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Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the NetherlandsKlimmendaal Rehabilitation Center, Arnhem, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the NetherlandsKlimmendaal Rehabilitation Center, Arnhem, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the NetherlandsKlimmendaal Rehabilitation Center, Arnhem, the NetherlandsDepartment of Medical Psychology, Radboud University Medical Center, Nijmegen, the NetherlandsVincent van Gogh Institute for Psychiatry, Venray, the Netherlands
Cognitive rehabilitation and mindfulness reduced cognitive complaints.
•
Positive effects on cognitive complaints did not persist six months post-treatment.
•
Mindfulness had a long-term positive effect on processing speed.
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Cognitive rehabilitation showed long-term benefits on personalized goals.
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Thus both treatments have specific contributions when treating cognitive problems.
Abstract
Background
Cognitive problems, both complaints and objective impairments, are frequent and disabling in patients with multiple sclerosis (MS) and profoundly affect daily living. However, intervention studies that focus on cognitive problems that patients experience in their daily lives are limited. This study therefore aimed to investigate the effectiveness of cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT) on patient-reported cognitive complaints in MS.
Methods
In this randomized-controlled trial, MS patients with cognitive complaints completed questionnaires and underwent neuropsychological assessments at baseline, post-treatment and 6-month follow-up. Patient-reported cognitive complaints were primarily investigated. Secondary outcomes included personalized cognitive goals and objective cognitive function. CRT and MBCT were compared to enhanced treatment as usual (ETAU) using linear mixed models.
Results
Patients were randomized into CRT (n = 37), MBCT (n = 36) or ETAU (n = 37), of whom 100 completed the study. Both CRT and MBCT positively affected patient-reported cognitive complaints compared to ETAU at post-treatment (p<.05), but not 6 months later. At 6-month follow-up, CRT had a positive effect on personalized cognitive goals (p=.028) and MBCT on processing speed (p=.027). Patients with less cognitive complaints at baseline benefited more from CRT on the Cognitive Failures Questionnaire (i.e. primary outcome measuring cognitive complaints) at post-treatment (p=.012–.040), and those with better processing speed at baseline benefited more from MBCT (p=.016).
Conclusion
Both CRT and MBCT alleviated cognitive complaints in MS patients immediately after treatment completion, but these benefits did not persist. In the long term, CRT showed benefits on personalized cognitive goals and MBCT on processing speed. These results thereby provide insight in the specific contributions of available cognitive treatments for MS patients.
Cognitive problems, including both patient-reported complaints and objective impairments, are common in multiple sclerosis (MS) and negatively affect patients’ daily functioning, including social engagement and employment status (
Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial.
). A compensatory (e.g. strategy training) rather than restorative approach (e.g. retraining lost cognitive functions) may be most promising to treat patient-reported cognitive complaints, as compensatory CRT specifically focuses on the management of cognitive problems in daily life. Correspondingly, previous studies showed that patients achieved personalized cognitive goals after compensatory CRT, which indicated better coping with daily life cognitive problems, although this was not compared to controls (
Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial.
Another promising behavioral treatment is a mindfulness-based therapy, which is far less-studied than CRT. Mindfulness teaches individuals to direct their attention to the present moment in a non-judgmental manner (
). The few studies that focused on mindfulness and MS-related cognitive problems showed a reduction of patient-reported cognitive complaints in severely fatigued MS patients (
The effectiveness of mindfulness-based stress reduction on psychological distress and cognitive functioning in patients with multiple sclerosis: a pilot study.
Mindfulness-based interventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials.
J. Neurol. Neurosurg. Psychiatry.2019; 90: 1051-1058
), positive effects on everyday life cognitive problems may be expected.
To provide more conclusive evidence, we performed a randomized-controlled trial (RCT) to investigate the effectiveness of compensatory CRT and mindfulness-based cognitive therapy (MBCT) compared to enhanced treatment as usual (ETAU) on patient-reported cognitive complaints in MS (REMIND-MS study) (
). Effects were examined immediately and 6 months after treatment completion. Secondary outcomes included personalized cognitive problems using goal-setting and objective cognitive function using neuropsychological tests. We hypothesized that both therapies would have a favorable outcome on patient-reported, personalized and objective cognitive functioning.
