The Brain-heart-gut Connection (BHG-CONNECT): Targeting the Frontal-vagal Pathway to Personalize Noninvasive Brain Stimulation
Major Depressive Disorder (MDD) often co-occurs with cardiovascular and gastrointestinal symptoms, highlighting the importance of the brain-heart-gut connection in developing comprehensive treatments. Previous research suggests that key hubs in the depression network, such as the dorsolateral prefrontal cortex (DLPFC) and the subgenual anterior cingulate cortex (sgACC), overlap with structures that are involved in autonomic control, particularly the vagus nerve. Repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC is an established treatment for MDD; however, antidepressant efficacy varies greatly across individuals, and optimal DLPFC targeting remains a significant challenge. Personalized rTMS based on DLPFC-sgACC connectivity improves outcomes but is limited by practical and financial constraints. Recently, rTMS-induced heart-brain coupling (HBC) has emerged as a promising method to utilize heart rate responses to guide treatment. The primary goal of this project is to personalize HBC to improve DLPFC-based targeting for the treatment of MDD while also probing additional readouts of the frontal-vagal system. In Study Arm 1, we will implement an innovative frontal mapping technique to identify the personalized Grid-Spot that elicits the strongest HBC in healthy participants. In subsequent visits, we will compare heart rate responses during the 10Hz Dash protocol between the Grid-Spot, conventional DLPFC targeting using Beam-F3 and an active control region (Cz). Additionally, we will integrate various autonomic nervous system (ANS) measures, including gut motility, pupil dilation and electrodermal activity (EDA), to explore the brain-heart-gut axis and assess their utility in improving target engagement. Furthermore, we will extend our methodology to the personalized application of high-definition transcranial direct current stimulation (HD-tDCS). Specifically, we will explore the effects of anodal versus sham HD-tDCS over the HBC-guided Grid-Spot on ANS readouts and compare these outcomes to those observed with rTMS. In Study Arm 2, we will repeat experimental rTMS visits from Study Arm 1 with participants exhibiting elevated symptom scores in depression, autonomic dysfunction and functional dyspepsia. In Study Arm 2 we will also validate our optimal Grid-Spot identification through neuroimaging of DLPFC-sgACC connectivity. This project will deepen our understanding of the brain-heart-gut connection and contribute to more accessible, personalized brain stimulation treatments for MDD.
⁃ In study arm 1, all participants are healthy between 18 and 65 years of age, and able to give written informed consent.
⁃ In study arm 2, all participants must be between 18 and 65 years of age and additionally fulfill the following criteria:
• Elevated autonomic symptom score (\> 20) on the Composite Autonomic Symptom Score
• Depressive symptoms indicated by an elevated score (\>5) in the Patient Health Care Questionnaire (PHQ-9?) or elevated scores (\>9) in the Depression Anxiety and Stress Scale (DASS).
• Elevated Score on Selected questions of the Subchapter symptoms in the Stomach or Intestines of the Rome IV Diagnostic Questionnaire for Adult Functional Gastrointestinal Disorders (Drossman, D. A. (Ed.). (2016). Rome IV: Functional Gastrointestinal Disorders - Disorders of Gut-Brain Interaction (4th ed.). Rome Foundation)
⁃ For both arms, the following criteria must be fulfilled:
• Normal or corrected-to-normal vision and hearing.
• Willingness to participate and signed informed consent
• No Medication with cognitive side effects (e.g. psychoactive medications or sleeping pills) or medication affecting gastric motility
• No ectopic heartbeat
• No history of epilepsy or seizure
• No metal implants or devices (e.g. cardiac pacemakers)
• No substance abuse or recent drug consumption
• No pregnancy
• No history of brain- heart- or gastrointestinal surgery
• No skin conditions
• BMI \<30