36. Degli–Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. The novel receptor TRAIL-R4 induces NFkappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997;7:813– 820. 37. Jeremias I, Herr I, Boehler T, Debatin KM. TRAIL/Apo-2ligand-induced apoptosis in human T cells. Eur J Immunol 1998;28:143–152.
CME
38. Martinez–Lorenzo MJ, Alava MA, Gamen S, et al. Involvement of APO2 ligand/TRAIL in activation-induced death of Jurkat and human peripheral blood T cells. Eur J Immunol 1998;28:2714 –2725. 39. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS. Neurology 1999;53:457– 465.
Fatigue and declines in cognitive functioning in multiple sclerosis Lauren B. Krupp, MD; and Leigh E. Elkins, PhD
Article abstract—Objective: To determine whether cognitive fatigue, defined as a decline in cognitive performance over a single testing session, could be identified in MS. Methods: Forty-five individuals with MS and 14 healthy control participants completed a 4-hour session of cognitive testing that involved a baseline neuropsychological battery, a continuous effortful cognitive task (completing mental arithmetic problems administered on a computer), and a repeat neuropsychological battery. Self-report measures of fatigue and affect were completed before each step of the testing session. Results: The pattern of change in cognitive performances over the testing session significantly differed between the MS and control participants. Individuals with MS showed declines on measures of verbal memory and conceptual planning, whereas the control participants showed improvement. Although there were no significant differences between the groups on any of the baseline cognitive measures, the MS participants performed worse than the control subjects on tests of visual memory, verbal memory, and verbal fluency that were repeated following the continuous effortful cognitive task. Both MS and control participants reported increased mental and physical fatigue across the testing session compared with their baseline values. Conclusion: Individuals with MS show declines in cognitive performance during a single testing session and fail to show the improvement exemplified by healthy control subjects. NEUROLOGY 2000;55:934–939
Cognitive dysfunction is a disabling feature of MS.1 Individuals with MS often report that fatigue adversely affects their cognitive functioning.2,3 Whereas motor and muscle fatigue have been reliably identified in MS,4,5 assessments of fatigue and cognitive functioning have been limited. Prior investigations have relied on correlations between self-report measures of fatigue and neuropsychological tests, an approach that has yielded conflicting findings.6-8 To overcome the limitations of relying on subjective selfreport measures, this study used a performancebased approach to examine objectively fatigue and cognitive functioning. We defined cognitive fatigue as a decline in cognitive performance over a single testing session and compared cognitive fatigue in individuals with MS with that in nonpatient control subjects. The few studies in MS that have examined changes in cognitive functioning over a single testing session have been inconsistent in their methods of assessment and results.9-11 A pilot study that used
physical exercise between the administration of two neuropsychological batteries given to a group of MS participants did not show a decline in cognitive functioning following the exercise.12 Unfortunately, a control group was not included for comparison. The findings raised the issue that cognitive rather than physical exertion can induce cognitive fatigue. Three previous investigations have measured cognitive fatigue in MS with paradigms of cognitive exertion. Two of the three studies10,11 found that both patients with MS and healthy control subjects showed similar patterns of improvement on repeated cognitive measures. One study used repeated administrations of a complex attention task (Paced Auditory Serial Addition Test) to test for fatigue and observed improvement in both MS and control participants.10 Similarly, subjects improved in another study in which grip strength, verbal memory, and vigilance were assessed before and after a larger neuropsychological battery was administered. However, both investigations employed general “work bat-
From the Department of Neurology, State University of New York at Stony Brook. Supported in part by the National Multiple Sclerosis Society (grant no. RG3042-A-2), NIH (grant no. HD38107-01), National Institutes for Disability and Rehabilitation Research (grant no. H133G990058), and a General Clinical Research Center grant from the NIH (grant no. 5M01RR1071002). Presented in part in abstract form at the annual meeting of the American Academy of Neurology, Minneapolis, MN, April 28, 1998. Received March 17, 2000. Accepted in final form June 6, 2000. Address correspondence and reprint requests to Dr. L.B. Krupp, Department of Neurology, HSC, T12-020, State University of New York, Stony Brook, NY 11794-8121; e-mail:
[email protected] 934
Copyright © 2000 by AAN Enterprises, Inc.
