Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial

Participants are recruited through the participating centres (VU University Medical Center and Klimmendaal Rehabilitation Center), the ‘VUmc MS Center Amsterdam’ website and MS patient associations. All potentially eligible participants who express interest in the study are provided with written trial information, which contains information about the rationale, purpose and personal implications of the study. The information sheet also includes contact details of the trial coordinator and of an independent medical doctor who is not part of the research team, who can both be contacted for additional information. After sufficient time for consideration, potential participants who are still interested to participate are invited by the trial coordinator to sign the informed consent form. After signing the informed consent form, it will be checked whether the participants are fully eligible.

On the informed consent form, participants have the option to give permission for an informant to be contacted. If permission is given, an informant of the participants will also receive written information and an informed consent form, as informants will be asked to complete one questionnaire at three time-points (see outcome measures). On the informed consent form, participants and their informants also have the option to give permission for using their data for other research, for sharing their data with researchers outside of the European Union and to be contacted again for follow-up research.

Participants are eligible to participate if they meet the following criteria: (1) between 18 and 65 years of age, (2) confirmed diagnosis of MS according to the McDonald 2010 criteria [21], (3) a minimum score of 23 on the Multiple Sclerosis Neuropsychological Questionnaire – Patient version (MSNQ-P), which measures subjective cognitive complaints [22].

Participants who meet any of the following criteria are excluded from participation: (1) psychosis, (2) suicidal ideation, (3) an inability to speak or read Dutch, (4) previous experience with a similar intervention (e.g. a comparable cognitive rehabilitation training or mindfulness training), (5) physical or cognitive disabilities, comorbidities or treatments that would interfere too much with the interventions to enrol in this study (to be evaluated on an individual level). The reasons for excluding participants who express interest in the study will be accurately documented.

Mixed model analyses will be applied with three measurements comparing two groups (MBCT vs. ETAU, CRT vs. ETAU). There are no previous studies with MS patients that investigated the effect of CRT or MBCT on the primary outcome measure, the Cognitive Failure Questionnaire (CFQ) [23]. Based on a previous RCT using a comparable outcome measure, a medium effect size can be expected [24, 25]. With an alpha of .05, a power of .80, an intra-class correlation of .06, and 33 participants per group, a minimal difference of 0.62 SD can be detected between two groups. Taking into account drop-out and loss to follow-up, we intend to recruit 40 MS patients per group.

The CRT protocol focuses on the following cognitive domains: speed of information processing, memory, executive function and mental fatigue. Cognitive impairments will be treated by a combination of compensatory strategy training and psycho-education. The proposed strategies are based on MS-tailored variants of evidence-based treatments that have been developed in CRT research with brain-injured subjects. Treatment of problems in information processing speed will be based on ‘Time Pressure Management’ [26, 27], memory on ‘Training Memory strategies’ [28], executive function on a ‘Multifaceted Treatment for Executive Dysfunction’ [29, 30] and mental fatigue on ‘Cognitive and Graded Activity Training’ [31, 32]. These four treatments are incorporated in the protocol as described by Geusgens, Baars-Elsinga, Visser-Meily and van Heugten [33]. In addition to cognitive strategy training, CRT focuses on emotional and behavioural changes, and grief resolution. Grief resolution will be included by explaining the stages of bereavement and by discussing the loss of physical independence, mobility, cognitive ability and emotional control on self-esteem and future perspective. The participants will receive homework assignments aimed at identifying their own cognitive problems and at applying the learned strategies in daily life situation. These homework assignments will take 30 to 45 min a day, 6 days per week.

The MBCT protocol is primarily based on the MBCT program by Segal, Williams and Teasdale [34]. MBCT is an intervention in which aspects of mindfulness meditation are combined with aspects of cognitive behavioural therapy. MBCT focuses on increasing awareness of the present moment. To achieve this, participants will be trained in both self-regulation of attention and non-judgmental awareness of moment-to-moment experience. Patients will become more aware of their emotions, thoughts and behaviours and will learn to use more adaptive behaviour to respond to their symptoms. The program will be adapted to the MS patients in terms of tailoring psycho-educative elements to themes relevant to the MS patient (e.g. cognitive problems) and modified movement exercises (for patients suffering from physical impairments). Participants will receive guided mindfulness meditation exercises of 30 to 45 min, 6 days per week, for home practice and a reader with home practice instructions and background information. All therapists will fulfil the advanced criteria of the Association of Mindfulness Based Teachers in the Netherlands and Flanders, which are in concordance with those of the UK Mindfulness-Based Teacher Trainer Network [35].

