Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

doi:10.1093/braincomms/fcab254

. 2021 Oct 27;3(4):fcab254.

doi: 10.1093/braincomms/fcab254. eCollection 2021.

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

Sook-Lei Liew^{1

2}, Artemis Zavaliangos-Petropulu^{3

4}, Nicolas Schweighofer⁵, Neda Jahanshad⁴, Catherine E Lang^{6

7

8}, Keith R Lohse⁹, Nerisa Banaj¹⁰, Giuseppe Barisano^{3

11}, Lee A Baugh^{12

13

14

15}, Anup K Bhattacharya¹⁶, Bavrina Bigjahan¹⁷, Michael R Borich¹⁸, Lara A Boyd¹⁹, Amy Brodtmann^{20

21}, Cathrin M Buetefisch^{18

22

23}, Winston D Byblow²⁴, Jessica M Cassidy²⁵, Charalambos C Charalambous^{26

27}, Valentina Ciullo¹⁰, Adriana B Conforto^{28

29}, Richard C Craddock³⁰, Adrienne N Dula³⁰, Natalia Egorova^{20

31}, Wuwei Feng³², Kelene A Fercho^{33

34}, Chris M Gregory³², Colleen A Hanlon^{35

36}, Kathryn S Hayward^{20

37

38}, Jess A Holguin¹, Brenton Hordacre³⁹, Darryl H Hwang^{17

40}, Steven A Kautz^{32

41}, Mohamed Salah Khlif²⁰, Bokkyu Kim⁴², Hosung Kim², Amy Kuceyeski⁴³, Bethany Lo¹, Jingchun Liu⁴⁴, David Lin⁴⁵, Martin Lotze⁴⁶, Bradley J MacIntosh^{47

48}, John L Margetis¹, Feroze B Mohamed⁴⁹, Jan Egil Nordvik⁵⁰, Matthew A Petoe^{51

52}, Fabrizio Piras¹⁰, Sharmila Raju⁵³, Ander Ramos-Murguialday^{54

55}, Kate P Revill⁵⁶, Pamela Roberts^{1

57

58}, Andrew D Robertson^{59

60}, Heidi M Schambra⁵³, Na Jin Seo^{32

41

61}, Mark S Shiroishi^{4

17}, Surjo R Soekadar⁶², Gianfranco Spalletta^{10

63}, Cathy M Stinear⁶⁴, Anisha Suri⁶⁵, Wai Kwong Tang⁶⁶, Gregory T Thielman⁶⁷, Vincent N Thijs^{20

