Persistence of the effects of attention and executive functions intensive rehabilitation in relapsing remitting multiple sclerosis

Multiple Sclerosis and Related Disorders 1 (2012) 168–173

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Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard

Persistence of the effects of attention and executive functions intensive rehabilitation in relapsing remitting multiple sclerosis F. Mattioli a,n, C. Stampatori a, C. Scarpazza a, G. Parrinello c, R. Capra b a

Neuropsychology Unit, Spedali Civili of Brescia, V. Nikolajewka, 13, 25123 Brescia, Italy Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, Italy c Statistics, University of Brescia, Brescia, Italy b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 October 2011 Received in revised form 24 February 2012 Accepted 24 June 2012

Background: Neuropsychological rehabilitation efficacy in multiple sclerosis (MS) is a currently investigated issue. We reported, in a single blind controlled study, that an intensive short duration cognitive training of attention and executive functions significantly improves the treated functions and reduces depression in MS. The persistence of these effects over time are unknown. Objective: To evaluate the persistence over time of neuropsychological improvement due to cognitive training nine months after rehabilitation onset. Methods: This is a single blind randomized controlled study. 24 MS patients were randomly assigned to experimental group (n ¼ 13) and received PC assisted neuropsychological treatment for three months, or to control group (n ¼ 11), receiving no treatment. Patients were submitted to neuropsychological evaluation, depression and quality of life questionnaires at baseline, three months and nine months later. Results: Nine months follow up compared to baseline evaluation shows a statistically significant improvement (p o 0.05) in attention, information processing and executive functions tests (PASAT 300 , COWA/S, WCSTpe), in depression and quality of life questionnaires in rehabilitated patients only. reliable change index (RCI) and modified RCI confirmed the clinical significance of this improvement in rehabilitated patients. Conclusions: Three months intensive neuropsychological rehabilitation of attention, information processing and executive functions induces a long lasting and clinically relevant neuropsychological improvement over time and a persistent depression and quality of life amelioration in patients with RR MS. & 2012 Elsevier B.V. All rights reserved.

Keywords: Multiple sclerosis Attention Rehabilitation Information processing Reliability Executive function

1. Introduction Multiple sclerosis (MS) is one of the most frequent neurological diseases with an early onset in young adult life (Koutsouraki et al., 2010). Cognitive impairment is a common feature, affecting approximately 43–70% of patients (Rao et al., 1991). The main affected cognitive areas are executive functions, memory and information processing speed (Calabrese, 2006; Prakash et al., 2008; Duque et al., 2008). A significant impairment in the ability to inhibit automatic responses (measured by the Stroop test) (Vitkovitch et al., 2002), cognitive flexibility (measured by the Wisconsin card sorting test, WCST) (Foong et al., 1997; Santiago et al., 2007), verbal fluency (Henry and Beatty, 2006) and attention (McCarthy et al., 2005) has also been found in patients. Working memory, the ability to

n Corresponding author. Tel.: þ 39 30 2027226, mobile: þ 39 328 5969276; fax: þ 39 30 2027201. E-mail address: fl[email protected] (F. Mattioli).

2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.06.004

maintain and manipulate information in the brain for a short time period, is also affected, as well as the speed of information processing (Chiaravalloti and DeLuca, 2008). Depression, a common symptom in the MS population (Siegert and Abernethy, 2005), interferes with everyday activities and cognitive performance. It often appears to be associated with cognitive impairment, although the relationship between neuropsychological deficits and depression is unclear (Demaree et al., 2003). A consistent positive link has been found between depression and cognitive functioning, particularly with poor working memory (Arnett et al., 1999), learning, planning abilities (Arnett et al., 2001) and processing speed (Landrø et al., 2004). In other studies, depression has been related mainly to motor disability, rather than to the neuropsychological deficits in newlydiagnosed MS (Siepman et al., 2008). Both cognitive and mood disorders deeply affect quality of life in MS patients, so that the appropriate treatment of these deficits is mandatory. The definition of the most appropriate type, intensity and duration of cognitive rehabilitation techniques for each disorder is also a matter of debate and needs to be

