Effects of Cognitive-Behavioral Therapy (CBT) on Brain Connectivity Supporting Catastrophizing in Fibromyalgia

ORIGINAL ARTICLE

Asimina Lazaridou, PhD,* Jieun Kim, PhD,wz Christine M. Cahalan, BSc,* Marco L. Loggia, PhD,*w Olivia Franceschelli, BSc,* Chantal Berna, MD,* Peter Schur, MD,y Vitaly Napadow, PhD,*w and Robert R. Edwards, PhD*

Discussion: The results add to the growing support for the clinically Objective(s): Fibromyalgia (FM) is a chronic, common pain disorder important associations between S1-insula connectivity, clinical characterized by hyperalgesia. A key mechanism by which cognitive- pain, and catastrophizing, and suggest that CBT may, in part via behavioral therapy (CBT) fosters improvement in pain outcomes is via reductions in catastrophizing, help to normalize pain-related brain reductions in hyperalgesia and pain-related catastrophizing, a dys- responses in FM. functional set of cognitive-emotional processes. However, the neural underpinnings of these CBT effects are unclear. Our aim was to assess Key Words: cognitive behavioral therapy (CBT), insula, fibro- CBT’s effects on the brain circuitry underlying hyperalgesia in FM myalgia, fMRI, catastrophizing patients, and to explore the role of treatment-associated reduction in catastrophizing as a contributor to normalization of pain-relevant (Clin J Pain 2017;33:215–221) brain circuitry and clinical improvement. Methods: In total, 16 high-catastrophizing FM patients were enrolled in the study and randomized to 4 weeks of individual treatment with either CBT or a Fibromyalgia Education (control) ibromyalgia (FM) is a chronic musculoskeletal pain condition. Resting state functional magnetic resonance imaging Fcondition that affects 2% to 4% of the population and is scans evaluated functional connectivity between key pain- characterized by anatomically widespread pain symptoms processing brain regions at baseline and posttreatment. Clinical accompanied by fatigue, disturbed sleep, and mood.1–5 FM outcomes were assessed at baseline, posttreatment, and 6-month pain is experienced predominantly in the muscles and soft follow-up. tissue, although the diverse and widespread symptoms may Results: Catastrophizing correlated with increased resting state also extend to nearly any anatomic region. This breadth of functional connectivity between S1 and anterior insula. The CBT symptomatology is consistent with the view that FM is a group showed larger reductions (compared with the education pervasive nervous system disorder6 involving a complex group) in catastrophizing at posttreatment (P < 0.05), and CBT interaction of biopsychosocial mechanisms. Some of the produced significant reductions in both pain and catastrophizing at hallmarks of FM include: (1) alterations in central pain- the 6-month follow-up (P < 0.05). Patients in the CBT group also showed reduced resting state connectivity between S1 and anterior/ modulatory processes in the spinal cord and brain, (2) a medial insula at posttreatment; these reductions in resting state prominent role of negative affective factors in maintaining connectivity were associated with concurrent treatment-related pain and disability, (3) a relative lack of efficacy of many reductions in catastrophizing. “peripheral” treatments such as local trigger point injections. Although FM is often considered challenging to treat, Received for publication December 5, 2015; revised August 11, 2016; some pharmacologic and nonpharmacologic interventions accepted July 16, 2016. have shown promise in reducing its symptoms and impact. y From the Departments of *Anesthesiology; Medicine, Division of Recent meta-analyses and reviews suggest that cognitive- Rheumatology, Harvard Medical School, Brigham & Women’s Hospital, Chestnut Hill; wMGH/MIT/HMS Athinoula A. Martinos behavioral therapy (CBT), compared with other active Center for Biomedical Imaging, Charlestown, MA; and zClinical treatments, reduces pain intensity, disability, and emo- Research Division, Korea Institute of Oriental Medicine, Daejeon, tional distress among individuals with FM.7 CBT uses Korea. active, structured techniques to alter distorted thoughts V.N. and R.R.E. contributed equally. Supported by NIH grant R01-AR064367, by grants to RRE from the and negative moods, and with as few as 2 to 4 sessions, can Arthritis Foundation and the American College of Rheumatology produce adaptive, lasting changes in pain-related and grant P01-AT006663, R01-AT007550 to VN by the National outcomes.8–10 Center for Complementary and Integrative Health (NCCIH). The Although the mechanisms supporting CBT’s benefits project was carried out in part at the Athinoula A. Martinos Center 11 for Biomedical Imaging at the Massachusetts General Hospital, have not been fully elucidated, it is known that CBT acts Charlestown, MA, using resources provided by the Center for to reduce negative affective responses to pain such as those Functional Neuroimaging Technologies, P41EB015896, a P41 characterized by pain-related catastrophizing.12 Catas- Biotechnology Resource Grant supported by the National Institute trophizing, commonly measured by the Pain Catastroph- of Biomedical Imaging and Bioengineering (NIBIB), National 13 Institutes of Health and the KIOM grant K16051. The authors izing Scale (PCS), is a pain-specific psychosocial construct declare no conflict of interests. comprised of cognitive and emotional processes such as Reprints: Robert R. Edwards, PhD, Brigham & Women’s Hospital, helplessness, pessimism, rumination about pain-related Pain Management Center, 850 Boylston St., Chestnut Hill, MA symptoms, and magnification of pain.10,14 Although cata- 02467 (e-mail: [email protected]). Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. strophizing positively correlates with general measures of DOI: 10.1097/AJP.0000000000000422 negative affect such as depressive symptoms and anxiety, it

