<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/NCT03836976</url>
  </required_header>
  <id_info>
    <org_study_id>N3162-P</org_study_id>
    <secondary_id>I21RX003162</secondary_id>
    <nct_id>NCT03836976</nct_id>
  </id_info>
  <brief_title>Detection and Amelioration of Gamma Oscillation Abnormalities in Blast-Related Brain Injury</brief_title>
  <acronym>DAGABBI</acronym>
  <official_title>Detection and Amelioration of Gamma Oscillation Abnormalities in Blast-Related Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Combat Veterans of post-9/11 conflicts have experienced serious cognitive and emotional&#xD;
      problems resulting from exposure to blasts. Recent work suggests that a critical factor&#xD;
      influencing the consequences of blast exposure is distance from the blast, rather than the&#xD;
      presence or absence of concussion symptoms. Exposure to blasts from a distance of &lt;10 m has&#xD;
      been associated with significantly greater cognitive and neural problems than exposure to&#xD;
      blasts from &gt;10 m. So far, the effects of blast-related brain injury on the brain are poorly&#xD;
      understood, as to date the effects of blast exposure have received little research focus. The&#xD;
      investigators propose to use oscillations in the gamma band (30-100 Hz) of the&#xD;
      electroencephalogram (EEG; brain waves) to detect and remediate neural circuit dysfunction&#xD;
      related to blast injury in Veterans. If successful, this project could lead to new approaches&#xD;
      to detect and remediate the effects of blast exposure on Veterans and aid in their functional&#xD;
      recovery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Veterans of recent conflicts have experienced serious cognitive and emotional problems&#xD;
      resulting from exposure to blasts. Recent work suggests that a critical factor in the&#xD;
      sequelae of blast exposure is distance from the blast, rather than the presence or absence of&#xD;
      concussion symptoms. Exposure to blasts from a distance of &lt;10 m has been associated with&#xD;
      significantly greater cognitive and neural disturbances than exposure to blasts from &gt;10 m.&#xD;
      The neural correlates of blast-related brain injury are poorly understood, as to date this&#xD;
      type of brain injury has received little research focus. The investigators propose to use&#xD;
      oscillations in the gamma band (30-100 Hz) of the electroencephalogram (EEG) to detect and&#xD;
      remediate neural circuit dysfunction related to blast injury in Veterans. Gamma band&#xD;
      oscillations have been shown to be involved in several brain functions, including visual&#xD;
      perception, selective attention, working memory, long term memory, and motor control. Recent&#xD;
      studies in animal models have linked the effects of traumatic brain injury to&#xD;
      parvalbumin-expressing (PV+) inhibitory interneurons, which are a critical element of the&#xD;
      cortical circuitry that generates gamma oscillations. PV+ interneuron dysfunction is&#xD;
      associated with deficits in evoked gamma oscillations and increased power of broadband gamma&#xD;
      &quot;noise&quot;, as well as cognitive deficits. It has also recently been shown that stimulation of&#xD;
      PV+ interneurons by patterned stimuli in the gamma band can improve the function of these&#xD;
      interneurons, as well as cognitive function, in animal models of neuropsychiatric disorders.&#xD;
      Hence, the investigators believe that gamma oscillations and stimulation provide promising&#xD;
      targets for investigation in Veterans who suffer from blast-related brain injury. The&#xD;
      investigators will investigate gamma band activity and stimulation in 50 Veterans who will be&#xD;
      recruited from the participant pool of the VA Translational Research Center for TBI and&#xD;
      Stress Disorders (TRACTS) at the VA Boston Healthcare System.&#xD;
&#xD;
        -  Aim 1: To assess whether evoked gamma deficits and increased gamma noise are present in&#xD;
           individuals exposed to Close (&lt;10 m) vs. Far (&gt;10 m) blasts. The investigators predict&#xD;
           that evoked gamma will be reduced in power and phase synchrony, while gamma noise will&#xD;
           be increased in power, in Close compared to Far blast groups.&#xD;
&#xD;
        -  Aim 2: To determine whether gamma oscillation abnormalities associated with close blast&#xD;
           exposure can be remediated by non-invasive patterned sensory stimulation in the gamma&#xD;
           band. The investigators will administer 6 min of auditory steady-state stimulation at 40&#xD;
           Hz. The investigators predict that gamma conditioning will increase evoked gamma&#xD;
