Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: J Pain. 2015 Apr 30;16(8):692–699. doi: 10.1016/j.jpain.2015.04.003

The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients

Marco L Loggia 1,2,*, Chantal Berna 3, Jieun Kim 1, Christine M Cahalan 2, Marc-Olivier Martel 2, Randy L Gollub 1,4, Ajay D Wasan 2,5, Vitaly Napadow 1,2,6,#, Robert R Edwards 2,#
PMCID: PMC4522376  NIHMSID: NIHMS686299  PMID: 25937162

Abstract

While high levels of negative affect and cognitions have been associated in chronic pain conditions with greater pain sensitivity, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation, and that 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing, in fibromyalgia (FM) patients. Using functional Magnetic Resonance Imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex (IPFC). A bootstrapped mediation analysis revealed that pain-anticipatory activity in lateral prefrontal cortex (IPFC) mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of IPFC in the pathophysiology of FM related hyperalgesia, and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well validated measure of negative cognitions and psychological distress.

Perspective

This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions towards pain.

Keywords: fibromyalgia, catastrophizing, negative affect, functional magnetic resonance imaging, psychophysics

Introduction

Fibromyalgia (FM) is a chronic, common disorder characterized by persistent, widespread pain and myofascial tenderness. It is a primary cause of disability and one of the most challenging-to-treat rheumatologic conditions41. The diversity of symptoms reported by FM patients is consistent with the view that FM is a pervasive nervous system disorder involving a complex interaction of biopsychosocial mechanisms. While recent evidence of small fiber neuropathy suggests that peripheral alterations contribute to the pathophysiology of FM in a subset of patients26, 45, it is well established that negative cognitive and affective factors play a prominent role in maintaining pain and disability in this and other pain disorders6. In fact, FM is characterized by a strong association with psychiatric comorbidities, including anxiety and depression, and has been considered an affective spectrum disorder16. Catastrophizing is a pain-specific psychosocial construct comprised of cognitive and emotional processes such as helplessness, pessimism, rumination about pain-related symptoms, and magnification of pain complaints. While catastrophizing positively correlates with general measures of negative affect such as depressive symptoms, anxiety, or neuroticism, it also shows a unique and specific influence on pain-related outcomes6. Several brain imaging studies have found that greater catastrophizing in FM, compared to healthy controls (HC), was associated with enhanced pain-evoked activation in dorsolateral and medial prefrontal, and dorsal anterior cingulate cortices12. However, the brain mechanisms mediating the hyperalgesic effect of catastrophizing are unknown.

In addition to catastrophizing and hyperalgesia, FM patients also demonstrate lower brain reactivity to pain anticipatory cues (as well as relief anticipatory cues) than healthy individuals21. This observation, which we argued may be in part the result of alterations in dopaminergic53, 54 and/or GABAergic10 neurotransmission that have been documented in these patients, adds to a growing literature supporting reduced responsiveness of FM patients to a variety of experimental manipulations19, 44, 54.

The pain experience can be dramatically shaped by anticipatory processes, and the brain state preceding a painful stimulation has been shown to predict responses to experimental2, 31, as well as clinical pain23. Thus, in the present study, we used functional magnetic resonance imaging (fMRI) and mediation analyses in a cohort of patients with FM and a wide range of catastrophizing scores to test the hypotheses that 1) individual levels of catastrophizing modulate brain responses to pain anticipation in FM and that 2) anticipatory brain activity mediates the hyperalgesic effect of higher catastrophizing.

Materials and Methods

Subjects

104 FM patients (n=13 male) were initially screened by phone for probable eligibility to participate in this experiment at the Brigham and Women's Hospital Pain Management Center and Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston, MA, USA. Patients were screened and enrolled over a 16-month period between September 2010 and December 2011. Of the 104 patients initially contacted, 53 (n=7 male) signed a consent form and were invited for a screening visit; the others were either not interested (n=18), or ineligible –most commonly due to claustrophobia, being on opioids, or peripheral neuropathy– (n=22), or had scheduling conflicts (n=11). Of the subjects who were invited to the screening visit, 5 were determined to be ineligible excluded at the behavioral session –for implanted metal, leg edema, or neuropathy- and 4 subsequently dropped out. Of the remaining 44 (n=6 male) who proceeded to the scan visit, only 31 (n=4 male) had complete and analyzable data for the purposes of the present study. Thus, 13 subjects did not successfully complete the fMRI scanning noted below due to: inability to tolerate pain procedures (n=5), scanner time constraints (n=4), and scanner/equipment failure (n=4).