F. Mattioli et al. / Multiple Sclerosis and Related Disorders 1 (2012) 168–173

addressed, as to whether rehabilitation techniques are considered in terms of health care strategies. Studies investigating the effectiveness of neurobehavioral rehabilitative procedures on neuropsychological and psychological outcomes in MS state that cognitive behavioural approaches seem to be beneficial, although the diversity of psychological intervention and the multiple outcome measures prevent definite conclusions from being drawn (Thomas et al., 2007). In particular, 16 randomized studies were recently 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. However, most studies included patients with different levels of disability at the expanded disability status scale (EDSS) (Kurtzke, 1983) and different durations of disease. Furthermore, long term changes of neuropsychological deficits or depression were not assessed in all studies. For these reasons results were controversial and methodological aspects have been underlined in the Cochrane review (Thomas et al., 2007). For exemple, Jonsson et al. (1993) randomized 40 patients with MS who had mild-to-moderate cognitive and behavioural impairment to either cognitive treatment or non-specific ‘‘mental stimulation’’. Treatment lasted on average 46 day. 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. After six months, only this group showed a significant effect on the visuo-spatial memory task and depression scores. However, the experimental group was submitted to direct training, compensatory strategies and neuropsychotherapy, so that it is impossible to determine which of these techniques was responsible for the observed improvement. The efficacy of a computer-based retraining of four different attention domains has been studied in an open study conducted on 22 patients (Plohmann et al., 1998). 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 nine weeks. Any effects on activities of daily living were assessed using a self-rating inventory. Significant improvements in performance, which remained stable for nine weeks, were achieved by the attention training program. Unfortunately, only attention has been studied and a short follow up has been provided. Fink et al. (2010) compared in a controlled study, a cognitive intervention on executive functions with placebo compared to no therapy and found, at one year follow up, a significant improvement on verbal learning in treated patients. Depression and quality of life were not assessed. We have previously conducted a single-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 (Mattioli et al., 2010a). The findings suggest that three months intensive information processing, attention and executive function abilities rehabilitation leads to significant improvement of trained cognitive skills, as demonstrated by significant paced auditory serial-addition task (PASAT) (Gronwall, 1977) and Wisconsin card sorting test (WCST) (Berg, 1948) greater improvement in post rehabilitation neuropsychological assessment, as well as in greater reduction of depression scores. A non specific effect of decreased depression on neuropsychological performance was excluded by means of a regression analysis. However, the persistence over time of such effects were not assessed, for this reason a follow up study to examine patients’ cognitive profile six months after the end of training was necessary. Hence, the present study is the logical next step, with the aim to evaluate the long term effectiveness of this specific and intense

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rehabilitation procedure, i.e., the stability of the previously obtained improvement at six month follow up. Though the methodological limitation of the study design – the lack of a ‘‘control treatment’’ –, we introduced a methodological improvement using reliable change index (RCI), which is a statistical index used to assess the real change in clinical practice, i.e., at individual level.

2. Materials and methods 2.1. Patients Twenty four clinically stable patients with RR MS were included in the study. Between June 2007 and December 2008, 150 patients affected with RR MS, according to the (Poser and Brinar, 2001) criteria were examined at Spedali Civili di Brescia. Patients were included in this controlled single-blind study if they had a ‘‘stable’’ course (no relapses in the previous year), EDSSo4 and if their scores fell below z ¼ 1.5 (Benedict et al., 2004) for PASAT (either 200 or 300 interval) and T¼35 for WCST in any of the tests measures: total errors (WCST te), number of perseverative errors (WCST pe) and number of perseverative responses (WCST pr), according to Heaton et al. (2008). Exclusion criteria were the following: one or more clinical exacerbations in the previous year (in order to minimize the occurrence of silent progression of the disease possibly inducing cognitive changes), loss of visual acuity, ongoing major psychiatric disorder, substance abuse and a mini mental state examination (MMSE (Folstein et al., 1975)) score of o24. We considered clinically stable patients in order to minimize a possible cognitive change due to spontaneous fluctuation of the disease and not to the direct effect of rehabilitation. During the study period no relapses occurred. Immunomodulating therapy was taken by 5/11 patients in the control group (interferon b 1A), whereas by 6/13 patients in the study group (three copolimer and three interferon b 1A). The remaining patients did not take any therapy. Eligible patients providing written informed consent, were alternatively assigned by a neurologist to either a study group (SG) or a control group (CG), respectively, including 13 and 11 patients, whose clinical characteristic, summarized in Table 1, were not different. Both SG and CG patients underwent pre and post treatment neuropsychological evaluation with a blinded psychologist, whereas cognitive training was carried out with a second unblended psychologist. Patients were the same as those examined in Mattioli et al. (2010a) plus three patients in the SG and one in the CG, who performed the baseline cognitive assessment after the publication of the previous work. 2.2. Methods SG patients were submitted to intensive neuropsychological training for three consecutive months (1 h session for three times/ week), whereas CG patients were not rehabilitated. Both groups Table 1 Demographic and clinical characteristics of the control group (CG) and the study group (SG).

