Functional disconnectivity of the hippocampal network and neural correlates of memory impairment in treatment-resistant depression

Abstract

Background: Major depressive disorder (MDD) is a disabling neuropsychiatric condition associated with cognitive impairment. Neuroimaging studies have consistently linked memory deficits with hippocampal atrophy in MDD patients. However, there has been a paucity of research examining how the hippocampus functionally contributes to memory impairments in MDD. The present study examined whether hippocampal networks distinguish treatment-resistant depression (TRD) patients from healthy controls (HCs), and whether these networks underlie declarative memory deficits in TRD. We hypothesized that functional connectivity (FC) of the posterior hippocampus would correlate preferentially with memory in patients, whereas FC pattern of the anterior and intermediate hippocampus would correlate with emotion-mediated regions and show a significant correlation with memory.

Methods: Resting-state functional magnetic resonance imaging (fMRI) scans were acquired in 56 patients and 42 age- and sex-matched HCs. We parcellated the hippocampus into three subregions based on a sparse representation-based method recently developed by our group. FC networks of hippocampal subregions were compared between patients and HCs and correlated with clinical measures and cognitive performance.

Results: Decreased connectivity of the right intermediate hippocampus (RIH) with the limbic regions was a distinguishing feature between TRD and HCs. These functional abnormalities were present in the absence of structural volumetric differences. Furthermore, lower right amygdalar connectivity to the RIH related to a longer current depressive episode. Declarative memory deficits in TRD were significantly associated with left posterior and right intermediate hippocampal FC patterns.

Limitations: Our patient samples were treatment-resistant, the conclusions from this study cannot be generalized to all MDD patients directly. Task-based imaging studies are needed to demonstrate hippocampal engagement in the memory deficits of patients. Finally, our findings are strongly in need of replication in independent validation samples.

Conclusions: These findings demonstrate a transitional property of the intermediate hippocampal subregion between its anterior and posterior counterparts in TRD patients, and provide new insights into the neural network-level dysfunction of the hippocampus in TRD.

Keywords: Depression; Functional connectivity; Hippocampus; RAVLT; Resting state FMRI; Subregion.