Effectiveness of non-invasive brain stimulation on depressive symptoms targeting prefrontal cortex in functional magnetic resonance imaging studies: a combined systematic review and meta-analysis

The prefrontal cortex (PFC) is a critical non-invasive brain stimulation (NIBS) target for treating depression. However, the alterations of brain activations post-intervention remain inconsistent and the clinical moderators that could improve symptomatic effectiveness are unclear. The study aim was to systematically review the effectiveness of NIBS on depressive symptoms targeting PFC in functional magnetic resonance imaging (fMRI) studies. In our study, we delivered a combined activation likelihood estimation (ALE) meta-analysis and meta-regression. Until November 2020, three databases (PubMed, Web of Science, EMBASE) were searched and 14 studies with a total sample size of 584 were included in the ALE meta-analysis; after NIBS, four clusters in left cerebrum revealed significant activation while two clusters in right cerebrum revealed significant deactivation (P < 0.001, cluster size >150 mm³). Eleven studies were statistically reanalyzed for depressive symptoms pre-post active-NIBS and the pooled effect size was very large [(d = 1.82, 95%CI (1.23, 2.40)]; significant moderators causing substantial heterogeneity (Chi squared = 75.25, P < 0.01; I ² = 87%) were detected through subgroup analysis and univariate meta-regression. Multivariate meta-regression was then conducted accordingly and the model suggested good fitness (Q = 42.32, P < 0.01). In all, NIBS targeting PFC balanced three core depressive-related neurocognitive networks (the salience network, the default mode network, and the central executive network); the striatum played a central role and might serve as a candidate treatment biomarker; gender difference, treatment-resistant condition, comorbidity, treatment duration, and localization all contributed to moderating depressive symptoms during NIBS. More high-quality, multi-center randomized controlled trails delivering personalized NIBS are needed for clinical practice in the future.