Efficacy of cognitive rehabilitation in cognition and brain networks: A randomised clinical trial in patients with multiple sclerosis

Abstract

This study evaluated the efficacy of the computerised Guttmann, NeuroPersonalTrainer® (GNPT) cognitive rehabilitation (CR) and characterised the induced changes in cerebral networks in patients with multiple sclerosis (MS). This multicentre, double-blind, randomised clinical trial compared upward intensity training (active treatment) to low-intensity static training (static treatment). Cognition was assessed using the Brief Repeatable battery before and after 12 weeks of training and at 10-months follow-up, and patients were classified as having a mild or severe cognitive impairment (CI). Brain MRI pre- and post-CR were analysed using an advanced tractography algorithm, based on multishell diffusion MRI, to obtain node-based graph metrics (local efficiency and strength) from microscopic fractional anisotropy. Seventy MS patients completed the study (age 48.9 ± 8.8, disease duration 16.8 ± 9.0 years); active treatment: 36, static treatment: 34. Verbal memory improved significantly post-CR in both groups (55 % active; 34 % static treatment), accompanied by increases in local efficiency and strength in multimodal regions. At follow-up, verbal memory declined in both groups but remained above the pre-CR assessment (-25 % and -17 %, respectively). Patients with severe-CI (n = 36) showed improvement only with active treatment, while those with mild-CI (n = 34) improved regardless of intensity treatment. Network changes were more pronounced in patients in active treatment and in those with severe-CI. Quality of life did not change at post-CR, and cognitive improvement was influenced by cognitive reserve (p = 0.011). In MS, GNPT temporarily improves verbal memory and increases network connectivity, reinforcing the CR as a valuable tool for enhancing cognitive skills and promoting neuronal plasticity.

Keywords: Cognition; Cognitive rehabilitation; MRI; Multiple sclerosis; Structural networks.

Fig. 1

Study design and participants. Fig. 1A shows the study design. Cognitive assessment was done using the Brief Repeatable Battery of Neuropsychological Tests. Self-administered questionnaires include the MS Quality of Life-54, Cognitive Reserve Questionnaire, Hospital Anxiety and Depression Scale, and Modified Fatigue Impact Scale. Clinical assessment included the Expanded Disability Status Scale. Fig. 1B is the flow diagram of participants through recruitment and study visits. CR: cognitive rehabilitation; MRI: magnetic resonance imaging; CI: cognitive impairment.

Fig. 2

Cognitive domains z-score at the study visits in each treatment group. The cognitive z-scores were modelled by spline models with two knots indicating each study visit and represented by dotted black vertical lines. The active treatment group is represented in blue and the static treatment group in orange. All models were fitted using the lme4 package in R version 4.2.2 (R Foundation for Statistical Computing: *p < 0.05). Vertical asterisk represents significant differences between treatment groups at pre-CR. Horizontal asterisks represents significant differences from the analyses of pre-CR, post-CR and FU. Baseline time point was not part of the statistical analyses. B: baseline; CR: cognitive rehabilitation; FU: follow-up; IPS: information processing speed. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Microstructural connectivity changes induced by CR and its association with verbal memory performance. Depiction of statistically significant nodes between pre- and post-CR using µFA. The circle size depends on the estimated β value and the circle colour depends on the association with verbal memory performance. The figure was generated using Netplotbrain, a Python-based tool accessible at https://www.netplotbrain.org. CI: cognitive impairment.