Rheumatology International

, Volume 28, Issue 6, pp 561–566

Automated neuropsychiatric measurements of information processing in fibromyalgia

Authors

    • Washington Hospital Center
  • Tresa Roebuck-Spencer
    • National Rehabilitation Hospital
  • Joseph Bleiberg
    • National Rehabilitation Hospital
  • Gregory Foster
    • MedStar Research Institute
  • Arthur Weinstein
    • Washington Hospital Center
Original Article

DOI: 10.1007/s00296-007-0487-2

Cite this article as:
Walitt, B., Roebuck-Spencer, T., Bleiberg, J. et al. Rheumatol Int (2008) 28: 561. doi:10.1007/s00296-007-0487-2

Abstract

Aberrant central neurological functioning is believed to contribute to the abnormal sensations of fibromyalgia (FM). Most patients with FM complain of diminished cognitive function. This study sought to compare objective cognitive function between FM and healthy controls at baseline and to determine if symptomatic improvement was related to objective cognitive improvement. Automated neuropsychological assessment metrics (ANAM) was used to quantify neurocognitive function. Performance on ANAM was compared between subjects with FM, musculoskeletal pain, and pain-free controls. Ten separate FM subjects completed an 8-week comprehensive treatment program. Serial testing with ANAM and the Fibromyalgia Impact Questionnaire was conducted. Statistical analysis was performed using repeated Wilcoxon signed rank tests. No differences were noted on ANAM between controls and subjects with pain disorders. A clinical improvement (FIQ median change 33.9, P = 0.002) was noted with treatment without concomitant change in ANAM scores. No cognitive impairment in FM was demonstrated using ANAM.

Keywords

FibromyalgiaNeuropsychological testsANAM

Introduction

Fibromyalgia (FM) is a chronic disorder of abnormal sensations, primarily pain. Clouded mentation, forgetfulness, and difficulty concentrating affect up to 70% of individuals with FM and contribute to the overall disability of the disorder [1, 2]. Whether this psychological ‘sensation’ of abnormal cognitive ability has related objective changes in neurocognitive function is unclear. Initial studies noted alterations in short- and long-term memory in FM, with perceived deficits being greater than objective findings [3]. Other studies suggest that the cognitive disturbances in FM are related to depression, similar to normal aging, and similar to other pain disorders [46]. Recent studies challenge these findings, noting that earlier studies did not adequately account for differences in education and effort [5, 7]. Thus, it remains unclear how much of the sensation of abnormal cognition in FM can be attributed to objective dysfunction.

The automated neuropsychological assessment metrics (ANAM) is a computerized test of neurocognitive function that consistently correlates with conventional neuropsychological tests [8]. The ANAM provides precise measurements of information processing, speed, complex attention, working memory, and short-term memory. ANAM has a number of technical advantages that make it ideal for prospective assessments when compared to conventional neuropsychological tests. ANAM is able to randomly alter its answers after each administration, which minimizes an individual’s ability to ‘learn’ the test. All ANAM measurements are made using a computer, which helps standardize the experience between subjects and minimizes observer biases. ANAM has been effectively used to detect subtle differences in cognitive performance secondary to medication interventions and to monitor patients with a variety of medical conditions including traumatic brain injury, migraine, and systemic lupus erythematosus [913]. For these reasons, ANAM may represent an efficient method to assess neurocognitive function in FM.

This study was designed to investigate the relations between objective cognitive function and FM. The study also sought to expand our understanding of the strengths and limitations of ANAM in the study of FM. To achieve these aims, we performed two simultaneous studies. The first, a cross-sectional survey, measured baseline differences in ANAM scores between FM participants, participants with musculoskeletal pain, and controls. The second, a longitudinal study, sought to determine if improvement in FM symptoms after participating in an individualized multidisciplinary therapeutic regimen would alter ANAM scores.

