Anxiety and depressive symptoms in fibromyalgia are related to poor perception of health but not to pain sensitivity or cerebral processing of pain.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 62, No. 11, November 2010, pp 3488–3495 DOI 10.1002/art.27649 © 2010, American College of Rheumatology Anxiety and Depressive Symptoms in Fibromyalgia Are Related to Poor Perception of Health but Not to Pain Sensitivity or Cerebral Processing of Pain Karin B. Jensen,1 Frank Petzke,2 Serena Carville,3 Peter Fransson,1 Hanke Marcus,2 Steven C. R. Williams,4 Ernest Choy,3 Yves Mainguy,5 Richard Gracely,6 Martin Ingvar,1 and Eva Kosek1 Objective. Mood disturbance is common among patients with fibromyalgia (FM), but the influence of psychological symptoms on pain processing in this disorder is unknown. We undertook the present study to investigate the differential effect of depressive symptoms, anxiety, and catastrophizing on 1) pain symptoms and subjective ratings of general health status and 2) sensitivity to pain and cerebral processing of pressure pain. Methods. Eighty-three women (mean ⴞ SD age 43.8 ⴞ 8.1 years) who fulfilled the American College of Rheumatology 1990 criteria for the classification of FM participated in the study. Patients rated pain intensity (100-mm visual analog scale [VAS]), severity of FM (Fibromyalgia Impact Questionnaire), general health status (Short Form 36), depressive symptoms (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and catastrophizing (Coping Strategies Questionnaire). Experimental pain in the thumb was induced using a computer-controlled pressure stimulator. Event-related functional magnetic resonance imaging was performed during administration of painful stimuli representing 50 mm on a pain VAS, as well as nonpainful pressures. Results. A correlation analysis including all selfratings showed that depressive symptoms, anxiety, and catastrophizing scores were correlated with one another (P < 0.001), but did not correlate with ratings of clinical pain or with sensitivity to pressure pain. However, the subjective rating of general health was correlated with depressive symptoms and anxiety (P < 0.001). Analyses of imaging results using self-rated psychological measures as covariates showed that brain activity during experimental pain was not modulated by depressive symptoms, anxiety, or catastrophizing. Conclusion. Negative mood in FM patients can lead to a poor perception of one’s physical health (and vice versa) but does not influence performance on assessments of clinical and experimental pain. Our data provide evidence that 2 partially segregated mechanisms are involved in the neural processing of experimental pain and negative affect. This study was performed in collaboration with Pierre Fabre Médicament, Labège, France. The results in this study are derived in part from a placebo-controlled drug intervention study (EudraCT #2004-004249-16) financed by Pierre Fabre Médicament. 1 Karin B. Jensen, PhD (current address: Massachusetts General Hospital and Harvard Medical School, Boston), Peter Fransson, PhD, Martin Ingvar, MD, PhD, Eva Kosek, MD, PhD: Stockholm Brain Institute, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden; 2Frank Petzke, MD, Hanke Marcus, MD: Department of Anesthesiology and Postoperative Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; 3Serena Carville, PhD, Ernest Choy, MD, FRCP: King’s Musculoskeletal Clinical Trials Unit, Academic Department of Rheumatology, King’s College London, London, UK; 4Steven C. R. Williams, PhD: Centre for Neuroimaging Science, Institute of Psychiatry, King’s College London, London, UK; 5Yves Mainguy, MD, PhD: Pierre Fabre Médicament, Labège, France; 6Richard Gracely, PhD: Center for Neurosensory Disorders, University of North Carolina, Chapel Hill. Dr. Petzke has received speaking fees from Pierre Fabre Médicament (less than $10,000) and has provided expert testimony on behalf of Pierre Fabre Médicament. Dr. Choy has received consulting fees, speaking fees, and/or honoraria from Pierre Fabre Médicament (more than $10,000). Dr. Gracely has received consulting fees, speaking fees, and/or honoraria from Pierre Fabre Médicament (more than $10,000). Address correspondence and reprint requests to Karin B. Jensen, PhD, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129. E-mail: email@example.com. Submitted for publication November 17, 2009; accepted in revised form July 1, 2010. Pain represents an emotional construct (1,2), and the neural processing of pain can be altered with changes in emotional status (3–6). Mood disorders are 3488 MOOD DISTURBANCE AND PAIN IN FM common among individuals with chronic pain (7), but the causality is unknown. One study using functional magnetic resonance imaging (MRI) has shown that the experience of sustained low back pain was associated with a selective activation of a prefrontal brain circuitry, an area that has been implicated in the cognitive and motivational-affective aspects of pain (8). In another functional MRI study, Schweinhardt et al (9) observed depression-related activity in the medial prefrontal cortex of patients with rheumatoid arthritis (RA) during provocation of clinical pain, but not during experimental pain. These results provide evidence of a complex interaction between brain processes underlying the specific circuitry of chronic pain and that of negative mood. In the present study, we addressed this clinically important interaction by investigating the effect of depressive symptoms, anxiety, and catastrophizing on pain processing in patients with fibromyalgia (FM). FM is a chronic pain syndrome characterized by widespread pain, disturbed sleep, fatigue, and tenderness (10). Early reports of a generalized increase in pain sensitivity (11) and lack of endogenous pain inhibition in FM patients (12,13) have now gained support from studies using functional MRI. Results include findings of augmented neural signaling in response to pain stimulation (14), reduced ability to activate brain areas involved in endogenous pain modulation (15), and other central nervous system abnormalities (16). The effect of psychological symptoms in FM is still an area of debate. There is a high frequency of comorbidity with major depressive disorder (17), and FM is still regarded by some as “occupying the grey area between medicine and psychiatry” (18). Two studies investigated the effect of mood on pain processing in FM, one focusing on depressive symptoms (19) and the other on catastrophizing thoughts (20). Depressive symptoms had no influence on the intensity of clinical pain or the sensory-discriminative processing of induced pressure pain. However, with increasing depressive symptoms, activity in 2 brain regions pertaining to emotional processing, i.e., the insula and the amygdala, increased during sustained pain provocation (19). Pain catastrophizing (20), independent of depressive symptoms, was associated with increased activity in many different brain areas, including the anterior cingulate cortex, cerebellum, secondary sensory cortex, and frontal gyrus (none of these regions overlapping with the brain regions found by Giesecke et al ). It is possible that negative affect has a selective impact on cognitive functions such as attention (21) and anticipation (22) but not on the processing of pain per 3489 se. In 2 previous functional MRI studies (21,22) the pressure pain stimulations were administered in blocks, making the pain predictable and introducing confounding due to the possible impact of negative affect on attention and anticipation of pain. The use of an unpredictable stimulation paradigm is thus preferable when investigating the influence of negative affect on pain processing. In a previous study, we were able to demonstrate a specific dysfunction in pain regulation among patients with FM, using functional MRI during randomly presented pain stimuli (15). In that study, FM patients were compared with healthy controls, and a possible difference in pain processing related to the presence of negative affect was not investigated. Using the same experimental paradigm, the present study addressed the differential effect of depressive symptoms, anxiety, and catastrophizing on cerebral processing of pain in a large number of FM patients (n ⫽ 83). Secondary aims were to assess the influence of depressive symptoms, anxiety, and catastrophizing on clinical pain, sensitivity to pressure pain, ratings of general health, and impact of FM symptoms. PATIENTS AND METHODS Patients were recruited as part of a pharmacologic multicenter study conducted at 3 sites in Europe: London, Stockholm, and Cologne (EudraCT #2004-004249-16). The present study was performed using data from the baseline measurements in that study, before patients were randomized and treatment initiated. All patients were female and were right-handed, and all had been recruited from primary care settings and had been diagnosed as having FM according to the 1990 American College of Rheumatology criteria (23). The patients ranged in age from 18 to 55 years. Criteria for enrollment included a self-reported average pain intensity of at least 40 mm on a 100-mm visual analog scale (VAS) over the last week, as well as discontinuation of all treatments that could influence the patient’s pain perception (i.e., antidepressants and mood stabilizers, analgesics, strong opioids, anticonvulsants, centrally acting relaxants, joint injections, trigger/ tender point injections, biofeedback, and transcutaneous electrical nerve stimulation). Patients with severe psychiatric illness or with significant risk of suicide were excluded from the study, as were patients with a history of substance, drug, or alcohol abuse. Qualified investigators (mainly rheumatologists) used the Beck Depression Inventory (BDI) (24) in combination with a clinical interview to ensure that patients were not severely depressed. This was done to ensure the safety of the patients during the