<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/NCT03782194</url>
  </required_header>
  <id_info>
    <org_study_id>IRB#18-000978</org_study_id>
    <nct_id>NCT03782194</nct_id>
  </id_info>
  <brief_title>Low Intensity Focused Ultrasound for Emotion Regulation</brief_title>
  <acronym>LIFUPEMOT</acronym>
  <official_title>Low Intensity Focused Ultrasound as a Non-Invasive Neural Prosthetic for the Improvement of Emotion Regulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Los Angeles</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of California, Los Angeles</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>
      Amygdala is highly involved in emotional response, emotional reactivity and anxiety. Amygdala&#xD;
      functions are therefore involved in a wide range of psychiatric disorders including&#xD;
      generalized and social anxiety, specific phobia, obsessive compulsive disorder and&#xD;
      posttraumatic stress disorder. Therefore, potential clinical implications of amygdala&#xD;
      stimulation are great. However, to date, such efforts have been limited by the inability of&#xD;
      non-invasive neuromodulation techniques (e.g. transcranial magnetic stimulation - TMS) to&#xD;
      reach the amygdala and the highly invasive (i.e. neurosurgical) nature of methods (e.g. deep&#xD;
      brain stimulation - DBS) which can, but to our knowledge has rarely been used, target these&#xD;
      areas. In order to overcome these current limitations, study invesitgators propose the use of&#xD;
      low intensity focused ultrasound pulsation (LIFUP) to affect amygdala activity to improve&#xD;
      emotion regulation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study investigators propose the use of personalized neuronavigation, based on each&#xD;
      participant's structural brain MRI, to aim LIFUP at the amygdala in the pursuit of&#xD;
      enhancement of emotionality in humans. A comprehensive approach will integrate behavioral and&#xD;
      multimodal neuroimaging to assess the utility of LIFUP to increase activity in deep neural&#xD;
      structures and in the regulation of anxiety. Further, this is the first study to use LIFUP in&#xD;
      (A) amygdala in humans and (B) for pro-cognitive effects. Findings from this study will&#xD;
      provide important insight into the utility of LIFUP modulation of subcortical regions and&#xD;
      their associated networks and functions, which have wide ranging implications for clinical&#xD;
      LIFUP as a therapeutic device for numerous patient populations. By characterizing the effect&#xD;
      of LIFUP on the amygdala and associated networks, this study will provide the foundation on&#xD;
      which LIFUP can be validated as an effective neural prosthetic and as a treatment tools for&#xD;
      psychiatric patient populations.&#xD;
&#xD;
      Participants will complete a brief T1-weighted structural brain scan. Then, they will be&#xD;
      removed from the scanner and, using the T1 image in Neurocare Brainsight software, the LIFUP&#xD;
      transducer will be aimed at the amygdala and gently strapped in place to their head.&#xD;
      Participants will then return to the scanner where a second T1 image will verify the position&#xD;
      of the LIFUP transducer and allow for estimation of the spatial location of the sonification&#xD;
      beam focus (approximately .5cm long x 7mm diameter). Blood oxygen level dependent (BOLD)&#xD;
      functional magnetic resonance imaging (fMRI) will be collected during two conditions: short&#xD;
      train sonification LIFUP and sham LIFUP: total time = 20min. Short train LIFUP (previously&#xD;
      used in primary sensory cortices47 will be administered in 75 sonifications at 210 Kilohertz&#xD;
      (KHz) frequency with pulse repetition frequency of 500 Hertz (Hz), 35mW/cm2, sonification&#xD;
      duration 0.5s with 7s inter-stimulation interval. Sham LIFUP will involve the same procedures&#xD;
      (e.g. participant provided the same instructions) except the sonification will not occur.&#xD;
      Before and after completing the scan and a short break, these participants will receive short&#xD;
      train LIFUP while they are administered a series of three computerized, amygdala-mediated&#xD;
      emotion reactivity and regulation tasks. Given that routine clinical neuropsychological&#xD;
      measures are designed to provide diagnostic information and are not sensitive or specific&#xD;
      enough to precisely measure longitudinal emotional change related to an intervention,&#xD;
      investigators will use validated experimental neurocognitive measures.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 28, 2019</start_date>
  <completion_date type="Actual">August 24, 2022</completion_date>
  <primary_completion_date type="Actual">August 24, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants will be blinded to whether or not the LIFUP transducer is on and, when on, what parameters are used. The investigator collecting the neuropsychological data will be blinded to which condition (LIFUP, sham) the participant completed during the session. The statistical analysts for both the neuropsychological and neuroimaging data will also be blinded to condition.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Emotion Reactivity</measure>
    <time_frame>Day 1</time_frame>
