Neural signatures of major depression across the episodic memory circuitry.

In major depressive disorder (MDD), episodic memory is compromised and linked to hippocampal dysfunction, yet the underlying neural circuitry remains poorly understood. We examined the circuits supporting episodic memory and assessed its MDD-associated anatomical connectivity fingerprints. Anatomical connectivity was assessed using magnetic resonance imaging (MRI) relaxometry-derived indices of regional volume and myelin content from 1339 community-dwelling adults (mean age 61 ± 9 y; 671 females). To obtain an unbiased definition of episodic memory circuits, we estimated whole-brain anatomical covariance patterns originating from hippocampal regions that, in an independent sample, showed differential MDD-related neural activity patterns during a functional MRI episodic memory task. The morphometry-based episodic memory circuit encompassing frontal, parietal and temporal cortex, amygdala, pallidum, and thalamus (all |r| > 0.106, P < .05), showed similar covariance patterns for the anterior and posterior hippocampal regions. Conversely, myelin content-defined circuits showed inverse covariance patterns between cortical and subcortical structures, yet convergent for the two hippocampal regions. Connectivity with the orbital gyri, pallidum, insula, and, in particular, the thalamic nuclei was discriminative (all |Z| > 1.96, all P < .05, two-tailed) for individuals with a lifetime MDD diagnosis (n = 700, mean age 59 ± 9 y; 432 females) compared to those without (n = 639, mean age 63 ± 10 y; 239 females). Our findings provide evidence of altered brain circuits underlying depression-related dysfunctional episodic memory. Altered connectivity in these circuits suggests roles for multiple pathways in the maintenance and aetiology of depression and represents a potential target for therapeutic interventions.