Nevertheless, these results indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS and perhaps in central fatigue in general. There are methodological weaknesses in this study regarding the small sample but also the inclusion into the study,

giving a selection of persons with MS who also had heat sensitivity. On the other hand heat sensitivity is common in MS; 60–80% are figures mentioned in scientific reports including our own, which means that the sample taken for this study Inhibitors,research,lifescience,medical still should be regarded as representative (Flensner et al. 2011). On the other hand, it would of course be interesting to analyze if the magnitude and quality of cognitive dysfunction function in persons with MS differ according to if they are heat sensitive Inhibitors,research,lifescience,medical or not. This would be the scope of further study. We suggest that effect of this selection bias (heat sensitivity) on the results of this study may be that the cognitive dysfunction in our population is worse than in an unselected MS population. In addition, pharmaceutical treatment concerning immunomodulating therapy or psychotropic drugs could have influenced the results. The character of this small

study, being a pilot study to test the Inhibitors,research,lifescience,medical plausibility of central neuronal networks having an impact on cognition, implies that it cannot control for these potential confounders, as such medications are common in an MS population and for ethical reasons hard to stop to improve the study design. Further studies are needed to clarify these issues.

Conclusions The aim of the Inhibitors,research,lifescience,medical current study was to explore if dysfunction of the thalamo-striato-cortical network could be a factor that explains fatigue in MS. The main findings were that MS participants showed altered brain responses in the thalamo-striato-cortical network during performance of a complex working memory task that challenged fatigue and that brain activation Inhibitors,research,lifescience,medical in certain cortical and subcortical areas of the network (the left PPC and the right substantia nigra) was positively correlated to perceived fatigue ratings. Furthermore, MS participants had different functional connectivity between science these fatigue-correlated areas and other nodes in the thalamo-striato-cortical network as compared to controls. In particular, MS participants had stronger cortical-to-cortical and subcortical-to-subcortical connections whereas they had weaker cortical-to-subcortical connections. Thus the findings in the present study indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS, and they provide support for the 5-Fluoracil datasheet theory of central fatigue in MS. However, due to the limited number of participants and the somewhat heterogeneous sample of MS participants these results have to be regarded as tentative, though they might serve as a basis for future studies. Acknowledgments The Swedish Research Council (Grant No.