Enhanced treatment as usual (ETAU) entails an appointment with an MS specialist nurse in addition to usual care. The appointment will focus on psycho-education. More specifically, the MS specialist nurse will provide the participants with information on the frequently affected cognitive domains in MS and their relation to brain pathology. This will occur in a standardised manner.

CRT and MBCT sessions will be recorded on video to evaluate teacher competence and protocol adherence. These video recordings will solely be used for the purpose of trainer evaluation, and the camera will be directed at the trainer. For the CRT sessions, adherence to the protocol will be checked using a checklist. For the MBCT sessions, the Mindfulness-Based Interventions - Teachers Assessment Criteria [36] will be used.

For all groups, attendance to the sessions will be documented. For the CRT group, adherence to homework assignments will be checked and evaluated during each visit of the treatment period. For the MBCT group, adherence will be assessed during the entire treatment period with a calendar on which participants fill out whether they adhere to both formal (e.g. the sitting meditation) and informal (e.g. 3-min breathing space) mindfulness exercises.

Participants can leave the study at any time for any reason without any consequences. Follow-up measurements will still be scheduled if the participant is willing and able to participate in follow-up measurements. There will be no replacement of individual participants after withdrawal. If a high rate of participants drops out during the study, more participants will be included in the study. These participants will be randomly allocated to one of three parallel groups using the randomisation and minimisation procedure as described under ‘randomisation and blinding’.

During the intervention period and the 6-months follow-up period, patients are asked not to follow an intervention outside this study that focuses on mindfulness or cognition, and to keep their level of care constant during this period when possible. Naturally, usual care should continue, as do new treatment options when the health situation of the patient changes.

The primary outcome measure is the level of subjective cognitive complaints and is measured with the CFQ [23]. Subjective cognitive complaints in terms of executive function will be measured with the Behaviour Rating Inventory of Executive Function – Adult Version (BRIEF-A) [40]. The BRIEF-A consists of a self- and an informant report version.

Data on demographic and clinical characteristics will be summarised in a table. For adherence and other feasibility indicators, frequencies and percentages will be calculated. Satisfaction with the program will be summarised in qualitative descriptions. Differences between groups (CRT vs. ETAU, MBCT vs. ETAU, CRT vs. MBCT, drop-outs vs. treatment completers) in demographic and clinical characteristics and outcome measurements at baseline are analysed using independent samples t-tests (normally distributed continuous outcome variables), Mann-Whitney U tests (skewed continuous outcome variables) and Pearson’s chi-square tests (categorical outcome variables).

To evaluate the effectiveness of the interventions, mixed-model analyses will be performed for the primary and secondary outcome measurements with time (baseline, post-intervention, follow-up) as a within subjects factor and condition (CRT vs. ETAU, MBCT vs. ETAU, and exploratory: CRT vs. MBCT) as a between-subjects factor. These analyses will be performed using an intention-to-treat approach, including all randomised participants regardless of adherence and measurement completion. Secondarily, per-protocol analyses will be performed for further exploration of the intervention effects.

To evaluate the secondary study aims, mediation and moderation analyses [61] will be performed to evaluate whether alterations in functional brain networks play a role in the effect of the interventions. In addition, cross-sectional associations between functional brain networks and cognitive function (subjective and objective) will be analysed using Pearson’s correlation and linear regression analyses. To evaluate whether alterations in secondary study parameters are mediating factors that determine subjective cognitive function, mediation analyses [61] and linear regression analyses will be performed. Finally, logistic and linear regression models will be performed to evaluate which factors determine whether a patient is likely to benefit from one of the therapies.

For all analyses, confounding variables will be inserted, such as age and education. Bonferroni corrections will be applied to correct for multiple comparisons within each objective.