The Brain-Heart-Gut Connection

NCT06748274 | Completed DMC

• 2 other identifiers: BHG-CONNECT2024-D0080
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Depression; Brain-Heart Coupling; Brain-Gut Axis; Non-invasive Brain Stimulation; TMS; tDCS; Functional dyspepsia; Connectivity

Outcome Measures

Primary Outcomes (2)

• Heart rate

  Objective 1: To improve and validate personalized DLPFC-targeting using a novel HBC-guided frontal mapping technique a) Personalization (Study Arm 1, 2): Compare the effects of the HBC protocol (256 sec) between DLPFC sites (Grid-spot versus Beam-F3) versus an active control region (Cz) to induce HBC (within-subjects) and between the three Study Arms (between-subjects). Primary outcome: Change in HR during the HBC-protocol (using the App "Heart Brain Connect").

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

• Heart Rate Variability

  Objective 3 (Study Arm 1): To extend HBC-guided rTMS to personalized application of HD-tDCS 1. Effects of HD-tDCS on the ANS: Compare the pre-post effects of anodal versus sham HD-tDCS (18.75 min) on ANS readouts. 2. HD-tDCS versus rTMS: Compare the effects of rTMS versus anodal HD-tDCS targeted to the Grid-Spot. Primary outcome: Change in HRV. Secondary outcomes (same): Change in HBC, HR, gut motility, pupil dilation and EDA.

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

Secondary Outcomes (7)

• Heart Rate Variability

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

• Gut Motility (GM)

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

• Heart rate

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

• Pupil dilation

  Pre-stimulation: 25 minutes, stimulation 15 minutes, post-stimulation: 15 minutes

• Salivary cortisol

  5 minutes (10 minutes before stimulation and 15 minutes after stimulation)

Study Arms (6)

Frontal Mapping

OTHER

To identify the individual TMS stimulation spot and intensity, the Heart-Brain Coupling protocols described by Dijkstra and colleagues (2023) are applied over 8 different spots. To identify the individual stimulation intensity, trains of 10 Hz for 5 seconds with an inter-train interval of 11 seconds are applied (Dash protocol). The subjects are stimulated with 15 different intensities, raising in 2% machine output steps. The starting intensity is set as 28% below the motor threshold (MT), leading to the highest intensity level of 120% MT at step 15. The intensity causing the HR to decelerate the most will be taken as the individual stimulation intensity for subsequent sessions.

Device: Transcranial Magnetic Stimulation (TMS)

TMS - Grid-spot

EXPERIMENTAL

Subjects receive active rTMS over the individual DLPFC spot. Both sessions follow the same protocol and procedures. The 10Hz Dash protocol is applied for about 18.75minutes with the individual intensity defined in the frontal mapping session (arm 1).

Device: Transcranial Magnetic Stimulation (TMS)

TMS control (Cz)

ACTIVE COMPARATOR

Subjects receive active TMS over the central midline. Both sessions follow the same protocol and procedures. The rTMS 10 Hz Dash protocol is applied for about 18.75 minutes with the individual intensity defined in the frontal mapping session (arm 1)

Device: Transcranial Magnetic Stimulation (TMS)

HD-tDCS (anodal)

EXPERIMENTAL

Subjects receive anodal tDCS over the personalized stipulation spot (arm 1) for a total of 18.75 minutes with an intensity of 2mA.

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

HD-tDCS control (cathodal)

ACTIVE COMPARATOR

Subjects receive cathodal tDCS over the personalized stimulation spot (arm 1) for a total of 18.75 minutes with an intensity of 2mA.

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

rTMS - Beam F3

ACTIVE COMPARATOR

Subjects receive active TMS over the Beam-F3 spot. All 3 TMS sessions follow the same protocol and procedures. The rTMS 10 Hz Dash protocol is applied for about 18.75 minutes with the individual intensity defined in the frontal mapping session (arm 1).

Device: Transcranial Magnetic Stimulation (TMS)

Interventions

Transcranial Magnetic Stimulation (TMS) DEVICE

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.

Frontal Mapping; TMS - Grid-spot; TMS control (Cz); rTMS - Beam F3

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

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.

HD-tDCS (anodal); HD-tDCS control (cathodal)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Universitäre Psychiatrische Dienste Bern (UPD), Switzerland: collaborator
• University of Bern: lead
• Medical School Berlin: collaborator

Study Sites (1)

University Hospital of Old Age Psychiatry and Psychotherapy Bern

Bern, Canton of Bern, 3000, Switzerland

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Anna-Katharine Brem, PD Dr.

  University Hospiltal of Old Age Psychiatry and Psychotherapy

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The participants will be held uninformed about the interventional condition undertaking. TMS will be single-blinded, as the stimulation is applied over three active control spots, while tDCS will be double-blinded, with protocols initiated remotely.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD Candidate

Model Details: For this bicentric (Bern and Berlin), cross-over, single-blind, controlled trial with partial randomization, we will recruit n=32 healthy participants (Study Arm 1, Bern and Berlin) and n=32 participants expressing predefined elevated scores in depressive and autonomic symptoms, including functional dyspepsia (Study Arm 2, Bern). Notably, sample sizes of Study Arms 1 and 2 are estimates and will be adjusted using Bayesian updating (see "Power considerations and key analysis plan"). Before starting any of the study arms, n=10 participants (n=5 in Bern, n=5 in Berlin) will be invited to undergo the protocol for Study Arm 1 to ensure technical feasibility and high data quality (Pilot Phase).

Study Record Dates

• First Submitted: December 10, 2024
• First Posted: December 27, 2024
• Study Start: June 1, 2025
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: April 8, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: After publication of primary results
• Access Criteria: Open access

Locations

CH (1)