Anxiety and Depressive Symptoms in Fibromyalgia Are Related to Poor Perception of Health but Not to Pain Sensitivity or Cerebral Processing of Pain

Anxiety and Depressive Symptoms in Fibromyalgia Are Related to Poor Perception of Health but Not to Pain Sensitivity or Cerebral Processing of Pain
                                                                                                       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                              Rheumatology 1990 criteria for the classification of FM
patients with fibromyalgia (FM), but the influence of                           participated in the study. Patients rated pain intensity
psychological symptoms on pain processing in this                               (100-mm visual analog scale [VAS]), severity of FM
disorder is unknown. We undertook the present study to                          (Fibromyalgia Impact Questionnaire), general health
investigate the differential effect of depressive symp-                         status (Short Form 36), depressive symptoms (Beck
toms, anxiety, and catastrophizing on 1) pain symptoms                          Depression Inventory), anxiety (State-Trait Anxiety In-
and subjective ratings of general health status and 2)                          ventory), and catastrophizing (Coping Strategies Ques-
sensitivity to pain and cerebral processing of pressure                         tionnaire). Experimental pain in the thumb was in-
pain.                                                                           duced using a computer-controlled pressure stimulator.
       Methods. Eighty-three women (mean ⴞ SD age                               Event-related functional magnetic resonance imaging
43.8 ⴞ 8.1 years) who fulfilled the American College of                         was performed during administration of painful stimuli
                                                                                representing 50 mm on a pain VAS, as well as nonpain-
          This study was performed in collaboration with Pierre Fabre           ful pressures.
Médicament, Labège, France. The results in this study are derived in                 Results. A correlation analysis including all self-
part from a placebo-controlled drug intervention study (EudraCT
#2004-004249-16) financed by Pierre Fabre Médicament.                          ratings showed that depressive symptoms, anxiety, and
            Karin B. Jensen, PhD (current address: Massachusetts Gen-           catastrophizing scores were correlated with one another
eral Hospital and Harvard Medical School, Boston), Peter Fransson,
PhD, Martin Ingvar, MD, PhD, Eva Kosek, MD, PhD: Stockholm
                                                                                (P < 0.001), but did not correlate with ratings of clinical
Brain Institute, Osher Center for Integrative Medicine, Karolinska              pain or with sensitivity to pressure pain. However, the
Institutet, Stockholm, Sweden; 2Frank Petzke, MD, Hanke Marcus,                 subjective rating of general health was correlated with
MD: Department of Anesthesiology and Postoperative Intensive Care
Medicine, University Hospital of Cologne, Cologne, Germany; 3Ser-               depressive symptoms and anxiety (P < 0.001). Analyses
ena Carville, PhD, Ernest Choy, MD, FRCP: King’s Musculoskeletal                of imaging results using self-rated psychological mea-
Clinical Trials Unit, Academic Department of Rheumatology, King’s               sures as covariates showed that brain activity during
College London, London, UK; 4Steven C. R. Williams, PhD: Centre
for Neuroimaging Science, Institute of Psychiatry, King’s College               experimental pain was not modulated by depressive
London, London, UK; 5Yves Mainguy, MD, PhD: Pierre Fabre                        symptoms, anxiety, or catastrophizing.
Médicament, Labège, France; 6Richard Gracely, PhD: Center for                        Conclusion. Negative mood in FM patients can
Neurosensory Disorders, University of North Carolina, Chapel Hill.
          Dr. Petzke has received speaking fees from Pierre Fabre               lead to a poor perception of one’s physical health (and
Médicament (less than $10,000) and has provided expert testimony on            vice versa) but does not influence performance on
behalf of Pierre Fabre Médicament. Dr. Choy has received consulting
fees, speaking fees, and/or honoraria from Pierre Fabre Médicament
                                                                                assessments of clinical and experimental pain. Our data
(more than $10,000). Dr. Gracely has received consulting fees, speak-           provide evidence that 2 partially segregated mecha-
ing fees, and/or honoraria from Pierre Fabre Médicament (more than             nisms are involved in the neural processing of experi-
          Address correspondence and reprint requests to Karin B.               mental pain and negative affect.
