What the studies say – Here things get very scientific!

“A frontal-vagal network theory for Major Depressive Disorder: Implications for optimizing neuromodulation techniques” von Iseger et. al.

Major depressive disorder (MDD) is a chronic, heterogeneous psychiatric illness with a course that involves both episodes and recurrences. It is characterized by a high comorbidity with cardiovascular disease. A combination of high heart rate (HR) and low heart rate variability (HRV) is often observed in patients. Despite the wide range of available treatment options, 40–50 percent of patients do not respond to current treatments. Antidepressants are considered the first-line treatment for MDD, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). New neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) show promising clinical benefits in MDD. They target key neural structures affected in depression, such as the dorsolateral prefrontal cortex (DLPFC), the dorsomedial prefrontal cortex (DMPFC), the subgenual cingulate cortex (sgACC), and the vagus nerve (VN). Stimulation of these regions is associated with an improvement in MDD symptoms.

Several studies report a slowing of the heart rate after stimulation of the DLPFC using rTMS. It is also known that the heart rate is often dysregulated in MDD. This manifests itself in an overall higher heart rate and lower heart rate variability (HRV). This normalizes after neuromodulatory treatment—but not, for example, after treatment with SSRIs!

rTMS is a non-invasive neuromodulatory antidepressant therapy that has been shown to affect heart rate when directed at the DLPFC. The efficacy of rTMS in the treatment of MDD has been well documented in recent years, particularly in patients who do not respond to conventional therapies. Currently, the remission rate (the disappearance or reduction of disease symptoms) after rTMS is around 37 percent. In combination with psychotherapy, it rises to 56 percent.

Since rTMS is limited to the cortical surface, it is assumed that the DLPFC exerts its antidepressant effect via transsynaptic activation of deeper regions such as the sgACC. The subgenual anterior cingulate cortex (sgACC) could transmit the signal further into deeper brain structures and influence heart rate (HR) via the ventral nucleus (VN). Fox et al. (2012) demonstrated a negative correlation between BOLD activity in the sgACC and the dorsolateral prefrontal cortex (DLPFC). This correlation was associated with the antidepressant mechanism of action of repetitive transcranial magnetic stimulation (rTMS): the stronger the negative correlation, the better the response to treatment.

Furthermore, deep brain stimulation (DBS) of the sgACC, which inhibits activity, leads to upregulation of activity in the DLPFC. It is assumed that DLPFC rTMS exerts its clinical effect via functional connectivity to the sgACC. The more negative the correlation between the two areas, the better a patient responded to rTMS. In summary, regardless of direction and causality, there is a complex interaction between the sgACC and the DLPFC that mediates the antidepressant effect of rTMS.

DBS of the sgACC, which inhibits activity, leads to an increase in activity in the DLPFC. The dorsolateral prefrontal cortex (DLPFC) is often chosen as a target area in non-invasive neuromodulation studies such as rTMS and tDCS due to its accessibility in the depression network.

Several studies have investigated the effects of rTMS and tDCS on heart rate (HR). In short, both methods were found to reduce HR, with the cardiac effects of TMS being more pronounced than those of tDCS. Furthermore, prefrontal stimulation was more effective in reducing HR than stimulation of the motor cortex. The DLPFC is usually stimulated either on the right side at a low frequency (1 Hz) or on the left side at a high frequency (10–20 Hz). A study in healthy subjects showed reduced HR after rTMS over both the left and right DLPFC, as well as reduced arterial blood pressure after rTMS over the left DLPFC.

In summary, various studies suggest that prefrontal TMS can transsynaptically lower heart rate (HR), influence heart rate variability (HRV), and possibly normalize parasympathetic function in major depression. Despite the promising clinical results of DLPFC stimulation, identifying an individual stimulation site remains a problem. Automatic bodily functions such as heart rate and heart rate variability could serve as potential target mechanisms for optimizing and individualizing neuromodulation treatments for depression.