White Matter Disruption in Pediatric Traumatic Brain Injury: Results From ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury

Emily L Dennis; Karen Caeyenberghs; Kristen R Hoskinson; Tricia L Merkley; Stacy J Suskauer; Robert F Asarnow; Talin Babikian; Brenda Bartnik-Olson; Kevin Bickart; Erin D Bigler; Linda Ewing-Cobbs; Anthony Figaji; Christopher C Giza; Naomi J Goodrich-Hunsaker; Cooper B Hodges; Elizabeth S Hovenden; Andrei Irimia; Marsh Königs; Harvey S Levin; Hannah M Lindsey; Jeffrey E Max; Mary R Newsome; Alexander Olsen; Nicholas P Ryan; Adam T Schmidt; Matthew S Spruiell; Benjamin S C Wade; Ashley L Ware; Christopher G Watson; Anne L Wheeler; Keith Owen Yeates; Brandon A Zielinski; Peter Kochunov; Neda Jahanshad; Paul M Thompson; David F Tate; Elisabeth A Wilde

doi:10.1212/WNL.0000000000012222

White Matter Disruption in Pediatric Traumatic Brain Injury: Results From ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury

Neurology. 2021 Jul 19;97(3):e298-e309. doi: 10.1212/WNL.0000000000012222.

Authors

Emily L Dennis¹, Karen Caeyenberghs¹, Kristen R Hoskinson¹, Tricia L Merkley¹, Stacy J Suskauer¹, Robert F Asarnow¹, Talin Babikian¹, Brenda Bartnik-Olson¹, Kevin Bickart¹, Erin D Bigler¹, Linda Ewing-Cobbs¹, Anthony Figaji¹, Christopher C Giza¹, Naomi J Goodrich-Hunsaker¹, Cooper B Hodges¹, Elizabeth S Hovenden¹, Andrei Irimia¹, Marsh Königs¹, Harvey S Levin¹, Hannah M Lindsey¹, Jeffrey E Max¹, Mary R Newsome¹, Alexander Olsen¹, Nicholas P Ryan¹, Adam T Schmidt¹, Matthew S Spruiell¹, Benjamin S C Wade¹, Ashley L Ware¹, Christopher G Watson¹, Anne L Wheeler¹, Keith Owen Yeates¹, Brandon A Zielinski¹, Peter Kochunov¹, Neda Jahanshad¹, Paul M Thompson¹, David F Tate¹, Elisabeth A Wilde¹

