The four studies evaluating neuronal activation after BoNT injection and potential central pathways involved in sensory processing, through expression of marker c-Fos in models of PIH, MDD, and trigeminal neuralgy [induced by either infraorbital nerve constriction (IoNC) or N-methyl-D-aspartate receptor (NMDA)], all reported a significant decrease in both ipsilateral and contralateral of ventrolateral periaqueductal gray, medullary dorsal horn, and TNC. This evidence concerns the gene FOS and major depressive disorder.