Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

Abstract

Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

“…This is in line with prior studies showing a negative correlation between childhood trauma and amygdala volume (54,56,57). However, the relationship between PTSD and amygdala volume was not even nominally significant in the subsample with available childhood trauma information, so we could not evaluate childhood trauma effects on the negative association between amygdala volume and PTSD.…”

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior – a TPH2 imaging genetics approach

“…Animal models suggest that prolonged stress during sensitive developmental periods detrimentally impacts dendritic growth in limbic and prefrontal regions (Radley et al 2008;Yang et al 2015) that could partially explain lower volumes observed on the macro-anatomic level (Brunson et al 2005;Ivy AS et al 2010;Molet et al 2015). The few previous studies that examined whether polymorphisms modulate the impact of ELS on brain structure in humans observed that specific allelic variants coding brain-derived neurotrophic growth factor and oxytocinergic pathways pathway genes exhibit pronounced volumetric decreases following ELS (Dannlowski et al 2016;van Velzen et al 2016). These results in accordance with the diathesis-stress perspective, have been interpreted as genetic vulnerability factors in partially mediating aversive environmental influences.…”

“…Initial studies that combined a candidate gene approach with neuroimaging reported that specific single-nucleotide polymorphisms (SNPs) of genes associated with neuroplasticity and stress reactivity, including brain derived neurotrophic factor, glucocorticoid and oxytocin receptor sensitivity, confer greater sensitivity to the detrimental impact of ELS, e.g. pronounced reductions of limbic volumes (Dannlowski et al 2016;Tozzi et al 2016;van Velzen et al 2016). Interestingly, two initial studies reported that specific allelic combinations associated with differences in central dopamine and serotonergic functioning exhibited ELS-associated changes in hippocampal and amygdala activation that may reflect improved threat learning and implicit emotion regulation following early aversive experiences (Hermann et al 2012;van Rooij et al 2017).…”

The complex neurobiology of resilient functioning after child maltreatment

“…Increases in pro-inflammatory cytokines and glucocorticoid systems have each been associated with structural changes in brain regions crucial for emotion regulation and stress response (i.e. lower PFC and hippocampal volumes and larger amygdala volumes (Andrea Danese & McEwen, 2012;Davidson, 2002;Etkin, Egner, & Kalisch, 2011;Gunnar & Quevedo, 2007;Sonia J Lupien, McEwen, Gunnar, & Heim, 2009;Bruce S McEwen, 2005;Numakawa et al, 2014;van Velzen et al, 2016). These regions are also implicated in neuroimaging studies of CM that utilized Magnetic Resonance Imaging (MRI) to investigate CM-related brain structures.…”

“…Other studies have focused on the effects of single genetic variations on resilience after CM (e.g. (Carballedo et al, 2013;Frodl et al, 2014;Molendijk et al, 2012;van Velzen et al, 2016), 5-HTT-LPR SLC6A4 (Frodl, Reinhold, Koutsouleris, Donohoe, et al, 2010; N. D. Walsh et al, 2012), NPY (Opmeer et al, 2013)), Monoamine oxidase A (MAOA) (Caspi et al, 2002;Kim-Cohen et al, 2006;Weder et al, 2009) or the FK506 binding protein 5 (FKBP-5) (Klengel et al, 2013) (Table 1). Although these studies support the relevance of specific resilience haplotypes, they must be viewed as preliminary, because they require replication in larger samples and the field suffers from publication bias towards positive results (Duncan & Keller, 2011;Molendijk et al, 2012).…”