<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04448327</url>
  </required_header>
  <id_info>
    <org_study_id>2020P001212</org_study_id>
    <secondary_id>1U54MH118919-01A1</secondary_id>
    <nct_id>NCT04448327</nct_id>
  </id_info>
  <brief_title>Impact of Transcutaneous Vagal Nerve Stimulation on Stress Response in Major Depression</brief_title>
  <acronym>tVNS_MDD_Sex</acronym>
  <official_title>Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will identify the sex-dependent impact of expiratory-gated transcutaneous vagus&#xD;
      nerve stimulation (tVNS) on the modulation of the stress response circuitry and associated&#xD;
      physiology in major depressive disorder (MDD). We will evaluate a sample of 80 adults with&#xD;
      recurrent MDD randomized to receive active or sham expiratory-gated tVNS during a functional&#xD;
      magnetic resonance imaging (fMRI) session, with simultaneous mood and physiological&#xD;
      assessments. We hypothesize that expiratory-gated tVNS will effectively modulate, in a&#xD;
      sex-dependent manner, specific brainstem-cortical pathways of the stress circuitry and&#xD;
      attenuate physiological deficits in MDD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Major depressive disorder (MDD) is a leading cause of morbidity and disability worldwide with&#xD;
      abnormalities in the stress response circuitry and central autonomic network. Many of these&#xD;
      regions are sexually dimorphic and related with sex differences in mood and&#xD;
      hypothalamic-pituitary-adrenal (HPA) axis modulation, the dysregulation of which is&#xD;
      associated with alterations of hormone and immune responses to stress, autonomic dysfunction&#xD;
      and increased cardiovascular risk. The primary goal of this study is to use non-invasive&#xD;
      neuromodulatory stimulation of the vagus to target the circuitry associated with&#xD;
      stress-immune function and map its neuroanatomic and physiological effects in MDD by sex.&#xD;
      Vagal nerve stimulation (VNS), FDA-approved for MDD, modulates brain circuitry implicated in&#xD;
      mood/anxiety and autonomic regulation, however, it is implanted and thus invasive. We propose&#xD;
      the use of a physiologically-enhanced transcutaneous VNS (tVNS) as a low risk, non-invasive,&#xD;
      and inexpensive alternative. While tVNS has had beneficial effects on depressive&#xD;
      symptomatology and autonomic regulation, current stimulation parameters are based on&#xD;
      historical iVNS data that included mostly male populations. We propose that tVNS effects on&#xD;
      the regulation of specific brainstem-cortical pathways is modulated by sex. Moreover, as the&#xD;
      dorsal medullary vagal system operates in tune with respiration, we recently demonstrated&#xD;
      that tVNS can be optimized by gating stimulation to respiration. Thus, this study proposes to&#xD;
      identify the sex-dependent impact of expiratory-gated tVNS on the modulation of stress&#xD;
      response circuitry alterations and physiological dysregulation of recurrent MDD. We will&#xD;
      evaluate a sample of 80 adults with recurrent MDD randomized to receive active tVNS or sham&#xD;
      stimulation during a functional magnetic resonance imaging (fMRI) session. The fMRI session&#xD;
      will include a stress challenge designed to elicit a sympatho-excitatory state, with&#xD;
      simultaneous mood and physiological assessments, including hormonal and dynamic cardiovagal&#xD;
      heart rate variability (HRV) evaluations. We hypothesize that expiratory-gated tVNS will&#xD;
      effectively modulate specific brainstem-cortical pathways of the stress response circuitry&#xD;
      and will attenuate physiological deficits of recurrent MDD patients. We further hypothesize&#xD;
      that tVNS will impact brain activity and physiology in sex-dependent ways.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 29, 2021</start_date>
  <completion_date type="Anticipated">November 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 15, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Brain activity during functional magnetic resonance imaging (fMRI)</measure>
    <time_frame>1 hour</time_frame>
    <description>Changes in fMRI BOLD signal (percent BOLD signal change) of the stress response circuitry between active and sham tVNS.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cardiac autonomic function during functional magnetic resonance imaging (fMRI)</measure>
    <time_frame>1 hour</time_frame>
    <description>Changes in cardiac autonomic function (High Frequency power-Heart Rate Variability) between active and sham tVNS.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in serum cortisol levels</measure>
    <time_frame>2 hours</time_frame>