teries” to precipitate fatigue rather than a sustained continuous cognitive task. Alternatively, when a sustained vigilance task was used to compare two groups of MS participants (one with and one without mild cognitive deficits) and a group of healthy control participants, significant differences emerged between the MS and control groups.9 Relative to the control subjects, both MS groups declined over time in their performance on measures of sustained attention. Unfortunately, other aspects of cognitive functioning were not measured. To address the limitations of previous studies, we used a range of cognitive measures administered before and after a continuous effortful cognitive task to examine cognitive fatigue. We hypothesized that the MS participants, in contrast to control subjects, would fatigue over time with a decline in cognitive performances. We also predicted that, similar to studies of motor and muscle fatigue,13 self-report would not accurately reflect objective changes in performance. Method. Participants. The study was approved by the Institutional Review Board for Human Subject Research at the State University of New York Medical Center at Stony Brook. Participants were 45 individuals with MS and 14 healthy nonpatient control subjects. The MS participants were recruited from the outpatient clinic of the MS Comprehensive Care Center and evaluated in the General Clinical Research Center at Stony Brook. Subjects were chosen based on their willingness to participate in a study designed to better understand cognitive functioning in MS. Among the MS group, all 31 women and 14 men were ambulatory and had Expanded Disability Status Scale14 scores of ⬍6.5 (mean ⫽ 3.8, range ⫽ 1.0 to 6.5, SD ⫽ 1.7). Eight participants had primary progressive MS, 13 had secondary progressive MS, and 24 had relapsing-remitting MS. The control group consisted of 11 women and 3 men recruited by advertisements throughout the local community. The MS and control groups were matched in aggregate ( p values ⬎0.05) according to age and years of education. The MS group had a mean age of 45 years (SD ⫽ 6.8), and the mean age for the control subjects was 41.8 years (SD ⫽ 6.6). The mean number of years of education for the MS group was 14.8 (SD ⫽ 2.6) and for the control subjects 15.1 (SD ⫽ 1.9). Participants with MS were diagnosed by a neurologist according to the Poser criteria.15 Concurrent antidepressants, antispasticity agents, anticholinergic medications, and disease-modifying therapies (interferon- or glatiramer acetate) were permitted as long as the dosage had been constant for at least 1 month before the evaluation. We excluded any potential participant currently taking benzodiazepines or other agents known to affect cognitive functioning. Exclusion criteria also included current alcohol or substance abuse, major depression or other primary psychiatric disorder, history of head injury, or history of other major medical illness. Procedure. After completing baseline descriptive selfreport measures, participants completed 1) the first administration of the neuropsychological testing battery; 2) the continuous cognitively effortful task, the AlphaArithmetic (A-A) Test; and 3) the repeat administration of the neuropsychological testing battery. Self-reported fa-
tigue and mood were recorded before each step. Administration time for the entire procedure was ⬃4 hours, and all participants completed the procedure in one session. Every effort was made to begin the cognitive testing in the late morning and to end midafternoon (i.e., between 11 AM and 3 PM). The sequence of tests included in the cognitive testing session is shown in the Appendix. Measures. Neuropsychological tests. The repeated battery of neuropsychological tests was derived from the Brief Repeatable Battery developed by the Cognitive Function Study Group of the National Multiple Sclerosis Society.16 With modifications of omission and addition of tests, our battery continued to be relatively brief and