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Restorative Neurology and Neuroscience 27 (2009) 225–235 DOI 10.3233/RNN-2009-0473 IOS Press
Working memory training in patients with multiple sclerosis – comparison of two different training schedules Annamarie Vogta , Ludwig Kappos b , Pasquale Calabrese a,b, Markus St¨ocklina , Leo Gschwind a, Klaus Opwisa and Iris-Katharina Pennera,∗ a
b
Department of Cognitive Psychology and Methodology, University of Basel, Basel, Switzerland Department of Neurology, University Hospital Basel, Basel, Switzerland
Abstract. Purpose: Evaluation of two different training schedules of a computer based working memory training (BrainStim) in patients with multiple sclerosis (MS). Method: Forty-five MS outpatients were allocated to two different training groups and a control group without training. Patients with treatment received 16 training sessions scheduled either as a high intensity training (4 times per week for 4 weeks) or as a distributed training (2 times per week for 8 weeks). A neuropsychological test battery including self-report measures was applied at baseline and at retest. The baseline assessment was performed twice at an interval of two weeks to control for possible learning effects. Results: In the outcome measures training for both intervention groups led to significantly improved fatigue symptoms as well as working memory -, and mental speed performances. Log files recorded during training showed a similar increase in levels of difficulty for both intervention groups as training progressed. No effects were found on short term memory, quality of life or depression. Conclusions: Since comparable improvements were observed in both training groups, BrainStim can be applied as a therapeutic intervention adjusted to the personal agenda of MS patients. Keywords: Multiple sclerosis, cognitive rehabilitation, working memory, computerized training, BrainStim
1. Introduction Neuropsychological deficits are a common symptom in patients with multiple sclerosis (MS; Bobholz and Rao, 2003). More than half of all patients are affected and impairments are regularly observed across disease courses and including patients with probable MS (Achiron and Barak, 2003), early onset MS (Amato et al., 1995) or clinically isolated syndromes suggestive of MS (Callanan et al., 1989). The most frequently impaired functions are working memory, long-term memory, attention, process∗ Corresponding author: Iris-Katharina Penner, PhD, Department of Cognitive Psychology, University of Basel, Missionsstr. 60/62, CH-4055 Basel, Switzerland. E-mail:
[email protected].
ing speed, mental flexibility and visuo-spatial skills, whereas immediate and implicit memory, primary language skills and verbal intelligence are usually unaffected (Beatty et al., 1995; Peyser et al., 1980; Rao et al., 1989; Thornton and Raz, 1997). In particular working memory deficits have been observed across disease courses (Grigsby et al., 1994; D’Esposito et al., 1996) as well as at the early stage of the disease (Pelosi et al., 1997) and account for a substantial part of the general cognitive deficits observed in MS (DeLuca et al., 1994; Demaree et al., 1999; Litvan et al., 1988). The construct of working memory conceptualized by Baddeley (1992, 2003) comprises a cognitive system that simultaneously but temporarily stores, processes and manipulates incoming information. It is not a single system but rather comprises complex cognitive processes such as language, comprehension, learning and
0922-6028/09/$17.00 2009 – IOS Press and the authors. All rights reserved
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A. Vogt et al. / Working memory training in patients with multiple sclerosis – comparison of two different training schedules
reasoning. Working memory plays an important role in cognitive processing when novel tasks are performed and in coordinating the transfer of information into long-term memory (Baddeley, 2000). Although it is evident that MS patients demonstrate impairments in working memory the specific mechanisms underlying those deficits are not well understood. A recent study showed that initial acquisition of new information is deficient in MS patients and may be responsible for the reduced learning efficiency (DeLuca et al., 1998). Some studies have proposed deficits in verbal aspects of working memory specifically with rehearsal of information as the underlying impairment (Diamond et al., 1997; Rao et al., 1993; Ruchkin et al., 1994). Considering the frequent occurrence of cognitive impairments in MS and the adverse consequences for patients’ careers and daily lives, only few studies on cognitive rehabilitation have been presented so far. Cognitive rehabilitation presents methodological challenges in terms of how to assess cognitive changes, control test-retest effects and set a schedule for intensity and duration of training without being too highly demanding on the patient. This can be further exacerbated by the fact that fatigue (Krupp and Elkins, 2000) and depression (Dalton and Heinrich, 2005; Landro et al., 2004) may also contribute to declines in cognitive performance. In a study by Jonsson et al. (1993) a rehabilitation program including cognitive training and psychological intervention showed no effect in cognitive functions but improved self-reported depression at retest and