Trial Outcomes & Findings for Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation (NCT NCT04467164)

Last Updated: 2025-03-27

Results Overview

A functional magnetic resonance imaging (fMRI) analysis was used to evaluate changes in brain activity \[blood oxygenation level-dependent (BOLD) signal\] in response to a visual stress challenge (post- and pre-stimulation). For this analysis a General Lineal Model analsysis with the statistical parametrical software (SPM) was used to model the change in BOLD signals during exposure to negative vs neutral images of the stress tasks. A voxel-wise height threshold of p \< 0.001, and a cluster correction with FWE p-value\<0.05 was used to identify brain areas with significant activation in response to the task. Mean beta weights within each significant cluster were extracted for each participant, and average differences in beta weights (Post minus Pre stimulation) were estimated for each group. A positive difference indicates increased activation of a particular brain region in response to the stimulation, whereas a negative difference indicates a reduction in brain activity.

Recruitment status

COMPLETED

Study phase

Target enrollment

20 participants

Primary outcome timeframe

1 hour

Results posted on

2025-03-27

Participant Flow

Participant milestones

Participant milestones
Measure	Exhalatory-gated tVNS Then Inhalatory-gated tVNS Participants first received exhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received inhalatory-gated tVNS for 30 minutes during a second fMRI session.	Inhalatory-gated tVNS Then Exhalatory-gated tVNS Participants first received inhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received exhalatory-gated tVNS for 30 minutes during a second fMRI session.
First Intervention (30 Minutes) STARTED	10	10
First Intervention (30 Minutes) COMPLETED	10	10
First Intervention (30 Minutes) NOT COMPLETED	0	0
Washout (1 Week) STARTED	10	10
Washout (1 Week) COMPLETED	8	10
Washout (1 Week) NOT COMPLETED	2	0
Second Intervention (30 Minutes) STARTED	8	10
Second Intervention (30 Minutes) COMPLETED	8	10
Second Intervention (30 Minutes) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Exhalatory-gated tVNS Then Inhalatory-gated tVNS Participants first received exhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received inhalatory-gated tVNS for 30 minutes during a second fMRI session.	Inhalatory-gated tVNS Then Exhalatory-gated tVNS Participants first received inhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received exhalatory-gated tVNS for 30 minutes during a second fMRI session.
Washout (1 Week) Lost to Follow-up	2	0

Baseline Characteristics

Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Exhalatory-gated tVNS Then Inhalatory-gated tVNS n=10 Participants Participants first received exhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received inhalatory-gated tVNS for 30 minutes during a second fMRI session.	Inhalatory-gated tVNS Then Exhalatory-gated tVNS n=10 Participants Participants first received inhalatory-gated tVNS for 30 minutes during a first functional MRI session. After a washout period of 1 week, they then received exhalatory-gated tVNS for 30 minutes during a second fMRI session.	Total n=20 Participants Total of all reporting groups
Age, Continuous	30.2 years STANDARD_DEVIATION 4.9 • n=5 Participants	30.5 years STANDARD_DEVIATION 4.7 • n=7 Participants	30.3 years STANDARD_DEVIATION 4.7 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Beck Depression Inventory score	30.1 units on a scale STANDARD_DEVIATION 6.1 • n=5 Participants	25.1 units on a scale STANDARD_DEVIATION 8.1 • n=7 Participants	27.3 units on a scale STANDARD_DEVIATION 7.2 • n=5 Participants

PRIMARY outcome

Timeframe: 1 hour

Population: This is a crossover study. 20 participants were enrolled. 20 subjects completed an exhalatory-gated tVNS session and 18 and inhalatory-gated session.

