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. 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.

• TES (Device), also known as LIP-tES intervention: 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.

Primary outcomes

• Change in Abnormal Magnetoencephalography (MEG) Slow-Waves (1-4 Hz) Activity [Baseline through end of treatment, an average of 6 weeks]: We will develop a voxel-wise whole brain MEG source imaging approach for detecting abnormal Magnetoencephalography (MEG) slow-waves (1-4 Hz) in mTBI Veterans. The unit of the abnormal MEG source activity was measured in pico Ampere-meter (or pA-m which is 10\^(-12) A-m). Natural logarithm transformation (i.e., e-based) was used. So, the unit of the MEG source imaging was log(pA-m). The range of the voxel-wise MEG source activity scale is 0-10. High amplitude of the MEG source activity suggests more serious injury. In the present study, we measured the Difference score in MEG exam pre- vs post the transcranial electrical stimulation (TES) treatment. Our primary measure is the reduction of the abnormal MEG source activity for slow waves (1-4 Hz), defined as the MEG activity at the pre-TES exam minus that at the post-TES exam. So, the higher this difference score is, the better outcomes due to the TES treatment in reducing the abnormal MEG signal.
• Rivermead Post Concussion Symptom Questionnaire [Baseline through end of treatment, an average of 6 weeks]: The Rivermead Post Concussion Symptom Questionnaire (RPQ) total score was used to assess change in post-concussion symptoms due to TES. Our focus in this analysis was the difference score in RPQ total score pre- vs post-treatment measures. The questionnaire has 16 items and uses scale of 0 - 4, with 0 as "not experienced at all" and 4 as "a severe problem." Value range: 0 - 64, where the higher scores mean a worse outcome. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.
• Neurobehavioral Symptoms Inventory [Baseline through end of treatment, an average of 6 weeks]: The Neurobehavioral Symptoms Inventory (NSI) total score was used to assess the changes of post-concussion symptoms due to TES. Our focus in this analysis was the difference score in NSI total score pre- vs post-treatment measures. The NSI has 22 items and uses a response scale of 0 - 4, with 0 as "none" and 4 as "very severe." Value range: 0 - 88, where the higher scores mean a worse outcome/more severe post-concussive symptoms. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.

Secondary outcomes

• The McGill Pain Questionnaire (MGPQ) [Baseline through end of treatment, an average of 6 weeks]: 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. Category scores range from 1-2 through 1-6. Minimum score = 0. Maximum score = 78. The higher the pain score, the greater the pain. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.
• Clinician-Administered PTSD Scale (CAPS-5) [Up to 6 weeks]: The CAPS-5 is a standard semi-structured interview used to assess PTSD diagnosis and severity. The primary traumatic event is elicited and will be used as the basis of assessing PTSD symptoms. The total symptom severity score is calculated by summing severity scores assessed in this 30-item questionnaire. PTSD diagnostic status will be assessed using the past month version of the CAPS-5A, in which total severity score of 33 or higher indicates full threshold PTSD. The past week version of the CAPS-5 will be given prior to treatment and at follow-up. Severity scores range on a response scale of 0-5, 0=absent, 5=extreme/incapacitating. CAPS-55 summary scores range from 0 to 80, with the higher scores indicating greater severity of PTSD symptoms. For this measure, we focused on the difference score: total score from prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.
• Post-Concussion Check List (PCL-5) [Up to 6 weeks]: PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. The PCL-5 uses a response scale of 0 - 4. 0 = "Not at all" to 4 = "Extremely." The total score can range from 0 - 80, with the higher the score corresponding to a higher level of distress to the very stressful experience. The difference between scores post-treatment and pre-treatment will analyzed in addition to the CAPS-5 (1 week version) outcomes. DSM-5 symptom cluster severity scores can be obtained by summing the scores for the items within a given cluster, i.e., cluster B (items 1-5), cluster C (items 6-7), cluster D (items 8-14), and cluster E (items 15-20); these subscale scores may be used in secondary analysis.
• California Verbal Learning Test-2nd Edition - Free Recall Total Correct T-score [Up to 6 weeks]: We will use T-scores from verbal learning and retrospective memory (California Verbal Learning Test-2nd Edition). Alternate CVLT forms were used during the post-treatment session. T-score ranges from 5 to 95, where the higher the T-score, the better the outcome. The T-score indicates the number of standard deviations away from the mean, where 50 is the mean with a standard deviation of 10, and is age- and gender-corrected. Analysis was based on the difference score between pre-treatment and post-treatment Free Recall Total Correct T-score. The lower the difference score, the more positive change was observed.
• Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Processing Speed Index [Up to 6 weeks]: We will use the sum of scaled scores from the WAIS-IV Symbol Search and Coding subtests to attain the Processing Speed Index. PSI ranged from 50 - 150, where the higher the score, the better the outcome. Analysis was based on the difference score between pre-treatment Processing Speed Index and post-treatment Processing Speed Index. The lower the difference score, the more positive change was observed.
• Delis-Kaplan Executive Function System (DKEFS) - Trail Number/Letter Switching Scaled [Up to 6 weeks]: Throughout the study, we used DKEFS Verbal Fluency, Trail-Making, and Color-Word Interference subtests to assess executive functioning. Analysis was based on the DKEFS Trailmaking Number/Letter Switching scaled score. Scaled scores range from 1-19, where the higher the scaled score, the better the outcome. Analysis was based on the difference score between pre-treatment scaled score and the post-treatment scaled score. The lower the difference score, the more positive change was observed.
• Connors Continuous Performance Task II (CPT-II) - Inattention Omissions T-Score [Up to 6 weeks]: The Connors Continuous Performance Task II (CPT-II) was included as a measure of attention and impulsivity. In this measure, converted T-scores represent the score of the individual relative to the population, who are of the same gender and same age group. A T-score of 50 represents the average for the comparison group. T-score ranges from under 40 (very good performance) to 65+ (markedly atypical). The higher the scores, the worse the performance. This analysis focused on the difference score between the Inattention Omissions T-score pre- and post-treatment. The higher the difference score, the more positive change was observed.
• Barratt Impulsivity Scale [Up to 6 weeks]: Impulsivity was also measured by Barratt Impulsivity Scale, a self-report questionnaire. This scale contains 30 items, with total scores that range from 30 - 120. The higher the score, the worse the outcome. Analysis was based on the difference score between pre- and post-treatment. The higher the difference score, the more positive change was observed.
• Frontal Systems Behavior Scale [Baseline through end of treatment, an average of 6 weeks]: Since frontal lobe areas are more prone to damage, the Frontal Systems Behavior Scale (FrSBe) will measure behavioral dysfunction associated with frontal subcortical impairment. FrSBe is a 46-item rating scale with three subscales: Apathy (14 items), Disinhibition (15 items), and Executive Function (17 items). Items are rated in a 5-point scale, where higher scores mean a worse outcome. The raw scores of these subscales were converted to T-scores, with range of 9 - >/= 140, where T-scores greater than 65 are considered clinically significant. For this measure, we focused on the difference score of the total T-score prior to treatment minus total score from end of treatment. Therefore, the higher the difference score, the more positive change was observed.

