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Applied Neuropsychology 8(1):12-22, 2001.
© 2001 Lawrence Erlbaum Associates, Inc.

Ella Daly Department of Psychiatry, Massachusetts General Hospital, Charleston, Massachusetts, USA; Anthony L. Komaroff Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Kerry Bloomingdale Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Scott Wilson Department of Psychiatry, Massachusetts General Hospital, Charleston, Massachusetts, USA; Marilyn S. Albert Departments of Psychiatry and Neurology, Massachusetts General Hospital, Charleston, Massachusetts, USA

Abstract

Patients with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and major depression were compared with controls and with each other on a neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability. A total of 101 participants were examined, including 29 participants with CFS, 24 with MS, 23 with major depressive disorder, and 25 healthy controls. There were significant differences among the groups in 3 out of 5 cognitive domains: memory, language, and spatial ability. Assessment of psychiatric symptoms indicated that all 3 patient groups had a higher prevalence of depression than the controls. A total measure of psychiatric symptomatology also differentiated the patients from the controls. After covarying the cognitive test scores by a measure of depression, the patient groups continued to differ from controls primarily in the area of memory. The findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients. [Applied Neuropsychology 8(1):12-22, 2001. © 2001 Lawrence Erlbaum Associates, Inc.]

Introduction

The majority of studies indicate that patients with chronic fatigue syndrome (CFS) have subtle cognitive deficits (Bastien, 1992; DeLuca, Johnson, Beldwicz, & Natelson, 1995; DeLuca, Johnson, & Natelson, 1993; McDonald, Cope, & David, 1993; Marcel, Komaroff, Fagioli, Kornish, & Albert, 1996; Marshall, Forstot, Caillies, Peterson, & Schenck, 1997; Millon, Salvato, & Blaney, 1989; Riccio, Thompson, Wilson, Morgan, & Lant, 1992; Sandman, Barron, Nackoul, Goldstein, & Fidler, 1993; Smith, 1991; Smith, Behan, Bell, Millar, & Bakheit, 1993), although some investigators report minimal or no impairment (Altay et al., 1990; Johnson, DeLuca, & Fiedler, 1994; Kane, Gantz, & DiPino, 1997; Scheffers, Johnson, Grafman, Dale, & Straus, 1992; Schmaling, DiClementi, Cullum, & Jones, 1994). There are, in addition, differing conclusions regarding which cognitive domains are primarily affected in CFS. Some investigators have hypothesized that selective auditory processing deficits (DeLuca et al., 1993) or motor slowing (Marshall et al., 1997) under-lie the impairments seen in CFS patients, whereas others have found deficits in areas such as memory and executive function, unrelated to sensory processing domain or speed (Marcel et al., 1996).

In addition, the underlying cause of the cognitive deficits observed in CFS remains unclear. As a result of the high prevalence of depression and anxiety found among CFS patients, many studies have assessed psychiatric symptoms in the CFS patients to determine their relation to cognitive performance. Most of these studies have shown that cognitive deficits persist in CFS, even after adjusting for the presence of psychiatric symptomatology (Cope, Pernet, Kendall, & David, 1995; DeLuca, Johnson, Ellis, & Natelson, 1997; DeLuca et al., 1993; DiPino & Kane, 1996; Grafman et al., 1993; Marcel et al., 1996; Schmaling et al., 1994; Smith et al., 1993). Several studies have, however, compared patients with CFS to those with major depression and found that they did not differ from one another in terms of overall neuropsychological performance (De Luca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994; Vollmer-Conna et al., 1997).

It has also been suggested that a disorder of the immune system may, by itself, produce cognitive decline. To address this issue, studies have compared CFS patients to patients with multiple sclerosis (MS), particularly because of the presence of fatigue in both disorders. In one study, investigators found that patients with MS obtained lower scores on all test measures compared to CFS patients and controls (Krupp, Sliwinski, Masur, Friedberg, & Coyle, 1994). Another study, however, reported that MS and CFS patients were not significantly different from one another, but both groups were more impaired than controls (DeLuca et al., 1993). To our knowledge, only one study has compared all three groups to one another (CFS vs. MS vs. depression) and to controls. This investigation reported that both the CFS and depression patients were significantly impaired in comparison to controls, but patients with MS did not differ statistically from either patient group or controls (DeLuca et al., 1995).