Jensen, PhD, Department of Psychiatry, Massachusetts General Hos-
pital, Harvard Medical School, Charlestown, MA 02129. E-mail:                         Pain represents an emotional construct (1,2), and
          Submitted for publication November 17, 2009; accepted in              the neural processing of pain can be altered with
revised form July 1, 2010.                                                      changes in emotional status (3–6). Mood disorders are
MOOD DISTURBANCE AND PAIN IN FM                                                                                             3489

common among individuals with chronic pain (7), but            se. In 2 previous functional MRI studies (21,22) the
the causality is unknown. One study using functional           pressure pain stimulations were administered in blocks,
magnetic resonance imaging (MRI) has shown that the            making the pain predictable and introducing confound-
experience of sustained low back pain was associated           ing due to the possible impact of negative affect on
with a selective activation of a prefrontal brain circuitry,   attention and anticipation of pain. The use of an unpre-
an area that has been implicated in the cognitive and          dictable stimulation paradigm is thus preferable when
motivational-affective aspects of pain (8). In another         investigating the influence of negative affect on pain
functional MRI study, Schweinhardt et al (9) observed          processing.
depression-related activity in the medial prefrontal cor-              In a previous study, we were able to demonstrate
tex of patients with rheumatoid arthritis (RA) during          a specific dysfunction in pain regulation among patients
provocation of clinical pain, but not during experimental      with FM, using functional MRI during randomly pre-
pain. These results provide evidence of a complex inter-       sented pain stimuli (15). In that study, FM patients were
action between brain processes underlying the specific         compared with healthy controls, and a possible differ-
circuitry of chronic pain and that of negative mood. In        ence in pain processing related to the presence of
the present study, we addressed this clinically important      negative affect was not investigated. Using the same
interaction by investigating the effect of depressive          experimental paradigm, the present study addressed the
symptoms, anxiety, and catastrophizing on pain process-        differential effect of depressive symptoms, anxiety, and
ing in patients with fibromyalgia (FM).                        catastrophizing on cerebral processing of pain in a large
        FM is a chronic pain syndrome characterized by         number of FM patients (n ⫽ 83). Secondary aims were
widespread pain, disturbed sleep, fatigue, and tender-         to assess the influence of depressive symptoms, anxiety,
ness (10). Early reports of a generalized increase in pain     and catastrophizing on clinical pain, sensitivity to pres-
sensitivity (11) and lack of endogenous pain inhibition in     sure pain, ratings of general health, and impact of FM
FM patients (12,13) have now gained support from               symptoms.
studies using functional MRI. Results include findings of
augmented neural signaling in response to pain stimu-
                                                                              PATIENTS AND METHODS
lation (14), reduced ability to activate brain areas in-
volved in endogenous pain modulation (15), and other                    Patients were recruited as part of a pharmacologic
central nervous system abnormalities (16).                     multicenter study conducted at 3 sites in Europe: London,
                                                               Stockholm, and Cologne (EudraCT #2004-004249-16). The
        The effect of psychological symptoms in FM is          present study was performed using data from the baseline
still an area of debate. There is a high frequency of          measurements in that study, before patients were randomized
comorbidity with major depressive disorder (17), and           and treatment initiated. All patients were female and were
FM is still regarded by some as “occupying the grey area       right-handed, and all had been recruited from primary care
between medicine and psychiatry” (18). Two studies             settings and had been diagnosed as having FM according to the
                                                               1990 American College of Rheumatology criteria (23). The
investigated the effect of mood on pain processing in          patients ranged in age from 18 to 55 years. Criteria for
FM, one focusing on depressive symptoms (19) and the           enrollment included a self-reported average pain intensity of at
other on catastrophizing thoughts (20). Depressive             least 40 mm on a 100-mm visual analog scale (VAS) over the
symptoms had no influence on the intensity of clinical         last week, as well as discontinuation of all treatments that
pain or the sensory-discriminative processing of induced       could influence the patient’s pain perception (i.e., antidepres-
                                                               sants and mood stabilizers, analgesics, strong opioids, anticon-
pressure pain. However, with increasing depressive             vulsants, centrally acting relaxants, joint injections, trigger/
symptoms, activity in 2 brain regions pertaining to            tender point injections, biofeedback, and transcutaneous
emotional processing, i.e., the insula and the amygdala,       electrical nerve stimulation).