represented a broad range of cognitive functions. The Selective Reminding Test (six-trial version; SRT)17 assesses learning and memory and has a test–retest reliability of 0.80. We used the two alternate forms (forms 2 and 4) that are most equivalent.18 The 10/36 Spatial Recall Test (10/36)15 assesses visuospatial memory. The Tower of Hanoi Test (TOH)19 measures conceptual planning as well as procedural learning. Two alternative forms were developed for this study by dividing the 12 original problems into two sets of 6 matched according to difficulty. The Digit Span19 measures basic auditory attention. The Controlled Oral Word Association Test (COWA) is a measure of verbal fluency.20 The two most commonly used letter triads (F-A-S and C-F-L) served as alternative forms. For analyses, the primary score from each test was used: sum recall from the SRT, total correct for the 10/36 (third trial), and total score from the TOH, Digit Span, and COWA. Continuous cognitive task: A-A Test. The two administrations of the neuropsychological battery were separated by a continuous cognitively effortful task, the A-A Test.21 The A-A Test has been used in other patient groups to examine different components of cognitive processing speed.22 The A-A Test is administered by computer and involves adding the numbers 0, 2, 3, or 4 to the letters A through T of the alphabet. The participant is presented with an equation (e.g., B ⫹ 1 ⫽ C or D ⫹ 2 ⫽ G) and judges whether it is true or false. The A-A Test was particularly suited for use as a cognitively effortful task as it requires continuous cognitive operations (counting) and prevents reliance on simple retrieval of previously learned information. For example, A ⫹ 2 ⫽ C typically requires a counting operation, whereas 2 ⫹ 2 ⫽ 4 can be stored in semantic memory. In the current study, participants received two sets of 160 equations across which each added value of 0, 2, 3, and 4 randomly occurred 40 times (20 true equations, 20 false equations). The A-A Test measure chosen for analyses was total reaction time (time for ⫹0, ⫹2, ⫹3, and ⫹4 equations). The test–retest reliability for different A-A Test measures ranges from 0.80 to 0.92. For the purposes of this study, analyses were limited to the true equations to reduce variability. Self-report measures. Participants completed two selfreport inventories at baseline to measure overall depressive symptoms and the degree of fatigue. The Center for Epidemiologic Studies–Depression (CES-D)23 is a 20-item self-report depression inventory, frequently used to screen for depression and psychological distress in medical populations. The Fatigue Severity Scale (FSS)24 is a nine-item inventory designed to assess the severity of fatigue and its October (1 of 2) 2000
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Table 1 Summary of neuropsychological test scores before and after cognitively effortful task First administration (before A-A Test) Measure*
Second administration (after A-A Test)
Change scores†
MS
Controls
MS
Controls
SRT Sum of Recall
48.2 (11.5)
51.2 (6.3)
46.4 (10.5)
53.8 (9.5)
⫺1.8 (6/7)
2.6 (6.1)
Tower of Hanoi
17.8 (9.3)
13.4 (10.2)
16.6 (10.3)
19.5 (9.8)
⫺1.2 (9.2)
6.2 (13.1)
7.4 (2.3)
7.9 (2.0)
6.9 (2.4)
8.5 (1.5)
⫺0.5 (2.2)
0.6 (1.7)
Controlled Oral Word Association
40.8 (12.1)
44.3 (12.7)
42.7 (10.4)
47.9 (11.6)
1.8 (7.0)
3.5 (6.9)
Digit Span
15.2 (4.0)
16.4 (4.8)
15.9 (4.6)
17.1 (5.7)
0.7 (2.4)
0.6 (2.8)
10/36 Spatial Recall
MS
Controls
Values are expressed as mean (SD). * Forty-five MS and 14 control participants were compared on all the cognitive measures except for the Controlled Oral Word Association Test, for which data were available only on 14 MS and 10 control participants. † The change scores of the first and second administration of the neuropsychological battery between the MS and control groups were significant for the Selective Reminding Test (SRT) sum of recall measure ( p ⫽ 0.04) and the Tower of Hanoi ( p ⫽ 0.03). A-A ⫽ Alpha-Arithmetic.