Materials and methods

Patients

Study one: cross-sectional survey

Eligible subjects between the ages of 18 and 60 were recruited into one of three groups. The fibromyalgia group (FM) met the 1990 American College of Rheumatology (ACR) classification criteria [14]. The control group consisted of subjects with no painful complaints. The musculoskeletal pain group (MSK) consisted of participants with diffuse pain above and below the diaphragm lasting >3 months in duration that did not meet ACR tender point criteria for FM. Demographics for the groups are presented in Table 1. Subjects and controls were recruited from local rheumatology clinics and from responses to local and national advertising. Exclusion criteria included pregnancy and concomitant major medical and/or psychiatric illnesses. Some of the major illnesses excluded from this study included inflammatory arthritis, connective tissue disease, untreated thyroid disease, malignancy, renal failure, Lyme disease history, schizophrenia, and bipolar disorder. Subjects taking medications used in the treatment of fibromyalgia were allowed to participate without any alteration of their dosing. Some examples of acceptable medications included tricyclics, NSAIDS, SSRIs, NSRIs, ultram, and gabapentin. However, subjects taking narcotic medications were strictly excluded from the study. Subjects were not screened for perceived cognitive impairment. The design of the study was approved by the MedStar Research Institute Institutional Review Board and informed consent was obtained from all subjects according to the Declaration of Helsinki (Br Med J 1996; 31:1448–9).
Table 1

Study demographics

Variable

Control

Fibromyalgia

Musculoskeletal pain

n

27

27

18

Age (mean)

41.5

45.2

47.9

% Caucasian

51.9

66.7

72.2

% African–American

40.7

25.9

27.8

% Married

37.0

40.9

64.3

% High school graduate

96.3

96.3

94.4

% College graduate

70.4

70.4

61.1

WRAT score (mean)

105.0

106.4

105.0

% Employed

92.6

74.1

77.8

Mean pain duration (months)

0

113.6

90.3

% CES-D score ≥16

7.4

74.1

44.4

% Headaches

20.8

88.9

53.9

% Sleep disorder

0

100.0

94.1

% Orthostatic symptoms

0

43.8

33.3

Study two: longitudinal study

A separate cohort that met the aforementioned FM inclusion and exclusion criteria was simultaneously recruited to participate in the longitudinal study. Individuals who were undergoing or had received multidisciplinary therapy for FM or who participated in the cross-sectional survey were excluded. Participants had to be willing to participate in an individualized, comprehensive treatment protocol. To be eligible, subjects could not take any psychotropic or analgesic medications except for NSAIDs for at least one month prior to enrollment.

Testing

Cognitive testing

The ANAM was chosen as our primary instrument for the measurement of cognitive function. It is a standardized, fully computerized test of neurocognitive function, which requires 30 min to complete [8]. Test stimuli change with each administration of ANAM, reducing the impact of practice on subsequent testing. ANAM records both accuracy and speed of all responses and calculates a throughput (TP) score based on those parameters. Higher TP represent greater accuracy rates per unit of time and indicate better cognitive performance. This study used seven of the subtests available in ANAM:
  • Code substitution delay (CDD): cued visual short-term memory

  • Code substitution (CDS): visual scanning and learning

  • Matching grids (MTG): spatial processing efficiency

  • Match to sample (MSP): forced choice short term working memory

  • Math processing (MTH): efficiency in arithmetic processing

  • Continual performance (CPT): working memory and sustained attention

  • Simple reaction time (SRT): simple reaction time

In addition, we employed two traditional pencil and paper tests that measure similar cognitive domains as ANAM. The trail making test (Trails A/B) is a two-part measure that focuses on attention, visual search, sequencing, mental flexibility, and motor speed [15]. The Stroop color and word test (Stroop) is a measure of selective attention and cognitive flexibility [16].