           oscillations elicited by tones at the conditioned vs. unconditioned frequency, while&#xD;
           gamma noise will be decreased. These effects will be greater in the Close compared to&#xD;
           the Far blast groups.&#xD;
&#xD;
      This project also has 2 exploratory aims:&#xD;
&#xD;
        -  1) To investigate whether resting state delta-band (1-4 Hz) EEG power is increased in&#xD;
           Close relative to Far blast exposure groups, as delta power is increased in individuals&#xD;
           who have experienced mild traumatic brain injury compared to healthy controls.&#xD;
&#xD;
        -  2) As blast exposure is associated with white matter deficits, and PV+ interneuron axons&#xD;
           are myelinated, the investigators will examine whether gamma abnormalities are&#xD;
           correlated with white matter deficits as assessed by diffusion tensor imaging (DTI)&#xD;
           measures in the auditory cortex, available from the TRACTS database.&#xD;
&#xD;
      In sum, this project seeks to advance the understanding of the effects of blasts on brain&#xD;
      function in Veterans by probing the effects of blast exposure on the neural circuits that&#xD;
      generate gamma oscillations, and by testing whether a new type of non-invasive brain&#xD;
      stimulation can improve brain function in Veterans exposed to blasts. If successful, this&#xD;
      project could lead to new approaches to detect and remediate the effects of blast exposure on&#xD;
      Veterans and aid in their functional recovery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 2, 2019</start_date>
  <completion_date type="Anticipated">July 29, 2025</completion_date>
  <primary_completion_date type="Anticipated">July 30, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Single arm. All participants will receive auditory gamma-frequency sensory stimulation.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in evoked gamma power of conditioned vs. unconditioned tones</measure>
    <time_frame>0 minutes</time_frame>
    <description>Evoked power of the early auditory-evoked gamma oscillation for conditioned vs. unconditioned tones relative to baseline at 0 min after conditioning stimulation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in evoked gamma power of conditioned vs. unconditioned tones</measure>
    <time_frame>20 minutes</time_frame>
    <description>Evoked power of the early auditory-evoked gamma oscillation for conditioned vs. unconditioned tones relative to baseline at 20 min after conditioning stimulation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in spontaneous gamma power</measure>
    <time_frame>0 minutes</time_frame>
    <description>Spontaneous broadband gamma power relative to baseline at 0 min after conditioning stimulation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in spontaneous gamma power</measure>
    <time_frame>20 minutes</time_frame>
    <description>Spontaneous broadband gamma power relative to baseline at 20 min after conditioning stimulation.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>mTBI</condition>
  <arm_group>
    <arm_group_label>All participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants receive auditory gamma sensory stimulation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Auditory gamma sensory stimulation</intervention_name>
    <description>Gamma-conditioning stimulation will be&#xD;
administered in 2 blocks of 3 min each. During each block, participants will be presented with a continuous&#xD;
tone at the CF (500 or 1200 Hz) that will be amplitude modulated at 40 H</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Research participants will be 50 veterans&#xD;
&#xD;
          -  Ages 18-65 years&#xD;
&#xD;
          -  Have experienced blast exposure&#xD;
&#xD;
          -  Recruited from the VA Translational Research Center for TBI and Stress Disorders&#xD;
             (TRACTS) at the VA Boston Healthcare System (VABHS)&#xD;
&#xD;
          -  Half of the participants will have experienced blast exposure from a Close distance&#xD;
             (&lt;10 m)&#xD;
&#xD;
          -  Half of the participants will have experienced blast exposure from a Far distance (&gt;10&#xD;
             m)&#xD;
&#xD;
          -  These groups will be matched on age and female/male ratio&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Initial exclusion criteria for TRACTS are:&#xD;
&#xD;
          -  History of neurological illness&#xD;
&#xD;
               -  Huntington's&#xD;
&#xD;
               -  Parkinson's&#xD;
&#xD;
               -  dementia, etc&#xD;
&#xD;
          -  History of seizure disorders unrelated to head injury&#xD;
&#xD;
          -  Current diagnosis of schizophrenia, bipolar, or other psychotic disorder&#xD;
&#xD;
