Clinical trial NCT05132881: Effect of (TaVNS) on Anxiety and Brain Function in Distressed Health Care Workers
Official title: Effect of Transcutaneous Auricular Vagus Nerve Stimulation (TAVNS) on Anxiety and Brain Function in Distressed Healthcare Professionals
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Anxiety
Distress, Emotional
Effects of Vibration
Healthy
Keywords: Vagal Nerve Stimulation
Distressed Workers
Work-related Stress
Magnetic Resonance Imaging (MRI)
Functional Magnetic Resonance Imaging (fMRI)
Healthy Controls
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
First posted: 2021-11-24
Enrollment: 90
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects will be assigned by randomization to place individuals into the TaVNS or wait-list groups using a permuted block design with a 1:1 ratio to the group assignments. Subjects will be assigned a study number that will be used on the research files. Each subject will be informed of their group assignment.
Primary purpose: SUPPORTIVE_CARE

Brief summary: The purpose of this research is to measure alterations in anxiety and brain activity associated with the use of an approved health device called Transauricular Vagal Nerve Stimulation (TaVNS) in distressed persons who work in a health care and distressed healthcare workers in the the Philadelphia, PA region. The Investigators will be using functional magnetic resonance imaging (or fMRI) to measure changes in each subject's brain function during the use of VNS. This study is designed to allow researchers to understand the changes in cerebral (brain) activity that occur when a subject uses VNS. Thus, the primary goal of the proposed study is to evaluate the ability of the TaVNS system to reduce distress and change neurophysiology among health care providers.

The Investigators, hypothesize that using the TaVNS device will help reduce distress in individuals.

In order to understand the mechanisms of change that occur while using the VNS study, the Investigators have added a substudy of participants who do not experience high levels of distress to evaluate the effects of the functional changes that may occur in the brain while using the TaVNS device.

In addition to the primary aims of the overalll study to assess distress in workers while enrolled in a TaVNS program, a subgroup of 50 subjects will undergo functional magnetic resonance imaging (fMRI) while using the VNS device to assess the changes in the brain including neurophysiological effects of TaVNS.

The goal of this substudy is to observe the changes in the brain while using the TaVNS earbuds in the MRI to increase our understanding of the mechanisms and processing involved while using TaVNS. In this substudy, which is amendment version 3.0, the investigators have increased the number of persons to include 50 subjects who will use the device in the MRI to evaluate the neural processes and cerebral blood flow while using TaVNS.

Detailed description: A total of up to 90 distressed persons who work in health care and health care providers in the Philadelphia, PA region, will be screened for this study. From that group, the researchers plan to enroll enough subjects to have 80 fully complete the study. The 90 screened subjects will allow for screen failures and subjects who withdraw early from the study. All subjects will receive an initial evaluation using symptom questionnaires (these will include the Global Severity Index of the Brief Symptom Inventory-18 which is the primary outcome, and secondary outcomes as measured by the Maslach Burnout Scale, GAD-7 (anxiety), PHQ-9 (depression), the Connor Davidson Resilience Scale-25 (CD-RISC), and the Insomnia Severity Index (ISI) and physiological measures that will consist of heart rate variability (HRV) and galvanic skin resistance (GSR). Subjects will then be randomized to either the 3 month TaVNS program or the 3 month waitlist group. At one month, subjects will receive a follow up request to complete the same questionnaires as in the initial evaluation for an interim evaluation. Then after receiving the TaVNS program or being in the waitlist control group for 3 months, the subjects will have a repeat of the questionnaires and physiological testing. Subjects in the waitlist group will then be provided the TaVNS program to be used for 3 months. This group will be asked to complete one final set of symptom questionnaires at the completion of using the TaVNS program.

