Mapping the "missing" pathways of the anterior cingulate cortex in the human brain

The anterior cingulate cortex (ACC) is functionally closely related with the insula and the ventral lateral prefrontal cortex (vlPFC). Extensive work on their functional relationships has led to the salience network theory and advanced understanding of value-based learning and decision making. However, the anatomical connections between the ACC and the two regions remain unknown in the human brain. Despite the anatomical ground truth established by nonhuman primate (NHP) tract-tracing, diffusion magnetic resonance imaging (dMRI) has not seen success identifying homologous pathways in humans. In this study we show that the negative finding does not reflect a cross-species discrepancy but rather a technical issue. We used NHP dMRI as a bridge to compare the ground-truth pathways in NHPs and dMRI-derived pathways in humans. The insight from NHP data helped pinpoint a bias in fiber orientation distribution functions (fODFs) caused by the disproportion of anterior-posterior vs. medial-lateral fibers in the human brain. Guided by this information, we successfully recovered the ACC-insula and ACC-vlPFC pathways that followed the same trajectories as in the NHP dMRI and tract-tracing data. Our findings provide an anatomical basis for the functional interactions among the ACC, the insula and the vlPFC.