<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/NCT03244475</url>
  </required_header>
  <id_info>
    <org_study_id>B1988-I</org_study_id>
    <secondary_id>RX001988-01A1</secondary_id>
    <nct_id>NCT03244475</nct_id>
  </id_info>
  <brief_title>Transcranial Electrical Stimulation for mTBI</brief_title>
  <acronym>TES for mTBI</acronym>
  <official_title>Passive Electrical Neurofeedback Treatment of mTBI: MEG and Behavioral Outcomes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>San Diego Veterans Healthcare System</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Mild traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive,&#xD;
      emotional, and behavioral deficits in OEF/OIF/OND Veterans and the general public. However,&#xD;
      the underlying pathophysiology is not completely understood, and there are few effective&#xD;
      treatments for post-concussive symptoms (PCS). In addition, there are substantial overlaps&#xD;
      between PCS and post-traumatic stress disorder (PTSD) symptoms in mTBI. IASIS is among a&#xD;
      class of passive neurofeedback treatments that combine low-intensity pulses for transcranial&#xD;
      electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. Nexalin is&#xD;
      another tES technique , with FDA approvals for treating insomnia, depression, and anxiety.&#xD;
      LIP-tES techniques have shown promising results in alleviating PCS individuals with TBI.&#xD;
      However, the neural mechanisms underlying the effects of LIP-tES treatment in TBI are&#xD;
      unknown, owing to the dearth of neuroimaging investigations of this therapeutic intervention.&#xD;
      Conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting&#xD;
      physiological abnormalities caused by mTBI, or in assessing the efficacy of mTBI treatments.&#xD;
      In acute and chronic phases, CT and MRI are typically negative even in mTBI patients with&#xD;
      persistent PCS. In contrast, evidence is mounting in support of resting-state&#xD;
      magnetoencephalography (rs-MEG) slow-wave source imaging (delta-band, 1-4 Hz) as a marker for&#xD;
      neuronal abnormalities in mTBI. The primary goal of the present application is to use rs-MEG&#xD;
      to identify the neural underpinnings of behavioral changes associated with IASIS treatment in&#xD;
      Veterans with mTBI. Using a double-blind placebo controlled design, the investigators will&#xD;
      study changes in abnormal MEG slow-waves before and after IASIS treatment (relative to a&#xD;
      'sham' treatment group) in Veterans with mTBI. For a subset of participants who may have&#xD;
      remaining TBI symptoms at the end of all IASIS treatment sessions, MEG slow-wave changes will&#xD;
      be recorded before and after additional Nexalin treatment. In addition, the investigators&#xD;
      will examine treatment-related changes in PCS, PTSD symptoms, neuropsychological test&#xD;
      performances, and their association with changes in MEG slow-waves. The investigators for the&#xD;
      first time will address a fundamental question about the mechanism of slow-waves in brain&#xD;
      injury, namely whether slow-wave generation in wakefulness is merely a negative consequence&#xD;
      of neuronal injury or if it is a signature of ongoing neuronal rearrangement and healing that&#xD;
      occurs at the site of the injury. Specific Aim 1 will detect the loci of injury in Veterans&#xD;
      with mTBI and assess the mechanisms underlying functional neuroimaging changes related to&#xD;
      IASIS treatment, and for a subset of Veterans with remaining symptoms, additional Nexalin&#xD;
      treatment, using rs-MEG slow-wave source imaging. The investigators hypothesize that MEG&#xD;
      slow-wave source imaging will show significantly higher sensitivity than conventional MRI in&#xD;
      identifying the loci of injury on a single-subject basis. The investigators also hypothesize&#xD;
      that in wakefulness, slow-wave generation is a signature of ongoing neural rearrangement /&#xD;
      healing, rather than a negative consequence of neuronal injury. Furthermore, the&#xD;
      investigators hypothesize IASIS will ultimately reduce abnormal MEG slow-wave generation in&#xD;
      mTBI by the end of the treatment course, owing to the accomplishment of neural rearrangement&#xD;
      / healing. Specific Aim 2 will examine treatment-related changes in PCS and PTSD symptoms in&#xD;
      Veterans with mTBI. The investigators hypothesize that compared with the sham group, mTBI&#xD;
      Veterans in the IASIS treatment group will show significantly greater decreases in PCS and&#xD;
      PTSD symptoms between baseline and post-treatment assessments. Specific Aim 3 will study the&#xD;
      relationship among IASIS treatment-related changes in rs-MEG slow-wave imaging, PCS, and&#xD;
      neuropsychological measures in Veterans with mTBI. The investigators hypothesize that Reduced&#xD;
      MEG slow-wave generation will correlate with reduced total PCS score, individual PCS scores&#xD;
      (e.g., sleep disturbance, post-traumatic headache, photophobia, and memory problem symptoms),&#xD;
      and improved neuropsychological exam scores between post-IASIS and baseline exams. The&#xD;
      success of the proposed research will for the first time confirm that facilitation of&#xD;
      slow-wave generation in wakefulness leads to significant therapeutic benefits in mTBI,&#xD;
      including an ultimate reduction of abnormal slow-waves accompanied by an improvement in PCS&#xD;
      and cognitive functioning.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mild traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive,&#xD;
      emotional, and behavioral deficits in OEF/OIF/OND Veterans and the general public. However,&#xD;
      the underlying pathophysiology is not completely understood, and there are few effective&#xD;
      treatments for post-concussive symptoms (PCS). In addition, there are substantial overlaps&#xD;
      between PCS and post-traumatic stress disorder (PTSD) symptoms in mTBI. Furthermore, a&#xD;
      substantial number of studies have shown higher (nearly double) rates of comorbid PTSD in&#xD;
      individuals with mTBI, observed in military and civilian settings. IASIS is among a class of&#xD;
      passive neurofeedback treatments that combine low-intensity pulses for transcranial&#xD;
      electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. Nexalin is&#xD;
      another tES technique , with FDA approvals for treating insomnia, depression, and anxiety.&#xD;
      LIP-tES techniques have shown promising results in alleviating PCS in individuals with TBI.&#xD;
      However, the neural mechanisms underlying the effects of LIP-tES treatment in TBI are&#xD;
      unknown, owing to the dearth of neuroimaging investigations of this therapeutic intervention.&#xD;
      Conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting&#xD;
      physiological abnormalities caused by mTBI, or in assessing the efficacy of mTBI treatments.&#xD;
      In acute and chronic phases, CT and MRI are typically negative even in mTBI patients with&#xD;
      persistent PCS. In contrast, evidence is mounting in support of resting-state&#xD;
      magnetoencephalography (rs-MEG) slow-wave source imaging as a non-invasive imaging marker for&#xD;
      neuronal abnormalities in mTBI. Using region of interest (ROI) and voxel-wise approaches, the&#xD;
      investigators demonstrated that MEG slowwave source imaging detects abnormal slow-waves&#xD;
      (delta-band, 1-4 Hz) with ~85% sensitivity in chronic and sub-acute mTBI patients with&#xD;
      persistent PCS. The primary goal of the present application is to use rs- MEG to identify the&#xD;
      neural underpinnings of behavioral changes associated with IASIS treatment in Veterans with&#xD;
      mTBI. Using a double-blind placebo controlled design, the investigators will study changes in&#xD;
