Risk of lead exposure, subcortical brain structure, and cognition in a large cohort of 9- to 10-year-old children

Background Lead, a toxic metal, affects cognitive development at the lowest measurable concentrations found in children, but little is known about its direct impact on brain development. Recently, we reported widespread decreases in cortical surface area and volume with increased risks of lead exposure, primarily in children of low-income families. Methods and findings We examined associations of neighborhood-level risk of lead exposure with cognitive test performance and subcortical brain volumes. We also examined whether subcortical structure mediated associations between lead risk and cognitive performance. Our analyses employed a cross-sectional analysis of baseline data from the observational Adolescent Brain Cognitive Development (ABCD) Study. The multi-center ABCD Study used school-based enrollment to recruit a demographically diverse cohort of almost 11,900 9- and 10-year-old children from an initial 22 study sites. The analyzed sample included data from 8,524 typically developing child participants and their parents or caregivers. The primary outcomes and measures were subcortical brain structure, cognitive performance using the National Institutes of Health Toolbox, and geocoded risk of lead exposure. Children who lived in neighborhoods with greater risks of environmental lead exposure exhibited smaller volumes of the mid-anterior (partial correlation coefficient [rp] = -0.040), central (rp = -0.038), and mid-posterior corpus callosum (rp = -0.035). Smaller volumes of these three callosal regions were associated with poorer performance on cognitive tests measuring language and processing speed. The association of lead exposure risk with cognitive performance was partially mediated through callosal volume, particularly the mid-posterior corpus callosum. In contrast, neighborhood-level indicators of disadvantage were not associated with smaller volumes of these brain structures. Conclusions Environmental factors related to the risk of lead exposure may be associated with certain aspects of cognitive functioning via diminished subcortical brain structure, including the anterior splenium (i.e., mid-posterior corpus callosum).

Subcortical brain structure in children with developmental coordination disorder: A T1-weighted volumetric study

Developmental coordination disorder (DCD) is a neurodevelopmental disorder occurring in 5–6% of school-aged children. Converging evidence suggests that dysfunction within cortico-striatal and cortico-cerebellar networks may contribute to motor deficits in DCD, yet limited research has examined the brain morphology of these regions. Using T1-weighted magnetic resonance imaging the current study investigated cortical and subcortical volumes in 37 children with DCD, aged 8 to 12 years, and 48 controls of a similar age. Regional brain volumes of the thalamus, basal ganglia, cerebellum and primary motor and sensory cortices were extracted using the FreeSurfer recon-all pipeline and compared between groups. Reduced volumes within both the left and right pallidum (Left: F = 4.43, p = 0.039; Right: F = 5.24, p = 0.025) were observed in children with DCD; however, these results did not withstand correction for multiple comparisons. These findings provide preliminary evidence of altered subcortical brain structure in DCD. Future studies that examine the morphology of these subcortical regions are highly encouraged in order replicate these findings.

Polygenic selection underlies evolution of human brain structure and behavioral traits

Seemingly paradoxical characteristics of psychiatric disorders, including moderate to high prevalence, reduced fecundity, and high heritability have motivated explanations for the persistence of common risk alleles for severe psychiatric phenotypes throughout human evolution. Proposed mechanisms include balancing selection, drift, and weak polygenic adaptation acting either directly, or indirectly through selection on correlated traits. While many mechanisms have been proposed, few have been empirically tested. Leveraging publicly available data of unprecedented sample size, we studied twenty-five traits (i.e., ten neuropsychiatric disorders, three personality traits, total intracranial volume, seven subcortical brain structure volume traits, and four complex traits without neuropsychiatric associations) for evidence of several different signatures of selection over a range of evolutionary time scales. Consistent with the largely polygenic architecture of neuropsychiatric traits, we found no enrichment of trait-associated single-nucleotide polymorphisms (SNPs) in regions of the genome that underwent classical selective sweeps (i.e., events which would have driven selected alleles to near fixation). However, we discovered that SNPs associated with some, but not all, behaviors and brain structure volumes are enriched in genomic regions under selection since divergence from Neanderthals ~600,000 years ago, and show further evidence for signatures of ancient and recent polygenic adaptation. Individual subcortical brain structure volumes demonstrate genome-wide evidence in support of a mosaic theory of brain evolution while total intracranial volume and height appear to share evolutionary constraints consistent with concerted evolution. We further characterized the biological processes potentially targeted by selection, through expression Quantitative Trait Locus (eQTL) and Gene Ontology (GO) enrichment analyses and found evidence for the role of regulatory functions among selected SNPs in immune and brain tissues. Taken together, our results suggest that alleles associated with neuropsychiatric, behavioral, and brain volume phenotypes have experienced both ancient and recent polygenic adaptation in human evolution, acting through neurodevelopmental and immune-mediated pathways.