• Morphological alterations and microstructural changes are related to fatigue in multiple sclerosis • Thalamic alterations in particular were related to fatigue in early MS • Fatigued patients exhibited subjective but not measurable cognitive impairment • Compensatory processes help preserve or maintain cognitive performance but also contribute to fatigue.

The perceived subjective visual vertical (SVV) is an important sign of a vestibular otolith tone imbalance in the roll plane. Previous studies suggested that unilateral pontomedullary brainstem lesions cause ipsiversive roll-tilt of SVV, whereas pontomesencephalic lesions cause contraversive roll-tilts of SVV. However, previous data were of limited quality and lacked a statistical approach. We therefore tested roll-tilt of the SVV in 79 human patients with acute unilateral brainstem lesions due to stroke by applying modern statistical lesionbehavior mapping analysis. Roll-tilt of the SVV was verified to be a brainstem sign, and for the first time it was confirmed statistically that lesions of the medial longitudinal fasciculus (MLF) and the medial vestibular nucleus are associated with ipsiversive tilt of the SVV, whereas contraversive tilts are associated with lesions affecting the rostral interstitial nucleus of the MLF, the superior cerebellar peduncle, the oculomotor nucleus, and the interstitial nucleus of Cajal. Thus, these structures constitute the anatomical pathway in the brainstem for verticality perception. Present data indicate that graviceptive otolith signals present a predominant role in the multisensory system of verticality perception.

The use of non-routine MRI sequences such as DIR has highlighted the role of gray matter (GM) pathology in multiple sclerosis (MS). The aim of this study was to assess the detection and relevance of cortical lesions (CLs) using MRI in early (<5 years) MS patients. 3D DIR and 3D FLAIR images at 3T from 122 patients [93 relapsing-remitting MS (RRMS), 29 clinically isolated syndrome (CIS)] were scored for CLs by two blinded readers. Patients were divided into two groups depending on the presence or absence of CLs. For FLAIR, 51 CLs were identified, of which 13 were purely intracortical and 38 mixed CLs; for DIR, this was 60 in total and 16 and 44, respectively. In both groups, there was no difference in GM fraction. Neuropsychological testing was performed for a subgroup of 66 patients. In 22.1 % of patients CLs were identified. The number of CLs revealed an association with lower working memory scores and semantical word fluency. Overall, CLs imaged with 3D FLAIR and 3D DIR sequences are found more frequently in RRMS patients than CIS and may also be a correlate for mild neuropsychological pathology.

Our data indicate that there are 2 anatomically distinct graviceptive signal processing mechanisms within the vestibular network in humans that lead, when damaged, to a vestibular tone imbalance either to the contraversive or to the ipsiversive side.