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Major Depressive Disorder (MDD) is a psychiatric disorder characterized by high comorbidity with cardiovascular disease. Furthermore, a combination of high heart rate (HR) and low heart rate variability (HRV) has been frequently reported in depressed patients. The present review proposes a frontal-vagal (brain-heart) network that overlaps with functional nodes of the depression network. Moreover, we summarize neuromodulation studies that have targeted key nodes in this depression network, with subsequent impact on heart rate (HR) or heart-rate-variability (HRV), such as the dorsolateral prefrontal cortex (DLPFC), subgenual anterior cingulate cortex (sgACC), and the vagus nerve (VN). Based on the interplay of this frontal-vagal network, we emphasize the importance of including HR and HRV measurements in human depression studies, in particular those that conduct neuromodulation, in order to obtain a better understanding of the pathways that are affected, and we explore the possibilities of using this frontal-vagal interplay as a method for target engagement in neuromodulation treatments. This frontal-vagal network theory opens-up the possibility for individualizing neuromodulation treatments such as rTMS. A recent development called Neuro-Cardiac-Guided TMS (NCG-TMS), was developed based on this theory, and an individual-participant meta-analysis is presented. Four studies provide consistent and replicable support for NCG-TMS as a target engagement method, with consistent HR deceleration during frontal TMS and HR acceleration during motor strip TMS.

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