Association of Cumulative Paternal Early Life Stress With White Matter Maturation in Newborns.

Importance: Early life stress (ELS) has been shown to affect brain development and health outcomes. Recent animal studies have linked paternal early stress exposures with next-generation outcomes. Epigenetic inheritance through the male germline has been suggested to be one of the mechanisms. Objectives: To test whether paternal ELS, as measured using the Trauma and Distress Scale, is associated with neonate brain development. Design, Setting, and Participants: This cohort study included data from participants from the prospective 2-generation FinnBrain Birth Cohort, which was collected from 2011 to 2015. Pregnant women and the fathers were consecutively recruited at gestational week 12 from maternity clinics in Finland. Magnetic resonance imaging data were analyzed in 2019. Participants in this study were 72 families (infant, father, mother). Exposure: Paternal exposure to ELS. Main Outcomes and Measures: Fractional anisotropy (FA) values in the major white-matter tracts of the newborn brain. Results: A total of 72 trios (infant, mother, and father) were analyzed. At the time of delivery, the mean (SD) age was 31.0 (4.4) years for fathers and 30.3 (4.5) years for mothers. Forty-one infants (57%) were boys; mean (SD) child age at inclusion was 26.9 (7.2) days from birth and 205 (8) days from estimated conception. Increasing levels of paternal ELS were associated with higher FA values in the newborn brain in the body of the corpus callosum, right superior corona radiata, and retrolenticular parts of the internal capsule. This association persisted after controlling for maternal ELS, maternal socioeconomic status (SES), maternal body mass index, maternal depressive symptoms during pregnancy, child sex, and child age from birth and gestation corrected age when imaged. In additional region-of-interest analyses, the association between FA values and paternal Trauma and Distress Scale sum scores remained statistically significant in the earliest maturing regions of the brain, eg, the genu of the corpus callosum (in the regression models, ß = 0.00096; 95% CI, 0.00034-0.00158; P = .003) and the splenium (ß = 0.00090; 95% CI, 0.00000-0.00180; P = .049). Conclusions and Relevance: This cohort study found a statistically significant association between paternal ELS and offspring brain development. This finding may have far-reaching implications in pediatrics, as it suggests the possibility of a novel route of intergenerational inheritance of ELS on next-generation brain development.

A Novel Approach for Manual Segmentation of the Amygdala and Hippocampus in Neonate MRI.

The gross anatomy of the infant brain at term is fairly similar to that of the adult brain, but structures are immature, and the brain undergoes rapid growth during the first 2 years of life. Neonate magnetic resonance (MR) images have different contrasts compared to adult images, and automated segmentation of brain magnetic resonance imaging (MRI) can thus be considered challenging as less software options are available. Despite this, most anatomical regions are identifiable and thus amenable to manual segmentation. In the current study, we developed a protocol for segmenting the amygdala and hippocampus in T2-weighted neonatal MR images. The participants were 31 healthy infants between 2 and 5 weeks of age. Intra-rater reliability was measured in 12 randomly selected MR images, where 6 MR images were segmented at 1-month intervals between the delineations, and another 6 MR images at 6-month intervals. The protocol was also tested by two independent raters in 20 randomly selected T2-weighted images, and finally with T1 images. Intraclass correlation coefficient (ICC) and Dice similarity coefficient (DSC) for intra-rater, inter-rater, and T1 vs. T2 comparisons were computed. Moreover, manual segmentations were compared to automated segmentations performed by iBEAT toolbox in 10 T2-weighted MR images. The intra-rater reliability was high ICC ≥ 0.91, DSC ≥ 0.89, the inter-rater reliabilities were satisfactory ICC ≥ 0.90, DSC ≥ 0.75 for hippocampus and DSC ≥ 0.52 for amygdalae. Segmentations for T1 vs. T2-weighted images showed high consistency ICC ≥ 0.90, DSC ≥ 0.74. The manual and iBEAT segmentations showed no agreement, DSC ≥ 0.39. In conclusion, there is a clear need to improve and develop the procedures for automated segmentation of infant brain MR images.

Test-retest reliability of Diffusion Tensor Imaging metrics in neonates.

Diffusion tensor imaging (DTI) has been widely used in children and adults to study the microstructural features of the brain. Its use in neonate brains has been limited. Neonate brains are almost completely unmyelinated, and this together with the tendency for babies to move during a scanning session may affect the reliability of the measurements. Here we divided a 96 direction acquisition into three segments, and analysed the intra scan test-retest reliability for pairs of segments. Each segment was subjected to a rigorous quality control, and from the surviving data we chose 25 diffusion encoding directions from each segment, and assessed the pairwise reliability of the most common DTI metrics. This pairwise reliability was assessed for data from 86 infants. We used tract-based spatial statistics (TBSS), voxelwise and ROI analysis schemes, to see potential differential effects of analysis strategy and post processing on the obtained DTI metrics. We found that intra class correlation coefficient (ICC) values were generally high (ICC > 0.80). Residual motion in the data, after quality control, was not found to associate with the diffusion metrics. The results indicate that DTI metrics from neonate data can be reliable, even at relatively low angular resolution that are common for neonate scans. The results lend confidence to the use of neonate DTI data in cross sectional and longitudinal analyses in brain white matter skeleton. Future studies should assess the reliability of fiber tracking techniques in neonate data.

Healthy full-term infants' brain responses to emotionally and linguistically relevant sounds using a multi-feature mismatch negativity (MMN) paradigm.

We evaluated the feasibility of a multi-feature mismatch negativity (MMN) paradigm in studying auditory processing of healthy newborns. The aim was to examine the automatic change-detection and processing of semantic and emotional information in speech in newborns. Brain responses of 202 healthy newborns were recorded with a multi-feature paradigm including a Finnish bi-syllabic pseudo-word/ta-ta/as a standard stimulus, six linguistically relevant deviant stimuli and three emotionally relevant stimuli (happy, sad, angry). Clear responses to emotional sounds were found already at the early latency window 100-200 ms, whereas responses to linguistically relevant minor changes and emotional stimuli at the later latency window 300-500 ms did not reach significance. Moreover, significant interaction between gender and emotional stimuli was found in the early latency window. Further studies on using multi-feature paradigms with linguistic and emotional stimuli in newborns are needed, especially those containing of follow-ups, enabling the assessment of the predictive value of early variations between subjects.