          -  Self-reported severe depression or anxiety requiring hospitalization overnight, or&#xD;
             current active homicidal and/or suicidal ideation with intent requiring crisis&#xD;
             intervention&#xD;
&#xD;
          -  Cognitive disorder due to general medical condition other than TBI&#xD;
&#xD;
          -  Unstable psychological diagnosis (suspected psychotic or personality disorder) that&#xD;
             would interfere with accurate data collection, determined by consensus of at least&#xD;
             three doctoral-level psychologists.&#xD;
&#xD;
        Additional exclusion criteria for participants in the present project will be:&#xD;
&#xD;
          -  Current alcohol or drug dependence, or abuse within the last 6 months (DSM-IV&#xD;
             criteria)&#xD;
&#xD;
          -  Hearing impairments as assessed by audiometry&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kevin M. Spencer, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kevin M Spencer, PhD</last_name>
    <phone>(774) 826-1375</phone>
    <email>Kevin.Spencer@va.gov</email>
  </overall_contact>
  <location>
    <facility>
      <name>VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02130-4817</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Terence M Keane, PhD</last_name>
      <phone>857-364-4551</phone>
      <email>terry.keane@va.gov</email>
    </contact>
    <investigator>
      <last_name>Kevin M. Spencer, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 30, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>June 8, 2023</last_update_submitted>
  <last_update_submitted_qc>June 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>mild traumatic brain injury</keyword>
  <keyword>EEG</keyword>
  <keyword>neuroplasticity</keyword>
  <keyword>gamma oscillation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</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/NCT03836976
org study id: N3162-P
secondary id: I21RX003162
nct id: NCT03836976
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Combat Veterans of post-9/11 conflicts have experienced serious cognitive and emotional
      problems resulting from exposure to blasts. Recent work suggests that a critical factor
      influencing the consequences of blast exposure is distance from the blast, rather than the
      presence or absence of concussion symptoms. Exposure to blasts from a distance of <10 m has
      been associated with significantly greater cognitive and neural problems than exposure to
      blasts from >10 m. So far, the effects of blast-related brain injury on the brain are poorly
      understood, as to date the effects of blast exposure have received little research focus. The
      investigators propose to use oscillations in the gamma band (30-100 Hz) of the
      electroencephalogram (EEG; brain waves) to detect and remediate neural circuit dysfunction
      related to blast injury in Veterans. If successful, this project could lead to new approaches
      to detect and remediate the effects of blast exposure on Veterans and aid in their functional
      recovery.
Veterans of recent conflicts have experienced serious cognitive and emotional problems
      resulting from exposure to blasts. Recent work suggests that a critical factor in the
      sequelae of blast exposure is distance from the blast, rather than the presence or absence of
      concussion symptoms. Exposure to blasts from a distance of <10 m has been associated with
      significantly greater cognitive and neural disturbances than exposure to blasts from >10 m.
      The neural correlates of blast-related brain injury are poorly understood, as to date this
      type of brain injury has received little research focus. The investigators propose to use
      oscillations in the gamma band (30-100 Hz) of the electroencephalogram (EEG) to detect and
      remediate neural circuit dysfunction related to blast injury in Veterans. Gamma band
      oscillations have been shown to be involved in several brain functions, including visual
      perception, selective attention, working memory, long term memory, and motor control. Recent
      studies in animal models have linked the effects of traumatic brain injury to
      parvalbumin-expressing (PV+) inhibitory interneurons, which are a critical element of the
      cortical circuitry that generates gamma oscillations. PV+ interneuron dysfunction is
      associated with deficits in evoked gamma oscillations and increased power of broadband gamma
      "noise", as well as cognitive deficits. It has also recently been shown that stimulation of
      PV+ interneurons by patterned stimuli in the gamma band can improve the function of these
      interneurons, as well as cognitive function, in animal models of neuropsychiatric disorders.