Age (years) Education (years) Illness (years) EDSS

CG N¼ 11

SG N ¼ 13

p valuea

46.90 10.63 20.00 2.40

45.46 8.80 16.69 2.34

p ¼ns p ¼ns p ¼ns p ¼ns

(10.24) (4.80) (8.91) (1.20)

(10.48) (3.70) (7.76) (1.19)

Values denote mean (standard deviation), ns¼ not significant. EDSS¼ expanded disability status scale. a

Mann–Whitney test.

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were submitted to neuropsychological evaluation at T0 (baseline), T1 (three months later) and T2 (nine months after baseline; six months after the end of training for SG). During these last six months both SG and CG were not submitted to any cognitive training. Neuropsychological evaluation included cognitive tests assessing the main cognitive functions damaged by MS: PASAT, WCST, controlled oral word association test with phonemic (COWA/P) and semantic (COWA/S) cues (Novelli et al., 1986), divided attention of test of everyday attention (TEA) (Zimmermann and Fimm, 1997), selective reminding test for verbal learning – consistent long-term retrieval (SRT/CLTR) and delayed recall (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) (Amato et al., 2006), Montgomery–Asberg depression rating scale (MADRS) (Montgomery and Asberg, 1979), and the self-reported multiple sclerosis quality of life (MSQoL) (Solari et al., 1999). All the tests corrected measures described in Heaton et al. (2008) were considered, plus the categories’ number (raw number), given that errors and perseverative responses are known to have problems with the norms when the performance on number of categories is adequate. For tests description see Mattioli et al. (2010a). 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 ABA design. The evaluating psychologist was unaware of the treatment of each patient.

Furthermore the reliable change index (Jacobson and Truax, 1991) was calculated for these tests which resulted to be significantly improved in SG than in CG, in order to assess the clinical significance of change. RCI was used in depression and quality of life measures, whereas a modified version (MRCI) was used to assess the efficacy of tests affected by practice effects. In its most basic form, the RCI expresses the difference in performance between two assessments (e.g., post-treatment performance minus baseline performance) as a function of the standard error of the difference (S.E. difference). Expressing the change in terms of its error allows the change in the individual to be viewed in context of the spread of the distribution. This provides an indication of the magnitude of the change. The RCI was calculated for each outcome measure of each treatment condition as follows: RCI¼(x2 x1)/SE diff, where x1 and x2 are the mean pre- and post-treatment scores. The MRCI was calculated as follows: (x2 x1 (mu2  mu1))/SE diff, where mu1 and mu2 were, respectively, the mean obtained from the sample in each neuropsychological pre and post rehabilitation test. Test retest reliability, which is used to calculate the SE diff (see Jacobson and Truax, 1991), was taken from previous data in literature: from Tombaugh (2006) for PASAT; from Novelli et al. (1986) for COWA/S; from Ingram et al. (1999) for WCSTpe; from Mundt et al. (2006) for MADRS and from Vickrey et al. (1995) for MSQoL. If a range of reliability was indicated (i.e., for PASAT 0.90 to 0.96), the mean value was chosen. Finally, to summarize the results, Fisher’s exact test was employed. All the presented values were corrected for multiple comparison using the Bonferroni approach.

2.3. Rehabilitation 3. Results Detailed neuropsychological rehabilitation procedures are described in Mattioli et al. (2010a). Briefly, SG underwent intensive computer-assisted neuropsychological treatment for three consecutive months, on an individual basis. Each session lasted for one hour, with a frequency of three sessions per week. The rehabilitation program was composed of attention, information processing and planning exercises for executive functions. The software used (plan a day and divided attention) were part RehaCom package (www.Schuhfried.at), which provides a special keyboard with large button, 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 data and duties to be organized within a single day; in divided attention, the patient is required to simulate a train driver, carefully observing the control panel of the train and the countryside and several distractions, as crossing animals, are provided. The strength of this rehabilitation program is that it is composed by ecological tests, which often increase patient’s motivation in tasks execution (Verdejo-Garcı´a and Pe´rez-Garcı´a, 2007). A specific information processing and working memory training, which has been shown to be effective in patients with brain injuries, was combined with divided attention training at each session, consisting of a modified PASAT task with numbers, words and months of the year (Serino et al., 2006).