Affiliation

¹ From the Department of Neurology (E.L.D., T.L.M., E.D.B., N.J.G.-H., E.S.H., H.M.L., B.S.C.W., B.A.Z., D.F.T., E.A.W.), University of Utah School of Medicine; George E. Wahlen Veterans Affairs Medical Center (E.L.D., N.J.G.-H., H.M.L., D.F.T., E.A.W.), Salt Lake City, UT; Cognitive Neuroscience Unit (K.C., N.P.R.), School of Psychology, Deakin University, Geelong, Australia; Center for Biobehavioral Health (K.R.H.), The Abigail Wexner Research Institute at Nationwide Children's Hospital; Department of Pediatrics (K.R.H.), The Ohio State University College of Medicine, Columbus; Department of Psychology (T.L.M., E.D.B., N.J.G.-H., C.B.H., H.M.L.) and Neuroscience Center (T.L.M., E.D.B.), Brigham Young University, Provo, UT; Kennedy Krieger Institute (S.J.S.); Departments of Physical Medicine & Rehabilitation and Pediatrics (S.J.S.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Psychiatry and Biobehavioral Sciences (R.F.A., T.B.), Semel Institute for Neuroscience and Human Behavior, Brain Research Institute (R.F.A.), and Department of Psychology (R.F.A.), UCLA; UCLA Steve Tisch BrainSPORT Program (T.B., K.B., C.C.G.), Los Angeles; Department of Radiology (B.B.-O.), Loma Linda University Medical Center; Departments of Neurology (K.B.) and Neurosurgery (C.C.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; Department of Pediatrics (L.E.-C., C.G.W.), Children's Learning Institute, University of Texas Health Science Center at Houston; Division of Neurosurgery (A.F.) and Neuroscience Institute (A.F.), University of Cape Town, South Africa; Department of Pediatrics (C.C.G.), Division of Neurology, UCLA Mattel Children's Hospital, Los Angeles, CA; Department of Physical Medicine and Rehabilitation (C.B.H.), Virginia Commonwealth University, Richmond; Ethel Percy Andrus Gerontology Center (A.I.), Leonard Davis School of Gerontology, and Department of Biomedical Engineering (A.I.), Viterbi School of Engineering, University of Southern California, Los Angeles; Emma Children's Hospital (M.K.), Amsterdam UMC, University of Amsterdam, Emma Neuroscience Group, the Netherlands; H. Ben Taub Department of Physical Medicine and Rehabilitation (H.S.L., M.R.N., M.S.S., E.A.W.), Baylor College of Medicine; Michael E. DeBakey Veterans Affairs Medical Center (H.S.L., M.R.N.), Houston, TX; Department of Psychiatry (J.E.M.), University of California, San Diego, La Jolla; Department of Psychiatry (J.E.M.), Rady Children's Hospital, San Diego, CA; Department of Psychology (A.O.), Norwegian University of Science and Technology, Trondheim; Department of Physical Medicine and Rehabilitation (A.O.), St. Olavs Hospital, Trondheim University Hospital, Norway; Department of Clinical Sciences (N.P.R.), Murdoch Children's Research Institute; Department of Paediatrics (N.P.R.), University of Melbourne, Australia; Department of Psychological Sciences (A.T.S.), Texas Tech University, Lubbock; Ahmanson-Lovelace Brain Mapping Center (B.S.C.W.), Department of Neurology, University of California, Los Angeles; Department of Psychology (A.L. Ware, K.O.Y.), University of Calgary, Alberta; Hospital for Sick Children (A.L. Wheeler), Neuroscience and Mental Health Program; Physiology Department (A.L. Wheeler), University of Toronto, Ontario; Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute (K.O.Y.) and Departments of Pediatrics and Clinical Neurosciences (K.O.Y.), University of Calgary, Alberta, Canada; Department of Pediatrics (B.A.Z.), University of Utah School of Medicine, Salt Lake City; Maryland Psychiatric Research Center (P.K.), University of Maryland School of Medicine, Baltimore; Imaging Genetics Center (N.J., P.M.T.), Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina Del Rey; and Departments of Neurology, Pediatrics, Psychiatry, Radiology, Engineering, and Ophthalmology (P.M.T.), USC, Los Angeles, CA.

Abstract

Objective: Our study addressed aims (1) to test the hypothesis that moderate-severe traumatic brain injury (TBI) in pediatric patients is associated with widespread white matter (WM) disruption, (2) to test the hypothesis that age and sex affect WM organization after injury, and (3) to examine associations between WM organization and neurobehavioral outcomes.

Methods: Data from 10 previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Pediatric Moderate/Severe TBI (msTBI) working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.

Results: Five hundred seven children and adolescents (244 with complicated msTBI and 263 controls) were included. Patients were clustered into 3 postinjury intervals: acute/subacute, <2 months; postacute, 2 to 6 months; and chronic, ≥6 months. Outcomes were dMRI metrics and postinjury behavioral problems as indexed by the Child Behavior Checklist. Our analyses revealed altered WM diffusion metrics across multiple tracts and all postinjury intervals (effect sizes range d = -0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time after injury. We observed a sex-by-group interaction: female patients with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (β = 0.043), which coincided with more parent-reported behavioral problems (β = -0.0027).

Conclusions: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically meaningful patient subtypes.

Abstract

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