TY - JOUR
T1 - In vivo evidence of functional disconnection between brainstem monoaminergic nuclei and brain networks in multiple sclerosis
AU - Carandini, Tiziana
AU - Mancini, Matteo
AU - Bogdan, Iulia
AU - Rae, Charlotte L.
AU - Barritt, Andrew W.
AU - Clerico, Marinella
AU - Sethi, Arjun
AU - Harrison, Neil
AU - Rashid, Waqar
AU - Scarpini, Elio
AU - Galimberti, Daniela
AU - Bozzali, Marco
AU - Cercignani, Mara
N1 - Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MM was funded by the Wellcome Trust through a Sir Henry Wellcome Postdoctoral Fellowship (213722/Z/18/Z). IB received travel and study support from Biogen, Merck, Novartis and Sanofi-Genzyme. NH has served on scientific advisory boards for Janssen and GSK Pharmaceuticals, is in receipt of grant funding from the Wellcome Trust and has received research funding support from Janssen Pharmaceutics and Action for ME. MB received honoraria from Biogen and Merk, and research support from the Italian Ministry of Health. MC received royalties from Taylor and Francis from the publication of a book, research funding from Wellcome Trust, Motor Neuron Disease Association, and the Academy of Medical Sciences. She also received institutional support from the University of Sussex and the University of Brighton. TC, CLR, AWM, MC, AS, WR, ES, and DG report no potential conflicts of interest.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - functional connectivity
KW - monoaminergic systems
KW - monoamines
KW - Multiple sclerosis
KW - resting-state fMRI
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U2 - 10.1016/j.msard.2021.103224
DO - 10.1016/j.msard.2021.103224
M3 - Article
AN - SCOPUS:85113611465
VL - 56
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
SN - 2211-0348
M1 - 103224
ER -