Brain growth until adolescence after a neonatal focal injury: sex related differences beyond lesion effect

Abstract

Introduction: Early focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional gray matter growth in childhood and adolescence, while accounting for lesion characteristics.

Methods: We relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at ages 7 and 16 were compared to age-matched controls. Non-lesioned volumes of gray matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F; Controls: 17 M, 18 F) and 16 (Patients: 18 M, 11 F; Controls: 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics.

Results: Whole hemisphere volumes were reduced at both ages in patients compared to controls (gray matter volume: -16% in males, -10% in females). In ipsilesional hemisphere, cortical gray matter and thalamic volume losses (average -13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in gray matter volumes, as only male volumes were smaller than in male controls (average -7.5%), mostly in territories mirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of female controls. Similar sex differences were found in both cerebellar hemispheres.

Discussion: These results suggest sex-dependent growth trajectories after an early brain lesion with a contralesional growth deficit in males only. The similarity of patterns at ages 7 and 16 suggests that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well-described perinatal vulnerability of the male brain, and with no compensation thereafter.

Keywords: brain growth trajectories; brain morphometry; early brain injury; male perinatal brain vulnerability; multifactorial comparative analysis; sex effect.

Figure 1

Lesion mapping per sex subgroup in the whole patient cohort. Superposition of all patient's lesion masks per sex and lesion side (females lesions represented on the left-hand side) and lesion side (left hemisphere lesions on the first row), visualized as a maximum intensity projection. Each subject, longitudinal or not, was counted only once. All masks were registered in MNI ICBM152 2009c symmetric template. Mask count per voxel was divided by the total size of sex subgroups.

Figure 2

Image processing pipeline performed on T1 images for the whole cohort. : quality check; : made/corrected by trained radiologist; GM, gray matter; WM, white matter; DK 40, Desikan Atlas.

Figure 3

LMM factors values for all regional volumes (fixed effects, main interactions and covariates). Post-hocs tests comparing controls to patients mean volume. For plotting purpose, volumes differences are divided by a mean control volume across age and sex (relative effect size) for the shown ROI. Cold colors represent a negative difference (smaller mean regional volume in patients than in controls); warm colors represent a positive difference (bigger patient volumes comparing to controls). *p < 0.05, **p < 0.01, ***p < 0.001 (uncorrected) after False-Discovery Rate correction.

Figure 4

Post-hoc t-tests comparing patients and controls for each age and sex (patients—controls). For plotting purpose, volumes differences are divided by a mean control volume across age and sex (relative effect size) for the shown ROI. Cold colors represent a negative difference (smaller mean regional volume in patients than in controls); warm colors represent a positive difference (bigger patient volumes comparing to controls). *p < 0.05 after False-Discovery Rate correction.

Figure 5

Patient to control volume differences (mean and std) for each sex and each age. Post-hoc t-tests assess if interaction product [(patient-control) male – (patient-control) female] is different from 0. Tests are performed on marginal means, hence typical male to female differences in the control group are residualized in the contrast. For plotting purpose, volume differences are divided by a mean control volume across age and sex (relative effect size) for the shown ROI. Upper dark gray lines represent male results, light gray the female ones. *p < 0.05 after False-Discovery Rate correction.

Figure 6

Contralesional volumes of patients compared to controls in 34 ROIs of Desikan-Killiany parcellation: LMM model and post-hoc tests. Patient volumes are compared to the mean of both hemispheres corresponding values in controls. (A) LMM coefficients values for each region of the DK40 (fixed effects, main interactions, and covariates). *p < 0.05, **p < 0.01, ***p < 0.001. Plotting parameters are the same as in Figure 3. (B) Post-hoc tests comparing patients and controls for each age and sex (patient – controls). Displayed p-values are FDR-corrected (* <0.05). Parameters are the same as Figure 4.