Clin J Pain Volume 33, Number 3, March 2017 www.clinicalpain.com | 215 Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved. Lazaridou et al Clin J Pain Volume 33, Number 3, March 2017 also has a unique and specific influence on pain-related outcomes.12 Overall, greater catastrophizing is associated with amplified attentional focus on pain,15–17 serves as a risk factor for long-term pain,18 and correlates with the presence of disproportionately negative sequelae of pain (eg, worsening physical and psychological disability and/or higher health care costs).19–21 Process analyses of CBT treatment studies indicate that changes in catastrophizing and negative affect precede changes in clinical pain, and that CBT’s effects on catastrophizing last for months or years.22,23 Despite a recent proliferation of research on CBT for chronic pain, however, there has been very limited investigation of its effects on the central nervous system’s processing of pain-related information in FM.24 Indeed, only 1 controlled, neuroimaging-based, study25 of a CBT treatment has been conducted in FM patients; the CBT group showed changes in activation and connectivity within regions of the prefrontal cortex at posttreatment, and reported reductions in anxiety and pain at the 3-month follow-up. FIGURE 1. Study flow. CBT indicates cognitive behavioral The Jensen et al25 trial represents an important step therapy. toward characterizing the neural mechanisms by which CBT shapes long-term improvements in pain-related outcomes. Unfortunately, there are no published studies of the them were randomized to treatment. The Partners Human role of catastrophizing in contributing to these outcomes. Research Committee approved this study, and written Given that previous non-neuroimaging CBT studies have informed consent was obtained from all participants. After identified catastrophizing as a crucial process variable, it the baseline visit, FM patients were randomly assigned into seems likely that changes in catastrophizing may contribute either a month-long 4-session individual CBT treatment critically to the putative “normalization” of brain function program or a month-long 4-session FM education treat- that CBT produces. Moreover, several recent functional ment program. The education group received CBT fol- magnetic resonance imaging (fMRI) studies have indicated lowing completion of their posttreatment assessment and that catastrophizing in patients with functional pain then both groups were followed up at 6 months conditions such as FM and irritable bowel syndrome is posttreatment. associated with the hyperalgesia that characterizes these Specific trial eligibility criteria were as follows: conditions, and also with alterations in pain-related brain Inclusion criteria: (1) At least 18 years old, (2) activation or functional connectivity.26–28 Specifically, Kim documented presence of rheumatologist-diagnosed et al26 found that pain-evoked increase in primary soma- FM for at least 1 year, (3) meet the revised Wolfe tosensory cortex (S1)-insula connectivity was correlated et al34 ACR criteria for FM, and (4) score on the PCS with catastrophizing—patients with greater PCS scores also of at least 21 (ie, a range that represents the top 50% demonstrated greater pain-evoked increases in S1-insula of FM patients in our earlier samples.27,29 connectivity. Our aim in the present randomized, controlled Exclusion criteria: (1) History of clinically significant trial was to assess CBT’s effects on brain circuitry under- anxiety symptoms interfering with fMRI procedures lying clinical pain and hyperalgesia, and to evaluate the (eg, claustrophobia, panic disorder), (2) recent association between treatment-related changes in catas- history of cardiac events such as myocardial infarc- trophizing and treatment-related changes in pain-related tion, (3) history of significant head injury, (4) brain circuitry. Our primary hypothesis was that CBT, peripheral neuropathy, (5) use of certain centrally compared with a control condition matched for pro- acting analgesic medications such as opioids, (6) fessional interaction, would reduce catastrophizing in FM history of substance abuse, (7) concurrent auto- patients, diminish functional connectivity between S1 and immune or inflammatory disease, (8) implanted insula cortex and regions of the default mode network metallic objects, (9) pregnancy, (10) diseases affecting (which have previously been linked to elevated FM pain the central nervous system (eg, multiple sclerosis, severity27,29–32), and produce long-term reductions in clin- Parkinson’s disease), (11) serious psychiatric con- ical pain. ditions precluding participation (eg, psychotic disorders).