To address the differences in outcome among the foregoing studies, we compared the neuropsychological performance of patients with CFS, MS, and depression. Psychiatric symptomatology, including depression and anxiety, were also evaluated in the same individuals to determine their relation to cognitive performance.

Method

Participants

A total of 101 patients participated in the study, all of whom provided informed consent consistent with institutional guidelines. Of these, 29 met the modified Centers for Disease Control (CDC) criteria for CFS (Schluederberg et al., 1992). Their mean age was 39.9 years. They had an average of 15.8 years of education. Their average duration of illness was 5.7 years. The CFS patients were recruited through the Chronic Fatigue Syndrome Cooperative Research Center at the Brigham and Women's Hospital, Boston. Twenty-three out of the 29 patients were found to have either an abnormal Rhomberg or an abnormal tandem gait on neurologic examination, but no neurologic disease was diagnosed in any participant (such findings are seen in 10%-20% of CFS patients seen at Brigham and Women's Hospital). Six patients had a history of depressive illness prior to the diagnosis of CFS, with 4 out of this group currently depressed. A total of 15 patients were on low doses (5-50 mg/day) of tricyclic antidepressant medication, primarily to treat coexisting sleep pathology.

A total of 24 MS patients participated in the study. All MS patients met the case definition for clinically definite MS (Poser et al., 1983) and had the relapse-remitting form of MS. The mean age of the MS group was 39.6 years, and they had an average of 14.3 years of education. Their mean disability rating was 1.6 (range = 0-4), based on the Expanded Disability Status Scale (Kurtzke, 1983). The MS patients were recruited from the MS Unit at Brigham and Women's Hospital. Three of the MS patients had a history of psychiatric illness: 1 patient had a past history of depression, 1 patient reported a current depressive episode, and 1 patient had a history of bipolar disorder. All three of these participants were taking antidepressant medication and were medically stable.

The depression group consisted of 23 patients. Their average age was 39.5 years, and they had a mean education of 14.1 years. Within this group, 20 patients had a history of major depressive disorder, and 3 had a diagnosis of bipolar disorder, depressed type. The diagnoses were based on clinical interviews obtained by research psychiatrists. Nineteen of the 23 patients in the depression group were currently on antidepressant medication, 9 were taking antipsychotic medication (e.g., Haldol, Melleril, or Stelazine), and 9 were on mood-stabilizing medication (e.g., lithium or carbamazepine). The depression patients were recruited from among inpatients and outpatients at the Brigham and Women's Hospital, the Deaconess Medical Center, and the Freedom Trail Clinic at the Erich Lindemann Mental Health Center, Boston.

A total of 25 control individuals participated in the study. Their mean age was 38.8 years, and they had an average of 16.3 years of education. They were recruited from advertisements in the local community. None had evidence of debilitating chronic fatigue within the past 6 months (first major criterion of the CDC case definition for CFS) or were suffering from any chronic organic or psychiatric illness that could produce chronic fatigue (second major criterion of the CDC case definition for CFS). All consecutively recruited participants who met study criteria agreed to participate.

The participants in the four groups did not differ in terms of age. There was, however, a significant difference among the groups in terms of education (p < .003). Post hoc planned comparisons indicated that the CFS patients and the controls did not differ in mean educational level, but the MS and depression groups had significantly less education than the other two groups.

Neuropsychological Test Battery

The participants were administered a neuropsychological test battery that contained a large number of standardized neuropsychological tests, as well as a battery of tasks adapted for administration by computer. The computerized battery was included because the patient groups examined in this study frequently complain of fatigue and slowness and computerized tasks can measure both speed and accuracy of response.

