Photobiomodulation to Improve Cognition in TBI, With fMRI

The purpose of this small, research study is to examine effectiveness of an at-home application of an experimental intervention, on thinking and memory in mild-moderate, closed-head, traumatic brain injury cases. The experimental intervention is light-emitting diode (LED) therapy, which is applied to the scalp and through the nose using a head frame device. Participants are expected to complete two, 5-week series of LED treatments, at home, 3 times a week. There will be a 1-month period between the two series. Each home treatment is 20 minutes. Participants will be trained to use the head frame device, in-office. The head frame device falls within the FDA category General Wellness, low-risk devices, and no medical claims are made. A two-hour paper and pencil testing (4 visits) and a one-hour MRI (3 visits) will be administered before and after each treatment series. Participants may be in the study for about 4 months. This study is supported by Vielight, Inc., Hayward, CA/ Toronto, Canada

Objectives: This small study examines effectiveness of an at-home experimental intervention that utilizes near-infrared (NIR) wavelengths of light (810nm) applied to the scalp, using light-emitting diodes (LEDs), to improve brain function. LEDs may directly improve the cellular activity of brain tissue that has been damaged by brain trauma. The intervention involves two series of 15 treatments, which are self-administered, at-home. Neuropsychological testing and structural and functional MRI (fMRI) scans will be administered to examine behavioral and brain changes before and after a series of LED treatments. MRI scans will examine some mechanism of LED intervention including changes in blood flow, functional connectivity and neurochemicals.

Research Design: This study is a blinded, randomized, sham-controlled, partial-crossover study, with 2 groups (n=10 per group (Sham, Real); ages 18-65). Participants are randomized, by computer into groups. At-home LED intervention is self-administered 3 times per week (20 minutes), for two 5-week series, with a one-month break between series. Group 1 receives both a series of Sham and a series of Real treatments and Group 2 receives two series of Real treatments. All participants will receive at least one series of Real treatments during participation.

Methods and General Study Procedure: Twenty veterans with traumatic brain injury, 18-65 years old, who are at least 6-months post- the latest mild-moderate traumatic brain injury (TBI) will be studied. A 1-hour, In-office neuropsychological (NP) screening, after consenting, will determine study eligibility and ensure participants meet the inclusion/exclusion criteria. Participants may be in the study for about 4 months.

Device Parameters: Vielight Neuro Alpha head frame device, NIR, 810nm, pulsed at 10 Hz, 50% duty cycle, 20-minute treatment with automatic shutoff. Total Energy Dose per head set plus intranasal: 225 J/cm2+ 15 J/cm2 = 240 J/cm2 per 20 min LED treatment. Total Energy Dose delivered (3x/Week, 5 Weeks) = 3600 J/cm2. The light from these LEDs is not visible to the eye. There is no potential for eye damage because the LEDs are not laser light.

Sham and Real devices are identical in look and feel, except no photons are emitted from the Sham devices. The head frame device falls within the FDA category General Wellness, low-risk devices, and no medical claims are made. It is approved for use by the VA Boston Healthcare System Safety and Human Subjects Committees.

Training: Each participant is assigned his/her own LED head frame device for hygiene reasons. The assigned device will be provided to each participant at a 1-hour in-office training session, after the first Neuropsychological (NP) Testing. Training that includes both verbal and written instructions will be provided, along with demonstration of use of the device. A treatment log, storage box and alcohol wipes for cleaning are provided. The first treatment is completed at the training session.

For each series of LED treatments, a 20-minute, LED treatment is completed at home, 3 times per week (Monday, Wednesday, and Friday), for 5 weeks. There must be at least 48 hours between treatments. There will be a total of 15 treatments in each series. The specific time of day is at the participant's convenience. Missed treatments will be completed at the end of the 5-week series, so all participants will complete all 15 LED treatments. If more than 1 treatment session in a week is not completed, due to unforeseen circumstances, the participant may be withdrawn from the study.

A staff person will telephone each participant weekly, to fill out a questionnaire about the intervention including inquiring if the LED treatments are being performed, if the treatment log sheets are being filled out, and note if there are any questions, concerns or problems.

Neuropsychological Testing: All NP testing is completed at the VA Boston Healthcare System, Jamaica Plain Campus, Boston, MA.

NP tests are administered at four time points (pre- intervention, with follow-up testing at 1 week and 1 month post- series 1, and 1 week post- series 2): The California Verbal Learning Test (CVLT), Long-Delay Free Recall (LDFR) is the Primary Outcome Measure which examines verbal learning, organization and memory. The subtest LDFR, CVLT-II specifically assesses long-delay (20 min), verbal memory, which can be affected after mild-moderate brain injury. Other NP, Psychosocial and General Health measures are considered Secondary Outcome Measures. To avoid practice effects, alternate versions of the NP tests will be used at the Post- LED testing times, when feasible.

