Voxelwise Lesion Symptom Mapping in Pediatric TBI: An ENIGMA Mega-Analysis

Focal lesions are common after complicated mild-to-severe traumatic brain injury (cmsTBI) in children, yet it is unclear whether the location of focal damage relates to cognitive outcome beyond overall lesion burden. Combining 13 international cohorts through the ENIGMA Pediatric cmsTBI working group, we conducted voxelwise lesion-symptom mapping (VLSM) to test whether focal lesion location relates to cognitive outcome, and how this compares with overall lesion volume. From 357 patients with imaging that passed quality assurance, 67 had a focal lesion visible on T1-weighted MRI along with at least one performance-based cognitive outcome (D-KEFS Trail Making conditions and WISC/WAIS Coding). We tested whether lesion location related to cognitive outcome using VLSM, adjusting for age, sex, and time since injury, and separately tested total lesion volume as a predictor of each outcome. Lesions in the right middle frontal gyrus were associated with poorer performance on number sequencing (D-KEFS Trail Making condition 2), a timed visuomotor sequencing task (false discovery rate corrected). In separate regression analyses, greater lesion volume was associated with poorer number-letter switching and motor speed. The switching association remained significant after adjusting for injury severity, whereas the motor-speed association did not. In the largest lesion sample assembled in pediatric cmsTBI to date, focal lesion location and injury burden index separable contributions to cognitive outcome, with number sequencing linked to focal prefrontal damage and switching and motor speed to overall lesion volume, underscoring the value of precise lesion characterization for large-scale multi-site neuroimaging.