Reduced structural connectivity in non-motor networks in children born preterm and the influence of early postnatal human cytomegalovirus infection.

Introduction: Preterm birth is increasingly recognized to cause lifelong functional deficits, which often show no correlate in conventional MRI. In addition, early postnatal infection with human cytomegalovirus (hCMV) is being discussed as a possible cause for further impairments. In the present work, we used fixel-based analysis of diffusion-weighted MRI to assess long-term white matter alterations associated with preterm birth and/or early postnatal hCMV infection. Materials and methods: 36 former preterms (PT, median age 14.8 years, median gestational age 28 weeks) and 18 healthy term-born controls (HC, median age 11.1 years) underwent high angular resolution DWI scans (1.5 T, b = 2 000 s/mm2, 60 directions) as well as clinical assessment. All subjects showed normal conventional MRI and normal motor function. Early postnatal hCMV infection status (CMV+ and CMV-) had been determined from repeated screening, ruling out congenital infections. Whole-brain analysis was performed, yielding fixel-wise metrics for fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). Group differences were identified in a whole-brain analysis, followed by an analysis of tract-averaged metrics within a priori selected tracts associated with cognitive function. Both analyses were repeated while differentiating for postnatal hCMV infection status. Results: PT showed significant reductions of fixel metrics bilaterally in the cingulum, the genu corporis callosum and forceps minor, the capsula externa, and cerebellar and pontine structures. After including intracranial volume as a covariate, reductions remained significant in the cingulum. The tract-specific investigation revealed further reductions bilaterally in the superior longitudinal fasciculus and the uncinate fasciculus. When differentiating for hCMV infection status, no significant differences were found between CMV+ and CMV-. However, comparing CMV+ against HC, fixel metric reductions were of higher magnitude and of larger spatial extent than in CMV- against HC. Conclusion: Preterm birth can lead to long-lasting alterations of WM micro- and macrostructure, not visible on conventional MRI. Alterations are located predominantly in WM structures associated with cognitive function, likely underlying the cognitive deficits observed in our cohort. These observed structural alterations were more pronounced in preterms who suffered from early postnatal hCMV infection, in line with previous studies suggesting an additive effect.

Structural brain connectivity in children after neonatal stroke: A whole-brain fixel-based analysis.

INTRODUCTION: Neonatal arterial ischemic stroke (NAIS) has been shown to affect white matter (WM) microstructure beyond the lesion. Here, we employed fixel-based analysis, a technique which allows to model and interpret WM alterations in complex arrangements such as crossing fibers, to further characterize the long-term effects of NAIS on the entire WM outside the primary infarct area. MATERIALS AND METHODS: 32 children (mean age 7.3 years (SD 0.4), 19 male) with middle cerebral artery NAIS (18 left hemisphere, 14 right hemisphere) and 31 healthy controls (mean age 7.7 years (SD 0.6), 16 male) underwent diffusion MRI scans and clinical examination for manual dexterity. Microstructural and macrostructural properties of the WM were investigated in a fixel-based whole-brain analysis, which allows to detect fiber-specific effects. Additionally, tract-averaged fixel metrics in interhemispheric tracts, and their correlation with manual dexterity, were examined. RESULTS: Significantly reduced microstructural properties were identified, located within the parietal and temporal WM of the affected hemisphere, as well as within their interhemispheric connecting tracts. Tract-averaged fixel metrics showed moderate, significant correlation with manual dexterity of the affected hand. No increased fixel metrics or contralesional alterations were observed. DISCUSSION: Our results show that NAIS leads to long-term alterations in WM microstructure distant from the lesion site, both within the parietal and temporal lobes as well as in their interhemispheric connections. The functional significance of these findings is demonstrated by the correlations with manual dexterity. The localization of alterations in structures highly connected to the lesioned areas shift our perception of NAIS from a focal towards a developmental network injury.

A connectome-based approach to assess motor outcome after neonatal arterial ischemic stroke.

OBJECTIVE: Studies of motor outcome after Neonatal Arterial Ischemic Stroke (NAIS) often rely on lesion mapping using MRI. However, clinical measurements indicate that motor deficit can be different than what would solely be anticipated by the lesion extent and location. Because this may be explained by the cortical disconnections between motor areas due to necrosis following the stroke, the investigation of the motor network can help in the understanding of visual inspection and outcome discrepancy. In this study, we propose to examine the structural connectivity between motor areas in NAIS patients compared to healthy controls in order to define the cortical and subcortical connections that can reflect the motor outcome. METHODS: Thirty healthy controls and 32 NAIS patients with and without Cerebral Palsy (CP) underwent MRI acquisition and manual assessment. The connectome of all participants was obtained from T1-weighted and diffusion-weighted imaging. RESULTS: Significant disconnections in the lesioned and contra-lesioned hemispheres of patients were found. Furthermore, significant correlations were detected between the structural connectivity metric of specific motor areas and manuality assessed by the Box and Block Test (BBT) scores in patients. INTERPRETATION: Using the connectivity measures of these links, the BBT score can be estimated using a multiple linear regression model. In addition, the presence or not of CP can also be predicted using the KNN classification algorithm. According to our results, the structural connectome can be an asset in the estimation of gross manual dexterity and can help uncover structural changes between brain regions related to NAIS.