    <description>Psychophysiological reactivity, measured via Galvonic skin response, to emotionally salient images.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>BOLD fMRI Signal in the Amygdala</measure>
    <time_frame>Day 1</time_frame>
    <description>BOLD data will be collected in real-time during the ultrasound sonication, which occurs in on-off blocks. Analyses will assess the statistical relationship between BOLD signal in the brain and the time series (on vs off) of the ultrasound sonication.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain</measure>
    <time_frame>Day 1</time_frame>
    <description>Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication in a within subject repeated measures design.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Psychiatric Disorder</condition>
  <condition>Anxiety Disorders</condition>
  <condition>PTSD</condition>
  <condition>Mood Disorders</condition>
  <condition>Social Anxiety</condition>
  <condition>Cognitive Impairment</condition>
  <arm_group>
    <arm_group_label>MRI ultrasound sonication</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low Intensity focused ultrasound pulsation will be administered to participants while they are in the fMRI scanner. Functional and perfusion MRI data will be collected before and after the sonication to allow for comparisons and investigation of pre and post sonication functional activation and connectivity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham Ultrasound</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>While in the fMRI scanner, participants will have the ultrasound transducer attached to their head in the same manner as during the actual ultrasound sonication. However, during this portion of the experiment, the transducer will not be turned on. Previous, published experiments indicate that participants are unable to differentiate between when the transducer is on and off.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Low Intensity Focused Ultrasound Pulsation</intervention_name>
    <description>A low intensity, focused ultrasound pulsation causes mechanical changed without causing heating or cavitation.</description>
    <arm_group_label>MRI ultrasound sonication</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham Ultrasound</intervention_name>
    <description>Low Intensity Focused Ultrasound Pulsation Transducer is left in place on the participant's head but is not turned on during the sham procedure.</description>
    <arm_group_label>Sham Ultrasound</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must be between 18-65 years of age&#xD;
&#xD;
          -  Must be right handed&#xD;
&#xD;
          -  English must be the dominant language&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  contraindications for MRI (e.g. metal implants, pregnancy)&#xD;
&#xD;
          -  history of head injury sufficient to warrant medical attention&#xD;
&#xD;
          -  history of alcohol abuse or dependence&#xD;
&#xD;
          -  history of substance abuse or dependence&#xD;
&#xD;
          -  history of major psychiatric illness requiring treatment&#xD;
&#xD;
          -  history of cancer or other neoplastic syndromes&#xD;
&#xD;
          -  history of major neurologic illness (e.g. epilepsy).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of California, Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>September 12, 2022</last_update_submitted>
  <last_update_submitted_qc>September 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, Los Angeles</investigator_affiliation>
    <investigator_full_name>Taylor Kuhn</investigator_full_name>
    <investigator_title>Adjunct Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Ultrasound</keyword>
  <keyword>MRI</keyword>
  <keyword>Emotion</keyword>
  <keyword>Reactivity</keyword>
  <keyword>Reappraisal</keyword>
  <keyword>Cognitive Neural Prosthetic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anxiety Disorders</mesh_term>
    <mesh_term>Mood Disorders</mesh_term>
    <mesh_term>Mental Disorders</mesh_term>
    <mesh_term>Problem Behavior</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>July 12, 2023</submitted>
    <returned>August 1, 2023</returned>
    <submitted>August 3, 2023</submitted>
    <returned>August 25, 2023</returned>
  </pending_results>
  <!-- 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/NCT03782194
org study id: IRB#18-000978
nct id: NCT03782194
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
Amygdala is highly involved in emotional response, emotional reactivity and anxiety. Amygdala
      functions are therefore involved in a wide range of psychiatric disorders including
      generalized and social anxiety, specific phobia, obsessive compulsive disorder and
      posttraumatic stress disorder. Therefore, potential clinical implications of amygdala
      stimulation are great. However, to date, such efforts have been limited by the inability of
      non-invasive neuromodulation techniques (e.g. transcranial magnetic stimulation - TMS) to
      reach the amygdala and the highly invasive (i.e. neurosurgical) nature of methods (e.g. deep
      brain stimulation - DBS) which can, but to our knowledge has rarely been used, target these
      areas. In order to overcome these current limitations, study invesitgators propose the use of
      low intensity focused ultrasound pulsation (LIFUP) to affect amygdala activity to improve
      emotion regulation.