at a 6-month follow-up in MS patients. However, another study failed to detect any significant effect of a similar cognitive intervention on mood, quality of life or cognitive impairment (Lincoln et al., 2002). Evaluations of computer-based interventions for memory impairment in MS also showed heterogeneous results with respect to cognitive measures, fatigue or quality of life. A randomized double-blind study by Solari et al. (2004) compared the efficacy of a computeraided memory and attention training to a visual coordination training in MS patients. The results showed an increase in performance in cognitive outcome measures in both groups. Therefore, cognitive intervention may be effective irrespective of specificity. In a randomized controlled trial by Tesar et al. (2005) patients showed significant improvements in executive functions, spatial-constructional abilities, memory and fatigue after a cognitive intervention. Hildebrandt et al. (2007) conducted a home-based computer training
for verbal and working memory in MS patients. A significant effect was found in a task for working memory but measures of fatigue and quality of life showed no improvement. Significant effects were found after working memory training by Vogt et al. (2008). The computer-based training with BrainStim (Penner et al., 2006) led to a strong improvement in working memory, mental speed and fatigue in MS patients. Moreover, healthy participants in the control group also showed an improvement in a mental speed test after training. The debate regarding the efficacy of various training schedules is still controversial. One study, comparing the effects of a conventional to a constraint-induced therapy, was done by Pulvermueller, Neininger et al. (2001) in aphasic patients following stroke. The authors found that a 10 days training consisting of 30 to 35 hours of language exercise led to better improvements on several clinical tests and self ratings of patient’s communicative effectiveness than the conventional therapy with 30 to 35 hours of practice over 4 weeks. In MS, training schedules with regard to intensity and amount have not been studied systematically, so far. The time schedules used to train cognitive aspects ranged from 45 minutes twice a week for eight weeks (Solari et al., 2004) to 30 minutes 3 times a week for six weeks (Hildebrandt et al., 2007) and from 60 minutes for 3 times a week for approximately 4 weeks (Tesar et al., 2000) to 45 minutes 4 times a week for 4 weeks (Vogt et al., 2008). Although it can be concluded that cognitive training in MS patients can lead to improvements in selfreported fatigue, depression and neuropsychological outcome measures there is still no consensus with regard to the optimal time frame of cognitive interventions. Moreover appropriate outcome measures have yet to be defined. Therefore, this study aimed to evaluate two different training schedules of the computerized working memory training BrainStim in MS patients. To determine appropriate outcome measures, a comprehensive neuropsychological test battery examining memory, working memory, attention, mental speed, quality of life, depression and fatigue was applied before and after the training. We hypothesized a) performance of patients in the two intervention groups to be better than performance of patients in the control group without intervention and b) that patients in the high intensity training program (according to the results by Pulvermueller et al., 2001) would profit more compared to patients in the distributed training and patients in the control group.
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2. Method
2.3. Training tool BrainStim
2.1. Patients
The training program BrainStim (Penner et al., 2006) is a specific working memory training program that can be installed on any home computer. It consists of 3 modules. The module City Map trains spatial orientation by either visual or verbal instructions to be remembered and finding the path using given arrows along a virtual city map. In the version with visual instructions arrows pointing a way through the virtual city map have to be remembered. In the verbal version, instructions such as “turn left after the library” are presented to the participant and have to be remembered. The module Find Pairs trains visual object memory and the updating function of working memory. The aim is to remember the location of cards that have been turned over and back again and find pairs of cards with the same image. In the third module Memorize Numbers, numbers that are presented for a short time have to be remembered meanwhile performing an arithmetic distraction task. BrainStim adapts level of difficulty to participants’ performance to ensure optimal training conditions. After a certain number of correct answers the participant is asked to go to the next level of difficulty. Conversely, the participant is asked to train on the previous level again if performance was insufficient. As the amount of memorized information increases with ascending levels of difficulty, the achievements in the tasks do not rely only on repetition or practise but also on the ability to develop strategies to improve working memory capacity. Log files are recorded automatically during training and allow verification of correct completion of training and collection of data on training progression.