increased during sustained pain provocation (19). Pain                  Patients with severe psychiatric illness or with signifi-
catastrophizing (20), independent of depressive symp-          cant risk of suicide were excluded from the study, as were
                                                               patients with a history of substance, drug, or alcohol abuse.
toms, was associated with increased activity in many           Qualified investigators (mainly rheumatologists) used the Beck
different brain areas, including the anterior cingulate        Depression Inventory (BDI) (24) in combination with a clinical
cortex, cerebellum, secondary sensory cortex, and fron-        interview to ensure that patients were not severely depressed.
tal gyrus (none of these regions overlapping with the          This was done to ensure the safety of the patients during the
brain regions found by Giesecke et al [19]).                   clinical trial. Additional exclusion criteria included risk of
                                                               significant cardiovascular/pulmonary disease (including elec-
        It is possible that negative affect has a selective    trocardiographic abnormalities and hypertension), liver dis-
impact on cognitive functions such as attention (21) and       ease, renal impairment, autoimmune disease, current systemic
anticipation (22) but not on the processing of pain per        infection, malignancy, sleep apnea, active peptic ulcer, unsta-
3490                                                                                                                        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
Figure 1. Cross-sectional representation of the pneumatic pain stim-
                                                                           field of view.
ulator. The thumb is inserted from the left side and rests on the wedge.
                                                                                    High-resolution T1-weighted structural images were
The thumbnail is positioned straight under the piston.
                                                                           acquired in coronal orientation for anatomic reference pur-
                                                                           poses and screening for cerebral anomalies. Parameters were
                                                                           as follows: spoiled gradient-recalled 3-dimensional sequence,
ble endocrine disease, pregnancy or breastfeeding, participa-              repetition time 24 msec, echo time 6 msec, flip angle 35°, 124
tion in a pharmacologic trial during the prior 3 months, and               contiguous 1.5-mm coronal slices (image resolution 256 ⫻
unwillingness to discontinue prohibited medications. The rea-              256 ⫻ 186 mm, voxel size 0.9 ⫻ 0.9 ⫻ 1.5 mm).
sons men were not included in the study were the possibility of                     The scanning procedure was standardized between
different pathogenetic presentations in men and women and                  sites by using written manuscripts for all oral instructions and
the male:female prevalence ratio of 1:9 in FM (25). Similar                providing practical training for all investigators involved in the
prevalence ratios have also been observed in related syn-                  study. A central coordinator made several visits to the 3 sites
dromes, such as chronic fatigue syndrome and headaches (26),               to ensure calibration of experimental procedures. Functional
but the mechanisms underlying these sex differences are still              data were collected in pilot patients in order to assure similar
poorly understood.                                                         results between sites. Full-factorial analysis of variance
          A total of 157 FM patients were screened, of whom 92             (ANOVA) including the 3 sites as well as the experimental
(mean ⫾ SD age 44 ⫾ 8.2 years [range 24–55 years]) fulfilled               conditions, probing for any possible difference in brain activa-
the inclusion criteria and were enrolled in the study. Nine of             tion for any of the conditions at any of the sites, was performed
the 92 patients were excluded from functional MRI analyses                 using SPM5 software. Data on the median, SD, and 95%
due to image artifacts or incidental findings of intracranial              confidence interval for the signal intensity at each site are
anomalies, leaving 83 patients for the functional MRI analysis.            available from the corresponding author upon request.
