Transcranial Electrical Stimulation for mTBI

NCT03244475 | Completed Results DMC FDA Device

• 2 other identifiers: B1988-IRX001988-01A1
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

mild Traumatic Brain Injury; transcranial electrical stimulation; neurofeedback; magnetoencephalography; post-traumatic stress disorder

Outcome Measures

Primary Outcomes (3)

• Change in Abnormal Magnetoencephalography (MEG) Slow-Waves (1-4 Hz) Activity

  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.

  Baseline through end of treatment, an average of 6 weeks

• Rivermead Post Concussion Symptom Questionnaire

  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.

  Baseline through end of treatment, an average of 6 weeks

• Neurobehavioral Symptoms Inventory

  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.

  Baseline through end of treatment, an average of 6 weeks

Secondary Outcomes (9)

• The McGill Pain Questionnaire (MGPQ)

  Baseline through end of treatment, an average of 6 weeks

• Clinician-Administered PTSD Scale (CAPS-5)

  Up to 6 weeks

• Post-Concussion Check List (PCL-5)

  Up to 6 weeks

• California Verbal Learning Test-2nd Edition - Free Recall Total Correct T-score

  Up to 6 weeks

• Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Processing Speed Index

  Up to 6 weeks

Study Arms (3)

Transcranial Electrical Stimulation (TES)

EXPERIMENTAL

mTBI Veterans blindly assigned to a 6 week of TES, either IASIS neurofeedback treatment or Nexalin, with 2-3 sessions per week.

Device: TES

Sham Treatment

PLACEBO COMPARATOR

mTBI Veterans blindly assigned to a sham treatment for 6 weeks with 2-3 sessions per week.

Device: TES

Control

NO INTERVENTION

Veterans who are age-, gender-, education-, combat exposure-, and socioeconomically-matched. They will not undergo a treatment.

Interventions

TES DEVICE

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.

Also known as: LIP-tES intervention

Sham Treatment; Transcranial Electrical Stimulation (TES)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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)
• Each patient must have at least 3 items of persistent PCS at the beginning of the study.
• Veterans that qualify as HCs will be age, education, combat exposure, and socioeconomically matched to the mTBI groups.

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead
• San Diego Veterans Healthcare System: collaborator

Study Sites (1)

VA San Diego Healthcare System, San Diego, CA

San Diego, California, 92161, United States

Location

Related Publications (13)

• Huang MX, Nichols S, Baker DG, Robb A, Angeles A, Yurgil KA, Drake A, Levy M, Song T, McLay R, Theilmann RJ, Diwakar M, Risbrough VB, Ji Z, Huang CW, Chang DG, Harrington DL, Muzzatti L, Canive JM, Christopher Edgar J, Chen YH, Lee RR. Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury. Neuroimage Clin. 2014 Jun 16;5:109-19. doi: 10.1016/j.nicl.2014.06.004. eCollection 2014.

  PMID: 25009772 BACKGROUND

• Huang M, Risling M, Baker DG. The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury. Psychoneuroendocrinology. 2016 Jan;63:398-409. doi: 10.1016/j.psyneuen.2015.02.008. Epub 2015 Feb 23.

  PMID: 25769625 BACKGROUND

• Robb Swan A, Nichols S, Drake A, Angeles A, Diwakar M, Song T, Lee RR, Huang MX. Magnetoencephalography Slow-Wave Detection in Patients with Mild Traumatic Brain Injury and Ongoing Symptoms Correlated with Long-Term Neuropsychological Outcome. J Neurotrauma. 2015 Oct 1;32(19):1510-21. doi: 10.1089/neu.2014.3654. Epub 2015 Jun 18.

  PMID: 25808909 BACKGROUND

• MacGregor AJ, Dougherty AL, Galarneau MR. Injury-specific correlates of combat-related traumatic brain injury in Operation Iraqi Freedom. J Head Trauma Rehabil. 2011 Jul-Aug;26(4):312-8. doi: 10.1097/HTR.0b013e3181e94404.

