Thus the “indirect pathway” results in increased inhibition of the thalamus. One nearly interpretation of our results might be that a higher activation of the substantia nigra in more fatigued participants results in a greater inhibition of thalamic influences of the cortex, which in turn leads to more fatigue. However, this interpretation remains Inhibitors,research,lifescience,medical tentative, especially as we could not discriminate the pars reticulata from the pars compacta of the substantia nigra in the ROI analysis. Another, perhaps somewhat contradictory, finding was that the controls showed more activation of the left substantia nigra selleck chem compared to MS participants with fatigue whereas more fatigued participants showed more

activation of the right substantia nigra. This asymmetry might be caused by the functional variety of different neurons of the substantia nigra. However, the spatial Inhibitors,research,lifescience,medical and temporal resolution of current fMRI is not sufficient for such detailed analysis. Perceived fatigue ratings were also Inhibitors,research,lifescience,medical positively correlated with activation of the left PPC. Results from the functional connectivity analysis showed that MS participants had stronger couplings between the PPC and DLPFC compared to controls. We interpret this finding as being in keeping with previous results of studies on the hyperactivation

of cortical task-related areas (Lenzi et al. 2008; Genova et al. 2009). Another finding related to the fatigue correlated activity in the parietal cortex was that MS participants exhibited weaker

couplings between the left PPC and Inhibitors,research,lifescience,medical the right caudate. Thus the MS participants had stronger intracortical couplings (PPC DLPFC) and weaker striato-cortical couplings (PPC Caudate) involving Inhibitors,research,lifescience,medical the parietal cortex. The findings of aberrant couplings of the PPC in MS participants is in agreement with the hypothesis that fatigue may be related to an attention deficit (Calabrese et al. 2010), as the PPC is an important node in the posterior attentional system (Posner 1990). Interestingly, Pellicano et al. (2010)reported that modified FIS scores correlated with the cortical thickness of the parietal lobe. MS participants had less activation in several areas of the basal ganglia, including the caudate nucleus. In addition, Entinostat the MS participants had weaker couplings between the parietal lobe and the right caudate compared to controls, as assessed by the functional connectivity analysis. Other evidence of the importance of the caudate in the pathophysiology of fatigue in MS is given by the study by Roelcke et al. (1997). In their PET study they found reduced glucose metabolism in the caudate, especially on the right side. In this context it is interesting to note that lesions to the caudate are related to lack of initiative and poor motivation (Bhatia and Marsden 1994).