The VLPFC-Engaged Voluntary Emotion Regulation: Combined TMS-fMRI Evidence for the Neural Circuit of Cognitive Reappraisal.

A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via the VMPFC during reappraisal only. This study provides combined TMS-fMRI evidence that downregulating negative emotion involves the prefrontal control system suppressing the subcortical affective system, with the VMPFC serving as a crucial hub within the VLPFC-subcortical network, suggesting an indirect pathway model of the ER circuit. Our findings outline potential protocols for improving ER ability by intensifying the VLPFC-VMPFC coupling in patients with mood and anxiety disorders.SIGNIFICANCE STATEMENT Using fMRI to examine the TMS effect, we uncovered that the opposite neural changes in prefrontal (enhanced) and subcortical (attenuated) regions are not a byproduct of emotion regulation (ER); instead, this prefrontal-subcortical activity per se causally contributes to the ER effect. Furthermore, using TMS to amplify the neural changes within the ER circuit, the "bridge" role of the VMPFC is highlighted under the reappraisal versus nonreappraisal contrast. This "perturb-and-measure" approach overcomes the correlational nature of fMRI data, helping us to identify brain regions that causally support reappraisal (the VLPFC and VMPFC) and those that are modulated by reappraisal (the amygdala and insula). The uncovered ER circuit is important for understanding the neural systems underlying reappraisal and valuable for translational research.