Two subgroups will be included in fMRI scans performed during the initial evaluation period (pre) and at 3 months (post). Subgroup I of 30 subjects (15 in TaVNS group and 15 in waitlist control) will undergo fMRI scans that will include structural imaging and functional imaging with Blood Oxygen Level Dependent Imaging (BOLD) scan and arterial spin labeling (ASL) scans. Specifically, during the ASL scans (each approximately 5 minutes long), a script of the subject's most distressing recollection(s) will be read from an audio file script while each subject is in the MRI scanner. Changes in brain function will be compared between the stress script and a neutral script (that describes a typical morning waking up). This same imaging protocol, which takes a total of about 45 minutes, will be performed initially and then after the 3 month TaVNS program or the waitlist period. All scans will be co-registered and comparable slices of the cerebral cortex will be examined.

Subgroup II will consist of 10 study subjects all receiving the TaVNS program who will undergo fMRI initially and then again at 3 months. This group will be scanned while wearing the TaVNS system (a special one that can be used in the MRI environment) and the fMRI will be used to evaluate the direct effects of the TaVNS while turned on and off in the scanner. The imaging protocol will take a total of about 45 minutes. In addition to the 10 study subjects, the researchers will also plan to recruit 10 healthy controls with no reports of psychological distress (i.e. less than 2 on the SUDS). These 10 healthy controls will have the TaVNS placed while receiving two fMRI scans approximately 3 months apart. These control subjects will be used to compare the subgroup of study subjects to ensure that any changes are not associated with test-retest effects.

The subgroups will be filled with eligible and interested subjects. If the subject is interested and is able to undergo fMRI scanning, the subject will be placed in Subgroup I until enrollment is filled and then subsequently subjects will be enrolled into Subgroup II until enrollment is filled. Any eligible subject that is unwilling or unable to undergo fMRI scanning will be placed in the general, non-scanning group. Once the two subgroups are filled, any remaining eligible subjects will be placed in the general, non-scanning group.

Substudy:

A total of 50 additional subjects will be screened to receive one MRI imaging while using the TaVNS earbuds. Subjects who are eligible to receive an MRI scan will be enrolled from the geographical region. Participants may also be self-referred by responding to flyers to inquire more about the study. The objective of the substudy (Subgroup III) is to increase our understanding of the mechanisms and neurophysiological response while using the TaVNS in the MRI scanner by evaluating cerebral blood and activation states while the TaVNS is "on" and "off" during a single fMRI session while using the TaVNS.

Endpoints for the Imaging Using TaVNS Substudy

A substudy (Subgroup III) of 50 subjects, with no randomization, will undergo fMRI scans with the TaVNS system being turned on and off while in the scanner to observe for any immediate effects. While the system is generally not supposed to be used in the MRI environment, a special non-magnetic version (that can be used in the MRI environment) will be used to test this change. Specifically, the unit itself will be outside of the MRI environment and will be attached to the earbuds using a non-magnetic wire.

Secondary Endpoints:

Secondary endpoints may include clinical measures including the Maslach Burnout Scale, GAD-7 (anxiety), PHQ-9 (depression), Connor Davidson Resilience Scale-25 (CD-RISC), Insomnia Severity Index (ISI), and physiological measures that will consist of heart rate variability (HRV) and blood pressure.

Additional secondary endpoints will be the baseline fMRI scans that will include structural imaging and functional imaging with Blood Oxygen Level Dependent Imaging (BOLD) scan and two arterial spin labeling (ASL) scans. fMRI scan data for this substudy may be compared between the MRI Imaging group and the TaVNS group and waitlist control.

Subgroup II will consist of 10 study subjects all receiving the TaVNS program who will undergo fMRI initially and then again at 1 month (+30 days). This group will be scanned while wearing the TaVNS system (a special one that can be used in the MRI environment) and the fMRI will be used to evaluate the direct effects of the TaVNS while turned on and off in the scanner. The imaging protocol will take a total of about 45 minutes.

