Meta-Analysis

. 2023 Nov 1;6(11):e2343410.

doi: 10.1001/jamanetworkopen.2023.43410.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

Finian Keleher¹, Hannah M Lindsey^{1

2}, Rebecca Kerestes³, Houshang Amiri⁴, Robert F Asarnow^{5

6

7}, Talin Babikian^{5

8}, Brenda Bartnik-Olson⁹, Erin D Bigler^{1

10

11}, Karen Caeyenberghs¹², Carrie Esopenko¹³, Linda Ewing-Cobbs¹⁴, Christopher C Giza^{8

15

16}, Naomi J Goodrich-Hunsaker^{1

2

10}, Cooper B Hodges^{10

17}, Kristen R Hoskinson^{18

19}, Andrei Irimia^{20

21}, Marsh Königs²², Jeffrey E Max^{23

24}, Mary R Newsome²⁵, Alexander Olsen^{26

27

28}, Nicholas P Ryan^{12

29

30}, Adam T Schmidt³¹, Dan J Stein^{32

33}, Stacy J Suskauer^{34

35

36}, Ashley L Ware^{1

37}, Anne L Wheeler^{38

39}, Brandon A Zielinski^{1

40

41

42}, Paul M Thompson^{43

44

45

46

47

48

49}, Ian H Harding^{3

50}, David F Tate^{1

2

10}, Elisabeth A Wilde^{1

2

25}, Emily L Dennis^{1

2}

Affiliations

¹ TBI and Concussion Center, Department of Neurology, University of Utah School of Medicine, Salt Lake City.
² George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah.
³ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴ Institute of Neuropharmacology, Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
⁵ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
⁶ Brain Research Institute, University of California, Los Angeles.
⁷ Department of Psychology, University of California, Los Angeles.
⁸ Steve Tisch BrainSPORT Program, University of California, Los Angeles.
⁹ Department of Radiology, Loma Linda University Medical Center, Loma Linda, California.
¹⁰ Department of Psychology, Brigham Young University, Provo, Utah.
¹¹ Neuroscience Center, Brigham Young University, Provo, Utah.
¹² Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Victoria, Australia.
¹³ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁴ Children's Learning Institute, Department of Pediatrics, University of Texas Health Science Center at Houston.
¹⁵ Division of Neurology, Department of Pediatrics, Mattel Children's Hospital University of California, Los Angeles.
¹⁶ Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles.
¹⁷ School of Social and Behavioral Sciences, Andrews University, Berrien Springs, Michigan.
¹⁸ Center for Biobehavioral Health, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
¹⁹ Department of Pediatrics, The Ohio State University College of Medicine, Columbus.
²⁰ Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles.
²¹ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles.
²² Emma Neuroscience Group, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
²³ Department of Psychiatry, University of California, San Diego, La Jolla.
²⁴ Department of Psychiatry, Rady Children's Hospital, San Diego, California.
²⁵ H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.
²⁶ Department of Psychology, Norwegian University of Science and Technology, Trondheim, Norway.
²⁷ Clinic of Rehabilitation, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁸ NorHEAD-Norwegian Centre for Headache Research, Trondheim, Norway.
²⁹ Department of Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
³⁰ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
³¹ Department of Psychological Sciences, Texas Tech University, Lubbock.
³² South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Cape Town University, Cape Town, South Africa.
³³ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, Cape Town University, Cape Town, South Africa.
³⁴ Kennedy Krieger Institute, Baltimore, Maryland.
³⁵ Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁶ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁷ Department of Psychology, Georgia State University, Atlanta.
³⁸ Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
³⁹ Physiology Department, University of Toronto, Toronto, Ontario, Canada.
⁴⁰ Department of Pediatrics, University of Florida, Gainesville.
⁴¹ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City.
⁴² Department of Neurology, University of Florida, Gainesville.
⁴³ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey.
⁴⁴ Department of Neurology, University of Southern California, Los Angeles.
⁴⁵ Department of Pediatrics, University of Southern California, Los Angeles.
⁴⁶ Department of Psychiatry, University of Southern California, Los Angeles.
⁴⁷ Department of Radiology, University of Southern California, Los Angeles.
⁴⁸ Department of Engineering, University of Southern California, Los Angeles.
⁴⁹ Department of Ophthalmology, University of Southern California, Los Angeles.
⁵⁰ Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.

PMID: 37966838
PMCID: PMC10652147
DOI: 10.1001/jamanetworkopen.2023.43410

Meta-Analysis

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

Finian Keleher et al. JAMA Netw Open. 2023.

. 2023 Nov 1;6(11):e2343410.

doi: 10.1001/jamanetworkopen.2023.43410.

