Mapping the structural connections between the anterior cingulate cortex and the insula/ventrolateral prefrontal cortex

Abstract The anterior cingulate cortex (ACC) is functionally closely related with the insula and the ventral lateral prefrontal cortex (vlPFC). The ACC and insula are the main hubs of the salience network, a set of functionally related brain regions involved in detecting salient stimuli and coordinating inter-network communication, while communication between ACC and vlPFC is closely linked to inhibitory control. However, despite strong indirect evidence from nonhuman primate (NHP) tract-tracing, the structural connections between the ACC and the insula/vlPFC remain poorly understood in the human brain, in part because standard approaches fail to capture this projection. In this study, we show that diffusion-weighted magnetic resonance imaging (dMRI) can reconstruct ACC-insula/vlPFC pathways after a technical adjustment to the fiber orientation distribution functions. First, using NHP dMRI as a diagnostic tool, we pinpointed an issue of fiber orientation biases in the deep white matter that uniquely impacts the streamlines connecting the ACC and the insula/vlPFC region. We introduced a reweighting approach based on individual variability to correct for the fiber orientation density function. Finally, we demonstrated that, by applying this fix, dMRI tractography can fully recover the ACC-insula/vlPFC pathways, supporting the anatomical basis of the functional relationships among these regions.