<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/NCT03229915</url>
  </required_header>
  <id_info>
    <org_study_id>B2017:029</org_study_id>
    <nct_id>NCT03229915</nct_id>
  </id_info>
  <brief_title>CPT-fMRI Study for PTSD</brief_title>
  <official_title>Identification of Neuroimaging-Based Biomarkers in the Treatment of Posttraumatic Stress Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Workers Compensation Board of Manitoba</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Manitoba</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>
      Posttraumatic stress disorder (PTSD) is prevalent mental illness (~9% life-time) that results&#xD;
      from exposure to trauma. As it is associated with vastly heterogeneous origins, accurate&#xD;
      diagnosis and optimal treatment strategies are sometimes very difficult to achieve. No known&#xD;
      biomarker exists, which makes it difficult to assess treatment response and functional&#xD;
      outcomes. The recent brain imaging studies have suggested that PTSD patients show abnormal&#xD;
      brain connectivity measured by functional magnetic resonance imaging (fMRI). The&#xD;
      investigators propose that cognitive processing therapy may ameliorate this functional&#xD;
      connectivity abnormality which may be related with their symptomatic improvement.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Posttraumatic stress disorder (PTSD) develops when a constellation of symptoms persist&#xD;
      following exposure to traumatic events such as actual or threatened death, serious injury,&#xD;
      and sexual violation, leading to significant interference with occupational and social&#xD;
      functioning. Epidemiological data indicate that the rate of lifetime PTSD in Canada is&#xD;
      approximately 9.2%, with a rate of current PTSD (symptoms for 1 month) estimated to be 2.4%.&#xD;
      Although significant advances have been made in the treatment of PTSD, e.g.,&#xD;
      cognitive-behavioural therapy; pharmacological interventions, a sizable proportion of&#xD;
      individuals do not respond to treatment. The lack of biomarkers and poor understanding of the&#xD;
      pathophysiology has hindered the efforts for advancing treatment of this disorder.&#xD;
&#xD;
      The meta-analysis on functional magnetic resonance imaging (fMRI) studies demonstrated that&#xD;
      patients with PTSD show reliable hyper-activity in the limbic brain regions including the&#xD;
      amygdala and hippocampus, while prefrontal brain regions associated with top-down executive&#xD;
      control, show decreased activity. These findings were in line with traditional neurocircuitry&#xD;
      models proposing that PTSD-related deficits in attention or awareness, including the&#xD;
      inability to suppress attention to trauma-related stimuli, are mediated by decreased&#xD;
      recruitment of the medial prefrontal cortex (PFC) whereas vivid and intrusive trauma&#xD;
      recollections are mediated by exaggerated amygdala activity. While the traditional&#xD;
      neurocircuity model proposed more of a unidirectional relationship (i.e., loss of top-down&#xD;
      prefrontal control results in exaggerated amygdala activity), later research suggested that&#xD;
      dysfunction in the PFC and limbic brain areas may stem from bidirectional alterations in&#xD;
      functional connectivity. An increasingly emerging body of studies has revealed PTSD symptoms&#xD;
      may arise from a breakdown in the interaction between larger-scale, neurocognitive networks.&#xD;
&#xD;
      Recent advances in fMRI methodology have allowed for a more comprehensive assessment of&#xD;
      network interactions in PTSD. Newly developed network analysis techniques have shifted the&#xD;
      focus toward a perspective that views the brain as a network system, and have suggested that&#xD;
      disconnection or hyper-connection between brain regions is more relevant to clinical symptom&#xD;
      expression than regional dysfunction itself. Relatively lower frontal connectivity and&#xD;
      hyper-connectivity of limbic-amygdala circuitry have been found in PTSD. However, due to the&#xD;
      unstable nature of the conventional brain imaging analysis techniques, replication studies&#xD;
      are generally lacking and test-retest variability is too high to be qualified as a&#xD;
      &quot;biomarker&quot; to be used in clinical settings. In the current study, the investigators have&#xD;