2. Material and methods
2.1 Study design and participants
The REMIND-MS study is a dual-center, single-blind RCT with three parallel groups: CRT, MBCT and ETAU (Fig. 1). The full protocol has been published previously (
). Measurements (baseline, post-treatment and 6-month follow-up) were performed at the MS Center Amsterdam between December 2017 and November 2020, and treatments were administered at the MS Center Amsterdam and Klimmendaal Rehabilitation Center in Arnhem. Approval was obtained from the institutional ethics review board of the Amsterdam UMC (2017.009), the Scientific Research Committee of Amsterdam Neuroscience (16–14), and the Institutional Review Board of Klimmendaal Rehabilitation Center (2017–01).
*Did not wish to continue measurements after dropping-out before or during the intervention phase. Overview of missing data: aDid not complete baseline questionnaires (n = 1); bDid not perform neuropsychological assessment at 6-month follow-up (n = 1); cDid not perform neuropsychological assessment (n = 2) or complete questionnaires (n = 1) at 6-month follow-up; dDid not complete the post-treatment measurement (neuropsychological assessment and questionnaires) due to disease-related reasons, but did return for the 6-month follow-up measurement (n = 1); eDid not perform neuropsychological assessment at 6-month follow-up (n = 1). Abbreviations: CRT = cognitive rehabilitation therapy; MBCT = mindfulness-based cognitive therapy; ETAU = enhanced treatment as usual.
Patients were recruited between May 2017 and January 2020 via referral from physicians, patient associations, websites, and social media. Main eligibility criteria were: (1) verified MS diagnosis (McDonald 2010 criteria) (
), (2) 18–65 years of age, (3) cognitive complaints (scoring ≥23 on the Multiple Sclerosis Neuropsychological Questionnaire – Patient version (MSNQ-P) (
) and all applied criteria are specified in Fig. 1. Initial eligibility was established through telephone or email, followed by an in-person eligibility screening (e.g. MSNQ-P) (Fig. 1). Participants gave written informed consent prior to inclusion.
2.2 Randomization and masking
For each location, patients were randomly assigned (1:1:1 ratio, variable blocks of 6 and 9) to CRT, MBCT or ETAU following baseline measurements. Additionally, minimization on the factors cognitive complaints, age, and sex was performed using equal weights. Randomization was performed by an independent researcher, assessors were blind to treatment allocation and patients were instructed not to disclose their treatment allocation.
2.3 Procedures
CRT and MBCT consisted of nine weekly group-based sessions of 2.5 h, except for one MBCT session that lasted 5 h (i.e. silent retreat). A detailed description has been published previously (
Effects of a multifaceted treatment program for executive dysfunction after acquired brain injury on indications of executive functioning in daily life.
), emotional and behavioral changes, and grief resolution. MBCT combined mindfulness-based stress reduction with elements of cognitive behavioral therapy (
), and patients were trained in self-regulation of attention and non-judgmental awareness of moment-to-moment experiences (e.g. emotions, thoughts and behaviors) (
). Patients received homework assignments during CRT and guided mindfulness meditation exercises during MBCT, which both took 30–45 min, 6 days a week. CRT groups consisted of 3–6 patients (mean=4.4) and MBCT groups of 4–7 patients (mean=5.8). ETAU consisted of one individual appointment with an MS specialist nurse that focused on psycho-education. Similar psycho-education content was incorporated during CRT and MBCT.
Adherence to sessions and homework exercises were documented. Therapist competence and protocol adherence were evaluated based on video and audio recordings of MBCT and CRT sessions respectively (
). Recordings of two randomly selected sessions were rated per therapist by experienced mindfulness trainers and clinical neuropsychologists respectively.
2.4 Outcomes
Demographic and disease-related characteristics were collected at baseline.
2.4.1 Patient-reported cognitive complaints
The primary outcome was the level of patient-reported cognitive complaints measured with the Cognitive Failures Questionnaire (CFQ) (
). The CFQ focuses on cognitive mistakes during everyday tasks. It entails 25 items related to memory, attention, actions and perception, with a five-point Likert scale ranging from 0 (never) to 4 (very often). The CFQ has been validated in a general Dutch population (
). Patient-reported cognitive complaints in terms of executive functioning were measured with the patient- and informant-version of the Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A) (
). It consists of a metacognition and behavioral regulation index and entails 70 items with a three-point Likert scale ranging from 1 (never) to 3 (often). The BRIEF-A has good psychometric properties in MS (
). These personalized goals concerned daily life problems experienced by patients due to cognitive difficulties. Outcome levels were defined on an individual level that corresponded to a 6-point Likert scale (e.g. expected level, (much) more than expected, (much) less than expected).