Average age (mean ± SD) was 44.0 ±11.9, symptom duration was 12.5 ± 12.2 years, current clinical pain intensity was 34.3 ± 25.2 (out of 100). For additional details on the patients' clinical and demographic characteristics, please refer to our previous publication21. Enrolled patients were diagnosed with FM (as confirmed by physician and medical records) and also met the recently-proposed Wolfe et al. criteria52, which require the presence of widespread pain and endorsement of multiple somatic and cognitive symptoms. Exclusion criteria included age below 18 years, history of claustrophobia, neurological disorders including peripheral neuropathy, history of significant head injury, serious cardiovascular disease, current use of opioids, implanted medical or metallic objects and pregnancy. While these criteria led to a sizable number of excluded subjects following initial screening, the criteria were either necessary (e.g. claustrophobia for MRI evaluation) or did not significantly compromise the generalizability of our study sample, as, for example, recent prospective studies and reviews suggest little evidence for the effectiveness of long-term opioid therapy in patients with fibromyalgia, and consequently fewer and fewer fibromyalgia patients are on chronic opioids29. All participants in the study provided written informed consent in accordance with the Hospitals' Human Research Committee. This was an exploratory study designed to power a larger clinical trial.

Study overview

After a training visit, which was used to familiarize subjects with the stimuli and rating procedures, subjects participated in a brain imaging visit, on a separate date. At the beginning of the visit, the intensity of stimulation needed to achieve a pain intensity rating of ∼50/100 was assessed (for more details, see 21). During a functional imaging scan run, brain activity was investigated using Blood Oxygen Level Dependent (BOLD) fMRI, while undergoing 3 separate tonic (i.e., 46 – 74 sec) cuff pressure pain stimuli at the predetermined intensity level.

Cuff pain algometry (CPA) stimuli were delivered using a 13.5cm-wide velcro-adjusted pressure cuff connected to a rapid cuff inflator (Hokanson Inc, Bellevue, WA, USA). CPA is a technique that has been successfully adopted in psychophysical investigations7, 32-35, including in FM patients17, and in neuroimaging studies we recently conducted18, 22. Among the advantages of CPA over other more commonly used methods of pain stimulation (e.g., contact heat), CPA stimuli have a preferential effect on deep tissue nociceptors, such as in muscles34, and thus may better mimic clinical pain38, particularly in conditions characterized by myofascial tenderness, such as FM. During the run, a fixation cross was presented visually using a mirror and projector system. The cross changed color (from black to green) 6-10s prior to cuff inflation to Signal the period of pain anticipation, and then turned black again at stimulus onset. Another change in crosshair color (from black to blue) 6-12s prior to stimulus offset induced anticipation of pain relief (not discussed here). Pain intensity and unpleasantness ratings were obtained at the end of each stimulus, eight seconds after stimulus offset, using a MR-compatible button box and the ePrime software (Psychology Software Tools, Sharpsburg, PA). The present study presents an analysis of a dataset previously described21. As opposed to the previous study, which compared brain activity across groups, in the present study we employed statistical approaches aimed at evaluating the relationship between pain-anticipatory activity, pain sensitivity and catastrophizing. Cuff pain sensitivity was the single main outcome measure of this study.

FMRI data were acquired using a 3T Siemens TIM Trio MRI System (Siemens Medical, Erlangen, Germany) equipped for echo planar imaging with a 32-channel head coil. A whole brain T2*-weighted gradient echo BOLD EPI pulse sequence was used (TR/TE=2sec/30ms, f.a.=90°, 32 AC-PC aligned axial slices, voxel size=3.1×3.1×4mm). We also collected anatomical data, using a multi-echo MPRAGE pulse sequence (TR/TE1/TE2/TE3/T4=2530/1.64/3.5/5.36/7.22 ms, flip angle=7°, voxel size=1mm isotropic). During the imaging procedures, electrocardiography and pneumobelt respiratory volume data were collected concurrently, for the purpose of correction for cardiorespiratory artifacts in the fMRI data.

