<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/NCT04467164</url>
  </required_header>
  <id_info>
    <org_study_id>2013P001259</org_study_id>
    <secondary_id>R21MH103468</secondary_id>
    <nct_id>NCT04467164</nct_id>
  </id_info>
  <brief_title>Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation</brief_title>
  <acronym>tVNS-MDD</acronym>
  <official_title>Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation</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>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study characterized the impact of respiratory-gated transcutaneous vagus nerve&#xD;
      stimulation (tVNS) on the modulation of the stress response circuitry, vagal tone and&#xD;
      depressed mood in patients with major depressive disorder (MDD). Twenty premenopausal women&#xD;
      with recurrent MDD in an active episode were recruited into a single-blind cross-over study&#xD;
      that included two functional MRI visits within a one week period with simultaneous mood and&#xD;
      physiological assessments. Randomization to exhalatory- or inhalatory-gated tVNS was&#xD;
      performed to control for order effects. The study hypothesis was that exhalatory-gated tVNS&#xD;
      would have a significantly greater impact on the regulation of brain activity in stress&#xD;
      response circuitry, vagal tone and depressed mood in MDD patients compared to&#xD;
      inhalation-gated tVNS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Major depressive disorder (MDD) has been associated with alterations of the stress response&#xD;
      circuitry, including the hypothalamus, amygdala, hippocampus, anterior cingulate cortex,&#xD;
      ventromedial, dorsolateral and orbital prefrontal cortices. Many of these regions are&#xD;
      morphologically and functionally sexually dimorphic and associated with vulnerability for sex&#xD;
      differences in MDD. A major role for the stress response circuitry is to assess potentially&#xD;
      stressful stimuli and respond with a neuroendocrine signal that coordinates homeostatic&#xD;
      responses throughout the body. Neuroimaging studies have suggested that alterations in this&#xD;
      circuitry are implicated in mood dysregulation, increased activation of the&#xD;
      hypothalamic-pituitary-adrenal (HPA) axis, and imbalance between the sympathetic and&#xD;
      parasympathetic nervous system in depressed persons. Thus, the development of novel&#xD;
      interventions that regulate this system may have a significant impact on the improvement of&#xD;
      clinical and physiological alterations of MDD.&#xD;
&#xD;
      Vagal nerve stimulation (VNS) is an FDA approved treatment for MDD that modulates circuitry&#xD;
      implicated in mood regulation. Recently, a non-invasive variant of VNS, transcutaneous&#xD;
      auricular vagus nerve stimulation (tVNS), which targets the auricular branch of the vagus&#xD;
      nerve (ABVN) has been proposed. Moreover, previous studies have suggested that the dorsal&#xD;
      medullary system receiving vagal afference inputs operates in tune with respiration and that&#xD;
      tVNS may be optimized by gating ABVN stimulation to the exhalatory phase of the respiratory&#xD;
      cycle. Thus, this study proposed to characterize the impact of respiratory-gated tVNS on the&#xD;
      modulation of the stress response circuitry, vagal tone and depressed mood in patients with&#xD;
      recurrent major depression (MDD).&#xD;
&#xD;
      Twenty premenopausal women with recurrent MDD in an active episode were recruited into a&#xD;
      single-blind cross-over study that included two functional MRI visits, within a one week&#xD;
      period, with simultaneous mood and physiological assessments. Randomization to exhalatory- or&#xD;
      inhalatory-gated tVNS was performed to control for order effects. Subjects were exposed to a&#xD;
      mild visual stress challenge that preceded and followed 30 minutes of exhalatory- or&#xD;
      inhalatory-gated tVNS. The study hypothesis was that exhalatory-gated tVNS would have a&#xD;
      significantly greater impact on the regulation of brain activity in stress response&#xD;
      circuitry, vagal tone and depressed mood in MDD patients compared to inhalation-gated tVNS&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 15, 2015</start_date>
  <completion_date type="Actual">September 22, 2018</completion_date>
  <primary_completion_date type="Actual">September 15, 2018</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>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Brain activity changes [percent blood oxygenation level dependent signal change] evaluated using functional magnetic resonance imaging during a visual stress challenge</measure>
    <time_frame>1 hour</time_frame>