Image artifacts included extensive head movement during                             The BDI was used to quantitatively assess depressive
scans or metal in the mouth causing image distortions. All                 symptoms. The BDI is a 21-item measure of the severity of
reported analyses are based on the 83 patients (mean ⫾ SD                  depressive symptoms, and it has been extensively validated
age 43.8 ⫾ 8.1 years) with intact data from both the behavioral            for use with both medical and mental health populations (24).
and the neuroimaging experiments.                                          Scoring allows for the identification of mild, moderate, and
          Pressure pain thresholds were assessed using a pres-             severe levels of depressive symptoms. The BDI does not
sure algometer (Somedic). An algometer is a handheld appa-                 provide information about possible specific major depressive
ratus with a 1-cm2 hard rubber probe that is held at a 90° angle           disorders according to the Diagnostic and Statistical Manual of
against the body and then pressed with a steady rate of                    Psychiatric Disorders (28); rather, it gives a quantified measure
pressure increase (30 kPa/second) in order to induce pain.                 of the degree of depressive symptoms. A high score on the BDI
Pressure pain thresholds were assessed bilaterally at 4 different          corresponds to a high level of depressive symptoms.
sites, i.e., trapezius muscle, elbows (lateral epicondyle), quad-                   The State-Trait Anxiety Inventory (STAI) was used to
riceps femoris muscle, and knees (medial fat pad proximal to               assess the participants’ levels of state anxiety. STAI is a
the joint line), with one assessment per anatomic site. The total          self-report questionnaire with 2 independent 20-item scales for
average pressure pain threshold was calculated for each pa-                measuring state-related or trait-related anxiety (29). A high
tient and used for further analysis.                                       score on the STAI corresponds to a high level of anxiety
          For the purpose of calibration and induction of pain             symptoms.
during functional MRI, a custom-made tool was used to inflict                       The Coping Strategies Questionnaire (CSQ) was used
pain to the thumbnail (27). The stimulations were performed                to assess levels of catastrophizing thoughts about pain, a
using an automated, pneumatic, computer-controlled stimula-                parameter commonly described in studies of chronic pain. The
tor with a plastic piston that applies pressure via a 1-cm2 hard           CSQ is a self-reported measure of cognitive and behavioral
MOOD DISTURBANCE AND PAIN IN FM                                                                                                 3491

responses utilized to cope with chronic pain, and patients are     aligned to the first volume, spatially normalized to a standard
asked to rate the frequency with which they use each strategy      EPI template, and finally smoothed using an 8-mm full-width
on a 7-point scale (30). A high score on the CSQ corresponds       at half-maximum isotropic Gaussian kernel (33). Data were
to a high level of catastrophizing.                                also subjected to high-pass filtering (cutoff period 128 seconds)
        The Short Form 36 (SF-36) is a well-established ques-      and correction for temporal autocorrelations. Data analysis
tionnaire measuring 8 domains of health status: physical           was performed using a generalized linear model and modeling
functioning, role limitations because of physical problems,        of the 2 different conditions (calibrated pain of 50 mm on a
bodily pain, general health perceptions, energy/vitality, social   VAS and nonpainful pressure) as delta functions convolved
functioning, role limitations due to emotional problems, and       with a canonical hemodynamic response function (HRF).
