Targeting VMPFC‐amygdala circuit with TMS in substance use disorder: A mechanistic framework

The ventromedial prefrontal cortex (VMPFC), located along the medial aspect of the frontal area, plays a critical role in regulating arousal/emotions. Its intricate connections with subcortical structures, including the striatum and amygdala, highlight the VMPFC's importance in the neurocircuitry of addiction. Due to these features, the VMPFC is considered a promising target for transcranial magnetic stimulation (TMS) in substance use disorders (SUD). By the end of 2023, all 21 studies targeting VMPFC for SUD used anatomical landmarks (e.g., Fp1/Fp2 in the EEG system) to define coil location with a fixed orientation. Nevertheless, one-size-fits-all TMS over VMPFC has yielded variable outcomes. Here, we suggested a pipeline based on a tailored TMS targeting framework aimed at optimally modulating the VMPFC-amygdala circuit on an individual basis. We collected MRI data from 60 participants with methamphetamine use disorders (MUDs). We examined the variability in TMS target location based on task-based functional connectivity between VMPFC and amygdala using psychophysiological interaction (PPI) analysis. Electric fields (EF) were calculated for fixed vs. optimized location (Fp1/Fp2 vs. individualized maximal PPI), orientation (AF7/AF8 vs. optimized algorithm) and intensity (constant vs. adjusted) to maximize target engagement. In our pipeline, the left medial amygdala, identified as the brain region with the highest (0.31 ± 0.29) fMRI drug cue reactivity, was selected as the subcortical seed region. The voxel with the most positive amygdala-VMPFC PPI connectivity in each participant was considered the individualized TMS target (MNI-coordinates: [12.6, 64.23, -0.8] ± [13.64, 3.50, 11.01]). This individualized VMPFC-amygdala connectivity significantly correlated with VAS craving after cue exposure (R = 0.27, p = 0.03). Coil orientation was optimized to increase EF strength over the targeted circuit (0.99 ± 0.21 V/m vs. the fixed approach: Fp1: 0.56 ± 0.22 and Fp2: 0.78 ± 0.25 V/m) and TMS intensity was harmonized across the population. This study highlights the potential of an individualized VMPFC targeting framework to enhance treatment outcomes for addiction, specifically modulating the personalized VMPFC-amygdala circuit.