The standard neuropsychological battery evaluated attention by means of the Digit Span Forward (Wechsler, 1945); language ability was assessed by the Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1982) and verbal fluency (Benton & Hamsher, 1976); memory was evaluated by the Russell version of the Wechsler Memory Scale (WMS; Russell, 1975; Wechsler, 1945) and a word list learning test (Weingartner, Cohen, Murphy, Martello, &Gerdt, 1981); set shifting and conceptualization (aspects of executive function) were assessed by means of the Stroop Interference Test (Stroop, 1935) and Proverb Interpretation (Gorham, 1956); spatial ability was evaluated by figure copying, as assessed by figures from the WMS(Wechsler, 1945) and cube copying from the Consortium to Establish a Registry for Alzheimer's Disease battery (Morris et al.,1989); and overall IQ was estimated by means of the vocabulary subtest of the Wechsler Adult Intelligence Scale (Wechsler, 1958).

The computerized battery evaluated comparable cognitive domains, using tasks adapted from standard neuropsychological procedures. A continuous performance task, which was based on standard tests of sustained attention (Rosvold, Mirsky, Sarason, Bransome, & Beck, 1956), was used to assess attentional capacity; an associate learning test measured verbal memory, and a pattern memory test assessed nonverbal memory (Warrington & James, 1967); spatial ability was evaluated by pattern matching (Acker, 1982) and a hand-eye coordination test (Hanninen, Eskilinen, & Nurminen, 1976); and set shifting was evaluated by a task that was an adaptation of a switching-attention test by Eckerman, Carrol, and Foree (1985).

Assessment of Psychiatric Symptoms

Psychiatric symptomatology was evaluated by means of the Hopkins Symptom Checklist-Revised (SCL-90-R; Derogatis & Melisaratos, 1983). The SCL-90-R is a self-administered instrument that assesses a broad range of symptomatology and consists of nine subscales, including depression, anxiety, somatization, obsessive-compulsive symptoms, inter-personal sensitivity, hostility, phobic anxiety, paranoid ideation, and psychoticism.

Statistical Analysis

Multivariate analysis of covariance (MANCOVA), analysis of covariance (ANCOVA), and analysis of variance (ANOVA) were used to compare the scores of the patient groups and the controls. When post hoc comparisons were performed following these analyses, Duncan's multiple range test was used to adjust for multiple comparisons.

In addition, an overall impairment rating (IR) was calculated for each participant to facilitate comparison with studies that have used a similar measure to contrast the performance of CFS patients to other patient groups (DeLuca et al., 1995; Krupp et al., 1994). The IR uses the standard deviation of the control group to determine the degree to which the patients differ from controls. The IR is calculated in the following manner: Scores for each test that were within 1 SD of the control group are assigned an IR of 0; scores between 1 and 2 SDs below the control group are assigned an IR of 1; scores between 2 and 3 SDs below the control group are assigned an IR of 2; and scores greater than 3 SDs below the control group receive an IR of 3. The IR scores for each test are then summed together for each participant and divided by the number of tasks the participant completed to give an overall IR for each participant. This summed IR was adjusted for any difference in education among the groups and used in subsequent analyses. It should be noted that 92 of 101 participants completed all of the tests in the battery. Of the remaining 9 participants, 7 completed all but one or two of the tests in the battery, and 1 participant completed 17 out of the 22 tests. Thus, the IR was based on the mean number of tests completed, rather than on the sum of the ratings assigned to each test.

Multiple regression analysis was used to evaluate the relation between the cognitive measures and potential modifying factors of psychiatric symptomatology and medication.

Results

Table 1. Mean Test Scores Adjusted for Education: Controls and Patients With CFS, MS, and Depression

Table 2. ANCOVAs and MANCOVAs for Controls and Patients With CFS, MS, and Depression

To further examine the specific cognitive tests within each of these three domains that differed among the groups, a series of post hoc planned comparisons, using ANCOVA, were performed, with years of education as the covariate. The results of the ANCOVAs are also shown in Table 2, which also summarizes the neuropsychological tests on which the patient groups differed from the controls.

