Hippocampal subregions and networks linked with antidepressant response to electroconvulsive therapy - PubMed (original) (raw)
Hippocampal subregions and networks linked with antidepressant response to electroconvulsive therapy
Amber M Leaver et al. Mol Psychiatry. 2021 Aug.
Abstract
Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome.
© 2020. The Author(s), under exclusive licence to Springer Nature Limited.
Conflict of interest statement
CONFLICT OF INTEREST
All authors declare no conflicts of interest.
Figures
Figure 1.
Regional CBF increases in responders and nonresponders to ECT within the hippocampus and surrounding tissue. A. Resting brain function measured with CBF increased over time (pre-treatment vs. post-index) in right middle and left posterior hippocampus in patients who responded to ECT (top left), while CBF increased in bilateral anterior hippocampus after ECT in responders (bottom left). Regions of increased CBF in all patients (top right) and interaction between time and response (bottom right) are also displayed.B. Mean regional CBF (corrected for global CBF) is plotted for the significant results shown in A for clusters of CBF change in responders and nonresponders. In each plot, data for responders is shown in black lines, nonresponders are plotted in dashed gray lines, and data from non-depressed control volunteers is plotted in open squares.
Figure 2.
Regional GMV increases after ECT in responders and nonresponders.A. GMV increased in right anterior hippocampus and amygdala in responders (top left) and throughout bilateral hippocampus in nonresponders after ECT (bottom left). Regions of increased GMV when analyzing all patients (upper right) and interactions between time and response (bottom right) area also displayed. B. Mean regional GMV is plotted for the significant results shown in A for clusters of GMV change identified in responders and for nonresponders. In each plot, data for responders is shown in black lines, nonresponders are plotted in dashed gray lines, and data from non-depressed control volunteers is plotted in open squares.
Figure 3.
Leave-one-out (LOO) subsampling validates the location of CBF and GMV increases in responders (R) and nonresponders (NR) to ECT. A. A schematic illustrates the validation method applied. For each group, data from one volunteer was removed from the dataset, and a linear mixed effects model (LMM) was applied to the remaining subsample to identify maps of significant change (Δ) in CBF and (separately) ΔGMV after ECT, voxelwise p < 0.05. This process was applied iteratively across all possible subsamples, and maps of 100% overlap across all subsamples were generated. Clusters k > 25 of voxels exhibiting 100% subsample overlap were considered significant, and retained for follow-up analysis with BOLD-fMRI data (for CBF clusters). B. Overlap maps are displayed for CBF (left panels) and GMV (right panels), separately validated in responders (top panels) and nonresponders (bottom panels). Voxel color denotes overlap across subsamples at p < 0.05 for responders in green and nonresponders in red; regions of 100% overlap k > 25 are shown in pink for responders and cyan for nonresponders. Note the locations of 100% overlap match clusters shown in Figures 1 & 2. C&D. The choice of voxelwise threshold p < 0.05 was exploratory and arguably arbitrary; therefore, mean voxel counts (C) and max cluster size (D) for across LOO subsamples are displayed for several voxelwise thresholds (x-axes). Asterisks mark values significantly higher than those obtained from control data (FDR-corrected p < 0.05; Supplemental Results).
Figure 4.
Seed-based functional connectivity analyses of BOLD-fMRI data from non-depressed control volunteers established spatially separable functional networks associated with each hippocampal region exhibiting regional CBF change validated with LOO subsampling (Figure 3).A. The hippocampal functional network (HCN) associated with regions of CBF change identified in nonresponders (NR) is shown in red (HCN-NR1), the network associated with increased CBF in right mid hippocampus in responders (R) is shown in green (HCN-R1), and in left posterior hippocampus in blue (HCN-R2). The location of the pair of seed regions used to define each network is displayed in white. B. Graph theory analyses assessed changes in network strength and hippocampal centrality over treatment course. Plots of network strength over time are displayed, with data from responders plotted in a solid black line, and data from nonresponders plotted in a dashed gray line. Corresponding hippocampal centrality data can be found in Supplementary Figure 1.
Figure 5.
Post-treatment changes (delta) in MRI metrics were modestly correlated with changes in memory scores in some hippocampal subregions and networks. Scatter plots display relationships between recall scores and hippocampal metrics p < 0.10 for this exploratory analysis.
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