68}, Daniela Vecchio¹⁰, Nick S Ward⁶⁹, Lars T Westlye^{70

71}, Carolee J Winstein^{5

72}, George F Wittenberg^{73

74}, Kristin A Wong⁷⁵, Chunshui Yu^{44

76}, Steven L Wolf^{77

78

79

80

81}, Steven C Cramer^{58

72}, Paul M Thompson⁴, ENIGMA Stroke Recovery Working Group

Affiliations

¹ Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA.
² Keck School of Medicine, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.
³ Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁵ Biokinesiology and Physical Therapy, Ostrow School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Departments of Physical Therapy, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁹ Department of Health and Kinesiology, University of Utah, Salt Lake City, UT, USA.
¹⁰ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
¹¹ Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
¹³ Sioux Falls VA Health Care System, Sioux Falls, SD, USA.
¹⁴ Center for Brain and Behavior Research, Vermillion, SD, USA.
¹⁵ Sanford Research, Sioux Falls, SD, USA.
¹⁶ Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
¹⁷ Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸ Department of Rehabilitation Medicine, Emory University, Atlanta, GA, USA.
¹⁹ Department of Physical Therapy & the Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
²⁰ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia.
²¹ Eastern Cognitive Disorders Clinic, Monash University, Melbourne, VIC, Australia.
²² Department of Neurology, School of Medicine, Emory University, Atlanta, GA, USA.
²³ Department of Radiology, Emory University, Atlanta, GA, USA.
²⁴ Department of Exercise Sciences and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
²⁵ Allied Health Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁶ Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus.
²⁷ Center for Neuroscience and Integrative Brain Research (CENIBRE), University of Nicosia Medical School, Nicosia, Cyprus.
²⁸ Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
²⁹ Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
³⁰ Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
³¹ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
³² Department of Health Sciences & Research, Medical University of South Carolina, Charleston, SC, USA.
³³ Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, OK, USA.
³⁴ Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
³⁵ Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA.
³⁶ College of Health Professions, Medical University of South Carolina, Charleston, SC, USA.
³⁷ Department of Physiotherapy, University of Melbourne, Heidelberg, VIC, Australia.
³⁸ NHMRC CRE in Stroke Rehabilitation and Brain Recovery, University of Melbourne, Heidelberg, VIC, Australia.
³⁹ Innovation, IMPlementation and Clinical Translation (IIMPACT) in Health, Allied Health and Human Performance, University of South Australia, Adelaide, SA, Australia.
⁴⁰ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
⁴¹ Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
⁴² Department of Physical Therapy Education, College of Health Professions, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴³ Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
⁴⁴ Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China.
⁴⁵ Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴⁶ Department of Diagnostic Radiology, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
⁴⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Jefferson Integrated Magnetic Resonance Imaging Center, Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA.
⁵⁰ CatoSenteret Rehabilitation Center, Son, Norway.
⁵¹ Bionics Institute, Melbourne, VIC, Australia.
⁵² Department of Medicine and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
⁵³ Department of Neurology, New York University Langone, New York, NY, USA.
⁵⁴ TECNALIA, Basque Research and Technology Alliance (BRTA), Health Division, San Sebastian Donostia, Spain.
⁵⁵ Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.
⁵⁶ Facility for Education and Research in Neuroscience, Emory University, Atlanta, GA, USA.
⁵⁷ Department of Physical Medicine and Rehabilitation, Cedars-Sinai, Los Angeles, CA, USA.
⁵⁸ California Rehabilitation Institute, Los Angeles, CA, USA.
⁵⁹ Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁶⁰ Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada.
⁶¹ Department of Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁶² Clinical Neurotechnology Laboratory, Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany.
⁶³ Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
⁶⁴ Department of Medicine, University of Auckland, Auckland, New Zealand.
⁶⁵ Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁶ Department of Psychiatry, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China.
⁶⁷ Department of Physical Therapy and Neuroscience, University of the Sciences, Philadelphia, PA, USA.
⁶⁸ Department of Neurology, Austin Health, Heidelberg, VIC, Australia.
⁶⁹ UCL Queen Square Institute of Neurology, London, UK.
⁷⁰ Department of Psychology, University of Oslo, Oslo, Norway.
⁷¹ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷² Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁷³ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷⁴ Neurology, Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
⁷⁵ Department of Physical Medicine & Rehabilitation, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
⁷⁶ Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China.
⁷⁷ Division of Physical Therapy Education, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁸ Division of Physical Therapy Education, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁹ Division of Physical Therapy Education, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.
⁸⁰ Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, USA.
⁸¹ Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, GA, USA.

PMID: 34805997
PMCID: PMC8598999
DOI: 10.1093/braincomms/fcab254

Free PMC article

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

Sook-Lei Liew et al. Brain Commun. 2021.

Free PMC article

. 2021 Oct 27;3(4):fcab254.

doi: 10.1093/braincomms/fcab254. eCollection 2021.