Forty-five outpatients from the University Hospital Basel with clinically definite multiple sclerosis according to the McDonald criteria (McDonald et al., 2001) participated in the study. Thirty out of the 45 patients were female, 36 had relapsing-remitting MS, 8 patients had secondary progressive MS and one patient had chronic progressive MS. The mean Expanded Disability Status Scale (EDSS; Kurtzke, 1983) score was 2.9 (SD = 1.6) and mean disease duration was 10.2 years (SD = 6.9). The EDSS quantifies disability in multiple sclerosis where EDSS steps 1.0 to 4.5 refer to patients who are fully ambulatory and EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation. Only patients with stable disease (no relapse), no change in symptomatic medication over the last 3 months, no treatment with steroids over the last month and no other neurological or mental illness were included. All patients gave their written informed consent to participate in this study, which was approved by the local ethical committee of the University of Basel, Switzerland. 2.2. Study design Patients were allocated based on their demographic data into the two intervention groups and the control group so that age, sex, education and disease parameters were comparable between the groups. Patients in the high intensity training received a 45-minute training 4 times per week for 4 weeks; patients in the distributed training underwent a 45-minute training 2 times per week for 8 weeks. All participants were requested to train at home according to an individual schedule so that training sessions and recovery times were evenly distributed over the training period. Patients in the control group had the opportunity to perform the training upon completion of the study. All patients (training groups and control group) underwent the neuropsychological test battery 3 times in total. The test battery for the baseline was performed twice at an interval of two weeks and averaged to control for possible learning effects. No consistent trend was observed between the two baseline tests. The retest was performed after completion of training (for the high intensity training group after 4 weeks, for the distributed training group after 8 weeks). Participants without training performed the retest after 4 weeks.
2.4. Neuropsychological test battery The neuropsychological test battery included the following tests: for working memory the Corsi Blocks backward and the Digit Span backward from the Wechsler Memory Scale revised (WMS-R; Haerting et al., 2000), the 2-back task, adapted from the Test Battery for Attention Performance (TAP; Zimmermann and Fimm, 1992) and the Paced Auditory Serial Addition Test (PASAT) from the Brief Repeatable Battery of Neuropsychological Tests (BRB-N; Rao, 1990). For short-term memory we applied the Corsi Blocks forward and the Digit Span forward from the WMSR (Haerting et al., 2000). For processing speed we used the Faces Symbol Test (FST), a recently developed language-independent screening instrument (Scherer et al., 2007) and the Symbol Digit Modalities Test
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A. Vogt et al. / Working memory training in patients with multiple sclerosis – comparison of two different training schedules Table 1 Biographical and baseline characteristics of MS-patients in the intervention groups and the control group high intensity training (n =15) Sex: Men Women
Patient groups distributed without training (n = 15) training (n =15)
Age (y) Education+ EDSS Disease duration (y)
M 43.20 1.60 3.23 9.13
4 11 SD 8.80 0.51 1.80 5.42
Working memory Corsi Blocks backward Digit Span backward 2-back, numbers correct 2-back, omissions 2-back, reaction time PASAT
8.11 6.63 54.37 1.23 822.0 46.71
1.58 1.87 2.59 1.53 296.1 9.01
8.07 6.63 54.63 0.93 800.6 49.87
1.16 2.27 4.12 2.15 272.4 7.18
8.13 6.50 54.46 0.41 817.9 47.90
1.51 1.42 4.35 0.91 224.7 11.26
0.99 0.97 0.98 0.36 0.97 0.65
8.86 6.86
2.00 1.50
8.40 7.47
1.24 1.45
8.41 6.97
2.00 1.20
0.71 0.46
Mental speed FST SDMT
2.91 51.47
0.94 13.52
2.45 56.31
0.69 10.99
2.59 54.83
0.89 16.82
0.32 0.63
Questionnaires FSMC (Fatigue) MFIS (Fatigue) ADS (Depression) FAMS (Qualitity of life)
66.83 39.61 14.20 117.2
18.60 14.92 10.09 29.41
62.53 34.23 11.86 133.7
23.12 19.66 6.70 23.02
65.71 36.73 12.83 125.9
16.79 18.43 10.35 32.56
0.82 0.71 0.78 0.31
Short term Memory Corsi blocks forward Digit span forward
M 43.40 1.47 2.30 8.13
6 9 SD 12.33 0.52 1.09 6.34
M 46.27 1.53 3.20 12.06
5 10 SD 10.53 0.52 1.63 8.99
p Valuet 0.68 0.78 0.18 0.18
Note. t One-way ANOVA, + Education: 0 = secondary school, 1 = college, 2 = university; RRMS = relapsing-remitting MS; SPMS = secondary progressive MS; PPMS = primary progressive MS; EDSS = Expanded Disability Status Scale; PASAT = Paced Auditory Serial Addition Test; FST = Faces Symbol Test; SDMT = Symbol Digit Modalities Test; FSMC = Fatigue Scale for Motor and Cognitive Functions; MFIS = Modified Fatigue Impact Scale; ADS = Allgemeine Depressionsskala; FAMS = Functional Assessment of MS.
