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Efficacy and specificity of intensive cognitive rehabilitation of attention and executive functions in multiple sclerosis
Journal of the Neurological Sciences 288 (2010) 101–105
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Efficacy and specificity of intensive cognitive rehabilitation of attention and executive functions in multiple sclerosis Mattioli Flavia a,⁎, Chiara Stampatori a, Deborah Zanotti a, Giovanni Parrinello b, Ruggero Capra c a b c
Clinical Neuropsychology, Spedali Civili of Brescia, V. Nikolajewka, 13, 25123 Brescia, Italy Medical Statistic Section, University of Brescia, Italy Multiple Sclerosis Center, Spedali Civili of Brescia, Italy
a r t i c l e
i n f o
Article history: Received 5 May 2009 Received in revised form 17 September 2009 Accepted 23 September 2009 Available online 13 October 2009 Keywords: Multiple sclerosis Attention Information processing Rehabilitation
a b s t r a c t Objective: To evaluate the efficacy of a computer-based intensive training program of attention, information processing and executive functions in patients with clinically-stable relapsing–remitting (RR) multiple sclerosis (MS) and low levels of disability. Design, patients and interventions: A total of 150 patients with RR MS and an Expanded Disability Status Scale (EDSS) score of ≤ 4 were examined. Information processing, working memory and attention were assessed by the Paced Auditory Serial Addition Test (PASAT) and executive functions by the Wisconsin Card Sorting Test (WCST). Twenty patients who scored below certain cut-off measures in both tests were included in this double-blind controlled study. Patients were casually assigned to a study group (SG) or a control group (CG) and underwent neuropsychological evaluation at baseline and after 3 months. Patients in the SG received intensive computer-assisted cognitive rehabilitation of attention, information processing and executive functions for 3 months; the CG did not receive any rehabilitation. Setting: Ambulatory patients were sent by the MS referral center. Outcome measures: Improvement in neuropsychological test and scale scores. Results: After rehabilitation, only the SG significantly improved in tests of attention, information processing and executive functions (PASAT 3″ p = 0.023, PASAT 2″ p = 0.004, WCSTte p = 0.037), as well as in depression scores (MADRS p = 0.01). Neuropsychological improvement was unrelated to depression improvement in regression analysis. Conclusions: Intensive neuropsychological rehabilitation of attention, information processing and executive functions is effective in patients with RR MS and low levels of disability, and also leads to improvement in depression. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Cognitive dysfunction is common in multiple sclerosis (MS), affecting approximately 43–70% of patients, depending on the setting of the study and investigational accuracy [1]. In patients with MS, cognitive dysfunction is thought to be related to poor social integration [2] and employability. The main cognitive areas affected by MS are attention, information processing, executive functions, memory and visuo-spatial abilities [3]. Depression is also a common symptom in the MS population and often appears to be associated with cognitive impairment [4], although the relationship between
⁎ Corresponding author. Tel.: +39 030 2027226, +39 328 5969276 (mobile); fax: +39 030 2027201. E-mail address: fl[email protected] (M. Flavia). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.09.024
neuropsychological deficits and depression is unclear. Cognitively impaired MS patients are less employable, less active (both socially and in the home) and more vulnerable to psychiatric illness than MS patients with only physical disabilities [5]. A consistent positive link has been found between depression and cognitive functioning, particularly with poor working memory, learning and planning abilities [6,7]. On the other hand, depression can also be explained by disability, rather than the neuropsychological deficits seen in newly-diagnosed MS [8]. In magnetic resonance imaging studies, cognitive impairment has been related to several brain lesion measures, particularly T1 and T2 lesion load, as well as diffuse brain damage, brain atrophy [9–11], white matter damage with normal appearance in benign MS [12] and gray matter damage with normal appearance [13]. Gray matter atrophy has otherwise been related to long-term disability in a 20-year follow-up study [14]. Although some studies with immunomodulatory drugs indicate positive effects on cognitive impairment [15], this kind of treatment is not an accepted strategy. A review of cognitive rehabilitation studies
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investigating the effectiveness of neurobehavioral rehabilitative procedures on neuropsychological and psychological outcomes reported that cognitive-behavioral approaches are beneficial, although the diversity of psychological intervention and the multiple outcome measures prevented definite conclusions from being drawn [16]. In particular, 16 randomized studies were reviewed, with a total of 1006 cases, a length of follow-up from start of treatment ranging from 5 weeks to 4 years, and psychological interventions addressing both mood and cognition. Most studies included patients with differing levels of disability by Expanded Disability Status Scale (EDSS) and different durations of disease. Benedict et al. [2] studied the effectiveness of cognitive-behavioral intervention in 15 patients with cognitive impairment associated with marked behavioral changes. Patients were randomly assigned to receive neuropsychological counseling or psychotherapy. After 2 weeks, subjects in the active treatment group showed significant improvements in disinhibition and socially aggressive behavior, compared with patients assigned to standard psychological counseling. Jonsson et al. [17] randomized 40 patients with MS who had mildto-moderate cognitive and behavioral impairment to either cognitive treatment or non-specific “mental stimulation”. Treatment lasted an average of 46 days. Short-term effects were assessed immediately after treatment and long-term effects after 6 months. Short-term effects on cognitive measures were not significant, but the specific cognitive treatment group reported significantly less depression, measured by the Beck Depression Inventory (BDI). After 6 months, only this group showed a significant effect on the visuo-spatial memory task and depression scores. The efficacy of computer-based retraining of four different attention domains has been studied in a single-group, open study of 22 patients with MS. Patients received 12 sessions of attention training. A computerized attention test battery was used to test performance at baseline, after each training period, and in the following 9 weeks. Any effects on activities of daily living were assessed using a self-rating inventory. Significant improvements in performance, which remained stable for 9 weeks, were achieved by the attention training program [18]. In a randomized, double-blind, controlled trial, Solari et al. [19] assessed the efficacy of computer-aided retraining of memory and attention in MS patients. At 8 weeks, 45% of patients who received memory and attention retraining showed an improvement in at least two scores from the Brief Repeatable Battery of Neuropsychological Tests (BRBNT), compared with 43% of control patients (odds ratio 1.07). The authors concluded that the trial did not support the efficacy of specific memory and attention training in MS. A study that compared psychotherapy with placebo found lower levels of depression but no reduction in anxiety scores in the group that received psychotherapy [20]. Other studies have compared cognitivebehavioral therapy with psychotherapy [21], and have reported lower depression levels with cognitive-behavioral therapy versus placebo [22], without significant differences between groups. The lack of conclusiveness of these results appears to be mainly caused by methodological problems, including inaccurate selection of homogeneous MS patients (in terms of disability, disease duration and specified neuropsychological deficits), incomplete neuropsychological evaluation at inclusion, unstandardized training tools for specific cognitive functions, and inadequate outcome measures. We conducted a double-blind, controlled study on a homogeneous group of relapsing–remitting (RR) MS patients with low levels of disability and a stable clinical course in the previous year. We used an intensive cognitive rehabilitation procedure specific for information processing, attention and executive function abilities, which were impaired in all of the enrolled patients. Appropriate neuropsychological measures and functional scales were obtained before and at the end of the training.