    <description>Changes in functional magnetic resonance imaging- blood oxygenation level dependent signal (percent signal change) in response to a visual stress challenge compared between exhalatory and inhalatory-gated tVNS</description>
  </primary_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 total score of the Beck Depression Inventory compared between exhalatory and inhalatory-gated tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cardiac autonomic function during functional magnetic resonance imaging</measure>
    <time_frame>1 hour</time_frame>
    <description>Changes from baseline to post-stimulation in cardiac autonomic function (percent change of High Frequency power index) compared between exhalatory- and inhalatory-gated tVNS.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Exhalatory-gated tVNS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>exhalatory-gated tVNS on the left auricle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Inhalatory-gated tVNS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>inhalatory-gated tVNS on the left auricle</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)</intervention_name>
    <description>Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.</description>
    <arm_group_label>Exhalatory-gated tVNS</arm_group_label>
    <other_name>e-RAVANS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)</intervention_name>
    <description>Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.</description>
    <arm_group_label>Inhalatory-gated tVNS</arm_group_label>
    <other_name>i-RAVANS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: Recurrent MDD diagnosis (≥ 2 episodes) with a current active depressive&#xD;
        episode.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of Axis I psychiatric diagnosis other than MDD or anxiety disorder - e.g.,&#xD;
             substance use disorder, psychotic disorder, or bipolar disorder.&#xD;
&#xD;
          -  Current Suicidal Ideation with intent and/or plan or history of suicide attempt within&#xD;
             the last year&#xD;
&#xD;
          -  Use of psychotropic medications within four weeks prior to study with the exception of&#xD;
             Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake&#xD;
             Inhibitors (SNRIs) class of antidepressant medication only&#xD;
&#xD;
          -  Use of Tricyclic antidepressants (TCAs), Monoamine oxidase inhibitors (MAOIs), and&#xD;
             Atypical agents&#xD;
&#xD;
          -  History of cardiovascular disease&#xD;
&#xD;
          -  History of neuroleptic use&#xD;
&#xD;
          -  Past history of substance abuse or dependence within the past 12 months (excludes&#xD;
             nicotine)&#xD;
&#xD;
          -  Bleeding disorder or use of anticoagulants.&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Metallic implants or devices contraindicating magnetic resonance imaging.&#xD;
&#xD;
          -  Use of beta blockers&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>premenopausal women only</gender_description>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jill M Goldstein, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 1, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>July 9, 2020</last_update_submitted>
  <last_update_submitted_qc>July 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Jill M. Goldstein, Ph.D.</investigator_full_name>
    <investigator_title>Professor &amp; Exec. Dir. Innovation Center on Sex Differences in Medicine</investigator_title>
  </responsible_party>
  <keyword>Transcutaneous vagus nerve stimulation</keyword>
  <keyword>Stress response circuitry</keyword>
  <keyword>functional magnetic resonance imaging</keyword>
  <keyword>respiration</keyword>
  <keyword>depression</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/NCT04467164
org study id: 2013P001259
secondary id: R21MH103468
nct id: NCT04467164
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
This study characterized the impact of respiratory-gated transcutaneous vagus nerve
      stimulation (tVNS) on the modulation of the stress response circuitry, vagal tone and
      depressed mood in patients with major depressive disorder (MDD). Twenty premenopausal women
      with recurrent MDD in an active episode were recruited into a single-blind cross-over study
      that included two functional MRI visits within a one week period with simultaneous mood and
      physiological assessments. Randomization to exhalatory- or inhalatory-gated tVNS was
      performed to control for order effects. The study hypothesis was that exhalatory-gated tVNS
      would have a significantly greater impact on the regulation of brain activity in stress
      response circuitry, vagal tone and depressed mood in MDD patients compared to
      inhalation-gated tVNS.