METHODS We screened 44 FM patients (Fig. 1). We required a PROCEDURES diagnosis of FM for at least 1 year (as confirmed by their Participants participated in 2 separate study baseline rheumatologist and past medical records), and patients also visits on different days: a behavioral visit and an imaging had to meet the recently promulgated American College of visit. The baseline behavioral visit included the process of Rheumatology (ACR) criteria (Wolfe and colleagues), informed consent, completion of self-report questionnaire which require the presence of widespread pain as well as a measures, psychophysical testing, and confirmation of eli- number of somatic and cognitive symptoms.33 We enrolled gibility. The behavioral visit also served to determine the a total of 17 high-catastrophizing patients who met the appropriate individually tailored stimulus intensities to be inclusion and exclusion criteria described below, and 16 of used subsequently in the imaging session.

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As described in prior studies26,27 we used cuff pain FMRI data were acquired using a 3 T Siemens TIM algometry (CPA) to produce tonic, deep-tissue pain. CPA Trio MRI System (Siemens Medical; Erlangen, Germany) stimuli can be applied tonically, and have a preferential equipped for echo planar imaging with a 32-channel head effect on deep tissue nociceptors.35,36 Mechanical stimuli coil. A whole-brain T2*-weighted gradient echo BOLD EPI were delivered on the calf using a 13.5-cm wide velcro- pulse sequence was used (TR/TE = 2 s/30 ms, fa = 90 adjusted pressure cuff, connected to a rapid cuff inflator degrees, 37 AC-PC aligned axial slices, voxel (Hokanson E20 AG101; Hokanson Inc., Bellevue, WA). At size = 3.13.13.6 mm). We also collected anatomic data, the behavioral visit, participants were familiarized with the using a multi-echo MPRAGE pulse sequence (TR/TE1/ CPA procedures. Participants sat comfortably on a chair TE2/TE3/T4 = 2530/1.64/3.5/5.36/7.22 ms, flip angle = 7 with their feet resting on a support at a slightly elevated degrees, voxel size = 1 mm isotropic). FMRI scans eval- position. The cuff was then secured around the belly of the uated resting state connectivity over the course of a 6- gastrocnemius muscle. Individual pressure calibration minute resting-state fMRI acquisition period (180 scans), began by inflating the cuff to 60 mm Hg of pressure and during which participants were asked to remain awake with making adjustments in 10 mm Hg increments until a pain eyes open. During the imaging procedures, electro- intensity rating of B50/100 (NRS ranged from 0, no pain cardiography and pneumobelt respiratory volume data to 100, worst pain imaginable) was first obtained. were collected concurrently, for the purpose of correction Standard demographic information and medical his- for cardiorespiratory artifacts in the fMRI data. Partic- tory information were collected by self-report. Ques- ipants’ head motion was minimized using foam pads placed tionnaires included the following: around the head along with a forehead strap.

