In vivo evidence of functional disconnection between brainstem monoaminergic nuclei and brain networks in multiple sclerosis

Background: brainstem monoaminergic (dopaminergic, noradrenergic, and serotoninergic) nuclei (BrMn) contain a variety of ascending neurons that diffusely project to the whole brain, crucially regulating normal brain function. BrMn are directly affected in multiple sclerosis (MS) by inflammation and neurodegeneration. Moreover, inflammation reduces the synthesis of monoamines. Aberrant monoaminergic neurotransmission contributes to the pathogenesis of MS and explains some clinical features of MS. We used resting-state functional MRI (RS-fMRI) to characterize abnormal patterns of BrMn functional connectivity (FC) in MS. Methods: BrMn FC was studied with multi-echo RS-fMRI in n = 68 relapsing-remitting MS patients and n = 39 healthy controls (HC), by performing a seed-based analysis, after producing standard space seed masks of the BrMn. FC was assessed between ventral tegmental area (VTA), locus coeruleus (LC), median raphe (MR), dorsal raphe (DR), and the rest of the brain and compared between MS patients and HC. Between-group comparisons were carried out only within the main effect observed in HC, setting p<0.05 family-wise-error corrected (FWE). Results: in HC, VTA displayed FC with the core regions of the default-mode network. As compared to HC, MS patients showed altered FC between VTA and posterior cingulate cortex (p<0.05FWE). LC displayed FC with core regions of the executive-control network with a reduced functional connection between LC and right prefrontal cortex in MS patients (p<0.05FWE). Raphe nuclei was functionally connected with cerebellar cortex, with a significantly lower FC between these nuclei and cerebellum in MS patients, as compared to HC (p<0.05FWE). Conclusions: our study demonstrated in MS patients a functional disconnection between BrMn and cortical/subcortical efferent targets of central brain networks, possibly due to a loss or a dysregulation of BrMn neurons. This adds new information about how monoaminergic systems contribute to MS pathogenesis and suggests new potential therapeutic targets.