Authors

Affiliations

¹ TBI and Concussion Center, Department of Neurology, University of Utah School of Medicine, Salt Lake City.
² George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah.
³ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴ Institute of Neuropharmacology, Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
⁵ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
⁶ Brain Research Institute, University of California, Los Angeles.
⁷ Department of Psychology, University of California, Los Angeles.
⁸ Steve Tisch BrainSPORT Program, University of California, Los Angeles.
⁹ Department of Radiology, Loma Linda University Medical Center, Loma Linda, California.
¹⁰ Department of Psychology, Brigham Young University, Provo, Utah.
¹¹ Neuroscience Center, Brigham Young University, Provo, Utah.
¹² Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Victoria, Australia.
¹³ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁴ Children's Learning Institute, Department of Pediatrics, University of Texas Health Science Center at Houston.
¹⁵ Division of Neurology, Department of Pediatrics, Mattel Children's Hospital University of California, Los Angeles.
¹⁶ Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles.
¹⁷ School of Social and Behavioral Sciences, Andrews University, Berrien Springs, Michigan.
¹⁸ Center for Biobehavioral Health, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
¹⁹ Department of Pediatrics, The Ohio State University College of Medicine, Columbus.
²⁰ Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles.
²¹ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles.
²² Emma Neuroscience Group, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
²³ Department of Psychiatry, University of California, San Diego, La Jolla.
²⁴ Department of Psychiatry, Rady Children's Hospital, San Diego, California.
²⁵ H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.
²⁶ Department of Psychology, Norwegian University of Science and Technology, Trondheim, Norway.
²⁷ Clinic of Rehabilitation, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁸ NorHEAD-Norwegian Centre for Headache Research, Trondheim, Norway.
²⁹ Department of Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
³⁰ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
³¹ Department of Psychological Sciences, Texas Tech University, Lubbock.
³² South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Cape Town University, Cape Town, South Africa.
³³ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, Cape Town University, Cape Town, South Africa.
³⁴ Kennedy Krieger Institute, Baltimore, Maryland.
³⁵ Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁶ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁷ Department of Psychology, Georgia State University, Atlanta.
³⁸ Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
³⁹ Physiology Department, University of Toronto, Toronto, Ontario, Canada.
⁴⁰ Department of Pediatrics, University of Florida, Gainesville.
⁴¹ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City.
⁴² Department of Neurology, University of Florida, Gainesville.
⁴³ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey.
⁴⁴ Department of Neurology, University of Southern California, Los Angeles.
⁴⁵ Department of Pediatrics, University of Southern California, Los Angeles.
⁴⁶ Department of Psychiatry, University of Southern California, Los Angeles.
⁴⁷ Department of Radiology, University of Southern California, Los Angeles.
⁴⁸ Department of Engineering, University of Southern California, Los Angeles.
⁴⁹ Department of Ophthalmology, University of Southern California, Los Angeles.
⁵⁰ Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.

PMID: 37966838
PMCID: PMC10652147
DOI: 10.1001/jamanetworkopen.2023.43410

Abstract

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning.

Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function.

Design, setting, and participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022.

Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury.

Main outcomes and measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning.

Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (β = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (β = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (β = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (β=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005).

Conclusions and relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bigler reported providing legal consultation outside the submitted work. Dr Esopenko reported receiving honoraria personal fees from New York University, International Neuropsychological Society, The Drake Foundation, National Athletic Training Association, and Eastern Athletic Training Association, and Safe Living Space. Dr Ewing-Cobbs reported receiving grants from the NIH during the conduct of the study. Dr Giza reported receiving grants from Hit-IQ, the NIH (R01 NS110757 and U54 NS121688), University of California, Los Angeles (UCLA) Brain Injury Research Center, and National Collegiate Athletic Association and US Department of Defense Care Consortium; honoraria and personal fees from the UCLA Steve Tisch BrainSPORT Program, UCLA Easton Clinic for Brain Health, Highmark Interactive; and serving as a clinical consultant providing clinical care for the National Basketball Association, National Football League Neurological Care Program, National Hockey League and National Hockey League Players Association, Los Angeles Lakers, Concussion in Sport Group, Major League Soccer, and US Soccer Federation outside the submitted work. Dr Max reported serving as a medical legal consultant outside the submitted work. Dr Olsen reported being a cofounder and owner of Nordic Brain Tech AS. Dr Stein reported receiving personal fees from Discovery Vitality, Johnson & Johnson, Khanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen outside the submitted work. Dr Suskauer reported receiving personal fees from Myomo Scientific outside the submitted work. Dr Harding reported receiving grants from National Health and Medical Research Council (Australian Government) during the conduct of the study. Dr Tate reported receiving grants from the University of Utah during the conduct of the study. Dr Wilde reported receiving grants from the University of Utah during the conduct of the study. No other disclosures were reported.

Figures

**Figure 1.. Primary Group Comparison**
Atlas-based effect size (Cohen d) maps and Montreal Neurological Institute-based coronal slices (top, y-axis = −72; bottom, y = −54) of the significant between-group differences for children with mild complicated severe traumatic brain injury vs controls. CM indicates corpus medullare; L, lobule.

**Figure 2.. Severity and Chronicity Analyses**
Atlas-based effect size (Cohen d) maps and Montreal Neurological Institute–based coronal slices are shown for group comparisons separated by severity (columns) and chronicity (rows). Lobules and vermal regions (Vermis [Ver.] VII-X) are labeled in the top left on the spatially unbiased infratentorial template flatmap. The corpus medullare (CM) is shown in the coronal slices. The color corresponds to the effect size, according to the color bar, with dark red for the largest effect sizes. Nonsignificant effect sizes are shown at 50% opacity, whereas significant ones are not opaque and outlined in blue. The number of traumatic brain injury (TBI) and non-TBI participants for each comparison are as follows: 12 participants with acute complicated mild TBI, 7 participants with acute moderate TBI, and 25 patients with acute severe TBI, who were each compared with 82 non-TBI participants; 26 patients with postacute complicated mild TBI, 12 patients with postacute moderate TBI, and 43 patients with postacute severe TBI, who each compared with 143 non-TBI participants; and 32 patients with chronic complicated mild TBI, 18 patients with chronic moderate TBI, and 71 patients with chronic severe, who were each compared with 209 non-TBI participants. No TBI participant was included twice in any of the 9 subanalyses, but non-TBI participants were included across multiple comparisons. Only negative effect sizes are shown; positive effect sizes were not significant and are not included.

See this image and copyright information in PMC

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Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

Affiliations

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical