Structural and functional magnetic resonance imaging correlates of fatigue and dual-task performance in progressive multiple sclerosis

Paolo Preziosa; Maria A Rocca; Elisabetta Pagani; Paola Valsasina; Maria Pia Amato; Giampaolo Brichetto; Nicolò Bruschi; Jeremy Chataway; Nancy D Chiaravalloti; Gary Cutter; Ulrik Dalgas; John DeLuca; Rachel Farrell; Peter Feys; Jennifer Freeman; Matilde Inglese; Alessandro Meani; Cecilia Meza; Robert W Motl; Amber Salter; Brian M Sandroff; Anthony Feinstein; Massimo Filippi; the CogEx Research Team

doi:10.1007/s00415-022-11486-0

Structural and functional magnetic resonance imaging correlates of fatigue and dual-task performance in progressive multiple sclerosis

J Neurol. 2023 Mar;270(3):1543-1563. doi: 10.1007/s00415-022-11486-0. Epub 2022 Nov 27.

Authors

Paolo Preziosa^{1

2

3}, Maria A Rocca^{1

2

3}, Elisabetta Pagani¹, Paola Valsasina¹, Maria Pia Amato^{4

5}, Giampaolo Brichetto^{6

7}, Nicolò Bruschi⁸, Jeremy Chataway^{9

10}, Nancy D Chiaravalloti^{11

12}, Gary Cutter¹³, Ulrik Dalgas¹⁴, John DeLuca^{11

12}, Rachel Farrell^{9

10}, Peter Feys¹⁵, Jennifer Freeman¹⁶, Matilde Inglese^{8

17}, Alessandro Meani¹, Cecilia Meza¹⁸, Robert W Motl¹⁹, Amber Salter²⁰, Brian M Sandroff^{11

12}, Anthony Feinstein^#¹⁸, Massimo Filippi^#^{21

22

23}; the CogEx Research Team

Affiliations

¹ Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
² Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³ Vita-Salute San Raffaele University, Milan, Italy.
⁴ Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.
⁵ IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁶ Scientific Research Area, Italian Multiple Sclerosis Foundation (FISM), Genoa, Italy.
⁷ AISM Rehabilitation Service, Italian Multiple Sclerosis Society, Genoa, Italy.
⁸ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
⁹ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.
¹⁰ National Institute for Health Research, Biomedical Research Centre, University College London Hospitals, London, UK.
¹¹ Kessler Foundation, West Orange, NJ, USA.
¹² Department of Physical Medicine and Rehabilitation, Rutgers NJ Medical School, Newark, NJ, USA.
¹³ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴ Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark.
¹⁵ REVAL, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium.
¹⁶ Faculty of Health, School of Health Professions, University of Plymouth, Plymouth, UK.
¹⁷ IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
¹⁸ Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹⁹ Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA.
²⁰ Department of Neurology, Section on Statistical Planning and Analysis, UT Southwestern Medical Center, Dallas, TX, USA.
²¹ Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected].
²² Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected].
²³ Vita-Salute San Raffaele University, Milan, Italy. [email protected].

^# Contributed equally.

PMID: 36436069
DOI: 10.1007/s00415-022-11486-0

Abstract

Background: Frontal cortico-subcortical dysfunction may contribute to fatigue and dual-task impairment of walking and cognition in progressive multiple sclerosis (PMS).

Purpose: To explore the associations among fatigue, dual-task performance and structural and functional abnormalities of frontal cortico-subcortical network in PMS.

Methods: Brain 3 T structural and functional MRI sequences, Modified Fatigue Impact Scale (MFIS), dual-task motor and cognitive performances were obtained from 57 PMS patients and 10 healthy controls (HC). The associations of thalamic, caudate nucleus and dorsolateral prefrontal cortex (DLPFC) atrophy, microstructural abnormalities of their connections and their resting state effective connectivity (RS-EC) with fatigue and dual-task performance were investigated using random forest.

Results: Thirty-seven PMS patients were fatigued (F) (MFIS ≥ 38). Compared to HC, non-fatigued (nF) and F-PMS patients had significantly worse dual-task performance (p ≤ 0.002). Predictors of fatigue (out-of-bag [OOB]-accuracy = 0.754) and its severity (OOB-R² = 0.247) were higher Expanded Disability Status scale (EDSS) score, lower RS-EC from left-caudate nucleus to left-DLPFC, lower fractional anisotropy between left-caudate nucleus and left-thalamus, higher mean diffusivity between right-caudate nucleus and right-thalamus, and longer disease duration. Microstructural abnormalities in connections among thalami, caudate nuclei and DLPFC, mainly left-lateralized in nF-PMS and more bilateral in F-PMS, higher RS-EC from left-DLPFC to right-DLPFC in nF-PMS and lower RS-EC from left-caudate nucleus to left-DLPFC in F-PMS, higher EDSS score, higher WM lesion volume, and lower cortical volume predicted worse dual-task performances (OOB-R² from 0.426 to 0.530).

Conclusions: In PMS, structural and functional frontal cortico-subcortical abnormalities contribute to fatigue and worse dual-task performance, with different patterns according to the presence of fatigue.

Keywords: Atrophy; Dual-task; Fatigue; MRI; Multiple sclerosis; Resting state; Tractography.

MeSH terms

Brain / pathology
Brain Mapping
Humans
Magnetic Resonance Imaging
Multiple Sclerosis* / complications
Multiple Sclerosis, Chronic Progressive* / diagnostic imaging
Multiple Sclerosis, Chronic Progressive* / pathology
Task Performance and Analysis

Grants and funding

#EGID3185/Multiple Sclerosis Society of Canada