      proposed using a novel method that can identify reliable brain network topography and&#xD;
      quantify the degree of abnormality which has great potential to be used as a biomarker for&#xD;
      PTSD.&#xD;
&#xD;
      In a preliminary study, the investigators analyzed the resting state fMRI data of 11 PTSD and&#xD;
      11 trauma-exposed control (TEC) subjects using a novel approach that combines graph theory&#xD;
      and scaled subprofile modeling (SSM), which identifies eigenvector centrality and its&#xD;
      group-discriminating topographical pattern, respectively. The eigenvector centrality&#xD;
      represents how a node is neighboring other important nodes with respect to information flow.&#xD;
      The resulting pattern was characterized by increased eigenvector centrality in the&#xD;
      orbitofrontal regions, left amygdala, left anterior cingulate, right middle frontal and right&#xD;
      angular cortices (Ko &amp; Patel, in preparation). Moreover, the degree of pattern expression was&#xD;
      significantly higher in PTSD patients compared to TEC (t(20)=2.165, p=0.043) and this pattern&#xD;
      expression was correlated with memory performance for negative versus positive information&#xD;
      only in the PTSD group (r=0.641, p=0.034). As SSM typically focuses on the principal&#xD;
      components with &gt;10% variance-accounted-for, it has historically demonstrated high&#xD;
      replicability which lends the proposed method to be a potentially more useful biomarker.&#xD;
&#xD;
      In the proposed project, the investigators will recruit 40 patients with PTSD, 20 patients&#xD;
      with trauma exposure but without PTSD (TEC; 1st control group) and 20 healthy normal subjects&#xD;
      (HC; 2nd control group). All participants will undergo a comprehensive assessment (including&#xD;
      a psychodiagnostic and neuropsychological assessment) followed by resting state fMRI. The&#xD;
      PTSD and TEC groups will then be re-scanned with resting-state fMRI after undergoing 12&#xD;
      sessions of cognitive-processing therapy (CPT; 1 session/week). The HC group will be&#xD;
      rescanned 12 weeks later but no intervention will be introduced. The investigators expect&#xD;
      that the investigators will be able to replicate the preliminary finding described above&#xD;
      (i.e., identifying a PTSD-related network configuration that is not present in the control&#xD;
      groups) and demonstrate that changes within the PTSD-related network pattern expression will&#xD;
      be correlated with clinical improvement after CPT. The anticipated neuroimaging results are&#xD;
      expected to reveal a reliable neurobiological biomarker associated with the treatment (i.e.,&#xD;
      symptom reduction) of PTSD. The use of objective neuroimaging-based biomarkers will benefit&#xD;
      clinicians, patients and caregivers by significantly advancing the ability to establish a&#xD;
      connection between brain-related changes and an improvement in clinical symptoms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">September 30, 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>
    <intervention_model_description>Group 1: PTSD patients Group 2: trauma-exposed control Group 3: no trauma healthy control Group 1 and 2 will undergo CPT.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinician-Administered PTSD Scale (CAPS) for the DSM-V</measure>
    <time_frame>13 weeks</time_frame>
    <description>The CAPS is the current gold-standard for psychodiagnostic assessment of PTSD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>functional connectivity</measure>
    <time_frame>13 weeks</time_frame>
    <description>fMRI-based connectivity analysis</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">68</enrollment>
  <condition>Stress Disorders, Post-Traumatic</condition>
  <arm_group>
    <arm_group_label>PTSD</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Will receive Cognitive Processing Therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Trauma-exponsed control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Will receive Cognitive Processing Therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>no trauma healthy control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Scanned twice (13 weeks apart) without any intervention</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>cognitive processing therapy</intervention_name>
    <description>Group therapy for PTSD patients</description>
    <arm_group_label>PTSD</arm_group_label>