      abnormal MEG slowwaves before and after IASIS treatment (relative to a 'sham' treatment&#xD;
      group), and for a subset, before and after additional Nexalin treatment, in Veterans with&#xD;
      mTBI. In addition, the investigators will examine treatment-related changes in PCS, PTSD&#xD;
      symptoms, neuropsychological test performances, and their association with changes in MEG&#xD;
      slow-waves. Pre-treatment baseline and posttreatment rs-MEG exams, symptoms assessments, and&#xD;
      neuropsychological tests will be performed. The investigators for the first time will address&#xD;
      a fundamental question about the mechanism of slow-waves in brain injury, namely whether&#xD;
      slow-wave generation in wakefulness is merely a negative consequence of neuronal injury or if&#xD;
      it is a signature of ongoing neuronal rearrangement and healing that occurs at the site of&#xD;
      the injury.&#xD;
&#xD;
      Specific Aim 1: To detect the loci of injury in Veterans with mTBI and assess the mechanisms&#xD;
      underlying functional neuroimaging changes related to IASIS treatment, and for a subset of&#xD;
      Veterans with remaining symptoms, additional Nexalin treatment, using rs-MEG slow-wave source&#xD;
      imaging. The investigators' voxel-wise rs-MEG source-imaging technique will be used to&#xD;
      identify abnormal slow-wave generation (delta band) in the baseline and post-treatment MEG&#xD;
      exams to assess treatment-related changes on a single-subject basis. Healthy control (HC)&#xD;
      Veterans, matched for combat exposure, will be used to establish an MEG normative database.&#xD;
      Test-retest reliability of MEG slow-wave source imaging for mTBI will also be examined.&#xD;
&#xD;
      Hypothesis 1: Veterans with mTBI will generate abnormal MEG slow-waves during the baseline&#xD;
      MEG exam. Voxel-wise MEG slow-wave source imaging will show significantly higher sensitivity&#xD;
      than conventional MRI in identifying the loci of injury on a single-subject basis. The&#xD;
      test-retest reliability of MEG slow-wave source imaging is expected to be high, with&#xD;
      intra-class correlation coefficient (ICC) 0.75 between two sequential MEG exams.&#xD;
&#xD;
      Hypothesis 2: In wakefulness, slow-wave generation is a signature of ongoing neural&#xD;
      rearrangement/ healing, rather than a negative consequence of neuronal injury. IASIS&#xD;
      treatment will enhance neural rearrangement/healing by initially potentiating slow-wave&#xD;
      generation immediately after each treatment session.&#xD;
&#xD;
      Hypothesis 3: IASIS will ultimately reduce abnormal MEG slow-wave generation in mTBI by the&#xD;
      end of the treatment course, owing to the accomplishment of neural rearrangement / healing.&#xD;
      In Veterans with mTBI who finish IASIS treatment, but not in the sham group, MEG source&#xD;
      imaging will show a significant decrease in abnormal slow-waves at post-treatment exam. Such&#xD;
      significant decreases will also be evident in both the voxel-wise and overall abnormal MEG&#xD;
      slow-wave measures.&#xD;
&#xD;
      Specific Aim 2: To examine treatment-related changes in PCS and PTSD symptoms in Veterans&#xD;
      with mTBI. PCS and PTSD symptoms will be assessed at the baseline and post-treatment&#xD;
      follow-up visits.&#xD;
&#xD;
      Hypothesis 4: Compared with the sham group, mTBI Veterans in the IASIS treatment group will&#xD;
      show significantly greater decreases in PCS symptoms between baseline and post-treatment&#xD;
      assessments.&#xD;
&#xD;
      Hypothesis 5: Compared with the sham group, mTBI Veterans in the IASIS treatment group will&#xD;
      also show significantly greater decreases in PTSD symptoms between baseline and&#xD;
      post-treatment assessments.&#xD;
&#xD;
      Specific Aim 3: To study the relationship among IASIS treatment-related changes in rs-MEG&#xD;
      slow-wave imaging, PCS, and neuropsychological measures in Veterans with mTBI. The&#xD;
      investigators will correlate changes between baseline and post-IASIS abnormal rs-MEG&#xD;
      slow-wave generation (i.e., total abnormal rs-MEG slow-wave and voxel-wise source imaging&#xD;
      measures) with changes in PCS and neuropsychological tests performance.&#xD;
&#xD;
      Hypothesis 6: Reduced MEG slow-wave generation will correlate with reduced total PCS score,&#xD;
      individual PCS scores (e.g., sleep disturbance, post-traumatic headache, photophobia, and&#xD;
      memory problem symptoms), and improved neuropsychological exam scores between post-IASIS and&#xD;
      baseline exams.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 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>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>After consent, Visit 1 (V1) for all 3 groups will include baseline NP and MHA. Then, baseline rs-MEG and MRI will be performed in V2 for all groups. At V3 the mTBI Veterans in IASIS and sham groups will undergo a pre-session MEG, the first IASIS/Sham treatment Session (S1), and a post-session MEG. Next, the mTBI Veterans continue their IASIS/Sham treatments S2-6 in V4-8. During V9, a pair of pre- and post-MEG exams and NP will be performed. The mTBI Veterans will continue treatments S8-11 in V10-13. During V14, a pair of pre- and post-MEG exams will be performed. 1 week after the Veterans finish their final IASIS/Sham treatment S12, a 1-week follow-up MEG and NP will be conducted during V15. A subset of IASIS group will be tested 1 month after the final treatment for a follow-up MEG V16. Veterans in the mTBI-sham group will be offered the real IASIS treatment. If, after IASIS treatment is complete and participants in the mTBI group have remaining PCS, Nexalin treatment will be offered.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>Sham treatment, double-blind design: During the sham treatment, we will prep and preplace the electrodes for common reference, A-, B-, plus the set of electrodes on the scalp of the participant following the 10-20 EEG configuration for A+ and A-, just like the procedure for real IASIS treatment. However, no LIP-tES pulses will be sent from the system during sham treatment, based a code entered to the system. A staff member (SRA #1) will assign a mTBI Veteran to either the mTBI-IASIS or the mTBSham group, with an attached code from an existing code bank. Then, the IASIS treatment operator (SRA #2) who is blind to the group assignment will enter the code to the IASIS system during treatments. Based on the code, the system automatically loads the protocol for either IASIS or Sham treatment. Only at the end of the study (after V16), the group assignment is revealed. Therefore, both the participant and IASIS treatment operator (SRA #2) are blind to the group assignment during the study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Number of Abnormal MEG Slow-Waves</measure>
    <time_frame>Baseline through end of treatment, an average of 6 weeks</time_frame>
    <description>We will develop a voxel-wise whole brain MEG source imaging approach for detecting abnormal MEG slow-waves in mTBI Veterans. MEG slow-wave source imaging will be used as an effective clinical tool for assisting in mTBI diagnosis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Combat and Post-battle Experiences Scales of the Deployed Risk and Resilience Inventory 2</measure>
    <time_frame>Baseline</time_frame>
    <description>At baseline, we will assess combat exposure using the Combat and Post-battle Experiences Scales of the Deployed Risk and Resilience Inventory 2 (DRRI-2), which takes into account the amount level of combat and post-battle exposures, and this coupled with a clinical interview that will detail the amount of times each participant has been exposed to a possible subconcussive blast. In patients with multiple mTBIs, a history of the most recent and all prior mTBIs (life-long) will also be documented for analyzing the effects of repetitive mTBI on MEG slow-wave source imaging. In patients with multiple TBIs, both old and new injuries may contribute to the generation of abnormal MEG slow-waves.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID)</measure>
