An expanded cortical map of von Economo neurons in the human medial prefrontal cortex

Von Economo neurons (VENs) are large bipolar projection cells, confined to the anterior cingulate and frontoinsular cortices, yet their broader cortical distribution remains unresolved. Previously, we reported these neurons in the dorsomedial portion of cortical area 9 and polar-medial area 10. Here, we describe the presence, density, and morphological features of VENs across seven cytoarchitectonic areas of the human medial prefrontal cortex (mPFC) (25, 32p, 32s, 10m, 14r, 11m, and 10r). Using immunohistochemistry and quantitative morphometry in postmortem tissue, we identified VENs and established consistent distribution patterns, with VENs significantly more abundant in dysgranular (32p, 32s, 25) than granular areas (10m, 10r, 11m, 14r), showing higher densities and larger somata preferentially located on cortical crests and in the right hemisphere. On average, VENs were 55% larger than neighboring pyramidal neurons, and their density covaried with soma size, revealing a regional efficiency gradient. These findings extend the known VEN map beyond previously described regions, indicating that their organization reflects cytoarchitectonic specialization and hemispheric asymmetry. By demonstrating that VENs populate a broader mPFC network implicated in interoception, motivation, and social cognition, these results support a proposed role for VENs as integrative nodes within prefrontal limbic circuits, with potential relevance for neuropsychiatric disorders.