Functional Inputs to the Subgenual Cingulate Cortex Distinguish Neurotypical Individuals with Severe and Mild Depressive Problems: Granger Causality and Clustering Analyses

Abstract

Extant research has implicated functional connectivity of the subgenual anterior cingulate cortex (sgACC) in major depressive disorders or depressive traits in neurotypical populations. However, prior studies have not distinguished the inputs and outputs of the sgACC, and the "diagnostic" accuracy of these connectivity metrics remains elusive. Here, we analyzed data of 890 subjects (459 women, age 22 to 35) from the Human Connectome Project using Granger causality analyses (GCA) with the sgACC as the seed and 268 regions of interest from the Shens atlas as targets. Individual connectivities were assessed with an F test and group results were evaluated with a binomial test, both at a corrected threshold. We identified brain regions with significant input to and output from the sgACC. Clustering analyses of Granger causality input, but not Granger causality output or resting state connectivity features revealed distinct subject clusters, effectively distinguishing individuals with severe and mild depressive symptoms and those with comorbidities. Specifically, weaker projections from the fronto-parietal and orbitofrontal cortices, anterior insula, temporal cortices, and cerebellum to the sgACC characterized five clusters with low to high scores of depression as well as comorbid internalizing and externalizing problems. Machine learning using a logistic classifier with the significant "GCA-in" features and 5-fold cross-validation achieved 87% accuracy in distinguishing subject clusters, including those with high vs. low depression. These new findings specify the functional inputs and outputs of the sgACC and highlight an outsized role of sgACC inputs in distinguishing individuals with depressive and comorbid problems. Significance StatementDepression affects millions worldwide. Understanding the neural mechanisms would facilitate treatment of depression. In this study, we investigated how different parts of the brain send signals to and/or receive signals from a key brain region - subgenual cingulate cortex - implicated in the pathophysiology of depression. Using brain scans from nearly 900 adults, we found that weaker signals coming into this area, especially from regions involved in thinking and emotion, were linked to higher levels of depression and other behavioral problems such as anxiety and aggression. These findings help us better understand how regional communications in the brain relate to emotional well-being and may support new ways to identify and treat people with a depressive disorder.