    <time_frame>Baseline</time_frame>
    <description>Lifetime history of TBI will be assessed using the Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Since sleep is often disrupted in mTBI, the Pittsburgh Sleep Quality Index (PSQI) will be given to assess for 7 different components of sleep: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction over the last month.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The McGill Pain Questionnaire (MGPQ)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>The McGill Pain Questionnaire (MGPQ) will evaluate the level of current pain, pain changes over time, and strength of pain, since pain is frequently co-morbid with mTBI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinician-Administered PTSD Scale (CAPS-5)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>The Clinician- Administered PTSD Scale (CAPS-5) for DSM-5. The CAPS-5 is a standard semi-structured interview used to assess PTSD diagnosis and severity. As part of as a structured interview, the primary traumatic event is elicited and will be used as the basis of assessing PTSD symptoms. The CAPS-5 total symptom severity score is calculated by summing severity scores for the DSM-5 PTSD symptoms that are assessed with this 30 item questionnaire. PTSD diagnostic status will be assessed using the past month version of the CAPS-5. The CAPS-5 has the advantages of categorical (diagnostic) or dimensional scoring of PTSD plus items for assessing social and occupational functioning, dissociation, and the validity of the items. A total severity score of 33 or higher indicates full threshold PTSD. The CAPS-5 past week version quantitative data will be given prior to treatment and at follow-up (Visit 15) and used for evaluation of treatment (IASIS or sham) and for correlation with MEG data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post-Concussion Check List (PCL-5)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>PCL-5 will also be given to track changes in PTSD symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)</measure>
    <time_frame>Baseline</time_frame>
    <description>We will utilize Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to assess alcohol and substance use over the lifetime and frequency of past 3 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alcohol Use Disorders Identification Test (AUDIT)</measure>
    <time_frame>Baseline</time_frame>
    <description>Alcohol Use Disorders Identification Test (AUDIT) will assess alcohol abuse problems.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>California Verbal Learning Test-2nd Edition</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>We will use scaled scores from verbal learning and retrospective memory (California Verbal Learning Test-2nd Edition).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>We will use scaled scores from the WAIS-IV Symbol Search and Coding subtests to compare processing speed. The Digit Span subtest will assess attention and working memory.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delis-Kaplan Executive Function System (DKEFS)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>We will use scaled scores from the DKEFS Verbal Fluency, Trail-Making, and Color-Word Interference subtests to assess executive functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Connors Continuous Performance Task II (CPT-II)</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>The Connors Continuous Performance Task II (CPT-II) will be included as a measure of attention and impulsivity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Barratt Impulsivity Scale</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Impulsivity will also be measured by Barratt Impulsivity Scale a self-report questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frontal Systems Behavior Scale</measure>
    <time_frame>Baseline</time_frame>
    <description>Since frontal lobe areas are more prone to damage, the Frontal Systems Behavior Scale will measure behavioral dysfunction associated with frontal subcortical impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Wechsler Test of Adult Reading</measure>
    <time_frame>Baseline</time_frame>
    <description>The Wechsler Test of Adult Reading will provide an estimate of premorbid ability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Test of Memory Malingering (TOMM)</measure>
    <time_frame>Baseline</time_frame>
    <description>Effort will be assessed using the Test of Memory Malingering (TOMM).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CogState Ltd</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>In order to measure change at multiple time points, we will administer the Detection, Identification, and Two-back tests from CogState Ltd, a tablet-administered battery optimized with multiple versions for use in clinical trials.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conventional MRI T1-weighted 3D-IRSPGR pulse sequence</measure>
    <time_frame>Baseline</time_frame>
    <description>Conventional MRI T1-weighted images will be used to construct a source grid for Fast VESTAL and a boundary element method (BEM) model for MEG forward calculation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Susceptibility-weighted MRI</measure>
    <time_frame>Baseline</time_frame>
    <description>Susceptibility-weighted imaging will also be performed to detect subtle blood products.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Mild Traumatic Brain Injury (mTBI)</condition>
  <condition>Post-traumatic Stress Disorder</condition>
  <arm_group>
    <arm_group_label>Neurofeedback</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>mTBI Veterans blindly assigned to a 6 week IASIS neurofeedback treatment with two sessions per week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham Treatment</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>mTBI Veterans blindly assigned to a sham treatment for 6 weeks with two sessions per week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Veterans who are age-, gender-, education-, combat exposure-, and socioeconomically-matched. They will not undergo a treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nexalin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After IASIS treatment is complete and participants in the mTBI group may have remaining PCS, additional Nexalin treatment will be offered.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>IASIS Micro Current Neurofeedback</intervention_name>
    <description>The EEG interface device is the J&amp;J Engineering I-330 C2, provided specifically for IASIS. The EEG sampling frequency is 256 Hz on each of 2 EEG acquisition channels. The feedback LIP-tES is delivered via the 4 EEG leads (A+, A-, B+, B-), with respect to the Common Neck Reference (isolated). During each session, 2 electrodes (A- and B-) are attached to the participant's left and right mastoids, while the remaining two electrodes (A+ and B+) are moved to various locations on the scalp to record EEG signals. All four (A+, A-, B+, B-) electrodes are involved in applying weak electric current pulses back to the brain (the feedback process). The feedback signal consists two types of narrow pulse trains, both with 150 mV in amplitude: A Type 1 pulse is 25 ms in duration and contains carrier waves at ~50 KHz. The repetition rate of Type 1 pulse train is fixed at 3.6 Hz; A Type 2 pulse is 120 ns in duration and contains carrier waves at ~100 MHz.</description>
    <arm_group_label>Neurofeedback</arm_group_label>
    <arm_group_label>Sham Treatment</arm_group_label>
    <other_name>LIP-tES intervention</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Nexalin</intervention_name>