Authors

Affiliations

¹ Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA.
² Keck School of Medicine, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.
³ Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁵ Biokinesiology and Physical Therapy, Ostrow School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Departments of Physical Therapy, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁹ Department of Health and Kinesiology, University of Utah, Salt Lake City, UT, USA.
¹⁰ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
¹¹ Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
¹³ Sioux Falls VA Health Care System, Sioux Falls, SD, USA.
¹⁴ Center for Brain and Behavior Research, Vermillion, SD, USA.
¹⁵ Sanford Research, Sioux Falls, SD, USA.
¹⁶ Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
¹⁷ Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸ Department of Rehabilitation Medicine, Emory University, Atlanta, GA, USA.
¹⁹ Department of Physical Therapy & the Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
²⁰ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia.
²¹ Eastern Cognitive Disorders Clinic, Monash University, Melbourne, VIC, Australia.
²² Department of Neurology, School of Medicine, Emory University, Atlanta, GA, USA.
²³ Department of Radiology, Emory University, Atlanta, GA, USA.
²⁴ Department of Exercise Sciences and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
²⁵ Allied Health Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁶ Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus.
²⁷ Center for Neuroscience and Integrative Brain Research (CENIBRE), University of Nicosia Medical School, Nicosia, Cyprus.
²⁸ Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
²⁹ Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
³⁰ Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
³¹ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
³² Department of Health Sciences & Research, Medical University of South Carolina, Charleston, SC, USA.
³³ Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, OK, USA.
³⁴ Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
³⁵ Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA.
³⁶ College of Health Professions, Medical University of South Carolina, Charleston, SC, USA.
³⁷ Department of Physiotherapy, University of Melbourne, Heidelberg, VIC, Australia.
³⁸ NHMRC CRE in Stroke Rehabilitation and Brain Recovery, University of Melbourne, Heidelberg, VIC, Australia.
³⁹ Innovation, IMPlementation and Clinical Translation (IIMPACT) in Health, Allied Health and Human Performance, University of South Australia, Adelaide, SA, Australia.
⁴⁰ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
⁴¹ Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
⁴² Department of Physical Therapy Education, College of Health Professions, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴³ Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
⁴⁴ Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China.
⁴⁵ Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴⁶ Department of Diagnostic Radiology, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
⁴⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Jefferson Integrated Magnetic Resonance Imaging Center, Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA.
⁵⁰ CatoSenteret Rehabilitation Center, Son, Norway.
⁵¹ Bionics Institute, Melbourne, VIC, Australia.
⁵² Department of Medicine and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
⁵³ Department of Neurology, New York University Langone, New York, NY, USA.
⁵⁴ TECNALIA, Basque Research and Technology Alliance (BRTA), Health Division, San Sebastian Donostia, Spain.
⁵⁵ Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.
⁵⁶ Facility for Education and Research in Neuroscience, Emory University, Atlanta, GA, USA.
⁵⁷ Department of Physical Medicine and Rehabilitation, Cedars-Sinai, Los Angeles, CA, USA.
⁵⁸ California Rehabilitation Institute, Los Angeles, CA, USA.
⁵⁹ Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁶⁰ Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada.
⁶¹ Department of Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁶² Clinical Neurotechnology Laboratory, Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany.
⁶³ Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
⁶⁴ Department of Medicine, University of Auckland, Auckland, New Zealand.
⁶⁵ Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁶ Department of Psychiatry, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China.
⁶⁷ Department of Physical Therapy and Neuroscience, University of the Sciences, Philadelphia, PA, USA.
⁶⁸ Department of Neurology, Austin Health, Heidelberg, VIC, Australia.
⁶⁹ UCL Queen Square Institute of Neurology, London, UK.
⁷⁰ Department of Psychology, University of Oslo, Oslo, Norway.
⁷¹ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷² Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁷³ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷⁴ Neurology, Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
⁷⁵ Department of Physical Medicine & Rehabilitation, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
⁷⁶ Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China.
⁷⁷ Division of Physical Therapy Education, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁸ Division of Physical Therapy Education, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁹ Division of Physical Therapy Education, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.
⁸⁰ Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, USA.
⁸¹ Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, GA, USA.

PMID: 34805997
PMCID: PMC8598999
DOI: 10.1093/braincomms/fcab254

Abstract

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T₁-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.

Keywords: MRI; rehabilitation; sensorimotor behaviour; stroke; subcortical volumes.

Figures

**Figure 1**
**Relationships between post-stroke sensorimotor behaviour and non-lesioned subcortical volumes.** Non-lesioned subcortical regions (D, bottom right) that relate to sensorimotor behaviour from linear mixed-effects models of people with subacute (A, top left) and chronic (B, bottom left) stroke. Non-lesioned subcortical volume relationships with chronic sensorimotor impairment are shown in C (top right). There were no significant volume relationships with chronic activity limitations. Colours represent the beta estimate (β) for sensorimotor behaviour from each model. Warmer colours represent stronger positive relationships (e.g. larger brain volumes relate to better behaviour), and cooler colours represent stronger negative relationships (e.g. larger brain volumes relate to worse behaviour).

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Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

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Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide

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