2.4.3 Objective cognitive function
Objective cognitive function was measured with an adaption (
), and consisted of four domains: processing speed, memory, visuospatial processing, and executive function. Processing speed was measured with the Symbol Digit Modalities Test (SDMT) with the total number of correctly substituted items (
). Memory was measured with the Dutch version of the California Verbal learning Test (CVLT), using the immediate recall, long-term recall and long-term recognition hits scores (
). Executive function was measured with the following three tests: (1) the Controlled Oral Word Association Test (COWAT) with the total score of three letters (
), which concerned card III corrected for cards I and II, (3) the Delis-Kaplan Executive Function System sorting test (D-KEFS) free sorting condition with the total number of correct sorts (
). For the SDMT, CVLT, BVMT-R, COWAT and D-KEFS, alternate forms were administered for repeated measurements to control for material-specific learning effects.
The raw test scores were converted into z-scores based on the whole-group means and averaged per test. If needed, z-scores were transformed such that higher scores represented better cognitive performance. Then, test-specific z-scores were averaged per domain. Regarding the memory domain, only immediate recall scores were used for this domain-specific z-score, and the delayed recall and recognition scores were analyzed separately as transformations did not result in normality. The domain-specific z-scores were used as outcome measures.
Additionally, at baseline, patients were categorized into cognitively impaired and cognitively preserved. For this categorization, the raw test scores were adjusted for the effects of age, sex and education when appropriate, based on a normative sample of Dutch healthy controls (
). Then, these corrected scores were converted into z-scores based on the same normative sample. Patients were classified as cognitively impaired if they scored at least 1.5 SDs below the mean of the healthy controls on at least 20% of the test scores (this corresponded to ≥3 deviant scores out of 13 test scores), as recommended previously (
) and was based on the primary outcome CFQ, three measurements and a comparison between two groups (MBCT vs. ETAU and CRT vs. ETAU) using mixed-model analyses. In total, 99 patients (33 per group) were needed to detect a medium effect between two groups (α=0.05, power=0.80, intra-class correlation=0.06). Taking into account drop-out and loss to follow-up, we intended to include 40 patients per group.
2.6 Statistical analysis
Statistical analyses were performed using SPSS 26 and STATA 14. JLO scores were log-transformed. GAS scores were transformed into t-scores (
). Pairwise group comparisons were performed at baseline using independent samples t-tests and chi-square tests (or their non-parametric alternatives).
Linear mixed-model analyses were performed for normally-distributed outcomes with time (post-treatment, 6-month follow-up) as a within-subjects factor and treatment (CRT vs. ETAU, MBCT vs. ETAU) as a between-subjects factor. Random intercepts accounted for the dependency of repeated observations within patients. Overall effects and effects at individual time-points (by inserting a group-by-time interaction) were estimated. Tobit mixed-model analyses using the same settings were performed for delayed recall and recognition scores (skewed distribution with ceiling effects) (
), as these analyses correct for censoring (i.e. when an outcome reaches a limit due to floor or ceiling effects). A modified intention-to-treat approach was applied including all patients with at least one follow-up assessment regardless of treatment completion. The analyses were also performed per-protocol by excluding patients who attended <50% of the treatment sessions or who participated in a similar intervention outside this study between baseline and 6-month follow-up. All analyses were adjusted for baseline performance (except for GAS, as baseline values were equal for all patients by definition), age, education and sex.
Furthermore, baseline moderators of treatment response on the CFQ at post-treatment were investigated. Mixed-model analyses as described above were performed on the intention-to-treat sample adjusting for baseline CFQ, while also entering a moderator-by-group-by-time interaction. The moderator-by-group interaction indicated moderation effects at post-treatment (i.e. set as reference category). Potential moderators were demographics, disease-related characteristics, cognitive complaints and objective cognitive function (i.e. four cognitive domains and categorization in cognitively impaired).
As a post-hoc analysis, the reliable change index (RCI) was estimated for the CFQ between baseline and post-treatment, using the ETAU group to correct for measurement errors (
). The following equation was used to calculate the RCI scores: , which represents the difference between the patient scores at post-treatment and baseline () and the standard error of the difference between both time-points in the ETAU group to correct for measurement errors (). The number of patients who reliably improved on the CFQ within each treatment group (i.e. RCI>1.645; 90% confidence interval) was calculated, and compared to ETAU using chi-square tests.
For all analyses, α was set at 0.05. For delayed recall and recognition scores, a Bonferroni-corrected α of 0.013 was applied (0.05/4 single scores).