clinical trial. Additional exclusion criteria included risk of significant cardiovascular/pulmonary disease (including electrocardiographic abnormalities and hypertension), liver disease, renal impairment, autoimmune disease, current systemic infection, malignancy, sleep apnea, active peptic ulcer, unsta- 3490 Figure 1. Cross-sectional representation of the pneumatic pain stimulator. The thumb is inserted from the left side and rests on the wedge. The thumbnail is positioned straight under the piston. ble endocrine disease, pregnancy or breastfeeding, participation in a pharmacologic trial during the prior 3 months, and unwillingness to discontinue prohibited medications. The reasons men were not included in the study were the possibility of different pathogenetic presentations in men and women and the male:female prevalence ratio of 1:9 in FM (25). Similar prevalence ratios have also been observed in related syndromes, such as chronic fatigue syndrome and headaches (26), but the mechanisms underlying these sex differences are still poorly understood. A total of 157 FM patients were screened, of whom 92 (mean ⫾ SD age 44 ⫾ 8.2 years [range 24–55 years]) fulfilled the inclusion criteria and were enrolled in the study. Nine of the 92 patients were excluded from functional MRI analyses due to image artifacts or incidental findings of intracranial anomalies, leaving 83 patients for the functional MRI analysis. Image artifacts included extensive head movement during scans or metal in the mouth causing image distortions. All reported analyses are based on the 83 patients (mean ⫾ SD age 43.8 ⫾ 8.1 years) with intact data from both the behavioral and the neuroimaging experiments. Pressure pain thresholds were assessed using a pressure algometer (Somedic). An algometer is a handheld apparatus with a 1-cm2 hard rubber probe that is held at a 90° angle against the body and then pressed with a steady rate of pressure increase (30 kPa/second) in order to induce pain. Pressure pain thresholds were assessed bilaterally at 4 different sites, i.e., trapezius muscle, elbows (lateral epicondyle), quadriceps femoris muscle, and knees (medial fat pad proximal to the joint line), with one assessment per anatomic site. The total average pressure pain threshold was calculated for each patient and used for further analysis. For the purpose of calibration and induction of pain during functional MRI, a custom-made tool was used to inflict pain to the thumbnail (27). The stimulations were performed using an automated, pneumatic, computer-controlled stimulator with a plastic piston that applies pressure via a 1-cm2 hard JENSEN ET AL rubber probe. The thumb is inserted into a cylindrical opening and positioned such that the probe applies pressure to the nailbed (Figure 1). Pressure pain was chosen as the stimulation modality, because it elicits a deep pain sensation that is clinically valid and represents a diagnostic criterion for FM. The thumb is not a commonly reported tender point, which makes it a suitable neutral target for stimulation. Images were collected using 3 different 1.5T scanners, programmed with identical scanning parameters. Multiple T2*-weighted single-shot gradient-echo echo planar imaging (EPI) sequences were used to acquire blood oxygen level– dependent contrast images. The following parameters were used: repetition time 3,000 msec (35 slices acquired), echo time 40 msec, flip angle 90°, field of view 24 ⫻ 24 cm, matrix 64 ⫻ 64, slice thickness 4 mm, slice gap 0.4 mm, sequential image acquisition order, and voxel size 2 ⫻ 2 ⫻ 4 mm. In the scanner, cushions and headphones were used to reduce head movement and dampen scanner noise. Visual distraction during scans was minimized by placing a blank screen in front of the patient’s field of view. High-resolution T1-weighted structural images were acquired in coronal orientation for anatomic reference purposes and screening for cerebral anomalies. Parameters were as follows: spoiled gradient-recalled 3-dimensional sequence, repetition time 24 msec, echo time 6 msec, flip angle 35°, 124 contiguous 1.5-mm coronal slices (image resolution 256 ⫻ 256 ⫻ 186 mm, voxel size 0.9 ⫻ 0.9 ⫻ 1.5 mm). The scanning procedure was standardized between sites by using written manuscripts for all oral instructions and providing practical training for all investigators involved in the study. A central coordinator made several visits to the 3 sites to ensure calibration of experimental procedures. Functional data were collected in pilot patients in order to assure similar results between sites. Full-factorial analysis of variance (ANOVA) including the 3 sites as well as the experimental conditions, probing for any possible difference in brain activation for any of the conditions at any of the sites, was performed using SPM5 software. Data on the median, SD, and 95% confidence interval for the signal intensity at each site are available from the corresponding author upon request. The BDI was used to quantitatively