    <description>Changes in serum cortisol levels from baseline to post-stimulation will be assessed and compared between active and sham tVNS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum levels of pro-inflammatory cytokines</measure>
    <time_frame>2 hours</time_frame>
    <description>Changes in serum levels of proinflammatory cytokines (IL1B, IL6, TNF alfa) from baseline to post-stimulation will be assessed and compared between active and sham tVNS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in depressive symptoms assessed by the Beck Depression Inventory</measure>
    <time_frame>2 hours</time_frame>
    <description>Changes from baseline to post-stimulation in the score of the Beck Depression Inventory will be compared between active and sham tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Active tVNS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham tVNS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham transcutaneous vagus nerve stimulation on the left auricle</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>active tVNS</intervention_name>
    <description>non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session</description>
    <arm_group_label>Active tVNS</arm_group_label>
    <other_name>transcutaneous vagus nerve stimulation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham tVNS</intervention_name>
    <description>Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session</description>
    <arm_group_label>Sham tVNS</arm_group_label>
    <other_name>transcutaneous vagus nerve stimulation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Current or past diagnosis of recurrent Major Depressive Disorder&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of neuroleptic use&#xD;
&#xD;
          -  Any psychiatric disorder involving a history of psychosis (e.g. schizophrenia, bipolar&#xD;
             I disorder)&#xD;
&#xD;
          -  Active suicidal ideation with intent and/or plan or history of a suicide attempt&#xD;
             within the last year&#xD;
&#xD;
          -  Moderate or severe substance use disorder within the past 12 months&#xD;
&#xD;
          -  Diagnosis of significant cardiovascular or cerebrovascular disease (e.g. congestive&#xD;
             heart failure, stroke, cardiac conduction disorders, history of asystole or&#xD;
             non-sustained ventricular tachycardia)&#xD;
&#xD;
          -  Diseases affecting the CNS (e.g. MS, epilepsy, neurodegenerative diseases, etc.)&#xD;
&#xD;
          -  Traumatic brain injury with cognitive sequelae&#xD;
&#xD;
          -  MRI or tVNS contraindications (e.g. claustrophobia, metallic implants or devices)&#xD;
&#xD;
          -  Pregnancy (uncommon, given the age of this cohort is 50+ years) due to unknown health&#xD;
             risks for the fetus&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ronald G Garcia, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ronald G Garcia, MD, PhD</last_name>
    <phone>617-643-4265</phone>
    <email>rgarciagomez@mgh.harvard.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Vitaly Napadow, PhD</last_name>
    <phone>617-724-3402</phone>
    <email>vitaly@mgh.harvard.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Charlestown</city>
        <state>Massachusetts</state>
        <zip>02129</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ronald G Garcia, MD, PhD</last_name>
      <phone>617-643-4265</phone>
      <email>rgarciagomez@mgh.harvard.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Ronald Garcia</investigator_full_name>
    <investigator_title>Instructor</investigator_title>
  </responsible_party>
  <keyword>Autonomic Nervous System</keyword>
  <keyword>Transcutaneous Vagus Nerve Stimulation</keyword>
  <keyword>Stress Response Circuitry</keyword>
  <keyword>Functional Magnetic Resonance Imaging</keyword>
  <keyword>Sex Differences</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04448327
org study id: 2020P001212
secondary id: 1U54MH118919-01A1
nct id: NCT04448327
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study will identify the sex-dependent impact of expiratory-gated transcutaneous vagus
      nerve stimulation (tVNS) on the modulation of the stress response circuitry and associated
      physiology in major depressive disorder (MDD). We will evaluate a sample of 80 adults with
      recurrent MDD randomized to receive active or sham expiratory-gated tVNS during a functional
      magnetic resonance imaging (fMRI) session, with simultaneous mood and physiological
      assessments. We hypothesize that expiratory-gated tVNS will effectively modulate, in a
      sex-dependent manner, specific brainstem-cortical pathways of the stress circuitry and
      attenuate physiological deficits in MDD.
