Late-life depression, mild cognitive impairment and hippocampal functional network architecture

Abstract

Late-life depression (LLD) and amnestic mild cognitive impairment (aMCI) are associated with medial temporal lobe structural abnormalities. However, the hippocampal functional connectivity (HFC) similarities and differences related to these syndromes when they occur alone or coexist are unclear. Resting-state functional connectivity MRI (R-fMRI) technique was used to measure left and right HFC in 72 elderly participants (LLD [n = 18], aMCI [n = 17], LLD with comorbid aMCI [n = 12], and healthy controls [n = 25]). The main and interactive relationships of LLD and aMCI on the HFC networks were determined, after controlling for age, gender, education and gray matter volumes. The effects of depressive symptoms and episodic memory deficits on the hippocampal functional connections also were assessed. While increased and decreased left and right HFC with several cortical and subcortical structures involved in mood regulation were related to LLD, aMCI was associated with globally diminished connectivity. Significant LLD-aMCI interactions on the right HFC networks were seen in the brain regions critical for emotion processing and higher-order cognitive functions. In the interactive brain regions, LLD and aMCI were associated with diminished hippocampal functional connections, whereas the comorbid group demonstrated enhanced connectivity. Main and interactive effects of depressive symptoms and episodic memory performance were also associated with bilateral HFC network abnormalities. In conclusion, these findings indicate that discrete hippocampal functional network abnormalities are associated with LLD and aMCI when they occur alone. However, when these conditions coexist, more pronounced vulnerabilities of the hippocampal networks occur, which may be a marker of disease severity and impending cognitive decline. By utilizing R-fMRI technique, this study provides novel insights into the neural mechanisms underlying LLD and aMCI in the functional network level.

Keywords: Depression; Depressive symptoms; Elderly; Episodic memory; Functional connectivity; Hippocampus; MRI; Mild cognitive impairment.

Fig. S1

Whole-brain voxelwise pattern of the left hippocampal functional connectivity (LHFC) networks in the four group subjects (p < 0.01, AlphaSim correction). Bright color indicates positive connectivity and blue color indicates negative or anticorrelated connectivity. Color bar is presented with z scores. Abbreviation: CN, control; Dep, depression; aMCI, amnestic mild cognitive impairment; dMCI, depressed mild cognitive impairment.

Fig. S2

Whole-brain voxelwise pattern of the right hippocampal functional connectivity (RHFC) networks in the four subject groups (p < 0.01, AlphaSim correction). Bright color indicates positive connectivity and blue color indicates negative or anticorrelated connectivity. Color bar is presented with z scores. Abbreviation: CN, cognitively normal; Dep, depression; aMCI, amnestic mild cognitive impairment; dMCI, depressed mild cognitive impairment.

