A tractometry principal component analysis of white matter tract network structure and relationships with cognitive function in relapsing-remitting multiple sclerosis.

Understanding the brain changes underlying cognitive dysfunction is a key priority in multiple sclerosis (MS) to improve monitoring and treatment of this debilitating symptom. Functional connectivity network changes are associated with cognitive dysfunction, but it is less well understood how changes in normal appearing white matter relate to cognitive symptoms. If white matter tracts have network structure it would be expected that tracts within a network share susceptibility to MS pathology. In the present study, we used a tractometry approach to explore patterns of variance in white matter metrics across white matter (WM) tracts, and assessed how such patterns relate to neuropsychological test performance across cognitive domains. A sample of 102 relapsing-remitting MS patients and 27 healthy controls underwent MRI and neuropsychological testing. Tractography was performed on diffusion MRI data to extract 40 WM tracts and microstructural measures were extracted from each tract. Principal component analysis (PCA) was used to decompose metrics from all tracts to assess the presence of any co-variance structure among the tracts. Similarly, PCA was applied to cognitive test scores to identify the main cognitive domains. Finally, we assessed the ability of tract co-variance patterns to predict test performance across cognitive domains. We found that a single co-variance pattern which captured microstructure across all tracts explained the most variance (65% variance explained) and that there was little evidence for separate, smaller network patterns of pathology. Variance in this pattern was explained by effects related to lesions, but one main co-variance pattern persisted after this effect was regressed out. This main WM tract co-variance pattern contributed to explaining a modest degree of variance in one of our four cognitive domains in MS. These findings highlight the need to investigate the relationship between the normal appearing white matter and cognitive impairment further and on a more granular level, to improve the understanding of the network structure of the brain in MS.

A Systematic Review of Resting-State Functional MRI Connectivity Changes and Cognitive Impairment in Multiple Sclerosis.

Introduction: Cognitive impairment in multiple sclerosis (MS) is increasingly being investigated with resting-state functional MRI (rs-fMRI) functional connectivity (FC). However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology. Methods: Embase, Medline, and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. Results: Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different magnetic resonance (MR) metrics. There was no clear link to increased FC during the early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings. Discussion: These results indicate an urgent need for greater standardization in the field-in terms of the choice of MRI analysis and the definition of cognitive impairment. This will allow us to use rs-fMRI FC as a biomarker in future clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.

Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers, there remains to be a full understanding of why they are affected in MS. In this cross-sectional study, we tested the hypothesis that functional network regions may be susceptible to disease-related "wear and tear" and that this can be observable on co-occurring abnormalities on other magnetic resonance metrics. We tested whether functional connectivity abnormalities in cognitively impaired patients with MS co-occur with (1) overlapping, (2) local, or (3) distal changes in anatomic connectivity and cerebral blood flow abnormalities. METHODS: Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests were performed in 102 patients with relapsing-remitting MS and 27 healthy controls. Patients with MS were classified as cognitively impaired if they scored ≥1.5 SDs below the control mean on ≥2 tests (n = 55) or as cognitively preserved (n = 47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated, and anatomic connectivity was assessed with anatomic connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomic connectivity were assessed within resting-state networks that showed functional connectivity abnormalities in cognitively impaired patients with MS. RESULTS: Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved patients with MS (threshold-free cluster enhancement corrected at p ≤ 0.05, 2 sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomic connectivity locally and distally but not in overlapping locations. DISCUSSION: We provide the first evidence that functional connectivity abnormalities are accompanied by local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathologic mechanism for altered functional connectivity in brain networks in MS.

Dispositional Mindfulness, Meditation, and Conditional Goal Setting.

Conditional goal setting (CGS, the tendency to regard high order goals such as happiness, as conditional upon the achievement of lower order goals) is observed in individuals with depression and recent research has suggested a link between levels of dispositional mindfulness and conditional goal setting in depressed patients. Since interventions which aim to increase mindfulness through training in meditation are used with patients suffering from depression it is of interest to examine whether such interventions might alter CGS. Study 1 examined the correlation between changes in dispositional mindfulness and changes in CGS over a 3-4 month period in patients participating in a pilot randomised controlled trial of Mindfulness-Based Cognitive Therapy (MBCT). Results indicated that increases in dispositional mindfulness were significantly associated with decreases in CGS, although this effect could not be attributed specifically to the group who had received training in meditation. Study 2 explored the impact of brief periods of either breathing or loving kindness meditation on CGS in 55 healthy participants. Contrary to expectation, a brief period of meditation increased CGS. Further analyses indicated that this effect was restricted to participants low in goal re-engagement ability who were allocated to loving kindness meditation. Longer term changes in dispositional mindfulness are associated with reductions in CGS in patients with depressed mood. However initial reactions to meditation, and in particular loving kindness meditation, may be counterintuitive and further research is required in order to determine the relationship between initial reactions and longer-term benefits of meditation practice.