Bihemispheric alterations in myelination in children following unilateral perinatal stroke

Abstract

Background: Stroke is a leading cause of perinatal brain injury with variable outcomes including cerebral palsy and epilepsy. The biological processes that underlie these heterogeneous outcomes are poorly understood. Alterations in developmental myelination are recognized as a major determinant of outcome in preterm brain injury but have not been explored in perinatal stroke. We aimed to characterize myelination in hemiparetic children after arterial perinatal stroke, hypothesizing that ipsilesional myelination would be impaired, the degree of which would correlate with poor outcome.

Methods: Retrospective, controlled cohort study. Participants were identified through the Alberta Perinatal Stroke Project (APSP), a population-based research cohort (n > 400). Inclusion criteria were: 1) MRI-confirmed, unilateral arterial perinatal stroke, 2) T1-weighted MRI after 6 months of age, 3) absence of other neurological disorders, 4) neurological outcome that included at least one of the following tests - Pediatric Stroke Outcome Measure (PSOM), Assisting Hand Assessment (AHA), Melbourne Assessment (MA), neuropsychological evaluation (NPE), and robotic sensorimotor measurements. FreeSurfer software measured hemispheric asymmetry in myelination intensity (primary outcome). A second method using ImageJ software validated the detection of myelination asymmetry. A repeated measures ANOVA was used to compare perilesional, ipsilesional remote, and contralesional homologous region myelination between stroke cases and typically developing controls. Myelination metrics were compared to clinical outcome measures (t-test, Pearson's correlation).

Results: Twenty youth with arterial stroke (mean age: 13.4 ± 4.2yo) and 27 typically developing controls (mean age: 12.5 ± 3.7yo) were studied in FreeSurfer. Participants with stroke demonstrated lower myelination in the ipsilesional hemisphere (p < 0.0001). Myelination in perilesional regions had lower intensity compared to ipsilesional remote areas (p < .00001) and contralesional homologous areas (p < 0.00001). Ipsilesional remote regions had decreased myelination compared to homologous regions on the contralesional hemisphere (p = 0.016). Contralesional myelination was decreased compared to controls (p < 0.00001). Myelination metrics were not strongly associated with clinical motor, robotic sensorimotor, or neuropsychological outcomes though some complex tests requiring speeded responses had moderate effect sizes.

Conclusion: Myelination of apparently uninjured brain in both the ipsilesional and contralesional hemispheres is decreased after perinatal stroke. Differences appear to radiate outward from the lesion. Further study is needed to determine clinical significance.

Keywords: Cerebral palsy; Developmental plasticity; Myelination; Perinatal stroke; White matter.

Fig. 1

Imaging methods. (A) The FreeSurfer method performed semi-automated segmentation with parcellation of the cerebral cortex based on the structure of gyri and sulci (A1), subcortical segmentation (A2), and further classification into perilesional (yellow), ipsilesional remote (blue), or contralesional regions (purple) to measure segmental white matter intensity (A3). (B) The ImageJ thresholding technique adjusted the threshold tool upwards until positive pixels first appeared in white matter regions bilaterally. The intensity value immediately below this was then used as a cut-off, with any remaining positive pixels measured as the hemispheric difference in myelination intensity (B1). Stroke lesion manually traced (B2), and excluded for intensity measurements of comparable areas between hemispheres (B3). Any remaining positive (greater T1 intensity) pixels in the homologous, contralateral white matter were then scored to represent the difference. Lesion indicated by arrow.

Fig. 2

Regional myelination: FreeSurfer method. Myelination intensity was lowest in perilesional white matter, followed by remote regions in the lesioned hemisphere. Myelination intensity in homologous regions of the contralesional hemisphere were higher but still less than both hemispheres in typically developing controls where right hemisphere values were higher than left.

Fig. 3

Myelination and motor outcome. Motor assessments were not related to FreeSurfer myelination ratios (AHA: p = 0.22, r = 0.33) (MA: p = 0.37, r = 0. 24).

Fig. 4

Myelination and stroke outcomes. (A) PSOM scores were not correlated with FreeSurfer myelination ratios (p = 0.07). (B) ImageJ myelination scores were not associated with PSOM scores (p = 0.99).