2. Materials and methods 2.1. Patients Between June 2007 and December 2008, 150 patients affected with RR MS, according to Poser and Brinar [23]criteria were examined. All patients had an EDSS [24] score of ≤4. Information processing, working memory and attention were assessed by the Paced Auditory Serial Addition Test 2″ and 3″ (PASAT [25]) and executive function by the Wisconsin Card Sorting Test (WCST [26]). Patients were included in the study if their scores in both tests fell below z = −1.5 for PASAT (either 2″ or 3″ interval) and T = 35 for WCST in any of the following measures: total errors (WCSTte), number of perseverative errors (WCSTpe) and number of perseverative responses (WCSTpr). Exclusion criteria were the following: one or more clinical exacerbations in the previous year, loss of visual acuity, ongoing major psychiatric disorder, substance abuse and a Mini Mental State Examination (MMSE [27]) score of b24. Twenty clinically-stable patients with RR MS were included in the study. Eligible patients providing written informed consent were casually assigned by a blinded psychologist to a study group (SG) and a control group (CG). Each group contained 10 patients. 2.2. Interventions and outcome assessment The SG underwent intensive neuropsychological treatment for 3 consecutive months, on an individual basis. Each session lasted for 1 h, with a frequency of three sessions per week. Sessions consisted of computer-assisted training of attention, information processing and planning exercises for executive functions. The software used, Plan a Day and Divided Attention, were part of the RehaCom package (www. Schuhfried.at), a software package with a special keyboard with large buttons, which limits the interference of motor and coordination impairments and expertise on computer use. The Plan a Day procedure trains the patient's ability to organize, plan and develop solution strategies employing realistic simulations of a set of scheduled dates and duties to be organized at specific places in a small city map. Times for planning and schedules were registered for each patient at each session and only improvement and acquisition of sufficient planning abilities for fulfilling all the appointments required let the level to be ameliorated in the following treatment session. This was considered a strategic behavior acquisition. In Divided Attention, the patient is required to simulate a train driver, carefully observing the control panel of the train and the countryside. Several distractions, such as crossing animals, and train speed must be taken into account with increasing levels of difficulty. Specific speed information training, which has been shown to be effective in patients with brain injuries, was combined with each Divided Attention session, consisting of a modified PASAT task with numbers, words and months of the year [28]. The control group did not receive any rehabilitation. Both the neuropsychological evaluations and the cognitive rehabilitation sessions were performed respectively by two blinded trained psychologists, in a quiet environment, according to published procedures. A detailed neuropsychological assessment was performed at baseline (T0) before the rehabilitation and 3 months later (at the end of rehabilitation for SG) (T1). The complete neuropsychological assessment includes some subtests of the Italian version of the BRBNT [29]: Selective Reminding Test for verbal learning — consistent long-term retrieval (SRT/CLTR) and delayed retrieval (SRT/DR), the 10/36 Spatial Recall Test for visuospatial learning — long-term retrieval (10/36 SRT LTR) and delayed recall (10/36 SRT DR), the Symbol Digit Modalities Test (SDMT) and the PASAT 2″ and 3″[25] for attention and working memory, the WCST
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[26] for reasoning ability and cognitive flexibility (WCST te, pe, pr), controlled oral word association test with phonemic and semantic cues (COWA/P, COWA/S) for cognitive flexibility and word fluency [30], divided attention of Test of Everyday Attention (TEA) — median for auditory stimulus (am), for visual stimulus (vm), total omitted stimuli (to) and total errors (te) [31] and two questionnaires: the Montgomery–Asberg Depression Rating Scale (MADRS) [32] for mood state, and the self-reported Multiple Sclerosis Quality of Life (MSQoL) [33]. To minimize familiarity and learning effect, two alternative forms of each test (except for WCST, TEA and questionnaires) were employed through testing sessions, according to an AB design. 2.3. Statistical analysis Descriptive statistics are expressed as mean± SD and/or as median and interquartile ranges, according to distribution. Groups were compared using the nonparametric Wilcoxon test for continuous variables, with corrections for multiple comparisons. A linear regression was conducted with the following variables: group (factor), age and EDSS for each test, as well as T1–T0 (delta) MADRS score, in order to control for changes in depression affecting neuropsychological changes.
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Table 2 Neuropsychological test scores in the study group (SG) and the control group (CG) at baseline (T0). CG N = 10 PASAT 2″ PASAT 3″ WCSTte WCSTpr WCSTpe COWA/P COWA/C TEAam TEAvm TEAto TEAte SRT/CLTR SRT/DR 10/36 SRT LTR 10.36 SRT DR SDMT MADRS MSQoL
00.00 14.25 48.50 31.75 33.25 23.00 29.00 547.50 902.75 2.75 3.00 14.00 4.00 13.25 4.00 30.25 6.25 165.5
0.00 18.50 55.50 53.50 40.00 27.50 39.50 698.50 1014.00 6.00 3.00 19.00 5.50 15.50 5.00 40.50 9.00 197.0
p valuea
SG N = 10 11.75 24.50 74.75 57.75 48.75 32.25 41.75 846.00 1093.00 8.75 10.50 19.75 6.75 20.00 6.00 49.75 15.50 202.0
0.00 11.50 55.75 34.50 37.50 23.75 32.50 560.75 864.50 2.25 4.25 18.00 5.25 14.25 4.00 27.25 3.25 148.5
6.50 20.00 64.50 54.50 49.50 29.00 37.50 577.00 933.00 5.00 7.00 19.50 6.00 15.00 5.50 32.50 12.00 168.0
19.0 28.50 76.00 66.75 53.00 34.75 42.00 613.50 994.50 7.75 10.25 26.00 8.50 16.75 6.75 37.50 19.00 178.5
p = 0.47 p = 0.91 p = 0.44 p = 0.61 p = 0.3 p = 0.94 p = 0.97 p = 0.56 p = 0.46 p = 0.56 p = 0.24 p = 0.32 p = 0.35 p = 0.63 p = 0.82 p = 0.25 p = 0.91 p = 0.23
For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
3. Results All 20 patients were female. The baseline clinical characteristics of the two groups were not significantly different (Table 1). At baseline, there were no significant differences between the SG and CG groups in all neuropsychological tests (all p values N 0.05; Table 2). After 3 months (T1), the comparison of neuropsychological scores between the SG and CG groups showed statistically significant differences in PASAT 2″ (p = 0.004), WCSTte (p = 0.037), WCSTpe (p = 0.051) and MADRS (p = 0.01) tests (Table 3). These results indicate that the SG group performed better in tests of information processing/attention and decision making, and also had lower depression scores. The differential T1–T0 (delta) scores for each neuropsychological test were compared between the SG and CG groups, with statistically significant differences in PASAT 3″ (p = 0.023), PASAT 2″ (p = 0.004), WCSTte (p = 0.037), WCSTpe (p = 0.051), and MADRS (p = 0.01) (Table 4). The between-group differences were confirmed when the comparisons were adjusted for the following confounding variables: EDSS, age, and T0 score in neuropsychological tests, applying a linear regression model. In particular, the regression analysis showed a significant difference in delta scores between the CG and SG groups for the TEAar (p = 0.031), TEAte (p = 0.0.04) and COWA/P (p = 0.009) tests. In the linear regression analysis, WCSTte appeared to be significantly affected by age, with younger patients showing significantly greater improvements than older patients (p = 0.052). These results indicate a significant difference between the two groups in neuropsychological profiles, with the SG group showing
Table 1 Clinical characteristics of the study group (SG) and the control group (CG). CG N = 10 Age (years) Education (years) Illness (years) EDSS
42.25 8.00 11.75 1.5
44.00 9.00 18.50 1.5
p valuea
SG N = 10 48.75 12.50 26.00 2.5
41.00 5.75 13.25 1.1
42.00 8.00 16.50 2.5
53.00 8.00 18.00 3.2
p = 0.855 p = 0.157 p = 0.419 p = 0.792
a, b, and c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. EDSS = Expanded Disability Status Scale. a Wilcoxon test.
