Frontopolar Engagement During DLPFC-Targeted rTMS and Craving Outcomes in Cocaine Use Disorder: An Individualized Electric-Field Modeling Study
DOI: Pending DOI
Synopsis
Repetitive transcranial magnetic stimulation (rTMS) for substance use disorder commonly targets the dorsolateral prefrontal cortex (DLPFC), but unintended frontopolar engagement may contribute to variable outcomes. We used individualized MRI-based electric-field modeling in a secondary analysis of a randomized sham-controlled 5-Hz left DLPFC rTMS trial. Among 25 participants, the left middle frontal gyrus/DLPFC proxy received broader stimulation, but frontal pole electric-field features showed more consistent associations with craving change. Greater broad frontopolar electric-field engagement was associated with smaller craving reductions. These findings suggest that frontopolar spillover may be clinically relevant and that more precise targeting or inhibitory frontopolar protocols warrant prospective study.
Background
Substance use disorders remain difficult to treat, and repetitive transcranial magnetic stimulation has been investigated as a circuit-based intervention for modulating craving, reward processing, and cognitive control. Most addiction rTMS studies have targeted the dorsolateral prefrontal cortex (DLPFC), particularly the left DLPFC. However, converging evidence from lesion-network mapping1, cue-reactivity neuroimaging2, and prior neuromodulation studies3 suggests that the frontopolar and medial prefrontal cortices may also be addiction-relevant nodes.
This raises an important targeting question: in DLPFC-targeted rTMS, clinically meaningful stimulation may not be limited to the nominal target. Electric-field modeling studies4 show that scalp-based or anatomical targeting can produce heterogeneous, spatially distributed cortical fields, and that the region receiving maximal or clinically relevant stimulation may differ across individuals because of variation in head anatomy, coil-to-cortex distance, and gyral geometry. Subject-specific electric-field modeling therefore provides a way to quantify actual regional target engagement and link stimulation exposure to clinical outcomes.
Using a randomized sham-controlled rTMS trial for cocaine use disorder, this study examined whether individualized frontopolar electric-field engagement during nominal left DLPFC stimulation helps explain variability in craving outcomes, compared with engagement of the left middle frontal gyrus as a DLPFC proxy.
Methods
We conducted a secondary analysis of the acute randomized phase of the SUDMEX-TMS trial5, a sham-controlled study of 5-Hz left dorsolateral prefrontal cortex rTMS for cocaine use disorder. The present analysis included participants with an identifiable baseline MRI fiducial marker for coil localization and available baseline and post-treatment craving data.
Subject-specific head models were generated from baseline T1-weighted structural MRI scans using SimNIBS version 4.5.06–8. The stimulation site was defined from the MRI-visible vitamin capsule fiducial marking the original scalp target. Electric fields were simulated using the trial stimulation parameters and a figure-of-eight coil model, with coil placement and orientation visually quality-controlled. Localization fidelity was assessed by calculating the Euclidean distance between the scanner-derived fiducial coordinate and the SimNIBS-projected scalp point.
Regions of interest were defined in standard space using Harvard-Oxford atlas labels and transformed to each participant’s native space. Primary regions were the frontal pole and left middle frontal gyrus, used as an anatomical proxy for the DLPFC. A medial frontal pole mask was examined as a sensitivity analysis. Within each region, electric-field strength and spatial extent were summarized using mean, median, 95th percentile, E100, and the percentage of voxels above 50, 75, and 100 V/m.
Craving outcomes included the Cocaine Craving Questionnaire-General, Cocaine Craving Questionnaire-Now, and visual analog craving ratings. Change scores were calculated as post-treatment minus baseline values. Associations between regional electric-field features and craving change were tested using active arm-only linear models and full-sample group-by-electric-field interaction models, with sham as the reference group.
Results
Of 31 participants with an MRI-visible fiducial marker for electric-field localization, 25 had post-treatment craving data and were included in the acute-phase analysis: 14 active and 11 sham. Localization quality control supported the modeling pipeline: the Euclidean distance between the scanner-derived fiducial coordinate and the SimNIBS-projected scalp point was small, with a mean of 1.30 mm, standard deviation of 0.47, and range of 0.45 to 2.67 mm. Baseline craving severity, sex, coil-to-cortex distance, and localization distance were generally balanced
Regional electric-field distributions differed between the frontal pole and the left middle frontal gyrus/DLPFC proxy. The left middle frontal gyrus showed higher mean electric field, median electric field, 95th percentile electric field, and percentage of voxels above 50, 75, and 100 V/m; all paired Wilcoxon p values were less than 0.001. In contrast, E100 was higher in the frontal pole than in the left middle frontal gyrus, suggesting that peak local fields could occur frontopolarly despite broader stimulation of the nominal DLPFC proxy.
Frontal pole electric-field features showed the clearest associations with Cocaine Craving Questionnaire-General change. In active arm-only linear models, greater frontal pole mean electric field, median electric field, 95th percentile electric field, and percentage of voxels above 50 V/m were associated with less favorable craving change, with active-only p values of 0.013, 0.019, 0.007, and 0.027, respectively. Full-sample group-by-electric-field interaction models showed corresponding differential active-versus-sham associations, with interaction p values of 0.016, 0.036, 0.003, and 0.011. Spearman sensitivity analyses in the active arm were consistent, including frontal pole mean electric field, which was positively correlated with Cocaine Craving Questionnaire-General change (ρ = 0.525, p = 0.044). Because change was defined as post-treatment minus baseline, this indicates that greater broad frontopolar engagement was associated with smaller craving reductions. Frontal pole 95th percentile electric field showed a similar association (ρ = 0.611, p = 0.016), whereas E100 showed an opposite association (ρ = −0.650, p = 0.009), suggesting that peak-field behavior may represent a distinct aspect of field distribution. The medial frontal pole sensitivity analysis was directionally similar to the full frontal pole analysis but less consistent.
Left middle frontal gyrus/DLPFC-proxy findings were more heterogeneous. For Cocaine Craving Questionnaire-General change, interaction models were significant for 95th percentile electric field, E100, and percentage of voxels above 100 V/m, but active-only models were not significant. For visual analog craving change, several left middle frontal gyrus metrics were significant in active-only models, but corresponding interaction terms were not significant.
Discussion
These findings suggest that nominal DLPFC targeting may not fully describe the clinically relevant stimulation pattern in addiction rTMS. Although the left middle frontal gyrus/DLPFC proxy received stronger overall stimulation, frontopolar electric-field features showed more coherent associations with craving change. This supports the use of individualized electric-field modeling to quantify actual regional engagement, rather than assuming that the intended scalp-based target is the only clinically meaningful site.
Clinically, the observed direction is important: greater broad frontopolar engagement was associated with smaller craving reductions during 5-Hz rTMS. This does not argue against the frontopolar cortex as an addiction-relevant node, but suggests that the direction, spatial extent, and physiological mode of modulation may matter. Future studies should prospectively test whether reducing unintended frontopolar spillover during DLPFC stimulation improves outcomes, and whether direct frontopolar protocols using inhibitory approaches, such as cTBS9 or low-frequency rTMS10, produce more favorable effects.
Because this was a secondary analysis with a modest sample size, the findings should be considered hypothesis-generating. Larger prospective trials integrating MRI-guided targeting, individualized electric-field modeling, and craving outcomes are needed to clarify whether frontopolar engagement can serve as a biomarker for optimizing neuromodulation treatment in substance use disorders.
Disclosures
Nothing to disclose by any author(s).
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