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Cognitive rehabilitation and mindfulness reduce cognitive complaints in multiple sclerosis (REMIND-MS): A randomized controlled trial

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.msard.2023.104529

      Highlights

      • 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.
      • Cognitive rehabilitation showed long-term benefits on personalized goals.
      • 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.

      Keywords

      Abbreviations:

      MS (multiple sclerosis), CRT (cognitive rehabilitation therapy), MBCT (mindfulness-based cognitive therapy), ETAU (enhanced treatment as usual), RCT (randomized-controlled trial), MSNQ-P (Multiple Sclerosis Neuropsychological Questionnaire – Patient version), CFQ (Cognitive Failures Questionnaire), (I-)BRIEF-A ((Informant) Behavior Rating Inventory of Executive Function – Adult Version), GAS (Goal Attainment Scaling), MACFIMS (Minimal Assessment of Cognitive Function in MS), SDMT (Symbol Digit Modalities Test), CVLT (California Verbal learning Test), BVMT-r (Brief Visuospatial Memory Test-Revised), JLO (Benton Judgment of Line Orientation Test), COWAT (Controlled Oral Word Association Test), D-KEFS (Delis-Kaplan Executive Function System sorting test), RCI (reliable change index), BR (behavioral regulation), MC (metacognition)

      1. Introduction

      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 (
      • Sumowski J.F.
      • Benedict R.
      • Enzinger C.
      • et al.
      Cognition in multiple sclerosis: state of the field and priorities for the future.
      ). Effective cognitive treatments are therefore important, and behavioral treatments seem most promising, particularly cognitive rehabilitation therapy (CRT) (
      • Chen M.H.
      • Chiaravalloti N.D.
      • DeLuca J.
      Neurological update: cognitive rehabilitation in multiple sclerosis.
      ;
      • DeLuca J.
      • Chiaravalloti N.D.
      • Sandroff B.M.
      Treatment and management of cognitive dysfunction in patients with multiple sclerosis.
      ). However, cognitive intervention studies mainly focus on improving objective cognitive impairments measured with neuropsychological tests (
      • DeLuca J.
      • Chiaravalloti N.D.
      • Sandroff B.M.
      Treatment and management of cognitive dysfunction in patients with multiple sclerosis.
      ;
      • Goverover Y.
      • Chiaravalloti N.D.
      • O'Brien A.R.
      • et al.
      Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016.
      ), which only weakly relate with patient-reported cognitive complaints (
      • Nauta I.M.
      • Balk L.J.
      • Sonder J.M.
      • et al.
      The clinical value of the patient-reported multiple sclerosis neuropsychological screening questionnaire.
      ) and may not capture real-world cognitive problems (
      • Sumowski J.F.
      • Benedict R.
      • Enzinger C.
      • et al.
      Cognition in multiple sclerosis: state of the field and priorities for the future.
      ). Intervention studies that focus on cognitive problems that patients experience in their daily lives are thereby limited (
      • DeLuca J.
      • Chiaravalloti N.D.
      • Sandroff B.M.
      Treatment and management of cognitive dysfunction in patients with multiple sclerosis.
      ;
      • Goverover Y.
      • Chiaravalloti N.D.
      • O'Brien A.R.
      • et al.
      Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016.
      ).
      There are indications that CRT also has favorable effects on patient-reported cognitive complaints (
      • Hanssen K.T.
      • Beiske A.G.
      • Landro N.I.
      • et al.
      Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.
      ;
      • Chiaravalloti N.D.
      • Moore N.B.
      • Nikelshpur O.M.
      • et al.
      An RCT to treat learning impairment in multiple sclerosis The MEMREHAB trial.
      ;
      • Mantynen A.
      • Rosti-Otajarvi E.
      • Koivisto K.
      • et al.
      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 (
      • Hanssen K.T.
      • Beiske A.G.
      • Landro N.I.
      • et al.
      Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.
      ;
      • Mantynen A.
      • Rosti-Otajarvi E.
      • Koivisto K.
      • et al.
      Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial.
      ). More CRT studies that focus on these everyday life cognitive problems are needed (
      • DeLuca J.
      • Chiaravalloti N.D.
      • Sandroff B.M.
      Treatment and management of cognitive dysfunction in patients with multiple sclerosis.
      ;
      • Goverover Y.
      • Chiaravalloti N.D.
      • O'Brien A.R.
      • et al.
      Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016.
      ).
      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 (
      • Segal Z.V.
      • Williams J.M.G.
      • Teasdale J.D
      Mindfulness-Based Cognitive Therapy For Depression.
      ). 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 (
      • Hoogerwerf A.E.W.
      • Bol Y.
      • Lobbestael J.
      • et al.
      Mindfulness-based cognitive therapy for severely fatigued multiple sclerosis patients: a waiting list controlled study.
      ), as well as improved objective cognitive function (i.e. processing speed (
      • Manglani H.R.
      • Samimy S.
      • Schirda B.
      • et al.
      Effects of 4-week mindfulness training versus adaptive cognitive training on processing speed and working memory in multiple sclerosis.
      ) and visuospatial processing (
      • Blankespoor R.J.
      • Schellekens M.P.J.
      • Vos S.H.
      • et al.
      The effectiveness of mindfulness-based stress reduction on psychological distress and cognitive functioning in patients with multiple sclerosis: a pilot study.
      )) in a general MS sample. Additionally, beneficial effects on depression and fatigue have been found in MS (
      • Grossman P.
      • Kappos L.
      • Gensicke H.
      • et al.
      MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial.
      ;
      • Simpson R.
      • Simpson S.
      • Ramparsad N.
      • et al.
      Mindfulness-based interventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials.
      ), and given their relation with patient-reported cognitive complaints (
      • Nauta I.M.
      • Balk L.J.
      • Sonder J.M.
      • et al.
      Interpretability of the patient-reported multiple sclerosis neuropsychological screening questionnaire: a cognitive screening tool?.
      ), 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) (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ). 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 (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ). 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).
      Fig 1
      Fig. 1Flow-chart REMIND-MS study.
      *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) (
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
      ), (2) 18–65 years of age, (3) cognitive complaints (scoring ≥23 on the Multiple Sclerosis Neuropsychological Questionnaire – Patient version (MSNQ-P) (
      • Benedict R.H.
      • Cox D.
      • Thompson L.L.
      • et al.
      Reliable screening for neuropsychological impairment in multiple sclerosis.
      )), (4) no previous experience with the interventions. Full eligibility criteria have been published elsewhere (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ) 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 (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ). In short, CRT focused on compensatory strategies for processing speed (
      • Winkens I.
      • Van Heugten C.M.
      • Wade D.T.
      • et al.
      Training patients in time pressure management, a cognitive strategy for mental slowness.
      ), memory (
      • van Kessel M.
      • Fasotti L.
      • Berg I.
      • et al.
      Training Geheugenstrategieën.
      ), executive function (
      • Spikman J.M.
      • Boelen D.H.
      • Lamberts K.F.
      • et al.
      Effects of a multifaceted treatment program for executive dysfunction after acquired brain injury on indications of executive functioning in daily life.
      ), mental fatigue (
      • Zedlitz A.M.
      • Rietveld T.C.
      • Geurts A.C.
      • et al.
      Cognitive and graded activity training can alleviate persistent fatigue after stroke: a randomized, controlled trial.
      ), emotional and behavioral changes, and grief resolution. MBCT combined mindfulness-based stress reduction with elements of cognitive behavioral therapy (
      • Segal Z.V.
      • Williams J.M.G.
      • Teasdale J.D
      Mindfulness-Based Cognitive Therapy For Depression.
      ), and patients were trained in self-regulation of attention and non-judgmental awareness of moment-to-moment experiences (e.g. emotions, thoughts and behaviors) (
      • Segal Z.V.
      • Williams J.M.G.
      • Teasdale J.D
      Mindfulness-Based Cognitive Therapy For Depression.
      ). 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 (
      • Crane R.S.
      • Kuyken W.
      • Williams J.M.
      • et al.
      Competence in teaching mindfulness-based courses: concepts, development and assessment.
      ). 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) (
      • Merckelbach H.
      • Muris P.
      • Nijman H.
      • et al.
      Self-reported cognitive failures and neurotic symptomatology.
      ). 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 (
      • Ponds R.W.H.M.
      • Van Boxtel M.
      • Jolles J.
      De cognitive failure questionnaire als maat voor subjectief cognitief functioneren.
      ) and a previous study reports a high internal consistency in a Dutch MS population (
      • Bol Y.
      • Duits A.A.
      • Hupperts R.M.
      • et al.
      The impact of fatigue on cognitive functioning in patients with multiple sclerosis.
      ). 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) (
      • Roth R.M.
      • Isquith P.K.
      • Gioia G.A.
      • et al.
      Development of the behavior rating inventory of executive function-adult version.
      ). 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 (
      • Kim S.
      • Zemon V.
      • Foley F.W.
      • et al.
      Poster 8 construct validation of the behavior rating inventory of executive function-adult version in multiple sclerosis.
      )

