People with Multiple Sclerosis (MS) often experience cognitive difficulties such as memory problems, concentration issues, and reduced processing speed. These symptoms can have a negative impact on daily functioning and overall quality of life. Previous research on cognitive rehabilitation has shown that regular training focused on memory and concentration can have positive effects on cognitive functioning, including processing speed, memory, and executive functions that support daily activities. Moreover, fMRI studies (brain scans that measure brain activity) have revealed changes in brain activation following cognitive rehabilitation.

Recently, the idea has emerged that a more personalized approach could improve treatment outcomes. Specifically, researchers have identified a link between personality traits and cognitive functioning. Since every individual is different, current cognitive rehabilitation programs often fail to take these personal differences into account.

In this project, the investigators aim to enhance the effectiveness of cognitive rehabilitation by focusing more closely on individual characteristics through an app-based training program. Participants will complete a 12-week app training prior to a 6-week cognitive rehabilitation program. The first app focuses on mindset training, supported by a coach. Afterwards, all participants will use a second app designed to train processing speed and memory. In addition to cognitive functioning, the investigators will also examine psychological, (neuro)biological, and social changes using questionnaires and fMRI. This research may provide valuable insights into how cognitive functioning and quality of life in people with MS can be improved.

This study is funded by the National MS Fund and is a collaboration between several institutions: the Department of Health, Medical and Neuropsychology at Leiden University (The Netherlands), the University at Buffalo (USA), and Reha Rheinfelden (Switzerland).

Rationale: Cognitive impairment displays a common and impacting symptom in people with multiple sclerosis (PwMS). It has been shown that PwMS benefit from cognitive rehabilitation (CR), but group-effects are mild-to-moderate and effect sizes vary between patients, highlighting the need for including individual factors in investigating CR. It has been shown that PwMS with high conscientiousness, a personality trait that is associated with being well-organised, schema driven, achievement-striving and goal-directed show higher improvement on cognitive functions. Very recent data shows that it is possible to enhance conscientiousness in PwMS and that this increase led to more goal-directed behaviour, decreased depressive symptoms and improvements in QoL.

Objective: To investigate if conscientiousness coaching (C-Coach) before CR will enhance the treatment effects of CR, in which treatment effect is operationalised as improvement from a full comprehensive perspective of well-being of PwMS Study design: This experimental multicentre study in the Netherlands, United States and Switzerland follows a longitudinal, parallel group, controlled design with three assessment sessions including behavioural testing for both study groups and brain imaging in a subsample. Additionally, both groups will undergo either 12-weeks of C-Coach or sham training before six weeks of CR.

Study population: The study population consists of 126 PwMS aged between 18 and 65 years, of which group 1 (N= 63) will undergo C-Coach before CR and group 2 (N= 63) will undergo a sham intervention before CR.

Intervention: All interventions will be performed on mobile devices and can thus be done at home. Group 1 will undergo 12 weeks of C-Coach, which consists of a pre-session and two booster sessions with a coach to explain goals, values and the training application as well as the self-use of the smartphone application C-Coach between sessions to track goals and values. Group 2 will undergo 12 weeks of sham intervention, consisting of a pre-session and two booster sessions with a coach to discuss early life memories and the self-use of the smartphone application Daily Notes to journal about early life memories. Both groups will undergo CR after C-Coach or sham intervention, where they are asked to perform two 60-minutes training sessions per week for the duration of 6 weeks using the CR training application BrainHQ.

Main study parameters/endpoints: Main endpoint will be subjective and objective cognitive changes between baseline and post-intervention on processing speed task and improved cognitive functioning in daily life in PwMS in the intervention group compared to PwMS in the control group. As secondary endpoints, changes between baseline and post-intervention on goal attainment, meaning of life, fatigue, depression, anxiety, cognitive functioning, functional brain networks and social support in PwMS in the intervention group (C-Coach prior to CR) compared to PwMS in the control group (sham intervention prior to CR) will be studied.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risk of proposed interventions and procedures including MRI scan is negligible, as both can be seen as safe and non-invasive. All participants in the subsample undergoing MRI scans will undergo a detailed screening for MRI contradictions to exclude any risks. The confined space inside the MRI device for the duration of 25 minutes of the scan as well as the time investment of the participant for travel to study location and participation involves some burden for the participants. This study will offer valuable insights in the development of effective cognitive rehabilitation strategies, which will in turn positively impact patients' QoL and their ability to participate in society as they see fit.

Inclusion Criteria:

• Confirmed relapsing remitting or secondary progressive MS diagnosis according to the McDonald 2017 criteria
• Expanded Disability Status Scale (EDSS) score < 7
• Relapse free period ≥ 3 months
• Unchanged disease modifying therapy for ≥ 2 months at time of inclusion
• Age 18-65 years
• Language Dutch, English or German for each centre respectively

Exclusion Criteria:

• High conscientiousness, measured with a T score 65 or higher on the BFI-2 subscale for conscientiousness
• Current or prior brain trauma or neurological condition (other than MS)
• Psychiatric disorder that heavily impacts cognitive and/or daily functioning
• Medication intake and/or substance abuse that has an influence on cognitive functioning
• For Dutch subsample undergoing MRI: Contradiction for MRI