Interleaved TMS-fMRI Demonstrates Target Engagement in the Orbitofrontal Cortex

Abstract

Introduction

Transcranial magnetic stimulation (TMS) is an FDA-approved non-invasive treatment for treatment-resistant depression, but remission rate of conventional DLPFC-TMS treatment is limited to 79% in best cases [1]. Recent research suggests that the orbitofrontal cortex (OFC) may be a promising alternative target for TMS, potentially addressing limitations in current TMS clinical protocols [2], [3]. Here, we used interleaved TMS-fMRI to investigate whether stimulating novel cortical targets at AF8 and F8 EEG sites produces dose-dependent engagement at the target and downstream effects on subdivisions within the cortico-striatal loop circuit—including the medial and lateral OFC, nucleus accumbens, and other subcortical regions.

Method

We conducted a proof-of-concept study with one healthy adult participant, designed to establish feasibility and inform future research. The participant underwent three experimental sessions: one resting-state fMRI session and two interleaved TMS-fMRI sessions targeting AF8 and F8, respectively. Each TMS-fMRI session included three runs with different stimulation intensities—90%, 95%, and 100% of the individual motor threshold. During each run, 12 minutes of echo-planar imaging (EPI) data were acquired, consisting of three stimulation blocks (each lasting 4 minutes) and one baseline block. BOLD (blood-oxygen-level-dependent) signal changes were analyzed using a general linear model (GLM), with stimulation intensity and target site as independent variables and regional brain activation as the dependent variable. Statistical maps were thresholded at p < 0.001 (uncorrected) at the voxel level, and cluster-level family-wise error (FWE) correction was applied for significance at p < 0.05. 

Results

Dose-dependent modulation: Decreased activity was observed in medial and lateral OFC regions when 100% of rMT stimulation was applied for AF8, and 95% of rMT for F8.

TMS network effect: AF8 evoked more than twice as many activation peaks (defined as significant BOLD signal increases, p < 0.05, cluster-corrected) compared to F8. Both targets induced inhibitory effects in areas such as the angular gyrus, precuneus, medial temporal lobe, anterior to posterior cingulate cortex, fusiform gyrus, insula, and amygdala.

Conclusion

Above-threshold stimulation intensity appears more effective in activating subregions of the OFC via AF8, while below-threshold intensity at F8 may achieve better modulation. The observed co-modulation of medial and lateral OFC may help explain variability in clinical response to OFC-TMS in depression, potentially due to under- or overstimulation. Further research is needed to clarify the functional interplay between lateral and medial OFC and its relevance to therapeutic outcomes.

References

[1] E. Cole, S. J. O’Sullivan, M. Tik, and N. R. Williams, “Accelerated theta burst stimulation: Safety, efficacy, and future advancements,“ Biol. Psychiatry, vol. 95, no. 6, pp. 523–535, 2024. doi: 10.1016/j.biopsych.2023.12.004.

[2] A. Prentice et al., “Sequential bilateral dorsolateral prefrontal versus right lateral orbitofrontal/left dorsolateral prefrontal TMS for major depression: A large naturalistic case series,“ Brain Stimul., vol. 18, no. 3, p704-706, 2025. doi: 10.1016/j.brs.2025.03.002.

[3] K. Feffer, P. Fettes, P. Giacobbe, Z. J. Daskalakis, D. M. Blumberger, and J. Downar, “1 Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes,“ Eur. Neuropsychopharmacol., vol. 28, no. 1, pp. 109–117, 2017. doi: 10.1016/j.euroneuro.2017.11.011.