(SDMT; Smith, 1973). Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC; Penner et al., 2005) and the Modified Fatigue Impact Scale (MFIS; Fisk et al., 1994), depression with the German version of the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977; Allgemeine Depressionsskala, ADS; Hautzinger and Bailer, 1993) and quality of life with the Functional Assessment of MS (FAMS; Cella et al., 1996).
3. Results 3.1. Patients Table 1 lists sex, age, education, disease parameters and baseline characteristics of the three different patient groups. The groups were compared using a one-way
analysis of variance (one-way ANOVA). There were no significant differences between the three patient groups in age, education, EDSS, disease duration or in baseline tests. Patients’ performance at baseline was evaluated and depending on the particular test, performance lower than one standard deviation below the published population norms was defined as cognitively impaired. According to these criteria 3 patients in the high intensity training, 7 in the distributed training and 5 in the control group without training were impaired in the Corsi Blocks forward. In the Corsi Blocks backward, 4 patients in the high intensity training, 6 in the distributed training and 5 in the control group without training were impaired. As for the Digit Span forward, 5 patients in the high intensity training, 5 in the distributed training and 10 in the control group without training were impaired. In the Digit Span backward, 5 patients
A. Vogt et al. / Working memory training in patients with multiple sclerosis – comparison of two different training schedules 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
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City Map visual instructions City Map verbal instructions
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Find Pairs
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distributed training high intensity training
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Memorize Numbers
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Fig. 1. Averaged achievements of patients in the two different training groups (high intensity and distributed training) in the module City Map with visual and verbal instructions (A), in the module Find Pairs (B) and the module Memorize Numbers (C). Level of difficulty = level reached after a defined number of consecutively correct responses. Highest level of difficulty is indicated in each figure. (Colours are visible in the online version of the article at www.iospress.nl.)
in the high intensity training, 4 in the distributed training and 10 in the control group without training were impaired. 6 patients in the high intensity training, 3 in the distributed training and 6 in the control group without training were impaired in the PASAT. For the
FST performances above the cut-off score of 3 were defined as cognitively impaired. 6 patients in the high intensity training, 5 in the distributed training and 6 in the control group without training were impaired in the FST. No published population norm exists for the
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A. Vogt et al. / Working memory training in patients with multiple sclerosis – comparison of two different training schedules Table 2 Means and standard deviations in the two intervention groups in the training tool BrainStim
City map visual instructions City map verbal instructions Find Pairs Memorize Numbers
High intensity training (n = 15) First training Last training M SD M SD 3.48 1.29 11.72 2.75 4.13 0.77 7.13 2.84 3.70 1.90 7.44 1.74 2.60 0.99 7.57 2.38
2-back task, as it is an adaptation from the TAP. Mean fatigue scores in the FSMC were above cut off value for clinically relevant fatigue in all three patient groups (cut off value: 43). According to this cut off value 14 patients in the high intensity training, all 15 in the distributed training and all 15 in the control group without training suffered from fatigue. For the MFIS, the mean fatigue score of patients in the high intensity training was marginally above the cut off value (cut off value: 38). According to this cut off value 8 patients in the high intensity training, 10 in the distributed training and 9 in the control group without training suffered from fatigue. Mean depression scores in the ADS were below cut off value in all three groups (cut off value: > 23). According to this cut off value 3 of patients in the high intensity training, 1 in the distributed training and 2 in the control group without training suffered from depression. 3.2. Training tool BrainStim Log files recorded during training revealed that patients in both intervention groups (distributed training and high intensity training) were able to master increasing levels of difficulty in all three modules as training progressed (see Fig. 1). Table 2 shows means and standard deviations of level of difficulty in the first and in the last training and in both intervention groups. With regard to differences in performance between the two intervention groups and changes from the first training to the last training, a 2 × 2 mixed ANOVA with the two different training groups as between-subjects factor and mean of first and last session level of difficulty as within-subjects factor was executed. An alpha level of 0.05 was used for all statistical tests. Significant main effects were found for mean level of difficulty in the first training compared to mean level of difficulty in the last training in all modules: Module City Map with visual instructions (F (1,28) = 320.36, p < 0.00, partial η 2 = 0.96), module City Map with verbal instructions (F (1,28) = 40.69, p < 0.00, partial η 2 = 0.77), module Find Pairs (F (1,28) = 81.63, p
