Arthritis & Rheumatology

Vol. 0, No. 0, Month 2023, pp 1–11

DOI 10.1002/art.42672
© 2023 American College of Rheumatology

A Randomized Controlled Neuroimaging Trial of Cognitive

Behavioral Therapy for Fibromyalgia Pain
Jeungchan Lee,1 Asimina Lazaridou,2 Myrella Paschali,2 Marco L. Loggia,3 Michael P. Berry,3
Dan-Mikael Ellingsen,4 Kylie Isenburg,3 Alessandra Anzolin,1 Arvina Grahl,1 Ajay D. Wasan,5 Vitaly Napadow,1
2
and Robert R. Edwards

Objective. Fibromyalgia (FM) is characterized by pervasive pain-related symptomatology and high levels of nega-
tive affect. Mind–body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via
reductions in pain-related catastrophizing, a set of negative, pain-amplifying cognitive and emotional processes. How-
ever, the neural underpinnings of CBT’s catastrophizing-reducing effects remain uncertain. This randomized controlled
mechanistic trial was designed to assess CBT’s effects on pain catastrophizing and its underlying brain circuitry.
Methods. Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized
to 8 weeks of individual CBT or a matched FM education control (EDU) condition.
Results. Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment (P < 0.05)
and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant
role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between
the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and
salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to soma-
tomotor and salience network areas was reduced.
Conclusion. Our results suggest clinically important and CBT-specific associations between somatosensory/
motor- and salience-processing brain regions and the DMN in chronic pain. These patterns of connectivity may con-
tribute to individual differences (and treatment-related changes) in somatic self-awareness. CBT appears to provide
clinical benefits at least partially by reducing pain-related catastrophizing and producing adaptive alterations in DMN
functional connectivity.

INTRODUCTION pain-processing circuitry, a prominent role of negative affective

Fibromyalgia (FM) is a nociplastic pain disorder characterized
by function-impairing symptoms such as widespread pain,
fatigue, cognitive difficulties, and psychosocial distress.1 FM pre-
dominantly affects women, and the broad array of FM symptoms
and contributory factors suggests a strong biopsychosocial
basis.2 Hallmarks of FM include alterations in central
factors in maintaining pain, and a lack of efficacy of many periph-
erally focused treatments. Although FM is challenging to treat,
numerous nonpharmacologic interventions, many of which target
psychosocial factors, have shown promise in reducing its symp-
toms and impact.1–3 Meta-analyses and reviews suggest that
cognitive behavioral therapy (CBT), compared with other active
treatments, reduces pain intensity, disability, and emotional

ClinicalTrials.gov Identifier: NCT01345344.

Supported by National Institutes of Health: National Center for Comple-
mentary and Integrative Health (grants R01-AT-007550, R33-AT-009306, and
P01-AT-009965), National Institute of Arthritis and Musculoskeletal and Skin
Diseases (grants R01-AR-064367, and R01-AR-079110), and the National Cen-
ter for Research Resources (grants P41-RR-14075, S10-RR-021110, and
S10-RR-023043).
1
Jeungchan Lee, PhD, Alessandra Anzolin, PhD, Arvina Grahl, PhD, Vitaly
Napadow, PhD: Massachusetts General Hospital and Spaulding Rehabilita-
tion Hospital, Harvard Medical School, Charlestown; 2Asimina Lazaridou,
PhD, Myrella Paschali, MD, Robert R. Edwards, PhD: Brigham & Women’s Hos-
pital, Harvard Medical School, Boston, Massachusetts; 3Marco L. Loggia, PhD,
Michael P. Berry, BS, Kylie Isenburg, BS: Massachusetts General Hospital, Har-
vard Medical School, Charlestown; 4Dan-Mikael Ellingsen, PhD: Kristiania
University College and Oslo University Hospital, Oslo, Norway; 5Ajay
D. Wasan, MD: University of Pittsburgh, Pittsburgh, Pennsylvania.
Additional supplementary information cited in this article can be found
online in the Supporting Information section (http://onlinelibrary.wiley.com/
doi/10.1002/art.42672).
Drs. Lee and Lazaridou contributed equally to this work. Drs. Napadow
and Edwards contributed equally to this work.
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.
1002/art.42672.
Address correspondence via email to Jeungchan Lee, PhD at
JLEE196@mgh.harvard.edu.
Submitted for publication May 10, 2023; accepted in revised form August
3, 2023.

