Unveiling the Multifaceted Networks of the TMS-Targeted Left Prefrontal Cortex for Precision Neurostimulation

Abstract

The left dorsolateral prefrontal cortex (lDLPFC) is the standard transcranial magnetic stimulation (TMS) target for treatment-resistant depression (TRD), yet non-response rates remain high. TMS efficacy has been linked to the stimulation sites functional connectivity, particularly its anti-correlation with the subgenual cingulate cortex (SGC). While this pragmatic strategy has demonstrated clinical utility, it offers limited insight into how the lDLPFCs network interactions contribute to site-dependent variability in treatment response. Here, we used connectivity-based parcellation within a region of interest encompassing common TMS targets in the left prefrontal cortex (TMS-PFC) to delineate functionally distinct subregions and characterize their large-scale network connectivity and behavioral associations. Our results revealed a hierarchical organization: a coarse two-pole antagonism between anterior-central and superior-posterior subregions and a finer nine-cluster architecture exposing the heterogeneity along anterior-posterior and ventral-dorsal axes within TMS-PFC. Anterior-central areas were strongly anti-correlated with SGC and default-mode network, positively connected with salience, dorsal attention, and control networks, and associated with cognitive control. In contrast, superior-posterior subregions displayed the inverse pattern, while ventral clusters engaged somatomotor and visual networks, and language-related processes. Central and superior-anterior clusters showed differentiated profiles, including associations with inhibition, social cognition, and perceptual functions. To aid clinical translation, we derived a likelihood map integrating granularities, highlighting the anterior-central subregion as the strongest TMS candidate given its connectivity and behavioral relevance in depression, while indicating that neighboring subregions have distinct functions. These findings underscore the hierarchical and heterogeneous organization of TMS-PFC and provide a network-informed reference for developing individualized, symptom-specific TMS interventions. HighlightsO_LITMS targets within the left PFC encompass nine functionally distinct subregions C_LIO_LISubregions differ in SGC, DMN, salience, attention, and control network connectivity C_LIO_LIAnterior-central and superior-posterior subregions show antagonistic profiles C_LIO_LIA likelihood map identifies the anterior-central subregion as optimal TMS target C_LIO_LIFindings provide a network-informed reference for symptom-specific TMS targeting C_LI