Neuroanatomical pathways of TMS therapy for depression

TMS therapy for depression delivered to the dorsolateral prefrontal cortex (DLPFC) aims to modulate activity in the subgenual cingulate cortex (SGC). However, these regions lack direct axonal connections, and the neuroanatomical mechanisms underlying the therapy's efficacy remain unknown. Here, we use connectome modelling to map polysynaptic fibre pathways from the DLPFC to the SGC that are associated with TMS treatment response in depression. We show that polysynaptic communication through the structural connectome is correlated with treatment response in two independent cohorts of patients treated with TMS to the left DLPFC (r = -0.56, p = 0.0018; r = -0.52, p = 0.0047), and that DLPFC sites of stronger negative functional connectivity to the SGC are connected to it via shorter fibre pathways. Our results shed light onto the neuroanatomical basis of TMS therapy for depression and pave the way for brain stimulation protocols based on polysynaptic communication via the connectome.