1
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2 LEE ET AL

distress among individuals with FM and related chronic pain con- PATIENTS AND METHODS
ditions.3,4 CBT uses structured techniques to alter distorted
Participants and study design. The trial was preregis-
thoughts and negative moods and, within only a few sessions,
tered (ClinicalTrials.gov identifier: NCT01345344) and conducted
can produce lasting changes in pain-related outcomes.5
from 2017 to 2022. Similar to our pilot trial,9 the primary clinical
One mechanistic pathway supporting CBT’s benefits
study outcome was the pain interference subscale of the Brief
appears to involve reductions in negative affective processes
Pain Inventory (BPI). Our secondary clinical outcomes were BPI
such as pain-related catastrophizing.6 Catastrophizing, com-
pain severity, the Fibromyalgia Impact Questionnaire Revised
monly measured by the Pain Catastrophizing Scale (PCS), is a
(FIQR), and the PCS, which was also assessed as a psychosocial
pain-specific psychosocial construct comprising cognitive and
mediator of pain-related improvements, based on prior results.9
emotional processes such as helplessness, rumination, and
We screened a total of 534 female patients with FM; 114 patients
magnification of pain complaints. Although catastrophizing is
met the inclusion criteria (described below) and were enrolled.
related to general measures of negative affect, it also has a
This study was approved by the Partners Human Research Com-
unique and specific influence on pain-related outcomes.7 Prior
mittee, and written informed consent was obtained from all partic-
CBT studies have identified catastrophizing as a crucial pro-
ipants. The study followed the consolidated standards of
cess variable contributing to the pain-reducing benefits of
reporting trials (CONSORT) reporting guidelines (Figure 1).
mind–body therapies.6 Thus, changes in the brain circuitry
Inclusion criteria for the study were age of 18 to 75 years,
underlying pain catastrophizing may underpin the clinical
female sex, health care provider–confirmed FM diagnosis for at
improvements and putative “normalization” of brain function
least 6 months and meeting the American College of Rheumatol-
following CBT.8,9
ogy clinical criteria for FM,21 baseline pain intensity during screen-
Functional neuroimaging studies show that catastrophizing
ing of at least 4 of 10 on average, and fluency in English and ability
is associated with altered activation and connectivity in pain-
to provide written informed consent. The exclusion criteria were
related brain areas.10–12 For example, we reported that patients
comorbid acute or chronic pain condition rated as more painful
with FM with higher PCS scores showed greater pain-evoked
than FM, current use of stimulant medications, being pregnant
increases in connectivity between the primary somatosensory
or nursing, any psychiatric disorder involving a history of psycho-
cortex (S1) and insular cortex.13 Longitudinal neuroimaging stud-
sis (eg, schizophrenia), psychiatric hospitalization in the past
ies have found that CBT enhanced patients’ pain-evoked activa-
6 months, use of illicit drugs within the past 6 months, current par-
tions in critical inhibitory areas, such as the ventrolateral
ticipation in a mind–body intervention, active suicidal ideation,
prefrontal cortex and lateral orbitofrontal cortex.14 Subsequently,
lower limb vascular surgery or vascular dysfunction, history of sig-
our pilot study of high-catastrophizing patients with FM showed
nificant head injury, history of anxiety disorders interfering with
that resting-state connectivity between the S1 and anterior/mid-
functional magnetic resonance imaging (fMRI) procedures (eg,
insula was reduced after CBT and was correlated with
panic disorder), and any other magnetic resonance imaging
treatment-related reductions in catastrophizing.9 Although these
(MRI) contraindications.
prior studies offer enticing hints regarding CBT’s neural mecha-
The baseline behavioral visit included informed consent,
nisms, their limitations include small sample sizes,9 absence of
questionnaires (including BPI, FIQR, and PCS), and confirmation
an active control,14 and lack of direct imaging-based measures
of eligibility. Sociodemographic and medical history information
of catastrophizing.
was collected (Table 1). All patient-reported assessments took
Our study assessed CBT’s effects on pain interference, pain
place via the REDCap platform. After the baseline behavioral visit,
catastrophizing, and the brain circuitry underlying catastrophizing
patients participated in a baseline MRI session, followed by ran-
cognitions in FM. We hypothesized that CBT, compared with a
domization to the CBT or education control (EDU) intervention
dose-matched active control condition, would reduce pain inter-
group. Posttreatment behavioral and MRI visits were completed
ference as well as pain catastrophizing in patients with FM and,
after the eight intervention visits.
correspondingly, alter functional connectivity between pain-
related brain regions and networks (eg, the default mode network
[DMN; critically important in self-referential cognitive processes], Randomization. We used an unbalanced randomization
salience network [SLN; regulates dynamic switching between approach with a ratio of 2:1 (CBT:EDU), to maximize the data
interoceptive and exteroceptive cognitive modes], and somato- available within the CBT arm for post hoc sensitivity analyses.22
motor network [SMN; processes physical stimuli and motor We stratified randomization based on baseline PCS scores using
responses]).15–19 Because our prior study20 highlighted the role a pre-established PCS cutoff score of 20 for high catastrophizing.
of a key DMN region, the ventral posterior cingulate cortex Randomization followed the baseline MRI scan. An external sta-
(vPCC), in catastrophizing cognitions, we focused on vPCC con- tistical collaborator assigned study participants to intervention
nectivity during the experience of catastrophizing to assess possi- conditions according to a pregenerated randomization list. Any-
ble adaptive changes following CBT. one involved in study outcome assessment, including research
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COGNITIVE BEHAVIORAL THERAPY FOR FIBROMYALGIA 3

