If the theory correctly predicted fatigue based on disruptions of the thalamo-striato-cortical network caused by axonal loss and demyelination, we expected altered brain activation in this network in MS participants while performing a complex cognitive task that challenged fatigue. We also expected that brain activation in this network would be correlated to measures of perceived fatigue. Finally, we expected that Inhibitors,research,lifescience,medical the connections between regions of the brain that are correlated to fatigue and regions in the thalamo-striato-cortical

network would be altered in MS participants. For the purpose of this study we used a complex working memory task during fMRI. This task employs a parametric design enabling Inhibitors,research,lifescience,medical analysis of the cerebral responses to increasing cognitive demands, modeled as increasing task difficulty. In this way, cognitive effort (and fatigue) is challenged. We have previously used this complex working memory task in a study of brain function in patients with periodic idiopathic hypersomnia (Engström et al. 2009, 2013). In order to explore the theory of central fatigue in MS we analyzed the blood oxygen level dependent (BOLD) responses to cerebral activity during performance of the Inhibitors,research,lifescience,medical complex working memory task by adding perceived fatigue scores as Adriamycin cell line covariates in the analysis and by calculating

the functional connectivity between regions in the thalamo-striato-cortical network in MS participants and controls. All image analyses were performed in regions of interest (ROIs) based on the theory of functional architecture of basal ganglia circuits described by Alexander and Crutcher (1990) (Fig. ​(Fig.11). Figure 1 Schematic diagram of the thalamo-striato-cortical Inhibitors,research,lifescience,medical circuits that are hypothesized to be affected in central fatigue disorders. Continuous lines depict excitatory pathways and dotted lines depict inhibitory pathways. The diagram is adapted from Alexander … Methods Participants

The present study Inhibitors,research,lifescience,medical is a continuation of a project on the topic of fatigue in MS (Flensner et al. 2008, 2011, 2013) and part of a randomized controlled trial (RCT) studying the effects of a cooling suit on fatigue, cognition, depression, and health-related quality of life. Initially individuals living in the eastern part of Sweden diagnosed with MS, registered in the Swedish MS-register and having an Expanded Disability Status Scale (EDSS) (Kurtzke 1983) in the interval 0 ≤ EDSS ≤ 6.5, age between 20 and 65 years, were unless invited to participate (n = 334), 256 responded. Among the respondents, 131 reported fatigue as one of their worst problem and heat sensitivity (Flensner et al. 2011). Power calculation indicated 48 participants, 24 in each group in the following randomized study. Exclusion criteria were ongoing use of a cooling suit and participation in another study. From 81 invited individuals, 19 responded and were included in the randomized study. Further eight participants were invited whereof six decided to participate.