A frontal-vagal network theory for Major Depressive Disorder: Implications for optimizing neuromodulation techniques

Abstract

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.

Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway

“…FC3 C3 that heart rate deceleration at FC3 compared to C3 was not significant, unlike the previous study [16]. Notwithstanding, the effect size for this comparison (d ¼ 0.42) is similar to the effect size for FC3/FC4 compared with C3/C4 (d ¼ 0.47) generated by a recent individual participant meta-analyses [26]. The meta-analysis combined available high-frequency NCG-TMS datasets, including the data in the current study (n ¼ 66 healthy participants with left and/or right hemisphere data), with the objective of increasing power and to test any laterality effects.…”

Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion

“…Such improvements could be due to alterations in brain activity in the prefrontal cortex and the limbic system after invasive (Nahas et al, 2007;Pardo et al, 2008) and noninvasive VNS (Badran et al, 2018;Yakunina et al, 2017). Since these mesocorticolimbic structures are characteristically dysregulated in depression (Anand et al, 2005;Groenewold et al, 2013;Iseger et al, 2020) and critically involved in cost-benefit decision-making (Husain & Roiser, 2018;Kroemer et al, 2014Kroemer et al, , 2016, taVNS may provide a means to improve mood, particularly after effort exertion.…”

Applications of Non-invasive Neuromodulation for the Management of Disorders Related to COVID-19

“…The possible presence of an autonomic imbalance in COVID-19 and the importance of vagus nerve activity in the control of inflammation may represent key features to the use of NiN in the treatment of COVID-19 patients, markedly those with high levels of inflammatory profile. Vagus nerve activity can be increased via the cerebral cortex through areas that modulate it indirectly such as the left dorsolateral prefrontal cortex (DLPFC) ( 130 ), corresponding to the F3 position of the 10–20 International EEG System, or temporal cortices. Also, the vagus nerve innervates the ear, mainly the pinna of the outer ear ( 131 ), making it possible to stimulate these areas transcutaneously to influence vagus activity ( 9 , 10 ).…”