Regional and Global Changes in Brain Structure 1-Year Post Pediatric "Mild" Traumatic Brain Injury

Abstract

Objective: Despite the high prevalence of pediatric "mild" traumatic brain injury (pmTBI), very little is known about the long-term effects of injury on brain structure and how injuries manifest in the context of dynamic and regionally specific neurodevelopmental changes.

Methods: Prospective study design characterizing long-term effects of pmTBI on both global (brain age) and regional (hippocampal volume, hippocampal subfields, and cortical thickness) brain structure at approximately 7 days, 4 months, and 1-year post-injury. A large sample of age- and sex-matched healthy controls was imaged at identical temporal intervals to account for typical neurodevelopmental changes, and to assess how trauma potentially affects developmental trajectories.

Results: A total of 269 pmTBI (age = 14.4 ± 2.9; 41.6% female) and 232 healthy controls (age = 14.1 ± 2.9; 44.8% female) were included in the final analyses (>70% 1-year retention). Results demonstrated that the presence of loss of consciousness and/or post-traumatic amnesia was associated with increased brain age up to 1-year post-injury, increased frontal cortical thickness at 4 months, as well as hippocampal atrophy across all time points relative to controls. "Mild" head trauma also interfered with hippocampal neurodevelopment in a dose-dependent fashion, including within the CA1 subfield. In contrast, post-concussive symptom burden was not associated with any structural abnormalities or alterations to neurodevelopment.

Interpretation: Current findings suggest a dose-dependent relationship between injury severity and alterations in both global and regional brain structure within the spectrum of pmTBI. Our results emphasize the importance of using objective biomarkers rather than subjective self-reported symptoms to better understand the long-term effects of injury. ANN NEUROL 2025;98:341-353.

FIGURE 1

Participant recruitment and retention. Flowchart of enrolment, inclusion and data quality control from visits 1 (V1), 2 (V2), and 3 (V3) for patients with pediatric “mild” traumatic brain injury (pmTBI) and matched healthy controls (HC). The asterisk denotes the total number of participants who were eligible to return, which is a sum of participants with usable clinical and magnetic resonance imaging (MRI) data and those whose data was excluded at previous visits because of quality assurance issues.

FIGURE 2

Brain age analysis. (A) Depicts the brain age estimation method. Raw T₁‐weighted (T1w) data were first preprocessed using N4 bias correction, followed by brain extraction and affine normalization to the Montreal Neurological Institute (MNI) space. Brain age was estimated from the median of 80 slices (sl), followed by the calculation of predicted brain age difference (PAD: estimated brain age minus chronological age). (B) Depicts residualized (scanner version) boxplots for predicted brain age difference for patient subgroups based on the presence (denoted by + sign; green) or absence (denoted by − sign; blue) of post‐traumatic amnesia and/or loss of consciousness (LOC/PTA), and healthy controls (HC; coral) at visits 1 (V1), 2 (V2), and 3 (V3). The LOC/PTA+ group exhibited increased predicted brain age difference relative to HC at V1 and V3, and relative to LOC/PTA− group at V1. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Cortical thickness analysis. (A) Presents an inflated brain rendering of significant cluster within the right (R) superior frontal gyrus (rSFG). (B) Presents residualized (scanner version, age) boxplots depicting results from the cortical thickness analysis for patient subgroups based on the presence (denoted by + sign; green) or absence (denoted by − sign; blue) of post‐traumatic amnesia and/or loss of consciousness (LOC/PTA), and healthy controls (HC; coral) at visits 1 (V1), 2 (V2), and 3 (V3). Only the LOC/PTA+ group exhibited increased cortical thickness relative to HC at V2. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

Hippocampi volumetric analysis. (A) Presents a glass brain rendering for the hippocampal subfields including cornu ammonis (CA; cyan for all subfields) and dentate gyrus (DG; dark blue). (B) Presents residualized (scanner version, age, total intracranial volume) boxplots depicting results from the hippocampi volumetric analyses for patient subgroups based on the presence (denoted by + sign; green) or absence (denoted by − sign; blue) of post‐traumatic amnesia and/or loss of consciousness (LOC/PTA), as well as healthy controls (HC; coral) at visits 1 (V1), 2 (V2), and 3 (V3). Hippocampi volumes were significantly reduced for the LOC/PTA+ relative to HC at all 3 visits, and for the LOC/PTA− group relative to HC at visits 1 and 3. The LOC/PTA+ group uniquely exhibited evidence of reduced hippocampi volumes from V1 to V2 and V3, indicating atrophy for this group. [Color figure can be viewed at www.annalsofneurology.org]