Retraining Neural Pathways Improves Cognitive Skills After A Mild Traumatic Brain Injury

The proposed study tests the efficacy (Phase II) of 36 30-minute training sessions of PATH neurotraining followed by digit memory exercises to improve working memory, processing speed and attention in mTBI patients rapidly and effectively to provide clinical testing of a therapeutic training for the remediation of cognitive disorders caused by a concussion. This study will contribute to the fundamental knowledge of how to remediate concussions from a mTBI to enhance the health, lengthen the life and reduce the disabilities that result from a mTBI.

This study will provide clinical testing of therapeutic training for remediation of concussion-induced cognitive disorders. Our Phase I Clinical Trial determined the feasibility of targeting visual timing deficits in mTBI subjects to successfully remediate cognitive deficits. This trial identified PATH+DigitMemory (DM) neurotraining as the most effective intervention for post-mTBI cognitive remediation. Since Institutional Review Boards have classified these cognitive interventions as minimal risk and not yet proven treatments for mTBI, FDA approval is not required before study initiation. Upon protocol approval by Pearl IRB, recruitment materials will be distributed through clinicians with interested TBI patient waitlists. Participants will comprise two mTBI subgroups: 1) those who initially experienced a severe TBI (moderate TBI group) and 2) those with an initial mTBI. Prospective participants will undergo telephone screening to determine study eligibility. Groups will be balanced for age, sex, visual working memory performance, number of TBI incidents, duration of loss of consciousness, and locus/extent of mTBI. We anticipate 3-5 mTBI referrals monthly from community-based sources established during Phase I, facilitating recruitment of 90 mTBI subjects over the three-year study period. This study is designed to enhance understanding of and provide training targeted toward cortical timing processes (PATH+DM training), extending our Phase I findings to a substantially larger mTBI subject sample.

This Phase II research represents a randomized, within-subject clinical trial investigating cognitive and behavioral effects of different training frequencies-36 sessions of 30-minute PATH+DM training (20 minutes PATH followed by 10 minutes Digit Memory exercises) administered once, twice, or three times weekly in adults aged 18-60. We will show that after completing the PATH+DM training, subjects have significantly higher cognitive skills than before. Changes in test performance for the primary outcome variable: VWM, and secondary outcome measures: processing speed, selective attention, cognitive flexibility, AWM, reading speed, and questionnaires will be analyzed using mixed-factors Multivariate Analysis of Variance (MANOVA). These MANOVAS will compare standardized test percentiles, reading rate, and questionnaire scores, controlling for age, before and after PATH+DM neurotraining. The mixed factors MANOVA will be performed with the between-subjects factor of Training Group (PATH+DM training once, twice or three times/week) and the within-subjects factor of Time (Time1, Time2, and Time3), corresponding to Initial, 3 months and 6 months after starting PATH+DM training, to test the effects of dosage on the magnitude of improvements in cognitive skills (Aim 1). One analysis will be performed for each behavioral test to compare improvements in standardized percentiles, and reading rate scores following PATH+DM on the three different frequencies being investigated. Planned a-priori contrasts are predicted to reveal group differences such that improvements at Time 2 (3 months after starting intervention) will be largest for the PATH group doing PATH 3 times a week. Another question being answered is whether this advantage at Time 2 is also found at Time 3, 6 months after starting intervention. A related question is whether participants who have the lowest scores will also demonstrate the greatest improvements. We expect that those in the moderate TBI group will improve more than those in the mild TBI group for this reason. These answers will help to determine the relative efficacy of PATH training for a wide range of TBI patients who experience memory loss. The results from Aim 1 above, post-tests 3 and 6 months after starting PATH+DM training, as well as post-tests 12 months after starting PATH+DM neurotraining will be analyzed with Multi Level Modeling (MLM), a technique particularly well suited for capturing the effects in studies with complex variables that are nested within one another, and that will permit growth curve modeling over multiple measurements. To test whether improvements in cognitive skills after PATH+DM training are sustained over time (Aim 2), we will have measurement periods (x4) nested within the random effect of participants, and the between subjects, fixed effect of conditions of Training Group.

