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

Tiziana Carandini; Matteo Mancini; Iulia Bogdan; Charlotte L Rae; Andrew W Barritt; Arjun Sethi; Neil Harrison; Waqar Rashid; Elio Scarpini; Daniela Galimberti; Marco Bozzali; Mara Cercignani

doi:10.1016/j.nicl.2021.102587

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

Tiziana Carandini, Matteo Mancini, Iulia Bogdan, Charlotte L Rae, Andrew W Barritt, Arjun Sethi, Neil Harrison, Waqar Rashid, Elio Scarpini, Daniela Galimberti, Marco Bozzali, Mara Cercignani

School of Psychology

Research output: Contribution to journal › Article › peer-review

Abstract

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

© 2021 T. Carandini, M. Mancini, I. Bogdan, C. Rae, A. Barritt, A. Sethi, N. Harrison, W. Rashid, E. Scarpini, D. Galimberti, M. Bozzali, M. Cercignani. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

Original language	English
Pages (from-to)	102587
Journal	NEUROIMAGE-CLINICAL
Volume	30
Early online date	12 Feb 2021
DOIs	https://doi.org/10.1016/j.nicl.2021.102587
Publication status	E-pub ahead of print - 12 Feb 2021

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10.1016/j.nicl.2021.102587

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Carandini, T., Mancini, M., Bogdan, I., Rae, C. L., Barritt, A. W., Sethi, A., Harrison, N., Rashid, W., Scarpini, E., Galimberti, D., Bozzali, M., & Cercignani, M. (2021). Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis. NEUROIMAGE-CLINICAL, 30, 102587. Advance online publication. https://doi.org/10.1016/j.nicl.2021.102587

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abstract = "In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.{\textcopyright} 2021 T. Carandini, M. Mancini, I. Bogdan, C. Rae, A. Barritt, A. Sethi, N. Harrison, W. Rashid, E. Scarpini, D. Galimberti, M. Bozzali, M. Cercignani. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/ ",

author = "Tiziana Carandini and Matteo Mancini and Iulia Bogdan and Rae, {Charlotte L} and Barritt, {Andrew W} and Arjun Sethi and Neil Harrison and Waqar Rashid and Elio Scarpini and Daniela Galimberti and Marco Bozzali and Mara Cercignani",

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doi = "10.1016/j.nicl.2021.102587",

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Carandini, T, Mancini, M, Bogdan, I, Rae, CL, Barritt, AW, Sethi, A, Harrison, N, Rashid, W, Scarpini, E, Galimberti, D, Bozzali, M & Cercignani, M 2021, 'Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis', NEUROIMAGE-CLINICAL, vol. 30, pp. 102587. https://doi.org/10.1016/j.nicl.2021.102587

TY - JOUR

T1 - Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue

T2 - a fixel-based analysis

AU - Carandini, Tiziana

AU - Mancini, Matteo

AU - Bogdan, Iulia

AU - Rae, Charlotte L

AU - Barritt, Andrew W

AU - Sethi, Arjun

AU - Harrison, Neil

AU - Rashid, Waqar

AU - Scarpini, Elio

AU - Galimberti, Daniela

AU - Bozzali, Marco

AU - Cercignani, Mara

PY - 2021/2/12

Y1 - 2021/2/12

N2 - In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.© 2021 T. Carandini, M. Mancini, I. Bogdan, C. Rae, A. Barritt, A. Sethi, N. Harrison, W. Rashid, E. Scarpini, D. Galimberti, M. Bozzali, M. Cercignani. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

AB - In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.© 2021 T. Carandini, M. Mancini, I. Bogdan, C. Rae, A. Barritt, A. Sethi, N. Harrison, W. Rashid, E. Scarpini, D. Galimberti, M. Bozzali, M. Cercignani. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

U2 - 10.1016/j.nicl.2021.102587

DO - 10.1016/j.nicl.2021.102587

M3 - Article

C2 - 33610097

SN - 2213-1582

VL - 30

SP - 102587

JO - NEUROIMAGE-CLINICAL

JF - NEUROIMAGE-CLINICAL

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