Comparison Group Selection for Studies of Gray Matter Macrostructure Following Pediatric Mild Traumatic Brain Injury

Opio Lopai, Georgia State University, Tucker, United States
Michael Lee, Georgia State University, Atlanta, United States
Keith Yeates, University of Calgary, Calgary, Canada
Miriam Beauchamp, University of Montreal, Montreal, Canada
William Craig, University of Alberta, Edmonton, Canada
Quynh Doan, BC Children's Hospital Research, Vancouver, Canada
Catherine Lebel, University of Calgary, Calgary, Canada
Andree-Anne Ledoux, Children's Hospital of Eastern Ontario, Ottawa, Canada
Roger Zemek, Children's Hospital of Eastern Ontario, Ottawa, Canada
Ashley Ware, Georgia State University, Atlanta, United States
Bryce Geeraert, University of Calgary, Calgary, Canada


Mild traumatic brain injury (mTBI; i.e., concussion) is highly prevalent and can cause persisting difficulties in children. Advanced neuroimaging could be used to identify a biomarker of pediatric mTBI. However, results vary across studies, possibly because of the use of different comparison groups. Studies of white matter microstructure have indicated that comparison group selection could influence results, but no study has looked at the influence of comparison group selection on other indices of brain structure, such as cortical thickness and subcortical gray matter volume. This study compared gray matter macrostructure of children with mTBI to those with orthopedic injury or uninjured children to determine whether comparison group selection influenced results.

Participants and Methods:

Data were drawn from a subset of the A-CAP study, which recruited children aged 8.00 to 16.99 years from a children’s hospital emergency department within 48 hours of an mTBI or orthopedic injury. A group of uninjured, healthy children of the same age range were recruited from the community. All participants completed 3T T1-weighted MRI (i.e., ~2 weeks post-injury in the injured children) at Alberta Children’s Hospital Research Institute, from which regional cortical volume and thickness, and subcortical volume, were derived for 57 unique brain regions based on the MICCAI Pediatric Atlas using the Advanced Normalization Tools (ANTs) segmentation pipeline. Multiple linear mixed effects models compared groups on regional brain metrics, controlling for age at injury and biological sex, with participant included as a random effect. Results were adjusted for multiple comparisons using the false discovery rate.


Children with mTBI (n = 98) and OI (n = 49), and healthy controls (n = 41) did not differ in terms of age (mean age = 12.58, SD = 2.37 years) or sex (60% male). They also did not differ in cortical thickness of any of the examined regions after false discovery rate correction. However, groups did differ significantly (i.e., false discovery rate corrected p-value <.05) in volume of the hippocampus (OI < controls, Cohen’s d = -0.51, p = .001; OI < mTBI, d = -0.38, p = .006), pallidum (OI < controls, d = -0.40, p = .013), and ventral diencephalon (OI < mTBI, d = -0.27, p = .046).


Groups did not differ significantly in cortical thickness. However, they did differ in subcortical volumes in regions underlying motor and memory functioning. The OI group demonstrated the largest number of volumetric differences 2-weeks post-injury relative to the healthy comparison and mTBI groups, which could reflect specific effects of systemic injury (e.g., pain, neuroinflammation). Overall, the results suggest that comparison group selection can influence neuroimaging results and conclusions in studies of pediatric mTBI, but that the differences may be small and nuanced for subcortical gray matter macrostructure.

Category: Acquired Brain Injury (TBI/Cerebrovascular Injury and Disease - Child)

Keyword 1: child brain injury
Keyword 2: subcortical
Keyword 3: neuroimaging: structural