Transcranial Electrical Stimulation for mTBI
Condition: Mild Traumatic Brain Injury (mTBI); Post-traumatic Stress Disorder
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Brain Concussion; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional

Summary: 
      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 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 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.
    

Detailed description: 
      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.
    

Intervention name(s): TES
Intervention type(s): Device
Intervention description(s): The EEG interface device is the J&J Engineering I-330 C2. IASIS is delivered via the 4 EEG leads with respect to the Common Neck Reference. During each session, 2 electrodes are attached to the participant's left and right mastoids, while the remaining 2 electrodes are moved to various locations on the scalp to record EEG signals. All 4 electrodes are involved in applying weak electric current pulses back to the brain. The feedback signal consists 2 types of narrow pulse trains, both with 150mV in amplitude.
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 4Hz, 40Hz, and 77.5Hz at 0 to 15mA peak current. Evidence shows this waveform, at these frequencies, results in improved clinical outcomes for anxiety and pain. We hypothesize that repeated TES treatments serve to stimulate long-term neurochemical changes.
Other intervention name(s): LIP-tES intervention
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 TES and sham groups will undergo a pre-session MEG, the first TES/Sham treatment Session (S1), and a post-session MEG. Next, the mTBI Veterans continue their TES/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 TES/Sham treatment S12, a 1-week follow-up MEG and NP will be conducted during V15. A subset of TES 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 TES treatment.
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: mild Traumatic Brain Injury; transcranial electrical stimulation; neurofeedback; magnetoencephalography; post-traumatic stress disorder