    <description>The Nexalin device, FDA clearance (501K=K024377, Classification: Stimulator, Cranial Electrotherapy: CFR 882. 5800: U.S. Patent #6904322B2), produces a waveform that provides tES to the brain delivered at a frequency of 77.5 Hz at 0 to 4 mA peak current. There is evidence that this waveform, at this frequency, results in improved clinical outcomes in terms of anxiety and pain. The specific mechanisms of action are not known, but available evidence suggests that this waveform alters the function of the hypothalamus and related structures. In particular, tES may lead to increases in levels of enkephalins and beta-endorphins in brain and CSF. Other data suggest that tES can alter endogenous levels of both substance P and serotonin. Regardless of which neuropeptide or neurotransmitter is ultimately found to be modulated by tES, it is hypothesized that repeated TES treatments over time serve to stimulate long-term neurochemical changes.</description>
    <arm_group_label>Nexalin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion of Veterans for the mTBI groups:&#xD;
&#xD;
          -  All symptomatic mTBI patients will be evaluated in a clinical interview to document&#xD;
             the nature of the injuries and ongoing PCS.&#xD;
&#xD;
          -  The diagnosis of mTBI patients is based on standard VA/DOD diagnostic criteria.&#xD;
&#xD;
          -  Inclusion in the mTBI patient group requires a TBI that meets the following criteria:&#xD;
&#xD;
               -  a loss of consciousness (LOC) &lt; 30 minutes or transient confusion,&#xD;
                  disorientation, or impaired consciousness immediately after the trauma&#xD;
&#xD;
               -  post-traumatic amnesia (PTA) &lt; 24 hours&#xD;
&#xD;
               -  an initial Glasgow Coma Scale (GCS) [90] between 13-15 (if available)&#xD;
&#xD;
          -  Since the GCS assessment is often not available in theater, Veterans with missing GCS,&#xD;
             but who meet other inclusion criteria will also be recruited.&#xD;
&#xD;
          -  Each patient must have at least 3 items of persistent PCS at the beginning of the&#xD;
             study.&#xD;
&#xD;
        Inclusion of Healthy Control (HC) group:&#xD;
&#xD;
          -  Veterans that qualify as HCs will be age, education, combat exposure, and&#xD;
             socioeconomically matched to the mTBI groups.&#xD;
&#xD;
          -  In addition to exclusion criteria listed above, HC subjects must not have been&#xD;
             diagnosed with head injury, affective disorder, or PTSD (CAPS-5 &lt; 8) throughout life.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion criteria for study participations include:&#xD;
&#xD;
          -  history of other neurological, developmental, or psychiatric disorders (based on the&#xD;
             DSM-5 (MINI-7) [86] structured interview), e.g.,:&#xD;
&#xD;
               -  brain tumor&#xD;
&#xD;
               -  stroke&#xD;
&#xD;
               -  epilepsy&#xD;
&#xD;
               -  Alzheimer's disease&#xD;
&#xD;
               -  schizophrenia&#xD;
&#xD;
               -  bipolar disorder&#xD;
&#xD;
               -  ADHD&#xD;
&#xD;
               -  or other chronic neurovascular diseases such as hypertension and diabetes&#xD;
&#xD;
          -  substance or alcohol use disorders according to DSM-5 [87] criteria within the six&#xD;
             months prior to the study&#xD;
&#xD;
          -  history of metabolic or other diseases known to affect the central nervous system (see&#xD;
             [88] for similar criteria)&#xD;
&#xD;
          -  Metal objects (e.g., shrapnel or metal fragments) that fail MRI screening, or&#xD;
             extensive metal dental hardware, e.g.,:&#xD;
&#xD;
               -  braces and large metal dentures&#xD;
&#xD;
                    -  fillings are acceptable&#xD;
&#xD;
               -  other metal objects in the head&#xD;
&#xD;
               -  neck, or face areas that cause non-removable artifacts in the MEG data&#xD;
&#xD;
          -  Potential subjects will be administered the Beck Depression Inventory (BDI-II) to&#xD;
             evaluate level of depressive symptoms, and suicidal ideation&#xD;
&#xD;
               -  any participant who reports a &quot;2&quot; or &quot;3&quot; on the BDI-II: item 9 (suicidal thoughts&#xD;
                  or wishes) will also be excluded.&#xD;
&#xD;
               -  However, depression following mTBI or traumatic event of PTSD is common [89]:&#xD;
                  therefore, in two mTBI groups, the investigators will include and match patients&#xD;
                  with depression symptoms reported after their injury/event, and will co-vary&#xD;
                  BDI-II score in data analyses.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mingxiong Huang, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA San Diego Healthcare System, San Diego, CA</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA San Diego Healthcare System, San Diego, CA</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92161</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Huang MX, Nichols S, Baker DG, Robb A, Angeles A, Yurgil KA, Drake A, Levy M, Song T, McLay R, Theilmann RJ, Diwakar M, Risbrough VB, Ji Z, Huang CW, Chang DG, Harrington DL, Muzzatti L, Canive JM, Christopher Edgar J, Chen YH, Lee RR. Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury. Neuroimage Clin. 2014 Jun 16;5:109-19. doi: 10.1016/j.nicl.2014.06.004. eCollection 2014.</citation>
    <PMID>25009772</PMID>
  </reference>
  <reference>
    <citation>Huang M, Risling M, Baker DG. The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury. Psychoneuroendocrinology. 2016 Jan;63:398-409. doi: 10.1016/j.psyneuen.2015.02.008. Epub 2015 Feb 23.</citation>
    <PMID>25769625</PMID>
  </reference>
  <reference>
    <citation>Robb Swan A, Nichols S, Drake A, Angeles A, Diwakar M, Song T, Lee RR, Huang MX. Magnetoencephalography Slow-Wave Detection in Patients with Mild Traumatic Brain Injury and Ongoing Symptoms Correlated with Long-Term Neuropsychological Outcome. J Neurotrauma. 2015 Oct 1;32(19):1510-21. doi: 10.1089/neu.2014.3654. Epub 2015 Jun 18.</citation>
    <PMID>25808909</PMID>
  </reference>
  <reference>
    <citation>MacGregor AJ, Dougherty AL, Galarneau MR. Injury-specific correlates of combat-related traumatic brain injury in Operation Iraqi Freedom. J Head Trauma Rehabil. 2011 Jul-Aug;26(4):312-8. doi: 10.1097/HTR.0b013e3181e94404.</citation>
    <PMID>20808241</PMID>
  </reference>
  <reference>
    <citation>MacDonald CL, Johnson AM, Nelson EC, Werner NJ, Fang R, Flaherty SF, Brody DL. Functional status after blast-plus-impact complex concussive traumatic brain injury in evacuated United States military personnel. J Neurotrauma. 2014 May 15;31(10):889-98. doi: 10.1089/neu.2013.3173. Epub 2014 Feb 10.</citation>
    <PMID>24367929</PMID>
  </reference>
  <reference>
    <citation>Hoffman SW, Harrison C. The interaction between psychological health and traumatic brain injury: a neuroscience perspective. Clin Neuropsychol. 2009 Nov;23(8):1400-15. doi: 10.1080/13854040903369433.</citation>
    <PMID>19882478</PMID>
  </reference>
  <reference>
    <citation>Vasterling JJ, Brailey K, Proctor SP, Kane R, Heeren T, Franz M. Neuropsychological outcomes of mild traumatic brain injury, post-traumatic stress disorder and depression in Iraq-deployed US Army soldiers. Br J Psychiatry. 2012 Sep;201(3):186-92. doi: 10.1192/bjp.bp.111.096461. Epub 2012 Jun 28.</citation>
    <PMID>22743844</PMID>
  </reference>
  <reference>
    <citation>Nelson DV, Esty ML. Neurotherapy of Traumatic Brain Injury/Post-Traumatic Stress Symptoms in Vietnam Veterans. Mil Med. 2015 Oct;180(10):e1111-4. doi: 10.7205/MILMED-D-14-00696.</citation>
    <PMID>26444476</PMID>
  </reference>
  <reference>
    <citation>Schoenberger NE, Shif SC, Esty ML, Ochs L, Matheis RJ. Flexyx Neurotherapy System in the treatment of traumatic brain injury: an initial evaluation. J Head Trauma Rehabil. 2001 Jun;16(3):260-74. doi: 10.1097/00001199-200106000-00005.</citation>
    <PMID>11346448</PMID>
