According to the load theory, an active mechanism of cognitive control is involved in maintaining current task goals and reducing additional processing of irrelevant information. Based on this, increasing task difficulty may lead to a higher recruitment of cognitive resources [1]. The N-back is a task with increasing task difficulty and working memory request, which has been used in MS patients for the assessment of working memory and processing speed deficits [2-3]. In this study, we used a N-back working memory task with different levels of cognitive load to: 1) assess behavioral and fMRI abnormalities during this task in MS patients in comparison to healthy controls (HC); 2) identify alterations of recruitment of the N-back network across the various stages of the disease; 3) investigate the correlation between fMRI abnormalities and clinico-behavioural measures (including cognitive scores), as well as structural MRI damage.A N-back fMRI task was administered to 72 right-handed MS patients and 24 age- and gender-matched HC. There were 12 clinically isolated syndromes (CIS), 38 relapsing-remitting (RR), and 22 secondary progressive (SP) MS. The N-back had four levels of increasing difficulty (from 0 to 3 back), presented in a block design with a random order; stimuli were letters and subjects had to respond by pressing the MRI-compatible response box button when the letter matched the target. Dual-echo turbo spin echo and high-resolution 3D T1-weighted scans were also obtained from all study subjects for lesion and volumetric analysis, respectively. Cognitive assessment was performed by using the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) [4]. Based on the scores obtained by the patients at each BRB-N test, a global cognitive score (GCS) was calculated. Regions showing load-dependent activations/deactivations with increasing task difficulty (0- to 3-back and load contrasts) were modelled using SPM8. SPM8 and ANOVA models, adjusted for age and sex, were used to perform between-group comparisons of fMRI activations. SPM8 and multivariate regression analyses were used to assess correlations with behavioral (accuracy, reaction time), clinical (Expanded Disability Status Scale score, disease duration, GCS, attentive domain score), and structural MRI (T2 and T1 lesion volumes, normalized grey, white and brain volumes) variables.Compared to HC, MS patients had worse task performance and brain atrophy. All groups activated fronto-parietal and cerebellar regions and deactivated areas part of the default-mode network (DMN) (Figure 1 A-D). Compared to HC, MS patients had higher recruitment of the right parietal cortex and fronto-mesial areas during low cognitive load conditions as well as decreased recruitment of posterior regions during higher load conditions (Figure 1 E-F). The analysis of the load contrast showed that, compared to HC and RRMS, CIS patients had increased activations of anterior brain areas and right hippocampus, and decreased recruitment of the left postcentral and superior temporal gyrus (STG). SPMS patients showed decreased activation of left putamen when compared to RRMS (Figure 2). Worse performance at the attentional domain correlated with lower right precuneus recruitment, whereas higher global cognitive score was related to decreased deactivations of the right STG. No correlation was found between fMRI abnormalities and structural MRI measures.Load-dependent alterations of executive network recruitment occur in MS patients and vary according to disease phenotype. Increased recruitment of frontal regions was associated to early phase of MS. Conversely, the modulation of regions belonging to the DMN was more evident in patients with long-lasting disease and appeared to be related to the global cognitive profile, suggesting an increased need of cognitive resources to cope with task demand.