Catastrophizing was assessed at the first visit in all subjects using the Pain Catastrophizing Scale43. The PCS is a 13-item measure that asks respondents to self-report their tendency to catastrophize when in pain (e.g., during “illness, injury, dental procedures or surgery”). Subjects rate, from zero (“not at all”) to four (“all the time”), 13 statements on “the degree to which (they) have these thoughts and feelings when (they) are experiencing pain.” Factor analysis has revealed 3 PCS subscales: Magnification, rumination, and helplessness, which are moderately to highly inter-correlated, and most studies use the total PCS score. A number of studies have replicated this factor structure using confirmatory factor analytic methods in healthy adults, chronic pain patients, across different age and cultural groups, and in non-English languages37. Moreover, the factor structure of the PCS appears to be invariant across sexes and across chronic pain patients vs. pain-free controls5, 28. PCS scores are highly stable over time, suggesting that the measure assesses trait-like properties. For example, a recent study of fibromyalgia patients showed ICCs in the range of .85 - .9 for 1-month test-retest reliability for multiple translations of the PCS in different linguistic groups25. Measures of catastrophizing are moderately correlated with general measures of negative affect (e.g., symptom inventories for depression and anxiety), but in prospective studies catastrophizing emerges as a unique predictor of adverse pain-related outcomes such as the development of persistent pain, enduring pain-related disability, elevated healthcare costs, etc., making it a crucial target of study and treatment in pain populations6.

Statistical Analysis

FMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 5.98, part of FSL (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl). Data were corrected for cardiorespiratory artifacts using RETROICOR11. Following this procedure, data were corrected for slice timing (slicetimer), motion (MCFLIRT) and BO inhomogeneities (PRELUDE and FUGUE), and were skull stripped (BET), grand-mean intensity normalized by a single multiplicative factor, high-pass temporal filtered (Gaussian-weighted least-squares straight line fitting, with sigma=72s) and spatially smoothed (FWHM=5mm). Time-series statistical analysis was carried out using FILM with local autocorrelation correction. Cortical surface reconstruction was performed using FreeSurfer (http://surfer.nmr.mgh.harvard.edu/) for improved structural-functional co-registration, which was carried out using FreeSurfer's bbregistertool15, and visualization purposes.

A first level within-subject general linear model (GLM) analysis was performed by modeling the pain anticipation cue as regressor of interest. We also modeled the cuff pain stimulus application, an anticipation of pain relief cue, the period between stimulus offset and rating periods, and the rating periods as regressors of no-interest in the model (see 21). A canonical double-gamma hemodynamic response function was adopted.

The first-level parameter estimate and corresponding variance maps were then registered to the MNI152 standard space using the FMRIB's Nonlinear Image Registration Tool (FNIRT) for group analyses. The relationship between catastrophizing and brain responses to pain anticipation was then assessed in a whole-brain voxelwise multiple linear regression, with the demeaned PCS score as an explanatory variable in a GLM, using FLAME (FMRIB's Local Analysis of Mixed Effects) 1+2, with automatic outlier detection enabled. The resulting statistical map was cluster corrected for multiple comparisons using a cluster-forming voxel-wise threshold of Z>2.3, and a (corrected) cluster significance threshold of P<0.05. For visualization purposes, the statistically significant clusters were projected to a standard surface (fsaverage).

We then tested the hypothesis that the association between catastrophizing scores (independent variable, IV) and pain sensitivity (i.e., the cuff pressure values needed to reach the target rating of 50/100; dependent variable, DV) was mediated by the pain-anticipatory brain activity (mediator variable, M). While several regions demonstrated an association with catastrophizing (see Results), we elected to focus our mediation analysis on a single region (right lateral prefrontal cortex, IPFC, in a subregion extending over the anterior and ventral IPFC) as this region demonstrated the peak effect size (i.e., largest contrast of parameter estimates value, COPE), in the regression analysis against the catastrophizing scores. The BOLD percent signal change values (averaged over all voxels with a Z score ≥ 3) for this region were used as the M variable. The unstandardized path coefficients in this mediator model and the bootstrap 95% Confidence Intervals (CI) for total and specific indirect effects of IV on DV through M (5,000 bootstrap samples) were estimated using Preacher and Hayes Indirect Mediation Analysis tool36 for SPSS 20 (IBM). As recommended, the indirect (i.e., mediation) effect was considered statistically significant if the 95% CI did not include zero.

The association between catastrophizing and pain sensitivity was investigated by correlating the PCS scores and the cuff pressure values needed to reach the target rating of 50/100 (in mmHg). These behavioral analyses were performed with Statistica 10.0 (StatSoft Inc., USA), using an alpha level of 0.05.

Results

Psychophysical analyses

Patient PCS scores showed broad individual variability (range = 0-46, mean/SD = 23.4±13.6). As Figure 1 shows, PCS scores were negatively correlated with cuff pressure (r = -0.37, p<0.05), meaning that greater catastrophizing was associated with less cuff pressure needed to elicit similar pain ratings. No correlations were found between PCS scores and ratings of the patients' own clinical pain (intensity: r = 0.05, p = 0.78; unpleasantness: r = 0.19, p = 0.30).

Figure 1. Psychophysical results.

