Rostral anterior cingulate network effective connectivity in depressed adolescents and associations with treatment response in a randomized controlled trial

The rostral anterior cingulate cortex (rACC) is consistently implicated in the neurobiology of depression. While the functional connectivity of the rACC has been previously associated with treatment response, there is a paucity of work investigating the specific directional interactions underpinning these associations. We compared the fMRI resting-state effective connectivity of 94 young people with major depressive disorder and 91 healthy controls. Following the fMRI scan, patients were randomized to receive cognitive behavioral therapy for 12 weeks, plus either fluoxetine or a placebo. Using spectral dynamic causal modelling, we examined the effective connectivity of the rACC with eight other regions implicated in depression: the left and right anterior insular cortex (AIC), amygdalae, and dorsolateral prefrontal cortex (dlPFC); and in the midline, the subgenual (sgACC) and dorsal anterior cingulate cortex (dACC). Parametric empirical Bayes was used to compare baseline differences between controls and patients and responders and non-responders to treatment. Depressed patients demonstrated greater inhibitory connectivity from the rACC to the dlPFC, AIC, dACC and left amygdala. Moreover, treatment responders illustrated greater inhibitory connectivity from the rACC to dACC, greater excitatory connectivity from the dACC to sgACC and reduced inhibitory connectivity from the sgACC to amygdalae at baseline. The inhibitory hyperconnectivity of the rACC in depressed patients aligns with hypotheses concerning the dominance of the default mode network over other intrinsic brain networks. Surprisingly, treatment responders did not demonstrate connectivity which was more similar to healthy controls, but rather distinct alterations that may have predicated their enhanced treatment response.