Outcome measures

Outcome measures
Measure	Exhalatory-gated tVNS n=20 Participants exhalatory-gated tVNS on the left auricle exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS): Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.	Inhalatory-gated tVNS n=18 Participants inhalatory-gated tVNS on the left auricle Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS): Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Brain Activity Changes (Average Differences in Beta Weights From Significantly Activated Regions: Post-stimulation Minus Pre-stimulation) Evaluated Using Functional Magnetic Resonance Imaging. Subgenual anterior cingulate cortex activity (Beta weight difference post-pre stimulation)	0.60 Beta weight difference Standard Deviation 0.29	-0.05 Beta weight difference Standard Deviation 0.12
Brain Activity Changes (Average Differences in Beta Weights From Significantly Activated Regions: Post-stimulation Minus Pre-stimulation) Evaluated Using Functional Magnetic Resonance Imaging. Orbitofrontal cortex activity (Beta weight difference post-pre stimulation)	0.28 Beta weight difference Standard Deviation 0.27	-0.16 Beta weight difference Standard Deviation 0.11
Brain Activity Changes (Average Differences in Beta Weights From Significantly Activated Regions: Post-stimulation Minus Pre-stimulation) Evaluated Using Functional Magnetic Resonance Imaging. Ventromedial prefrontal cortex activity (Beta weight difference post-pre stimulation)	0.44 Beta weight difference Standard Deviation 0.38	-0.24 Beta weight difference Standard Deviation 0.13

SECONDARY outcome

Timeframe: 2 hours

Population: This is a crossover study. 20 participants were enrolled. 20 subjects completed an exhalatory-gated tVNS session and 18 and inhalatory-gated session.

Changes from baseline to post-stimulation in the total score of the Beck Depression Inventory (BDI) compared between exhalatory and inhalatory-gated tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms). A positive difference at post-stimulation compared to baseline indicates an increase in depressive symptoms, whereas a negative difference indicates a reduction in depressive symptomatology.

Outcome measures

Outcome measures
Measure	Exhalatory-gated tVNS n=20 Participants exhalatory-gated tVNS on the left auricle exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS): Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.	Inhalatory-gated tVNS n=18 Participants inhalatory-gated tVNS on the left auricle Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS): Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Change in Depressive Symptoms Assessed by the Beck Depression Inventory (1 Hour Post Intervention Minus Baseline)	-8.21 Difference in BDI scale score Standard Deviation 7.4	-3.58 Difference in BDI scale score Standard Deviation 4.83

SECONDARY outcome

Timeframe: 1 hour

Population: This is a crossover study that enrolled 20 participants. HRV data from four subjects were excluded due to low-quality cardiac pulsatility signals. Thus, the HRV-related analyses were performed on data from 16 exhalatory-gated and and 16 inhalatory-gated tVNS sessions.

Cardiac pulsatility data was collected during exposure to visual stress tasks pre- and post-stimulation and were used to estimate inter-beat intervals. A point process algorithm was then used to analyze the inter-beat intervals and evaluate heart rate variability (HRV) by separating its dynamics in the classic spectral components within the high-frequency (HF) and low-frequency (LF) ranges. Differences in normalized HF \[HFn= (HF/(LF + HF))\] were estimated during exposure to negative images in the fMRI stress task as a metric of parasympathetic cardiac regulation. Percent change in HFn-HRV values (Post vs Pre stimulation) were calculated for each intervention group. A positive percent change value indicates an increase in cardiovagal activity, whereas a negative change indicates a reduction in cardiovagal activity.

Outcome measures

Outcome measures
Measure	Exhalatory-gated tVNS n=16 Participants exhalatory-gated tVNS on the left auricle exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS): Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.	Inhalatory-gated tVNS n=16 Participants inhalatory-gated tVNS on the left auricle Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS): Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Changes in Cardiac Autonomic Function (Percent Change in Normalized High-frequency Power of Heart Rate Variability (HFn-HRV): Post-stimulation Versus Pre-stimulation)	28.1 Percent change in HF normalized units Standard Deviation 33.9	-0.31 Percent change in HF normalized units Standard Deviation 24.1

Adverse Events

Exhalatory-gated tVNS

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Inhalatory-gated tVNS

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Jill M. Goldstein

Massachusetts General Hospital, Harvard Medical School

Phone: 617-724-3776

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place