      2.4.2 Personalized cognitive goals

      Goal Attainment Scaling (GAS) was applied to determine two cognitive goals with each patient at baseline (
      • Kiresuk T.J.
      • Sherman R.E.
      Goal attainment scaling - general method for evaluating comprehensive community mental health programs.
      ). 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 (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ) of the Minimal Assessment of Cognitive Function in MS (MACFIMS) (
      • Benedict R.H.
      • Cookfair D.
      • Gavett R.
      • et al.
      Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS).
      ), 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 (
      • Smith A.
      Symbol Digit Modality Test (SDMT): Manual (revised).
      ), and the Stroop Color-Word Test with the time to complete cards I and II (
      • Hammes J.G.W.
      The STROOP Color-Word test: Manual.
      ). 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 (
      • Mulder J.L.
      • Dekker R.
      • Dekker D.H.
      Verbale Leer- & Geheugen test: Handleiding [Verbal Learning & Memory Test: Manual].
      ), and the Brief Visuospatial Memory Test-Revised (BVMT-R), using the immediate recall, long-term recall and long-term recognition scores (
      • Benedict R.H.B.
      • Schretlen D.
      • Groninger L.
      • et al.
      Revision of the brief visuospatial memory test: studies of normal performance, reliability, and validity.
      ). Visuospatial processing was measured with the Benton Judgment of Line Orientation Test (JLO), using the total number of correct items (
      • Benton A.L.
      • Hamsher K.D.
      • Varney N.R.
      • et al.
      Judgment of Line Orientation.
      ). Executive function was measured with the following three tests: (1) the Controlled Oral Word Association Test (COWAT) with the total score of three letters (
      • Benton L.A.
      • Hamsher K.D.
      • Sivan A.B.
      Controlled oral word association test.
      ), (2) the Stroop Color-Word Test interference score (
      • Hammes J.G.W.
      The STROOP Color-Word test: Manual.
      ), 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 (
      • Delis D.C.
      • Kaplan E.
      • Kramer J.H
      The Delis-Kaplan Executive Function System: Examiner's Manual.
      ). 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 (
      • Nauta I.M.
      • Bertens D.
      • van Dam M.
      • et al.
      Performance validity in outpatients with multiple sclerosis and cognitive complaints.
      ). 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 (
      • Benedict R.H.B.
      Standards for sample composition and impairment classification in neuropsychological studies of multiple sclerosis.
      ). Patients who did not fulfill these criteria were classified as cognitively preserved.

      2.5 Power analysis

      The power calculation is detailed elsewhere (
      • Nauta I.M.
      • Speckens A.E.M.
      • Kessels R.P.C.
      • et al.
      Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.
      ) 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 (
      • Turner-Stokes L.
      • Williams H.
      Goal attainment scaling: a direct comparison of alternative rating methods.
      ). 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) (
      • Twisk J.
      • Rijmen F.
      Longitudinal tobit regression: a new approach to analyze outcome variables with floor or 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 (
      • Jacobson N.S.
      • Truax P.
      Clinical significance: a statistical approach to defining meaningful change in psychotherapy research.
      ). The following equation was used to calculate the RCI scores: (XPTXBL)/SdiffETAU, which represents the difference between the patient scores at post-treatment and baseline (XPTXBL) and the standard error of the difference between both time-points in the ETAU group to correct for measurement errors (SdiffETAU). 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.
      Total sample