Figure 1. Consolidated standards of reporting trials (CONSORT) flow diagram of the study. CBT, cognitive behavioral therapy; fMRI, functional
magnetic resonance imaging; POST, post treatment; PPI, psychophysiological interaction; PRE, pretreatment.

assistants, statisticians, and principal investigators, were masked
to intervention group assignment.
Interventions. Participants were randomized to one of the
two eight-week interventions: CBT or EDU. The treatments were
matched for degree of professional contact; both treatments
involved eight individual 60- to 75-minute visits conducted by a
licensed mental health provider. After the end of the eight
treatment visits, participants underwent a posttreatment assess-
ment and scanning session.
CBT interventions generally use education and active struc-
tured techniques to alter negative thoughts.9 This CBT treatment
was based on a pain self-management paradigm and involved
the identification and reduction of maladaptive pain-related cogni-
tions (ie, catastrophizing) using techniques such as relaxation,
visual imagery, thought challenging, and distraction. CBT promi-
nently emphasized in vivo practice during each session and
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4 LEE ET AL

Table 1. Descriptive data for sociodemographic and clinical characteristics at baseline*

Characteristics CBT baseline (n = 64) EDU baseline (n = 34) P value
Age, mean ± SD, years 42.2 ± 11.8 41.1±12.7 0.76
College degree, % 60.0 61.8 0.52
Income <$45,000, % 40.6 35.3 0.67
Married, % 38.5 26.5 0.17
Employed full-time or part-time, % 47.7 58.8 0.29
Race and ethnicity, %
African American 7.7 2.9 0.17
White 84.6 64.7 0.02
Hispanic/Latino 3.1 11.8 0.08
Other 4.6 20.6 0.01
Pain duration, mean ± SD, years 9.4 ± 7.6 12.0 ± 9.2 0.14
Pain locations, mean ± SD, n 13.0 ± 4.0 10.8 ± 3.9 0.01
Current prescription opioid use, % 6.2 14.7 0.15
BPI pain interference (0–10), mean ± SD 5.9 ± 2.4 4.9 ± 2.4 0.04
BPI pain severity (0–10), mean ± SD 5.5 ± 1.9 4.4 ± 1.4 0.01
FIQR (0–100), mean ± SD 58.4 ± 16.5 51.9 ± 19.0 0.10
PCS (0–52), mean ± SD 24.7 ± 13.4 21.6 ± 9.4 0.23
PROMIS depression (T–score), mean ± SD 60.1 ± 9.4 57.7 ± 6.5 0.59
PROMIS anxiety (T–score), mean ± SD 60.7 ± 7.7 58.7 ± 6.6 0.19
ERS (0–100), mean ± SD 49.0 ± 19.0 50.4 ± 23.4 0.79
* PROMIS T scores were normalized. BPI, Brief Pain Inventory; CBT, cognitive behavioral therapy group; EDU, edu-
cation control group; ERS, Expectation of Relief Scale; FIQR, Fibromyalgia Impact Questionnaire Revised; PCS, Pain
Catastrophizing Scale; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold indicates sig-
nificant group difference between CBT and EDU at P < 0.05.

featured home practice using written exercises. Patients learned
to identify and evaluate negative thoughts and use cognitive
restructuring to diminish the degree of pain-related distress.
The fibromyalgia EDU, matched for therapist contact,
included education about FM and chronic pain. Sessions pro-
vided information about the nature and presumed causes of FM,
but they involved no active skills training. Education is often used
as a comparator condition for CBT23; it controls for nonspecific
factors related to therapist attention and expectancy as well as
natural history. To assess expectancy, the Expectation of Relief
Scale assessing the magnitude of anticipated treatment benefit
(0 = will not work at all, 100 = complete relief) was collected at
treatment visit 1.
Clinical outcome measures. The primary clinical out-
come of the trial was the BPI pain interference subscale score
(0 = does not interfere, 10 = completely interferes).24 In addition,
the pain severity subscale score (0 = no pain, 10 = pain as bad
as you can imagine) was included as a secondary outcome.
A key secondary clinical outcome was the total score of the
FIQR, which assesses the total impact of FM symptoms.25
Another secondary outcome measure (also examined as a pro-
cess variable or mediator contributing to changes in pain symp-
tomatology) was the total score of the PCS.26 It includes three
subscales: rumination, magnification, and helplessness, which
sum to create a total score (range = 0–52; each item rated from
0, not at all, to 4, all the time).
Additional clinical measures included the Patient-Reported
Outcomes Measurement Information System (PROMIS) anxiety
and depression short forms.27 PROMIS anxiety and depression
are presented as normalized T scores.
MRI. MRI data were acquired on a 3T Siemens Skyra scan-
ner (Siemens Medical) equipped with a 32-channel head coil at
Athinoula A. Martinos Center, Boston, Massachusetts. To assess
brain response during catastrophizing, two fMRI data scan runs
were obtained (Supplementary Material).
Pain catastrophizing fMRI task. We used an fMRI-
adapted task to investigate the neural circuitry supporting pain
catastrophizing.20 Briefly, the block-design fMRI task during each
scan run consisted of visually presenting six pain catastrophizing
(CAT) statements drawn from the PCS26 and six control neutral
(NEU) statements,29,30 which were of similar lexical difficulty and
word count (Supplementary Material). During CAT statement pre-
sentation, participants reflected on their engagement in such cog-
nitions during FM pain experiences. The statements were
presented in randomized order, and each of the CAT or NEU
statement blocks consisted of two consecutive statements (total
block duration = 20 seconds, 10 seconds per statement), with a
20-second rest period between blocks.
Following the pain catastrophizing fMRI task, participants’
levels of engagement and applicability of catastrophizing state-
ments to their own FM experience during the task were also col-
lected using our previously validated CAT Applicability
Questionnaire (CAQ; “During the scan today, I had this thought/
feeling”, 0 = not at all, 1 = to a slight degree, 2 = to a moderate
degree, 3 = to a great degree, 4 = all the time).20

COGNITIVE BEHAVIORAL THERAPY FOR FIBROMYALGIA
Statistical analysis. All behavioral data analyses were
conducted using IBM SPSS v.24 (IBM Corp). Descriptive data
for continuous variables are presented as means ± SDs
(Table 1). A sample size of N = 80 was calculated as capable of
detecting a minimum clinically important difference in BPI pain
interference between groups, with a statistical power of 80%
and a Type I error rate of 5%.
Univariate group differences at baseline were examined
using t-tests for continuous variables and chi-square tests for cat-
egorical variables. Mixed factorial analyses of variance (ANOVAs)
were used to compare changes in clinical symptoms before and
after the intervention. The statistical design includes the between
factor “group” with the two levels (ie, CBT and EDU) and the
within factor “time” with the two levels (ie, pretreatment and post
treatment). Post hoc tests for group differences were conducted
using Fisher’s least significant difference test. Given that several
outcome variables differed between groups at baseline (Table 1),
we compared the magnitude of change scores between CBT
and EDU with analysis of covariance (ANCOVA), controlling for
baseline scores and demographic covariates.
Relationships of outcome variable change scores with cata-
strophizing change scores were examined using Pearson correla-
tions. The magnitude of correlation coefficients was normalized
using Fisher’s Z-transformation, with subsequent testing for
group differences (CBT compared with EDU). Longitudinal media-
tion models examined whether group allocation was indirectly
associated with changes in pain-related outcomes via the media-
tor of changes in pain catastrophizing. Mediation analyses were
tested using 5,000 bootstrapped samples with the PROCESS
macro for SPSS. For this model, group allocation (CBT vs EDU)
was entered as the independent variable (X), changes in PCS
scores were entered as the mediator variable (M), and changes
in BPI pain interference, severity, and FIQR scores were entered
as the dependent variables (Y) in three separate models, control-
ling for demographic covariates as well as general measures of
negative affect (ie, PROMIS anxiety and depression, which are
generally moderately associated with pain catastrophizing).9 The
indirect effects were considered significant when the 95% boot-
strap confidence interval (95% CI) from 5,000 bootstrap samples
did not include zero.
Psychophysiological interaction analysis for brain
functional connectivity. To identify regions whose functional
connectivity strength with a region of interest (ROI) (Supplemen-
tary Materials) is modulated by a psychological task (ie, the cata-
strophizing task) and to examine treatment-related changes in
connectivity, we performed a conventional psychophysiological
interaction (PPI) analysis. Functional connectivity between vPCC
and the rest of the brain during the catastrophizing task was
assessed. For this analysis, individual fMRI data were coregis-
tered to standard Montreal Neurological Institute (MNI) space.
The extracted vPCC time series was used as the physiological
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5
regressor in the first-level general linear model (GLM) analysis.
CAT blocks served as the psychological regressor, whereas the
NEU and CATCH blocks were included as GLM regressors of
no interest. A psychophysiological regressor was then derived
as the interaction between the physiological regressor (de-
meaned, centered around zero) and the psychological regressor
(“+1” for CAT and “−1” for all other blocks). The psychophysio-
logical interaction data were used in mixed-effect models (FSL-
FLAME 1+2; FMRIB’s Local Analysis of Mixed Effect, FMRIB Soft-
ware Library) corrected for multiple comparisons (Pcorrected
< 0.05). Cluster-forming thresholds were Z > 3.1 for baseline
group analyses (larger samples with more power) and Z > 2.3
for difference (pretreatment vs posttreatment CBT) analyses
(inherently less power). Additionally, a two-way ANOVA evaluated
the interaction between factors “group” (CBT vs EDU) and “time”
(pretreatment vs post treatment) for any significant clusters
revealed by the voxel-wise CBT-only analysis noted above.
RESULTS
We enrolled 114 women with FM and randomized
98 patients to eight weeks of CBT or EDU. Sixty-four patients
were randomized to the CBT group, and 34 were randomized to
the EDU group. The CONSORT diagram depicts the study flow
(Figure 1), and baseline sociodemographic and clinical character-
istics are in Table 1. Although randomization was stratified by
PCS scores, baseline group differences included higher BPI
scores for CBT versus EDU groups (P < 0.05). The groups did
not differ in expectancies for pain relief.
CBT improves clinical outcomes more readily than
EDU. Primary outcome: pain interference. The main effects of
time (F1,81 = 11.5, P < 0.001, Wilk’s λ = 0.86), as well as the
group × time interaction (F1,81 = 5.96, P < 0.01, Wilk’s λ = 0.91),
were statistically significant. BPI pain interference scores were
significantly reduced from baseline (pretreatment) to post treat-
ment (Table 2, Figure 2A), with a significantly larger reduction in
the CBT group (as determined by the group × time interaction).
Pain catastrophizing. The main effect of time was statistically
significant (F1,81 = 41.6, P < 0.001, Wilk’s λ = 0.66). Similarly to
pain interference, a significant group × time interaction was found
(F1,81 = 4.15, P < 0.05, Wilk’s λ = 0.95), suggesting that the mag-
nitude of change in PCS scores over time varies as a function of
the treatment group. Although PCS scores significantly reduced
from baseline to post treatment in both groups, the reduction
was significantly larger in the CBT group (Table 2, Figure 2A).
Pain severity. The main effect of time was not significant
(F1,81 = 2.51, P = 0.1, Wilk’s λ = 0.96), and the group × time inter-
action approached (P = 0.07) but did not achieve statistical signif-
icance (F1,81 = 3.16, P = 0.07, Wilk’s λ = 0.96). Although these
findings reflect trends in the data, with the pattern of effects similar
to those seen for the other outcomes (ie, larger reductions in pain-
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6 LEE ET AL