    <arm_group_label>Trauma-exponsed control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION PTSD&#xD;
&#xD;
          1. Current diagnosis of PTSD as assessed by the Clinician Administered PTSD Scale (CAPS)&#xD;
             for the DSM-V [30]; CAPS ≥ 15&#xD;
&#xD;
          2. Presence of at least one intrusion symptom, two negative cognition and mood symptoms,&#xD;
             and two arousal symptoms.&#xD;
&#xD;
        Trauma Exposed Controls&#xD;
&#xD;
          1. experienced a traumatic event (as assessed by criterion A of the CAPS)&#xD;
&#xD;
          2. CAPS &lt; 15 Health Controls&#xD;
&#xD;
        1. Not experienced a traumatic event (as assessed by criterion A of the CAPS ≤15)&#xD;
&#xD;
        EXCLUSION All&#xD;
&#xD;
          1. substance dependence not in remission for at least three months&#xD;
&#xD;
          2. current uncontrolled bipolar or psychotic disorder, or severe cognitive impairment.&#xD;
&#xD;
          3. Contraindications for MRI (e.g., no metal implants, not pregnant)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Manitoba</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3E 0J9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 21, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>February 14, 2023</last_update_submitted>
  <last_update_submitted_qc>February 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Manitoba</investigator_affiliation>
    <investigator_full_name>Ji Hyun Ko, PhD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stress Disorders, Traumatic</mesh_term>
    <mesh_term>Stress Disorders, Post-Traumatic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03229915
org study id: B2017:029
nct id: NCT03229915
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Posttraumatic stress disorder (PTSD) is prevalent mental illness (~9% life-time) that results
      from exposure to trauma. As it is associated with vastly heterogeneous origins, accurate
      diagnosis and optimal treatment strategies are sometimes very difficult to achieve. No known
      biomarker exists, which makes it difficult to assess treatment response and functional
      outcomes. The recent brain imaging studies have suggested that PTSD patients show abnormal
      brain connectivity measured by functional magnetic resonance imaging (fMRI). The
      investigators propose that cognitive processing therapy may ameliorate this functional
      connectivity abnormality which may be related with their symptomatic improvement.
Posttraumatic stress disorder (PTSD) develops when a constellation of symptoms persist
      following exposure to traumatic events such as actual or threatened death, serious injury,
      and sexual violation, leading to significant interference with occupational and social
      functioning. Epidemiological data indicate that the rate of lifetime PTSD in Canada is
      approximately 9.2%, with a rate of current PTSD (symptoms for 1 month) estimated to be 2.4%.
      Although significant advances have been made in the treatment of PTSD, e.g.,
      cognitive-behavioural therapy; pharmacological interventions, a sizable proportion of
      individuals do not respond to treatment. The lack of biomarkers and poor understanding of the
      pathophysiology has hindered the efforts for advancing treatment of this disorder.

      The meta-analysis on functional magnetic resonance imaging (fMRI) studies demonstrated that
      patients with PTSD show reliable hyper-activity in the limbic brain regions including the
      amygdala and hippocampus, while prefrontal brain regions associated with top-down executive
      control, show decreased activity. These findings were in line with traditional neurocircuitry
      models proposing that PTSD-related deficits in attention or awareness, including the
      inability to suppress attention to trauma-related stimuli, are mediated by decreased
      recruitment of the medial prefrontal cortex (PFC) whereas vivid and intrusive trauma
      recollections are mediated by exaggerated amygdala activity. While the traditional
      neurocircuity model proposed more of a unidirectional relationship (i.e., loss of top-down
      prefrontal control results in exaggerated amygdala activity), later research suggested that
      dysfunction in the PFC and limbic brain areas may stem from bidirectional alterations in
      functional connectivity. An increasingly emerging body of studies has revealed PTSD symptoms
      may arise from a breakdown in the interaction between larger-scale, neurocognitive networks.