2.4. Statistical analysis Descriptive statistics are expressed as median, lower and upper quartiles. Due to small sample size, groups were compared using the nonparametric Mann–Whitney test (between group analysis) for continuous variables. Moreover, having only 13 SG and 11 CG, this should be considered a feasibility study.

At baseline, no significant differences between SG and CG groups in all neuropsychological tests were found (all p values 40.05; Table 2). The differential T1 T0 (delta) scores for each neuropsychological test were compared between the SG and CG groups. Results show a statistically significant greater change (p o0.05) in SG Table 2 Neuropsychological test scores in the control groups (CG) and in the study group (SG) at baseline (T0). CG N ¼11 PASAT 20 0 PASAT 30 0 WCSTcat WCSTte WCSTpr WCSTpe COWA/P COWA/S TEAam TEAvm TEAto TEAte SRT/CTRL SRT/DR 10/36 SRT LTR 10/36 SRT DR SDMT MADRS MNSQoL

0 0 2 49 38.5 33.5 23 27.5 535.5 885.5 2.5 3 14 4 13.5 4 28 6.5 56

0 15 3 60 57 45 30 32 614 998 5 3 19 5 17 5 34 13 188

p valuea

SG N ¼13 22 40 4 82 91 67 44 50 1252 1958 19 18 31 9 25 10 64 31 219

0 0 0 54 37 35 23 28 560 850 3 4 18 5 14 4 23 1 146

0 19 3 62 56 49 28 34 582 933 5 8 18 6 15 5 32 13 177

23 32 6 93 70 61 38 51 1250 1637 10 30 47 10 19 8 52 29 232

p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns

For test definitions, see Mattioli et al. (2010a, 2010b). The columns represent: the lower quartile, the median, and the upper quartile for continuous variables. ns¼not significant. a

Mann–Whitney test with Bonferroni correction.

F. Mattioli et al. / Multiple Sclerosis and Related Disorders 1 (2012) 168–173

Table 3 Comparison of delta (T1 T0) scores for each test in the control groups (CG) and in the study group (SG). CG N ¼11 PASAT 20 0 PASAT 30 0 WCSTcat WCSTte WCSTpr WCSTpe COWA/P COWA/S TEAam TEAvm TEAto TEAte SRT/CTRL SRT/DR 10/36 SRT LTR 10/36 SRT DR SDMT MADRS MNSQoL

0 8 1  31  27.5  23.5 6  1.5  55  67  2.5 2 9 0  3.5  1.5 4  1.5 17

p valuea

SG N ¼13

0 0 1  20 3 6 3 2  15 5 2 0 3 0 2 0 0 1 7

11 20 5 3 5 0 10 13 143 427 5 5 12 2 5 2 7  24.5 25

3 8 0  53  44  41 3 3  14  260 4 8 7 1 4 1 2 9 8

14 17 3  42  26  28 7 5 119 -51 2 4 4 0 2 0 0 4  14

46 41 6 0 1  13 17 16 255 541 3 3 28 3 10 5 28 1 49

p¼ o 0.05 p¼ o 0.05 p ¼ns p¼ o 0.05 p ¼ns p¼ o 0.05 p¼ o 0.05 p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p ¼ns p¼ o 0.05 p ¼ns

For test definitions, see Mattioli et al. (2010a, 2010b). The columns represent: the lower quartile, the median, and the upper quartile for continuous variables. ns¼ not significant. a

Mann–Whitney test with Bonferroni’s correction.