mental health (31). A low general health score on the SF-36                A file containing the movement parameters for each
corresponds to a poor rating of one’s health.                      individual (6 directions) was obtained from the realignment
        The Fibromyalgia Impact Questionnaire (FIQ) is a           step and saved for inclusion in the model. A design matrix
20-item questionnaire that assesses the overall symptom sever-     prepared for each patient included regressors for the 2 condi-
ity in patients with FM (32). A high score on the FIQ              tions (calibrated pain and no pain). Regression coefficients for
corresponds to a perceived high severity of FM.                    both regressors were estimated using least squares within
        The day before scanning, patients rated their pain         SPM5. Specific effects were tested with appropriate linear
using a VAS ranging from 0 mm to 100 mm. Patients were             contrasts of the parameter estimates for the HRF regressor of
asked to score their current pain and their average pain during    both conditions, resulting in a t-statistic for each voxel. Data
the last week.                                                     were analyzed for each patient individually (first-level analysis)
        For each patient, subjective pain ratings were cali-       and for the group (second-level analysis). To assess pain-
brated by application of one ascending series of pressure          specific cerebral activity and to control for individual differ-
stimuli to the thumbnail and one randomized series, using the      ences in cerebral responsiveness, brain activation during non-
automated thumb pressure device. Pressures with a duration of      painful pressures was individually subtracted from activity
2.5 seconds were delivered at 30-second intervals. Patients
                                                                   during calibrated pain. ANOVA was performed in order to
were instructed to rate the intensity of the pain evoked by each
                                                                   determine whether there was any difference in pain-evoked
stimulus, by placing a mark on a 100-mm horizontal VAS
                                                                   brain activity that could be explained by a study site–related
ranging from “no pain” to “worst imaginable pain.” During the
                                                                   factor. The effect of depressive symptoms, anxiety, or cata-
ascending series, the pressure stimuli were presented in steps
of 50 kPa of increased pressure. Data from the ascending series    strophizing on brain activity during pain processing was mea-
were used to determine each patients’ pain threshold (first        sured by performing 3 individual regression analyses using
VAS score of ⬎0 mm) and stimulation maximum (first rating          each patient’s depression, anxiety, or catastrophizing scores as
of ⬎60 mm). These values were then used to compute the             a covariate. In addition to the regression analysis, which is a
magnitude of 5 different pressure intensities within the range     sensitive measure for the full range of depressive scores,
of each patients’ threshold and maximum. A total of 15 stimuli,    2-sample t-tests were performed to compare brain activity
3 of each intensity, were delivered in a randomized order at       between the 20 highest-scoring and the 20 lowest-scoring
30-second intervals, preventing the patients from being able to    subjects for depression, anxiety, and catastrophizing scores.
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                                 RESULTS
15 ratings from the randomized series.                                     The mean ⫾ SD score on the BDI was 18 ⫾ 10
        Patients returned for scanning the day after the pro-
cedure for calibrating pain rating. Two types of stimulation       (range 0–47). Twelve patients had BDI scores of ⬎29
were used during scans: pain that would be rated 50 mm on a        (indicating severe depressive symptoms), 23 patients
VAS based on the previously obtained calibration and a             scored between 19 and 29 (indicating moderate to severe
nonpainful pressure perceived only as light touch. All stimu-      depressive symptoms), 30 patients scored between 10
lations were randomly applied over the scanning time, prevent-
ing patients from anticipating the onset time and event type.
                                                                   and 18 (indicating mild to moderate depressive symp-
The time interval between consecutive events was randomized,       toms), and 18 patients scored between 0 and 9 (normal
with a mean stimulus onset asynchronicity of 15 seconds (range     range). Mean ⫾ SD scores for the various psychological
10–20). Four different random sequences were created. Each         measures and pain assessments are shown in Table 1.
