Limits and reproducibility of resting-state functional MRI definition of DLPFC targets for neuromodulation

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation technique with therapeutic applications for the treatment of major depressive disorder (MDD). The standard protocol uses high frequency stimulation over the left dorsolateral prefrontal cortex (DLPFC) identified in a heuristic manner leading to moderate clinical efficacy. A proposed strategy to increase the anatomical precision in targeting, based on resting-state functional MRI (rsfMRI), identifies the subregion within the DLPFC having the strongest anticorrelated functional connectivity with the subgenual cortex (SGC) for each individual subject. OBJECTIVE: In this work, we comprehensively test the reliability and reproducibility of this targeting method for different scan lengths on 100 subjects from the Human Connectome Project (HCP) where each subject had a four 15-min rsfMRI scan on 2 different days. METHODS: We quantified the inter-scan and inter-day distance between the rsfMRI-guided DLPFC targets for each subject controlling for a number of expected sources of noise using volumetric as well as surface analyses. RESULTS: Our results show that the average inter-day distance (with fMRI scans lasting 30 min on each day) is 25% less variable than the inter-scan distance, which uses 50% less data. Specifically, the inter-scan distance was more than 37 mm, while for the longer-scan, the inter-day distance had lower variability at 25 mm. Finally, we tested the same rsfMRI strategy using the nucleus accumbens (NAc) as a control region relevant to MDD but less susceptible to artifacts, using both volume and surface rsfMRI data. The results showed similar variability to the SGC-DLPFC functional connectivity. Moreover, our results suggest that a smoothing kernel with 12 mm full-width half maximum (FWHM) lead to more stable and reliable target estimates. CONCLUSION: Our work provides a quantitative assessment of the topographic precision of this targeting method, describing an anatomical variability that may surpass the spatial resolution of some forms of focal TMS as it is commonly applied, and provides recommendations for improved accuracy.