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| ID | Type | Description | Link |
|---|---|---|---|
| P01AT009965 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Center for Complementary and Integrative Health (NCCIH) | NIH |
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This study design has two components: 1) a cross-sectional assessment of brain activity and inflammation in migraine patients compared to healthy controls and 2) an assessment of 8 weeks of a combination therapy approach to treating migraine.
Chronic pain is the most prevalent and disabling medical condition, and no single therapy has proven to be completely successful for alleviating pain, such as migraine headache. It is well documented, and recommended in the recent Institute of Medicine (IOM) report, that a multimodal approach is optimal for pain management. This study will evaluate a combination transcutaneous vagus nerve stimulation and stress reduction training for migraine.
Investigators will recruit participants who have migraines and randomize to one of four potential treatment arms (real or sham stimulation + real or sham stress reduction training). Brain imaging (MRI and PET) and clinical data will be collected before and after 8 weeks of the combination therapy.
Healthy controls will also be recruited for collection of the same baseline brain imaging and clinical data, but with no treatment or second data collection phase.
Findings from this research will help elucidate brain activity and inflammation associated with migraines and evaluate the efficacy of the combination therapy in reducing migraine.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active tVNS + SRT A | Experimental | active tVNS and Stress Reduction Training A |
|
| active tVNS + SRT B | Experimental | active tVNS and Stress Reduction Training B |
|
| sham tVNS + SRT A | Other | sham stimulation and Stress Reduction Training A |
|
| sham tVNS + SRT B | Other | sham tVNS and Stress Reduction Training B |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Stress Reduction Training A | Behavioral | twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions |
|
| Measure | Description | Time Frame |
|---|---|---|
| Brain Activity Changes in Migraine Patients in Response to Treatment | Post-treatment versus baseline change in intervention-evoked cortical amplification ratio (left posterior insula to spinal trigeminal nucleus ratio of fMRI BOLD percent signal change) for trigeminal afferent stimulation (i.e. forehead stimulation). | 8 weeks (i.e. post-treatment) |
| Brain Inflammation Changes in Migraine Patients in Response to Treatment | PET [11C]PBR28 signal, quantified as Standardized Uptake Value Ratio (SUVR; i.e., tissue radioactivity / injected dose / weight) change from baseline to post-treatment, compared across treatment groups for migraine patients. [11C]PBR28 SUVR was measured in the insula (average of left and right insula), using cerebellum SUV as a pseudo-reference region. | 8 weeks (post-treatment) |
| Measure | Description | Time Frame |
|---|---|---|
| Brain Activity Differences Between Migraine Patients and Healthy Controls | Amygdala fMRI BOLD signal differences from stressful imagery task (percent BOLD signal change, negative minus neutral image blocks), contrasting migraine patients (at baseline) and healthy controls. | Week 0-3 (Baseline window) |
| Brain Inflammation Differences Between Migraine Patients and Healthy Controls |
| Measure | Description | Time Frame |
|---|---|---|
| Primary Clinical Outcome (HIT6) | The Headache Impact Test (HIT-6) is a 6-item self-report evaluation of headache disability. The HIT6 is measured on a scale from 36 to 78 points, with higher scores indicating greater headache-related disability. Participants completed the HIT-6 at baseline and post-treatment. The reported outcome measure is a difference score (post-treatment HIT-6 minus baseline HIT-6). | 8 weeks (post-treatment) |
Inclusion Criteria:
Healthy Volunteers between the ages of 18 and 65 can participate in this study.
Exclusion Criteria:
Healthy Volunteers have the same eligibility constraints with the addition of current or past history of migraine.
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| Name | Affiliation | Role |
|---|---|---|
| Vitaly Napadow, PhD,Lic.Ac. | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Anthinoula A. Martinos Center | Charlestown | Massachusetts | 02129 | United States |
Participants completed a daily headache log run-in to assess eligibility prior to randomization. Participants were excluded if they reported fewer than 4 or greater than 20 headache days within a 28-day period. Final eligibility was assessed by doctoral-level review, and eligible participants were randomized to one of 4 study arms. In total, 193 participants began the run-in period; 14 healthy controls and 43 migraine participants were found ineligible and excluded prior to randomization.