Table 4 Comparison of delta (T2 T0) scores for each test in the control groups (CG) and in the study group (SG). CG N ¼ 11 PASAT 20 0 0 0 PASAT 30 0 0 3 WCSTcat 0 2 WCSTte 27  17 WCSTpr 30  14 WCSTpe 20.7  15 COWA/P 0.5 2 COWA/S  3.5 0 TEAam 126.5  13 TEAvm 136  55 TEAto 4 1 TEAte  4.5  3 SRT/CTRL 0 2 SRT/DR 0.5 1 10/36 SRT LTR 3 1 10/36 SRT DR  1.5  1 SDMT 3 2 MADRS  2.5 3 MNSQoL 22.5  13

21 21 4 35 30 21 9 7 129 148 3 1 34 3 7 4 11 28 46

SG N ¼13

p valuea

7 14 0  54  45  45 1 0 10  119 5 6 3 0 1 0 0  15  17

p¼ ns p ¼ o 0.05 p¼ ns p¼ ns p¼ ns p ¼ o 0.05 p¼ ns p ¼ o 0.05 p¼ ns p¼ ns p¼ ns p¼ ns p¼ ns p¼ ns p¼ ns p¼ ns p¼ ns p ¼ o 0.05 p ¼ o 0.05

11 46 20 30 3 6  40.31 4  31.5 8  27 19 8 12 8 21 16 309  98 395 1 2 3 4 0 16 2 3 0 4 1 5 3 29 8 6 33 104

For test definitions, see Mattioli et al. (2010a, 2010b). The columns represent: the lower quartile , the median, and the upper quartile for continuous variables. ns¼ not significant. a

Mann–Whitney test with Bonferroni’s correction.

than in CG in PASAT 300 , PASAT 200 , WCSTte, WCSTpe, COWA/P and MADRS, as shown in Table 3. The comparison of differential T2 T1 (delta) score between SG and CG reveals no statistically significant change in the cognitive performance from the end of the rehabilitation to the nine months follow up, in all the measures, indicating a stable cognitive profile from T1 to T2 in both groups. In order to assess the long term persistence of improvement in SG, we compared T2 with T0 scores in both CG and SG. In SG, the comparison of neuropsychological scores between T0 and T2 reveals a statistically significant improvement (po0.05) in PASAT 200 , PASAT 300 , COWA/P, COWA/S, WCSTte, WCSTpr, WCSTpe, TEAto, TEAte, SRT/ DR, MADRS and MSQoL at T2. CG improves too: the comparison of

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Table 5 Analysis of change between T0 and T2 in the control groups (CG) and in the study group (SG). Test

Test retest Analysis of changea reliability CG n¼11

SG n¼13

p

Increased Decreased Increased Decreased PASAT 3 COWA/S WCST pe MADRS MSQoL

0,93 0,75 0,64 0,85 0,81

3 0 4 1 1

(27%) (36%) (9%) (9%)

1 (9%) 0 0 4 (36%) 3 (27%)

11 4 12 6 6

(84%) (31%) (92%) (46%) (46%)

1 (8%) 1 (8%) 0 0 0

o 0.05 o 0.05 ns o 0.05 o 0.05

p denotes significance at Fischer’s exact test with Bonferroni correction. Values denotes number of subjects (percentage) achieving a reliable change between T0 and T2. a

RCI for MSQoL and MADRS; MRCI for PASAT 3, COWA/S and WCST pe.

neuropsychological scores between T0 and T2 in CG group reveals statistically significant differences (po0.05) in SRT/DR, TEAvm, TEAte, WCSTpr, WCSTpe. This indicates that, in some tests and at different extents, both SG and CG improve at follow up. In order to compare improvements in both groups, the differential T2 T0 (delta) scores for each neuropsychological test were compared between the groups. A significantly higher improvement (p o0.05) in PASAT 300 , WCSTpe, COWA/S, MADRS and MSQoL was found in SG than in CG (Table 4), indicating that the rehabilitated patients improved more than not rehabilitated ones in tests of information processing/attention, decision making and verbal fluency with a semantic cue and also had lower depression scores and higher subjective quality of life perception six months after the end of the specific rehabilitation. RCI and MRCI confirmed the training induced improvement also at the individual level (Table 5). Indeed, compared to CG, significantly more patients in the SG are significantly improved in PASAT 3 and WCSTpe and less deteriorated also at six month follow up. The number of rehabilitated subjects with less depression and quality of life after nine months is significantly higher in SG than in CG.