patient received all 4 sequences, but the order of the sequences           Correlation analysis (Spearman’s rho) including
was randomized for each. The total duration of the scans was
⬃35 minutes. Before scanning, patients were instructed to          all self-ratings (n ⫽ 83) demonstrated that depressive
focus on the pressures on the thumb and to use no distraction      symptoms, anxiety, and catastrophizing scores were sig-
or coping techniques.                                              nificantly correlated with one another (␳ ⫽ 0.8 for
        Behavioral data and self-ratings were analyzed using       depression and anxiety, 0.5 for depression and cata-
Spearman’s rank correlation coefficient with SPSS version          strophizing, and 0.5 for anxiety and catastrophizing; P ⬍
16.0. P values less than 0.001, with Bonferroni correction for
multiple comparisons, were considered significant.                 0.001), but did not correlate with any measure of pain
        Imaging data were analyzed using Matlab 7.1 (Math-         sensitivity (weekly pain, sensitivity to pressure pain
Works) and SPM5. All functional brain volumes were re-             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†                                    136 ⫾ 94
BDI score                                                   18 ⫾ 10
STAI-T score                                                48 ⫾ 11
CSQ score                                                   15 ⫾ 8
Average pain in a week, 100-mm VAS                          65 ⫾ 15
Thumb pressure, kPa‡                                       401 ⫾ 165
Algometer pressure, kPa§                                   160 ⫾ 107
FIQ score                                                   65 ⫾ 15
SF-36 general health score                                  38 ⫾ 19

* BDI ⫽ Beck Depression Inventory; STAI-T ⫽ trait anxiety on the
State-Trait Anxiety Inventory; CSQ ⫽ Coping Strategies Question-
naire; FIQ ⫽ Fibromyalgia Impact Questionnaire; SF-36 ⫽ Short
Form 36.
† From the time the patient first subjectively reported fibromyal-
gia (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.

                                                                         Figure 3. Main effect of brain activity evoked by painful stimulation
                                                                         minus that evoked by nonpainful sensory stimulation in the 83 patients
tive measure of general health (SF-36) was inversely
                                                                         with fibromyalgia. The sections shown represent the anterior cingulate
correlated with ratings of depressive symptoms (␳ ⫽                      cortex, thalamus, cerebellum, insula, and S1. Coordinates correspond
⫺0.36, P ⬍ 0.001) (Figure 2) as well as anxiety (␳ ⫽                     to the anatomic space as defined in the Montreal Neurological
⫺0.40, P ⬍ 0.001), but not with any measure of pain                      Institute Standard Brain Atlas (36).
sensitivity. The subjective rating of FM symptom sever-
ity (FIQ) correlated both with psychological measures
and with ratings of pain (for depressive symptoms, ␳ ⫽                   correlate with any other variables in the correlation
0.49, P ⬍ 0.001; for anxiety, ␳ ⫽ 0.51, P ⬍ 0.001; for                   matrix.
weekly pain, ␳ ⫽ 0.43, P ⬍ 0.001; for pressure pain                              To validate the pain provocation paradigm, we
thresholds, ␳ ⫽ 0.34, P ⬍ 0.01; for self-rated general                   calculated the main effect of brain activity occurring
health, ␳ ⫽ ⫺0.54, P ⬍ 0.001). The variables time since                  during calibrated pain minus that occurring during non-
onset of FM symptoms and calibrated pain did not                         painful pressure in the 83 FM patients, using a 1-sample
                                                                         t-test. The results showed significant increases in pain-
                                                                         related 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 [36]) was ascertained for each patient.
                                                                         Values for pain-evoked brain intensity in S2 were com-
                                                                         pared 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).