In addition to the 10 study subjects in the distressed workers group, we intend to recruit 50 healthy controls with no reports of psychological distress (i.e. less than 2 on the SUDS) with no biofeedback evaluation. These 50 healthy controls will have the TaVNS placed while receiving one fMRI scans. These control subjects will be used to compare the subgroup of study subjects to understand the changes in the brain while using the TaVNS. These participants will be consented with an informed consent form that describes the substudy in more detail. Subjects in the substudy Group III will receive only one fMRI imaging session on one day and will be asked to complete surveys. Participants in this substudy will have heart rate collected at baseline, during and after the fMRI while using the VNS.

All subjects will receive an initial evaluation using symptom questionnaires (these will include the Global Severity Index of the Brief Symptom Inventory-18 which is the primary outcome, and secondary outcomes as measured by the Maslach Burnout Scale, GAD-7 (anxiety), PHQ-9 (depression), the Connor Davidson Resilience Scale-25 (CD-RISC), and the Insomnia Severity Index (ISI).

The eligibility for imaging is the same for all groups with the exception of Subjective Units of Distress Scores.

Eligibility criteria: Inclusion Criteria:

1. Healthy male and female persons who work in health care and health care workers (all races and ethnicity) \>21 years of age
2. All subjects must have a smartphone device that can be used in conjunction the Neuvana 2.0
3. Drug-free from medications that may affect brain physiology such that the imaging results will not be useful as determined by the PI.
4. Able to understand and provide signed informed consent. Available and willing to be followed -up according to study protocol
5. Female subjects of childbearing potential have a negative pregnancy test
6. Subjects have no significant medical neurological or psychological disorders
7. Stable health problems that should have no substantial effect on cerebral blood flow will be allowed (i.e. controlled hypertension, medication controlled diabetes).
8. Current medications and supplements will be reviewed by the Principal Investigator or a designated physician or health practitioner. Subjects may take medications or supplements but should be on a stable dose regimen for at least 3 months. For those receiving TaVNS program, it is preferable that subjects remain on that dose for the full TaVNS program period (with the exception of having an adverse reaction in which the medication or supplement must be stopped).
9. PI will evaluate each subject for any potential medical issues that might be a problem and will consult with the subject's primary care provider if there are any questions about it.

Additional Inclusion Criteria for the TaVNS program for Distressed Workers

1. Distress scored as at least a 6 or greater on the SUDS distress level from 1 to 10.
2. Distressing recollection(s) that causes physiological reactivity (i.e., increased heart rate and/or increased skin conductance level - SCL), as described above.

Healthy control with no distress or other exclusion criteria

Exclusion Criteria:

1. Any medical conditions that may interfere with cerebral blood flow as determined by the PI.
2. Currently taking medication that might affect cerebral blood flow as per the P.I. (i.e. antidepressants, antipsychotics, anxiolytics, benzodiazepines, sedatives, anti-seizure medications, but with the exception of those described above)
3. Subject is unable or unwilling to lie still in the scanner (i.e. due to claustrophobia or weight)
4. Subject has metal in their body or other reason that they cannot undergo magnetic resonance imaging.
5. Previous brain surgery or intracranial abnormalities they may complicate interpretation of the brain scans (e.g., stroke, tumor, vascular abnormality).
6. Pregnancy or breastfeeding
7. Concurrent participation in another research protocol that might affect the outcome of this study.
8. Use of a defibrillator or pacemaker or other implanted or metallic electronic device. Doing so could cause electric shock, burns, electrical interference, or death.
9. Epilepsy
10. History of Seizures
11. Temporomandibular Joint Disorder, Bell's Palsy, impaired cranial nerve function, or facial pain.