Depression and premorbid intelligence are known to influence cognitive function. The Center for Epidemiologic Studies—Depression scale (CES-D) was used to estimate the presence and severity of depressive symptoms. The CES-D is a self-report scale for depression screening that has been used widely in studies of systemic pain, including fibromyalgia [1719]. High scores indicate higher levels of depressive symptoms. A score ≥16 suggests a clinically significant level of psychological distress. This score is not a surrogate for the clinical diagnosis of depression. In a general population, about 20% would be expected to score in this range. The wide range achievement test-3 (WRAT-3) was used to estimate premorbid intelligence. In the reading subtest, subjects are presented with and asked to read a list of words that increase in difficulty level. This test of reading recognition estimates premorbid intellectual functioning [20].

Measures of FM disease symptom severity

The Fibromyalgia Impact Questionnaire (FIQ) was selected as our measure of FM disease symptom severity. It is a standardized, self-administered instrument that consists of visual analogue scales and questions regarding limitations on activities of daily living. The FIQ has construct and content validity and decreases in FIQ scores correlate with clinical improvement [2123]. A decrease in score of 12 or greater is typically considered a clinically significant improvement. Moreover, the FIQ does not consider perceived cognitive function in its scoring algorithm.

Protocol

Study one: cross-sectional survey

Subjects underwent a history and physical exam by a rheumatologist (BW), including a tender point count and calculation of the FIQ. Subjects then underwent neuropsychological testing using ANAM, Trails A/B, Stroop, CES-D, and WRAT-3. Testing was performed under the supervision of a licensed neuropsychologist.

Study two: longitudinal study

Subjects underwent the same protocol as the subjects in the cross-sectional survey. Subjects then started in an individualized, comprehensive FM treatment protocol. The treatment protocol consisted of medications, cognitive behavioral therapy, physical therapy, and weekly physician phone calls. Medications were selected by the primary investigator based on the individual’s description of their symptoms. Medications used in the study included tricyclic antidepressants for sleep disturbances (n = 6), gabapentin for burning and tingling sensations (n = 6), selective serotonin reuptake inhibitors for anxiety and mood complaints (n = 7), tramadol for musculoskeletal soreness (n = 8) and over-the-counter non-steroidal anti-inflammatory drugs and acetaminophen as needed. Efficacy and tolerability of prescribed medications were assessed during weekly phone calls. Medication doses were adjusted or discontinued over the course of the study based on the subjects’ reported responses and side effects. There were no major medication side effects during the study course. Physical and cognitive behavioral therapy was provided by licensed practitioners. The physical therapy regimen included an assessment visit and weekly sessions. The cognitive behavioral therapy regimen included an assessment visit and 3–6 follow-up sessions. Re-evaluations, including interim history, physical exam, and repeat ANAM and FIQ testing, were performed at 4 and 8 weeks after enrollment.

Statistical analysis

The cross-sectional survey sample size was calculated using the null hypothesis that there is no difference in the mean ANAM TP scores between FM and control subjects. Conservative estimates of the standard deviation and clinically significant difference of ANAM TP were determined from previous ANAM studies. At a one-sided α = 0.05 and (1 − β) = 0.8, a sample size of 30 patients in these two groups was calculated. The longitudinal study sample size was calculated using the null hypothesis that there is no difference in the median ANAM TP scores collected at baseline and at 8 weeks. Taking advantage of the quasi-experimental time series design, at a one-sided α = 0.05 and (1 − β) = 0.8, a sample size of 12 patients was calculated.

T tests were performed to test for differences between control and FM participants and between control and MSK participants in ANAM TP, Trails A/B, Stroop, and FIQ scores. Stroop scores were converted to standardized scores adjusted for age. Trails A/B scores were converted to standardized scores adjusted for age and education according to published normative data. The distribution of FIQ scores was highly skewed. A transformation for making the FIQ distribution approximate normality was determined using the Box-Cox procedure [24]. A square root transformation was found and used for all parametric tests using FIQ. Back transformed means and the standard deviations of untransformed FIQ are reported. Multiple linear regressions were performed to test for differences in FIQ after adjusting for CES-D and WRAT-3, differences in the ANAM and Stroop subtests after adjusting for CES-D, WRAT-3, and the square root of FIQ, and differences in trails subtests after adjusting for CES-D and the square root of FIQ. Fisher’s exact tests were used to test for differences in accuracy on the ANAM subtests by study group. Repeated measures Wilcoxon signed rank tests were performed to test for differences between baseline and 8-week ANAM TP and FIQ scores.