significantly greater improvements in tests of attention/information processing (PASAT, TEA) and executive functions (WCST, COWA/P), as well as a significant reduction in depression score. A possible indirect influence on neuropsychological improvement caused by reductions in MADRS scores was excluded by correcting for delta MADRS scores in the regression analysis, which was not statistically significant (Table 5). In addition, the changes in R2 coefficients of determination in the model were always irrelevant. 4. Discussion In our study of MS patients with low levels of disability and clinically-stable disease in the previous year, we found that patients harbouring deficits in attention and information processing, as well as poor executive functions, significantly improved after undergoing Table 3 Neuropsychological test scores in the study group (SG) and the control group (CG) after 3 months (T1). GC N = 10 PASAT 2″ 0.00 0.00 12.75 17.00 PASAT 3″ 14.25 18.50 24.50 11.50 WCSTte 21.50 45.00 62.75 15.25 WCSTpr 21.5 37.0 59.5 16.0 WCSTpe 14.25 28.50 42.50 11.25 COWA/P 17.75 27.50 39.75 27.50 COWA/S 29.00 35.50 42.00 27.25 TEAam 551.75 580.00 670.75 596.50 TEAvm 829.75 1040.00 1105.50 857.25 TEAto 3.00 6.00 6.75 2.00 TEAte 4.0 6.5 8.0 2.0 SRT.CLTR 7.0 16.0 29.0 14.0 SRT.DR 4.25 5.50 7.75 4.50 10/36 SRT LTR 11.25 14.00 17.50 14.50 10/36 SRT DR 3.25 4.00 5.75 4.25 SDMT 28.50 38.00 45.75 31.00 MADRS 8.75 14.00 22.50 3.00 MSQoL 165.5 197.0 202.0 148.5
GS N = 10
pa
22.00 27.00 p = 0.004 20.00 28.50 p = 0.913 20.00 27.50 p = 0.037 17.5 27.5 p = 0.088 14.50 18.75 p = 0.051 36.00 44.50 p = 0.236 44.50 47.00 p = 0.398 724.00 848.75 p = 0.097 902.00 1040.00 p = 0.771 3.00 4.75 p = 0.141 2.5 4.5 p = 0.104 19.0 29.5 p = 0.559 6.50 8.75 p = 0.607 17.50 19.50 p = 0.204 6.00 6.75 p = 0.353 34.50 44.75 p = 0.942 4.50 6.50 p = 0.01 168.0 178.5 p = 0.236
For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
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Table 4 Comparison of delta (T1–T0) scores for each test in the study group (SG) and the control group (CG). GC N = 10
pa
GS N = 10
PASAT 2″ 0.00 0.00 12.75 17.00 22.00 27.00 p = 0.004 PASAT 3″ 0.00 7.00 26.50 24.50 36.00 44.75 p = 0.023 WCSTte 21.50 45.00 62.75 15.25 20.00 27.50 p = 0.037 WCSTpr 21.5 37.0 59.5 16.0 17.5 27.5 p = 0.08 WCSTpe 14.25 28.50 42.50 11.25 14.50 18.75 p = 0.051 COWA/P 17.75 27.50 39.75 27.50 36.00 44.50 p = 0.236 COWA/S 29.00 35.50 42.00 27.25 44.50 47.00 p = 0.398 TEAam 551.75 580.00 670.75 596.50 724.00 848.75 p = 0.097 TEAvm 829.75 1040.00 1105.50 857.25 902.00 1040.00 p = 0.771 TEAto 3.00 6.00 6.75 2.00 3.00 4.75 p = 0.141 TEAte 4.00 6.5 8.00 2.00 2.5 4.5 p = 0.104 SRT/CLTR 7.00 16.00 29.00 14.00 19.00 29.50 p = 0.559 SRT/DR 4.25 5.50 7.75 4.50 6.50 8.75 p = 0.607 10/36 SRT LTR 11.25 14.00 17.50 14.50 17.50 19.50 p = 0.204 10/36 SRT DR 3.25 4.00 5.75 4.25 6.00 6.75 p = 0.353 SDMT 28.50 38.00 45.75 31.00 34.50 44.75 p = 0.942 MADRS 8.75 14.00 22.50 3.00 4.50 6.50 p = 0.01 MSQoL 142.50 155.00 184.50 165.75 189.00 208.75 p = 0.285 For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
cognitive training specifically tailored for the impaired abilities. There was no generalization to other neuropsychological functions. The patients who received cognitive training also showed a significant decrease in depression score. This finding indicates that specific neuropsychological rehabilitation tailored to the clinical deficits of the patient can improve both the cognitive deficit itself and mood state. A non-specific effect of decreased depression on neuropsychological improvement at follow-up was excluded by controlling for delta MADRS scores in the regression analysis, as well as by the fact that a selective improvement in trained functions was achieved by rehabilitated patients. If there was a non-specific effect of reduced depression, then an improvement in all the neuropsychological tests (including, for example, memory and visuo-spatial abilities) would be expected. Our study focused on rehabilitation of attention, information processing and executive functions, which are frequently impaired in patients with MS and cause functional dependence and depression [3]. Information processing refers to the ability to maintain and manipulate information for a short time period (working memory)
Table 5 Results of linear regression corrected for depression score (delta MADRS).
PASAT 2″ PASAT 3″ WCSTte WCSTpr WCSTpe COWA/P COWA/S TEAam TEAvm TEAto TEAte SRT/CLTR SRT/DR 10/36 SRT LTR 10/36 SRT DR SDMT MADRS MSQoL
Beta weights
R2
R2 changes
− 0.234 − 0.436 0.662 0.876 0.508 0.509 0.346 − 6.970 − 6.679 0.055 − 0.112 0.073 − 0.027 − 0.085 − 0.076 0.036 0.388 0.302
0.456 0.591 0.415 0.438 0.409 0.481 0.377 0.554 0.277 0.433 0.347 0.462 0.367 0.251 0.59 0.482 0.477 0.243
0.018 0.039 0.049 0.062 0.039 0.095 0.053 0.124 0.062 0.022 0.025 0.001 0.006 0.017 0.046 0 0.103 0.003
and the speed with which that information is processed (processing speed). A reduced processing speed is the most common cognitive deficit in MS [34], and tests of processing speed are used to predict long-term cognitive decline [35] and impairment of executive functions [36]. Decrements in divided attention [37] and executive functioning are also frequent in MS. Executive functioning refers to the cognitive ability for complex goal-directed behavior and adaptation to environmental changes or demands [38]. Executive function deficits affect activities of daily living; functional impairments that are commonly seen in MS include difficulties in shopping independently, doing housework such as washing clothes and ironing, completing home repairs, cooking, driving, and using public transportation [39]. Considerable evidence indicates that quality of life (QoL) is decreased in individuals diagnosed with MS [40] and the magnitude of the reduction in QoL correlates with deficits in cognitive functioning, depressive symptomatology, increased disability, severity and progression of disease, disease duration and decreased ability to perform everyday activities [3]. All of these considerations provide rationale for investigating the effectiveness of specific and cost-effective neuropsychological training to improve information processing, attention and executive functions in patients with MS. Our study, which aimed to demonstrate the efficacy of intensive training in clinically-stable low disability MS patients, showed positive effects on sensitive and specific outcome measures. A learning effect was ruled out by using alternative forms of the tests, and by the comparison between delta scores, which was significantly lower for tasks assessing attention, working memory and executive functions in the group of patients who received treatment, compared with the control group. The effect observed was due to the training, rather than spontaneous disease fluctuation, because patients were clinically stable and were not receiving any medication. The difference between our results and those from previous studies is mainly explained by our methodological approach. Other studies have also used the RehaCom procedure, although with software for memory and attention in the study group and visuoconstructional and visuo-motor software in the control group [19]. Another reason for the difference in results is the patient selection criteria. The study by Solari et al. included MS patients with a wide range of disability (EDSS range 1.5–7) and disease duration; inclusion criteria were self-reported memory problems and poor results in at least two tests of the BRBNT. This selection bias may have resulted in the inclusion and treatment of patients with impairments in cognitive domains other than memory and attention, which were the domains treated in the study. Furthermore, in the Solari et al. study, the control group was also treated with a visuo-constructional task. This may have induced