  PMID: 20808241 BACKGROUND

• MacDonald CL, Johnson AM, Nelson EC, Werner NJ, Fang R, Flaherty SF, Brody DL. Functional status after blast-plus-impact complex concussive traumatic brain injury in evacuated United States military personnel. J Neurotrauma. 2014 May 15;31(10):889-98. doi: 10.1089/neu.2013.3173. Epub 2014 Feb 10.

  PMID: 24367929 BACKGROUND

• Hoffman SW, Harrison C. The interaction between psychological health and traumatic brain injury: a neuroscience perspective. Clin Neuropsychol. 2009 Nov;23(8):1400-15. doi: 10.1080/13854040903369433.

  PMID: 19882478 BACKGROUND

• Vasterling JJ, Brailey K, Proctor SP, Kane R, Heeren T, Franz M. Neuropsychological outcomes of mild traumatic brain injury, post-traumatic stress disorder and depression in Iraq-deployed US Army soldiers. Br J Psychiatry. 2012 Sep;201(3):186-92. doi: 10.1192/bjp.bp.111.096461. Epub 2012 Jun 28.

  PMID: 22743844 BACKGROUND

• Nelson DV, Esty ML. Neurotherapy of Traumatic Brain Injury/Post-Traumatic Stress Symptoms in Vietnam Veterans. Mil Med. 2015 Oct;180(10):e1111-4. doi: 10.7205/MILMED-D-14-00696.

  PMID: 26444476 BACKGROUND

• Schoenberger NE, Shif SC, Esty ML, Ochs L, Matheis RJ. Flexyx Neurotherapy System in the treatment of traumatic brain injury: an initial evaluation. J Head Trauma Rehabil. 2001 Jun;16(3):260-74. doi: 10.1097/00001199-200106000-00005.

  PMID: 11346448 BACKGROUND

• Huang MX, Nichols S, Robb A, Angeles A, Drake A, Holland M, Asmussen S, D'Andrea J, Chun W, Levy M, Cui L, Song T, Baker DG, Hammer P, McLay R, Theilmann RJ, Coimbra R, Diwakar M, Boyd C, Neff J, Liu TT, Webb-Murphy J, Farinpour R, Cheung C, Harrington DL, Heister D, Lee RR. An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. Neuroimage. 2012 Jul 16;61(4):1067-82. doi: 10.1016/j.neuroimage.2012.04.029. Epub 2012 Apr 20.

  PMID: 22542638 BACKGROUND

• Huang MX, Theilmann RJ, Robb A, Angeles A, Nichols S, Drake A, D'Andrea J, Levy M, Holland M, Song T, Ge S, Hwang E, Yoo K, Cui L, Baker DG, Trauner D, Coimbra R, Lee RR. Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients. J Neurotrauma. 2009 Aug;26(8):1213-26. doi: 10.1089/neu.2008.0672.

  PMID: 19385722 BACKGROUND

• Lewine JD, Davis JT, Bigler ED, Thoma R, Hill D, Funke M, Sloan JH, Hall S, Orrison WW. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J Head Trauma Rehabil. 2007 May-Jun;22(3):141-55. doi: 10.1097/01.HTR.0000271115.29954.27.

  PMID: 17510590 BACKGROUND

• Lewine JD, Davis JT, Sloan JH, Kodituwakku PW, Orrison WW Jr. Neuromagnetic assessment of pathophysiologic brain activity induced by minor head trauma. AJNR Am J Neuroradiol. 1999 May;20(5):857-66.

  PMID: 10369357 BACKGROUND

MeSH Terms

Conditions

Brain Concussion; Stress Disorders, Post-Traumatic

Condition Hierarchy (Ancestors)

Brain Injuries, Traumatic; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds and Injuries; Wounds, Nonpenetrating; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

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.

Results Point of Contact

• Title: Dr. Mingxiong Huang
• Organization: VA San Diego Health System

mingxiong.huang@va.gov

858-534-1254

Study Officials

• Mingxiong Huang, PhD

  VA San Diego Healthcare System, San Diego, CA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 24, 2017
• First Posted: August 9, 2017
• Study Start: February 1, 2017
• Primary Completion: September 30, 2022
• Study Completion: September 30, 2022
• Last Updated: January 18, 2024
• Results First Posted: January 18, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)