3. Results
In total, 110 patients (75% women, mean age 48.7 ± 9.8 years, 66% relapsing remitting MS, 57% cognitively impaired) were randomized into CRT (n = 37), MBCT (n = 36) and ETAU (n = 37). Ten patients were lost to both post-treatment and 6-month follow-up, and our primary analyses therefore concerned 100 patients (Fig. 1). Per-protocol analyses involved 95 patients. Demographic and disease-related characteristics did not differ between groups (p>.05; Table 1).
Table 1Demographic, disease-related and cognitive characteristics of all randomized patients.
Education was coded according to Verhage and categorized as low (i.e. completed average-level secondary education or lower; levels 1–5) or high (i.e. completed high level secondary education or university degree; levels 6–7).
Disease duration represents the time between the first onset of neurological complaints and the visit date. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; RR=relapsing remitting; SP=secondary progressive; PP=primary progressive; EDSS=Expanded Disability Status Scale; DMT=disease modifying therapy; CIRS= Cumulative Illness Rating Scale.
median (IQR)
13.5 (18.2)
15.2 (14.1)
11.8 (16.5)
14.2 (21.0)
EDSS, median (range)
4.0 (2.0–8.0)
3.5 (2.0–8.0)
3.8 (2.0–7.0)
4.0 (2.5–7.5)
DMT use (yes), n (%)
58 (53)
22 (60)
19 (53)
17 (46)
Comorbidities (CIRS score), median (range)
3 (3–9)
3 (3–7)
3 (3–7)
3 (3–9)
Cognitive impairment
Cognitively impaired, n (%)
63 (57)
21 (57)
23 (64)
19 (51)
Note. No significant differences between groups were found (p>.05).
a Education was coded according to Verhage and categorized as low (i.e. completed average-level secondary education or lower; levels 1–5) or high (i.e. completed high level secondary education or university degree; levels 6–7).
b Unclear indicates that the MS type could not be specified by the neurologist.
c Disease duration represents the time between the first onset of neurological complaints and the visit date.Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; RR=relapsing remitting; SP=secondary progressive; PP=primary progressive; EDSS=Expanded Disability Status Scale; DMT=disease modifying therapy; CIRS= Cumulative Illness Rating Scale.
For both CRT and MBCT, median attendance was 89% (8/9 sessions; IQR=3 and IQR=2 respectively). Median homework completion was 86% for CRT and 63% for MBCT. Regarding ETAU, 36 out of 37 patients (97%) visited the appointment.
3.1.2 Therapist competence and protocol adherence
The two mindfulness therapists who provided MBCT were considered beginner (n = 18 analyzed patients) and proficient (n = 14 analyzed patients) (
). Four neuropsychologists who provided CRT were considered proficient (n = 22 analyzed patients, of whom 1 did not start and 1 discontinued CRT, see Fig. 1) and one advanced (n = 10 analyzed patients).
3.1.3 Protocol adaptations during the COVID-19 pandemic
Due to a COVID-19 lockdown between March and June 2020, one CRT and MBCT group completed the last four sessions through group video calls (Zaurus application) after an interval of two-to-three weeks without treatment sessions. Also, neuropsychological evaluations at post-treatment (n = 10) and 6-month follow-up (n = 15) were performed one-to-nine weeks later than originally planned.
3.2 Intervention effects
Table 2 displays outcomes per group. At baseline, the informant BRIEF-A metacognition index was lower in CRT than ETAU (p=.042). Other outcome measures did not differ between groups at baseline. Fig. 2 shows intervention effects.
Table 2Outcome measures per time-point of the intention-to-treat sample stratified per treatment group.
At baseline, GAS scores are similar for each patient by definition. Therefore, no mean scores and SDs are available per group. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; CFQ=Cognitive Failure Questionnaire; (I-)BRIEF-A = (Informant) Behavior Rating Inventory of Executive Function – Adult Version; BR=behavioral regulation; MC=metacognition; GAS=Goal Attainment Scaling.
At baseline, GAS scores are similar for each patient by definition. Therefore, no mean scores and SDs are available per group. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; CFQ=Cognitive Failure Questionnaire; (I-)BRIEF-A = (Informant) Behavior Rating Inventory of Executive Function – Adult Version; BR=behavioral regulation; MC=metacognition; GAS=Goal Attainment Scaling.
