Cognitive impairment frequently affects patients with multiple sclerosis (MS) (in proportions depending on the population studied, the tests used and cut-off values applied [1,2]). Depression is also a frequent symptom in MS [3]. The relationship between the occurrence of depression and psychosocial factors, cognitive impairment, fatigue and side effects of medication has not been fully elucidated yet [3]. Cognitive impairment has been associated to the presence of a widespread cortical atrophy, especially in frontal and temporal regions and the thalamus [4-7], while depression has been associated with atrophy of the middle and inferior frontal gyri [4,8]. However, investigations of the specific effects of cognitive impairment and depression on cortical atrophy in MS are lacking. High-resolution brain 3D T1-weighted scans were acquired at 3.0 T from 126 patients with MS (52/74 men/women, mean age=37.7 years, SD=11.7 years) and 59 matched healthy controls (28/31 men/women, mean age=37.9 years, SD=9.6 years). Cognitive assessment was performed by using the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) [1]. Patients with at least two abnormal tests (defined as a score more than 2 SDs below the Italian normative values provided by Amato et al. [10]) were considered cognitively impaired (CI). Depression was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) [9]. Patients were classified as depressed (D) if their MADRS score was >9. After refilling of T1 hypointensities, reconstruction of cortical surfaces and cortical thickness assessment was performed with FreeSurfer 5.3 (http://surfer.nmr.mgh.harvard.edu). A vertex-by-vertex analysis was used to assess differences of cortical thickness between controls and MS patients, as well as among patient subgroups. The following effects were tested: a) main effect of disease (healthy controls vs MS patients); b) main effect of depression (D vs non-D MS patients); c) main effect of cognitive impairment (CI MS vs CP MS patients); d) conjunction analyses to test specific effects of cognitive impairment (on both D and non-D MS) and depression (on both CI and CP MS). T-statistics were thresholded at p=0.01, cluster extent = 50 mm2. Significance was also tested at p<0.05, false-discovery rate corrected for multiple comparisons.Sixty-five MS patients (51%) were classified as D, while 34 MS patients (27%) were CI. The concomitant presence of depression and cognitive impairment was detected in 15 MS patients (12%). Compared with controls, MS patients exhibited a widespread bilateral cortical thinning involving all brain lobes. Regions showing significant cortical atrophy included the bilateral middle frontal, inferior frontal and orbitofrontal cortex, anterior cingulate cortex, bilateral pre- and postcentral gyrus, inferior and superior parietal and temporal cortices, bilateral precuneus, lingual gyrus and entorhinal cortex (Figure 1). No regions of significantly increased cortical thickness were detected in MS vs controls. Compared with CP MS, CI MS patients showed significant decrease of cortical thickness in several bilateral regions of the frontal, temporal and parietal lobes, including the middle and superior frontal and temporal gyrus, pre- and postcentral gyrus, inferior and superior parietal lobule, precuneus and posterior cingulate cortex (Figure 2). No region of significantly increased cortical thickness was detected in CI vs CP MS patients. Compared with non-D MS, D MS patients showed significant cortical thinning of the frontal lobe, including the bilateral medial and lateral orbitofrontal cortex, bilateral middle frontal gyrus and left inferior frontal gyrus. D MS patients showed also significant atrophy of the bilateral entorhinal cortex and pericalcarine cortex, left insula, temporal pole and inferior frontal gyrus (Figure 3). No region of increased cortical thickness was detected in D vs non-D MS. The conjunction analysis showed a selective effect of cognitive impairment on cortical thinning of the bilateral superior frontal gyrus, bilateral superior parietal lobule, left entorhinal cortex and right precuneus (Figure 4). Conversely, a selective effect of depression was found on cortical thinning of the bilateral orbitofrontal cortex and right temporal pole (Figure 4). Cortical thickness analysis is able to detect specific effects of clinical symptoms on cortical atrophy in MS. While cognitive impairment seems to be associated with atrophy of regions located in the fronto-parietal lobes, depression seems to be linked to atrophy of the orbitofrontal cortex.