4. Discussion The main result of this follow up controlled study is the long term persistence of the efficacy of a short duration cognitive training of attention, information processing and executive functions in MS. We found that the improvement of attention/information processing and executive functions, achieved after the end of rehabilitation, remained stable six months after the end of the cognitive training itself. A learning effect is unlikely as the main cause of the improvement in SG, as it would happen also in CG, which is not the case. In addition, the improvement extends to mood and quality of life and is significantly greater in patients who performed the cognitive training. More interestingly, the results have a clinically relevant effect, as shown by RCI and MRCI indices. Although is not possible to certainty state that neuropsychological improvement have a clinical relevance in patients daily life, we think that amelioration in depression score and subjective perceived quality of life could be considered as an indirect cue of the importance of cognitive enhancement in everyday life. Taken together, these results support the hypothesis of efficacy of a specific cognitive approach in MS and suggest that rehabilitation induced changes in cognition have some beneficial influence on mood and on

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quality of life. The improvement in depression score, which was shown to occur independently from cognitive amelioration after three month treatment, extends to quality of life at six month follow up. This was not found in the previous study, where at three months follow up MSQoL was not different between SG and CG (Mattioli et al., 2010a). Our paper is, to our knowledge, the first one demonstrating that a specific – and repeatable by others – cognitive training is not only useful after its duration, but also produces long lasting effects six months after its end. The effects of this training not only consist in attention/information processing and executive functions improvement, but extend to depression and quality of life. This finding is of notable clinical importance, as most studies on neuropsychological rehabilitation do not include functional scales on quality of life. Our results agree with previous studies. Jonsson et al. (1993) found that six months after the end of a non structured neurobehavioral intervention, MS patients showed an improvement in depression. They were not able to find a neuropsychological improvement and quality of life was not assessed. Fink et al. (2010) also longitudinally examined MS patients within a controlled trial, but functional scales were not used and neuropsychological improvement was not specific for the trained cognitive ability (executive function). Compared with previous studies on cognitive rehabilitation in MS, the present research is enriched by the introduction of innovative aspects. First of all, the adoption of highly ecological training exercise, instead of relatively simplified stimuli that significantly differ from the complex, dynamic and contextuallyembedded stimuli present in the real patient’ environment, makes the rehabilitation more ecological and with a higher likelihood to be translated into daily life activities. Second, the introduction of methodological improvement, such as RCI, help us to examine not only group effectiveness of rehabilitation, but above all, efficacy of training at individual level, excluding practice effects. Preliminary functional MRI data (Mattioli et al., 2010b) suggested that the possible neural correlates of this neuropsychological training could be an exercise-induced activation of prefrontal and cingulate cortices, brain structures notably involved in attention and decision making. This also indicates that a specific and repeated cognitive task has, as a consequence, a functional reactivation of those networks which are functionally related to this cognitive ability. The persistence over time of clinical findings could be related to a persistence over time of such a brain plasticity. These results are worth nothing both on the clinical point of view and on the health care governance aspect. Clinically, it is relevant for patients to have a helpful treatment, without side effects, able to provide significant improvements in cognitive, mood as well as ecological aspects of their life. The size of such an improvement appears to exceed the effects on cognitive domains shown by the currently used immunomodulating drugs, in MS (Patti et al., 2010). Furthermore, the short duration of the follow up and the similarly low number of treated patients in both SG and CG, do not support a possible effect of the immunomodulating therapies, taken by some of the patients, in our study. Vogt et al. (2009) compared two different schedules of a computer based working memory training. Patients received 16 training sessions schedules either as a high intensity training (4 times per week for 4 weeks) or a distributed training (2 times per week for 8 weeks). Results showed that both intervention led to improved working memory, but there were no effects on short term memory, quality of life or depression. Our study did not compare different treatment duration or intensity, but analyzed short duration high intensity treatment only. As cognitive training realization needs to be subjected to economical and organization