The post hoc planned comparisons within the memory domain demonstrated that on three out of four of the memory tests, all three patient groups were impaired in comparison to controls. These tests were the Mental Quotient (MQ) of the WMS, the Associate Learning task, and the List Learning task. Two of the three patient groups, the CFS group and the depression group, were significantly impaired in comparison to controls, on the nonverbal Pattern Recognition task. Only the MS group was not impaired in comparison to controls on this task.

When memory performance was compared among the patient groups, the results varied depending on the task in question and the groups that were being compared. The CFS patients performed significantly better than the MS group on one of the memory tasks (the MQ subtest of the WMS). There was no statistical difference between the CFS and MSgroups on the other three memory tasks (Associate Learning, List Learning, Pattern Recognition). In comparison to the depression patients, the CFS group performed better on two of the memory tasks (MQ of the WMS and Associate Learning) but showed no difference in performance on the other tasks (List Learning and Pattern Recognition). The depression and MS groups did not differ from one another on the memory tasks.

The post hoc planned comparisons within the language domain indicated that the depression patients were the most impaired overall. This group was impaired in comparison to the controls on all four of the language tests (Boston Naming, letter fluency, and the category fluency tests for animals and vegetables). The CFS and MS patients were only impaired in comparison to controls on the category fluency test for animals.

When language performance was compared among the patient groups, the depression patients were impaired in comparison to the CFS and MS patients on one task (the Boston Naming Test). The depression patients were also impaired in comparison to the CFS group on the letter fluency task. However, on both of the category fluency tasks, the patient groups did not differ from one another.

The post hoc planned comparisons within the spatial domain indicated, although several of the tests approached significance (contributing to the overall significance of the domain), only the cube copying task significantly differentiated the groups. On this task, the depressed patients were impaired in comparison to the controls. However, none of the patient groups were significantly different from one another on this task.

ANOVA was then performed to examine the differences among the groups in the summed IR. This revealed an overall significant difference among the groups (F = 5.58, p < .0014). Post hoc planned comparisons demonstrated that the depression group and the MS group were significantly impaired in comparison to the controls. The CFS group was not impaired in comparison to the controls on this overall measure of impairment. The MS group and the CFS group were not significantly different from one another (see Figure 1).

Figure 1. This figure compares the mean summed IR scores in the four groups of participants (NC = normal controls; CFS = chronic fatigue syndrome; MS = multiple sclerosis; DEP = depression). The data were covaried for years of education. A significant difference compared to controls at p < .05 is indicated by (*) and a significant difference compared to CFS patients at p < .05 is indicated by (#).

Psychiatric Symptomatology

ANOVA was used to compare the degree of psychiatric symptomatology among the groups. All of the three patient groups had significantly higher total scores on the SCL-90-R in comparison to the controls.

In addition, the SCL-90-R total score was significantly higher in the depression patients in comparison to the other patient groups (see Table 3).

Table 3. Mean Total and Subscale Scores on SCL-90-R for Controls Versus Patients With CFS, MS, and Depression

In addition, the depression patients had significantly higher scores than the CFSandMSpatients on7out of 10 of the subscales of the SCL-90-R (they did not differ on the somatization, obsessive-compulsive, and hostility subscales). The CFS patients had higher mean scores than the MS patients on 6 of the 10 subscales, including depression, anxiety, phobic anxiety, somatization, obsessive-compulsive, and hostility. The MS patients had the lowest level of psychiatric symptomatology in comparison to the other patient groups.

Because each of the patient groups was significantly more symptomatic in the area of depression, a separate MANCOVA was performed for each of the five cognitive domains, covarying the scores from the depression subscale of the SCL-90-R, in addition to education.

The same three cognitive domains that differed among the groups following the MANCOVA in which only education was covaried differed among the groups when depression scores were also covaried (i.e., memory, language, and spatial ability). In addition, the level of significance was similar. The MANCOVA for the cognitive domain of memory was statistically significant at the .01 level (F = 2.45, p < .005); the MANCOVAs for language and spatial ability were significant at the .05 level (F = 2.077, p < .019 and F = 2.03, p < .023, respectively).