a general neuropsychological improvement independent of group assignment, and reduced the difference in outcome between the two groups. Our study only included patients with poor PASAT and WCST scores, independent of their self-report, and treatment was conducted on attention, working memory and executive functions only. Training intensity (frequency and duration of treatment) may be relevant in facilitating learning strategies, as reported in other cognitive domains such as language rehabilitation in aphasia [41]. Our treatment was very specific for divided attention, information processing and executive functions, consisting of visuo-spatial and memory tests unaffected by rehabilitation. This study indicates the usefulness of a “cognitive approach” for treating multifaceted neuropsychological deficits, which are common in patients with MS. Hildebrandt et al. [42] also found a significant improvement in verbal memory and working memory performance in a controlled study using home-based auto-performed computer training focusing on memory and working memory, but could not find any effect on depression or fatigue. The amelioration of depression observed in our SG, which is associated with but independent from attention, information processing and executive functions, is of particular
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relevance in MS patients, especially in this initial disease stage. Interactive training and communication with the psychologist may have been responsible for the improvement in depression, in contrast to the study that used home-based training. Larger studies with longer follow-up periods are needed to generalize these results and to verify that the effects of this training persist over time. The question of the best age and disease duration for cognitive training must also be addressed. It appears from our results that executive functions (measured by the WCST) may be more susceptible to improvement following cognitive training in younger patients. This result has implications for the recruitment of patients who may not be considered candidates for neuropsychological rehabilitation but could in fact derive greater benefits from it. To make further progress in the field of neuropsychological rehabilitation in MS, it seems essential to validate sensitive, costeffective and reliable screening instruments that can be used, in clinical settings, to identify the nature of patients' neuropsychological impairment. Appropriate rehabilitation techniques can then be used for a group of patients with similar impairment, therefore optimizing cognitive therapies.
References [1] Rao SM, et al. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41(5):685–91. [2] Benedict RH, et al. Neuropsychological counseling improves social behavior in cognitively-impaired multiple sclerosis patients. Mult Scler 2000;6(6):391–6. [3] Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7(12):1139–51. [4] Arnett PA, Barwick FH, Beeney JE. Depression in multiple sclerosis: review and theoretical proposal. J Int Neuropsychol Soc 2008;14(5):691–724. [5] Rao SM, et al. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 1991;41(5):692–6. [6] Arnett PA, Higginson CI, Randolph JJ. Depression in multiple sclerosis: relationship to planning ability. J Int Neuropsychol Soc 2001;7(6):665–74. [7] Gilchrist AC, Creed FH. Depression, cognitive impairment and social stress in multiple sclerosis. J Psychosom Res 1994;38(3):193–201. [8] Siepman TA, et al. The role of disability and depression in cognitive functioning within 2 years after multiple sclerosis diagnosis. J Neurol 2008;255(6):910–6. [9] Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci 2006;245(1–2):111–6. [10] Benedict RH, et al. Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy. J Neurol Neurosurg Psychiatry 2009;80(2):201–6. [11] Houtchens MK, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007;69(12):1213–23. [12] Rovaris M, et al. Cognitive impairment and structural brain damage in benign multiple sclerosis. Neurology 2008;71(19):1521–6. [13] Lin X, et al. Use of combined conventional and quantitative MRI to quantify pathology related to cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008;79(4):437–41. [14] Fisniku LK, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008;64(3):247–54. [15] Patti F. Cognitive impairment in multiple sclerosis. Mult Scler 2009;15(1):2–8.
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[16] Thomas PW, Thomas S, Hillier C. Psychological interventions for multiple sclerosis (submitted for publication)., in The Cochrane Collaboration, L.p. John Wiley and Sons, Editor. 2007. p. 1–51. [17] Jonsson A, et al. Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurol Scand 1993;88(6):394–400. [18] Plohmann AM, et al. Computer assisted retraining of attentional impairments in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64(4):455–62. [19] Solari A, et al. Computer-aided retraining of memory and attention in people with multiple sclerosis: a randomized, double-blind controlled trial. J Neurol Sci 2004;222(1–2):99–104. [20] Crawford JD, McIvor GP. Group psychotherapy: benefits in multiple sclerosis. Arch Phys Med Rehabil 1985;66(12):810–3. [21] Foley FW, et al. A prospective study of depression and immune dysregulation in multiple sclerosis. Arch Neurol 1992;49(3):238–44. [22] Rigby SA, et al. Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale. Mult Scler 2003;9(1): 73–81. [23] Poser CM, Brinar VV. Diagnostic criteria for multiple sclerosis. Clin Neurol Neurosurg 2001;103(1):1–11. [24] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52. [25] Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977;44(2):367–73. [26] Berg EA. A simple objective technique for measuring flexibility in thinking. J Gen Psychol 1948;39:15–22. [27] Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3): 189–98. [28] Serino A, et al. A rehabilitative program for central executive deficits after traumatic brain injury. Brain Cogn 2006;60(2):213–4. [29] Rao SM. Cognitive function study group. National Multiple Sclerosis Society. New York; 1990. [30] Novelli G, P.C., Capitani E, Laiacona N, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali. Arch Psicol Neurol Psichiatr 1986;47(4):477–506. [31] Zimmermann P, Fimm B. Batteria di Test per l'esame dell'attenzione (TEA). 1997, Italian Edition by Pizzamiglio L., Zoccolotti P. and Pittau P.A. [32] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9. [33] Solari A, et al. Validation of Italian multiple sclerosis quality of life 54 questionnaire. J Neurol Neurosurg Psychiatry 1999;67(2):158–62. [34] DeLuca J, et al. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol 2004;26(4): 550–62. [35] Bergendal G, Fredrikson S, Almkvist O. Selective decline in information processing in subgroups of multiple sclerosis: an 8-year longitudinal study. Eur Neurol 2007;57(4): 193–202. [36] Kalmar JH, et al. The relationship between cognitive deficits and everyday functional activities in multiple sclerosis. Neuropsychology 2008;22(4):442–9. [37] McCarthy M, et al. Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis. Arch Clin Neuropsychol 2005;20(6):705–18. [38] Drew M, et al. Executive dysfunction and cognitive impairment in a large community-based sample with Multiple Sclerosis from New Zealand: a descriptive study. Arch Clin Neuropsychol 2008;23(1):1–19. [39] Cutajar R, et al. Cognitive function and quality of life in multiple sclerosis patients. J Neurovirol 2000;6(Suppl 2):S186–90. [40] Grima DT, et al. Cost and health related quality of life consequences of multiple sclerosis. Mult Scler 2000;6(2):91–8. [41] Bhogal SK, Teasell R, Speechley M. Intensity of aphasia therapy, impact on recovery. Stroke 2003;34(4):987–93. [42] Hildebrandt H, et al. Cognitive training in MS: effects and relation to brain atrophy. Restor Neurol Neurosci 2007;25(1):33–43.
