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Abstract

Background:

Depression is frequently associated with multiple sclerosis (MS). However, the biological background underlying such association is poorly understood.

Objective:

Investigating the functional connections of neurotransmitter-related brainstem nuclei, along with their relationship with white matter (WM) microstructure, in MS patients with depressive symptomatology (MS-D) and without depressive symptomatology (MS-nD).

Methods:

Combined resting-state functional magnetic resonance imaging (fMRI) and diffusion-weighted MRI (dMRI) study on 50 MS patients, including 19 MS-D and 31 MS-nD patients, along with 37 healthy controls (HC). Main analyses performed are (1) comparison between groups of raphe nuclei (RN)-related functional connectivity (FC); (2) correlation between RN-related FC and whole brain dMRI-derived fractional anisotropy (FA) map; and (3) comparison between groups of FA in the RN-related WM area.

Results:

(1) RN-related FC was reduced in MS-D when compared to MS-nD and HC; (2) RN-related FC positively correlated with FA in a WM cluster mainly encompassing thalamic/basal ganglia regions, including the fornix; and (3) FA in such WM area was reduced in MS-D.

Conclusion:

Depressive symptomatology in MS is specifically associated to a functional disconnection of neurotransmitter-related nuclei, which in turn may be traced to a distinct spatial pattern of WM alterations mainly involving the limbic network.

Keywords

Multiple sclerosis depression raphe nuclei ventral tegmental area functional connectivity white matter

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References

Inglese

Petracca

. MRI in multiple sclerosis: Clinical and research update. Curr Opin Neurol 2018; 31(3): 249–255.

Turner

Alschuler

Hughes

, et al. Mental health comorbidity in MS: Depression, anxiety, and bipolar disorder. Curr Neurol Neurosci Rep 2016; 16(12): 106.

Marrie

Reingold

Cohen

, et al. The incidence and prevalence of psychiatric disorders in multiple sclerosis: A systematic review. Mult Scler 2015; 21(3): 305–317.

Feinstein

Magalhaes

Richard

, et al. The link between multiple sclerosis and depression. Nature Rev Neurol 2014; 10(9): 507–517.

Pujol

Bello

Deus

, et al. Lesions in the left arcuate fasciculus region and depressive symptoms in multiple sclerosis. Neurology 1997; 49(4): 1105–1110.

Feinstein

Roy

Lobaugh

, et al. Structural brain abnormalities in multiple sclerosis patients with major depression. Neurology 2004; 62(4): 586–590.

Feinstein

O’Connor

Akbar

, et al. Diffusion tensor imaging abnormalities in depressed multiple sclerosis patients. Mult Scler 2010; 16(2): 189–196.

Gobbi

Rocca

Riccitelli

, et al. Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. Mult Scler 2014; 20(2): 192–201.

Shen

Bai

Gao

, et al. Depressive symptoms in multiple sclerosis from an in vivo study with TBSS. Biomed Res Int 2014; 2014: 148465.

10.

Nigro

Passamonti

Riccelli

, et al. Structural ‘connectomic’ alterations in the limbic system of multiple sclerosis patients with major depression. Mult Scler 2015; 21(8): 1003–1012.

11.

Rocca

Pravata

Valsasina

, et al. Hippocampal-DMN disconnectivity in MS is related to WM lesions and depression. Hum Brain Mapp 2015; 36(12): 5051–5063.

12.

van Geest

Boeschoten

Keijzer

, et al. Fronto-limbic disconnection in patients with multiple sclerosis and depression. Mult Scler 2019; 25: 715–726.

13.

Riccelli

Passamonti

Cerasa

, et al. Individual differences in depression are associated with abnormal function of the limbic system in multiple sclerosis patients. Mult Scler 2016; 22(8): 1094–1105.

14.

Bonavita

Sacco

Esposito

, et al. Default mode network changes in multiple sclerosis: A link between depression and cognitive impairment. Eur J Neurol 2017; 24(1): 27–36.

15.

Conio

Martino

Magioncalda

, et al. Opposite effects of dopamine and serotonin on resting-state networks: Review and implications for psychiatric disorders. Molec Psychiatry. Epub ahead of print 5 April 2019. DOI: 10.1038/s41380-019-0406-4.

16.

Krishnan

Nestler

. The molecular neurobiology of depression. Nature 2008; 455(7215): 894–902.

17.

Anand

Jones

Lowe

, et al. Resting state functional connectivity of dorsal raphe nucleus and ventral tegmental area in medication-free young adults with major depression. Front Psychiatry 2018; 9: 765.

18.

Han

Duan

, et al. Dysfunctional connectivity between raphe nucleus and subcortical regions presented opposite differences in bipolar disorder and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2018; 92: 76–82.

19.

Krupp

LaRocca

Muir-Nash

, et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46(10): 1121–1123.

20.

Beck

Steer

. Internal consistencies of the original and revised beck depression inventory. J Clin Psychol 1984; 40(6): 1365–1367.

21.

Polman

Reingold

Banwell

, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302.

22.

Edlow

Takahashi

, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012; 71(6): 531–546.

23.

Keuken

Bazin

Crown

, et al. Quantifying inter-individual anatomical variability in the subcortex using 7 T structural MRI. Neuroimage 2014; 94: 40–46.

24.

Nichols

Holmes

. Nonparametric permutation tests for functional neuroimaging: A primer with examples. Hum Brain Mapp 2002; 15(1): 1–25.

25.

Purves

Augustine

Fitzpatrick

, et al. The limbic system, in neuroscience. 2nd ed. Sunderland, MA: Sinauer Associates, 2001.

26.

Hoogenboom

Perlis

Smoller

, et al. Limbic system white matter microstructure and long-term treatment outcome in major depressive disorder: A diffusion tensor imaging study using legacy data. World J Biol Psychiatry 2014; 15(2): 122–134.

27.

Piaggio

Schiavi

Martino

, et al. Exploring mania-associated white matter injury by comparison with multiple sclerosis: A diffusion tensor imaging study. Psychiatry Res Neuroimaging 2018; 281: 78–84.

28.

Savitz

. The kynurenine pathway: A finger in every pie. Mol Psychiatry. Epub ahead of print 12 April 2019. DOI: 10.1038/s41380-019-0414-4.

29.

Gold

Kern

O’Connor

, et al. Smaller cornu ammonis 2-3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms. Biol Psychiatry 2010; 68(6): 553–559.

30.

Melief

de Wit

van Eden

, et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol 2013; 126(2): 237–249.

31.

Colasanti

Guo

Giannetti

, et al. Hippocampal neuroinflammation, functional connectivity, and depressive symptoms in multiple sclerosis. Biol Psychiatry 2016; 80(1): 62–72.

32.

Miller

Raison

. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16(1): 22–34.

33.

Magioncalda

Martino

Tardito

, et al. White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder. Brain Behav Immun 2018; 73: 192–204.

34.

Mechawar

Savitz

. Neuropathology of mood disorders: Do we see the stigmata of inflammation? Transl Psychiatry 2016; 6(11): e946.

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Depression is associated with disconnection of neurotransmitter-related nuclei in multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material