considerations within the health care system, a demonstration of the usefulness of a reproducible training, repeated for a low number of session (approximately 36 in three months per patient), with the help of a psychologist may well be a starting point for developing effective strategies for helping MS population. The possibility that our results were influenced by regression to the mean bias is worth to be considered. Regression toward the mean refers to the statistical phenomenon in which patients who are chosen for the more extreme scores on a variables, as in this study, will tend to have a scores closer to the mean on retest, without any intervention. This statistical artifact, which might have created a selection bias (because selected patients might not have a truly impaired performance in some tests) is unlikely, in our opinion. Our patients performance at inclusion was under the cut off in more than one measures (exceeding the inclusion criteria requirements), so that the possibility that a single patient was poor in more than one test due to an artifact, is unlikely. The dimension of the patients’ sample, which is quite small, due to strict inclusion criteria, may be a limitation of the study, as well as the inclusion of only one year stable RRMS—not representing the entire MS population. Therefore the results could not be generalizable to the entire MS population. It is also worth noting that the selection of homogeneous patients, with stable disease course and low disability, has been deliberately done, in order to detect the effect of rehabilitation itself and to avoid the methodological problems presented by the majority of previously published papers on cognitive rehabilitation (different disability, different course of the disease’s patients, possible worsening due to progression of disability, as well as of brain demielinization). Another limitation of the study is the lack of a placebo (a specific cognitive intervention) group, which is, on the other hand, difficult to realize in cognitive interventions. This study may well be considered a pilot study and further research including a placebo treatment arm will be useful. On the other hand, an important clinical finding of our paper is the specificity of the cognitive training used on attention and executive functions. This is of particular relevance, as in the previously published papers, the used outcome measures were often not specific to detect neuropsychological improvement. The persistence over time and the clinical efficacy of the rehabilitation is also notably. The finding of such an effect on low disability patients (although suffering cognitive impairment) suggests possible good effects also on more severe cases. In conclusion this study aimed at investigating, in MS patients, the long term persistence of cognitive improvement obtained with short term rehabilitation of attention and executive functions, gave positive results and prompts further investigations on larger samples. Conflict of Interest None to declare

References Amato MP, Portaccio E, Goretti B, Zipoli V, Ricchiuti L, De Caro MF, et al. The Rao’s brief repeatable battery and Stroop test: normative values with age, education and gender corrections in an Italian population. Multiple Sclerosis 2006;12: 787–93. Arnett PA, Higginson CI, Voss WD, Bender WI, Wurst JM, Tippin JM. Depression in multiple sclerosis: relationship to working memory capacity. Neuropsychology 1999;13:434–46. Arnett PA, Higginson CI, Randolph JJ. Depression in multiple sclerosis: relationship to planning ability. Journal of the International Neuropsychological Society 2001;7(6):665–74. Benedict RHB, Cox D, Thompson LL, Foley F, Weinstock-Guttman B. Reliable screening for neuropsychological impairment in multiple sclerosis. Multiple Sclerosis 2004;10:675–8.

F. Mattioli et al. / Multiple Sclerosis and Related Disorders 1 (2012) 168–173

Berg EA. A simple objective technique for measuring flexibility in thinking. Journal of General Psychology 1948;39:15–22. Calabrese P. Neuropsychology of multiple sclerosis. An overview. Journal of Neurology 2006;253(suppl1):I/10–5. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurology 2008;7(12):1139–51. Demaree HA, Gaudino E, DeLuca J. The relationship between depressive symptoms and cognitive dysfunction in multiple sclerosis. Cognitive Neuropsychiatry 2003;8:161–71. Duque B, Sepulcre J, Bejarano B, Samarach L, Pastor P, Villoslada P. Memory decline evolves independently of disease activity in MS. Multiple Sclerosis 2008;14: 947–53. Fink F, Rischkau E, Butt M, Klein J, Eling P, Hilderbrandt H. Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudorandomized trial. Multiple Sclerosis 2010;16(9):1148–51. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatry Research 1975;12(3):189–98. Foong J, Rozewicz L, Quaghebeur G, Davie CA, Kartsounis LD, Thompson AJ, et al. Executive function in multiple sclerosis: the role of frontal lobe pathology. Brain 1997;120:15–26. Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Perceptual & Motor Skills 1977;44(2):367–73. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G. WCST forma completa revisionata. Adattamento italiano a cura. In: di MC, Harday MG, Carta, Cabras PL, editors. Firenze: Giunti OS; 2008. Henry J, Beatty W. Verbal fluency deficits in multiple sclerosis. Neuropsychologia 2006;44:1166–74. Ingram F, Greve KW, Ingram PT, Soukup VM. Temporal stability of the Wisconsin card sorting test in an untreated patient sample. British Journal of Clinical Psychology 1999;38:209–11. Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology 1991;59(1):12–9. Jonsson A, Korfitzez EM, Heltberg A, Ravnborg MH, Byskov-Ottosen E. Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurologica Scandinavica 1993;88(6):394–400. Koutsouraki E, Costa V, Baloyannis S. Epidemiology of multiple sclerosis in Europe: a review. International Review of Psychiatry 2010;22(1):2–13. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52. Landrø NI, Celius EG, Sletvold H. Depression symptoms account for deficient information processing speed but not for impaired working memory in early phase multiple sclerosis. Journal of Neurological Sciences 2004;217:211–6. Mattioli F, Stampatori C, Zanotti D, Parrinello G, Capra R. Efficacy and specificity of intensive cognitive rehabilitation of attention and executive functions in multiple sclerosis. Journal of Neurological Sciences 2010a;288:101–5. Mattioli F, Stampatori C, Bellomi F, Capra R, Rocca M, Filippi M. Neuropsychological rehabilitation in adult multiple sclerosis. Neurological Scences 2010b;31(suppl2): S271–4. McCarthy M, Beaumont JG, Thompson R, Peacock S. Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis. Archives of Clinical Neuropsychologia 2005;20:705–18. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. British Journal of Psychiatry 1979;134:382–9.

173

Mundt JC, Katzelnick DJ, Kennedy SH, Eisfeld BS, Bouffard BB, Greist JH. Validation of an IVRS version of the MADRS. Journal of Psychiatric Research 2006;40: 243–6. Novelli G, Papagno C, Capitani E, Laiacona N, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali. Archivio di Psicologia, Neurologia e Psichiatria 1986;47(4):477–506. Patti F, Amato MP, Bastianello S, Caniatti L, Di Monte E, Ferrazza P, et al. COGIMUS study group. Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis 2010;16(1):68–77. Plohmann AM, Kappos L, Ammann W, Thordai A, Wittwer A, Huber S, et al. Computer assisted retraining of attentional impairments in patients with multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 1998;64(4): 455–62. Poser CM, Brinar VV. Diagnostic criteria for multiple sclerosis. Clinical Neurolology and Neurosurgery 2001;103(1):1–11. Prakash RS, Snook EM, Lewis JM, Molt RW, Kramer AF. Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis. Multiple Sclerosis 2008;14:1250–61. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41(5): 685–91. Santiago O, Gua rdia J, Casado V, Carmona O, Arbizu T. Specificity of frontal dysfunction in relapsing remitting multiple sclerosis. Archives of Clinical Neuropsychology 2007;22:623–9. Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. Journal of Neurology, Neurosurgery and Psychiatry 2005;76:469–75. Siepman TA, Janssens AC, De Koning I, Polman CH, Boringa JB, Hintzen RQ. The role of disability and depression in cognitive functioning within 2 years after multiple sclerosis diagnosis. Journal of Neurology 2008;255(6):910–6. Serino A, Ciaramelli E, Di Santantonio A, La´davas E. A rehabilitative program for central executive deficits after traumatic brain injury. Brain Cognition 2006; 60(2):213–4. Solari A, Filippini G, Mendozzi L, Ghezzi A, Cifani S, Barbieri E, et al. Validation of Italian multiple sclerosis quality of life 54 questionnaire. Journal of Neurology, Neurosurgery and Psychiatry 1999;67(2):158–62. Thomas PW, Thomas S, Hillier C. Psychological interventions for multiple sclerosis (review). in The Cochrane collaboration, L.p. John Wiley and Sons; 2007. 1–51. Tombaugh TN. A comprehensive review of the paced auditory serial addition test (PASAT). Archives of Clinical Neuropsychology 2006;21(1):53–76. Verdejo-Garcı´a A, Pe´rez-Garcı´a M. Ecological assessment of executive functions in substance dependent individuals. Drug Alcohol Dependent 2007;90(1):48–55. Vitkovitch M, Bishop S, Dancey C, Richards A. Stroop interference and negative priming in patients with multiple sclerosis. Neuropsychologia 2002;40: 1570–6. Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Quality of Life Research 1995;4:187–206. Vogt A, Kappos L, Calabrese P, Stocklin M, Gschwind L, Opwis K, Penner IK. Working memory training in patients with multiple sclerosis-comparison of two different training schedules. Restorative Neurology and Neuroscience 2009;27(3):225–35. Zimmermann P, Fimm B. Batteria di test per l’esame dell’attenzione (TEA); 1997 (Italian edition by Pizzamiglio L, Zoccolotti P and Pittau PA).