At baseline, GAS scores are similar for each patient by definition. Therefore, no mean scores and SDs are available per group. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; CFQ=Cognitive Failure Questionnaire; (I-)BRIEF-A = (Informant) Behavior Rating Inventory of Executive Function – Adult Version; BR=behavioral regulation; MC=metacognition; GAS=Goal Attainment Scaling.
Note. Scores per group per time-point of the patients included in the intention-to-treat analyses.
Significant difference between CRT and ETAU at baseline (p=.042). No other baseline values differed between groups (p>.05).
a One patient of the ETAU group did not have a post-treatment measurement.
b Mean (SD).
c Median (IQR).
d At baseline, GAS scores are similar for each patient by definition. Therefore, no mean scores and SDs are available per group. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; CFQ=Cognitive Failure Questionnaire; (I-)BRIEF-A = (Informant) Behavior Rating Inventory of Executive Function – Adult Version; BR=behavioral regulation; MC=metacognition; GAS=Goal Attainment Scaling.
The means and 95%-CIs are presented at baseline, post-treatment and 6-month follow-up per treatment group. *significant effect compared to ETAU. (a) Change of the primary outcome measure CFQ, (b) Change of the BRIEF-A behavioral regulation index, (c) Change of the BRIEF-A metacognition index, (d) Change of the GAS, (e) Change of processing speed. Abbreviations: CFQ=Cognitive Failure Questionnaire; BRIEF-A=Behavior Rating Inventory of Executive Function – Adult Version; BR=behavioral regulation; MC=metacognition; GAS=Goal Attainment Scaling.
CRT had a positive overall effect on the primary outcome CFQ compared to ETAU (β=−4.0, p=.041, Cohen's d=−0.28, Table 3). At post-treatment, CRT had a positive effect on the CFQ (β=−6.2, p=.006, Cohen's d=−0.42) and MBCT on the BRIEF-A behavioral regulation index (β=−3.6, p=.032, Cohen's d=−0.34) compared to ETAU. Also, CRT (β=−5.2, p=.008, Cohen's d=−0.36) and MBCT (β=−5.7, p=.020, Cohen's d=−0.37) had a positive effect on the BRIEF-A metacognition index at post-treatment. No effects were found at 6-month follow-up (p>.05). Neither treatments had an effect on cognitive complaints reported by informants (p>.05). Per-protocol analyses showed that besides CRT (p=.037), MBCT also had a positive effect on the CFQ at post-treatment compared to ETAU (p=.048; Supplementary Table).
Table 3Intention-to-treat intervention effects.
CRT vs. ETAU
MBCT vs. ETAU
β (95%CI)
p
Cohen's d
β (95%CI)
p
Cohen's d
Cognitive complaints
CFQ
Overall
−4.0 (−7.9, −0.2)
.041
−0.28
−3.4 (−7.7, 1.0)
.135
−0.22
Post-treatment
−6.2 (−10.6, −1.8)
.006
−0.42
−4.8 (−9.8, 0.2)
.058
−0.32
6-month follow-up
−2.0 (−6.4, 2.4)
.379
−0.13
−2.0 (−7.0, 2.9)
.427
−0.13
BRIEF-A behavioral regulation
Overall
−0.3 (−3.0, 2.4)
.811
−0.03
−2.4 (−5.2, 0.4)
.091
−0.23
Post-treatment
−1.0 (−4.2, 2.2)
.549
−0.09
−3.6 (−6.9, −0.3)
.032
−0.34
6-month follow-up
0.3 (−2.9, 3.5)
.857
0.03
−1.2 (−4.5, 2.1)
.465
−0.12
BRIEF-A metacognition
Overall
−3.1 (−6.5, 0.3)
.074
−0.22
−3.6 (−8.0, 0.7)
.100
−0.24
