Intrinsic inter-network brain dysfunction correlates with symptom dimensions in late-life depression

Abstract

Prior studies have demonstrated dysfunctions within the core neurocognitive networks (the executive control [ECN], default mode [DMN] and salience [SN] networks) in late-life depression (LLD). Whether inter-network dysfunctional connectivity is present in LLD, and if such disruptions are associated with core symptom dimensions is unknown. A cross-sectional resting-state functional connectivity magnetic resonance imaging investigation was conducted of LLD (n = 39) and age- and gender-equated healthy comparison (HC) (n = 29) participants. Dual regression independent component analysis approach was used to identify components that represented the ECN, DMN and SN. The intrinsic inter-network connectivity was compared between LLD and HC participants and the relationship of inter-network connectivity abnormalities with dimensional measures was examined. Relative to HC participants, LLD subjects showed decreased inter-network connectivity between the bilateral ECN and default mode subcortical (thalamus, basal ganglia and ventral striatum) networks, and the left ECN and SN insula component; and increased inter-network connections between the left ECN and posterior DMN and salience (dorsal anterior cingulate) network components. Distinct inter-network connectivity abnormalities correlated with depression and anxiety severity, and executive dysfunction in LLD participants. LLD subjects also showed pronounced intra-network connectivity differences within the ECN, whereas fewer but significant DMN and SN disruptions were also detected. Investigating the intrinsic inter-network functional connectivity could provide a mechanistic framework to better understand the neural basis that underlies core symptom dimensions in LLD. Inter-network connectivity measures have the potential to be neuroimaging biomarkers of symptom dimensions comprising LLD, and may assist in developing symptom-specific treatment algorithms.

Keywords: Brain networks; ICA; Inter-network; Late-life depression; Resting-state functional connectivity; Symptom dimensions.

Figure 1. Disrupted inter-network intrinsic connectivity in late-life depression

The inter-network INC was calculated as the partial-correlation among the unique time courses of the seven independent components, which were selected to indicate the three intrinsic functional connectivity networks (i.e. ECN, blue color; DMN, orange color; and SN, green color). The thick black lines between each pair of components represent functional connectivity differences between the HC and LLD groups. The box plots show the details of the between-group comparisons (two-sample t-test, FDR-corrected q < 0.05). The vertical axes represent the functional connectivity. The black and red boxes represent the HC and LLD groups, respectively. Abbreviations: ECN, executive control network; DMN, default mode network; SN, salience network; FDR, false discovery rate; HC, healthy comparison; LLD, late-life depression.

Figure 2. Relationships between the multi-domain symptom measurements and abnormal INC

Distinct inter-network functional connectivity abnormalities in the LLD group predicted symptom dimension scores (i.e., GDS, HAM-A, LMII-DR, and MDRS-2 Init/Pers). The linear regression models were adjusted for age, gender, education, and whole-brain GMR. Each scatter plot shows predicted symptom dimension score based on internetwork functional connectivity value (x-axis) plotted against observed symptom dimension score (y-axis). Each red dot represents individual LLD participant. Abbreviations: INC, intrinsic network connectivity; LLD, late-life depression; GDS, geriatric depression scale; HAM-A, Hamilton anxiety scale; LMII-DR, education-adjusted Logical Memory II Delayed Paragraph Recall subscale from the Wechsler Memory Scale-Revised; MDRS-2 Init/Pers, Mattis Dementia Rating Scale – 2 Initiation/Perseveration subscale; dACC, dorsal anterior cingulate.

Figure 3. Voxelwise intra-network functional connectivity differences between HC and LLD groups in the ECN

Voxelwise two-sample t-test (top, magenta colored regions) shows the spatial extent of the intra-network abnormalities in the ECN (p < 0.0167 and 3dClustSim corrected cluster size > 664 mm³). The box plots (bottom) indicate the quantitative data distribution of the individual groups (HC: black color and LLD: red color). In the box plots, the bands, from the top, represent the 75%, median, and 25%, respectively. The square in each box indicates the mean and whiskers shows the first standard deviation of the data. Abbreviations: HC, healthy comparison; LLD, late-life depression; L/R, left/right; sACC, subgenual anterior cingulate cortex; MCC, middle cingulate cortex; PCC, posterior cingulate cortex; PHG, parahippocampal gyrus; Amy, amygdala; Hipp, hippocampus; IPL, inferior parietal lobe.

Figure 4. Voxelwise intra-network functional connectivity differences between HC and LLD groups in the DMN and SN

Voxelwise two-sample t-tests (top, magenta colored regions) show the spatial extent of the intra-network abnormalities in the (A) DMN and (B) SN (p < 0.0167 and 3dClustSim corrected cluster size > 664 mm³). The box plots (bottom) indicate the quantitative data distribution of the individual groups (HC: black color and LLD: red color). In the box plots, the bands, from the top, represent the 75%, median, and 25%, respectively. The square in each box indicates the mean and whiskers shows the first standard deviation of the data. Abbreviations: HC, healthy comparison; LLD, late-life depression; L/R, left/right; SPL, superior parietal lobe; PHG, parahippocampal gyrus; SFG, superior frontal gyrus; DLPFC, dorsolateral prefrontal cortex.