  </reference>
  <reference>
    <citation>Huang MX, Nichols S, Robb A, Angeles A, Drake A, Holland M, Asmussen S, D'Andrea J, Chun W, Levy M, Cui L, Song T, Baker DG, Hammer P, McLay R, Theilmann RJ, Coimbra R, Diwakar M, Boyd C, Neff J, Liu TT, Webb-Murphy J, Farinpour R, Cheung C, Harrington DL, Heister D, Lee RR. An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. Neuroimage. 2012 Jul 16;61(4):1067-82. doi: 10.1016/j.neuroimage.2012.04.029. Epub 2012 Apr 20.</citation>
    <PMID>22542638</PMID>
  </reference>
  <reference>
    <citation>Huang MX, Theilmann RJ, Robb A, Angeles A, Nichols S, Drake A, D'Andrea J, Levy M, Holland M, Song T, Ge S, Hwang E, Yoo K, Cui L, Baker DG, Trauner D, Coimbra R, Lee RR. Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients. J Neurotrauma. 2009 Aug;26(8):1213-26. doi: 10.1089/neu.2008.0672.</citation>
    <PMID>19385722</PMID>
  </reference>
  <reference>
    <citation>Lewine JD, Davis JT, Bigler ED, Thoma R, Hill D, Funke M, Sloan JH, Hall S, Orrison WW. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J Head Trauma Rehabil. 2007 May-Jun;22(3):141-55. doi: 10.1097/01.HTR.0000271115.29954.27.</citation>
    <PMID>17510590</PMID>
  </reference>
  <reference>
    <citation>Lewine JD, Davis JT, Sloan JH, Kodituwakku PW, Orrison WW Jr. Neuromagnetic assessment of pathophysiologic brain activity induced by minor head trauma. AJNR Am J Neuroradiol. 1999 May;20(5):857-66.</citation>
    <PMID>10369357</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>October 24, 2022</last_update_submitted>
  <last_update_submitted_qc>October 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>mild Traumatic Brain Injury</keyword>
  <keyword>transcranial electrical stimulation</keyword>
  <keyword>neurofeedback</keyword>
  <keyword>magnetoencephalography</keyword>
  <keyword>post-traumatic stress disorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Brain Concussion</mesh_term>
    <mesh_term>Stress Disorders, Traumatic</mesh_term>
    <mesh_term>Stress Disorders, Post-Traumatic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>One or more data sets without personal identifiers will be generated during the data analysis phase of this study. Publications from this research will be made available to the public through the National Library of Medicine PubMed Central website within one year after the date of publication. The data sets will include all data underlying any publications generated by this study and therefore, these will be sufficient to reproduce or verify any published findings.&#xD;
Requests for access to final data sets must be made in writing signed by a requestor from the United States and include an email address for delivery and an assurance that the recipient will not attempt to identify or re-identify any individual. The request should reference the publication underlying the request. Requests may be made to the PI/lead point-of-contact for the publication. If the investigator leaves the VASDHS the requests may be sent to the Associate Chief of Staff for Research.</ipd_description>
  </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/NCT03244475
org study id: B1988-I
secondary id: RX001988-01A1
nct id: NCT03244475
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Mild traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive,
      emotional, and behavioral deficits in OEF/OIF/OND Veterans and the general public. However,
      the underlying pathophysiology is not completely understood, and there are few effective
      treatments for post-concussive symptoms (PCS). In addition, there are substantial overlaps
      between PCS and post-traumatic stress disorder (PTSD) symptoms in mTBI. IASIS is among a
      class of passive neurofeedback treatments that combine low-intensity pulses for transcranial
      electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. Nexalin is
      another tES technique , with FDA approvals for treating insomnia, depression, and anxiety.
      LIP-tES techniques have shown promising results in alleviating PCS individuals with TBI.
      However, the neural mechanisms underlying the effects of LIP-tES treatment in TBI are
      unknown, owing to the dearth of neuroimaging investigations of this therapeutic intervention.
      Conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting
      physiological abnormalities caused by mTBI, or in assessing the efficacy of mTBI treatments.
      In acute and chronic phases, CT and MRI are typically negative even in mTBI patients with
      persistent PCS. In contrast, evidence is mounting in support of resting-state
      magnetoencephalography (rs-MEG) slow-wave source imaging (delta-band, 1-4 Hz) as a marker for
      neuronal abnormalities in mTBI. The primary goal of the present application is to use rs-MEG
      to identify the neural underpinnings of behavioral changes associated with IASIS treatment in
      Veterans with mTBI. Using a double-blind placebo controlled design, the investigators will
      study changes in abnormal MEG slow-waves before and after IASIS treatment (relative to a
      'sham' treatment group) in Veterans with mTBI. For a subset of participants who may have
      remaining TBI symptoms at the end of all IASIS treatment sessions, MEG slow-wave changes will
      be recorded before and after additional Nexalin treatment. In addition, the investigators
      will examine treatment-related changes in PCS, PTSD symptoms, neuropsychological test
      performances, and their association with changes in MEG slow-waves. The investigators for the
      first time will address a fundamental question about the mechanism of slow-waves in brain
      injury, namely whether slow-wave generation in wakefulness is merely a negative consequence
      of neuronal injury or if it is a signature of ongoing neuronal rearrangement and healing that
      occurs at the site of the injury. Specific Aim 1 will detect the loci of injury in Veterans
      with mTBI and assess the mechanisms underlying functional neuroimaging changes related to
      IASIS treatment, and for a subset of Veterans with remaining symptoms, additional Nexalin
      treatment, using rs-MEG slow-wave source imaging. The investigators hypothesize that MEG
      slow-wave source imaging will show significantly higher sensitivity than conventional MRI in
      identifying the loci of injury on a single-subject basis. The investigators also hypothesize
      that in wakefulness, slow-wave generation is a signature of ongoing neural rearrangement /
      healing, rather than a negative consequence of neuronal injury. Furthermore, the
      investigators hypothesize IASIS will ultimately reduce abnormal MEG slow-wave generation in
      mTBI by the end of the treatment course, owing to the accomplishment of neural rearrangement
      / healing. Specific Aim 2 will examine treatment-related changes in PCS and PTSD symptoms in
      Veterans with mTBI. The investigators hypothesize that compared with the sham group, mTBI
      Veterans in the IASIS treatment group will show significantly greater decreases in PCS and
      PTSD symptoms between baseline and post-treatment assessments. Specific Aim 3 will study the
      relationship among IASIS treatment-related changes in rs-MEG slow-wave imaging, PCS, and
      neuropsychological measures in Veterans with mTBI. The investigators hypothesize that Reduced
      MEG slow-wave generation will correlate with reduced total PCS score, individual PCS scores
      (e.g., sleep disturbance, post-traumatic headache, photophobia, and memory problem symptoms),
      and improved neuropsychological exam scores between post-IASIS and baseline exams. The
      success of the proposed research will for the first time confirm that facilitation of
      slow-wave generation in wakefulness leads to significant therapeutic benefits in mTBI,
      including an ultimate reduction of abnormal slow-waves accompanied by an improvement in PCS
      and cognitive functioning.
