Early Influences of Microbiota on White Matter Development in Germ-Free Piglets

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans; however, the influence of microbiota on gyral WM development remains elusive. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T1-W/T2-W Ratio

Objective:To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term-equivalent, 7 and 13 years of age based on the ratio of T1-weighted and T2-weighted magnetic resonance images (T1-w/T2-w), including: (1) whether longitudinal changes differ between birth groups or sexes; (2) associations with perinatal risk factors in VP children, and; (3) relationships with neurodevelopmental outcomes at 13 years.Methods:Prospective longitudinal cohort study of VP (born <30 weeks’ gestation or <1250 g) and FT infants born between 2001-2004 and followed up at term-equivalent age, 7 years of age and 13 years of age, including magnetic resonance imaging studies and neurodevelopmental assessments. T1-w/T2-w images were parcellated into 48 white matter regions of interest.Results:Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had usable T1-w/T2-w data from at least one timepoint. T1-w/T2-w values increased between term-equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age and postnatal infection were associated with reduced regional T1-w/T2-w values in childhood and adolescence. Increased T1-w/T2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T1-w/T2-w values from term-equivalent to 7 years were associated with poorer attention and executive function, and higher T1-w/T2-w values at 7 years were associated with poorer mathematics.Conclusion:VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T1-w/T2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Furthermore, increased T1-w/T2-w ratio at 13 years appeared to be associated with better motor and working memory function, and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning and mathematics.

Dissociating experience-dependent and maturational changes in fine motor function during adolescence

Adolescence is a sensitive period in motor development but little is known about how long-term learning dependent processes shape hand function in tasks of different complexity. We mapped two fundamental aspects of hand function: simple repetitive and complex sequential finger movements, as a function of the length of musical instrumental training. We controlled maturational factors such as chronological and biological age of adolescent female participants (11 to 15 years of age, n=114). We demonstrated that experience improves performance as a function of task complexity, the more complex task being more susceptible for experience driven performance changes. Overall, these results suggest that fine motor skills involving cognitive control and relying on long-range functional brain networks are substantially shaped by experience. On the other hand, performance in a simple repetitive task that explains fine motor speed is primarily shaped by white matter development driven by maturational factors.

Longitudinal changes of ADHD symptoms in association with white matter microstructure: a tract-specific fixel-based analysis

Background: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18-34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax=1.092, standardized effect[SE]=0.044, pFWE=0.016), and improvement in combined symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax=3.775, SE=0.051, pFWE=0.019). Conclusions: Aberrant white matter development involves both lCST micro- and macrostructural alterations and its path may be moderated by preceding symptom trajectory.

Listening to Mom in the NICU: effects of increased maternal speech exposure on language outcomes and white matter development in infants born very preterm

Background Infants born very preterm (< 32 weeks gestational age (GA)) are at risk for developmental language delays. Poor language outcomes in children born preterm have been linked to neurobiological factors, including impaired development of the brain’s structural connectivity (white matter), and environmental factors, including decreased exposure to maternal speech in the neonatal intensive care unit (NICU). Interventions that enhance preterm infants’ exposure to maternal speech show promise as potential strategies for improving short-term health outcomes. Intervention studies have yet to establish whether increased exposure to maternal speech in the NICU offers benefits beyond the newborn period for brain and language outcomes. Methods This randomized controlled trial assesses the long-term effects of increased maternal speech exposure on structural connectivity at 12 months of age (age adjusted for prematurity (AA)) and language outcomes between 12 and 18 months of age AA. Study participants (N = 42) will include infants born very preterm (24–31 weeks 6/7 days GA). Newborns are randomly assigned to the treatment (n = 21) or standard medical care (n = 21) group. Treatment consists of increased maternal speech exposure, accomplished by playing audio recordings of each baby’s own mother reading a children’s book via an iPod placed in their crib/incubator. Infants in the control group have the identical iPod setup but are not played recordings. The primary outcome will be measures of expressive and receptive language skills, obtained from a parent questionnaire collected at 12–18 months AA. The secondary outcome will be measures of white matter development, including the mean diffusivity and fractional anisotropy derived from diffusion magnetic resonance imaging scans performed at around 36 weeks postmenstrual age during the infants’ routine brain imaging session before hospital discharge and 12 months AA. Discussion The proposed study is expected to establish the potential impact of increased maternal speech exposure on long-term language outcomes and white matter development in infants born very preterm. If successful, the findings of this study may help to guide NICU clinical practice for promoting language and brain development. This clinical trial has the potential to advance theoretical understanding of how early language exposure directly changes brain structure for later language learning. Trial registration NIH Clinical Trials (ClinicalTrials.gov) NCT04193579. Retrospectively registered on 10 December 2019.