Baseline Questionnaires Interventions Widespread Pain Index and Symptom Severity Following the baseline assessment, participants were Questionnaire33 randomized to 1 of the two 4-week individual therapy We defined FM using the modified 2010 ACR Diag- interventions: CBT or the Education (control) condition. nostic Criteria for Fibromyalgia (ACR 2010), which has The treatments were matched for degree of professional been validated as a self-reported method for measuring FM contact; both treatments involved four 60- to 70-minute in a population with chronic pain. visits conducted by the same licensed clinical psychologist. Study participants were informed that they would be Short form 36 Health Survey37 randomized to receive “one of two behavioral interventions The Short Form 36 health survey includes 36 questions to improve quality of life in fibromyalgia patients.” After assessing health-related quality of life. It has 2 global the end of the 4 treatment visits, participants underwent a indices of quality of life, a Physical Health subscale, and a second scanning session which was identical to the baseline Mental Health subscale Scores range from 0 to 100, with scan to assess intervention-related changes. higher scores indicating better quality of life.

38 CBT Visual Analog Scale for Fatigue Treatment sessions used active, structured techniques A Visual Analog Scale was used for rating the severity to alter distorted thoughts, with a focus on acquiring and of fatigue experienced by patients within the past 2 weeks. practicing cognitive and emotion-regulation skills. CBT This scale consisted of a vertical line 10 cm in length, and was based on a pain self-management paradigm, and the scale is anchored by “no fatigue” (score of 0) and involved the identification and reduction of maladaptive “fatigue as bad as it could be” (score of 10). pain-related cognitions (ie, catastrophizing) using techni- Outcome Measures (Assessed at Baseline, ques such as relaxation, visual imagery, thought challeng- Posttreatment, and 6-Month Follow-up) ing, and distraction. CBT prominently emphasized in vivo 39 practice during each session, and featured home practice The Brief Pain Inventory (BPI) is a well-validated, using written exercises. In particular, cognitive restructur- widely used, and commonly recommended instrument that ing was used to help patients recognize the relationships measures pain severity and pain-related interference for between thoughts, feelings, and behaviors. Patients learned patients with FM and other chronic pain conditions. 40 to identify, evaluate, and challenge negative thoughts and The Beck Depression Inventory (BDI) is a well- to diminish the degree of catastrophizing about pain. validated, commonly used, general measure of depressive symptomatology. The PCS41 is a widely used self-report measure of Education catastrophic thinking associated with pain. The PCS has This condition, matched for amount of professional good psychometric properties in pain patients and controls. contact, included information about FM and about chronic The PCS includes 3 subscales: rumination, magnification, pain. The sessions provided a variety of information about and helplessness. the nature and presumed causes of FM, but they involved no active skills training or homework assignments. Edu- FMRI Procedures cation is often utilized as an active control condition that Before undergoing the scanning procedures, partic- provides a comparator in CBT in controlled trials.42 This ipants completed a Safety Screening Checklist for MRI. educational intervention was developed to control for Participants underwent fMRI scanning at a baseline time- important nonspecific factors related to therapist attention point, before being randomized to one of the interventions and outcome expectancy, as well as natural history and (ie, the preintervention scan). Participants underwent the regression to the mean. Following completion of the edu- same fMRI procedures following completion of the inter- cation intervention, all patients in this arm of the study vention visits (ie, the postintervention scan). were offered the 4-session CBT treatment.