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Efficacy and specificity of intensive cognitive rehabilitation of attention and executive functions in multiple sclerosis Mattioli Flavia a,⁎, Chiara Stampatori a, Deborah Zanotti a, Giovanni Parrinello b, Ruggero Capra c a b c
Clinical Neuropsychology, Spedali Civili of Brescia, V. Nikolajewka, 13, 25123 Brescia, Italy Medical Statistic Section, University of Brescia, Italy Multiple Sclerosis Center, Spedali Civili of Brescia, Italy
a r t i c l e
i n f o
Article history: Received 5 May 2009 Received in revised form 17 September 2009 Accepted 23 September 2009 Available online 13 October 2009 Keywords: Multiple sclerosis Attention Information processing Rehabilitation
a b s t r a c t Objective: To evaluate the efficacy of a computer-based intensive training program of attention, information processing and executive functions in patients with clinically-stable relapsing–remitting (RR) multiple sclerosis (MS) and low levels of disability. Design, patients and interventions: A total of 150 patients with RR MS and an Expanded Disability Status Scale (EDSS) score of ≤ 4 were examined. Information processing, working memory and attention were assessed by the Paced Auditory Serial Addition Test (PASAT) and executive functions by the Wisconsin Card Sorting Test (WCST). Twenty patients who scored below certain cut-off measures in both tests were included in this double-blind controlled study. Patients were casually assigned to a study group (SG) or a control group (CG) and underwent neuropsychological evaluation at baseline and after 3 months. Patients in the SG received intensive computer-assisted cognitive rehabilitation of attention, information processing and executive functions for 3 months; the CG did not receive any rehabilitation. Setting: Ambulatory patients were sent by the MS referral center. Outcome measures: Improvement in neuropsychological test and scale scores. Results: After rehabilitation, only the SG significantly improved in tests of attention, information processing and executive functions (PASAT 3″ p = 0.023, PASAT 2″ p = 0.004, WCSTte p = 0.037), as well as in depression scores (MADRS p = 0.01). Neuropsychological improvement was unrelated to depression improvement in regression analysis. Conclusions: Intensive neuropsychological rehabilitation of attention, information processing and executive functions is effective in patients with RR MS and low levels of disability, and also leads to improvement in depression. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Cognitive dysfunction is common in multiple sclerosis (MS), affecting approximately 43–70% of patients, depending on the setting of the study and investigational accuracy [1]. In patients with MS, cognitive dysfunction is thought to be related to poor social integration [2] and employability. The main cognitive areas affected by MS are attention, information processing, executive functions, memory and visuo-spatial abilities [3]. Depression is also a common symptom in the MS population and often appears to be associated with cognitive impairment [4], although the relationship between
⁎ Corresponding author. Tel.: +39 030 2027226, +39 328 5969276 (mobile); fax: +39 030 2027201. E-mail address: fl[email protected] (M. Flavia). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.09.024
neuropsychological deficits and depression is unclear. Cognitively impaired MS patients are less employable, less active (both socially and in the home) and more vulnerable to psychiatric illness than MS patients with only physical disabilities [5]. A consistent positive link has been found between depression and cognitive functioning, particularly with poor working memory, learning and planning abilities [6,7]. On the other hand, depression can also be explained by disability, rather than the neuropsychological deficits seen in newly-diagnosed MS [8]. In magnetic resonance imaging studies, cognitive impairment has been related to several brain lesion measures, particularly T1 and T2 lesion load, as well as diffuse brain damage, brain atrophy [9–11], white matter damage with normal appearance in benign MS [12] and gray matter damage with normal appearance [13]. Gray matter atrophy has otherwise been related to long-term disability in a 20-year follow-up study [14]. Although some studies with immunomodulatory drugs indicate positive effects on cognitive impairment [15], this kind of treatment is not an accepted strategy. A review of cognitive rehabilitation studies
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investigating the effectiveness of neurobehavioral rehabilitative procedures on neuropsychological and psychological outcomes reported that cognitive-behavioral approaches are beneficial, although the diversity of psychological intervention and the multiple outcome measures prevented definite conclusions from being drawn [16]. In particular, 16 randomized studies were reviewed, with a total of 1006 cases, a length of follow-up from start of treatment ranging from 5 weeks to 4 years, and psychological interventions addressing both mood and cognition. Most studies included patients with differing levels of disability by Expanded Disability Status Scale (EDSS) and different durations of disease. Benedict et al. [2] studied the effectiveness of cognitive-behavioral intervention in 15 patients with cognitive impairment associated with marked behavioral changes. Patients were randomly assigned to receive neuropsychological counseling or psychotherapy. After 2 weeks, subjects in the active treatment group showed significant improvements in disinhibition and socially aggressive behavior, compared with patients assigned to standard psychological counseling. Jonsson et al. [17] randomized 40 patients with MS who had mildto-moderate cognitive and behavioral impairment to either cognitive treatment or non-specific “mental stimulation”. Treatment lasted an average of 46 days. Short-term effects were assessed immediately after treatment and long-term effects after 6 months. Short-term effects on cognitive measures were not significant, but the specific cognitive treatment group reported significantly less depression, measured by the Beck Depression Inventory (BDI). After 6 months, only this group showed a significant effect on the visuo-spatial memory task and depression scores. The efficacy of computer-based retraining of four different attention domains has been studied in a single-group, open study of 22 patients with MS. Patients received 12 sessions of attention training. A computerized attention test battery was used to test performance at baseline, after each training period, and in the following 9 weeks. Any effects on activities of daily living were assessed using a self-rating inventory. Significant improvements in performance, which remained stable for 9 weeks, were achieved by the attention training program [18]. In a randomized, double-blind, controlled trial, Solari et al. [19] assessed the efficacy of computer-aided retraining of memory and attention in MS patients. At 8 weeks, 45% of patients who received memory and attention retraining showed an improvement in at least two scores from the Brief Repeatable Battery of Neuropsychological Tests (BRBNT), compared with 43% of control patients (odds ratio 1.07). The authors concluded that the trial did not support the efficacy of specific memory and attention training in MS. A study that compared psychotherapy with placebo found lower levels of depression but no reduction in anxiety scores in the group that received psychotherapy [20]. Other studies have compared cognitivebehavioral therapy with psychotherapy [21], and have reported lower depression levels with cognitive-behavioral therapy versus placebo [22], without significant differences between groups. The lack of conclusiveness of these results appears to be mainly caused by methodological problems, including inaccurate selection of homogeneous MS patients (in terms of disability, disease duration and specified neuropsychological deficits), incomplete neuropsychological evaluation at inclusion, unstandardized training tools for specific cognitive functions, and inadequate outcome measures. We conducted a double-blind, controlled study on a homogeneous group of relapsing–remitting (RR) MS patients with low levels of disability and a stable clinical course in the previous year. We used an intensive cognitive rehabilitation procedure specific for information processing, attention and executive function abilities, which were impaired in all of the enrolled patients. Appropriate neuropsychological measures and functional scales were obtained before and at the end of the training.
