Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression

Abstract

Background:

Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered.

Objective:

The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue.

Methods:

Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression.

Results:

SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression.

Conclusion:

Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.

Keywords

Multiple sclerosis fatigue MRI voxel-wise analysis diffusion tensor imaging

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References

Comi

Leocani

Rossi

et al. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001; 248(3): 174–179.

Bakshi

Fatigue associated with multiple sclerosis: Diagnosis, impact and management. Mult Scler 2003; 9(3): 219–227.

Cavallari

Palotai

Glanz

et al. Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients. Mult Scler 2016; 22(14): 1841–1849.

Runia

Jafari

Siepman

et al. Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry 2015; 86(5): 543–546.

Induruwa

Constantinescu

Gran

Fatigue in multiple sclerosis—A brief review. J Neurol Sci 2012; 323(1–2): 9–15.

Kos

Kerckhofs

Nagels

et al. Origin of fatigue in multiple sclerosis: Review of the literature. Neurorehabil Neural Repair 2008; 22(1): 91–100.

Andreasen

Spliid

Andersen

et al. Fatigue and processing speed are related in multiple sclerosis. Eur J Neurol 2010; 17(2): 212–218.

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.

Rocca

Parisi

Pagani

et al. Regional but not global brain damage contributes to fatigue in multiple sclerosis. Radiology 2014; 273: 511–520.

10.

Pardini

Bonzano

Mancardi

et al. Frontal networks play a role in fatigue perception in multiple sclerosis. Behav Neurosci 2010; 124(3): 329–336.

11.

Genova

Rajagopalan

Deluca

et al. Examination of cognitive fatigue in multiple sclerosis using functional magnetic resonance imaging and diffusion tensor imaging. PLoS ONE 2013; 8(11): e78811.

12.

Gobbi

Rocca

Pagani

et al. Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis. Mult Scler 2014; 20(12): 1633–1640.

13.

Bisecco

Caiazzo

d’Ambrosio

et al. Fatigue in multiple sclerosis: The contribution of occult white matter damage. Mult Scler 2016; 22(13): 1676–1684.

14.

Wilting

Rolfsnes

Zimmermann

et al. Structural correlates for fatigue in early relapsing remitting multiple sclerosis. Eur Radiol 2016; 26(2): 515–523.

15.

Palotai

Mike

Cavallari

et al. Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis. Mult Scler 2017; 24: 1105–1114.

16.

Finke

Schlichting

Papazoglou

et al. Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Mult Scler 2015; 21(7): 925–934.

17.

Johansson

Ytterberg

Hillert

et al. A longitudinal study of variations in and predictors of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008; 79(4): 454–457.

18.

Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: Evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America, 1998.

19.

Amtmann

Bamer

Noonan

et al. Comparison of the psychometric properties of two fatigue scales in multiple sclerosis. Rehabil Psychol 2012; 57(2): 159–166.

20.

Radloff

LS.

The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1: 385–401.

21.

Flachenecker

Kumpfel

Kallmann

et al. Fatigue in multiple sclerosis: A comparison of different rating scales and correlation to clinical parameters. Mult Scler 2002; 8(6): 523–526.

22.

Lewinsohn

Seeley

Roberts

et al. Center for Epidemiologic Studies Depression scale (CES-D) as a screening instrument for depression among community-residing older adults. Psychol Aging 1997; 12(2): 277–287.

23.

Kurtzke

JF.

Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983; 33(11): 1444–1452.

24.

Andersson

JLR

Sotiropoulos

. An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage 2016; 125: 1063–1078.

25.

Behrens

Woolrich

Jenkinson

et al. Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magn Reson Med 2003; 50(5): 1077–1088.

26.

Ashburner

SPM: A history. Neuroimage 2012; 62(2): 791–800.

27.

VanHecke

Leemans

DeBacker

et al. Comparing isotropic and anisotropic smoothing for voxel-based DTI analyses: A simulation study. Hum Brain Mapp 2010; 31(1): 98–114.

28.

Meier

Guttmann

CRG

Tummala

et al. Dual-Sensitivity Multiple Sclerosis Lesion and CSF Segmentation for Multichannel 3T Brain MRI. J Neuroimaging 2018; 28(1): 36–47.

29.

Inglese

Bester

Diffusion imaging in multiple sclerosis: Research and clinical implications. NMR Biomed 2010; 23(7): 865–872.

30.

Hannoun

Durand-Dubief

Confavreux

et al. Diffusion tensor-MRI evidence for extra-axonal neuronal degeneration in caudate and thalamic nuclei of patients with multiple sclerosis. AJNR Am J Neuroradiol 2012; 33(7): 1363–1368.

31.

Feinstein

Magalhaes

Richard

et al. The link between multiple sclerosis and depression. Nat Rev Neurol 2014; 10: 507–517.

32.

Fuchs

Vaughn

Benedict

RHB

et al. Lower self-report fatigue in multiple sclerosis is associated with localized white matter tract disruption between amygdala, temporal pole, insula, and other connected structures. Mult Scler Relat Disord 2019; 27: 298–304.

33.

Moller

Poettgen

Broemel

et al. HAGIL (Hamburg Vigil Study): A randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Mult Scler 2011; 17(8): 1002–1009.

34.

Ledinek

Sajko

Rot

Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis—Result of a pilot randomized, blind study. Clin Neurol Neurosurg 2013; 115(Suppl1): S86–S89.

35.

Sheng

Hou

Wang

et al. Efficacy of modafinil on fatigue and excessive daytime sleepiness associated with neurological disorders: A systematic review and meta-analysis. PLoS ONE 2013; 8(12): e81802.

36.

Lange

Volkmer

Heesen

et al. Modafinil effects in multiple sclerosis patients with fatigue. J Neurol 2009; 256(4): 645–650.

37.

Shaygannejad

Janghorbani

Ashtari

et al. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: A randomized, blinded, crossover study. Neurol Res 2012; 34(9): 854–858.

38.

Rammohan

Rosenberg

Lynn

et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: A two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72(2): 179–183.