Towards a better management of cognitive decline in multiple sclerosis: Linking neuropsychology to neurophysiology: Linking neuropsychology to neurophysiology

In this thesis we aimed to better understand and treat cognitive problems in patients with MS. We demonstrated that several factors hamper the detection of cognitive impairments in MS, both before and during neuropsychological examination. Before neuropsychological examination, clinicians should be aware of cognitive impairments irrespective of whether patients report these complaints, as patient-reported complaints were found to be a weak indicator of actual cognitive impairments. During neuropsychological testing, clinicians should be aware of whether patients perform optimally in order to draw valid conclusions regarding their cognitive status, as suboptimal performance regularly occurred (20%) in MS patients with self-reported cognitive complaints. Suboptimal performance could not be predicted by patient- or clinical characteristics, and it therefore remains unpredictable which MS patients perform suboptimally. We subsequently investigated the underlying brain mechanisms of cognitive impairment in MS. Patients with cognitive impairments showed neuronal slowing, a stronger overlap between their functional and structural brain network, and a less integrated functional brain network compared to cognitively preserved patients and/or healthy controls. Functional connectivity alterations were also linked to cognitive impairment, but the direction of change was not consistent. Patients with suboptimal performance showed functional alterations similar to cognitively preserved patients, whereas their structural damage was more similar to that of cognitively impaired patients. This patient group therefore seems heterogeneous in terms of pathology and likely consists of both cognitively impaired and preserved patients. Regarding the longitudinal predictive value of brain measures, we found that patients with specific network characteristics (i.e. a less integrated delta band network and a more integrated beta band network) and lower cortical grey matter volumes were most prone to cognitive decline over a period of five years. Lastly, we investigated the effects of two non-pharmacological therapies, cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT), on different aspects of cognition. Both CRT and MBCT led to a reduction in patient-reported complaints directly following treatment completion, but these benefits did not persist. Regarding the long-term effects, CRT had a positive effect on personalized cognitive goal achievement and MBCT on information processing speed. This positive effect on personalized goals emphasizes the clinical relevance of CRT, as the training effects seem to transfer to daily life. The positive finding of mindfulness on cognition, including the short-term effect on patient-reported cognitive complaints and the long-term effect on information processing speed, may contribute to an improved treatment of MS-related cognitive problems, as mindfulness has rarely been studied as a cognitive treatment in MS. Furthermore, we found that patients who were less cognitively affected showed the greatest reductions in their self-reported cognitive complaints, whereas patients who were more affected in terms of cognitive function, physical disability and brain function showed the greatest improvements in processing speed after MBCT. Combined, the findings in this thesis provide insight into the detection, understanding and treatment of cognitive