Linking major depression and the neural substrates of associative processing

Abstract

It has been proposed that mood correlates with the breadth of associative thinking. Here we set this hypothesis to the test in healthy and depressed individuals. Generating contextual associations engages a network of cortical regions including the parahippocampal cortex (PHC), retrosplenial complex, and medial prefrontal cortex. The link between mood, associative processing, and its underlying cortical infrastructure provides a promising avenue for elucidating the mechanisms underlying the cognitive impairments in major depressive disorder (MDD). The participants included 15 nonmedicated individuals with acute major depressive episodes and 15 healthy matched controls. In an fMRI experiment, participants viewed images of objects that were either strongly or weakly associated with a specific context (e.g., a beach chair vs. a water bottle) while rating the commonality of each object. Analyses were performed to examine the brain activation and structural differences between the groups. Consistent with our hypothesis, controls showed greater activation of the contextual associations network than did depressed participants. In addition, PHC structural volume was correlated with ruminative tendencies, and the volumes of the hippocampal subfields were significantly smaller in depressed participants. Surprisingly, depressed participants showed increased activity in the entorhinal cortex (ERC), as compared with controls. We integrated these findings within a mechanistic account linking mood and associative thinking and suggest directions for the future.

Keywords: Associations; Context; Depression; Entorhinal; Parahippocampus; Rumination.

Conflict of interest statement

EVH, RLT, and MB report no biomedical financial interests or potential conflicts of interest. For a list of lifetime disclosures for MF, please see http://mghcme.org/faculty/faculty-detail/maurizio_fava.

Figures

Figure 1

Task timeline. Subjects viewed objects presented briefly and in isolation (150ms), followed by a colorful backward mask (100ms) and then rated how common the object was (1.5s response period). In between trials subjects viewed a black fixation cross for variable durations.

Figure 2

Regions significantly associated with contextual processing in (a) Healthy Controls and (b) Depressed patients (threshold p

Figure 3

Compared to Healthy Controls (HC), Depressed Patients (MDD) display reduced parahippocampal cortex (PHC) but increased entorhinal cortex (ERC) and medial frontal gyrus (MFG) differential activity during contextual processing (p

Figure 4

PHC volume is significantly associated with ruminative tendency (RRS-RSQ score) after adjusting for Total Brain Volume and MDD status (β = 5.6 (±1.92); p=0.007). (Red = healthy controls, Black = Depressed patients)