Extended‐amygdala intrinsic functional connectivity networks: A population study

Abstract

Pre‐clinical and human neuroimaging research implicates the extended‐amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance‐use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task‐free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter‐individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST‐CeA intrinsic functional connectivity (iFC) was heritable and further examined co‐heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST—CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co‐heritability associations with our principal components either across the ICNs or for specific BST‐Amygdala iFC. Possible differences in phenotype associations across task‐free, task‐based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well‐established ExtA ICNs.

Subiculum–BNST structural connectivity in humans and macaques

“…Whilst not specific to the BNST, white matter abnormalities of the fornix in adults with heavy drinking and alcohol use disorder have been reported ( Cardenas et al., 2013 ), although the diffusion MRI literature in general with regards to correlates of substance abuse is somewhat inconsistent ( Benear et al., 2020 ). Similar to our dispositional negativity component, a reason we did not find such an association could be that our sample consisted of a screened, relatively healthy population (median drinks consumed per week being two), which likely reduced our chances of finding any association ( Berry et al., 2020 ). Studies that have found associations between alcohol use and white matter metrics have generally been conducted either with clinical populations, or following experimental manipulations ( Campbell et al., 2019 ; Cardenas et al., 2013 ; Flook et al., 2021 ).…”

“…The BNST mask was downloaded from the NeuroVault website ( https://neurovault.org/collections/3245 ), originally uploaded by Theiss et al ( Mai et al., 2015 ; Theiss et al., 2017 ; Tillman et al., 2018 ). This mask was thresholded to a minimum probability of 25%, in accordance with previous studies ( Berry et al., 2020 ; Theiss et al., 2017 ). The thalamic nuclei mask centred on the anteroventral ROI taken from the Automated Anatomical Labelling Atlas 3 ( Rolls et al., 2020 ).…”

“…To assess the association between measures of white matter microstructure and stress-related traits and behaviours, we utilised the HCP self-report questionnaire data relating to these constructs ( Weintraub et al., 2013 ). In previously published work we used principal component analysis (PCA) to reduce nine questionnaire items relating to anxiety, depression, perceived stress, fear, and substance use to two principal components, one representing ‘Dispositional negativity’ and one ‘Alcohol use’ (see Berry et al., 2020 for details). These two principal components were thus used as our phenotypes of interest.…”

“…Next, we repeated the dMRI tractography analysis in a large human sample, the Young Adults Human Connectome Project (HCP) (n = 1206). As well as containing high quality neuroimaging data ( Sotiropoulos et al., 2013 ; Van Essen et al., 2012 ), this sample has been richly phenotyped; allowing for the examination of relationships between dMRI white matter microstructure and stress-related traits (reflecting dispositional negativity and alcohol use, derived in a previous study ( Berry et al., 2020 )). Finally, we used the family structure of the HCP ( Van Essen et al., 2012 ) to assess the heritability, and co-heritability, of our dMRI microstructure measures and derived stress-related traits.…”

Subiculum – BNST Structural Connectivity in Humans and Macaques

“…Next, we repeated the dMRI tractography analysis in a large human sample, the Young Adults Human Connectome Project (HCP) (n = 1206). As well as containing high quality neuroimaging data (Sotiropoulos et al, 2013;Van Essen et al, 2012), this sample has been richly phenotyped; allowing for the examination of relationships between dMRI white matter microstructure and stress-related traits (reflecting dispositional negativity and alcohol use, derived in a previous study (Berry et al, 2020). Finally, we used the family structure of the HCP to assess the heritability, and co-heritability, of our dMRI microstructure measures and derived stress-related traits.…”