Mild traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive,
      emotional, and behavioral deficits in OEF/OIF/OND Veterans and the general public. However,
      the underlying pathophysiology is not completely understood, and there are few effective
      treatments for post-concussive symptoms (PCS). In addition, there are substantial overlaps
      between PCS and post-traumatic stress disorder (PTSD) symptoms in mTBI. Furthermore, a
      substantial number of studies have shown higher (nearly double) rates of comorbid PTSD in
      individuals with mTBI, observed in military and civilian settings. IASIS is among a class of
      passive neurofeedback treatments that combine low-intensity pulses for transcranial
      electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring. Nexalin is
      another tES technique , with FDA approvals for treating insomnia, depression, and anxiety.
      LIP-tES techniques have shown promising results in alleviating PCS in individuals with TBI.
      However, the neural mechanisms underlying the effects of LIP-tES treatment in TBI are
      unknown, owing to the dearth of neuroimaging investigations of this therapeutic intervention.
      Conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting
      physiological abnormalities caused by mTBI, or in assessing the efficacy of mTBI treatments.
      In acute and chronic phases, CT and MRI are typically negative even in mTBI patients with
      persistent PCS. In contrast, evidence is mounting in support of resting-state
      magnetoencephalography (rs-MEG) slow-wave source imaging as a non-invasive imaging marker for
      neuronal abnormalities in mTBI. Using region of interest (ROI) and voxel-wise approaches, the
      investigators demonstrated that MEG slowwave source imaging detects abnormal slow-waves
      (delta-band, 1-4 Hz) with ~85% sensitivity in chronic and sub-acute mTBI patients with
      persistent PCS. The primary goal of the present application is to use rs- MEG to identify the
      neural underpinnings of behavioral changes associated with IASIS treatment in Veterans with
      mTBI. Using a double-blind placebo controlled design, the investigators will study changes in
      abnormal MEG slowwaves before and after IASIS treatment (relative to a 'sham' treatment
      group), and for a subset, before and after additional Nexalin treatment, in Veterans with
      mTBI. In addition, the investigators will examine treatment-related changes in PCS, PTSD
      symptoms, neuropsychological test performances, and their association with changes in MEG
      slow-waves. Pre-treatment baseline and posttreatment rs-MEG exams, symptoms assessments, and
      neuropsychological tests will be performed. The investigators for the first time will address
      a fundamental question about the mechanism of slow-waves in brain injury, namely whether
      slow-wave generation in wakefulness is merely a negative consequence of neuronal injury or if
      it is a signature of ongoing neuronal rearrangement and healing that occurs at the site of
      the injury.

      Specific Aim 1: To detect the loci of injury in Veterans with mTBI and assess the mechanisms
      underlying functional neuroimaging changes related to IASIS treatment, and for a subset of
      Veterans with remaining symptoms, additional Nexalin treatment, using rs-MEG slow-wave source
      imaging. The investigators' voxel-wise rs-MEG source-imaging technique will be used to
      identify abnormal slow-wave generation (delta band) in the baseline and post-treatment MEG
      exams to assess treatment-related changes on a single-subject basis. Healthy control (HC)
      Veterans, matched for combat exposure, will be used to establish an MEG normative database.
      Test-retest reliability of MEG slow-wave source imaging for mTBI will also be examined.

      Hypothesis 1: Veterans with mTBI will generate abnormal MEG slow-waves during the baseline
      MEG exam. Voxel-wise MEG slow-wave source imaging will show significantly higher sensitivity
      than conventional MRI in identifying the loci of injury on a single-subject basis. The
      test-retest reliability of MEG slow-wave source imaging is expected to be high, with
      intra-class correlation coefficient (ICC) 0.75 between two sequential MEG exams.

      Hypothesis 2: In wakefulness, slow-wave generation is a signature of ongoing neural
      rearrangement/ healing, rather than a negative consequence of neuronal injury. IASIS
      treatment will enhance neural rearrangement/healing by initially potentiating slow-wave
      generation immediately after each treatment session.

      Hypothesis 3: IASIS will ultimately reduce abnormal MEG slow-wave generation in mTBI by the
      end of the treatment course, owing to the accomplishment of neural rearrangement / healing.
      In Veterans with mTBI who finish IASIS treatment, but not in the sham group, MEG source
      imaging will show a significant decrease in abnormal slow-waves at post-treatment exam. Such
      significant decreases will also be evident in both the voxel-wise and overall abnormal MEG
      slow-wave measures.

      Specific Aim 2: To examine treatment-related changes in PCS and PTSD symptoms in Veterans
      with mTBI. PCS and PTSD symptoms will be assessed at the baseline and post-treatment
      follow-up visits.

      Hypothesis 4: Compared with the sham group, mTBI Veterans in the IASIS treatment group will
      show significantly greater decreases in PCS symptoms between baseline and post-treatment
      assessments.

      Hypothesis 5: Compared with the sham group, mTBI Veterans in the IASIS treatment group will
      also show significantly greater decreases in PTSD symptoms between baseline and
      post-treatment assessments.

      Specific Aim 3: To study the relationship among IASIS treatment-related changes in rs-MEG
      slow-wave imaging, PCS, and neuropsychological measures in Veterans with mTBI. The
      investigators will correlate changes between baseline and post-IASIS abnormal rs-MEG
      slow-wave generation (i.e., total abnormal rs-MEG slow-wave and voxel-wise source imaging
      measures) with changes in PCS and neuropsychological tests performance.

      Hypothesis 6: Reduced MEG slow-wave generation will correlate with reduced total PCS score,
      individual PCS scores (e.g., sleep disturbance, post-traumatic headache, photophobia, and
      memory problem symptoms), and improved neuropsychological exam scores between post-IASIS and
      baseline exams.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: After consent, Visit 1 (V1) for all 3 groups will include baseline NP and MHA. Then, baseline rs-MEG and MRI will be performed in V2 for all groups. At V3 the mTBI Veterans in IASIS and sham groups will undergo a pre-session MEG, the first IASIS/Sham treatment Session (S1), and a post-session MEG. Next, the mTBI Veterans continue their IASIS/Sham treatments S2-6 in V4-8. During V9, a pair of pre- and post-MEG exams and NP will be performed. The mTBI Veterans will continue treatments S8-11 in V10-13. During V14, a pair of pre- and post-MEG exams will be performed. 1 week after the Veterans finish their final IASIS/Sham treatment S12, a 1-week follow-up MEG and NP will be conducted during V15. A subset of IASIS group will be tested 1 month after the final treatment for a follow-up MEG V16. Veterans in the mTBI-sham group will be offered the real IASIS treatment. If, after IASIS treatment is complete and participants in the mTBI group have remaining PCS, Nexalin treatment will be offered.