      Recent advances in fMRI methodology have allowed for a more comprehensive assessment of
      network interactions in PTSD. Newly developed network analysis techniques have shifted the
      focus toward a perspective that views the brain as a network system, and have suggested that
      disconnection or hyper-connection between brain regions is more relevant to clinical symptom
      expression than regional dysfunction itself. Relatively lower frontal connectivity and
      hyper-connectivity of limbic-amygdala circuitry have been found in PTSD. However, due to the
      unstable nature of the conventional brain imaging analysis techniques, replication studies
      are generally lacking and test-retest variability is too high to be qualified as a
      "biomarker" to be used in clinical settings. In the current study, the investigators have
      proposed using a novel method that can identify reliable brain network topography and
      quantify the degree of abnormality which has great potential to be used as a biomarker for
      PTSD.

      In a preliminary study, the investigators analyzed the resting state fMRI data of 11 PTSD and
      11 trauma-exposed control (TEC) subjects using a novel approach that combines graph theory
      and scaled subprofile modeling (SSM), which identifies eigenvector centrality and its
      group-discriminating topographical pattern, respectively. The eigenvector centrality
      represents how a node is neighboring other important nodes with respect to information flow.
      The resulting pattern was characterized by increased eigenvector centrality in the
      orbitofrontal regions, left amygdala, left anterior cingulate, right middle frontal and right
      angular cortices (Ko & Patel, in preparation). Moreover, the degree of pattern expression was
      significantly higher in PTSD patients compared to TEC (t(20)=2.165, p=0.043) and this pattern
      expression was correlated with memory performance for negative versus positive information
      only in the PTSD group (r=0.641, p=0.034). As SSM typically focuses on the principal
      components with >10% variance-accounted-for, it has historically demonstrated high
      replicability which lends the proposed method to be a potentially more useful biomarker.

      In the proposed project, the investigators will recruit 40 patients with PTSD, 20 patients
      with trauma exposure but without PTSD (TEC; 1st control group) and 20 healthy normal subjects
      (HC; 2nd control group). All participants will undergo a comprehensive assessment (including
      a psychodiagnostic and neuropsychological assessment) followed by resting state fMRI. The
      PTSD and TEC groups will then be re-scanned with resting-state fMRI after undergoing 12
      sessions of cognitive-processing therapy (CPT; 1 session/week). The HC group will be
      rescanned 12 weeks later but no intervention will be introduced. The investigators expect
      that the investigators will be able to replicate the preliminary finding described above
      (i.e., identifying a PTSD-related network configuration that is not present in the control
      groups) and demonstrate that changes within the PTSD-related network pattern expression will
      be correlated with clinical improvement after CPT. The anticipated neuroimaging results are
      expected to reveal a reliable neurobiological biomarker associated with the treatment (i.e.,
      symptom reduction) of PTSD. The use of objective neuroimaging-based biomarkers will benefit
      clinicians, patients and caregivers by significantly advancing the ability to establish a
      connection between brain-related changes and an improvement in clinical symptoms.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Group 1: PTSD patients Group 2: trauma-exposed control Group 3: no trauma healthy control Group 1 and 2 will undergo CPT.
primary purpose: Treatment
masking: None (Open Label)
measure: Clinician-Administered PTSD Scale (CAPS) for the DSM-V
time frame: 13 weeks
description: The CAPS is the current gold-standard for psychodiagnostic assessment of PTSD.
measure: functional connectivity
time frame: 13 weeks
description: fMRI-based connectivity analysis
arm group label: PTSD
arm group type: Active Comparator
description: Will receive Cognitive Processing Therapy
arm group label: Trauma-exponsed control
arm group type: Active Comparator
description: Will receive Cognitive Processing Therapy
arm group label: no trauma healthy control
arm group type: No Intervention
description: Scanned twice (13 weeks apart) without any intervention
intervention type: Behavioral
intervention name: cognitive processing therapy
description: Group therapy for PTSD patients
arm group label: PTSD
arm group label: Trauma-exponsed control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of Manitoba
investigator full name: Ji Hyun Ko, PhD
investigator title: Assistant Professor
mesh term: Stress Disorders, Traumatic
mesh term: Stress Disorders, Post-Traumatic
sharing ipd: Undecided