Associations between contralesional neuroplasticity and motor impairment through deep learning-derived MRI regional brain age in chronic stroke (ENIGMA): a multicohort, retrospective, observational study.
Authors
Affiliations (40)
Affiliations (40)
- Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.
- Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA; Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
- Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada; Department of Sport, Exercise and Rehabilitation, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
- Department of Clinical Neuroscience and Neurorehabilitation, Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
- Rehabilitation Medicine and Physical Therapy, Emory University, Atlanta, GA, USA.
- Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada.
- Cognitive Health Initiative, School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
- Department of Radiology, Medical University of South Carolina, Mount Pleasant, SC, USA.
- Department of Neurology, Emory University, Atlanta, GA, USA.
- LIM-44, Laboratory of Magnetic Resonance Imaging in Neuroradiology, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
- Department of Neurology, UCLA, Los Angeles, CA, USA; California Rehabilitation Institute, Los Angeles, CA, USA.
- UM Rehabilitation and Orthopaedic Institute, University of Maryland, Baltimore, MD, USA.
- Core Unit Functional Imaging, University Medicine Greifswald, Greifswald, Germany.
- Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA.
- Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
- Department of Neurology, University of Maryland, Baltimore, MD, USA.
- Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
- Department of Brain Sciences, Imperial College London, London, UK.
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA.
- Innovation, Implementation, and Clinical Translation in Health, University of South Australia, Adelaide, SA, Australia.
- Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Health Sciences and Research.
- Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China.
- Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Jefferson Integrated Magnetic Resonance Imaging Center, Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA.
- CatoSenteret Rehabilitation Center, Son, Norway.
- Facility for Education and Research in Neuroscience, Emory University, Atlanta, GA, USA.
- Kinesiology and Health Sciences, University of Waterloo, Waterloo, ON, Canada.
- Department of Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC, USA.
- Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, USA.
- Department of Health Sciences and Research; Department of Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC, USA.
- Clinical Neurotechnology, Charité-University Medicine Berlin, Berlin, Germany.
- Courage Kenny Rehabilitation Institute, Allina Health, Minneapolis, MN, USA.
- Department of Psychology, University of California, Riverside, Riverside, CA, USA.
- Department of Physical Therapy and Neuroscience, Saint Joseph's University, Philadelphia, PA, USA.
- Department of Psychology, University of Oslo, Oslo, Norway.
- GRECC, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
- Graduate Program in Rehabilitation Sciences, University of British Columbia, Vancouver, BC, Canada; Gerontology Research Centre, Simon Fraser University, Vancouver, BC, Canada.
- Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA; Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA. Electronic address: [email protected].
- Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA. Electronic address: [email protected].
Abstract
Stroke leads to complex chronic structural and functional brain changes that specifically affect motor outcomes. The brain predicted age difference (PAD) has emerged as a sensitive biomarker of both sensorimotor and cognitive function after stroke. Our previous study showed a higher global brain PAD associated with poorer motor function after stroke. However, the association between local stroke lesion load, regional brain age, and motor impairment is unclear. This study aimed to investigate the associations between focal lesion damage, regional brain PAD in both hemispheres, and motor outcomes in chronic stroke, and to identify key predictors of motor impairment. In this multicohort, retrospective, observational study, we included individuals with chronic unilateral stroke (>180 days post stroke) from the ENIGMA Stroke Recovery Working Group dataset and used individuals from the UK Biobank cohort to train the regional brain age prediction model. Structural T1-weighted MRI scans were used to estimate regional brain PAD in 18 predefined functional subregions via a graph convolutional network algorithm. Lesion load for each region was calculated on the basis of lesion overlap. Linear mixed-effects models assessed associations between lesion size, local lesion load, and regional brain PAD. Machine learning classifiers predicted motor outcomes using lesion loads and regional brain PADs. Structural equation modelling examined directional relationships among corticospinal tract lesion load, ipsilesional brain PAD, motor outcomes, and contralesional brain PAD. We included 501 individuals from the ENIGMA Stroke Recovery Working Group dataset (34 cohorts in eight countries) and 17 791 individuals from the UK Biobank dataset. Larger total lesion size was positively associated with higher ipsilesional regional brain PADs (older brain age) across most regions (β=0·5420 to 0·9458 across significantly correlated regions, false discovery rate [FDR]-corrected p<0·05), and with lower brain PAD in the contralesional ventral attention and language network region (β=-0·3747, 95% CI -0·6961 to -0·0534, FDR-corrected p<0·05). Higher local lesion loads showed similar patterns. Specifically, lesion load in the salience network significantly influenced regional brain PADs across both hemispheres. Machine learning models identified corticospinal tract lesion load (adjusted mean difference -0·0905, 95% CI -0·1221 to -0·0589, p<0·0001), salience network lesion load (-0·0632, -0·0906 to -0·0358, p<0·0001), and regional brain PAD in the contralesional frontoparietal network (0·9939, 0·4929 to 1·4950, p=0·0001) as the top three predictors of motor outcomes. Structural equation modelling revealed that higher corticospinal tract lesion load was associated with poorer motor outcomes (β=-0·355, 95% CI -0·446 to -0·267, p<0·0001), which were further linked to younger contralesional brain age (0·204, 0·111 to 0·295, p<0·0001), suggesting that severe motor impairment is linked to compensatory decreases in contralesional brain age. Our findings reveal that larger stroke lesions are associated with accelerated ageing in the ipsilesional hemisphere and paradoxically decelerated brain ageing in the contralesional hemisphere, suggesting compensatory neural mechanisms. Assessing regional brain age might serve as a biomarker for neuroplasticity and inform targeted interventions to enhance motor recovery after stroke. US National Institutes of Health.