Participants were recruited through the Mass General Brigham (MGB) Rally for Research platform, MGB Research Participant Data Registry (RPDR), Facebook ads, referrals from providers at MGB and CHA, and flyers. Participants were recruited from Massachusetts and surrounding states, primarily in the Boston area. The recruitment period occurred from August 2019 to November 2024.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active tVNS + MBSR | active tVNS and Mindfulness-Based Stress Reduction (MBSR) MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions active tVNS: non-painful electrical stimulation of the auricle |
| FG001 | Active tVNS + NEC | active tVNS and Nature Education Control (NEC) active tVNS: non-painful electrical stimulation of the auricle NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions |
| FG002 | Sham tVNS + MBSR | sham stimulation and Mindfulness-Based Stress Reduction MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
| FG003 | Sham tVNS + NEC | sham tVNS and Nature Education Control (NEC) NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
| FG004 | Healthy Controls | Healthy volunteers without migraine headache completed baseline assessments and did not complete an intervention. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Active tVNS + MBSR | active tVNS and Mindfulness-Based Stress Reduction (MBSR) MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions active tVNS: non-painful electrical stimulation of the auricle |
| BG001 | Active tVNS + NEC |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Brain Activity Changes in Migraine Patients in Response to Treatment | Post-treatment versus baseline change in intervention-evoked cortical amplification ratio (left posterior insula to spinal trigeminal nucleus ratio of fMRI BOLD percent signal change) for trigeminal afferent stimulation (i.e. forehead stimulation). | Only participants who successfully completed a pre- and post-treatment 7T fMRI scan are included in this analysis. Some participants completed the overall study but were excluded from fMRI scanning due to MRI contraindications, e.g. metal implants, claustrophobia. | Posted | Mean | Standard Deviation | Log ratio % signal change (Insula/Sp5) | 8 weeks (i.e. post-treatment) |
|
Adverse event data were collected over the 6 months that participants were in the study.
The definitions do not differ. Staff monitored adverse events (AEs) through participant self-report. AEs were rated by severity, relatedness, and expectedness with regular DSMB review. All-Cause Mortality was not monitored/assessed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active tVNS + MBSR | active tVNS and Mindfulness-Based Stress Reduction (MBSR) MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions active tVNS: non-painful electrical stimulation of the auricle |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Surgery | Surgical and medical procedures | Systematic Assessment | Participant was hospitalized and received surgery to treat a broken femur. Not study related. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Incidental Finding | Nervous system disorders | Systematic Assessment | An incidental finding was reported at the 3T PET-MR scan and at the 7T fMRI scan. After discussion with the Clinical Core team, DSMB Safety Officer, and neurologists, the participant was informed of the finding. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Vitaly Napadow | Spaulding Rehabilitation Hospital | 617-952-6480 | vitaly@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 25, 2024 | Jan 13, 2026 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 15, 2024 | Jan 13, 2026 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 18, 2024 | Jun 11, 2025 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D008881 | Migraine Disorders |
| ID | Term |
|---|---|
| D051270 | Headache Disorders, Primary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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|
| active tVNS | Device | non-painful electrical stimulation of the auricle |
|
|
| Stress Reduction Training B | Behavioral | twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions |
|
|
| sham tVNS | Device | sham stimulation |
|
PET [11C]PBR28 signal, quantified as Standardized Uptake Value Ratio (SUVR; i.e., tissue radioactivity / injected dose / weight), differences between healthy controls and migraine patients at baseline. [11C]PBR28 SUVR was measured in the insula (average of left and right insula), using cerebellum SUV as a pseudo-reference region. |
| Week 0-3 (Baseline window) |
| Secondary Clinical Outcome (PCS) | The Pain Catastrophizing Scale (PCS) is a 13-item evaluation of a participant's subjective pain experience. The PCS is measured on a scale from 0 to 52 points, with higher scores indicating a greater degree of pain catastrophizing. The PCS includes three subscales (Rumination, Magnification, and Helplessness), and the scores from the subscales were summed to determine the total score. Participants completed the PCS at baseline and post-treatment. The reported outcome measure is a difference score (post-treatment PCS minus baseline PCS). | 8 weeks (post-treatment) |
