Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex-striatum-anterior cingulate cortex (vmPFC-Str-ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal-Insula-Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.