      (n = 110)
      CRT

      (n = 37)
      MBCT

      (n = 36)
      ETAU

      (n = 37)
      Demographics
      Age (years), mean (SD)48.7 (9.8)50.2 (8.8)46.2 (10.3)49.5 (10.0)
      Sex (women), n (%)82 (75)29 (78)25 (69)28 (76)
      Education (high),
      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).
      n (%)
      64 (58)21 (57)22 (61)21 (57)
      Work status, n (%)
       Employed (paid)23 (21)9 (24)5 (14)9 (24)
       Employed (unpaid)2 (2)1 (3)1 (3)0 (0)
       Employed with sickness benefits (partly/fully)14 (13)6 (16)6 (17)2 (5)
       Disability pension61 (56)15 (41)21 (58)25 (68)
       Unemployed6 (6)3 (8)2 (6)1 (3)
       Other (student, homemaker, retired)4 (4)3 (8)1 (3)0 (0)
      Disease-related characteristics
      MS type (RRMS/SPMS/PPMS/unclear
      Unclear indicates that the MS type could not be specified by the neurologist.
      ),%
      66/17/12/565/16/14/564/19/11/670/16/11/3
      Disease duration (years),
      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.

      3.1 Adherence

      3.1.1 Patients’ adherence

      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) (
      • Crane R.S.
      • Kuyken W.
      • Williams J.M.
      • et al.
      Competence in teaching mindfulness-based courses: concepts, development and assessment.
      ). 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.
      BaselinePost-treatment6-month follow-up
      CRT

      (n = 32)
      MBCT (n = 32)ETAU (n = 36)CRT

      (n = 32)
      MBCT (n = 32)ETAU (n = 35)
      One patient of the ETAU group did not have a post-treatment measurement.
      CRT

      (n = 32)
      MBCT (n = 32)ETAU (n = 36)
      Cognitive complaints
      Mean (SD).
      CFQ52.6 (11.2)50.2 (15.3)51.3 (14.1)44.3 (15.6)43.2 (14.3)49.7 (13.8)45.1 (15.4)42.6 (17.6)45.9 (13.9)
      BRIEF-A BR53.1 (11.7)51.8 (9.3)54.1 (9.6)51.5 (11.2)47.8 (8.8)53.2 (10.0)51.3 (11.1)49.0 (11.1)52.0 (11.6)
      BRIEF-A MC79.4 (10.9)76.3 (14.4)79.4 (13.4)74.3 (13.0)70.6 (13.4)79.6 (14.5)75.6 (14.0)72.1 (17.6)76.7 (15.0)
      I-BRIEF-A BR50.6 (10.6)49.1 (11.4)50.3 (11.2)51.3 (11.0)47.7 (10.8)50.5 (10.4)50.3 (10.5)49.2 (12.7)49.7 (11.2)
      I-BRIEF-A MC70.2 (13.2)
      Significant difference between CRT and ETAU at baseline (p=.042). No other baseline values differed between groups (p>.05).
      73.3 (14.2)77.4 (12.8)
      Significant difference between CRT and ETAU at baseline (p=.042). No other baseline values differed between groups (p>.05).
      71.7 (13.0)69.1 (15.7)78.1 (11.5)71.1 (15.1)72.4 (17.0)75.4 (14.3)
      Personalized goals
      Mean (SD).
      GASn/a
      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.
      n/a
      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.
      n/a
      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.
      49.3 (8.4)49.4 (9.7)46.3 (7.4)51.8 (10.3)50.3 (9.5)47.5 (11.4)
      Cognitive function
      Domains (z-scores)
      Mean (SD).
      Processing speed0.02 (0.5)0.10 (1.1)−0.12 (1.0)0.07 (0.6)0.19 (0.9)−0.24 (1.1)0.06 (0.6)0.20 (0.9)−0.22 (1.1)
      Memory (immediate)−0.04 (0.8)0.13 (0.8)−0.06 (1.0)−0.03 (0.9)0.07 (0.8)−0.10 (1.0)−0.002 (0.9)0.04 (0.8)−0.07 (0.9)
      Visuospatial processing0.10 (1.0)0.14 (1.1)−0.12 (1.0)0.04 (1.0)−0.05 (0.9)0.01 (1.1)0.18 (1.1)0.05 (1.0)−0.20 (1.0)
      Executive functioning−0.001 (0.5)0.12 (0.6)−0.09 (1.0)0.03 (0.5)0.06 (0.7)−0.08 (0.9)0.06 (0.5)0.07 (0.7)−0.11 (0.9)
      Scores (raw)
      Median (IQR).
      Verbal recall11.0 (6.0)11.0 (6.0)12.0 (6.0)12.0 (5.0)12.0 (5.0)13.0 (8.0)13.0 (4.0)12.0 (7.0)13.0 (5.0)
      Verbal recognition14.5 (2.0)15.0 (2.0)15.0 (2.0)15.0 (2.0)15.0 (2.0)15.0 (2.0)15.0 (2.0)16.0 (1.0)16.0 (1.0)
      Visual recall9.0 (5.0)9.0 (5.0)8.5 (4.0)9.0 (6.0)9.0 (5.0)9.0 (4.0)10.0 (5.0)10.0 (4.0)10.0 (4.0)
      Visual recognition12.0 (1.0)12.0 (1.0)12.0 (0.0)12.0 (1.0)12.0 (1.0)12 (0.0)12.0 (0.0)12.0 (1.0)12 (1.0)
      Note. Scores per group per time-point of the patients included in the intention-to-treat analyses.
      low asterisk 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.
      Fig 2
      Fig. 2Observed intervention effects.
      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.