Major depressive disorder (MDD) has been associated with alterations of the stress response
      circuitry, including the hypothalamus, amygdala, hippocampus, anterior cingulate cortex,
      ventromedial, dorsolateral and orbital prefrontal cortices. Many of these regions are
      morphologically and functionally sexually dimorphic and associated with vulnerability for sex
      differences in MDD. A major role for the stress response circuitry is to assess potentially
      stressful stimuli and respond with a neuroendocrine signal that coordinates homeostatic
      responses throughout the body. Neuroimaging studies have suggested that alterations in this
      circuitry are implicated in mood dysregulation, increased activation of the
      hypothalamic-pituitary-adrenal (HPA) axis, and imbalance between the sympathetic and
      parasympathetic nervous system in depressed persons. Thus, the development of novel
      interventions that regulate this system may have a significant impact on the improvement of
      clinical and physiological alterations of MDD.

      Vagal nerve stimulation (VNS) is an FDA approved treatment for MDD that modulates circuitry
      implicated in mood regulation. Recently, a non-invasive variant of VNS, transcutaneous
      auricular vagus nerve stimulation (tVNS), which targets the auricular branch of the vagus
      nerve (ABVN) has been proposed. Moreover, previous studies have suggested that the dorsal
      medullary system receiving vagal afference inputs operates in tune with respiration and that
      tVNS may be optimized by gating ABVN stimulation to the exhalatory phase of the respiratory
      cycle. Thus, this study proposed to characterize the impact of respiratory-gated tVNS on the
      modulation of the stress response circuitry, vagal tone and depressed mood in patients with
      recurrent major depression (MDD).

      Twenty premenopausal women with recurrent MDD in an active episode were recruited into a
      single-blind cross-over study that included two functional MRI visits, within a one week
      period, with simultaneous mood and physiological assessments. Randomization to exhalatory- or
      inhalatory-gated tVNS was performed to control for order effects. Subjects were exposed to a
      mild visual stress challenge that preceded and followed 30 minutes of exhalatory- or
      inhalatory-gated tVNS. The study hypothesis was that exhalatory-gated tVNS would have a
      significantly greater impact on the regulation of brain activity in stress response
      circuitry, vagal tone and depressed mood in MDD patients compared to inhalation-gated tVNS
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: Brain activity changes [percent blood oxygenation level dependent signal change] evaluated using functional magnetic resonance imaging during a visual stress challenge
time frame: 1 hour
description: Changes in functional magnetic resonance imaging- blood oxygenation level dependent signal (percent signal change) in response to a visual stress challenge compared between exhalatory and inhalatory-gated 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 total score of the Beck Depression Inventory compared between exhalatory and inhalatory-gated tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)
measure: Changes in cardiac autonomic function during functional magnetic resonance imaging
time frame: 1 hour
description: Changes from baseline to post-stimulation in cardiac autonomic function (percent change of High Frequency power index) compared between exhalatory- and inhalatory-gated tVNS.
arm group label: Exhalatory-gated tVNS
arm group type: Experimental
description: exhalatory-gated tVNS on the left auricle
arm group label: Inhalatory-gated tVNS
arm group type: Active Comparator
description: inhalatory-gated tVNS on the left auricle
intervention type: Device
intervention name: exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)
description: Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
arm group label: Exhalatory-gated tVNS
other name: e-RAVANS
intervention type: Device
intervention name: Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)
description: Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
arm group label: Inhalatory-gated tVNS
other name: i-RAVANS
criteria: 
gender: Female
gender based: Yes
gender description: premenopausal women only
minimum age: 25 Years
maximum age: 40 Years
healthy volunteers: No
last name: Jill M Goldstein, PhD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Jill M. Goldstein, Ph.D.
investigator title: Professor & Exec. Dir. Innovation Center on Sex Differences in Medicine
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
sharing ipd: No