Sex: All, ages: 18 Years to 60 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Change in Abnormal Magnetoencephalography (MEG) Slow-Waves (1-4 Hz) Activity (Primary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 1.8 +/- 1.2; TES Sham Treatment 0.2 +/- 1.4; Control 0 +/- 0 (p 0.01)
• Rivermead Post Concussion Symptom Questionnaire (Primary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 11.1 +/- 9.7; TES Sham Treatment 10.9 +/- 11.2; Control 0 +/- 0 (p 0.05)
• Neurobehavioral Symptoms Inventory (Primary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 12.3 +/- 13.0; TES Sham Treatment 12.7 +/- 10.7; Control 0 +/- 0 (p 0.05)
• The McGill Pain Questionnaire (MGPQ) (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 14.8 +/- 16.9; TES Sham Treatment -5.1 +/- 18.1; Control 0 +/- 0 (p 0.05)
• Clinician-Administered PTSD Scale (CAPS-5) (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 6.5 +/- 13.4; TES Sham Treatment 4.2 +/- 9.6; Control 0 +/- 0 (p 0.05)
• Post-Concussion Check List (PCL-5) (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 14.9 +/- 15.9; TES Sham Treatment 12.1 +/- 24.3; Control 0 +/- 0 (p 0.05)
• California Verbal Learning Test-2nd Edition - Free Recall Total Correct T-score (Secondary), Mean, CVLT Free Recall Total Correct t-score: Transcranial Electrical Stimulation (TES) -6.7 +/- 9.8; TES Sham Treatment -2.8 +/- 7.4; Control 0 +/- 0 (p 0.05)
• Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Processing Speed Index (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) -5.06 +/- 10.53; TES Sham Treatment -11.48 +/- 11.21; Control 0 +/- 0 (p 0.05)
• Delis-Kaplan Executive Function System (DKEFS) - Trail Number/Letter Switching Scaled (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) -0.77 +/- 1.13; TES Sham Treatment -2.08 +/- 2.03; Control 0 +/- 0 (p 0.05)
• Connors Continuous Performance Task II (CPT-II) - Inattention Omissions T-Score (Secondary), Mean, Inattention Omissions T-score: Transcranial Electrical Stimulation (TES) 5.71 +/- 8.04; TES Sham Treatment -0.89 +/- 10.02; Control 0 +/- 0 (p 0.05)
• Barratt Impulsivity Scale (Secondary), Mean, units on a scale: Transcranial Electrical Stimulation (TES) 7.6 +/- 8.1; TES Sham Treatment 2.4 +/- 10.8; Control 0 +/- 0 (p 0.05)
• Frontal Systems Behavior Scale (Secondary), Mean, T-score: Transcranial Electrical Stimulation (TES) 9.1 +/- 13.1; TES Sham Treatment 3.2 +/- 17.2; Control 0 +/- 0 (p 0.05)

Adverse events

Time frame: 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)

Limitations and caveats: 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.

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• Study Protocol and Statistical Analysis Plan (PDF, 2023-07-09)
• Informed Consent Form (PDF, 2022-05-19)

• Mingxiong Huang, PhD, Principal investigator, VA San Diego Healthcare System, San Diego, CA