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Data Analysis patients.26 For connectivity analyses, we extracted the The CBT and education groups were compared from averaged fMRI time-series signal from a 4 mm radius baseline to posttreatment using 22 factorial analyses of sphere centered on the identified peak coordinates. Resul- variance (ANOVAs) on the clinical outcome measures: BPI tant connectivity maps, and their variance, from each Pain severity, BPI Pain Interference, PCS, and BDI scores. individual were passed up to group level analyses to explore A repeated measures ANOVA was used to evaluate differences between the CBT and Education intervention whether, at the 6-month follow-up (when all patients had groups from pretreatment to posttreatment using FMRIB’s received CBT), changes from baseline were observed. We Local Analysis of Mixed Effects (steps 1 + 2). We also then evaluated relationships between changes in outcome performed whole-brain voxel-wise linear regression analysis variables and changes in brain connectivity (see below) to investigate the link between changes in functional con- using Pearson correlations. nectivity and changes in PCS scores. For this linear FMRI data were processed using FMRI Expert regression analysis, we combined participants from both Analysis Tool version 5.0, which is part of Functional the CBT with education groups as both groups showed Magnetic Resonance Imaging of the Brain (FMRIB) significantly decreased PCS scores after treatment. All brain Software Library (online at: http://www.fmrib.ox.ac.uk/ maps were thresholded using cluster correction for multiple fsl). Data underwent the following preprocessing: phys- comparisons with a cluster-forming threshold of Z > 2.3 iologic (cardiorespiratory) artifact correction using RET- and a cluster-size threshold of P < 0.05 to control for ROICOR, motion correction, slice timing correction, family-wise error. nonbrain removal. Time-series statistical analysis was All statistical analyses for behavioral data were per- performed using FMRIB’s Improved Linear Model with formed using SPSS 22.0 with an a level of 0.05. local autocorrelation correction. Cortical surface recon- struction was performed using FreeSurfer software (online at: http://surfer.nmr.mgh.harvard.edu/) for improved RESULTS structural/functional coregistration purposes. A recently In this trial, all 16 randomized participants completed developed automated boundary-based registration algo- the study successfully; 1 participant dropped out following rithm (FreeSurfer’s bbregister tool) was used for the baseline assessment (the participant did not attend any coregistration. Scans were registered to the Montreal treatment visits and was unreachable following the baseline Neurological Institute (MNI) template MNI152 standard assessment). Among the 16 completers, all participants space using FMRIB’s Nonlinear Image Registration Tool. completed all 4 treatment visits. Demographic and clinical Data were then resampled to 2-mm isotopic voxels and data are presented in Table 1. The Education and CBT spatially smoothed (full-width half-maximum of 6mm), groups did not differ at baseline in BPI, PCS, or BDI followed by high-pass temporal filtering (f =0.006Hz). scores. ANOVAs on the pretreatment to posttreatment Parameter estimates and relative variances for each data revealed a significant effect of time and a grouptime explanatory variable were then included in mixed-effects interaction for PCS scores: F1,15 = 4.5, P < 0.05, for the group level analyses, performed using FMRIB’s Local interaction (Fig. 2). Both groups showed reductions in PCS Analysis of Mixed Effects, with enabled automatic outlier scores, but the decrease was larger in the CBT relative to detection. the education group. The follow-up assessment was con- Functional connectivity was computed using seed- ducted 6 months after treatment, and was completed by 15 based correlation analysis. On the basis of our previous patients. Repeated measures ANOVAs revealed that PCS results,26,27 we defined a seed representing lower leg area (Pr0.01) and BDI Pain Interference (Pr0.05) scores were (S1leg:8,38, 68 mm in MNI coordinates). Our previous significantly reduced from baseline at the 6-month follow- analysis found that this seed (S1leg) showed decreased up (Table 2, Figs. 2, 3). Overall, treatment-related changes resting connectivity to other S1 subregions in FM in catastrophizing tended to be larger than changes in other outcome variables (eg, a 64% reduction in PCS scores at the completion of 6-month follow-up). Collectively, changes in catastrophizing were strongly related to long- TABLE 1. Sociodemographics and Clinical Variables at Baseline term changes in pain over the course of the study: the Age (mean ± SD) (y) 45.7 ± 12.2 correlation of 6-month changes in PCS with 6-month % Male 17.1 changes in BPI Pain Severity is r = 0.74, P < 0.01, and with % Married 37.1 6-month changes in BPI Pain Interference is r = 0.79, %White 81.4 P < 0.01. %Employed 27.1 Our brain connectivity analysis then explored whether %Postsecondary degree 14.3 changes in S1 connectivity following therapy were asso- Fibromyalgia symptom duration (mean ± SD) (y) 12.5 ± 12.2 Weight (mean ± SD) (pounds) 177.4 ± 41.7 ciated with the reductions in PCS reported by participants. Questionnaire data (mean ± SD) Whole-brain voxel-wise linear regression analysis demon- BPI (Severity) 5.6 ± 1.7 strated that changes in connectivity between S1 and ante- BPI (Interference) 6.2 ± 1.7 rior/medial insula was correlated with posttreatment Pain Catastrophizing Scale 33.9 ± 6.7 (combined CBT and EDU) changes in PCS scores (Fig. 4). Beck Depression Inventory 18.2 ± 8.8 Other regions demonstrating associations between changes Fatigue Severity (VAS), 0-10 scale 2.9 ± 2.0 in PCS and changes in S1 connectivity were cuneus, pre- SF-36 Physical Health 37.4 ± 22.2 cuneus, occipital cortex, inferior frontal gyrus, thalamus, SF-36 Mental Health 50.0 ± 19.2 and cerebellum (Table 3). BPI indicates Brief Pain Inventory; VAS, Visual Analog Scale; SF-36, Furthermore, z statistics extracted from the S1-ante- Short Form 36 Health Survey. rior/medial insula connectivity cluster demonstrated that patients randomized to CBT showed more reduced resting

