Causal connectivity maps derived from single-pulse interleaved TMS/fMRI

Understanding causal interactions between cortical and subcortical brain regions is critical for mapping human functional connectivity. While non-invasive methods such as fMRI and diffusion imaging have provided valuable insights into brain connectivity, these approaches remain correlational and cannot establish causal circuit mechanisms. Here, we aimed to generate reliable causal connectivity maps using interleaved single-pulse transcranial magnetic stimulation with functional MRI (spTMS/fMRI). In over 80 participants, personalized connectivity-guided targets in the left hemisphere were selected to engage either the subgenual anterior cingulate cortex (sgACC) or basolateral amygdala (BLA). Voxelwise event-related BOLD maps quantified TMS-evoked responses, and group-level analyses controlled for head motion, pain, and somatosensory effects to isolate stimulation-specific activation. Stimulation of frontal regions targeting the sgACC induced responses in the sgACC and modulated distributed cortical and subcortical areas. Ventrolateral targets elicited negative BOLD responses in the amygdala and engaged widespread downstream regions. ROI-based analyses revealed no significant differences in evoked responses between sgACC- and BLA-targeted stimulations across participants. These results validate that image-guided TMS can causally engage distributed brain circuits, providing a robust framework for functional connectivity mapping. The publicly available causal connectivity maps offer a resource for future studies linking cortical stimulation sites with subcortical network responses.Clinical Trial Registration This study was registered on ClinicalTrials.gov under the identifier NCT04014959, and was open to enrollment from January 15, 2017 to October 1, 2020.