Transcranial Electrical Stimulation for mTBI

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. 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) 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 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.