impact on an individual’s functioning. The FSS was chosen as a brief general measure of fatigue. Participants completed momentary assessments of mood and subjective physical and mental fatigue at three timepoints during the evaluation. The Positive and Negative Affect Schedule25 requires the participants to rate 20 adjectives according to how they feel “right now” or “at this moment.” Ten items indicate positive affect (PA), similar to arousal or activated engagement, and the remaining 10 items indicate negative affect (NA), similar to anxiety and distress. Participants also marked a horizontal visual analogue scale according to the degree that they were experiencing mental and physical fatigue “right now” or “at this moment.” Analysis. Neuropsychological performance. First, we compared the groups according to performances on the neuropsychological tests before and after the A-A Test with five separate mixed factor analyses of variance (ANOVA) with group as the between-subjects factor and the neuropsychological variables as repeated measures. Each ANOVA included the primary variable from each neuropsychological test at the first administration and at the second administration (following the A-A Test). Next, we examined change scores for the five neuropsychological measures and compared them between MS and control groups with t-tests. Finally, we compared test scores from the baseline and follow-up neuropsychological batteries by t-test. Self-report measures. Change in momentary assessments of PA, NA, and mental and physical fatigue across the three timepoints during the testing session were analyzed with separate repeated measures ANOVA. Comparisons between the two groups for baseline FSS and CES-D measures were done with t-tests. Results. Neuropsychological performance. The scores for the measures of SRT (verbal memory), 10/36 (visual memory), TOH (conceptual planning), Digit Span (attention), and COWA (verbal fluency) for the MS and control subjects before and after the A-A Test are summarized in table 1. Overall, analyses indicated that performances declined for the MS participants and improved for the control 936 NEUROLOGY 55
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participants on the SRT, 10/36, and TOH following the A-A Test. There were no significant group differences in the pattern of change following the A-A Test for Digit Span or COWA. As shown in the figure, analyses for the SRT sum of recall revealed a substantial Group ⫻ Time interaction (F[1,57] ⫽ 4.69, p ⫽ 0.03) with a MS group decline and control group improvement at the second administration. There was a trend toward a main effect for Group (F[1,57] ⫽ 2.96, p ⫽ 0.09). Analyses for the TOH total score revealed a similar pattern of results. MS participants declined over time on the TOH, whereas control subjects improved, with a significant Group ⫻ Time interaction (F[1,53] ⫽ 5.16, p ⫽ 0.03). There was not a main effect for Group (F[1,53] ⫽ 0.09, p ⫽ 0.77). There was also a trend toward significance for this pattern in the 10/36, with a
Figure. Verbal learning before and after a continuous cognitively effortful task in MS and control participants. Circles ⫽ control subjects (n ⫽ 14); squares ⫽ patients with MS (n ⫽ 45). Group ⫻ Time: F(1,57) ⫽ 2.96, p ⫽ 0.035. Time 1 indicates battery administered before the continuous cognitively effortful task; time 2 indicates battery administered following the continuous cognitively effortful task.
Table 2 Self-reported mood* and fatigue† across evaluation Positive affect Time point
Negative affect
Mental fatigue
Physical fatigue
MS
Controls
MS
Controls
MS
Controls
MS
Controls
1
32.5 (8.4)
35.3 (6.6)
12.8 (4.7)
11.8 (1.6)
2.7 (1.5)
2.5 (1.2)
3.1 (1.6)
2.1 (1.3)
2
32.4 (9.4)
31.9 (7.4)
13.9 (6.0)
14.6 (5.4)
3.2 (1.5)
3.1 (1.4)
3.1 (1.5)
3.1 (1.4)
3
28.0 (9.8)
31.4 (8.9)
12.0 (3.9)
11.7 (1.3)
3.9 (1.6)
3.7 (1.2)
3.6 (1.5)
3.5 (1.2)
Values are expressed as mean (SD). * Positive and negative affect scores from the Positive and Negative Affect Schedule, with range from 10 to 50. † Mental and physical fatigue were rated along a visual analog scale, with “1” being the least fatigue and “7” being the most fatigue. Time points: 1 ⫽ beginning of the evaluation session; 2 ⫽ following the first neuropsychological battery administration; 3 ⫽ following the Alpha-Arithmetic Test.