The PATH+DM intervention promotes sustained functional recovery from an mTBI, when currently there are no proven solutions for mTBI: 80% of TBIs. MEG recordings before and after training will provide a biomarker, a neural correlate, to determine whether PATH training improves the function of the dorsal, attention, and working memory networks. Preliminary data suggest that MEG imaging is sensitive in detecting brain functional changes in dlPFC and ACC which are part of the VWM network. MEG may be a unique biomarker of timing deficits in mTBI. MEG pre-post recordings will be examined to understand the distribution of timing-based deficits across a population of mTBI patients. Resting-state MEG is sensitive in detecting neuronal abnormalities in mTBI on an individual-subject basis. We will use MEG functional imaging-based neurophysiological recordings to test whether the dorsal stream visual, attention, and memory networks improve in function significantly more following PATH+DM training than before PATH+DM training (Aim 3). A structural MRI to superimpose the functional activity on top of the brain anatomy will be collected before the initial MEG recording. To evaluate PATH+DM training effectiveness across different doses, we will analyze improvements in MEG neurophysiological recordings during two time intervals: 100-200 milliseconds (examining visual system functional changes) and 200-1000 milliseconds (studying later responses of the working memory network). Voxel-wise MEG neurophysiological recordings will be collected from all qualifying mTBI subjects, serving as a biomarker to demonstrate PATH+DM neurotraining's feasibility for cognitive improvement. Whole-brain MEG images across frequency bands will be analyzed using the Fast-VESTAL procedure to measure time-locked signals during an N-Back working memory task, evaluating brain function improvements as implemented in our pilot studies. We hypothesize that MEG timing deficits will predict which mTBI subjects respond optimally to PATH+DM training, and that subjects demonstrating large MEG recording differences will exhibit the largest behavioral improvements. We further hypothesize that individuals receiving PATH+DM training three times weekly will show significantly stronger neuronal signals, better performance accuracy, and shorter reaction times compared to those training once weekly. We also expect to observe more significant increases in response magnitude and coupled theta/gamma and/or alpha/gamma oscillations following PATH+DM training compared to baseline, as suggested by our pilot studies. These hypotheses will be examined in an expanded participant sample to establish effect sizes for larger cohorts than studied in Phase I, comparing improvement magnitude between moderate and mild TBIs, and assessing whether improvements in different cortical areas persist over time. To increase its commercialization ability, PATH+DM training must be shown to improve brain function using a biomarker, as stated by neurologists and therapists in letters of support.

We will also examine moderators that may determine training outcome (Aim 4). The goal is to use MEG-based neural correlates of timing deficits in conjunction with behavioral cognitive assessments to understand the distribution of timing-based deficits across a population of mTBI subjects, and how these deficits predict cognitive skill deficits, that are moderated by individual factors. We will determine whether individual differences at initial assessment predict improvements following training for different subpopulations: 1) Moderate vs. mild TBI, 2) different age groups (18-28, 29-41, 42-60), 3) concussion frequency, and 4) varying loci and extent of mTBI deficits. We will investigate whether MEG functional imaging-based neurophysiological recordings of timing-based deficits predict cognitive skill deficits, and whether these relationships are moderated by individual factors including concussion frequency, duration of loss of consciousness, nature and extent of cognitive deficits, injury severity (moderate versus mild), and age. Studies incorporating MEG biomarker assessment will establish pre-post timing and functional capabilities of different cortical areas within visual, attention, and executive control pathways, complemented by pre-post behavioral neuropsychological testing of cognitive abilities. This exploratory aim will help determine whether different therapeutic approaches should be developed for different mTBI types and age groups.

Implementation Plan To ensure standardized test administration, written instructions will be delivered verbatim.

Training (PATH+DM) will be conducted using the subject's own computer (Macintosh, Windows, or Chromebook) by the PI either at PDI's Solana Beach office or remotely via Zoom. Training sessions will occur each morning at times convenient for participants to complete 36 training sessions of 30 minutes each, 1-3 days weekly. The PI will implement PATH+DM training with high fidelity, supported by training videos. Each subject will receive one-on-one instruction to ensure proper task execution. The PI will monitor subject engagement by examining computer data and providing additional training when necessary. All sessions will be supervised to ensure consistent implementation at the same time of day. This supervision is essential since mTBI subjects are relearning attention and memory skills, making independent task completion less reliable. Text reminders will be sent to encourage timely attendance. If a subject experiences discomfort (e.g., boredom, mild headache, fatigue, or dizziness) from visual or memory tasks, they will be instructed to look away from the screen and take a brief break. Such side effects are uncommon.

Dr. Lawton, the PI, brings over 45 years of experience conducting controlled validation studies. She will oversee staff training and manage daily operations, including scheduling and supervising pre-post neuropsychological testing and administering PATH+DM training. She will also coordinate MEG examinations at UCSD. To prevent bias, the PI will not be involved in data collection. Staff will collect standardized test data, while the PATH+DM web application will automatically record training data. Behavioral data will be analyzed exclusively by our statistician, Dr. Shelley-Tremblay, who will enter all behavioral test data into REDCap and FITBIR databases and conduct all behavioral data analyses.

Professor Huang and his team will conduct MEG functional imaging-based neurophysiological recordings from all qualifying mTBI subjects to provide biomarker data. Voxel-wise MEG source magnitude images covering the whole brain and each frequency band, following the Fast-VESTAL procedure to measure time-locked signals during an N-back working memory task, will evaluate brain function improvements, replicating methods used in Phase I. These MEG recordings will determine pre-post timing and functional capabilities of different cortical areas in the visual, attention, and executive control pathways, complementing behavioral pre-post standardized neuropsychological assessments of cognitive abilities. A distinctive feature of this study is Dr. Huang's innovative, patented techniques for analyzing MEG functional imaging-based neurophysiological data to detect changes in cognitive function and provide biomarkers for cognitive improvement.

Our team will convene periodically via Zoom to ensure we have a rigorous study implementation and to prepare results for scientific meetings and high-impact journal publications.