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FIGURE 3. Brief Pain Inventory (BPI) Pain Interference scores at FIGURE 2. Pain catastrophizing scale scores at baseline, post, baseline, post, and 6-month follow-up. and 6-month follow-up. CBT indicates cognitive behavioral therapy; PCS, Pain Catastrophizing Scale. than changes in a more general affective factor such as state connectivity between S1-anterior/medial insula at depressive symptomatology (ie, BDI scores). A substantial posttreatment compared with the education group (see bar portion of CBT’s effectiveness for pain management is graph in Fig. 4). Such differences between groups were not likely attributable to its emphasis on cognitive skills (eg, found for the other regions whose S1 connectivity changes cognitive restructuring, distraction) that can be honed were associated with PCS changes—that is, cuneus, pre- through practice and deployed to manage daily pain cuneus, occipital cortex, inferior frontal gyrus, thalamus, symptoms.43,44 It is important to note that the present trial and cerebellum. enrolled only high-catastrophizing patients, and there is some recent evidence suggesting that the highest- catastrophizing patients may benefit most from these cog- DISCUSSION nitive coping skills.45 It is unknown how effective this CBT The present results support prior findings that indi- treatment program would be in low-catastrophizing vidual CBT in patients with FM produces long-term patients, though a larger trial that will eventually be able improvements in pain, and that reductions in catastroph- to answer this question is underway. izing may serve as an important process factor in shaping Our neuroimaging results add to a growing body of these outcomes. It is noteworthy that treatment-related literature suggesting important links between clinical changes in catastrophizing in this study were much larger outcomes in FM and the degree of connectivity between the anterior/middle insula cortex and brain regions not typically connected to the insula in a resting state (ie, TABLE 2. Changes in BPI, PCS, and BDI Between Baseline, primary somatosensory and default mode network Posttreatment and 6-Month Follow-up areas).29,31,32 These results extend our previous work on 6mo FM patients showing increased connectivity (relative to a Postbaseline Baseline* matched group of healthy controls) between S1 and 26 Outcome Mean Diff. Mean Diff. anterior insula in response to pain at baseline. The Variables Group (SD) P (SD) P present pilot findings suggest that CBT reduces potentially dysfunctional brain states and improve clinical outcomes Pain Severity (BPI) (0-10 scale) such as pain-related disability in part by reducing catas- CBT 0.35 (2.0) 0.47 1.23 (2.19) 0.18 EDU 0.28 (1.8) 0.17 1.85 (3.34) 0.19 trophizing. Such a conclusion is supported by the Pain Interference (BPI) (0-10 scale) substantial reduction in connectivity between insula and CBT 1.5 (2.9) 0.21 2.5 (2.7) 0.05 primary somatosensory cortex that was observed in the EDU 0.39 (1.6) 0.78 1.5 (3.1) 0.21 CBT group, and by the large proportion of shared var- Pain Catastrophizing Scale (PCS) (0-52) iance between changes in PCS scores and changes in CBT 14.1 (6.6) 0.001 16.2 (12.7) 0.01 this connectivity metric. Our findings hint that CBT’s EDU 8.5 (9.2) 0.06 20.5 (13.1) 0.006 effectiveness may result directly from its ability to reduce Beck Depression Inventory (BDI) (0-63) catastrophizing and “normalize” connectivity between CBT 3.5 (7.9) 0.23 5.6 (11.1) 0.22 salience processing areas such as the insula cortex and EDU 2.0 (4.4) 0.25 0.07 (4.8) 0.97 primary somatosensory regions that are known to both *The education group received CBT between the “post” evaluation and localize pain and ascribe magnitude to this perception. 6-month follow-up. However, we did not compare CBT with other active, BPI indicates Brief Pain Inventory; CBT, cognitive behavioral therapy; empirically supported behavioral treatments (eg, exercise, Diff, difference; EDU, education. Bold values are statistical significant Pr0.05. meditation), and are thus unable to definitively determine the specificity of these effects to CBT.