Group ⫻ Time interaction (F[1,57] ⫽ 3.00, p ⫽ 0.09) and a main effect of Group (F[1,57] ⫽ 2.9, p ⫽ 0.09). Analyses of the Digit Span and COWA did not indicate any significant Group ⫻ Time interactions. MS and control participants showed no significant differences on any of the neuropsychological measures at baseline. In contrast, following the A-A Test, the MS participants had lower scores than the control individuals at the second administration of the 10/36 ( p ⫽ 0.02), SRT ( p ⫽ 0.02), and COWA ( p ⫽ 0.02). To further compare performance changes between the two groups, we examined change scores for the neuropsychological tests. As shown in table 1, there was a significant decline in the MS group and an improvement in the control group on the SRT sum of recall and TOH change scores. A-A Test. Performances across the A-A Test on reaction time were compared between groups for the first half and the second half of the A-A Test. Although all subjects completed the continuous mental arithmetic task, data available for analyses were limited to the 12 control subjects and 35 MS participants in whom the data set was complete. During the first half of the A-A Test, the MS and control group showed no significant differences. During the second half of the A-A Test, the MS group had a slower reaction time than the control subjects ( p ⫽ 0.03). Self-report measures. Baseline depression and fatigue. Table 2 summarizes the baseline levels of fatigue and depression in both groups. The MS group reported increased depression symptoms measured by the CES-D as compared with the control subjects (mean ⫽ 11.96, SD ⫽ 10.1; mean ⫽ 6.07, SD ⫽ 5.2; p ⫽ 0.006). As would be expected, the MS participants also reported a greater level of general fatigue severity on the FSS than control subjects (mean ⫽ 4.9, SD ⫽ 1.7; mean ⫽ 2.9, SD ⫽ 1.1; p ⬍ 0.001). Mood and fatigue across evaluation. The MS participants had higher ratings of physical fatigue at baseline ( p ⫽ 0.02). There were no group differences between mental or physical fatigue ratings at the other time points. The ANOVA for physical and mental fatigue revealed that both groups reported an increase in physical fatigue during the session as demonstrated by a main effect of time (F[2,110] ⫽ 16.5, p ⬍ 0.001). In addition, there was a significant Group ⫻ Time interaction (F[2,110] ⫽ 5.46, p ⫽ 0.01). With respect to mental fatigue, there was a significant main effect of Time (F[2,110] ⫽ 25.8), but the Group ⫻ Time interactions were not significant.
The groups did not significantly differ in ratings of PA or NA at any of the three timepoints. Both groups reported changes in PA and NA across the session. There was a main effect of Time for PA (F[2,110] ⫽ 9.1, p ⬍ 0.001) and NA (F[2,110] ⫽ 7.4, p ⬍ 0.01). The Group ⫻ Time interactions were not significant for either PA or NA. Relation between self-reported fatigue and cognitive performance. To determine whether self-reported fatigue severity influenced cognitive performance, we repeated the significant analyses to include baseline FSS scores as a covariate. These results did not indicate a change in the pattern of findings for the significant Group ⫻ Time interactions for the SRT sum of recall, TOH, or the trend for a Group ⫻ Time interaction for the 10/36 visual memory measure. Correlations between FSS score and baseline cognitive measures and change in neuropsychological test scores were not significant. Finally, when we compared the MS subgroup with low fatigue scores (FSS ⬍ 4.0) with the other participants, there were no group differences in change scores on the SRT or TOH. We also compared the MS participants with cognitive impairment with those without cognitive impairment (based on the total z scores for the neuropsychological tests using the control subjects as a reference) and found that there were no significant differences in change scores between the two subgroups. Therefore, neither baseline self-reported fatigue nor degree of cognitive impairment appeared to influence the pattern of change in cognitive performance.