Post hoc planned comparisons between the patient groups and the controls within the memory domain revealed a very similar pattern of impairment to that found after covarying education alone. Once again, all three patient groups were significantly impaired in comparison to controls on three out of the four memory tasks (MQ of the WMS, List Learning, and Associate Learning). Two of the three patient groups (depression and CFS) were also impaired in comparison to controls on the Pattern Memory task.

When the patient groups were compared with one another in memory performance with depression covaried, the differences among the groups were very similar to those following the covariance of education alone. The CFS group continued to have a significantly higher score on the MQof the WMS than either the MS group or the depression group; the CFS group also continued to have significantly better scores on the Associate Learning task than the depression patients. The depression patient group did not differ significantly from the MS group on any of the memory tasks.

The pattern of difference among the groups in the spatial domain was also relatively unchanged when depression was covaried. There continued to be a significant difference among the patient groups on the cube copying test when performance was adjusted for level of depression in addition to education.

In the language domain, the differences among the groups were, however, attenuated following a statistical adjustment for level of depression in addition to education. All three groups continued to differ in comparison to controls on the category fluency test for animals, and the depression patients were also impaired in comparison to controls on the Boston Naming Test. The difference between the depression patients and the controls on the other fluency tasks (verbal fluency and category fluency for vegetables) were no longer significant when performance was adjusted by the level of depression.

A series of regression analyses were also conducted to determine if the medications used by the participants had an impact on cognitive function, over and above that of the psychiatric symptoms of the participants. For each regression, the dependent variable was a cognitive test measure and the independent variables were the total score on the SCL-90-R and a code representing medication use (no medication = 0, antidepressant medication = 1, the number of other medications [i.e., antipsychotic, mood stabilizing, or tranquilizing medication] = 2-4). In no instance was medication use a significant predictor of cognitive test score beyond that contributed by psychiatric symptoms.

Discussion

These findings indicate that cognitive deficits are found in CFS patients and MS patients, but they are mild in comparison to those seen in depression. When the three patient groups are compared, the depression patients have the greatest overall level of impairment. The MS patients appeared to be slightly more impaired than the CFS patients, particularly with respect to the summed IR, but this difference was not significant. In addition, the depression patients had evidence of a different pattern of impairment across the five cognitive domains than either the CFS or MS patients.

Although the CFS patients were only mildly impaired in comparison to the depression patients, there was evidence of impairment in comparison to controls. The CFS group was impaired on all four of the memory tasks compared to controls, including the nonverbal Pattern Recognition task. On one of the memory tasks, the MQ of the WMS, both the depression group and the MS group were significantly more impaired than the CFS patients. In addition, compared to the control participants, CFS patients were impaired on one of the language tasks (category fluency for animals), suggesting difficulties with both language skills and planning and organizational abilities related to executive function.

These findings also clearly demonstrate that MS produces cognitive impairments. In agreement with numerous other studies, cognitive impairments were primarily found in the memory domain (Beatty &Monson 1991a, 1991b, 1994; Brassington & Marsh, 1998; D'Esposito et al., 1996; Diamond, DeLuca, Kim, & Kelley, 1997; Grafman, Rao, Bernardin, & Leo, 1991; Litvan & Grafman, 1988; Minden & Schiffer, 1990; Penman, 1991; Rao, 1995). Impaired memory function has, in fact, been reported in 40% to 60% of patients (Rao et al., 1993).

ThesummedIR, whichevaluated performance across all cognitive domains, suggested that the MS patients were slightly more impaired than the CFS patients, although this difference did not reach statistical significance. Previous studies that havecomparedpatients with CFS and MS have found differences in the level of impairment between the groups (e.g., DeLuca et al., 1995; Krupp et al., 1994), although this finding has not been uniformly reported (e.g., DeLuca et al., 1993).