      3.2.1 Patient-reported cognitive complaints

      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. ETAUMBCT vs. ETAU
      β (95%CI)pCohen's dβ (95%CI)pCohen's d
      Cognitive complaints
      CFQOverall−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 regulationOverall−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-up0.3 (−2.9, 3.5).8570.03−1.2 (−4.5, 2.1).465−0.12
      BRIEF-A metacognitionOverall−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 regulationOverall−0.3 (−3.5, 3.0).876−0.02−2.0 (−5.2, 1.2).225−0.18
      Post-treatment0.7 (−2.8, 4.2).6990.06−3.0 (−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 metacognitionOverall2.2 (−1.2, 5.6).2090.16−1.4 (−4.8, 2.0).406−0.10
      Post-treatment2.7 (−1.4, 6.7).2000.19−3.3 (−7.5, 0.9).124−0.22
      6-month follow-up1.6 (−2.3, 5.6).4120.120.4 (−3.7, 4.5).8620.02
      Personalized goals
      GASOverall4.1 (0.8, 7.4).0150.432.4 (−1.4, 6.2).2100.25
      Post-treatment3.4 (−0.9, 7.8).1190.362.6 (−1.9, 7.0).2590.27
      6-month follow-up4.8 (0.5, 9.1).0280.502.3 (−2.1, 6.7).3110.24
      Cognitive function
      Domains (z-scores)
      Processing speedOverall0.1 (−0.002, 0.3).0540.160.2 (0.02, 0.4).0260.20
      Post-treatment0.1 (−0.01, 0.3).0710.160.2 (−0.004, 0.4).0540.19
      6-month follow-up0.1 (−0.02, 0.3).0850.160.2 (0.03, 0.4).0270.22
      Memory (immediate)Overall0.1 (−0.1, 0.2).3770.080.01 (−0.2, 0.2).9270.01
      Post-treatment0.1 (−0.1, 0.3).4210.090.04 (−0.2, 0.3).7650.04
      6-month follow-up0.1 (−0.1, 0.3).5230.07−0.02 (−0.3, 0.2).875−0.02
      Visuospatial processingOverall0.04 (−0.2, 0.3).7690.04−0.1 (−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-up0.2 (−0.1, 0.5).1950.200.03 (−0.3, 0.3).8200.04
      Executive functioningOverall0.1 (−0.1, 0.2).2680.10−0.03 (−0.2, 0.1).733−0.03
      Post-treatment0.04 (−0.1, 0.2).6070.06−0.1 (−0.2, 0.1).587−0.06
      6-month follow-up0.1 (−0.1, 0.3).1890.14−0.004 (−0.2, 0.2).965−0.01
      Skewed memory scores (raw)
      Verbal delayed recallOverall0.4 (−0.6, 1.4).475n/a0.6 (−0.5, 1.8).298n/a
      Post-treatment0.5 (−0.6, 1.7).387n/a0.8 (−0.6, 2.1).266n/a
      6-month follow-up0.2 (−0.9, 1.4).715n/a0.5 (−0.9, 1.9).507n/a
      Verbal delayed recognitionOverall−0.1 (−1.3, 1.0).814n/a0.3 (−0.8, 1.3).621n/a
      Post-treatment−0.2 (−1.5, 1.2).788n/a0.1 (−1.1, 1.4).818n/a
      6-month follow-up−0.1 (−1.5, 1.3).892n/a0.4 (−0.9, 1.8).509n/a
      Visual delayed recallOverall−0.3 (−1.1, 0.6).522n/a0.04 (−0.9, 0.9).929n/a
      Post-treatment−0.3 (−1.4, 0.7).552n/a0.1 (−0.9, 1.2).802n/a
      6-month follow-up−0.2 (−1.3, 0.8).653n/a−0.04 (−1.1, 1.0).942n/a
      Visual delayed recognitionOverall−0.3 (−1.3, 0.7).522n/a−0.3 (−1.3, 0.8).615n/a
      Post-treatment−0.9 (−2.1, 0.2).117n/a−0.7 (−1.9, 0.6).306n/a
      6-month follow-up0.5 (−0.7, 1.8).390n/a0.2 (−1.1, 1.5).764n/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 (
      • Hanssen K.T.
      • Beiske A.G.
      • Landro N.I.
      • et al.
      Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.
      ;
      • Chiaravalloti N.D.
      • Moore N.B.
      • Nikelshpur O.M.
      • et al.
      An RCT to treat learning impairment in multiple sclerosis The MEMREHAB trial.
      ). 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 (
      • Spikman J.M.
      • Fasotti L.
      Recovery and treatment.
      ). 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 (