Imaging will be conducted on the 3T Philips MRI system located at the Boston University Center for Biomedical Imaging (BU CBI). One-hour scans are acquired at 3 time points, in all participants. No contrast or x-rays are used.

Participants are permitted to have an MRI brain scan, if it has been determined at Entry, that MRI scanning would be safe using an MRI safety checklist. On the day of the MRI scan at the BU CBI, the BU Safety Checklist will also be reviewed before any scanning will occur. The light therapy portion of the study may be completed, even if participants cannot undergo MRI scanning for medical or safety reasons.

Functional MRI: resting-state functional-connectivity Magnetic Resonance Imaging (rs-fc MRI) is the Primary Imaging Outcome Measure. Rs-fc MRI examines the correlation of low frequency signal between voxels in the brain in different areas. Rs-fc MRI abnormalities have been shown in mild-moderate TBI cases. Other imaging sequences are considered exploratory measures. These will provide information on brain structure, blood flow and neurochemicals.

Statistical Analysis Plan

Neuropsychological, Psychosocial, and Health Data Analysis: VA Biostatistician, Robert Lew, PhD.

This study has two 5-week Series (I and II). In Series I, 10 subjects will be assigned to (A), and 10 assigned to (B). In Series II, all remaining A-subjects will continue on A, and all remaining B subjects will switch to A. Switching increases power and reduces dropout. For subjects in treatment B and then A, the model will include a compound symmetry correlation term (r=0.30). Treated subjects are Series I A; and Series II, switch-to-A.

To test if the change between consecutive times, delta, is positive for A, we will model the response, as measured by the CVLT, LDFR in mixed design random effects model of analysis. The formal hypothesis test is a linear contrast, a t-test that assumes an effect size of 0.5. For all Secondary Outcome Measures, exploratory analyses will confirm or not the results for primary hypothesis, CVLT, LDFR. A mixed design random effects model should enable handling of missing data points.

Statistical Analyses for MRI/fMRI data MRI data will be analyzed using Matlab, parametric statistics, and available standard Imaging software. All analyses will be parametric and corrections for multiple comparisons will be made.

Between group comparison of MRI data for the active vs. control groups (at time points T1-T3) will be completed.

Longitudinal impact of treatment over time on MRI scans Analyses will be a within-subject design, which compares changes pre- to 1-week post- and 1-month post- Series 1 intervention.

Eligibility Criteria:
Inclusion Criteria:

* 18-65 years old
* Must have had one (or more) closed-head, traumatic brain injuries
* Loss of consciousness 24 hours or less; or no loss of consciousness/ A period of altered mental status (post-traumatic amnesia)/mental confusion for 24 hours or less
* Must be able to come to VA Boston Healthcare System, Jamaica Plain Campus for testing visits and Boston University Center for Biomedical Imaging, Boston University School of Medicine for MRI scans

Must meet the following Screening requirements:

* Participants must score at least 2 SD below normal on at least 1 of the NP tests; or 1 SD below on at least 2 of these NP tests administer at Entry testing: Trail Making Test A \& B; Controlled Oral Word Association Test (COWAT/FAS); California Verbal Learning Test II; DKEFS Color-Word Interference Test (Stroop).

Exclusion Criteria:

* Diagnosis of a neurological disease such amyotrophic lateral sclerosis (ALS), Parkinson's, Alzheimer's disease
* History of craniotomy or craniectomy
* A current life-threatening disease such as cancer
* Disease requiring organ transplant
* A severe mental disorder such as schizophrenia, bipolar disorder (not associated with clinically diagnosed PTSD)
* Current substance abuse or active treatment; within the last 6 months
* The Test of Memory Malingering is administered at screening; Participants must not have scores that indicate evidence of malingering, a score of less than 45 on either Part 1 or 2 would show evidence of malingering, with the following exception: If a participant fails Trial 1, but does not fail Trial 2, he/she would not be excluded if he/she also show evidence of poor learning on other NP Screening tests, such as the CVLT. If he/she fails Trial 2, alone, or Trial 1 and Trial 2, then this would exclude the participant from the study.
* Self-reported pain questionnaires (VAS Pain Rating and the Short Form McGill Pain Questionnaire) are also administered. Participants may not have a level of pain greater than 7/10 on VAS or 38/50 on the McGill pain questionnaires at the time of screening.

Exclusion for Magnetic Resonance Imaging Only

* A BU MRI safety screening form will be reviewed at the time of study screening, as well as at each MRI scan appointment to ensure the participant can safely have an MRI. Participants must tell the investigator about any operations and any metal in his/her body, so it can be decided if it is safe for you to proceed with the scan.

Participants cannot have a MRI scan:

* if pregnant.
* if he/she has pacemakers, ear implants, shrapnel injuries, or other types of metal or electric device in their body