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FIGURE 4. Functional connectivity effects, with group differences in pretreatment to posttreatment changes in S1-a/mINS connectivity and a scatterplot of the association between pretreatment to posttreatment changes in PCS and pretreatment to posttreatment changes in S1-a/mINS connectivity. CBT indicates cognitive behavioral therapy; PCS, Pain Catastrophizing Scale.

Although the present study has some crucial strengths, Collectively, these preliminary results support the such as the carefully matched (for duration and type of pro- potential effectiveness of CBT in reducing catastrophizing, fessional contact) education condition, a number of limi- improving pain interference, and resolving amplified tations will need to be addressed in future studies. First, we insula-S1 connectivity in patients with FM who are high in did not formally assess the amount of time patients continued catastrophizing. Catastrophizing may serve both as an to practice specific skills during and following completion of important phenotyping variable (which could guide the the treatment programs. Therefore, we cannot draw clear selection of optimal treatments for individual patients) and conclusions on which particular CBT skills were most bene- as a key process variable (changes in which are partly ficial to patients in reducing pain interference and catas- responsible for changes in pain-related outcomes). More- trophizing. Second, because the education group underwent over, it is important to highlight the potential sequential CBT after completing their posttreatment assessment, we did associations that were apparent in this treatment study. not have a control condition for CBT at the 6-month post- Catastrophizing and insula-S1 resting state connectivity treatment timepoint. Although we did observe improvements changed over the short-term course of treatment (ie, over in BPI pain interference across this time frame, and we suspect approximately 1 month, after 4 sessions of individual CBT) that these improvements are CBT-related, we are not able to while significant changes in pain interference were only definitively quantify that effect in a controlled manner. A final observed at 6-month follow-up. Such temporal sequences limitation was the relatively small sample size for this type of highlight the possibility that fMRI might be used to identify functional connectivity MRI analysis, which may have early-treatment biomarkers that predict long-term treat- restricted our overall power, though even with this small ment benefits. Future longitudinal studies using fMRI- sample we were able to observe significant associations derived variables as biomarkers, and including substantially between changes in brain connectivity and long-term changes larger sample sizes will be needed to identify the clinical in clinical outcomes. potential of these preliminary findings.

TABLE 3. Brain Regions Showing Significant Correlation Between Changes in S1leg Connectivity (Post-Pre) and Changes in PCS (Post- Pre) Scores MNI Coordinates Side Size (mm3) X (mm) Y (mm) Z (mm) Peak z-stat Cuneus R 1600 6 88 18 5.31 Cuneus L 6584 6 90 34 6.79 Precuneus L 3984 18 72 24 4.58 Occipital cortex R 2312 36 86 4 4.66 Occipital cortex L 944 42 70 10 4.07 Anterior/mid insula L 1272 30 6 10 5.21 Thalamus L 1272 16 12 10 3.26 Inferior frontal gyrus L 560 32 26 8 4.11 Cerebellum L 440 26 42 44 3.60

L indicates left; MNI, Montreal Neurological Institute; PCS, Pain Catastrophizing Scale; R, right.

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