The Brain-heart-gut Connection (BHG-CONNECT): Targeting the Frontal-vagal Pathway to Personalize Noninvasive Brain Stimulation

Major Depressive Disorder is estimated to affect 5% of the global population, which makes it the most common mental disorder in the world. It is well-established that it is associated with abnormal autonomic nervous system function. Commonly co-occurring symptoms such as increased heart rate, reduced heart rate variability, or gastric hypomotility suggest a complex interplay of pathological brain networks and autonomic regulation. Notably, individuals with depression face a higher likelihood of developing cardiovascular disease, whereas individuals with cardiovascular diseases have a higher probability of developing depression. Gastrointestinal symptoms such as delayed gastric emptying, diarrhea, or abdominal pain are found significantly more often in depressed compared to non-depressed individuals. Therefore, a deeper understanding of the brain-heart-gut connection is crucial for developing more comprehensive and effective treatment strategies.

The frontal-vagal network theory offers a neuroanatomical framework for understanding the comorbidity of cardiovascular and gastrointestinal diseases in depression. The theory states that major hubs of the depression network, such as the dorsolateral prefrontal cortex and the subgenual anterior cingulate, overlap with structures that are involved in autonomic control, particularly the vagus nerve. Stimulation of these areas using neuromodulation therapies such as repetitive transcranial magnetic stimulation, deep brain stimulation, or vagus nerve stimulation has been linked to symptom improvement. Interestingly, vagus nerve stimulation has also been identified as a potential therapy for cardiovascular disorders, such as cardiac arrest and stroke. Furthermore, recent studies demonstrate promising results in applying transcutaneous auricular vagus nerve stimulation to treat functional dyspepsia, a common functional gastrointestinal disorder characterized by altered motility, which contributes to symptoms such as postprandial fullness, early satiation, epigastric pain, and burning.

The left dorsolateral prefrontal cortex is the most accessible and most used target within the frontal-vagal network for applying repetitive transcranial magnetic stimulation in depression treatment. However, the antidepressant efficacy of repetitive transcranial magnetic stimulation varies significantly between individuals and may depend on the exact stimulation location. To localize the left dorsolateral prefrontal cortex, clinicians often rely on head measurements, such as the '5 cm rule' or the 'Beam-F3 method.' While the '5 cm rule' identifies the left dorsolateral prefrontal cortex as being 5 cm anterior to the motor hotspot, the 'Beam-F3 method' is based on the 10-20 electroencephalography system to account for differences in head dimensions. Software has been developed to estimate the F3 electrode position based on a few head measurements. Both methods are cost-efficient but are not reliable in localizing the optimal left dorsolateral prefrontal cortex stimulation site. More importantly, repetitive transcranial magnetic stimulation has been conceptualized as a depression network therapy. Although stimulation is commonly applied to the left dorsolateral prefrontal cortex, its effects are mediated via distributed networks. In fact, it has been shown that functional connectivity between the left dorsolateral prefrontal cortex and the subgenual anterior cingulate predicts antidepressant response robustly. More specifically, dorsolateral prefrontal cortex stimulation sites with better clinical efficacy were more negatively correlated (anticorrelated) with the subgenual anterior cingulate. Therefore, repetitive transcranial magnetic stimulation personalization based on individual anticorrelation patterns is highly recommended and gained importance with the recent clearance of Stanford Neuromodulation Therapy, an accelerated intermitted theta burst stimulation protocol with functional-connectivity-guided targeting. However, practical and financial challenges constrain the feasibility of utilizing functional magnetic resonance imaging-derived connectivity data in clinical practice.

Based on these considerations, the authors' collaborator and his group have recently proposed a novel approach for guiding stratified transcranial magnetic stimulation treatment of depression. The so-called neurocardiac-guided transcranial magnetic stimulation requires the use of heart rate monitoring during prefrontal repetitive transcranial magnetic stimulation to measure heart rate deceleration as an index of frontal-vagal activation. Several studies were able to replicate this effect in healthy as well as in depressed individuals. Even more recently, the method of neurocardiac-guided transcranial magnetic stimulation evolved through an investigation focusing on the entrainment of the cardiac rhythm as a function of transcranial magnetic stimulation cycle time, the so-called heart-brain coupling. It is hypothesized that stimulation results in bradycardia, whereas the subsequent rest period allows normalization of heart rate, leading to a specific rhythm depending on stimulation parameters. Repetitive transcranial magnetic stimulation-induced heart-brain coupling was validated for the 10 Hz Dash protocol, which shortens the inter-train interval to 11 seconds, enabling faster delivery of stimulation trains without losing efficacy. Notably, the protocol was cleared in 2016, allowing for more convenient depression treatment sessions with a reduced duration of 18.75 minutes. Heart-brain coupling assessed during the Dash protocol has been used for site selection (left versus right) and to determine which of the two commonly used targets ('5 cm rule' versus 'Beam-F3 method') is more effective, indicating that Beam-F3 leads to a stronger frontal-vagal involvement. In addition, this method allows measuring the 'frontal excitability threshold,' defined as the lowest intensity needed to induce heart-brain coupling and therefore recommended to effectively stimulate the dorsolateral prefrontal cortex. Importantly, neuroimaging data supports the underlying role of the prefrontal-subgenual pathway showing maximal heart-brain coupling at dorsolateral prefrontal cortex sites that were anti-correlated with the subgenual anterior cingulate. Thus, repetitive transcranial magnetic stimulation-induced heart-brain coupling has shown the potential to stratify individuals to dorsolateral prefrontal cortex targets with negative subgenual anterior cingulate connectivity and may serve as a biomarker for target engagement with non-invasive brain stimulation. However, the heart-brain coupling protocol currently only enables stratification between dorsolateral prefrontal cortex targets according to the '5 cm rule' and the 'Beam-F3 method,' potentially overlooking the optimal stimulation site based on the strongest negative subgenual anterior cingulate connectivity. This underscores the need to incorporate personalized targets into this approach.

As a cost-effective and easily accessible alternative to transcranial magnetic stimulation, high-definition transcranial direct current stimulation could also be enhanced through personalized targeting via heart-brain coupling. Similar to conventional transcranial direct current stimulation, high-definition transcranial direct current stimulation can facilitate or inhibit the neuronal excitability in the target area, based on the polarity of the center electrode in relation to the surrounding electrodes. To date, there is little knowledge about the link of high-definition transcranial direct current stimulation to autonomic function and the frontal-vagal pathway. In contrast to transcranial magnetic stimulation, transcranial direct current stimulation does not induce action potentials but shifts the resting membrane potential, which in turn influences the firing pattern of the neuronal networks. However, a study showed that the application of anodal high-definition transcranial direct current stimulation over the dorsolateral prefrontal cortex induced modulation of heart rate and heart rate variability in healthy subjects. Additionally, anodal transcranial direct current stimulation of the left dorsolateral prefrontal cortex was found to enhance vagus nerve activity compared to sham stimulation. These findings indicate that transcranial direct current stimulation over the dorsolateral prefrontal cortex activates the frontal-vagal pathway, causing effects comparable to transcranial magnetic stimulation. Therefore, incorporating the heart-brain coupling protocol to personalize high-definition transcranial direct current stimulation targeting could lead to stronger stimulation effects.