      • Sumowski J.F.
      • Benedict R.
      • Enzinger C.
      • et al.
      Cognition in multiple sclerosis: state of the field and priorities for the future.
      ). This finding corresponds to one of the few previous RCTs on MBCT and cognition in MS (
      • Manglani H.R.
      • Samimy S.
      • Schirda B.
      • et al.
      Effects of 4-week mindfulness training versus adaptive cognitive training on processing speed and working memory in multiple sclerosis.
      ), 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 (
      • Segal Z.V.
      • Williams J.M.G.
      • Teasdale J.D
      Mindfulness-Based Cognitive Therapy For Depression.
      ;
      • Manglani H.R.
      • Samimy S.
      • Schirda B.
      • et al.
      Effects of 4-week mindfulness training versus adaptive cognitive training on processing speed and working memory in multiple sclerosis.
      ;
      • Chiesa A.
      • Calati R.
      • Serretti A.
      Does mindfulness training improve cognitive abilities? A systematic review of neuropsychological findings.
      ). 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 (
      • Sumowski J.F.
      • Benedict R.
      • Enzinger C.
      • et al.
      Cognition in multiple sclerosis: state of the field and priorities for the future.
      ;
      • Winkens I.
      • Van Heugten C.M.
      • Wade D.T.
      • et al.
      Training patients in time pressure management, a cognitive strategy for mental slowness.
      ;
      • Chiaravalloti N.D.
      • Moore N.B.
      • Weber E.
      • et al.
      The application of strategy-based training to enhance memory (STEM) in multiple sclerosis: a pilot RCT.
      ). 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 (
      • Hanssen K.T.
      • Beiske A.G.
      • Landro N.I.
      • et al.
      Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.
      ;
      • Chiaravalloti N.D.
      • Moore N.B.
      • Nikelshpur O.M.
      • et al.
      An RCT to treat learning impairment in multiple sclerosis The MEMREHAB trial.
      ), such as the modified Story Memory Technique (i.e. imagery and context based memory retraining program) (
      • Chiaravalloti N.D.
      • Moore N.B.
      • Nikelshpur O.M.
      • et al.
      An RCT to treat learning impairment in multiple sclerosis The MEMREHAB trial.
      ).
      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.

      CRediT authorship contribution statement

      Ilse M. Nauta: Methodology, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Project administration. Dirk Bertens: Methodology, Investigation, Resources, Writing – review & editing, Supervision. Luciano Fasotti: Conceptualization, Methodology, Writing – review & editing, Supervision. Jay Fieldhouse: Investigation, Writing – review & editing. Bernard M.J. Uitdehaag: Conceptualization, Writing – review & editing. Roy P.C. Kessels: Conceptualization, Methodology, Writing – review & editing, Supervision. Anne E.M. Speckens: Conceptualization, Methodology, Writing – review & editing, Supervision. Brigit A. de Jong: Conceptualization, Methodology, Writing – review & editing, Supervision, Project administration, Funding acquisition.

      Declaration of Competing Interest

      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.

      Appendix. Supplementary materials

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