Figure 1

Open in a new tab

Catastrophizing scores correlated negatively with the pressure required to reach the target pain intensity rating.

Imaging analyses

In whole-brain voxelwise analyses (Figure 2, Table 1), brain responses to pain anticipation were found to be negatively correlated to PCS scores in the right LPFC, superior parietal lobule (SPL), and precuneus. The pain-anticipatory activity of the IPFC region (Figure 3A) not only exhibited an association with the PCS scores, as revealed by the multiple linear regression analysis (Figures 2 and 3B, scatterplot shown for illustrative purposes), but also with the cuff pressure needed to achieve the target percept (Figure 3C). No brain regions demonstrated positive correlation to PCS.

Figure 2. Catastrophizing is associated with pain-anticipatory brain activity.

Figure 2

Open in a new tab

A. Whole brain linear regression analyses revealed that PCS scores were negatively correlated with pain-anticipatory activation in a widespread group of regions. For abbreviations, see main text.

Table 1. Brain regions demonstrating a significant association between pain anticipatory activity and catastrophizing.

Only negative associations were observed.

Cluster size
(# voxels)		 Cluster
P-value		 Local maxima
Z X y z Label
Positive correlations
n.s.
Negative correlations
1043 0.00849 3.93 26 -48 64 R superior parietal lobule
3.31 2 -44 56   R precuneus
843 0.026 3.64 36 38 16 R lateral prefrontal cortex
Open in a new tab

Figure 3. Pain-anticipatory activity of the lateral prefrontal cortex mediates the effect of catastrophizing on pain sensitivity.

Figure 3

Open in a new tab

A. VIPFC/alPFC mask used to extract percent signal change for regression and mediation analyses. B,C. The pain-anticipatory activity of this region correlated both with PCS (B) and cuff pressure needed to achieve the target pain intensity rating (C). D. A bootstrapped mediation analysis revealed that the relationship between PCS and cuff pressure was significantly mediated by vIPFC/alPFC activity. Path coefficients are unstandardized. Values within parentheses represent bootstrapping SEs. #p=0.07, *p<0.05, **p<0.01

Mediation analyses

As the pain-anticipatory activity of the right anterior/ventral IPFC was the most prominently associated with the catastrophizing scores, and was also correlated with cuff pressure, we performed a bootstrapped mediation analysis to investigate the relation between these variables (Figure 3D). This analysis revealed that, while the association between PCS and cuff pressure was statistically significant (path c; β±bootstrap SE= -1.46±0.67, p<0.05), it was no longer significant after including the IPFC activity in the model (path c'; β= -0.82±0.73, p = 0.27, n.s.). The bias-corrected 95% Confidence Intervals (CI) for the specific indirect effect of PCS on cuff pressure through the IPFC activity (path a X b; β= -0.63±0.54) yielded a lower limit of -2.11 and an upper limit of -0.001. As the CI did not include zero36, this analysis indicated that the association between catastrophizing and cuff pressure was significantly mediated by the pain-anticipatory activity of the anterior/ventral IPFC.

Discussion

Our results demonstrated that individual levels of catastrophizing were associated with reduced pain-anticipatory brain activity, and that this reduced activity contributed to the hyperalgesic effect of catastrophizing in FM. More specifically, by using bootstrapped mediation analysis, we observed that the anticipatory activity of lateral prefrontal cortex mediated the association between levels of catastrophizing/ or catastrophizing scores and mechanical (cuff) pain sensitivity.

Psychophysical studies have revealed that FM is associated with amplified central nervous system processing of nociceptive afference, with apparent enhancement of pain-facilitatory processes accompanying a reduction in endogenous pain inhibition4. Catastrophizing has shown similar associations, as elevated catastrophizing scores are linked with enhanced temporal summation and reduced effectiveness of conditioned pain modulation8, 14, 46, 49. In agreement with these reports, we also observed that higher levels of catastrophizing in a population suffering from chronic pain were associated with elevated pain sensitivity, specifically lower pressure values needed to achieve target pain intensity ratings (Figure 1). Furthermore, fMRI studies in healthy adults42 and FM patients12 have reported significant correlations between pain catastrophizing and evoked-pain brain responses in dorsolateral prefrontal, insula, and anterior cingulate cortices, i.e. brain regions associated with emotional and motivational modulation of the pain experience. A recent study showed that inducing a depressed mood state increased levels of pain catastrophizing and broadly amplified cortical responses to a noxious stimulus1. Collectively, these findings strongly indicate that catastrophizing affects both brain processing and subjective reports of pain.

However, while high levels of catastrophizing have been associated in FM and other conditions with higher pain sensitivity and stronger brain activations within pain processing areas, our knowledge of the brain mechanisms mediating the pain-amplifying effect of catastrophizing is still limited. By showing that lower pain-anticipatory lateral prefrontal activity mediates the hyperalgesic effect of catastrophizing, our study demonstrated that catastrophizing was associated with reduced engagement of the descending pain modulatory system, and more generally identified neural mechanisms underpinning the sensitizing effect of negative cognitive and emotional processes in chronic pain patients. Future studies will need to investigate whether our observations are specific to the effect of catastrophizing in FM, or are generalizable to other chronic pain conditions.

The vIPFC and alPFC (also known as the frontal pole or the rostral frontal cortex39) are key brain regions involved in emotion regulation and implementation of cognitive strategies that reduce negative emotional experience, such as reappraisal3, 27, 51. These regions, predominantly right lateralized, have been implicated in high-level pain-modulatory mechanisms that are recruited when the pain experience is altered by changing expectations, beliefs, and judgments about pain20, 30, 40, 47, 50, 51. VLPFC activation is observed during pain anticipation21, including visceral pain24, and subjects with greater anticipatory vIPFC activation report less pain in response to uncontrollable noxious stimuli40. Moreover, enhanced activity in right vIPFC predicts placebo-related symptom improvement in irritable bowel syndrome, which is mediated by attenuated activity of the dorsal anterior cingulate cortex during visceral stimulation20. Similarly, the activity of the alPFC was found to be more activated during self-controlled than externally-controlled pain stimulation, and to mediate the analgesic effect of perceived control over pain51. Given the role of the lateral prefrontal cortex in high-level pain-modulatory mechanisms, our findings suggest the possibility that catastrophizing induces hyperalgesia by disrupting the adaptive recruitment of vIPFC/alPFC-dependent pain-inhibitory processes, which normally attenuate the effects of incoming painful stimulation. Of note, altered vIPFC physiology in FM has also been reported using magnetic resonance spectroscopy, which demonstrated neurochemical alterations (i.e., increased glutamate/glutamine concentration) in this region9. Thus, our results provide further evidence implicating lateral prefrontal cortex in FM pathophysiology. However, in the absence of a comparison with well-powered groups of healthy volunteers and other pain patients, from our study it is impossible to assess whether the mediational role of LPFC on the hyperalgesic effect of catastrophizing is unique to FM. In particular, future work in this area may benefit from investigating other pain conditions that involve central sensitization-like processes. Additionally, future studies should further investigate the mechanisms underlying the inverse relationship between catastrophizing and PFC activity. For instance, it is possible that this phenomenon be due to a heightened tonic activation of this structure in high catastrophizers, a hypothesis that would be best tested with other imaging modalities, more sensitive to the detection of sustained activation, such as Arterial Spin Labeling48.

When interpreting our results, it is important to keep in mind that mediation analyses are not sufficient to demonstrate the presence of a directional effect. In order to provide further corroboration to our interpretation on the role of LPFC as mediating the hyperalgesic effects of catastrophizing, other designs will need to be adopted (for instance, by monitoring the effects of LPFC neuromodulation on the relation between PCS and pain sensitivity, or by evaluating the effects of cognitive behavioral therapy aimed at reducing catastrophizing). Another factor complicating the interpretation of our observation is that it is extremely difficult to assess whether patients with high catastrophizing expressed higher pain ratings because they were genuinely more sensitive to pain, or because they exhibited greater report bias. However, our previous study21 as well as others (e.g., 13) have shown that FM patients demonstrate very similar pain-related brain activations as healthy controls when expressing similar amount of pain, even despite large differences in nociceptive stimulus intensity. While not definitive, these observations support our contention that ratings expressed by FM subjects reflect their subjective pain experience, rather than report bias. Finally, it should be noted that the sample size of our dataset was relatively small for mediation analyses. Therefore, while our observations are compatible with the literature implicating the lateral prefrontal cortex in emotion regulation, reappraisal and pain modulation3, 20, 27, 30, 40, 47, 50, 51, they will need to be further corroborated in the context of larger N studies.

In sum, our results highlight the role of the lateral prefrontal cortex in shaping the impact of negative cognitive and emotional processes on the experience of pain in a clinical population. Such findings have implications for understanding the pathophysiology and optimal treatment of FM, and may help to identify the pathways by which pharmacological and non-pharmacological interventions, such as cognitive behavioral therapy, can reduce pain and hyperalgesia in patients with persistent widespread pain.