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: Sham treatment, double-blind design: During the sham treatment, we will prep and preplace the electrodes for common reference, A-, B-, plus the set of electrodes on the scalp of the participant following the 10-20 EEG configuration for A+ and A-, just like the procedure for real IASIS treatment. However, no LIP-tES pulses will be sent from the system during sham treatment, based a code entered to the system. A staff member (SRA #1) will assign a mTBI Veteran to either the mTBI-IASIS or the mTBSham group, with an attached code from an existing code bank. Then, the IASIS treatment operator (SRA #2) who is blind to the group assignment will enter the code to the IASIS system during treatments. Based on the code, the system automatically loads the protocol for either IASIS or Sham treatment. Only at the end of the study (after V16), the group assignment is revealed. Therefore, both the participant and IASIS treatment operator (SRA #2) are blind to the group assignment during the study.
measure: Change in Number of Abnormal MEG Slow-Waves
time frame: Baseline through end of treatment, an average of 6 weeks
description: We will develop a voxel-wise whole brain MEG source imaging approach for detecting abnormal MEG slow-waves in mTBI Veterans. MEG slow-wave source imaging will be used as an effective clinical tool for assisting in mTBI diagnosis.
measure: Combat and Post-battle Experiences Scales of the Deployed Risk and Resilience Inventory 2
time frame: Baseline
description: At baseline, we will assess combat exposure using the Combat and Post-battle Experiences Scales of the Deployed Risk and Resilience Inventory 2 (DRRI-2), which takes into account the amount level of combat and post-battle exposures, and this coupled with a clinical interview that will detail the amount of times each participant has been exposed to a possible subconcussive blast. In patients with multiple mTBIs, a history of the most recent and all prior mTBIs (life-long) will also be documented for analyzing the effects of repetitive mTBI on MEG slow-wave source imaging. In patients with multiple TBIs, both old and new injuries may contribute to the generation of abnormal MEG slow-waves.
measure: Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID)
time frame: Baseline
description: Lifetime history of TBI will be assessed using the Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID).
measure: Pittsburgh Sleep Quality Index (PSQI)
time frame: Up to 6 weeks
description: Since sleep is often disrupted in mTBI, the Pittsburgh Sleep Quality Index (PSQI) will be given to assess for 7 different components of sleep: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction over the last month.
measure: The McGill Pain Questionnaire (MGPQ)
time frame: Up to 6 weeks
description: The McGill Pain Questionnaire (MGPQ) will evaluate the level of current pain, pain changes over time, and strength of pain, since pain is frequently co-morbid with mTBI.
measure: Clinician-Administered PTSD Scale (CAPS-5)
time frame: Up to 6 weeks
description: The Clinician- Administered PTSD Scale (CAPS-5) for DSM-5. The CAPS-5 is a standard semi-structured interview used to assess PTSD diagnosis and severity. As part of as a structured interview, the primary traumatic event is elicited and will be used as the basis of assessing PTSD symptoms. The CAPS-5 total symptom severity score is calculated by summing severity scores for the DSM-5 PTSD symptoms that are assessed with this 30 item questionnaire. PTSD diagnostic status will be assessed using the past month version of the CAPS-5. The CAPS-5 has the advantages of categorical (diagnostic) or dimensional scoring of PTSD plus items for assessing social and occupational functioning, dissociation, and the validity of the items. A total severity score of 33 or higher indicates full threshold PTSD. The CAPS-5 past week version quantitative data will be given prior to treatment and at follow-up (Visit 15) and used for evaluation of treatment (IASIS or sham) and for correlation with MEG data.
measure: Post-Concussion Check List (PCL-5)
time frame: Up to 6 weeks
description: PCL-5 will also be given to track changes in PTSD symptoms.
measure: Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)
time frame: Baseline
description: We will utilize Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to assess alcohol and substance use over the lifetime and frequency of past 3 months.
measure: Alcohol Use Disorders Identification Test (AUDIT)
time frame: Baseline
description: Alcohol Use Disorders Identification Test (AUDIT) will assess alcohol abuse problems.
measure: California Verbal Learning Test-2nd Edition
time frame: Up to 6 weeks
description: We will use scaled scores from verbal learning and retrospective memory (California Verbal Learning Test-2nd Edition).
measure: Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV)
time frame: Up to 6 weeks
description: We will use scaled scores from the WAIS-IV Symbol Search and Coding subtests to compare processing speed. The Digit Span subtest will assess attention and working memory.
measure: Delis-Kaplan Executive Function System (DKEFS)
time frame: Up to 6 weeks
description: We will use scaled scores from the DKEFS Verbal Fluency, Trail-Making, and Color-Word Interference subtests to assess executive functioning.
measure: Connors Continuous Performance Task II (CPT-II)
time frame: Up to 6 weeks
description: The Connors Continuous Performance Task II (CPT-II) will be included as a measure of attention and impulsivity.
measure: Barratt Impulsivity Scale
time frame: Up to 6 weeks
description: Impulsivity will also be measured by Barratt Impulsivity Scale a self-report questionnaire.
measure: Frontal Systems Behavior Scale
time frame: Baseline
description: Since frontal lobe areas are more prone to damage, the Frontal Systems Behavior Scale will measure behavioral dysfunction associated with frontal subcortical impairment.
measure: Wechsler Test of Adult Reading
time frame: Baseline
description: The Wechsler Test of Adult Reading will provide an estimate of premorbid ability.
measure: Test of Memory Malingering (TOMM)
time frame: Baseline
description: Effort will be assessed using the Test of Memory Malingering (TOMM).
measure: CogState Ltd
time frame: Up to 6 weeks
description: In order to measure change at multiple time points, we will administer the Detection, Identification, and Two-back tests from CogState Ltd, a tablet-administered battery optimized with multiple versions for use in clinical trials.
measure: Conventional MRI T1-weighted 3D-IRSPGR pulse sequence
time frame: Baseline
description: Conventional MRI T1-weighted images will be used to construct a source grid for Fast VESTAL and a boundary element method (BEM) model for MEG forward calculation.
measure: Susceptibility-weighted MRI
time frame: Baseline
description: Susceptibility-weighted imaging will also be performed to detect subtle blood products.
arm group label: Neurofeedback
arm group type: Experimental
description: mTBI Veterans blindly assigned to a 6 week IASIS neurofeedback treatment with two sessions per week.
arm group label: Sham Treatment
arm group type: Placebo Comparator
description: mTBI Veterans blindly assigned to a sham treatment for 6 weeks with two sessions per week.
arm group label: Control
arm group type: No Intervention
description: Veterans who are age-, gender-, education-, combat exposure-, and socioeconomically-matched. They will not undergo a treatment.
arm group label: Nexalin
arm group type: Experimental
description: After IASIS treatment is complete and participants in the mTBI group may have remaining PCS, additional Nexalin treatment will be offered.
intervention type: Device
intervention name: IASIS Micro Current Neurofeedback
description: The EEG interface device is the J&J Engineering I-330 C2, provided specifically for IASIS. The EEG sampling frequency is 256 Hz on each of 2 EEG acquisition channels. The feedback LIP-tES is delivered via the 4 EEG leads (A+, A-, B+, B-), with respect to the Common Neck Reference (isolated). During each session, 2 electrodes (A- and B-) are attached to the participant's left and right mastoids, while the remaining two electrodes (A+ and B+) are moved to various locations on the scalp to record EEG signals. All four (A+, A-, B+, B-) electrodes are involved in applying weak electric current pulses back to the brain (the feedback process). The feedback signal consists two types of narrow pulse trains, both with 150 mV in amplitude: A Type 1 pulse is 25 ms in duration and contains carrier waves at ~50 KHz. The repetition rate of Type 1 pulse train is fixed at 3.6 Hz; A Type 2 pulse is 120 ns in duration and contains carrier waves at ~100 MHz.
