Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis

In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant neurotransmission is increasingly considered major contributor to fatigue pathophysiology. this study, we aimed compare the integrity white matter fibre tracts projecting from brainstem nuclei in group patients with MS (n = 68) healthy controls 34), investigate its association fatigue. Fibre was assessed novel fixel-based analysis that simultaneously estimates axonal density, by means ‘fibre density’, atrophy, ‘cross section’. We focused on ventral tegmental area, locus coeruleus, raphe main source dopaminergic, noradrenergic, serotoninergic fibres within brainstem, respectively. Fourteen interest these were reconstructed using diffusion tractography, compared product fibre-density cross-section (FDC). Finally, correlations damage modified impact scale scores evaluated MS. Fixel-based revealed significant – measured FDC reduction selective fibre-tracts patients, comparison controls; particularly dopaminergic-mesolimbic pathway, noradrenergic-projections prefrontal cortex, serotoninergic-projections cerebellum. Moreover, observed between severity cognitive mesocorticolimbic well coeruleus projections suggesting potential contribution dopaminergic noradrenergic pathways central Our findings support hypothesis along contributes reduction/dysfunction monoamines add new information mechanisms which contribute pathogenesis This supports need for further research into therapeutic targets aiming combat alleviate