active tVNS and Nature Education Control (NEC) active tVNS: non-painful electrical stimulation of the auricle NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions |
| BG002 | Sham tVNS + MBSR | sham stimulation and Mindfulness-Based Stress Reduction MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
| BG003 | Sham tVNS + NEC | sham tVNS and Nature Education Control (NEC) NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
| BG004 | Healthy Controls | Healthy volunteers without migraine headache completed baseline assessments and did not complete an intervention. |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Headache frequency | Average number of days with headache attacks during 4 weeks of daily diary completion. Healthy controls were excluded during the run-in if they self-reported headaches, so the healthy controls included here all reported 0 headache days in a 28-day period. | Mean | Standard Deviation | Days |
|
| Disease Duration | Average of the total years that participants have experienced migraines. | Measure not collected for some participants. | Mean | Standard Deviation | years |
|
| OG001 | Active tVNS + NEC | active tVNS and Nature Education Control (NEC) active tVNS: non-painful electrical stimulation of the auricle NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions |
| OG002 | Sham tVNS + MBSR | sham stimulation and Mindfulness-Based Stress Reduction MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
| OG003 | Sham tVNS + NEC | sham tVNS and Nature Education Control (NEC) NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation |
|
|
| Primary | Brain Inflammation Changes in Migraine Patients in Response to Treatment | PET [11C]PBR28 signal, quantified as Standardized Uptake Value Ratio (SUVR; i.e., tissue radioactivity / injected dose / weight) change from baseline to post-treatment, compared across treatment groups for migraine patients. [11C]PBR28 SUVR was measured in the insula (average of left and right insula), using cerebellum SUV as a pseudo-reference region. | Only participants who successfully completed a pre- and post-treatment 3T PET-MR scan are included in this analysis. Some participants completed the overall study but were excluded from PET-MR scanning due to MRI contraindications (e.g. metal implants, claustrophobia) and/or the presence of the Ala147Thr polymorphism which is associated with low-affinity binding to the radiotracer. | Posted | Mean | Standard Deviation | Uptake ratio | 8 weeks (post-treatment) |
|
|
|
| Secondary | Brain Activity Differences Between Migraine Patients and Healthy Controls | Amygdala fMRI BOLD signal differences from stressful imagery task (percent BOLD signal change, negative minus neutral image blocks), contrasting migraine patients (at baseline) and healthy controls. | Only participants who successfully completed a pre-treatment 7T fMRI scan are included in this analysis. Some participants completed the overall study but were excluded from PET-MR scanning due to MRI contraindications (e.g. metal implants, claustrophobia). | Posted | Mean | Standard Deviation | Percent Signal Change | Week 0-3 (Baseline window) |
|
|
|
| Secondary | Brain Inflammation Differences Between Migraine Patients and Healthy Controls | PET [11C]PBR28 signal, quantified as Standardized Uptake Value Ratio (SUVR; i.e., tissue radioactivity / injected dose / weight), differences between healthy controls and migraine patients at baseline. [11C]PBR28 SUVR was measured in the insula (average of left and right insula), using cerebellum SUV as a pseudo-reference region. | Only participants who successfully completed a pre-treatment 3T PET-MR scan are included in this analysis. Some participants completed the overall study but were excluded from PET-MR scanning due to MRI contraindications (e.g. metal implants, claustrophobia) and/or the presence of the Ala147Thr polymorphism which is associated with low-affinity binding to the radiotracer. | Posted | Mean | Standard Deviation | Uptake ratio | Week 0-3 (Baseline window) |
|
|
|
| Other Pre-specified | Primary Clinical Outcome (HIT6) | The Headache Impact Test (HIT-6) is a 6-item self-report evaluation of headache disability. The HIT6 is measured on a scale from 36 to 78 points, with higher scores indicating greater headache-related disability. Participants completed the HIT-6 at baseline and post-treatment. The reported outcome measure is a difference score (post-treatment HIT-6 minus baseline HIT-6). | Posted | Mean | Standard Deviation | units on a scale | 8 weeks (post-treatment) |
|
|
|