Primary outcomes:
measure: Subjective Units of Distress Survey
timeFrame: Screening Measure Subjects will be evaluated at baseline.
measure: Subjective Units of Distress Survey
timeFrame: Change from baseline and after using the TaVNS system approximately 90 days (~3 months)] .
measure: Subjective Units of Distress Survey
timeFrame: Evaluate at baseline to evaluate distress for healthy controls in Group III
measure: Heart Rate Variability for Active and Waitlist
timeFrame: Screening Measure Subjects will be evaluated at baseline
measure: Heart Rate Variability for Active and Waitlist
timeFrame: Change from baseline and after using the TaVNS system approximately 90 days (~3 months)] .
measure: Galvanic Skin Resistance (GSR) for Active and Waitlist
timeFrame: Screening Measure Subjects will be evaluated at baseline
measure: Galvanic Skin Resistance (GSR) for Active and Waitlist
timeFrame: Change from baseline and after using the TaVNS System approximately 90 days (~3 months)]
measure: Functional magnetic resonance imaging (fMRI) in all groups
timeFrame: Subjects will be evaluated at baseline
measure: Functional magnetic resonance imaging (fMRI) in Active and Waitlist Groups
timeFrame: Change from baseline and after using the TaVNS system approximately 90 days (~3 months)] .
measure: Blood Oxygen Level Dependent Imaging scan in all groups
timeFrame: Subject will be evaluated at baseline
measure: Blood Oxygen Level Dependent Imaging scan in Active and Waitlist Groups
timeFrame: Change from baseline and after using the TaVNS System approximately 90 days (~3 months)]
measure: Arterial spin labeling scan in all groups
timeFrame: Subjects will be evaluated at baseline
measure: Arterial spin labeling scan in Active and Waitlist Groups
timeFrame: Change from baseline and after using the TaVNS System approximately 90 days (~3 months)]
Secondary outcomes:
measure: The Maslach Burnout Scale
timeFrame: Subjects will be evaluated at baseline with questionnaires.
measure: The Maslach Burnout Scale
timeFrame: Subjects will be evaluated at approximately three months follow up with questionnaires.
measure: The Maslach Burnout Scale
timeFrame: Subjects will be evaluated approximately six months follow up with questionnaires.
measure: Patient Health Questionnaire
timeFrame: Subjects will be evaluated at baseline with questionnaires.
measure: Patient Health Questionnaire
timeFrame: Subjects will be evaluated at approximately three months follow up with questionnaires.
measure: Patient Health Questionnaire (PHQ-9)(depression)
timeFrame: Subjects will be evaluated at baseline and approximately six months follow up with questionnaires.
measure: General Anxiety Disorder
timeFrame: Subjects will be evaluated at baseline with questionnaires.
measure: General Anxiety Disorder
timeFrame: Subjects will be evaluated at baseline and approximately three months follow up with questionnaires.
measure: General Anxiety Disorder
timeFrame: Subjects will be evaluated at baseline and approximately six months follow up with questionnaires.
measure: Connor Davidson Resilience Scale-25 (CD-RISC)
timeFrame: Subjects will be evaluated at baseline with questionnaires.
measure: Connor Davidson Resilience Scale-25
timeFrame: Subjects will be evaluated at approximately three months follow up with questionnaires.
measure: Connor Davidson Resilience Scale-25
timeFrame: Subjects will be evaluated at baseline and approximately six months follow up with questionnaires.
measure: Insomnia Severity Index
timeFrame: Subjects will be evaluated at baseline with questionnaires.
measure: Insomnia Severity Index
timeFrame: Subjects will be evaluated at baseline and approximately three months follow up with questionnaires.
measure: Insomnia Severity Index
timeFrame: Subjects will be evaluated at baseline and approximately six months follow up with questionnaires.
measure: Global Severity Index of the Brief Symptom Inventory-18
timeFrame: Subjects will be evaluated at baseline .
measure: Global Severity Index of the Brief Symptom Inventory-18
timeFrame: Subjects will be evaluated at three months after using the TaVNS system.
measure: Global Severity Index of the Brief Symptom Inventory-18
timeFrame: Subjects will be evaluated at six months after using the TaVNS system.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Marcus Institute of Integrative Health Centers
state: Pennsylvania
Study officials:
affiliation: Department of Integrative Medicine and Nutritional Sciences
name: Andrew B Newberg
role: PRINCIPAL_INVESTIGATOR
References: