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.

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.

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.

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.

mTBI Veterans enrolled in a blinded study group. At the end of their study sessions, they were informed of their study group. If they were originally in a sham group, they had the option of receiving TES sessions. Questionnaires and MEG imaging continued if they chose to receive actual TES sessions. Therefore, the number of analysis TES population (n=38) is higher than the number of enrolled participants since some participants completed sham treatments and then opted for TES treatments.

Time period for collection of adverse event data: pre-treatment collection (1 week - 1 month), treatment/sham collection (6 weeks), and post-treatment collection (1 week - 1 month)

Out of 66 total participants, we had 30 originally in the TES category, 17 in Sham, and 19 as controls. But 8 in the Sham requested to do TES afterwards. Therefore, we ended up with 38 TES overall.

Due to COVID restrictions and a long lock down period, this study was unable to enroll and consent Veteran participants for 7 months. Furthermore, some of the participants who enrolled pre-COVID were unable to complete all their treatment sessions nor their post-treatment MEG, neuropsychological testing, and mental health sessions. This has severely impacted data collection. We were able to start enrolling in October 2020. However, recruitment has been much slower than in the pre-COVID period.

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 TES 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-TES or the mTBI Sham group, with an attached code from an existing code bank. Then, the TES treatment operator (SRA #2) who is blind to the group assignment will enter the code to the TES system during treatments. Based on the code, the system automatically loads the protocol for either TES or Sham treatment. Only at the end of the study (after V16), the group assignment is revealed. Therefore, both the participant and TES treatment operator (SRA #2) are blind to the group assignment during the study.