Results

Patient characteristics

A total of 72 subjects participated in the cross-sectional study across the three groups. Baseline demographics were well balanced between the groups (Table 1). The clinical characteristics of the groups were similar to what would be expected from prior studies [14]. Twelve subjects were recruited for the longitudinal treatment study. Two subjects dropped out after the initial visit for personal reasons. Two participants did not have complete ANAM data at week 8. For these reasons, a total of eight patients were considered for the ANAM analyses, decreasing our statistical power to 0.56.

ANAM results: cross-sectional survey

Prior experience with ANAM has shown that education and subject effort can affect scoring considerably. Education and estimated premorbid intelligence (WRAT-3) were similar in all three groups. Subject effort was grossly estimated by analyzing subtest accuracy on ANAM between the groups. There were no statistically significant differences in accuracy noted.

The results of the cross-sectional survey are shown in Table 2. As expected, a significant difference in the FIQ scores was noted between the control and pain groups. Despite FIQ differences, performance on ANAM and traditional testing was similar between the three groups. Unadjusted, there were no differences noted on ANAM between FM subjects and controls. After adjustment for WRAT-3 and CES-D scores, FM subjects had a significantly better performance on MTH and Stroop subtests than pain-free controls. Unadjusted, the MSK group had a significantly worse performance on CDD and CDS subtests when compared to controls. This finding disappeared after adjusting for WRAT-3 and CES-D scores, replaced by a significantly better Stroop performance.
Table 2

Symptomatic impairment and neuropsychological testing scores: cross-sectional survey

Test

Control

Fibromyalgia

Musculoskeletal

Fibromyalgia impact questionnaire

7.0 (0.3)

48.1 (14.0)**

38.5 (14.8)***

ANAM subtests

Code substitution delay (CDD)

39.0 (10.5)

41.9 (12.1)

30.9 (10.7)*

Code substitution (CDS)

46.3 (10.4)

43.9 (8.5)***

39.3 (8.2)*

Matching grids (MTG)

32.1 (9.6)

33.8 (8.4)

28.9 (7.5)

Match to sample (MSP)

25.9 (9.8)

27.9 (6.4)

23.2 (6.6)

Math processing (MTH)

23.9 (6.5)

24.6 (5.7)

21.0 (6.6)

Continual performance (CPT)

88.3 (16.7)

86.5 (18.1)

84.1 (19.4)

Simple reaction time (SRT)

187.7 (44.0)

188.6 (32.1)

188.5 (33.5)

Traditional neuropsychological tests

Trails A

51.5 (10.2)

54.6 (14.3)

50.0 (8.8)

Trails B

48.1 (11.2)

52.1 (10.2)

49.1 (9.6)

Stroop word

52.3 (8.5)

50.9 (8.6)

49.1 (6.9)

Stroop color

50.4 (7.2)

49.7 (7.9)

47.4 (7.3)

Stroop color–word

50.0 (9.7)

54.1 (9.5)***

52.9 (9.3)***

Scores are reported as: mean (standard deviation)

* Statistically significant according to t test (P < 0.05) difference from control group, unadjusted

** Statistically significant according to t test (P < 0.0001) difference from control group, unadjusted

*** Statistically significant difference according to multiple linear regression (P < 0.05) from control group, adjusted for WRAT-3 and CES-D

ANAM results: longitudinal study

The results of the longitudinal study are shown in Table 3. A median improvement in FIQ scores of 33.9 points (P = 0.002) suggested that our interventions produced a clinically significant improvement in symptoms after 8 weeks. All ten subjects completing the study had improvements in FIQ scores over 8 weeks, with seven having clinically significant improvements (change in FIQ score ≥12). Despite clinical improvement, there was no concomitant improvement in ANAM performance. A trend towards improved performance was noted with MSP (P = 0.08) and MTH (P = 0.11). No relationship between magnitude of change in FIQ score and ANAM performance was noted.
Table 3