Major depressive disorder (MDD) is a leading cause of morbidity and disability worldwide with
      abnormalities in the stress response circuitry and central autonomic network. Many of these
      regions are sexually dimorphic and related with sex differences in mood and
      hypothalamic-pituitary-adrenal (HPA) axis modulation, the dysregulation of which is
      associated with alterations of hormone and immune responses to stress, autonomic dysfunction
      and increased cardiovascular risk. The primary goal of this study is to use non-invasive
      neuromodulatory stimulation of the vagus to target the circuitry associated with
      stress-immune function and map its neuroanatomic and physiological effects in MDD by sex.
      Vagal nerve stimulation (VNS), FDA-approved for MDD, modulates brain circuitry implicated in
      mood/anxiety and autonomic regulation, however, it is implanted and thus invasive. We propose
      the use of a physiologically-enhanced transcutaneous VNS (tVNS) as a low risk, non-invasive,
      and inexpensive alternative. While tVNS has had beneficial effects on depressive
      symptomatology and autonomic regulation, current stimulation parameters are based on
      historical iVNS data that included mostly male populations. We propose that tVNS effects on
      the regulation of specific brainstem-cortical pathways is modulated by sex. Moreover, as the
      dorsal medullary vagal system operates in tune with respiration, we recently demonstrated
      that tVNS can be optimized by gating stimulation to respiration. Thus, this study proposes to
      identify the sex-dependent impact of expiratory-gated tVNS on the modulation of stress
      response circuitry alterations and physiological dysregulation of recurrent MDD. We will
      evaluate a sample of 80 adults with recurrent MDD randomized to receive active tVNS or sham
      stimulation during a functional magnetic resonance imaging (fMRI) session. The fMRI session
      will include a stress challenge designed to elicit a sympatho-excitatory state, with
      simultaneous mood and physiological assessments, including hormonal and dynamic cardiovagal
      heart rate variability (HRV) evaluations. We hypothesize that expiratory-gated tVNS will
      effectively modulate specific brainstem-cortical pathways of the stress response circuitry
      and will attenuate physiological deficits of recurrent MDD patients. We further hypothesize
      that tVNS will impact brain activity and physiology in sex-dependent ways.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Outcomes Assessor)
measure: Brain activity during functional magnetic resonance imaging (fMRI)
time frame: 1 hour
description: Changes in fMRI BOLD signal (percent BOLD signal change) of the stress response circuitry between active and sham tVNS.
measure: Cardiac autonomic function during functional magnetic resonance imaging (fMRI)
time frame: 1 hour
description: Changes in cardiac autonomic function (High Frequency power-Heart Rate Variability) between active and sham tVNS.
measure: Change in serum cortisol levels
time frame: 2 hours
description: Changes in serum cortisol levels from baseline to post-stimulation will be assessed and compared between active and sham tVNS
measure: Change in serum levels of pro-inflammatory cytokines
time frame: 2 hours
description: Changes in serum levels of proinflammatory cytokines (IL1B, IL6, TNF alfa) from baseline to post-stimulation will be assessed and compared between active and sham tVNS
measure: Change in depressive symptoms assessed by the Beck Depression Inventory
time frame: 2 hours
description: Changes from baseline to post-stimulation in the score of the Beck Depression Inventory will be compared between active and sham tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)
arm group label: Active tVNS
arm group type: Experimental
description: Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle
arm group label: Sham tVNS
arm group type: Sham Comparator
description: Sham transcutaneous vagus nerve stimulation on the left auricle
intervention type: Device
intervention name: active tVNS
description: non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
arm group label: Active tVNS
other name: transcutaneous vagus nerve stimulation
intervention type: Device
intervention name: Sham tVNS
description: Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
arm group label: Sham tVNS
other name: transcutaneous vagus nerve stimulation
criteria: 
gender: All
minimum age: 50 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ronald G Garcia, MD, PhD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Ronald G Garcia, MD, PhD
phone: 617-643-4265
email: rgarciagomez@mgh.harvard.edu
last name: Vitaly Napadow, PhD
phone: 617-724-3402
email: vitaly@mgh.harvard.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Ronald Garcia
investigator title: Instructor
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
sharing ipd: No