Post-treatment
−5.2 (−9.0, −1.3)
.008
−0.36
−5.7 (−10.4, −0.9)
.020
−0.37
6-month follow-up
−1.1 (−5.0, 2.7)
.564
−0.08
−1.7 (−6.4, 3.1)
.489
−0.11
I-BRIEF-A behavioral regulation
Overall
−0.3 (−3.5, 3.0)
.876
−0.02
−2.0 (−5.2, 1.2)
.225
−0.18
Post-treatment
0.7 (−2.8, 4.2)
.699
0.06
−3.0 (−6.5, 0.5)
.098
−0.27
6-month follow-up
−1.3 (−4.7, 2.2)
.481
−0.12
−1.0 (−4.5, 2.6)
.595
−0.08
I-BRIEF-A metacognition
Overall
2.2 (−1.2, 5.6)
.209
0.16
−1.4 (−4.8, 2.0)
.406
−0.10
Post-treatment
2.7 (−1.4, 6.7)
.200
0.19
−3.3 (−7.5, 0.9)
.124
−0.22
6-month follow-up
1.6 (−2.3, 5.6)
.412
0.12
0.4 (−3.7, 4.5)
.862
0.02
Personalized goals
GAS
Overall
4.1 (0.8, 7.4)
.015
0.43
2.4 (−1.4, 6.2)
.210
0.25
Post-treatment
3.4 (−0.9, 7.8)
.119
0.36
2.6 (−1.9, 7.0)
.259
0.27
6-month follow-up
4.8 (0.5, 9.1)
.028
0.50
2.3 (−2.1, 6.7)
.311
0.24
Cognitive function
Domains (z-scores)
Processing speed
Overall
0.1 (−0.002, 0.3)
.054
0.16
0.2 (0.02, 0.4)
.026
0.20
Post-treatment
0.1 (−0.01, 0.3)
.071
0.16
0.2 (−0.004, 0.4)
.054
0.19
6-month follow-up
0.1 (−0.02, 0.3)
.085
0.16
0.2 (0.03, 0.4)
.027
0.22
Memory (immediate)
Overall
0.1 (−0.1, 0.2)
.377
0.08
0.01 (−0.2, 0.2)
.927
0.01
Post-treatment
0.1 (−0.1, 0.3)
.421
0.09
0.04 (−0.2, 0.3)
.765
0.04
6-month follow-up
0.1 (−0.1, 0.3)
.523
0.07
−0.02 (−0.3, 0.2)
.875
−0.02
Visuospatial processing
Overall
0.04 (−0.2, 0.3)
.769
0.04
−0.1 (−0.4, 0.1)
.343
−0.12
Post-treatment
−0.1 (−0.4, 0.2)
.433
−0.12
−0.3 (−0.6, 0.03)
.076
−0.27
6-month follow-up
0.2 (−0.1, 0.5)
.195
0.20
0.03 (−0.3, 0.3)
.820
0.04
Executive functioning
Overall
0.1 (−0.1, 0.2)
.268
0.10
−0.03 (−0.2, 0.1)
.733
−0.03
Post-treatment
0.04 (−0.1, 0.2)
.607
0.06
−0.1 (−0.2, 0.1)
.587
−0.06
6-month follow-up
0.1 (−0.1, 0.3)
.189
0.14
−0.004 (−0.2, 0.2)
.965
−0.01
Skewed memory scores (raw)
Verbal delayed recall
Overall
0.4 (−0.6, 1.4)
.475
n/a
0.6 (−0.5, 1.8)
.298
n/a
Post-treatment
0.5 (−0.6, 1.7)
.387
n/a
0.8 (−0.6, 2.1)
.266
n/a
6-month follow-up
0.2 (−0.9, 1.4)
.715
n/a
0.5 (−0.9, 1.9)
.507
n/a
Verbal delayed recognition
Overall
−0.1 (−1.3, 1.0)
.814
n/a
0.3 (−0.8, 1.3)
.621
n/a
Post-treatment
−0.2 (−1.5, 1.2)
.788
n/a
0.1 (−1.1, 1.4)
.818
n/a
6-month follow-up
−0.1 (−1.5, 1.3)
.892
n/a
0.4 (−0.9, 1.8)
.509
n/a
Visual delayed recall
Overall
−0.3 (−1.1, 0.6)
.522
n/a
0.04 (−0.9, 0.9)
.929
n/a
Post-treatment
−0.3 (−1.4, 0.7)
.552
n/a
0.1 (−0.9, 1.2)
.802
n/a
6-month follow-up
−0.2 (−1.3, 0.8)
.653
n/a
−0.04 (−1.1, 1.0)
.942
n/a
Visual delayed recognition
Overall
−0.3 (−1.3, 0.7)
.522
n/a
−0.3 (−1.3, 0.8)
.615
n/a
Post-treatment
−0.9 (−2.1, 0.2)
.117
n/a
−0.7 (−1.9, 0.6)
.306
n/a
6-month follow-up
0.5 (−0.7, 1.8)
.390
n/a
0.2 (−1.1, 1.5)
.764
n/a
Note. Bold=significant intervention effect. Cohen's d is not available (n/a) for skewed variables (raw memory scores) analyzed with Tobit mixed-model analyses. Abbreviations: CRT=cognitive rehabilitation therapy; MBCT=mindfulness-based cognitive therapy; ETAU=enhanced treatment as usual; CFQ=Cognitive Failure Questionnaire; (I-)BRIEF-A=(Informant) Behavior Rating Inventory of Executive Function – Adult Version; GAS=Goal Attainment Scaling.
The effect of MBCT on the BRIEF-A indexes was similar to the intention-to-treat analysis (p<.05), whereas the effect of CRT on the BRIEF-A metacognition index at post-treatment was no longer significant (p=.074). Similar to the intention-to-treat analyses, no effects were found at 6-month follow-up nor on cognitive complaints reported by informants (p>.05).
3.2.2 Personalized cognitive goals
CRT had a positive overall effect on GAS (β=4.1, p=.015, Cohen's d = 0.43) and at 6-month follow-up (β=4.8, p=.028, Cohen's d = 0.50; Table 3) compared to ETAU. Per-protocol analyses only showed an overall effect of CRT (p=.038), not at 6-month follow-up (p>.05; Supplementary Table). MBCT had no effect on GAS (p>.05).
3.2.3 Objective cognitive function
CRT had no effect on cognitive performance (p>.05; Table 3). MBCT had a positive overall effect on processing speed (β=0.2, p=.026, Cohen's d = 0.20) and at 6-month follow-up (β=0.2, p=.027, Cohen's d = 0.22; Table 3) compared to ETAU. Per-protocol analyses showed similar results (Supplementary Table).
3.2.4 Treatment response at post-treatment
Regarding CRT, cognitive complaints at baseline measured with the CFQ (β (95%CI)=0.5 (0.1, 0.8), p=.012) and BRIEF-A metacognition index (β (95%CI)=0.4 (0.02, 0.7), p=.040) moderated treatment response: patients with less cognitive complaints at baseline benefited more from CRT on the CFQ at post-treatment. For MBCT, processing speed at baseline (β (95%CI)=−5.7 (−10.4, −1.1), p=.016) moderated treatment response: patients with better processing speed at baseline benefited more from MBCT on the CFQ at post-treatment. Demographic and disease-related variables were no significant moderators (p>.05).
Based on RCI analyses, 5 (16%) patients who received CRT reliably improved and 9 (28%) who received MBCT. These percentages did not differ from ETAU (p=.469 and p=.058 respectively), where 3 (9%) patients reliably improved.
4. Discussion
This study investigated the effectiveness of CRT and MBCT on patient-reported cognitive complaints, personalized goals and objective cognitive function in MS patients with cognitive complaints. Our findings indicate a positive effect of both interventions on patient-reported cognitive complaints immediately after treatment completion compared to the control group, but not 6 months later. In addition, 6 months after treatment completion, patients in the CRT group better achieved their personalized cognitive goals and MBCT had a positive effect on processing speed.
Our findings confirm previous studies on compensatory CRT, where a reduction in patient-reported cognitive complaints in MS was also reported (
). With regard to MBCT, our study is the first to show that patients with MS-related cognitive complaints benefit from mindfulness. Interestingly, both treatments were more effective among patients with relatively mild cognitive problems at baseline: CRT was more effective in patients with fewer cognitive complaints, whereas MBCT was more effective in patients with better processing speed at baseline. A potential explanation may be that both treatments utilize patients’ preserved abilities to learn and apply new information and skills, and relatively better cognitive function may thereby be advantageous (
). In contrast to these group-level effects, reliable improvements on an individual level were not found after treatment completion (i.e. measured with the reliable change index). Also, the post-treatment beneficial effects on cognitive complaints were not found 6 months after treatment completion. This might be explained by a reduction in cognitive complaints observed in the control group over this period, whereas both treatment groups remained stable during this time. Possibly, a longer intervention period or booster sessions might have led to a further reduction in cognitive complaints in both treatment groups.
Notably, we found long-lasting effects of CRT on personalized cognitive goals. This positive effect was specifically found 6 months after treatment completion, suggesting that it takes time for cognitive strategies to be implemented in daily life to such an extent that everyday goals can be achieved. This finding shows that treatment effects can transfer to everyday life cognitive problems, emphasizing the treatment's clinical relevance. We did not find an effect of MBCT on these personalized goals, which may be due to the nature of the intervention: MBCT is a generic treatment, aimed at acceptance and relating to cognitive symptoms in a different way. CRT has a more tailored approach, where patients are encouraged to incorporate the learnt strategies purposefully in their everyday lives.
With regard to neuropsychological test performance, only MBCT had a positive effect on objective cognitive performance 6 months after treatment completion. This effect was specific to processing speed, which is one of the most frequently affected cognitive domains in MS (
), and our study extends those findings, by showing that MBCT has a long-lasting effect on processing speed in MS. No effects were found on memory, visuospatial function and executive function. The specific effect on processing speed may be explained by increased awareness and reduction in mind-wandering trained during the MBCT sessions (
). In contrast to MBCT, CRT was not superior to the control group regarding objective cognitive performance. This could be due to the compensatory (rather than restorative) nature of the therapy (
). Other compensatory CRT studies that did report beneficial effects on cognitive function in MS seem to use strategies that are more applicable during neuropsychological assessments (
There are some limitations that need to be taken into account. Due to the nature of the interventions, the study was single-blind, and effects found on subjective measures could therefore be biased. Also, CRT and MBCT were group-based treatments and ETAU entailed an individual appointment, which could suggest that the findings were affected by group dynamics. Furthermore, due to the COVID-19 pandemic lockdown, a few treatment sessions were given through video calls and several neuropsychological assessments (n = 25) were postponed for a maximum of nine weeks, which may have influenced intervention effects. Additionally, although both treatments show promising results, multiple cognitive outcomes were not improved by the treatments. These results, in combination with the costs of the intervention, should be taken into consideration when offering these treatments in clinical care. Future studies should analyze the cost-effectiveness of the treatments to further investigate their clinical potential. Lastly, it would be relevant to investigate whether changes in mood and fatigue could have mediated intervention effects found in this study. Despite these limitations, this study is, to our knowledge, the first to simultaneously compare CRT and MBCT with a control group as potential cognitive treatments in MS.
5. Conclusions
To conclude, both CRT and MBCT positively affected cognitive problems experienced by MS patients in their daily lives, as both treatments alleviated patient-reported cognitive complaints and CRT promoted personalized goal achievement. Whereas the effect on personalized cognitive goals was specifically found 6 months after treatment completion, the benefits on patient-reported cognitive complaints did not persist 6 months after treatment completion in current set-up. An effect on objective cognitive function was only found for MBCT: long-term benefits on processing speed were found. These findings provide insight in specific contributions of available cognitive treatments for MS patients, which contribute to customized healthcare decisions to treat cognitive problems in MS.
Ilse M. Nauta was supported by the Dutch MS Research Foundation (project number 15–911) and National MS Foundation. Dirk Bertens was partially supported by a grant from the Netherlands Brain Foundation (Hersenstichting, grant number DR.−2019–00,315). Dirk Bertens, Luciano Fasotti and Roy P.C. Kessels were partially supported by a grant from the European Regional Development Fund (ERDF/EFRO, grant number PROJ-00,928). Jay Fieldhouse was supported by Stichting Dioraphte. Bernard M.J. Uitdehaag reported research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Immunic Therapeutics. Roy P.C. Kessels is associate editor for Neuropsychology Review, member of the editorial board of the Journal of the International Neuropsychological Society, member of the scientific advisor board of Alzheimer Nederland, and chair of the scientific advisory board of the Korsakoff Knowledge Center Netherlands (Korsakov Kenniscentrum). Anne E.M. Speckens reported no disclosures. Brigit A. de Jong reported receiving grants from Dutch MS Research Foundation (project number 15–911) and National MS Foundation. B.A. de Jong is member of the medical advisory board of the Dutch MS Society, chair of the committee for the revision of the guideline on disease modifying therapy and MS for the Netherlands Society of Neurology, and chair of the committee of the Dutch National MS registration of the Netherlands Society of Neurology.
Acknowledgements
The authors would like to thank the therapists for providing the treatment sessions. We thank the research assistants, researchers and neuropsychologists-in-training of the Amsterdam UMC, Department of Neurology, MS Center Amsterdam for their help with the data acquisition. We thank M. van Dam for her help with the normative scores of healthy controls. We also thank all patients for their participation.
Funding
This investigator-initiated trial was funded by the Dutch MS Research Foundation (project number 15–911). The funder had no influence in the study design, data collection, analysis and interpretation of data, writing of the report and in the decision to submit the article for publication.
Data sharing statement
Anonymized data, not published in the article, will be shared upon reasonable request from a qualified investigator.
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Significant difference between CRT and ETAU at baseline (p=.042). No other baseline values differed between groups (p>.05).
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