2. Materials and methods 2.1. Patients Between June 2007 and December 2008, 150 patients affected with RR MS, according to Poser and Brinar [23]criteria were examined. All patients had an EDSS [24] score of ≤4. Information processing, working memory and attention were assessed by the Paced Auditory Serial Addition Test 2″ and 3″ (PASAT [25]) and executive function by the Wisconsin Card Sorting Test (WCST [26]). Patients were included in the study if their scores in both tests fell below z = −1.5 for PASAT (either 2″ or 3″ interval) and T = 35 for WCST in any of the following measures: total errors (WCSTte), number of perseverative errors (WCSTpe) and number of perseverative responses (WCSTpr). Exclusion criteria were the following: one or more clinical exacerbations in the previous year, loss of visual acuity, ongoing major psychiatric disorder, substance abuse and a Mini Mental State Examination (MMSE [27]) score of b24. Twenty clinically-stable patients with RR MS were included in the study. Eligible patients providing written informed consent were casually assigned by a blinded psychologist to a study group (SG) and a control group (CG). Each group contained 10 patients. 2.2. Interventions and outcome assessment The SG underwent intensive neuropsychological treatment for 3 consecutive months, on an individual basis. Each session lasted for 1 h, with a frequency of three sessions per week. Sessions consisted of computer-assisted training of attention, information processing and planning exercises for executive functions. The software used, Plan a Day and Divided Attention, were part of the RehaCom package (www. Schuhfried.at), a software package with a special keyboard with large buttons, which limits the interference of motor and coordination impairments and expertise on computer use. The Plan a Day procedure trains the patient's ability to organize, plan and develop solution strategies employing realistic simulations of a set of scheduled dates and duties to be organized at specific places in a small city map. Times for planning and schedules were registered for each patient at each session and only improvement and acquisition of sufficient planning abilities for fulfilling all the appointments required let the level to be ameliorated in the following treatment session. This was considered a strategic behavior acquisition. In Divided Attention, the patient is required to simulate a train driver, carefully observing the control panel of the train and the countryside. Several distractions, such as crossing animals, and train speed must be taken into account with increasing levels of difficulty. Specific speed information training, which has been shown to be effective in patients with brain injuries, was combined with each Divided Attention session, consisting of a modified PASAT task with numbers, words and months of the year [28]. The control group did not receive any rehabilitation. Both the neuropsychological evaluations and the cognitive rehabilitation sessions were performed respectively by two blinded trained psychologists, in a quiet environment, according to published procedures. A detailed neuropsychological assessment was performed at baseline (T0) before the rehabilitation and 3 months later (at the end of rehabilitation for SG) (T1). The complete neuropsychological assessment includes some subtests of the Italian version of the BRBNT [29]: Selective Reminding Test for verbal learning — consistent long-term retrieval (SRT/CLTR) and delayed retrieval (SRT/DR), the 10/36 Spatial Recall Test for visuospatial learning — long-term retrieval (10/36 SRT LTR) and delayed recall (10/36 SRT DR), the Symbol Digit Modalities Test (SDMT) and the PASAT 2″ and 3″[25] for attention and working memory, the WCST
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[26] for reasoning ability and cognitive flexibility (WCST te, pe, pr), controlled oral word association test with phonemic and semantic cues (COWA/P, COWA/S) for cognitive flexibility and word fluency [30], divided attention of Test of Everyday Attention (TEA) — median for auditory stimulus (am), for visual stimulus (vm), total omitted stimuli (to) and total errors (te) [31] and two questionnaires: the Montgomery–Asberg Depression Rating Scale (MADRS) [32] for mood state, and the self-reported Multiple Sclerosis Quality of Life (MSQoL) [33]. To minimize familiarity and learning effect, two alternative forms of each test (except for WCST, TEA and questionnaires) were employed through testing sessions, according to an AB design. 2.3. Statistical analysis Descriptive statistics are expressed as mean± SD and/or as median and interquartile ranges, according to distribution. Groups were compared using the nonparametric Wilcoxon test for continuous variables, with corrections for multiple comparisons. A linear regression was conducted with the following variables: group (factor), age and EDSS for each test, as well as T1–T0 (delta) MADRS score, in order to control for changes in depression affecting neuropsychological changes.
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Table 2 Neuropsychological test scores in the study group (SG) and the control group (CG) at baseline (T0). CG N = 10 PASAT 2″ PASAT 3″ WCSTte WCSTpr WCSTpe COWA/P COWA/C TEAam TEAvm TEAto TEAte SRT/CLTR SRT/DR 10/36 SRT LTR 10.36 SRT DR SDMT MADRS MSQoL
00.00 14.25 48.50 31.75 33.25 23.00 29.00 547.50 902.75 2.75 3.00 14.00 4.00 13.25 4.00 30.25 6.25 165.5
0.00 18.50 55.50 53.50 40.00 27.50 39.50 698.50 1014.00 6.00 3.00 19.00 5.50 15.50 5.00 40.50 9.00 197.0
p valuea
SG N = 10 11.75 24.50 74.75 57.75 48.75 32.25 41.75 846.00 1093.00 8.75 10.50 19.75 6.75 20.00 6.00 49.75 15.50 202.0
0.00 11.50 55.75 34.50 37.50 23.75 32.50 560.75 864.50 2.25 4.25 18.00 5.25 14.25 4.00 27.25 3.25 148.5
6.50 20.00 64.50 54.50 49.50 29.00 37.50 577.00 933.00 5.00 7.00 19.50 6.00 15.00 5.50 32.50 12.00 168.0
19.0 28.50 76.00 66.75 53.00 34.75 42.00 613.50 994.50 7.75 10.25 26.00 8.50 16.75 6.75 37.50 19.00 178.5
p = 0.47 p = 0.91 p = 0.44 p = 0.61 p = 0.3 p = 0.94 p = 0.97 p = 0.56 p = 0.46 p = 0.56 p = 0.24 p = 0.32 p = 0.35 p = 0.63 p = 0.82 p = 0.25 p = 0.91 p = 0.23
For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
3. Results All 20 patients were female. The baseline clinical characteristics of the two groups were not significantly different (Table 1). At baseline, there were no significant differences between the SG and CG groups in all neuropsychological tests (all p values N 0.05; Table 2). After 3 months (T1), the comparison of neuropsychological scores between the SG and CG groups showed statistically significant differences in PASAT 2″ (p = 0.004), WCSTte (p = 0.037), WCSTpe (p = 0.051) and MADRS (p = 0.01) tests (Table 3). These results indicate that the SG group performed better in tests of information processing/attention and decision making, and also had lower depression scores. The differential T1–T0 (delta) scores for each neuropsychological test were compared between the SG and CG groups, with statistically significant differences in PASAT 3″ (p = 0.023), PASAT 2″ (p = 0.004), WCSTte (p = 0.037), WCSTpe (p = 0.051), and MADRS (p = 0.01) (Table 4). The between-group differences were confirmed when the comparisons were adjusted for the following confounding variables: EDSS, age, and T0 score in neuropsychological tests, applying a linear regression model. In particular, the regression analysis showed a significant difference in delta scores between the CG and SG groups for the TEAar (p = 0.031), TEAte (p = 0.0.04) and COWA/P (p = 0.009) tests. In the linear regression analysis, WCSTte appeared to be significantly affected by age, with younger patients showing significantly greater improvements than older patients (p = 0.052). These results indicate a significant difference between the two groups in neuropsychological profiles, with the SG group showing
Table 1 Clinical characteristics of the study group (SG) and the control group (CG). CG N = 10 Age (years) Education (years) Illness (years) EDSS
42.25 8.00 11.75 1.5
44.00 9.00 18.50 1.5
p valuea
SG N = 10 48.75 12.50 26.00 2.5
41.00 5.75 13.25 1.1
42.00 8.00 16.50 2.5
53.00 8.00 18.00 3.2
p = 0.855 p = 0.157 p = 0.419 p = 0.792
a, b, and c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. EDSS = Expanded Disability Status Scale. a Wilcoxon test.