arm group label: Neurofeedback
arm group label: Sham Treatment
other name: LIP-tES intervention
intervention type: Device
intervention name: Nexalin
description: The Nexalin device, FDA clearance (501K=K024377, Classification: Stimulator, Cranial Electrotherapy: CFR 882. 5800: U.S. Patent #6904322B2), produces a waveform that provides tES to the brain delivered at a frequency of 77.5 Hz at 0 to 4 mA peak current. There is evidence that this waveform, at this frequency, results in improved clinical outcomes in terms of anxiety and pain. The specific mechanisms of action are not known, but available evidence suggests that this waveform alters the function of the hypothalamus and related structures. In particular, tES may lead to increases in levels of enkephalins and beta-endorphins in brain and CSF. Other data suggest that tES can alter endogenous levels of both substance P and serotonin. Regardless of which neuropeptide or neurotransmitter is ultimately found to be modulated by tES, it is hypothesized that repeated TES treatments over time serve to stimulate long-term neurochemical changes.
arm group label: Nexalin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mingxiong Huang, PhD
role: Principal Investigator
affiliation: VA San Diego Healthcare System, San Diego, CA
facility: 
country: United States
citation: Huang MX, Nichols S, Baker DG, Robb A, Angeles A, Yurgil KA, Drake A, Levy M, Song T, McLay R, Theilmann RJ, Diwakar M, Risbrough VB, Ji Z, Huang CW, Chang DG, Harrington DL, Muzzatti L, Canive JM, Christopher Edgar J, Chen YH, Lee RR. Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury. Neuroimage Clin. 2014 Jun 16;5:109-19. doi: 10.1016/j.nicl.2014.06.004. eCollection 2014.
PMID: 25009772
citation: Huang M, Risling M, Baker DG. The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury. Psychoneuroendocrinology. 2016 Jan;63:398-409. doi: 10.1016/j.psyneuen.2015.02.008. Epub 2015 Feb 23.
PMID: 25769625
citation: Robb Swan A, Nichols S, Drake A, Angeles A, Diwakar M, Song T, Lee RR, Huang MX. Magnetoencephalography Slow-Wave Detection in Patients with Mild Traumatic Brain Injury and Ongoing Symptoms Correlated with Long-Term Neuropsychological Outcome. J Neurotrauma. 2015 Oct 1;32(19):1510-21. doi: 10.1089/neu.2014.3654. Epub 2015 Jun 18.
PMID: 25808909
citation: MacGregor AJ, Dougherty AL, Galarneau MR. Injury-specific correlates of combat-related traumatic brain injury in Operation Iraqi Freedom. J Head Trauma Rehabil. 2011 Jul-Aug;26(4):312-8. doi: 10.1097/HTR.0b013e3181e94404.
PMID: 20808241
citation: MacDonald CL, Johnson AM, Nelson EC, Werner NJ, Fang R, Flaherty SF, Brody DL. Functional status after blast-plus-impact complex concussive traumatic brain injury in evacuated United States military personnel. J Neurotrauma. 2014 May 15;31(10):889-98. doi: 10.1089/neu.2013.3173. Epub 2014 Feb 10.
PMID: 24367929
citation: Hoffman SW, Harrison C. The interaction between psychological health and traumatic brain injury: a neuroscience perspective. Clin Neuropsychol. 2009 Nov;23(8):1400-15. doi: 10.1080/13854040903369433.
PMID: 19882478
citation: Vasterling JJ, Brailey K, Proctor SP, Kane R, Heeren T, Franz M. Neuropsychological outcomes of mild traumatic brain injury, post-traumatic stress disorder and depression in Iraq-deployed US Army soldiers. Br J Psychiatry. 2012 Sep;201(3):186-92. doi: 10.1192/bjp.bp.111.096461. Epub 2012 Jun 28.
PMID: 22743844
citation: Nelson DV, Esty ML. Neurotherapy of Traumatic Brain Injury/Post-Traumatic Stress Symptoms in Vietnam Veterans. Mil Med. 2015 Oct;180(10):e1111-4. doi: 10.7205/MILMED-D-14-00696.
PMID: 26444476
citation: Schoenberger NE, Shif SC, Esty ML, Ochs L, Matheis RJ. Flexyx Neurotherapy System in the treatment of traumatic brain injury: an initial evaluation. J Head Trauma Rehabil. 2001 Jun;16(3):260-74. doi: 10.1097/00001199-200106000-00005.
PMID: 11346448
citation: Huang MX, Nichols S, Robb A, Angeles A, Drake A, Holland M, Asmussen S, D'Andrea J, Chun W, Levy M, Cui L, Song T, Baker DG, Hammer P, McLay R, Theilmann RJ, Coimbra R, Diwakar M, Boyd C, Neff J, Liu TT, Webb-Murphy J, Farinpour R, Cheung C, Harrington DL, Heister D, Lee RR. An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. Neuroimage. 2012 Jul 16;61(4):1067-82. doi: 10.1016/j.neuroimage.2012.04.029. Epub 2012 Apr 20.
PMID: 22542638
citation: Huang MX, Theilmann RJ, Robb A, Angeles A, Nichols S, Drake A, D'Andrea J, Levy M, Holland M, Song T, Ge S, Hwang E, Yoo K, Cui L, Baker DG, Trauner D, Coimbra R, Lee RR. Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients. J Neurotrauma. 2009 Aug;26(8):1213-26. doi: 10.1089/neu.2008.0672.
PMID: 19385722
citation: Lewine JD, Davis JT, Bigler ED, Thoma R, Hill D, Funke M, Sloan JH, Hall S, Orrison WW. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J Head Trauma Rehabil. 2007 May-Jun;22(3):141-55. doi: 10.1097/01.HTR.0000271115.29954.27.
PMID: 17510590
citation: Lewine JD, Davis JT, Sloan JH, Kodituwakku PW, Orrison WW Jr. Neuromagnetic assessment of pathophysiologic brain activity induced by minor head trauma. AJNR Am J Neuroradiol. 1999 May;20(5):857-66.
PMID: 10369357
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Brain Concussion
mesh term: Stress Disorders, Traumatic
mesh term: Stress Disorders, Post-Traumatic
sharing ipd: Yes
ipd description: One or more data sets without personal identifiers will be generated during the data analysis phase of this study. Publications from this research will be made available to the public through the National Library of Medicine PubMed Central website within one year after the date of publication. The data sets will include all data underlying any publications generated by this study and therefore, these will be sufficient to reproduce or verify any published findings.
Requests for access to final data sets must be made in writing signed by a requestor from the United States and include an email address for delivery and an assurance that the recipient will not attempt to identify or re-identify any individual. The request should reference the publication underlying the request. Requests may be made to the PI/lead point-of-contact for the publication. If the investigator leaves the VASDHS the requests may be sent to the Associate Chief of Staff for Research.