Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

Abstract

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer-term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

The BDNF Val 66 Met polymorphism is associated with structural neuroanatomical differences in young children

“…Further, we observed volumetric differences only in the right hippocampus, which may be a feature of asymmetric hippocampal structure development as young infants have been previously reported to have a larger right hippocampus, an asymmetry not found in adults (Thompson et al , 2009). Indeed, our finding is consistent with (Marusak et al , 2015), who found larger right (only) hippocampal volume for children, who were Met carriers. Developmental changes in hippocampal volume may reflect general u-shaped developmental trajectories of subcortical volumes which peak in adolescence (Giedd et al , 1999, Giedd & Rapoport, 2010, Wierenga et al , 2014), as well as, variable expression of BDNF over the lifespan (Webster et al , 2006).…”

“…In sum, the juxtaposition of our findings and those from the adult literature, in particular studies by Marusak et al (2015) and Hashimoto et al (2016), suggests that the BDNF Val 66 Met polymorphism exerts a significant influence on the cortical and subcortical structures of the brain, but does so differently in children and adults. These differences are likely driven by developmental differences in both structural brain development and BDNF expression, and suggest the need for more research on gene-brain relationships that take a developmental approach.…”

“…For example, in a cohort of Japanese children aged 5–18, Hashimoto et al (2016) found greater grey matter volume in the right cuneus for Met homozygotes (Met/Met) relative to Val homozygotes (a finding not previously observed in adults), whereas they observed greater left insula and left ventromedial prefrontal cortex volumes in Val homozygotes relative to Met homozygotes which is consistent with the adult studies. Further, Marusak et al (2015) reported larger right hippocampal volume among children and adolescents aged 7–15 who were Met carriers, whereas adult studies report larger volumes for Val carriers. Finally, Thomason et al (2009) found that 11–12-year-old children who were Met carriers showed reduced resting state connectivity between the hippocampus and parahippocampal gyrus with cortical regions (middle temporal lobe, posterior cingulate, inferior parietal lobule, precuneus), compared to Val homozygotes, which is consistent with the adult literature and may reflect less robust hippocampal-cortical projections among children who are Met carriers.…”

“…Both animal and human studies suggested that common genetic polymorphisms in bdnf / BDNF are related to the structure and function of the developing brain; see Bath and Lee (2006) for a review of human and animal findings and see Hanover et al (1999), Huang et al (1999) for studies of mouse visual cortex. Despite these studies having established a link between BDNF and synaptic changes over development, few studies have examined the relationship between BDNF and brain function or structure in young children (Hashimoto et al , 2016, Marusak et al , 2015, Thomason et al , 2009). Here, we examine the association between the BDNF Val 66 Met polymorphism (dbSNP rs6265) and individual differences in brain structure in a sample of neurotypical children.…”

Amygdala responses to salient social cues vary with oxytocin receptor genotype in youth

“…Intraclass correlation coefficient (ICC) was computed using the total number of voxels in each brain mask; reliability was confirmed by ICC > 0.9. Whole-brain masks and MR image volumes were then processed using BrainSuite to produce participant-specific segmentation of brain areas and derive total GMV of regions of interest (ROIs) in left and right hemispheres (additional detail provided in Supplemental Material; see also Marusak, Kuruvadi, et al, 2015). The amygdala was selected as an a priori ROI.…”