (n < 100) and may explain the variability in results. Meta-analysis could be used to overcome this limitation in neuroimaging, however individual studies normally only report on specific brain regions 7,19 . ...
... These spheres were created using the Marsbar toolbox 37 . Given thousands of brain connections exist, to limit the number of variables, the connectivity of the posterior cingulate cortex to the angular gyrus (AG; x, y, z = − 52, − 66, 36) 8 and the medial prefrontal cortex to the nucleus accumbens (NAc; x, y, z = 10, 12, − 8) 18 were extracted due to their importance in prior research (Supplementary Fig. 1). Correlation coefficients (Fisher-transformed) across the time series between the PCC-AG and mPFC-NAc were used in subsequent analyses. ...
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The classification of non-specific chronic low back pain (CLBP) according to multidimensional data could guide clinical management; yet recent systematic reviews show this has not been attempted. This was a prospective cross-sectional study of participants with CLBP (n = 21) and age-, sex- and height-matched pain-free controls (n = 21). Nervous system, lumbar spinal tissue and psychosocial factors were collected. Dimensionality reduction was followed by fuzzy c-means clustering to determine sub-groups. Machine learning models (Support Vector Machine, k-Nearest Neighbour, Naïve Bayes and Random Forest) were used to determine the accuracy of classification to sub-groups. The primary analysis showed that four factors (cognitive function, depressive symptoms, general self-efficacy and anxiety symptoms) and two clusters (normal versus impaired psychosocial profiles) optimally classified participants. The error rates in classification models ranged from 4.2 to 14.2% when only CLBP patients were considered and increased to 24.2 to 37.5% when pain-free controls were added. This data-driven pilot study classified participants with CLBP into sub-groups, primarily based on psychosocial factors. This contributes to the literature as it was the first study to evaluate data-driven machine learning CLBP classification based on nervous system, lumbar spinal tissue and psychosocial factors. Future studies with larger sample sizes should validate these findings.
... Participants-Inclusion/exclusion criteria: Briefly, the inclusion criteria consists of (a) male and female patients, (b) aged between 19-65 years old, (c) with persistent and stable unilateral or bilateral idiopathic CNP (C0-C7) for ≥ 6 months, (d) with pain intensity ≥ 30% on the selfreport numerical pain scale, (e) neck disability index ≥10/50, (f) never received SMT, (g) no contraindication to have MRI (pacemaker, claustrophobia), (h)willing to participate in the study. We chose 6 months or more of persistent neck pain since patients suffering from pain for longer times have a higher likelihood to present brain structural and functional reorganization (neuroplasticity) (36). Besides, higher scores of neck disability have been associated with abnormal FC(26) and diminished cerebral perfusion (37). ...
Research Proposal
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Project supported by Canadian Chiropractic Research Foundation SUMMARY OF RESEARCH PROPOSAL (ABSTRACT) SCOPE: Neck pain is a common musculoskeletal problem in the general population, second only to low back pain in frequency among spine-specific conditions (1). Causes of chronic neck pain are multifactorial (2). Nociplastic pain is thought to be the most prevalent mechanism of chronic neck pain (3). Nociplastic pain involves anatomical and functional changes in the peripheral and central nociceptive pathways, and, importantly, these changes may be reversed (3,4). Studies using magnetic resonance imaging (MRI) have recently demonstrated that chronic neck pain leads to decreased gray matter volume as well as abnormal white matter functional connectivity in several pain-related brain areas (5,6).Spinal manipulation (SM) is a safe (7,8), effective and widely accepted treatment for chronic neck pain (9,10). SM therapy (SMT) is a mechanical intervention that causes deformation of the spine and its surrounding soft tissues (11,12), and activates mechanosensitive paraspinal and articular primary afferent neurons (13-15). Alterations in neural functions such as muscle reflexes, spinal and supraspinal pathways have been reported after SM and chiropractic care (15-17). Furthermore, a hallmark study using medical and surgical treatment for chronic low back pain demonstrated reversal of changes in anatomical and functional brain activity in conjunction with symptom improvement (18). However, there are no similar studies using SMT and chiropractic care. In particular, the effect of a single cervical manipulation (cSM) or the longer-term effect of chiropractic care on abnormal functional connectivity has not yet been investigated. Therefore, the purpose of this study is, as a precursor to longer term studies, to use functional MRI (fMRI) to determine, quantitatively, the acute effects of a single cSM on pain-related brain areas. Understanding the potential modulatory role of cSM in abnormal pain-related areas is crucial to improving our understanding of the mechanisms of SMT, and, possibly, other chiropractic care treatments that act through similar mechanisms. Purpose: Using quantitative fMRI technique, this study aims: (1) to determine the acute effects of a single cSM on the structure and functional connectivity of pain-related brain network areas in chronic neck pain patients, and to compare it with baseline (pre-intervention) and sham-treatment; (2) to examine the feasibility of conducting a longer-term study involving serial treatments of chiropractic care on the structure and function of pain-related brain areas in chronic neck pain population. Methodology: Study design: Randomized control trial (RCT). Recruitment: persistent chronic neck pain≥6 months, VAS≥ 3, Neck Disability Index ≥10/50, M=F, without radiculopathy or neurological symptoms, never received cSM before with no contraindications to SMT. Study participants will be recruited from SPARC - KITE - Toronto Rehab Institute-Toronto. Ontario. Recruited participants will randomly be allocated to cSM(7) vs cervical sham(17). fMRI will be performed at baseline and after the intervention. Furthermore, according to Thabane et al. (2010)(19) and Eldridge et al. (2016)(20), we also aim to determine the feasibility of conducting an RCT study after a course of chiropractic care by assessing recruitment rates, provision of SMT, and consent of study subjects' for performing the fMRI as part of a. Preliminary fMRI metrics will be used to provide estimates for fractional anisotropy allowing for accurate sample size estimation for a future RCT with longer-term care. Outcomes: (1) Acute change in functional connectivity after one cSM (informs the acute reversibility of functional changes that may be present), self-report pain, pain pressure threshold, and neck disability and (2) Feasibility measures for long-term chiropractic care, e.g. recruitment rate, %drop outs, and %refusal to have MRI. Hypotheses: In chronic neck pain patients, abnormal functional connectivity between pain-related brain areas will be modulated by a single cSM but not by a sham treatment.
... NMDA receptor activation is involved not only in learning and memory but also in pathological conditions such as chronic/persistent pain [32]. Much evidence showed that structural changes at postsynaptic sites are linked to the creation of memories after learning [33], but at the same time, the reorganization of synapses, cells, and circuits at the brain level could intervene in the maintenance of chronic pain involving several neurotransmitter factors [34][35][36][37][38][39]. ...
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Pain is a very important problem of our existence, and the attempt to understand it is one the oldest challenges in the history of medicine. In this review, we summarize what has been known about pain, its pathophysiology, and neuronal transmission. We focus on orofacial pain and its classification and features, knowing that is sometimes purely subjective and not well defined. We consider the physiology of orofacial pain, evaluating the findings on the main neurotransmitters; in particular, we describe the roles of glutamate as approximately 30–80% of total peripheric neurons associated with the trigeminal ganglia are glutamatergic. Moreover, we describe the important role of oxidative stress and its association with inflammation in the etiogenesis and modulation of pain in orofacial regions. We also explore the warning and protective function of orofacial pain and the possible action of antioxidant molecules, such as melatonin, and the potential influence of nutrition and diet on its pathophysiology. Hopefully, this will provide a solid background for future studies that would allow better treatment of noxious stimuli and for opening new avenues in the management of pain.
Background: Chronic pain is a common, poorly-understood condition. Genetic studies including genome wide association studies (GWAS) identify many relevant variants, which have yet to be translated into full understanding of chronic pain. Transcriptome wide association study using transcriptomic imputation (TI) methods such as S-PrediXcan can help bridge this genotype-phenotype gap. Methods: We carried out TI using S-PrediXcan to identify genetically regulated gene expression (GREX) associated with Multisite Chronic Pain (MCP), in thirteen brain tissues and whole blood. We then imputed GREX for over 31,000 Mount Sinai BioMe™ participants and performed phenome-wide association study (PheWAS) to investigate clinical relationships in chronic pain associated gene expression changes. Results: We identified 95 experiment-wide significant gene-tissue associations (p<7.97x10-7), including 35 unique genes, and an additional 134 gene-tissue associations reaching within-tissue significance, including 53 additional unique genes. Of 89 unique genes total, 59 were novel for MCP and 18 are established drug targets. Chronic pain GREX for 10 unique genes was significantly associated with cardiac dysrhythmia, metabolic syndrome, disc disorders/ dorsopathies, joint/ligament sprain, anemias, and neurological disorder phecodes. PheWAS analyses adjusting for mean painscore showed associations were not driven by mean painscore. Conclusions: We carried out the largest TI study of any chronic pain trait to date. Results highlight potential causal genes in chronic pain development, and tissue and direction of effect. Several gene results were also drug targets. PheWAS results showed significant association for phecodes including cardiac dysrhythmia and metabolic syndrome, indicating potential shared mechanisms.
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Pain is an unpleasant sensory and emotional experience. Both pain and emotions are warning signals against outside harm. Interoception, bodily sensations of emotions can be assessed with the emBODY tool where participants colour the body parts where they feel different emotions. Bodily maps of emotions (BMoE) have been shown to be similar between healthy individuals independent of age, sex, cultural background, and language. We used this tool to analyze how these body maps may differ between healthy controls and patients with persistent pain. We recruited 118 patients with chronic pain. An algorithm-selected matched controls from 2348 individuals who were recruited through social media, message boards, and student mailing lists. After providing background information, the participants completed the bodily topography colouring tasks with the emBODY tool using tablets (patients) and online using their own devices (controls), for pain, sensitivity for tactile, nociceptive and hedonic stimuli, and for the 6 basic emotions and a neutral state. Patients with pain coloured significantly larger areas for pain and more negative emotions. On the whole, their BMoEs were dampened compared with healthy controls. They also coloured more areas for nociceptive but not for tactile or hedonic sensitivity. Patients and controls marked different body areas as sensitive to nociceptive and tactile stimulation, but there was no difference in sensitivity to hedonic touch. Our findings suggest that emotional processing changes when pain persists, and this can be assessed with these colouring tasks. BMoEs may offer a new approach to assessing pain.