Figure 2. Scatterplot of the fibromyalgia patients’ scores for depres-           The 3 regression analyses in which depressive
sive symptoms (measured using the Beck Depression Inventory [BDI])
and subjective ratings of physical health (measured using the Short
                                                                         symptoms, anxiety, or catastrophizing scores were used
Form 36 [SF-36]). A significant inverse correlation was found (␳ ⫽       as covariates showed no significant results, i.e., brain
⫺0.36, P ⬍ 0.001).                                                       activity during pain was not modulated by different
MOOD DISTURBANCE AND PAIN IN FM                                                                                                     3493

Table 2. Representation of brain activity during painful stimulation         matrix (37), i.e., all expected brain regions involved in
minus brain activity during nonpainful sensory stimulation, in the 83        pain processing were activated. Several regions of the
patients with FM*
                                                                             brain have been associated with depression and anxiety,
                                                                   Peak      including altered function of the prefrontal cortex and
 Brain region          Laterality       X        Y        Z       T score    limbic structures (38). In order to create a situation that
PAG                 Bilateral           10      ⫺24      ⫺12        5.31     closely corresponded to the emotional stress associated
Amygdala            Bilateral          ⫺24        0       ⫺8        6.56     with uncontrollable clinical pain, the paradigm used in
S1                  Contralateral      ⫺28      ⫺24       70        7.41
S2                  Contralateral      ⫺40      ⫺18       16        6.92     this study was a randomized design that precluded
ACC                 Bilateral            2       20       32        6.88     prediction of the pain stimuli. Despite the large varia-
Left posterior      Bilateral          ⫺54        0        0        8.14     tions in depressive symptoms and anxiety, we found no
Right posterior     Bilateral            56     ⫺16           8     6.82     brain regions with significant covariation with depressive
  insula                                                                     symptoms, anxiety, or catastrophizing during pain.
Cerebellum                 ⫺             26     ⫺56      ⫺24       10.08             Giesecke et al (19) found increased neuronal
Mid-insula                 ⫺             38       6        2        7.24
Thalamus                   ⫺             10      ⫺4        2        6.44     activity in the bilateral amygdalae and contralateral
                                                                             anterior insula in association with depressive symptoms,
* Coordinates (X, Y, and Z) correspond to the anatomic space as
defined in the Montreal Neurological Institute Standard Brain At-            indicating more involvement of emotional processing in
las (36). Laterality in relation to the painful stimuli on the right thumb   response to the pain stimulation in depressed patients.
is shown where applicable. FM ⫽ fibromyalgia; PAG ⫽ periaqueductal           The paradigm they used was a block design with inher-
gray matter; ACC ⫽ anterior cingulate cortex.
                                                                             ent predictability of the pain stimuli. It is possible that
                                                                             with this paradigm, nondepressed patients were not
                                                                             challenged enough, since they could have coped better
levels of depressive symptoms, anxiety, or catastrophiz-                     with the situation by steeling themselves prior to pain
ing. In analyses using SPM5, there was no significant                        block, therefore not activating the emotional structures
finding for any brain region, and there were no signifi-                     as much as occurred in the depressed patients. Thus,
cant clusters, Z values, or P values to report (threshold                    previously reported results could be due to a difference
was set at P ⬍ 0.001, uncorrected for multiple compar-                       in pain anticipation and do not necessarily provide any
isons). Further post hoc analyses of the data included                       information about pain processing per se. This possible
t-tests, which revealed no significant differences in brain                  effect was controlled for in the present design. More-
activity during pain provocation among the 20 patients                       over, Gracely et al (20) found an association between
with the highest depression scores versus the 20 with the                    high levels of catastrophizing and increased brain activ-
lowest depression scores (threshold set at P ⬍ 0.001,                        ity in regions involved in attention to pain and anticipa-
uncorrected for multiple comparisons). When the 20                           tion of pain. That finding was not reproduced in the
patients with the highest scores on the BDI, STAI, and                       present study. However, the high and low catastrophiz-
CSQ combined (range 100–143) were compared with                              ing patients in Gracely and colleagues’ study differed in
the 20 patients with the lowest scores on these 3 tests                      levels of clinical pain as well as sensory and affective
combined (range 31–59), there was also no significant                        measures.
difference in brain activity.                                                        Therefore, we conclude that mood does not
                                                                             affect the perception or processing of experimentally
                                                                             induced nociceptive stimuli in FM patients when antic-
                                                                             ipation and differences in behavioral measures are con-
        We found no relationship between negative                            trolled for. An alternative explanation for the differ-
mood and cerebral processing of pain among patients                          ences between previous and current findings is that the
with FM. We also found that patients’ reports of clinical                    duration of the painful stimuli in the present study was
and experimentally induced pain were not affected by                         only 2.5 seconds, compared with blocks of 25 seconds.