Study investigators propose the use of personalized neuronavigation, based on each
      participant's structural brain MRI, to aim LIFUP at the amygdala in the pursuit of
      enhancement of emotionality in humans. A comprehensive approach will integrate behavioral and
      multimodal neuroimaging to assess the utility of LIFUP to increase activity in deep neural
      structures and in the regulation of anxiety. Further, this is the first study to use LIFUP in
      (A) amygdala in humans and (B) for pro-cognitive effects. Findings from this study will
      provide important insight into the utility of LIFUP modulation of subcortical regions and
      their associated networks and functions, which have wide ranging implications for clinical
      LIFUP as a therapeutic device for numerous patient populations. By characterizing the effect
      of LIFUP on the amygdala and associated networks, this study will provide the foundation on
      which LIFUP can be validated as an effective neural prosthetic and as a treatment tools for
      psychiatric patient populations.

      Participants will complete a brief T1-weighted structural brain scan. Then, they will be
      removed from the scanner and, using the T1 image in Neurocare Brainsight software, the LIFUP
      transducer will be aimed at the amygdala and gently strapped in place to their head.
      Participants will then return to the scanner where a second T1 image will verify the position
      of the LIFUP transducer and allow for estimation of the spatial location of the sonification
      beam focus (approximately .5cm long x 7mm diameter). Blood oxygen level dependent (BOLD)
      functional magnetic resonance imaging (fMRI) will be collected during two conditions: short
      train sonification LIFUP and sham LIFUP: total time = 20min. Short train LIFUP (previously
      used in primary sensory cortices47 will be administered in 75 sonifications at 210 Kilohertz
      (KHz) frequency with pulse repetition frequency of 500 Hertz (Hz), 35mW/cm2, sonification
      duration 0.5s with 7s inter-stimulation interval. Sham LIFUP will involve the same procedures
      (e.g. participant provided the same instructions) except the sonification will not occur.
      Before and after completing the scan and a short break, these participants will receive short
      train LIFUP while they are administered a series of three computerized, amygdala-mediated
      emotion reactivity and regulation tasks. Given that routine clinical neuropsychological
      measures are designed to provide diagnostic information and are not sensitive or specific
      enough to precisely measure longitudinal emotional change related to an intervention,
      investigators will use validated experimental neurocognitive measures.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: Participants will be blinded to whether or not the LIFUP transducer is on and, when on, what parameters are used. The investigator collecting the neuropsychological data will be blinded to which condition (LIFUP, sham) the participant completed during the session. The statistical analysts for both the neuropsychological and neuroimaging data will also be blinded to condition.
measure: Emotion Reactivity
time frame: Day 1
description: Psychophysiological reactivity, measured via Galvonic skin response, to emotionally salient images.
measure: BOLD fMRI Signal in the Amygdala
time frame: Day 1
description: BOLD data will be collected in real-time during the ultrasound sonication, which occurs in on-off blocks. Analyses will assess the statistical relationship between BOLD signal in the brain and the time series (on vs off) of the ultrasound sonication.
measure: Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain
time frame: Day 1
description: Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication in a within subject repeated measures design.
arm group label: MRI ultrasound sonication
arm group type: Experimental
description: Low Intensity focused ultrasound pulsation will be administered to participants while they are in the fMRI scanner. Functional and perfusion MRI data will be collected before and after the sonication to allow for comparisons and investigation of pre and post sonication functional activation and connectivity.
arm group label: Sham Ultrasound
arm group type: Sham Comparator
description: While in the fMRI scanner, participants will have the ultrasound transducer attached to their head in the same manner as during the actual ultrasound sonication. However, during this portion of the experiment, the transducer will not be turned on. Previous, published experiments indicate that participants are unable to differentiate between when the transducer is on and off.
intervention type: Device
intervention name: Low Intensity Focused Ultrasound Pulsation
description: A low intensity, focused ultrasound pulsation causes mechanical changed without causing heating or cavitation.
arm group label: MRI ultrasound sonication
intervention type: Device
intervention name: Sham Ultrasound
description: Low Intensity Focused Ultrasound Pulsation Transducer is left in place on the participant's head but is not turned on during the sham procedure.
arm group label: Sham Ultrasound
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, Los Angeles
investigator full name: Taylor Kuhn
investigator title: Adjunct Assistant Professor
mesh term: Anxiety Disorders
mesh term: Mood Disorders
mesh term: Mental Disorders
mesh term: Problem Behavior
sharing ipd: Undecided
submitted: July 12, 2023
returned: August 1, 2023
submitted: August 3, 2023
returned: August 25, 2023