Individualized single-session iTBS modulates functional networks and neural activation to predict cognitive gain

BACKGROUND: Intermittent theta burst stimulation (iTBS) targeting the dorsolateral prefrontal cortex (DLPFC) shows promise for enhancing cognitive performance. However, behavioral findings remain inconsistent, likely due to methodological limitations in prior research and the poorly understood role of individual variability in neural responsiveness. Only one prior study has utilized individualized targeting. The effects of iTBS on resting-state functional networks remain unexplored. METHODS: We employed fMRI during an N-back task to identify individualized left DLPFC stimulation targets, based on the 2-back > 1-back contrast. A total of 56 healthy participants were randomly assigned to receive a single session of either active or sham iTBS (28 per group). Resting-state and task-based fMRI (2-back and 3-back) were acquired before and after stimulation. RESULTS: Compared to sham, iTBS increased neural activity in the middle cingulate cortex (MCC) and calcarine cortex during the 3-back task. Moreover, iTBS increased FC between the stimulation target and insula whilst reduced FCs within the default mode network (DMN) and between the DMN and frontoparietal network (FPN). Notably, in the iTBS group, greater MCC activation and enhanced target-insula FC were associated with faster 3-back reaction time (RT), whereas greater DMN FC reductions correlated with improved 3-back accuracy. Behaviorally, individuals with slower baseline 3-back RT in the iTBS group exhibited faster post-stimulation RT - an effect absent in the sham. CONCLUSIONS: These findings suggest that individualized iTBS modulates neural activity and distributed functional networks to support cognitive improvement - particularly in individuals with lower baseline ability - and highlight its potential for personalized cognitive interventions.