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Published on: August 14, 2019
White Matter Disruption in Pediatric Traumatic Brain Injury: Results From ENIGMA Pediatric Moderate to Severe
Emily L Dennis1, Karen Caeyenberghs1, Kristen R Hoskinson1
1From 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.
Insights
Moderate-to-severe traumatic brain injury (TBI) in children causes widespread white matter (WM) disruption. This disruption persists over time and is influenced by sex and injury severity, impacting neurobehavioral outcomes.
Area of Science:
- Neuroscience
- Radiology
- Pediatrics
Background:
- Traumatic brain injury (TBI) in pediatric populations can lead to long-term neurological deficits.
- Understanding the extent and persistence of white matter (WM) changes after moderate-to-severe TBI (msTBI) is crucial for predicting outcomes.
- Existing research often lacks large, harmonized datasets for robust analysis.
Purpose of the Study:
- To test if pediatric msTBI is associated with widespread WM disruption.
- To investigate the influence of age and sex on WM organization post-TBI.
- To examine the relationship between WM integrity and neurobehavioral outcomes in pediatric TBI patients.
Main Methods:
- Utilized data from 10 existing cohorts, harmonized by the ENIGMA Pediatric msTBI working group.
- Applied a coordinated diffusion MRI (dMRI) analysis pipeline to 507 participants (244 msTBI, 263 controls).
- Assessed WM diffusion metrics and behavioral problems using the Child Behavior Checklist across acute, postacute, and chronic intervals.
Main Results:
- Confirmed widespread and persistent WM alterations across multiple tracts in pediatric msTBI patients, evident in all postinjury intervals.
- Injury severity significantly contributed to WM alterations, with its influence diminishing over time.
- A significant sex-by-group interaction revealed lower fractional anisotropy in females' uncinate fasciculus, correlating with increased behavioral problems.
Conclusions:
- Pediatric msTBI leads to widespread and enduring WM disruption.
- Demographic (sex) and clinical (injury severity) factors significantly influence WM integrity and neurobehavioral outcomes.
- Future research should focus on harmonizing neurocognitive data to identify patient subtypes and improve clinical management.
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.
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