assess depressive symptoms. The BDI is a 21-item measure of the severity of depressive symptoms, and it has been extensively validated for use with both medical and mental health populations (24). Scoring allows for the identification of mild, moderate, and severe levels of depressive symptoms. The BDI does not provide information about possible specific major depressive disorders according to the Diagnostic and Statistical Manual of Psychiatric Disorders (28); rather, it gives a quantified measure of the degree of depressive symptoms. A high score on the BDI corresponds to a high level of depressive symptoms. The State-Trait Anxiety Inventory (STAI) was used to assess the participants’ levels of state anxiety. STAI is a self-report questionnaire with 2 independent 20-item scales for measuring state-related or trait-related anxiety (29). A high score on the STAI corresponds to a high level of anxiety symptoms. The Coping Strategies Questionnaire (CSQ) was used to assess levels of catastrophizing thoughts about pain, a parameter commonly described in studies of chronic pain. The CSQ is a self-reported measure of cognitive and behavioral MOOD DISTURBANCE AND PAIN IN FM responses utilized to cope with chronic pain, and patients are asked to rate the frequency with which they use each strategy on a 7-point scale (30). A high score on the CSQ corresponds to a high level of catastrophizing. The Short Form 36 (SF-36) is a well-established questionnaire measuring 8 domains of health status: physical functioning, role limitations because of physical problems, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations due to emotional problems, and mental health (31). A low general health score on the SF-36 corresponds to a poor rating of one’s health. The Fibromyalgia Impact Questionnaire (FIQ) is a 20-item questionnaire that assesses the overall symptom severity in patients with FM (32). A high score on the FIQ corresponds to a perceived high severity of FM. The day before scanning, patients rated their pain using a VAS ranging from 0 mm to 100 mm. Patients were asked to score their current pain and their average pain during the last week. For each patient, subjective pain ratings were calibrated by application of one ascending series of pressure stimuli to the thumbnail and one randomized series, using the automated thumb pressure device. Pressures with a duration of 2.5 seconds were delivered at 30-second intervals. Patients were instructed to rate the intensity of the pain evoked by each stimulus, by placing a mark on a 100-mm horizontal VAS ranging from “no pain” to “worst imaginable pain.” During the ascending series, the pressure stimuli were presented in steps of 50 kPa of increased pressure. Data from the ascending series were used to determine each patients’ pain threshold (first VAS score of ⬎0 mm) and stimulation maximum (first rating of ⬎60 mm). These values were then used to compute the magnitude of 5 different pressure intensities within the range of each patients’ threshold and maximum. A total of 15 stimuli, 3 of each intensity, were delivered in a randomized order at 30-second intervals, preventing the patients from being able to anticipate the intensity of the next stimulus. A polynomial regressed function was used to determine each individual’s calibrated pain rating of 50 mm on the VAS, derived from the 15 ratings from the randomized series. Patients returned for scanning the day after the procedure for calibrating pain rating. Two types of stimulation were used during scans: pain that would be rated 50 mm on a VAS based on the previously obtained calibration and a nonpainful pressure perceived only as light touch. All stimulations were randomly applied over the scanning time, preventing patients from anticipating the onset time and event type. The time interval between consecutive events was randomized, with a mean stimulus onset asynchronicity of 15 seconds (range 10–20). Four different random sequences were created. Each patient received all 4 sequences, but the order of the sequences was randomized for each. The total duration of the scans was ⬃35 minutes. Before scanning, patients were instructed to focus on the pressures on the thumb and to use no distraction or coping techniques. Behavioral data and self-ratings were analyzed using Spearman’s rank correlation coefficient with SPSS version 16.0. P values less than 0.001, with Bonferroni correction for multiple comparisons, were considered significant. Imaging data were analyzed using Matlab 7.1 (MathWorks) and SPM5. All functional brain volumes were re- 3491 aligned to the first volume, spatially normalized to a standard EPI template, and finally smoothed using an 8-mm full-width at half-maximum isotropic Gaussian kernel (33). Data were also subjected to high-pass filtering (cutoff period 128 seconds) and correction for temporal autocorrelations. Data analysis was performed using a generalized linear model and modeling of the 2 different conditions (calibrated pain of 50 mm on a VAS and nonpainful pressure) as delta functions convolved with a canonical hemodynamic response function (HRF). A file containing the movement parameters for each individual (6 directions) was obtained from the realignment step and saved for inclusion in the model. A design matrix prepared for each patient included regressors for the 2 conditions (calibrated pain and no pain). Regression coefficients for both regressors were estimated using least squares within SPM5. Specific effects were tested with appropriate linear contrasts of the parameter estimates for the HRF regressor of both conditions, resulting in a t-statistic for each voxel. Data were analyzed for each patient individually (first-level analysis) and for the group (second-level analysis). To assess painspecific cerebral activity and to control for individual differences in cerebral responsiveness, brain activation during nonpainful pressures was individually subtracted from activity during calibrated pain. ANOVA was performed in order to determine whether there was any difference in pain-evoked brain activity that could be explained by a study site–related factor. The effect of depressive symptoms, anxiety, or catastrophizing on brain activity during pain processing was measured by performing 3 individual regression analyses using each patient’s depression, anxiety, or catastrophizing scores as a covariate. In addition to the regression analysis, which is a sensitive measure for the full range of depressive scores, 2-sample t-tests were performed to compare brain activity between the 20 highest-scoring and the 20 lowest-scoring subjects for depression, anxiety, and catastrophizing scores. RESULTS The mean ⫾ SD score on the BDI was 18 ⫾ 10 (range 0–47). Twelve patients had BDI scores of ⬎29 (indicating severe depressive symptoms), 23 patients scored between 19 and 29 (indicating moderate to severe depressive symptoms), 30 patients scored between 10 and 18 (indicating mild to moderate depressive symptoms), and 18 patients scored between 0 and 9 (normal range). Mean ⫾ SD scores for the various psychological measures and pain assessments are shown in Table 1. Correlation analysis (Spearman’s rho) including all self-ratings (n ⫽ 83) demonstrated that depressive symptoms, anxiety, and catastrophizing scores were significantly correlated with one another ( ⫽ 0.8 for depression and anxiety, 0.5 for depression and catastrophizing, and 0.5 for anxiety and catastrophizing; P ⬍ 0.001), but did not correlate with any measure of pain sensitivity (weekly pain, sensitivity to pressure pain thresholds, and calibrated pain). However, the subjec- 3492 JENSEN ET AL Table 1. Mean ⫾ SD values for all variables investigated in the 83 patients with FM* Duration of FM, months† BDI score STAI-T score CSQ score Average pain in a week, 100-mm VAS Thumb pressure, kPa‡ Algometer pressure, kPa§ FIQ score SF-36 general health score 136 ⫾ 94 18 ⫾ 10 48 ⫾ 11 15 ⫾ 8 65 ⫾ 15 401 ⫾ 165 160 ⫾ 107 65 ⫾ 15 38 ⫾ 19 * BDI ⫽ Beck Depression Inventory; STAI-T ⫽ trait anxiety on the State-Trait Anxiety Inventory; CSQ ⫽ Coping Strategies Questionnaire; FIQ ⫽ Fibromyalgia Impact Questionnaire; SF-36 ⫽ Short Form 36. † From the time the patient first subjectively reported fibromyalgia (FM) symptoms. ‡ Pressure needed to evoke calibrated pain scored at 50 mm on a 100-mm visual analog scale (VAS). § Average pain threshold from locations all over the body. tive measure of general health (SF-36) was inversely correlated with ratings of depressive symptoms ( ⫽ ⫺0.36, P ⬍ 0.001) (Figure 2) as well as anxiety ( ⫽ ⫺0.40, P ⬍ 0.001), but not with any measure of pain sensitivity. The subjective rating of FM symptom severity (FIQ) correlated both with psychological measures and with ratings of pain (for depressive symptoms, ⫽ 0.49, P ⬍ 0.001; for anxiety, ⫽ 0.51, P ⬍ 0.001; for weekly pain, ⫽ 0.43, P ⬍ 0.001; for pressure pain thresholds, ⫽ 0.34, P ⬍ 0.01; for self-rated general health, ⫽ ⫺0.54, P ⬍ 0.001). The variables time since onset of FM symptoms and calibrated pain did not Figure 2. Scatterplot of the fibromyalgia patients’ scores for depressive symptoms (measured using the Beck Depression Inventory [BDI]) and subjective ratings of physical health (measured using the Short Form 36 [SF-36]). A significant inverse correlation was found ( ⫽ ⫺0.36, P ⬍ 0.001). Figure 3. Main effect of brain activity evoked by painful stimulation minus that evoked by nonpainful sensory stimulation in the 83 patients with fibromyalgia. The sections shown represent the anterior cingulate cortex, thalamus, cerebellum, insula, and S1. Coordinates correspond to the anatomic space as defined in the Montreal Neurological Institute Standard Brain Atlas (36). correlate with any other variables in the correlation matrix. To validate the pain provocation paradigm, we calculated the main effect of brain activity occurring during calibrated pain minus that occurring during nonpainful pressure in the 83 FM patients, using