levels of depressive symptoms, anxiety, or catastrophiz-                     Even if the blocks were highly predictable in earlier
ing. These findings add to evidence from earlier studies                     studies, they could have been more distressing and
that 2 different, partially segregated neural mechanisms                     thereby more sensitive to emotional activation.
are involved with pain processing and negative affect in                             In a study of patients with RA (9), no relationship
FM patients.                                                                 was found between depressive symptoms and cerebral
        The pressure pain stimulation paradigm used in                       pain processing in RA patients during experimental pain
this study produced an adequate response of the pain                         (heat). However, there was a positive correlation be-
3494                                                                                                                JENSEN ET AL

tween ratings of depressive symptoms and activation of       tion between depression, anxiety, and the subjective
the medial prefrontal cortex during provoked joint pain      rating of one’s health (general health score on the SF-36
in RA patients. We might have observed a similar effect      and FIQ) suggests that negative mood affects the per-
in the present study had we used pressure to a tender        ception of one’s health status. Negative mood in FM
point instead of the thumbnail. Furthermore, RA pa-          patients could thus lead to a poor perception of physical
tients do not differ from healthy controls in heat pain      health but not to poor performance on clinical and
sensitivity (39), whereas FM patients have been shown        experimental pain assessments. Furthermore, the dura-
to be more sensitive to pressure also at the thumbnail       tion of disease did not correlate with any other measure-
(27). Increased cerebral processing of pain (14), disin-     ment, indicating that symptoms in FM are relatively
hibition (15), and normalization after successful treat-     stable over time, and that there is no linear relationship
ment (40) have repeatedly been demonstrated using            between FM duration and development of depression
thumb pressure in patients with FM, demonstrating            and anxiety.
aberrations in central pain processing in this disorder.             In conclusion, among patients with FM, depres-
The current results show that these aberrations exist        sion, anxiety, and catastrophizing did not correlate with
independent of psychological factors such as depressive      ratings of clinical experimental pain and did not modu-
symptoms, anxiety, and catastrophizing.                      late brain activity during experimental pain. Our data
        The generalized, multimodal increase in pain         therefore provide evidence that there are 2 different,
sensitivity and widespread pain that are characteristic of   partially segregated neural mechanisms involved in pain
FM make it difficult to clearly distinguish between          processing and negative affect in FM.
experimental and “clinical” pain stimulation. This is a
limitation to our study design that hinders clear inter-
                                                                                AUTHOR CONTRIBUTIONS
pretation of our data. Another major difference between
                                                                       All authors were involved in drafting the article or revising it
the present study and the RA study is the pronounced         critically for important intellectual content, and all authors approved
difference in depressive symptoms. In our study, depres-     the final version to be published. Dr. Jensen had full access to all of the
sive symptoms were severe in 12 patients, moderate to        data in the study and takes responsibility for the integrity of the data
                                                             and the accuracy of the data analysis.
severe in 23, mild to moderate in 30, and low (normal) in    Study conception and design. Jensen, Petzke, Fransson, Marcus,
18. In the RA study, there was no representation of          Williams, Choy, Mainguy, Gracely, Ingvar, Kosek.
severe depressive symptoms at all, and only 3 patients       Acquisition of data. Jensen, Petzke, Carville, Marcus, Williams, Choy,
                                                             Mainguy, Ingvar, Kosek.
had scores that indicated moderate to severe depression.     Analysis and interpretation of data. Jensen, Petzke, Fransson, Marcus,
        It has been speculated that emotional response is    Williams, Choy, Mainguy, Gracely, Ingvar, Kosek.
generally exaggerated in FM patients, suggesting that
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