significantly greater improvements in tests of attention/information processing (PASAT, TEA) and executive functions (WCST, COWA/P), as well as a significant reduction in depression score. A possible indirect influence on neuropsychological improvement caused by reductions in MADRS scores was excluded by correcting for delta MADRS scores in the regression analysis, which was not statistically significant (Table 5). In addition, the changes in R2 coefficients of determination in the model were always irrelevant. 4. Discussion In our study of MS patients with low levels of disability and clinically-stable disease in the previous year, we found that patients harbouring deficits in attention and information processing, as well as poor executive functions, significantly improved after undergoing Table 3 Neuropsychological test scores in the study group (SG) and the control group (CG) after 3 months (T1). GC N = 10 PASAT 2″ 0.00 0.00 12.75 17.00 PASAT 3″ 14.25 18.50 24.50 11.50 WCSTte 21.50 45.00 62.75 15.25 WCSTpr 21.5 37.0 59.5 16.0 WCSTpe 14.25 28.50 42.50 11.25 COWA/P 17.75 27.50 39.75 27.50 COWA/S 29.00 35.50 42.00 27.25 TEAam 551.75 580.00 670.75 596.50 TEAvm 829.75 1040.00 1105.50 857.25 TEAto 3.00 6.00 6.75 2.00 TEAte 4.0 6.5 8.0 2.0 SRT.CLTR 7.0 16.0 29.0 14.0 SRT.DR 4.25 5.50 7.75 4.50 10/36 SRT LTR 11.25 14.00 17.50 14.50 10/36 SRT DR 3.25 4.00 5.75 4.25 SDMT 28.50 38.00 45.75 31.00 MADRS 8.75 14.00 22.50 3.00 MSQoL 165.5 197.0 202.0 148.5
GS N = 10
pa
22.00 27.00 p = 0.004 20.00 28.50 p = 0.913 20.00 27.50 p = 0.037 17.5 27.5 p = 0.088 14.50 18.75 p = 0.051 36.00 44.50 p = 0.236 44.50 47.00 p = 0.398 724.00 848.75 p = 0.097 902.00 1040.00 p = 0.771 3.00 4.75 p = 0.141 2.5 4.5 p = 0.104 19.0 29.5 p = 0.559 6.50 8.75 p = 0.607 17.50 19.50 p = 0.204 6.00 6.75 p = 0.353 34.50 44.75 p = 0.942 4.50 6.50 p = 0.01 168.0 178.5 p = 0.236
For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
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Table 4 Comparison of delta (T1–T0) scores for each test in the study group (SG) and the control group (CG). GC N = 10
pa
GS N = 10
PASAT 2″ 0.00 0.00 12.75 17.00 22.00 27.00 p = 0.004 PASAT 3″ 0.00 7.00 26.50 24.50 36.00 44.75 p = 0.023 WCSTte 21.50 45.00 62.75 15.25 20.00 27.50 p = 0.037 WCSTpr 21.5 37.0 59.5 16.0 17.5 27.5 p = 0.08 WCSTpe 14.25 28.50 42.50 11.25 14.50 18.75 p = 0.051 COWA/P 17.75 27.50 39.75 27.50 36.00 44.50 p = 0.236 COWA/S 29.00 35.50 42.00 27.25 44.50 47.00 p = 0.398 TEAam 551.75 580.00 670.75 596.50 724.00 848.75 p = 0.097 TEAvm 829.75 1040.00 1105.50 857.25 902.00 1040.00 p = 0.771 TEAto 3.00 6.00 6.75 2.00 3.00 4.75 p = 0.141 TEAte 4.00 6.5 8.00 2.00 2.5 4.5 p = 0.104 SRT/CLTR 7.00 16.00 29.00 14.00 19.00 29.50 p = 0.559 SRT/DR 4.25 5.50 7.75 4.50 6.50 8.75 p = 0.607 10/36 SRT LTR 11.25 14.00 17.50 14.50 17.50 19.50 p = 0.204 10/36 SRT DR 3.25 4.00 5.75 4.25 6.00 6.75 p = 0.353 SDMT 28.50 38.00 45.75 31.00 34.50 44.75 p = 0.942 MADRS 8.75 14.00 22.50 3.00 4.50 6.50 p = 0.01 MSQoL 142.50 155.00 184.50 165.75 189.00 208.75 p = 0.285 For test definitions, see Materials and methods. a, b, and c represent: the lower quartile a, the median b, and the upper quartile c for continuous variables. a Wilcoxon test.
cognitive training specifically tailored for the impaired abilities. There was no generalization to other neuropsychological functions. The patients who received cognitive training also showed a significant decrease in depression score. This finding indicates that specific neuropsychological rehabilitation tailored to the clinical deficits of the patient can improve both the cognitive deficit itself and mood state. A non-specific effect of decreased depression on neuropsychological improvement at follow-up was excluded by controlling for delta MADRS scores in the regression analysis, as well as by the fact that a selective improvement in trained functions was achieved by rehabilitated patients. If there was a non-specific effect of reduced depression, then an improvement in all the neuropsychological tests (including, for example, memory and visuo-spatial abilities) would be expected. Our study focused on rehabilitation of attention, information processing and executive functions, which are frequently impaired in patients with MS and cause functional dependence and depression [3]. Information processing refers to the ability to maintain and manipulate information for a short time period (working memory)
Table 5 Results of linear regression corrected for depression score (delta MADRS).
PASAT 2″ PASAT 3″ WCSTte WCSTpr WCSTpe COWA/P COWA/S TEAam TEAvm TEAto TEAte SRT/CLTR SRT/DR 10/36 SRT LTR 10/36 SRT DR SDMT MADRS MSQoL
Beta weights
R2
R2 changes
− 0.234 − 0.436 0.662 0.876 0.508 0.509 0.346 − 6.970 − 6.679 0.055 − 0.112 0.073 − 0.027 − 0.085 − 0.076 0.036 0.388 0.302
0.456 0.591 0.415 0.438 0.409 0.481 0.377 0.554 0.277 0.433 0.347 0.462 0.367 0.251 0.59 0.482 0.477 0.243
0.018 0.039 0.049 0.062 0.039 0.095 0.053 0.124 0.062 0.022 0.025 0.001 0.006 0.017 0.046 0 0.103 0.003
and the speed with which that information is processed (processing speed). A reduced processing speed is the most common cognitive deficit in MS [34], and tests of processing speed are used to predict long-term cognitive decline [35] and impairment of executive functions [36]. Decrements in divided attention [37] and executive functioning are also frequent in MS. Executive functioning refers to the cognitive ability for complex goal-directed behavior and adaptation to environmental changes or demands [38]. Executive function deficits affect activities of daily living; functional impairments that are commonly seen in MS include difficulties in shopping independently, doing housework such as washing clothes and ironing, completing home repairs, cooking, driving, and using public transportation [39]. Considerable evidence indicates that quality of life (QoL) is decreased in individuals diagnosed with MS [40] and the magnitude of the reduction in QoL correlates with deficits in cognitive functioning, depressive symptomatology, increased disability, severity and progression of disease, disease duration and decreased ability to perform everyday activities [3]. All of these considerations provide rationale for investigating the effectiveness of specific and cost-effective neuropsychological training to improve information processing, attention and executive functions in patients with MS. Our study, which aimed to demonstrate the efficacy of intensive training in clinically-stable low disability MS patients, showed positive effects on sensitive and specific outcome measures. A learning effect was ruled out by using alternative forms of the tests, and by the comparison between delta scores, which was significantly lower for tasks assessing attention, working memory and executive functions in the group of patients who received treatment, compared with the control group. The effect observed was due to the training, rather than spontaneous disease fluctuation, because patients were clinically stable and were not receiving any medication. The difference between our results and those from previous studies is mainly explained by our methodological approach. Other studies have also used the RehaCom procedure, although with software for memory and attention in the study group and visuoconstructional and visuo-motor software in the control group [19]. Another reason for the difference in results is the patient selection criteria. The study by Solari et al. included MS patients with a wide range of disability (EDSS range 1.5–7) and disease duration; inclusion criteria were self-reported memory problems and poor results in at least two tests of the BRBNT. This selection bias may have resulted in the inclusion and treatment of patients with impairments in cognitive domains other than memory and attention, which were the domains treated in the study. Furthermore, in the Solari et al. study, the