Transcranial Electrical Stimulation for mTBI

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Passive Electrical Neurofeedback Treatment of mTBI: MEG and Behavioral Outcomes

Conditions
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Mild Traumatic Brain Injury (mTBI), Post-traumatic Stress Disorder

Intervention / Treatment
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* Device: IASIS Micro Current Neurofeedback
* Device: Nexalin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion of Veterans for the mTBI groups: All symptomatic mTBI patients will be evaluated in a clinical interview to document the nature of the injuries and ongoing PCS. The diagnosis of mTBI patients is based on standard VA/DOD diagnostic criteria. Inclusion in the mTBI patient group requires a TBI that meets the following criteria: a loss of consciousness (LOC) < 30 minutes or transient confusion, disorientation, or impaired consciousness immediately after the trauma post-traumatic amnesia (PTA) < 24 hours an initial Glasgow Coma Scale (GCS) [90] between 13-15 (if available) Since the GCS assessment is often not available in theater, Veterans with missing GCS, but who meet other inclusion criteria will also be recruited. Each patient must have at least 3 items of persistent PCS at the beginning of the study. Inclusion of Healthy Control (HC) group: Veterans that qualify as HCs will be age, education, combat exposure, and socioeconomically matched to the mTBI groups. In addition to exclusion criteria listed above, HC subjects must not have been diagnosed with head injury, affective disorder, or PTSD (CAPS-5 < 8) throughout life. Exclusion Criteria: Exclusion criteria for study participations include: history of other neurological, developmental, or psychiatric disorders (based on the DSM-5 (MINI-7) [86] structured interview), e.g.,: brain tumor stroke epilepsy Alzheimer's disease schizophrenia bipolar disorder ADHD or other chronic neurovascular diseases such as hypertension and diabetes substance or alcohol use disorders according to DSM-5 [87] criteria within the six months prior to the study history of metabolic or other diseases known to affect the central nervous system (see [88] for similar criteria) Metal objects (e.g., shrapnel or metal fragments) that fail MRI screening, or extensive metal dental hardware, e.g.,: braces and large metal dentures fillings are acceptable other metal objects in the head neck, or face areas that cause non-removable artifacts in the MEG data Potential subjects will be administered the Beck Depression Inventory (BDI-II) to evaluate level of depressive symptoms, and suicidal ideation any participant who reports a 2 or 3 on the BDI-II: item 9 (suicidal thoughts or wishes) will also be excluded. However, depression following mTBI or traumatic event of PTSD is common [89]: therefore, in two mTBI groups, the investigators will include and match patients with depression symptoms reported after their injury/event, and will co-vary BDI-II score in data analyses.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurofeedback<br>mTBI Veterans blindly assigned to a 6 week IASIS neurofeedback treatment with two sessions per week. | Device: IASIS Micro Current Neurofeedback<br>* 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.<br>* Other names: LIP-tES intervention;|
| Placebo Comparator: Sham Treatment<br>mTBI Veterans blindly assigned to a sham treatment for 6 weeks with two sessions per week. | Device: IASIS Micro Current Neurofeedback<br>* 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.<br>* Other names: LIP-tES intervention;|
| No Intervention: Control<br>Veterans who are age-, gender-, education-, combat exposure-, and socioeconomically-matched. They will not undergo a treatment. | |
| Experimental: Nexalin<br>After IASIS treatment is complete and participants in the mTBI group may have remaining PCS, additional Nexalin treatment will be offered. | Device: Nexalin<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Abnormal MEG Slow-Waves | 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. | Baseline through end of treatment, an average of 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combat and Post-battle Experiences Scales of the Deployed Risk and Resilience Inventory 2 | 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. | Baseline | 
| Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID) | Lifetime history of TBI will be assessed using the Ohio State University Traumatic Brain injury Identification method (OSU TBI-ID). | Baseline | 
| Pittsburgh Sleep Quality Index (PSQI) | 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. | Up to 6 weeks | 
| The McGill Pain Questionnaire (MGPQ) | 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. | Up to 6 weeks | 
| Clinician-Administered PTSD Scale (CAPS-5) | 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. | Up to 6 weeks | 
| Post-Concussion Check List (PCL-5) | PCL-5 will also be given to track changes in PTSD symptoms. | Up to 6 weeks | 
| Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) | 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. | Baseline | 
| Alcohol Use Disorders Identification Test (AUDIT) | Alcohol Use Disorders Identification Test (AUDIT) will assess alcohol abuse problems. | Baseline | 
| California Verbal Learning Test-2nd Edition | We will use scaled scores from verbal learning and retrospective memory (California Verbal Learning Test-2nd Edition). | Up to 6 weeks | 
| Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) | 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. | Up to 6 weeks | 
| Delis-Kaplan Executive Function System (DKEFS) | We will use scaled scores from the DKEFS Verbal Fluency, Trail-Making, and Color-Word Interference subtests to assess executive functioning. | Up to 6 weeks | 
| Connors Continuous Performance Task II (CPT-II) | The Connors Continuous Performance Task II (CPT-II) will be included as a measure of attention and impulsivity. | Up to 6 weeks | 
| Barratt Impulsivity Scale | Impulsivity will also be measured by Barratt Impulsivity Scale a self-report questionnaire. | Up to 6 weeks | 
| Frontal Systems Behavior Scale | Since frontal lobe areas are more prone to damage, the Frontal Systems Behavior Scale will measure behavioral dysfunction associated with frontal subcortical impairment. | Baseline | 
| Wechsler Test of Adult Reading | The Wechsler Test of Adult Reading will provide an estimate of premorbid ability. | Baseline | 
| Test of Memory Malingering (TOMM) | Effort will be assessed using the Test of Memory Malingering (TOMM). | Baseline | 
| CogState Ltd | 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. | Up to 6 weeks | 
| Conventional MRI T1-weighted 3D-IRSPGR pulse sequence | 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. | Baseline | 
| Susceptibility-weighted MRI | Susceptibility-weighted imaging will also be performed to detect subtle blood products. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mild Traumatic Brain Injury, transcranial electrical stimulation, neurofeedback, magnetoencephalography, post-traumatic stress disorder