Median symptomatic impairment and neuropsychological testing scores: longitudinal study

Test

N

Baseline

Week 4

Week 8

P value* (change week 0 and week 8)

Fibromyalgia impact questionnaire

10

57.9

37.5

24.0

0.002

Code substitution delay (CDD)

8

32.9

27.2

32.9

0.25

Code substitution (CDS)

8

39.4

41.9

41.2

0.64

Matching grids (MTG)

8

31.1

25.4

27.8

0.20

Match to sample (MSP)

8

18.4

21.5

24.1

0.08

Math processing (MTH)

8

22.0

20.4

22.5

0.11

Continual performance (CPT)

8

74.3

79.2

77.3

0.74

Simple reaction time (SRT)

8

176.7

204.3

195.8

0.55

P values are from Wilcoxon signed rank test

Discussion

Our study reports that short-term memory, cognitive efficiency, concentration, and reaction time, as measured by ANAM, were not different between subjects with pain disorders and pain-free controls. We also did not find any significant relation between FM symptom severity and cognitive function. This absence of a relationship was seen in both the cross-sectional and the longitudinal study. These negative findings are not inconsistent with some of the published literature [4, 7]. However, prior studies had led us to hypothesize that cognitive deficits in FM would be similar in magnitude to those seen in other disease states where ANAM was shown to be sensitive, such as mild brain injury, migraines, and systemic lupus erythematosus [3, 5, 6, 1113]. Instead, our data suggests that any cognitive impairment associated with FM is likely to be confined to specific, complex cognitive tasks or that the perceived cognitive abnormalities of FM are mostly a subjective phenomenon.

The ANAM is arguably more sensitive than traditional testing for measuring attention deficits and has detected subtle cognitive impairment in other populations [813, 2527]. However, it possesses several limitations that are inherent to computerized testing. ANAM relies heavily on visual information processing and does not assess verbal fluency or auditory information processing, which have both been shown to be deficient in FM [5]. Computerized testing also employs memory cues and presents fixed choices in its testing methodology. These techniques do not effectively assess the more difficult tasks of non-cued memory retrieval and spontaneous recall. Also, our testing protocol was of short duration and may not have captured cognitive changes due to mental fatigability or distractibility. Our data confirms the previous findings that there does not appear to be a gross alteration in attention or information processing speed [3, 5], but may not have been sensitive enough to observe previously reported differences on measures of memory recall. However, our data do suggest that there is no dramatic difference in efficiency of information processing in FM. Rather, if cognitive impairment is objectively present in FM it appears to be specific, requiring complex cognitive tasks to observe.

Subjective measures of cognitive function were not explicitly collected in our study. However, the majority of our recruited participants did note cognitive alterations. Prior studies also demonstrate that a high percentage of FM participants in the general community experience subjective cognitive impairment [1]. Our inability to demonstrate differences in cognitive function in FM suggests that a disparity between perceived and objective symptoms may exist. Further comment on this possibility would require coupling cognitive testing with an instrument that measures perceived cognitive impairment.

In summary, this study was unable to demonstrate differences in neurocognitive function between individuals with FM and pain free controls or in FM participants with symptomatic improvement after treatment. The results suggest that information processing is undisturbed and if objective cognitive impairment is present in FM that it is only apparent in specific, complex cognitive tasks that were not adequately tested by ANAM.

Acknowledgments

The study group would like to acknowledge the efforts of Teresa Hunt, Cognitive Behavioral Therapist, Nancy Shaw, Physical Therapist, and Daniel Frisch, Neuroscience Research Associate for their efforts. This study would not have been possible without the grant support from the MedStar Research Institute and Pfizer Pharmaceuticals.

Copyright information

© Springer-Verlag 2007