a 1-sample t-test. The results showed significant increases in painrelated structures such as S1, S2, the anterior cingulate cortex, bilateral insulae, periaqueductal gray matter, amygdalae, thalamus, and cerebellum (Figure 3 and Table 2), thus reproducing the pain matrix previously described in the literature (34,35). ANOVA, performed with SPM5, revealed no site-specific variation in pain-evoked brain activity among the 3 study sites (Stockholm, London, Cologne). In order to further investigate for possible variance among study sites, the signal intensity in S2 (⫺42, ⫺20, 20 in the Montreal Neurological Institute Standard Brain Atlas ) was ascertained for each patient. Values for pain-evoked brain intensity in S2 were compared statistically, by ANOVA using SPSS, among the 3 study sites, and no significant difference between sites was revealed (F[2,81] ⫽ 0.69, P ⫽ 0.51). The 3 regression analyses in which depressive symptoms, anxiety, or catastrophizing scores were used as covariates showed no significant results, i.e., brain activity during pain was not modulated by different MOOD DISTURBANCE AND PAIN IN FM 3493 Table 2. Representation of brain activity during painful stimulation minus brain activity during nonpainful sensory stimulation, in the 83 patients with FM* Brain region Laterality X Y Z Peak T score PAG Amygdala S1 S2 ACC Left posterior insula Right posterior insula Cerebellum Mid-insula Thalamus Bilateral Bilateral Contralateral Contralateral Bilateral Bilateral 10 ⫺24 ⫺28 ⫺40 2 ⫺54 ⫺24 0 ⫺24 ⫺18 20 0 ⫺12 ⫺8 70 16 32 0 5.31 6.56 7.41 6.92 6.88 8.14 56 ⫺16 8 6.82 26 38 10 ⫺56 6 ⫺4 ⫺24 2 2 10.08 7.24 6.44 Bilateral ⫺ ⫺ ⫺ * Coordinates (X, Y, and Z) correspond to the anatomic space as defined in the Montreal Neurological Institute Standard Brain Atlas (36). Laterality in relation to the painful stimuli on the right thumb is shown where applicable. FM ⫽ fibromyalgia; PAG ⫽ periaqueductal gray matter; ACC ⫽ anterior cingulate cortex. levels of depressive symptoms, anxiety, or catastrophizing. In analyses using SPM5, there was no significant finding for any brain region, and there were no significant clusters, Z values, or P values to report (threshold was set at P ⬍ 0.001, uncorrected for multiple comparisons). Further post hoc analyses of the data included t-tests, which revealed no significant differences in brain activity during pain provocation among the 20 patients with the highest depression scores versus the 20 with the lowest depression scores (threshold set at P ⬍ 0.001, uncorrected for multiple comparisons). When the 20 patients with the highest scores on the BDI, STAI, and CSQ combined (range 100–143) were compared with the 20 patients with the lowest scores on these 3 tests combined (range 31–59), there was also no significant difference in brain activity. DISCUSSION We found no relationship between negative mood and cerebral processing of pain among patients with FM. We also found that patients’ reports of clinical and experimentally induced pain were not affected by levels of depressive symptoms, anxiety, or catastrophizing. These findings add to evidence from earlier studies that 2 different, partially segregated neural mechanisms are involved with pain processing and negative affect in FM patients. The pressure pain stimulation paradigm used in this study produced an adequate response of the pain matrix (37), i.e., all expected brain regions involved in pain processing were activated. Several regions of the brain have been associated with depression and anxiety, including altered function of the prefrontal cortex and limbic structures (38). In order to create a situation that closely corresponded to the emotional stress associated with uncontrollable clinical pain, the paradigm used in this study was a randomized design that precluded prediction of the pain stimuli. Despite the large variations in depressive symptoms and anxiety, we found no brain regions with significant covariation with depressive symptoms, anxiety, or catastrophizing during pain. Giesecke et al (19) found increased neuronal activity in the bilateral amygdalae and contralateral anterior insula in association with depressive symptoms, indicating more involvement of emotional processing in response to the pain stimulation in depressed patients. The paradigm they used was a block design with inherent predictability of the pain stimuli. It is possible that with this paradigm, nondepressed patients were not challenged enough, since they could have coped better with the situation by steeling themselves prior to pain block, therefore not activating the emotional structures as much as occurred in the depressed patients. Thus, previously reported results could be due to a difference in pain anticipation and do not necessarily provide any information about pain processing per se. This possible effect was controlled for in the present design. Moreover, Gracely et al (20) found an association between high levels of catastrophizing and