Fig. 1

Main effects of depression and mild cognitive impairment on the left hippocampal functional connectivity (LHFC) networks across all subjects (p < 0.05, AlphaSim correction). Left: Brain regions with significant main effects of depression and cognitive impairment on the LHFC network. Bright color indicates increased connectivity and blue color indicates decreased connectivity. Color bar is presented with z scores. Right: Numerical representation of significant main effects of depression and mild cognitive impairment on the LHFC network (m is z value from the cross-correlation coefficient after Fisher's z transformed, same below). Abbreviations: Non-Dep: no depression; Dep: depression; Non-CI: no amnestic mild cognitive impairment; CI: amnestic mild cognitive impairment. R1: left posterior cingulate cortex/precuneus (LPCC/Pcu); R2: right posterior cingulate cortex/precuneus (RPCC/Pcu); R3: right dorsomedial prefrontal cortex (RDMPFC); R4: right dorsolateral prefrontal cortex (RDLPFC); R5: left dorsolateral prefrontal cortex (LDLPFC); R6: left postcentral gyrus; R7: left inferior parietal cortex (LIPC); R8: left posterior middle temporal gyrus (LpMTG); R9: left dorsomedial prefrontal cortex (LDMPFC); R10: left retrosplenial cortex (LRSC); R11: right inferior parietal cortex (RIPC); R12: right superior parietal cortex (RSPC); R13: right dorsolateral prefrontal cortex (RDLPFC); R14: right dorsomedial prefrontal cortex (RDMPFC); R15: right dorsal cingulate cortex (RdACC); R16: right retrosplenial cortex (RRSC). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Main effects of depression and mild cognitive impairment on the right hippocampal functional connectivity (RHFC) networks across all subjects (p < 0.05, AlphaSim correction). Left: Brain regions with significant main effects of depression and mild cognitive impairment on the RHFC network. Bright color indicates increased connectivity and blue color indicates decreased connectivity. Color bar is presented with z scores. Right: Numerical representation of significant main effects of depression and mild cognitive impairment on the RHFC network. Abbreviations: Non-Dep: no depression; Dep: depression; Non-CI: no amnestic mild cognitive impairment; CI: amnestic mild cognitive impairment. R1: left dorsolateral prefrontal cortex (LDLPFC); R2: left middle occipital gyrus (LMOG); R3: left hippocampus; R4: left thalamus; R5: left putamen; R6: left caudate; R7: right lentiform nucleus; R8: right thalamus; R9: right middle occipital gyrus (RMOG); R10: left ventrolateral prefrontal cortex (LvlPFC); R11: left anterior temporal pole (LaTP); R12: left inferior parietal cortex (LIPC); R13: left posterior middle temporal gyrus (LpMTG); R14: right supramarginal gyrus/inferior parietal cortex; R15: right anterior temporal pole (RaTP); R16: left parahippocampal gyrus (LPHG); R17: right inferior temporal cortex (RITG). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Interactive effects of late-life depression and amnestic mild cognitive impairment on the right hippocampal functional connectivity (RHFC) networks (p < 0.05, AlphaSim correction). Top: Brain regions with significant interactive effects between late-life depression and mild cognitive impairment on the RHFC network. Bottom: Numerical representation of significant interactive effects of depression and cognitive impairment on the RHFC network. *: p < 0.05; **: p < 0.01. Abbreviations: LMOG, left middle temporal gyrus; LdACC, left dorsal cingulate cortex; vmPFC, ventromedial prefrontal cortex; RdACC, right dorsal cingulate cortex; RMOG, right middle temporal gyrus; RDLPFC, right dorsolateral prefrontal cortex; RvmPFC, right vmPFC; LvmPFC, left vmPFC; CN, cognitively normal; aMCI, amnestic mild cognitive impairment; Dep, Late-life depression; dMCI, comorbid late-life depression and amnestic mild cognitive impairment.

Fig. 4

Behavioral significance of the bilateral hippocampal functional connectivity networks across all subjects (p < 0.05, AlphaSim correction). Top row: Main effects of the depressive symptoms on the bilateral HFC networks; Middle row: Main effects of the episodic memory scores (LMIIDR scores) on the bilateral HFC networks. Bright color indicates positive correlation and blue color indicates negative correlation; Bottom row: Interaction of depressive symptoms and memory function on the bilateral HFC networks. Bright color indicates that the interactive effects are positively correlated with bilateral HFC; blue color demonstrates that the interactive effects are negatively correlated with bilateral HFC. Color bar is presented with z scores. Abbreviations: GDS, geriatric depression scale; LHFC, left hippocampal functional connectivity; RHFC, right hippocampal functional connectivity; LDLPFC, left dorsolateral prefrontal cortex; RDLPFC, right dorsolateral prefrontal cortex; LDMPFC, left dorsomedial prefrontal cortex; RDMPFC, right dorsomedial prefrontal cortex; LITC, left inferior temporal cortex; RITC, right inferior temporal cortex; LHip/PHG, left hippocampus/parahippocampal gyrus; RHip/PHG, right hippocampus/parahippocampal gyrus; LIPC, left inferior parietal cortex; RIPC, right inferior parietal cortex; LaI/fO, left anterior insula/frontal operculum; RaI/fO, right anterior insula/frontal operculum; LIFG, left inferior frontal gyrus; LTha, left thalamus; L Pcu/PCG, precuneus/postcentral gyrus; Pcu/PCG, precuneus/postcentral gyrus; vmPFC, ventromedial prefrontal cortex; Amy/PHG, amygdala/parahippocampal gyrus; RpMTG, right posterior middle temporal gyrus. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)