The Brain-Heart-Gut Connection

Summary

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.

Conditions

• Major Depression
• Functional Dyspepsia
• Autonomous Dysfunction

Interventions

DEVICE

Transcranial Magnetic Stimulation (TMS)

Transcranial Magnetic Stimulation (TMS) is a sophisticated neuromodulation technique that involves the use of a magnetic coil placed against the scalp to generate brief magnetic pulses. These pulses induce electric currents in the cortical neurons, leading to depolarization or hyperpolarization depending on the parameters of the stimulation.

DEVICE

High-definition transcranial direct current stimulation (HD-tDCS)

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that involves applying a low-intensity electrical current to specific areas of the scalp. The electric current induces alterations in the membrane potentials of underlying neuronal networks. The application of tDCS with concentric ring electrodes is a more targeted form of tDCS, allowing for more precise modulation of cortical activity compared to traditional tDCS methods.

Sponsors & Collaborators

• Medical School Berlin

  collaborator OTHER

• Universitäre Psychiatrische Dienste Bern (UPD), Switzerland

  collaborator UNKNOWN

• University of Bern

  lead OTHER

Principal Investigators

• Anna-Katharine Brem, PD Dr. · University Hospiltal of Old Age Psychiatry and Psychotherapy

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-06-01

Primary Completion

2025-12-31

Completion

2025-12-31

Countries

• Switzerland

Study Locations