      Hence, the investigators believe that gamma oscillations and stimulation provide promising
      targets for investigation in Veterans who suffer from blast-related brain injury. The
      investigators will investigate gamma band activity and stimulation in 50 Veterans who will be
      recruited from the participant pool of the VA Translational Research Center for TBI and
      Stress Disorders (TRACTS) at the VA Boston Healthcare System.

        -  Aim 1: To assess whether evoked gamma deficits and increased gamma noise are present in
           individuals exposed to Close (<10 m) vs. Far (>10 m) blasts. The investigators predict
           that evoked gamma will be reduced in power and phase synchrony, while gamma noise will
           be increased in power, in Close compared to Far blast groups.

        -  Aim 2: To determine whether gamma oscillation abnormalities associated with close blast
           exposure can be remediated by non-invasive patterned sensory stimulation in the gamma
           band. The investigators will administer 6 min of auditory steady-state stimulation at 40
           Hz. The investigators predict that gamma conditioning will increase evoked gamma
           oscillations elicited by tones at the conditioned vs. unconditioned frequency, while
           gamma noise will be decreased. These effects will be greater in the Close compared to
           the Far blast groups.

      This project also has 2 exploratory aims:

        -  1) To investigate whether resting state delta-band (1-4 Hz) EEG power is increased in
           Close relative to Far blast exposure groups, as delta power is increased in individuals
           who have experienced mild traumatic brain injury compared to healthy controls.

        -  2) As blast exposure is associated with white matter deficits, and PV+ interneuron axons
           are myelinated, the investigators will examine whether gamma abnormalities are
           correlated with white matter deficits as assessed by diffusion tensor imaging (DTI)
           measures in the auditory cortex, available from the TRACTS database.

      In sum, this project seeks to advance the understanding of the effects of blasts on brain
      function in Veterans by probing the effects of blast exposure on the neural circuits that
      generate gamma oscillations, and by testing whether a new type of non-invasive brain
      stimulation can improve brain function in Veterans exposed to blasts. If successful, this
      project could lead to new approaches to detect and remediate the effects of blast exposure on
      Veterans and aid in their functional recovery.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single arm. All participants will receive auditory gamma-frequency sensory stimulation.
primary purpose: Other
masking: None (Open Label)
measure: Change in evoked gamma power of conditioned vs. unconditioned tones
time frame: 0 minutes
description: Evoked power of the early auditory-evoked gamma oscillation for conditioned vs. unconditioned tones relative to baseline at 0 min after conditioning stimulation.
measure: Change in evoked gamma power of conditioned vs. unconditioned tones
time frame: 20 minutes
description: Evoked power of the early auditory-evoked gamma oscillation for conditioned vs. unconditioned tones relative to baseline at 20 min after conditioning stimulation.
measure: Change in spontaneous gamma power
time frame: 0 minutes
description: Spontaneous broadband gamma power relative to baseline at 0 min after conditioning stimulation.
measure: Change in spontaneous gamma power
time frame: 20 minutes
description: Spontaneous broadband gamma power relative to baseline at 20 min after conditioning stimulation.
arm group label: All participants
arm group type: Experimental
description: All participants receive auditory gamma sensory stimulation.
intervention type: Other
intervention name: Auditory gamma sensory stimulation
description: Gamma-conditioning stimulation will be
administered in 2 blocks of 3 min each. During each block, participants will be presented with a continuous
tone at the CF (500 or 1200 Hz) that will be amplitude modulated at 40 H
arm group label: All participants
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Kevin M. Spencer, PhD
role: Principal Investigator
affiliation: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
last name: Kevin M Spencer, PhD
phone: (774) 826-1375
email: Kevin.Spencer@va.gov
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
sharing ipd: No