increased brain activity in regions involved in attention to pain and anticipation of pain. That finding was not reproduced in the present study. However, the high and low catastrophizing patients in Gracely and colleagues’ study differed in levels of clinical pain as well as sensory and affective measures. Therefore, we conclude that mood does not affect the perception or processing of experimentally induced nociceptive stimuli in FM patients when anticipation and differences in behavioral measures are controlled for. An alternative explanation for the differences between previous and current findings is that the duration of the painful stimuli in the present study was only 2.5 seconds, compared with blocks of 25 seconds. Even if the blocks were highly predictable in earlier studies, they could have been more distressing and thereby more sensitive to emotional activation. In a study of patients with RA (9), no relationship was found between depressive symptoms and cerebral pain processing in RA patients during experimental pain (heat). However, there was a positive correlation be- 3494 tween ratings of depressive symptoms and activation of the medial prefrontal cortex during provoked joint pain in RA patients. We might have observed a similar effect in the present study had we used pressure to a tender point instead of the thumbnail. Furthermore, RA patients do not differ from healthy controls in heat pain sensitivity (39), whereas FM patients have been shown to be more sensitive to pressure also at the thumbnail (27). Increased cerebral processing of pain (14), disinhibition (15), and normalization after successful treatment (40) have repeatedly been demonstrated using thumb pressure in patients with FM, demonstrating aberrations in central pain processing in this disorder. The current results show that these aberrations exist independent of psychological factors such as depressive symptoms, anxiety, and catastrophizing. The generalized, multimodal increase in pain sensitivity and widespread pain that are characteristic of FM make it difficult to clearly distinguish between experimental and “clinical” pain stimulation. This is a limitation to our study design that hinders clear interpretation of our data. Another major difference between the present study and the RA study is the pronounced difference in depressive symptoms. In our study, depressive symptoms were severe in 12 patients, moderate to severe in 23, mild to moderate in 30, and low (normal) in 18. In the RA study, there was no representation of severe depressive symptoms at all, and only 3 patients had scores that indicated moderate to severe depression. It has been speculated that emotional response is generally exaggerated in FM patients, suggesting that the disorder is caused by psychological vulnerability (41). However, the effects of antidepressants on pain seem to be independent of mood, since the antidepressant and analgesic effects are independent of each other in clinical trials (42,43). Also, recent studies have provided evidence that affective modulation is not increased in FM patients (44,45). We have previously demonstrated that FM patients do exhibit augmented pain sensitivity in response to pain provocation compared with controls, but there was no difference in the brain regions relating to the affective aspect of pain (15). The only difference in pain processing between FM patients and controls was seen in a specific region of the frontal lobe that is highly involved in descending inhibition of pain (the rostral anterior cingulate cortex) (15). In the present study, scores for depressive symptoms, anxiety, and catastrophizing did not correlate with any measure of pain sensitivity. Therefore, our results do not support the notion that there is pronounced affective pain modulation in FM. Rather, the significant correla- JENSEN ET AL tion between depression, anxiety, and the subjective rating of one’s health (general health score on the SF-36 and FIQ) suggests that negative mood affects the perception of one’s health status. Negative mood in FM patients could thus lead to a poor perception of physical health but not to poor performance on clinical and experimental pain assessments. Furthermore, the duration of disease did not correlate with any other measurement, indicating that symptoms in FM are relatively stable over time, and that there is no linear relationship between FM duration and development of depression and anxiety. In conclusion, among patients with FM, depression, anxiety, and catastrophizing did not correlate with ratings of clinical experimental pain and did not modulate brain activity during experimental pain. Our data therefore provide evidence that there are 2 different, partially segregated neural mechanisms involved in pain processing and negative affect in FM. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Jensen had 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. 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