Imaging studies of major depressive disorder (MDD) have demonstrated enhanced resting-state activity of the amygdala as well as exaggerated reactivity to negative emotional stimuli relative to healthy controls (HCs). However, the abnormalities in the intrinsic connectivity of the amygdala in MDD still remain unclear. As the resting-state activity and functional connectivity (RSFC) reflect fundamental brain processes, we compared the RSFC of the amygdala between unmedicated MDD patients and HCs. Seventy-four subjects, 55 adults meeting the DSM-IV criteria for MDD and 19 HCs, underwent a resting-state 3-T functional magnetic resonance imaging scan. An amygdala seed-based low frequency RSFC map for the whole brain was generated for each group. Compared with HCs, MDD patients showed a wide-spread reduction in the intrinsic connectivity of the amygdala with a variety of brain regions involved in emotional processing and regulation, including the ventrolateral prefrontal cortex, insula, caudate, middle and superior temporal regions, occipital cortex, and cerebellum, as well as increased connectivity with the bilateral temporal poles (p < 0.05 corrected). The increase in the intrinsic connectivity of amygdala with the temporal poles was inversely correlated with symptom severity and anxiety scores. Although the directionality of connections between regions cannot be inferred from temporal correlations, the reduced intrinsic connectivity of the amygdala predominantly with regions involved in emotional processing may reflect impaired bottom-up signaling for top-down cortical modulation of limbic regions leading to abnormal affect regulation in MDD.

BackgroundEarly-onset major depressive disorder (EO-MDD), beginning during childhood and adolescence, is associated with more illness burden and a worse prognosis than adult-onset MDD (AO-MDD), but little is known about the neural features distinguishing these subgroup phenotypes. Functional abnormalities of the amygdala are central to major depressive disorder (MDD) neurobiology; therefore, we examined whether amygdala intrinsic connectivity (IC) can differentiate EO-MDD from AO-MDD in a cohort of adult MDD patients.Subjects and methodsTwenty-one EO-MDD (age of onset ≤18 years), 31 AO-MDD patients (age of onset ≥19 years), and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (7 minutes). Amygdala seed-based resting-state functional connectivity was compared between groups.ResultsAO-MDD patients showed loss of inverse left amygdala–left dorsolateral prefrontal cortex IC and increased inverse left amygdala–left inferior parietal IC, compared to both HCs and EO-MDD. EO-MDD showed a switch from inverse to positive IC with right dorsomedial prefrontal cortex, compared to HCs and AO-MDD. This effect was removed when we controlled for illness burden.ConclusionAlterations in amygdala IC with the default-mode network were specifically related to EO-MDD, whereas amygdala IC with executive cognitive control regions was preferentially disrupted in AO-MDD. Increased illness burden, an important clinical marker of EO-MDD, accounted for its specific effects on amygdala IC. Brain imaging has the potential for validation of clinical subtypes and can provide markers of prognostic value in MDD patients.

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