The depression patients, as previously mentioned, were impaired over a broad range of cognitive domains compared to the other two patient groups and had evidence of impairment in all five cognitive domains when compared to controls. Most of these differences remained after adjustment for degree of depressive symptomatology. In addition, the summed IR demonstrated that the depression patients were significantly more impaired overall, compared to CFS patients and to the controls, but they were not significantly different from the MS group.

These findings are in agreement with many studies demonstrating that patients with depression can have substantial cognitive impairments (Byrne, 1977; Channon, Baker, & Robertson, 1993; Cornblatt, Lenzenweger, & Erlennmeyer-Kimmling, 1989; Elliot et al., 1996; Goodwin, 1997; Hertel & Rude, 1991; Lemelin & Baruch, 1998; Mialet, Pope, & Yurgelun-Todd, 1996; Paradiso, Lamberty, Garvey, & Robinson, 1997). In addition, many reports indicate that cognitive impairment persists in participants with depression even when their depression has remitted or levels of depression have been covaried (Abas, Sahakian, & Levy, 1990; Ferrier et al., 1991; Paradiso et al., 1997; Trichard et al., 1995).

Our findings are, however, at variance with several previous reports in which patients with DEP were compared to CFS patients (DeLuca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994; Vollmer-Conna et al., 1997). In these latter studies, the CFS patients were reported to be impaired to approximately the same degree as the patients with depression.

One possible reason for the discrepancy between these previous studies and our study is that the patient groups examined may have differed in terms of severity of illness. In particular, the depression patients in this study were more depressed in comparison to those used in several previous reports. All of the participants in this study had either a diagnosis of major depressive disorder or bipolar disorder (depressive type), and the majority (19 of 23) were on antidepressant medication. In contrast, in previous studies comparing CFS and depression patients, the patients with depression were reported to have had either a diagnosis of dysthmia or depression, and only a minority were on antidepressant medication (DeLuca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994).

Likewise, in the one previous study comparing the three patient groups examined here, patients with CFS had symptoms of "moderate" severity and presented with cognitive complaints (DeLuca et al., 1995). The MS group in that study was specifically chosen to contrast patients with "mild" physical symptoms with patients with CFS, based on a specific cutoff on the Expanded Disability Status Scale (Kurtzke, 1983). In contrast, whereas we used similar research criteria to define the CFS and MS groups in our study, we did not select participants on the basis of the severity of physical disability or the presence of cognitive complaints. Moreover, numerous studies have demonstrated that the presence of cognitive impairments in MS can be unrelated to the physical disability measured by the Expanded Disability Status Scale (e.g., Rao, Leo, Bernardin, & Unverzagt, 1991). It therefore seems likely that our study included a more clinically heterogeneous group of participants with CFS and MS.

There has been much discussion about the role that psychiatric symptomatology plays in the cognitive deficits observed in the patient groups. We assessed a broad range of psychiatric symptomatology in this study but found that the most consistent difference between the patient groups and the controls was the presence of depressive symptomatology. We therefore adjusted neuropsychological test scores for levels of depression. Our results support the view that the presence of depression cannot solely account for the cognitive differences among the patient groups or between the patient groups and the controls.

In summary, our findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients. They are, for example, consistent with reports of brain alterations in CFS patients (e.g., Lange et al., 1999).

Although the cognitive deficits of CFS patients appear somewhat similar to those of patients with MS, there was a trend in this study for the MS patients to be slightly more impaired. In addition, patients with depression were clearly more impaired than either of the other patient groups. These findings suggest that the degree of cognitive impairment observed in CFS, MS, and depression is highly dependent on the criteria used to select the patients. Among a heterogeneous sample of CFS and MS patients, cognitive impairments will be present, but relatively mild in nature. The cognitive impairments seen among patients with depression appear, however, to vary greatly, depending on the severity of illness in the patients. Moreover, even after adjusting for level of depression, differences in degree of cognitive impairment among the groups are relatively unchanged. This suggests that the underlying causes of cognitive deficits in CFS, MS and depression vary.

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