  • Fibromyalgia patients demonstrate altered pain anticipatory brain activity

  • Catastrophizing is negatively correlated with pain-anticipatory activation of IPFC

  • IPFC anticipatory activity mediates the hyperalgesic effects of catastrophizing

  • These findings implicate IPFC in pathophysiology of fibromyalgia

Acknowledgments

We thank Yumi Maeda, PhD (Research Fellow in Radiology at HMS, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA), for technical advice.

Disclosures: This research was supported by the following NIH grants (R01-AR064367, R01-AT004714, P01-AT002048, P01-AT006663, R01-AT005280; R01-AG034982, R21-AR057920, K23DA20681), and was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant numbers S10-RR021110, S10RR023401, and S10-RR023043. The funders had no role in this study.

Footnotes

The authors of the article declare that they have no competing financial interests.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Berna C, Leknes S, Holmes EA, Edwards RR, Goodwin GM, Tracey I. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness. Biol Psychiatry. 2010;67:1083–1090. doi: 10.1016/j.biopsych.2010.01.014. [DOI] [PubMed] [Google Scholar]
  • 2.Boly M, Balteau E, Schnakers C, Degueldre C, Moonen G, Luxen A, Phillips C, Peigneux P, Maquet P, Laureys S. Baseline brain activity fluctuations predict somatosensory perception in humans. Proc Natl Acad Sci U S A. 2007;104:12187–12192. doi: 10.1073/pnas.0611404104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H, Weber J, Ochsner KN. Cognitive Reappraisal of Emotion: A Meta-Analysis of Human Neuroimaging Studies. Cereb Cortex. 2014;24:2981–2990. doi: 10.1093/cercor/bht154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Clauw DJ, Arnold LM, McCarberg BH. The science of fibromyalgia. Mayo Clin Proc. 2011;86:907–911. doi: 10.4065/mcp.2011.0206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.D'Eon JL, Harris CA, Ellis JA. Testing factorial validity and gender invariance of the pain catastrophizing scale. J Behav Med. 2004;27:361–372. doi: 10.1023/b:jobm.0000042410.34535.64. [DOI] [PubMed] [Google Scholar]
  • 6.Edwards RR, Cahalan C, Mensing G, Smith M, Haythornthwaite JA. Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol. 2011;7:216–224. doi: 10.1038/nrrheum.2011.2. [DOI] [PubMed] [Google Scholar]
  • 7.Edwards RR, Mensing G, Cahalan C, Greenbaum S, Narang S, Belfer I, Schreiber KL, Campbell C, Wasan AD, Jamison RN. Alteration in pain modulation in women with persistent pain after lumpectomy: influence of catastrophizing. J Pain Symptom Manage. 2013;46:30–42. doi: 10.1016/j.jpainsymman.2012.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Edwards RR, Smith MT, Stonerock G, Haythornthwaite JA. Pain-related catastrophizing in healthy women is associated with greater temporal summation of and reduced habituation to thermal pain. Clin J Pain. 2006;22:730–737. doi: 10.1097/01.ajp.0000210914.72794.bc. [DOI] [PubMed] [Google Scholar]
  • 9.Feraco P, Bacci A, Pedrabissi F, Passamonti L, Zampogna G, Malavolta N, Leonardi M. Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3T MR spectroscopy study. AJNR. Am J Neuroradiol. 2011;32:1585–1590. doi: 10.3174/ajnr.A2550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Foerster BR, Petrou M, Edden RA, Sundgren PC, Schmidt-Wilcke T, Lowe SE, Harte SE, Clauw DJ, Harris RE. Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum. 2012;64:579–583. doi: 10.1002/art.33339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Glover GH, Li TQ, Ress D. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med. 2000;44:162–167. doi: 10.1002/1522-2594(200007)44:1<162::aid-mrm23>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  • 12.Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, Clauw DJ. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain : a journal of neurology. 2004;127:835–843. doi: 10.1093/brain/awh098. [DOI] [PubMed] [Google Scholar]
  • 13.Gracely RH, Petzke F, Wolf M, Clauw D. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343. doi: 10.1002/art.10225. [DOI] [PubMed] [Google Scholar]
  • 14.Granot M, Weissman-Fogel I, Crispel Y, Pud D, Granovsky Y, Sprecher E, Yarnitsky D. Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning stimulus painfulness, gender and personality variables matter? Pain. 2008;136:142–149. doi: 10.1016/j.pain.2007.06.029. [DOI] [PubMed] [Google Scholar]
