Unveiling the Multifaceted Networks of the Left DLPFC for Precision TMS Targeting

The left dorsolateral prefrontal cortex (lDLPFC) is the standard target for transcranial magnetic stimulation (TMS) to ameliorate treatment-resistant depression (TRD), yet non-response rates remain high. TMS efficacy has been linked to the stimulation site's 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 lDLPFC's network interactions contribute to site-dependent variability in treatment response. Here, we used connectivity-based parcellation within an lDLPFC region encompassing common TMS targets and adjacent areas to delineate functional subdivisions and characterize their connectivity to large-scale networks 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 lDLPFC's heterogeneity along anterior-posterior and ventral-dorsal axes. 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 an lDLPFC likelihood map integrating granularities, highlighting anterior-central lDLPFC as the strongest TMS candidate considering the relevance of its connectivity and behavioral profiles to depression, while indicating that neighboring subregions have distinct functions. These findings underscore the lDLPFC's hierarchical and heterogeneous organization and provide a network-informed reference for developing individualized, symptom-specific TMS interventions.