| Other Pre-specified | Secondary Clinical Outcome (PCS) | The Pain Catastrophizing Scale (PCS) is a 13-item evaluation of a participant's subjective pain experience. The PCS is measured on a scale from 0 to 52 points, with higher scores indicating a greater degree of pain catastrophizing. The PCS includes three subscales (Rumination, Magnification, and Helplessness), and the scores from the subscales were summed to determine the total score. Participants completed the PCS at baseline and post-treatment. The reported outcome measure is a difference score (post-treatment PCS minus baseline PCS). | Posted | Mean | Standard Deviation | units on a scale | 8 weeks (post-treatment) |
|
|
|
| 0 |
| 0 |
| 0 |
| 25 |
| 14 |
| 25 |
| EG001 | Active tVNS + NEC | active tVNS and Nature Education Control (NEC) active tVNS: non-painful electrical stimulation of the auricle NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions | 0 | 0 | 2 | 28 | 12 | 28 |
| EG002 | Sham tVNS + MBSR | sham stimulation and Mindfulness-Based Stress Reduction MBSR: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation | 0 | 0 | 0 | 25 | 18 | 25 |
| EG003 | Sham tVNS + NEC | sham tVNS and Nature Education Control (NEC) NEC: twice weekly "booster" sessions and weekly instructor-led sessions for 8 weeks plus home practice sessions sham tVNS: sham stimulation | 0 | 0 | 0 | 29 | 13 | 29 |
| EG004 | Healthy Controls | Healthy volunteers without migraine headache completed baseline assessments and did not complete an intervention. | 0 | 0 | 0 | 29 | 6 | 29 |
|
| Kidney Infection | Renal and urinary disorders | Systematic Assessment | Participant was hospitalized for treatment of a kidney infection. Not study-related. |
|
|
| Surgery | Surgical and medical procedures | Systematic Assessment | Participant underwent finger surgery to remove mental implants. The surgery was not study-related. |
|
| Kidney Infection | Renal and urinary disorders | Systematic Assessment | Participant was diagnosed with a kidney infection. Not study-related. |
|
| Illness | General disorders | Systematic Assessment | 3 participants developed a cold. Not study-related. Participant developed a sinus infection. Not study-related. Participant reported a mild fever. Not study-related. |
|
| Anxiety | Psychiatric disorders | Systematic Assessment | 5 Participants experienced heightened anxiety during study neuroimaging sessions. 2 Participants experienced heightened anxiety during booster sessions. |
|
| Skin Condition | Skin and subcutaneous tissue disorders | Systematic Assessment | 5 Participants reported mild skin irritation following use of electrode gel and and ECG sensors on the chest. 2 Participants reported rashes. Not study-related. |
|
| Stomach Pain | Gastrointestinal disorders | Systematic Assessment | Participant reported stomach pain. Not study-related. |
|
| Head Injury | General disorders | Systematic Assessment | 2 Participants reported head injuries with minor concussions. Not study-related. |
|
| Insomnia | General disorders | Systematic Assessment | Participant reported insomnia lasting 24-hours. Not study-related. |
|
| Muscle Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment | 4 participants reported shoulder pain (one participant reported such pain twice). Not study-related. Participant reported neck stiffness following a neuroimaging visit. Participant reported muscle spasms. Not study-related. |
|
| Chest Pain | Cardiac disorders | Systematic Assessment | Participant reported chest pain following use of chest ECG sensors. |
|
| Headache | Nervous system disorders | Systematic Assessment | Participant reported headache following a booster session. 2 Participants reported headache onset during neuroimaging visits. 3 Participants visited the emergency room to treat severe migraine symptoms. Not study-related. |
|
| Dizziness | General disorders | Systematic Assessment | 2 Pts reported dizziness during autonomic testing. 2 Pts reported dizziness during mindfulness meditation. 5 Pts reported dizziness during IV placement or removal. 10 Pts reported dizziness/nausea/vertigo during neuroimaging. |
|
| Ear Issue | Ear and labyrinth disorders | Systematic Assessment | Participant experienced ongoing vertigo due to fluid buildup in the ear. Not study-related. |
|
| Syncope | General disorders | Systematic Assessment | Participant experienced a syncope event while positive for COVID-19. The participant reported a loss of consciousness for approximately 2 minutes. All tests results came back normal. Not study-related. |
|
| Arterial Line Issue | General disorders | Systematic Assessment | 3 Participants experienced pain, weakness, and bruising on their arm following placement of an arterial line (A-line). 1 Participant developed a lump on their wrist following A-line placement. The lump resolved without treatment. |
|
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| D009422 | Nervous System Diseases |
| Male |
|
| Not Hispanic or Latino |
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| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|