Table 2. Clinical outcome measures*

Questionnaire ΔCBT ΔEDU P valuea
BPI pain interference (0–10), mean ± SD −1.3 ± 1.7b −0.2 ± 1.9 0.03
BPI pain severity (0–10), mean ± SD −0.6 ± 1.53c 0 ± 1.7 0.34
FIQR (total score, 0–100), mean ± SD −8.1 ± 13.6b −1.5 ± 11.7 0.05
PCS (total score, 0–52), mean ± SD −8.7 ± 9.1b −4.6 ± 1.7c 0.04
* BPI, Brief Pain Inventory; CBT, cognitive behavioral therapy group; EDU, education control group; FIQR, Fibromy-
algia Impact Questionnaire-Revised; PCS, Pain Catastrophizing Scale.
a
Significance of group comparison in difference scores, controlling for baseline values of outcomes and
demographic covariates.
b
P < 0.01.
c
P < 0.05.

Figure 2. Treatment-induced changes. (A) Changes in clinical outcome measures (BPI interference and severity, FIQR, and PCS).
(B) Intercorrelation between changes in outcome measures (BPI interference, FIQR, and PCS). Circles indicate a single patient. *P < 0.05, **P
< 0.01. BPI, Brief Pain Inventory; CBT, cognitive behavioral therapy group; EDU, education control group; FIQR, Fibromyalgia Impact Question-
naire Revised; PCS, Pain Catastrophizing Scale; PRE, baseline/before treatment; POST, post treatment.

COGNITIVE BEHAVIORAL THERAPY FOR FIBROMYALGIA
related symptomatology in the CBT group relative to the EDU
group), they did not achieve significance (Figure 2A).
FM impact. The main effect of time on FIQR scores was sta-
tistically significant (F1,81 = 9.91, P < 0.01, Wilk’s λ = 0.98), with a
significant group × time interaction (F1,81 = 4.69, P < 0.05, Wilk’s
λ = 0.94). FIQR scores significantly reduced from baseline to post
treatment in the CBT group, and the reduction was statistically
larger than that within the EDU group (Table 2, Figure 2A).
Given that several outcome variables differed between
groups at baseline (Table 1), we compared the magnitude of
change scores between CBT and EDU with ANCOVAs, control-
ling for baseline scores and demographic covariates. Collectively,
pretreatment to posttreatment changes in outcome measures
were observed primarily in the CBT group (Table 2, Figure 2A),
and ANCOVA-tested group differences in change scores (ie,
larger reductions in the CBT group) were significant for BPI pain
interference scores, PCS scores, and FIQR total scores (Table 2).
Intercorrelations between changes in pain
catastrophizing and changes in other outcomes. Only
the CBT group showed significant correlations between ΔPCS and
ΔBPI pain interference (CBT: r = 0.50, P < 0.001; EDU: r = 0.19,
P = 0.33). Fisher’s Z-tests revealed that the magnitude of those cor-
relations was significantly greater in the CBT compared with the EDU
group (Figure 2B). Correlations between ΔPCS and ΔBPI pain sever-
ity were similar and significant in both groups (CBT: r = 0.45,
P < 0.01; EDU: r = 0.40, P < 0.05). Correlations between ΔPCS
Figure 3. Mediation analysis evaluating changes in PCS scores as mediators for group differences of changes in clinical outcome measures.
Mediation models were controlled for demographic covariates as well as general measures of negative affect (ie, anxiety and depression,
which are generally moderately associated with pain catastrophizing). *P < 0.05, **P < 0.01. CBT, cognitive behavioral therapy group; EDU, edu-
cation control group; FIQR, Fibromyalgia Impact Questionnaire Revised; PCS, Pain Catastrophizing Scale.
23265205, 0, Downloaded from https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42672 by Eduardo Paiva - UFPR - Universidade Federal do Parana , Wiley Online Library on [01/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
7
and ΔFIQR scores were significant only in the CBT group (CBT:
r = 0.58, P < 0.01; EDU: r = 0.20, P = 0.31). Fisher’s Z-tests revealed
that the magnitude of those correlations was significantly greater in
the CBT compared to the EDU group (Figure 2B).
Pain catastrophizing as a mediator of group
differences in outcomes. There was a significant indirect effect
of group (CBT vs EDU) on the change in BPI pain interference via the
mediation of change in PCS scores (a*b = 0.56, P < 0.01, 95% CI
0.08–1.14). The direct effect of group on BPI pain interference was
no longer significant (c0 = 0.76, P = 0.13) when the change in pain
catastrophizing was included in the model (Figure 3).
Similar findings emerged for the secondary outcomes of
FIQR and BPI pain severity. In each case, change in pain cata-
strophizing (ie, PCS scores) significantly mediated the observed
effects of group on changes in pain-related outcomes. There
was a significant indirect effect of group on pain severity (changes
from baseline to post treatment) through PCS (a*b = 0.60,
P < 0.01, 95% CI 0.15–1.20). The direct effect of group on
changes in pain severity was no longer significant (c0 = 0.61,
P = 0.17) when the change in PCS scores was included in the
model. Similarly, there was a significant indirect effect of group
on FIQR (changes from baseline to post treatment) through pain
catastrophizing (a*b = 4.17, P < 0.01, 95% CI 0.79–9.35). The
direct effect of group on changes in FIQR scores was no longer
significant (c0 = 5.64, P = 0.13) when the change in PCS scores
was included (Figure 3).
 23265205, 0, Downloaded from https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42672 by Eduardo Paiva - UFPR - Universidade Federal do Parana , Wiley Online Library on [01/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 LEE ET AL

Neuroimaging outcomes. Baseline brain functional con-
nectivity using PPI was performed using all 98 randomized partic-
ipants (64 in CBT and 34 in EDU). Posttreatment fMRI data were
collected from 59 CBT and 27 EDU participants; fMRI data from
81 participants were collected from both time points (55 from
the CBT group and 26 from the EDU group both pretreatment
and post treatment) and were available for the PPI analysis of
post-pre changes in functional connectivity.
At baseline, pain catastrophizing produces vPCC activation.
vPCC was used as the a priori ROI for the PPI analysis because
this region showed a significant signal increase during pain cata-
strophizing (Supplementary Materials), and vPCC activity was sig-
nificantly correlated with the self-rated applicability of PCS
statements to patients’ own experiences of pain
catastrophizing.20 The CAQ scores for the catastrophizing state-
ments summed to 9.2 ± 4.8; this score falls within the moderate
range of CAQ scores for CAT statements and supports the fact
that patients indeed experienced the thoughts and feelings
described by the catastrophizing statements, at least to a moder-
ate degree for some of the statements, during the task.
At baseline, pain catastrophizing produces anticorrelation
between vPCC and other DMN subregions and increased
correlation between vPCC and SLN subregions. The baseline
PPI analysis showed significant negative interactions between
vPCC and other key DMN hubs, such as the precuneus
(PC) and medial prefrontal cortex (mPFC) (Figure 4A), even
though the pain catastrophizing task significantly activated these
DMN regions as well. In addition, during pain catastrophizing

Figure 4. vPCC functional connectivity during pain catastrophizing. (A) At baseline (N = 98), during engagement with pain catastrophizing state-
ments, whole-brain functional connectivity from vPCC was reduced to other default mode network areas (eg, PC and mPFC) and was increased to
salience network areas (ie, aINS, aMCC). (B) Following CBT, vPCC connectivity to somatomotor (S1, M1) and salience (aMCC) network areas was
reduced. The M1 cluster showed a significant interaction between group (CBT and EDU) and time (PRE and POST) (CBT, n = 55; EDU, n = 26).
aINS, anterior insula cortex; aMCC, anterior midcingulate cortex; CAT, pain catastrophizing; Caud, caudate nucleus; CBT, cognitive behavioral
therapy; EDU, education control; L, left hemisphere; M1, primary motor cortex; mPFC, medial prefrontal cortex; PC, precuneus; POST, post treat-
ment; PRE, pretreatment; R, right hemisphere; REST, baseline; S1, primary somatosensory cortex; SMA, supplementary motor area; vPCC, ven-
tral posterior cingulate cortex.

COGNITIVE BEHAVIORAL THERAPY FOR FIBROMYALGIA
blocks, there was significant positive vPCC connectivity with the
supplementary motor area (part of the SMN) and key SLN hubs
(anterior insula [aINS] and anterior midcingulate cortex [aMCC]).
Post-CBT, vPCC connectivity during catastrophizing was
reduced in SMN and SLN regions. Following CBT treatment,
patients demonstrated decreased vPCC functional connectivity
to SMN regions, such as the primary motor cortex (M1) and S1;
the caudate nucleus; and SLN regions (ie, aMCC) (Figure 4B).
Post hoc tests revealed that only the M1 cluster showed a signifi-
cant interaction between factors group (CBT vs EDU) and time
(pretreatment vs post treatment) (F1,158 = 4.76, P = 0.03).
DISCUSSION
This randomized controlled neuroimaging trial showed that
1) CBT was superior to a matched education treatment in reduc-
ing pain interference and FM’s functional impact; 2) within the
CBT group, improvements were at least partly attributable to
reductions in catastrophizing; and 3) following CBT treatment,
changes in DMN connectivity with the lateral (eg, primary somato-
motor) and medial pain system (eg, elements of the SLN) circuitry
were observed, which may reflect CBT-induced shifts in somatic
self-awareness.8,33,34
That catastrophizing itself serves as a crucial process vari-
able in nonpharmacologic treatment for chronic pain has been
established by prior CBT studies,6,9,35 and the present findings
also support its mediational role. Reductions in catastrophizing
were more strongly linked with pain-related improvements in the
CBT group relative to the EDU group, and the greater reductions
in catastrophizing produced by CBT accounted for the greater
improvements in pain interference and FM symptomatology that
were observed following CBT treatment. Such results highlight
the important role of targeting pain catastrophizing with psycho-
therapy, particularly for patients reporting high levels of cata-
strophizing cognitions.
Pain catastrophizing plays a substantial role in shaping the
biopsychosocial pathophysiology of FM, and our recent studies
have evaluated some of its neural circuitry.10,11,20 Engaging in
pain catastrophizing robustly activates DMN circuitry, consistent
with our prior results in FM20 and in healthy controls.36 Other neu-
roimaging studies have also linked DMN functioning with pain cat-
astrophizing; for example, increased connectivity between vPCC
and mPFC in patients with chronic pain was strongly associated
with rumination.37 Similarly, a self-appraisal task strongly acti-
vated DMN regions, especially in depressed individuals.38 Reduc-
ing catastrophizing has emerged as a key element of managing
FM pain,6,9,39,40 and it is possible that DMN, SMN, and SLN con-
nectivity may emerge as a valuable biomarker of catastrophizing-
related cognitive and affective processes.9,41,42 In particular,
catastrophizing-associated linkages of the DMN with medial pain
system circuitry, which has been tied to the experience of
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9
suffering,33,34 may serve as a crucial neurobiological target of
analgesic treatments.
DMN regions, such as vPCC,43 strongly linked with cata-
strophizing cognitions20 may play a significant role in shaping psy-
chosocial adaptation to chronic pain, underpinning cognitive
processes such as self-referential cognition and rumination. For
example, our group recently found that patients with persistent
low back pain, relative to healthy controls, showed increased
SLN (ie, aINS, aMCC) connectivity with PCC after back pain exac-
erbation.11 Notably, among patients with the highest pain cata-
strophizing scores, increased DMN/aINS connectivity induced
by back pain exacerbation was correlated with individual worsen-
ing of low back pain. In the present study, we observed distinct
therapeutic brain mechanisms of CBT compared with EDU, that
is, reductions in functional interconnectivity between DMN and
pain-relevant processing networks (which may reflect more adap-
tive processing of somatic self-awareness) were observed selec-
tively following CBT. Our results further suggest that our prior
findings that maladaptive enmeshment of DMN with other net-
works (eg, SLN), which encodes clinical pain and is modulated
by catastrophizing,11 may represent the instantiation of patients’
feeling “stuck” on internally directed action.44 Given the important
role of predictive biomarkers in identifying potential responders to
specific pain treatments,41,45 these findings warrant further inves-
tigation by studies of catastrophizing-reducing treatments such
as CBT, mindfulness-based interventions, physical therapy, and
others.35,46,47
Interestingly, during pain catastrophizing at baseline, vPCC
(which was activated by the catastrophizing task) reduced its
connectivity to other nodes of the DMN (eg, PC, mPFC) and
increased its connectivity to SLN regions (eg, aINS, aMCC). This
connectivity phenomenon is very much consistent with our prior
study of brain response to a nociceptive stimulus, sustained cuff
pressure pain, which is a somatosensory stimulus rather than a
cognitive task.48 Specifically, pressure pain also reduced connec-
tivity between the stimulus-activated region (ie, the contralateral
S1 representation for the site of applied pressure) and the “native”
resting-state network typically encompassing this activated
region (ie, the nonactivated S1 territory of the sensorimotor net-
work). In contrast to this phenomenon of reduced connectivity,
during cuff pressure pain, the stimulation-activated S1 represen-
tation showed increased connectivity to SLN regions, consistent
with the increased connectivity of vPCC to aINS and aMCC dur-
ing pain catastrophizing. Taken together, these shifts in connec-
tivity suggest an interesting generalized brain response to
evoked activation, that is, reduced connectivity to a native resting
network and increased connectivity to the SLN for both somato-
sensory and cognitive stimuli.
Although the present study has some crucial strengths, such
as the sample size, the matched EDU group, and the use of a val-
idated in-scanner task to elicit catastrophizing cognitions, some
limitations will need to be addressed. First, our findings were

10
limited to a sample of all-female participants. Although women
represent the majority of patients with FM, it will be important to
include men and nonbinary individuals in future trials. Second,
CBT for chronic pain includes a number of therapeutic modules,
and we cannot draw definitive conclusions regarding which par-
ticular CBT skills were most beneficial to patients in reducing cat-
astrophizing. Third, the group differences in baseline values of
several outcome variables may complicate the interpretation of
the clinical findings. Although change scores for pain interference,
pain catastrophizing, and FM symptoms were larger in the CBT
group than the EDU group, even when controlling for baseline val-
ues, it is possible that the greater baseline symptom severity
observed in the CBT group contributed to the clinical benefits
observed among those participants randomized to CBT (eg, there
may have been more regression to the mean in the CBT group).
Finally, future studies may benefit from adding long-term post-
treatment neuroimaging assessments to evaluate the stability of
the functional connectivity changes that we observed.
Collectively, these results support the effectiveness of CBT in
reducing catastrophizing, improving pain interference, and adap-
tively altering connectivity between specific elements of the DMN,
SLN, and SMN during the experience of catastrophizing about
pain. In future work, catastrophizing may serve as an important
phenotyping variable (which could guide the selection of optimal
treatments)41,49 and as a key process variable. Pain catastrophiz-
ing may also serve as a tool to probe brain activity and connectivity
during the cognitive and affective experiences that are so important
for shaping long-term pain-related outcomes.3,50
ACKNOWLEDGMENTS
We would like to express our appreciation to Ekaterina Protsenko,
Olivia Franceschelli, Laura Galenkamp, and Laura Isaro for their invalu-
able contribution to our research project. Their efforts in assisting in
recruiting and scheduling research participants, as well as data collec-
tion, have been critical to the success of our study.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically
for important intellectual content, and all authors approved the final ver-
sion to be published. Dr. Lee has full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy of
the data analysis.
Study conception and design. Lee, Lazaridou, Loggia, Ellingsen,
Wasan, Napadow, Edwards.
Acquisition of data. Lee, Lazaridou, Paschali, Berry, Ellingsen, Isen-
burg, Grahl.
Analysis and interpretation of data. Lee, Lazaridou, Loggia, Ellingsen,
Anzolin, Grahl, Napadow, Edwards.
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