  • 15.Greve DN, Fischl B. Accurate and robust brain image alignment using boundary-based registration. Neuroimage. 2009;48:63–72. doi: 10.1016/j.neuroimage.2009.06.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Hudson JI, Arnold LM, Keck PE, Jr, Auchenbach MB, Pope HG., Jr Family study of fibromyalgia and affective spectrum disorder. Biol Psychiatry. 2004;56:884–891. doi: 10.1016/j.biopsych.2004.08.009. [DOI] [PubMed] [Google Scholar]
  • 17.Jespersen A, Dreyer L, Kendall S, Graven-Nielsen T, Arendt-Nielsen L, Bliddal H, Danneskiold-Samsoe B. Computerized cuff pressure algometry: A new method to assess deep-tissue hypersensitivity in fibromyalgia. Pain. 2007;131:57–62. doi: 10.1016/j.pain.2006.12.012. [DOI] [PubMed] [Google Scholar]
  • 18.Kim J, Loggia ML, Edwards RR, Wasan AD, Gollub RL, Napadow V. Sustained deep-tissue pain alters functional brain connectivity. Pain. 2013;154:1343–1351. doi: 10.1016/j.pain.2013.04.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Lee SJ, Song HJ, Decety J, Seo J, Kim SH, Nam EJ, Kim SK, Han SW, Lee HJ, Do Y, Chang Y. Do patients with fibromyalgia show abnormal neural responses to the observation of pain in others? Neurosci Res. 2013 doi: 10.1016/j.neures.2013.01.013. [DOI] [PubMed] [Google Scholar]
  • 20.Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA. The neural correlates of placebo effects: a disruption account. Neuroimage. 2004;22:447–455. doi: 10.1016/j.neuroimage.2004.01.037. [DOI] [PubMed] [Google Scholar]
  • 21.Loggia ML, Berna C, Kim J, Cahalan CM, Gollub RL, Wasan AD, Harris RE, Edwards RR, Napadow V. Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis Rheumatol. 2014;66:203–212. doi: 10.1002/art.38191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Loggia ML, Edwards RR, Kim J, Vangel MG, Wasan AD, Gollub RL, Harris RE, Park K, Napadow V. Disentangling linear and nonlinear brain responses to evoked deep tissue pain. Pain. 2012;153:2140–2151. doi: 10.1016/j.pain.2012.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Loggia ML, Kim J, Gollub RL, Vangel MG, Kirsch I, Kong J, Wasan AD, Napadow V. Default mode network connectivity encodes clinical pain: an arterial spin labeling study. Pain. 2013;154:24–33. doi: 10.1016/j.pain.2012.07.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lu HC, Hsieh JC, Lu CL, Niddam DM, Wu YT, Yeh TC, Cheng CM, Chang FY, Lee SD. Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: a 3T-fMRI study. Pain. 2010;148:75–83. doi: 10.1016/j.pain.2009.10.012. [DOI] [PubMed] [Google Scholar]
  • 25.Morris LD, Grimmer-Somers KA, Louw QA, Sullivan MJ. Cross-cultural adaptation and validation of the South African Pain Catastrophizing Scale (SA-PCS) among patients with fibromyalgia. Health Qual Life Outcomes. 2012;10:137. doi: 10.1186/1477-7525-10-137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154:2310–2316. doi: 10.1016/j.pain.2013.06.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9:242–249. doi: 10.1016/j.tics.2005.03.010. [DOI] [PubMed] [Google Scholar]
  • 28.Osman A, Barrios FX, Gutierrez PM, Kopper BA, Merrifield T, Grittmann L. The Pain Catastrophizing Scale: further psychometric evaluation with adult samples. J Behav Med. 2000;23:351–365. doi: 10.1023/a:1005548801037. [DOI] [PubMed] [Google Scholar]
  • 29.Painter JT, Crofford LJ. Chronic opioid use in fibromyalgia syndrome: a clinical review. J Clin Rheumatol. 2013;19:72–77. doi: 10.1097/RHU.0b013e3182863447. [DOI] [PubMed] [Google Scholar]
  • 30.Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia--imaging a shared neuronal network. Science. 2002;295:1737–1740. doi: 10.1126/science.1067176. [DOI] [PubMed] [Google Scholar]
  • 31.Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Prestimulus functional connectivity determines pain perception in humans. Proc Natl Acad Sci U S A. 2010;107:355–360. doi: 10.1073/pnas.0906186106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Computer-controlled pneumatic pressure algometry--a new technique for quantitative sensory testing. Eur J Pain. 2001;5:267–277. doi: 10.1053/eujp.2001.0245. [DOI] [PubMed] [Google Scholar]
  • 33.Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Modality-specific facilitation and adaptation to painful tonic stimulation in humans. Eur J Pain. 2002;6:475–484. doi: 10.1016/s1090-3801(02)00058-7. [DOI] [PubMed] [Google Scholar]
  • 34.Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Pressure-pain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry. J Pain. 2002;3:28–37. doi: 10.1054/jpai.2002.27140. [DOI] [PubMed] [Google Scholar]
  • 35.Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Spatial and temporal aspects of deep tissue pain assessed by cuff algometry. Pain. 2002;100:19–26. doi: 10.1016/s0304-3959(02)00162-8. [DOI] [PubMed] [Google Scholar]
  • 36.Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behavior research methods. 2008;40:879–891. doi: 10.3758/brm.40.3.879. [DOI] [PubMed] [Google Scholar]
  • 37.Quartana PJ, Campbell CM, Edwards RR. Pain catastrophizing: a critical review. Expert review of neurotherapeutics. 2009;9:745–758. doi: 10.1586/ERN.09.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Rainville P, Feine JS, Bushneil MC, Duncan GH. A psychophysical comparison of sensory and affective responses to four modalities of experimental pain. Somatosens Mot Res. 1992;9:265–277. doi: 10.3109/08990229209144776. [DOI] [PubMed] [Google Scholar]
  • 39.Ramnani N, Owen AM. Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nat Rev Neurosci. 2004;5:184–194. doi: 10.1038/nrn1343. [DOI] [PubMed] [Google Scholar]
  • 40.Salomons TV, Johnstone T, Backonja MM, Shackman AJ, Davidson RJ. Individual differences in the effects of perceived controllability on pain perception: critical role of the prefrontal cortex. J Cogn Neurosci. 2007;19:993–1003. doi: 10.1162/jocn.2007.19.6.993. [DOI] [PubMed] [Google Scholar]
  • 41.Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol. 2011;7:518–527. doi: 10.1038/nrrheum.2011.98. [DOI] [PubMed] [Google Scholar]
  • 42.Seminowicz DA, Davis KD. Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain. 2006;120:297–306. doi: 10.1016/j.pain.2005.11.008. [DOI] [PubMed] [Google Scholar]
  • 43.Sullivan MJ, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and Validation. Psychol Assess. 1995;7:524–532. [Google Scholar]
  • 44.Thieme K, Rose U, Pinkpank T, Spies C, Turk DC, Flor H. Psychophysiological responses in patients with fibromyalgia syndrome. J Psychosom Res. 2006;61:671–679. doi: 10.1016/j.jpsychores.2006.07.004. [DOI] [PubMed] [Google Scholar]
  • 45.Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C. Small fibre pathology in patients with fibromyalgia syndrome. Brain : a journal of neurology. 2013;136:1857–1867. doi: 10.1093/brain/awt053. [DOI] [PubMed] [Google Scholar]
  • 46.van Wijk G, Veldhuijzen DS. Perspective on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes. J Pain. 2010;11:408–419. doi: 10.1016/j.jpain.2009.10.009. [DOI] [PubMed] [Google Scholar]
  • 47.Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain. Science. 2004;303:1162–1167. doi: 10.1126/science.1093065. [DOI] [PubMed] [Google Scholar]
  • 48.Wasan AD, Loggia ML, Chen LQ, Napadow V, Kong J, Gollub RL. Neural correlates of chronic low back pain measured by arterial spin labeling. Anesthesiology. 2011;115:364–374. doi: 10.1097/ALN.0b013e318220e880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Weissman-Fogel I, Sprecher E, Pud D. Effects of catastrophizing on pain perception and pain modulation. Exp Brain Res. 2008;186:79–85. doi: 10.1007/s00221-007-1206-7. [DOI] [PubMed] [Google Scholar]
  • 50.Wiech K, Farias M, Kahane G, Shackel N, Tiede W, Tracey I. An fMRI study measuring analgesia enhanced by religion as a belief system. Pain. 2008;139:467–476. doi: 10.1016/j.pain.2008.07.030. [DOI] [PubMed] [Google Scholar]
  • 51.Wiech K, Kalisch R, Weiskopf N, Pleger B, Stephan KE, Dolan RJ. Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006;26:11501–11509. doi: 10.1523/JNEUROSCI.2568-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62:600–610. doi: 10.1002/acr.20140. [DOI] [PubMed] [Google Scholar]
  • 53.Wood PB, Patterson JC, 2nd, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain. 2007;8:51–58. doi: 10.1016/j.jpain.2006.05.014. [DOI] [PubMed] [Google Scholar]
  • 54.Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushneil MC, Chizh BA. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007;25:3576–3582. doi: 10.1111/j.1460-9568.2007.05623.x. [DOI] [PubMed] [Google Scholar]

RESOURCES