control group was also treated with a visuo-constructional task. This may have induced a general neuropsychological improvement independent of group assignment, and reduced the difference in outcome between the two groups. Our study only included patients with poor PASAT and WCST scores, independent of their self-report, and treatment was conducted on attention, working memory and executive functions only. Training intensity (frequency and duration of treatment) may be relevant in facilitating learning strategies, as reported in other cognitive domains such as language rehabilitation in aphasia [41]. Our treatment was very specific for divided attention, information processing and executive functions, consisting of visuo-spatial and memory tests unaffected by rehabilitation. This study indicates the usefulness of a “cognitive approach” for treating multifaceted neuropsychological deficits, which are common in patients with MS. Hildebrandt et al. [42] also found a significant improvement in verbal memory and working memory performance in a controlled study using home-based auto-performed computer training focusing on memory and working memory, but could not find any effect on depression or fatigue. The amelioration of depression observed in our SG, which is associated with but independent from attention, information processing and executive functions, is of particular
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relevance in MS patients, especially in this initial disease stage. Interactive training and communication with the psychologist may have been responsible for the improvement in depression, in contrast to the study that used home-based training. Larger studies with longer follow-up periods are needed to generalize these results and to verify that the effects of this training persist over time. The question of the best age and disease duration for cognitive training must also be addressed. It appears from our results that executive functions (measured by the WCST) may be more susceptible to improvement following cognitive training in younger patients. This result has implications for the recruitment of patients who may not be considered candidates for neuropsychological rehabilitation but could in fact derive greater benefits from it. To make further progress in the field of neuropsychological rehabilitation in MS, it seems essential to validate sensitive, costeffective and reliable screening instruments that can be used, in clinical settings, to identify the nature of patients' neuropsychological impairment. Appropriate rehabilitation techniques can then be used for a group of patients with similar impairment, therefore optimizing cognitive therapies.
References [1] Rao SM, et al. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41(5):685–91. [2] Benedict RH, et al. Neuropsychological counseling improves social behavior in cognitively-impaired multiple sclerosis patients. Mult Scler 2000;6(6):391–6. [3] Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7(12):1139–51. [4] Arnett PA, Barwick FH, Beeney JE. Depression in multiple sclerosis: review and theoretical proposal. J Int Neuropsychol Soc 2008;14(5):691–724. [5] Rao SM, et al. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 1991;41(5):692–6. [6] Arnett PA, Higginson CI, Randolph JJ. Depression in multiple sclerosis: relationship to planning ability. J Int Neuropsychol Soc 2001;7(6):665–74. [7] Gilchrist AC, Creed FH. Depression, cognitive impairment and social stress in multiple sclerosis. J Psychosom Res 1994;38(3):193–201. [8] Siepman TA, et al. The role of disability and depression in cognitive functioning within 2 years after multiple sclerosis diagnosis. J Neurol 2008;255(6):910–6. [9] Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci 2006;245(1–2):111–6. [10] Benedict RH, et al. Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy. J Neurol Neurosurg Psychiatry 2009;80(2):201–6. [11] Houtchens MK, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007;69(12):1213–23. [12] Rovaris M, et al. Cognitive impairment and structural brain damage in benign multiple sclerosis. Neurology 2008;71(19):1521–6. [13] Lin X, et al. Use of combined conventional and quantitative MRI to quantify pathology related to cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008;79(4):437–41. [14] Fisniku LK, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008;64(3):247–54. [15] Patti F. Cognitive impairment in multiple sclerosis. Mult Scler 2009;15(1):2–8.
105
[16] Thomas PW, Thomas S, Hillier C. Psychological interventions for multiple sclerosis (submitted for publication)., in The Cochrane Collaboration, L.p. John Wiley and Sons, Editor. 2007. p. 1–51. [17] Jonsson A, et al. Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurol Scand 1993;88(6):394–400. [18] Plohmann AM, et al. Computer assisted retraining of attentional impairments in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64(4):455–62. [19] Solari A, et al. Computer-aided retraining of memory and attention in people with multiple sclerosis: a randomized, double-blind controlled trial. J Neurol Sci 2004;222(1–2):99–104. [20] Crawford JD, McIvor GP. Group psychotherapy: benefits in multiple sclerosis. Arch Phys Med Rehabil 1985;66(12):810–3. [21] Foley FW, et al. A prospective study of depression and immune dysregulation in multiple sclerosis. Arch Neurol 1992;49(3):238–44. [22] Rigby SA, et al. Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale. Mult Scler 2003;9(1): 73–81. [23] Poser CM, Brinar VV. Diagnostic criteria for multiple sclerosis. Clin Neurol Neurosurg 2001;103(1):1–11. [24] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52. [25] Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977;44(2):367–73. [26] Berg EA. A simple objective technique for measuring flexibility in thinking. J Gen Psychol 1948;39:15–22. [27] Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3): 189–98. [28] Serino A, et al. A rehabilitative program for central executive deficits after traumatic brain injury. Brain Cogn 2006;60(2):213–4. [29] Rao SM. Cognitive function study group. National Multiple Sclerosis Society. New York; 1990. [30] Novelli G, P.C., Capitani E, Laiacona N, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali. Arch Psicol Neurol Psichiatr 1986;47(4):477–506. [31] Zimmermann P, Fimm B. Batteria di Test per l'esame dell'attenzione (TEA). 1997, Italian Edition by Pizzamiglio L., Zoccolotti P. and Pittau P.A. [32] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9. [33] Solari A, et al. Validation of Italian multiple sclerosis quality of life 54 questionnaire. J Neurol Neurosurg Psychiatry 1999;67(2):158–62. [34] DeLuca J, et al. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol 2004;26(4): 550–62. [35] Bergendal G, Fredrikson S, Almkvist O. Selective decline in information processing in subgroups of multiple sclerosis: an 8-year longitudinal study. Eur Neurol 2007;57(4): 193–202. [36] Kalmar JH, et al. The relationship between cognitive deficits and everyday functional activities in multiple sclerosis. Neuropsychology 2008;22(4):442–9. [37] McCarthy M, et al. Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis. Arch Clin Neuropsychol 2005;20(6):705–18. [38] Drew M, et al. Executive dysfunction and cognitive impairment in a large community-based sample with Multiple Sclerosis from New Zealand: a descriptive study. Arch Clin Neuropsychol 2008;23(1):1–19. [39] Cutajar R, et al. Cognitive function and quality of life in multiple sclerosis patients. J Neurovirol 2000;6(Suppl 2):S186–90. [40] Grima DT, et al. Cost and health related quality of life consequences of multiple sclerosis. Mult Scler 2000;6(2):91–8. [41] Bhogal SK, Teasell R, Speechley M. Intensity of aphasia therapy, impact on recovery. Stroke 2003;34(4):987–93. [42] Hildebrandt H, et al. Cognitive training in MS: effects and relation to brain atrophy. Restor Neurol Neurosci 2007;25(1):33–43.