Discussion. Our results showed that whereas MS participants demonstrated declines on measures of verbal memory, visual memory, and conceptual planning following a continuous cognitively effortful task, the control subjects improved. Both MS and control participants reported increased physical and mental fatigue across the testing session. The decline in performance among the MS group with repeat administration of the neuropsychological battery during a single testing session provides an objective measurement of cognitive fatigue. Although this sample of MS participants did not differ from control participants on the baseline neuropsychological battery, they differed in their pattern of change with the repeat neuropsychological test administration. Differences between MS participants and control subjects in cognitive functioning over a testing October (1 of 2) 2000
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session were also observed in a prior investigation that applied a continuous cognitively effortful task to a subgroup of relatively cognitively intact individuals with MS.9 Two other previous studies10,11 did not find differential effects between MS and control participants with repeated cognitive testing. However, the cognitive task used to induce fatigue was not a continuous performance test and may not have been as mentally taxing as the A-A Test. Additional studies of cognitive fatigue should broaden the range of cognitive domains evaluated and further explore whether continuous cognitive activity is necessary to precipitate cognitive fatigue. Speculation about possible mechanisms is premature as the physiologic processes underlying sustained cognitive activity are not well defined. However, motor and muscle fatigue have been linked to metabolic processes,26 and cognitive activity may be susceptible to metabolic dysregulation as well. For instance, fluctuations in the supply or metabolism of glucose, the primary fuel for the brain, may be the final common pathway following any number of potential processes that lead to declines in cognitive performance.27 In addition to a decline over time, the MS participants also failed to show expected improvement with practice demonstrated by the control participants. The mild improvements by the control participants may be due to learning the procedural aspects of the tasks.28,29 One interpretation of the lack of improvement noted in the MS group is that they may have a relative weakness in procedural learning. However, the few studies of implicit or automatic memory in MS have suggested that these processes are relatively intact.30-32 Future studies specifically addressing both procedural learning and capacity for sustained cognitive activity in MS are needed. The observation that some, but not all, cognitive tasks showed decline for the MS group may simply reflect variations in task difficulty. However, it is possible that if metabolic factors underlie cognitive fatigue, areas of the brain may be differentially affected. For example, sleep deprivation, in which cognitive deficits are thought to be in part due to metabolic inefficiency,33 has selective effects on complex verbal learning and conceptual thinking.34 We found, as have others, that self-reported fatigue in MS is independent of neuropsychological measures of cognitive functioning.8,11 Neither the FSS nor the ratings of mental fatigue and physical fatigue corresponded to identifiable changes in cognitive functioning. Others have shown that the FSS does not respond to performance-based changes in motor activity.13 The lack of correspondence between self-report and performance highlights the need to include both subjective and objective measures in studies of fatigue. We have found that following a continuous cognitively effortful task, patients with MS show a decline in performance on specific measures of cognitive 938 NEUROLOGY 55
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functioning. These findings provide preliminary evidence that cognitive fatigue can be objectively assessed in individuals with MS. Acknowledgment The authors thank Drs. P.K. Coyle, J. Smiroldo, and S. Rizvi for referring individuals with MS into the study. They also thank Dr. X. Hussein for help with statistics, and Bill Scherl, Lauren Strober, Dean Pollina, and Pat Melville for help in data collection and analysis.
Appendix Measures and order of administration Fatigue Severity Scale, Center for Epidemiological Studies– Depression Self-report: Positive and Negative Affect Schedule (PANAS), physical and mental fatigue rating Neuropsychological battery Selective Reminding Test Tower of Hanoi 10/36 Spatial Recall Test Digit Span Controlled Oral Word Association Test Selective Reminding Test–Delay 10/36 Spatial Recall–Delay Self-report: PANAS, physical and mental fatigue rating Alpha-Arithmetic Test Self-report: PANAS, physical and mental fatigue rating Neuropsychological battery (using alternative forms)
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Fatigue and declines in cognitive functioning in multiple sclerosis Lauren B. Krupp and Leigh E. Elkins Neurology 2000;55;934-939 DOI 10.1212/WNL.55.7.934 This information is current as of October 10, 2000 Updated Information & Services
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