To identify clinical and MRI factors that may influence dynamic balance and the ability to change walking speed during challenging gait condition in multiple sclerosis (MS) patients and in the main clinical MS-phenotypes (RRMS and PMS).

Gait dysfunction and balance impairments are common symptoms in MS patients. Gait function relies on a network of several subcortical and cortical structures, usually affected by MS. Structural damage or functional abnormalities of this network may result in worse challenging gait condition performance.

In this cross-sectional study, 58 MS patients and 30 healthy controls (HC) were retrospectively analyzed. In all subjects, the timed up and go test was performed at comfortable (TUG) and maximum speed; the time difference (TUG-diff) was also calculated. Clinical data related to disability, aerobic capacity, upper limb function, walking capacity and cognitive performance, as well as structural and functional MRI data related to the thalamus, globus pallidus, putamen, caudate nucleus, primary motor cortex (M1), supplementary motor area (SMA), prefrontal (PFC) and premotor cortex (PMC) were obtained.

Compared to HC, MS had worse zTUG/zTUG-diff performance, reduced M1 and SMA cortical thickness (CT); and decreased resting state functional connectivity (RSFC) between the PFC and subcortical nuclei (all-p<0.01). RRMS had a preserved M1 and SMA CT (p>0.12) and a decreased RSFC only between PFC and the caudate nucleus (p=0.03). In MS patients, several motor factors were associated with zTUG/TUGdiff, while zTUGdiff was also correlated with cognitive performance (all-p<0.01). In RRMS, worse zTUG was associated with lower M1 CT (R=0.42), lower SMA CT (R=0.38), and increased RSFC between PFC and the caudate nucleus (R=-0.33; all-p<0.02).

MS patients present impairments in challenging gait condition performance, which are influenced by several motor and cognitive factors. Both structural and functional mechanisms of compensation seem to be present in initial phases of the disease.