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

The proposed study tests the feasibility (Phase I) of PATH neurotraining to improve working memory 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 the remediation of cognitive disorders caused by a concussion. A Phase I Clinical Trial will be conducted to determine the feasibility of targeting an etiology of visual timing deficits in mTBI subjects to be successful in remediating cognitive deficits caused by the mTBI. This clinical trial will increase not only our understanding of the range of cognitive deficits incurred after a mTBI, but also the best intervention to remediate cognitive deficits after a mTBI. As soon as study protocol is approved by an IRB, brochures will be posted at all therapy centers, and doctors's offices referring mTBI patients for this study. Interested subjects will be screened by phone to ascertain their eligibility for MEG/MRI study. This study is designed to provide a clearer understanding of, and training targeted toward cortical timing processes (PATH training). The investigators will extend previous results from a pilot study of 4 mTBI subjects to a much larger sample of mTBI subjects. The proposed study tests the feasibility (Phase I) of PATH neurotraining to improve processing speed and visual working memory (primary outcomes) and reading speed, auditory WM, selective attention, cognitive flexibility, sustained attention, reading proficiency, post-concussive symptoms, quality of life and MoCA (secondary outcomes) in mTBI subjects rapidly and effectively, by analyzing the difference in scores on standardized tests before and after intervention training. This study will compare PATH training, presenting dim gray patterns moving left or right to activate the dorsal stream, with Sham training, presenting high contrast colored stationary patterns tilted left or right to activate the parvocells in the ventral stream, with an N-Back Working Memory (WM) task to primarily activate dorsal lateral PreFrontal Cortex (dlPFC), as done by competition. The investigators predict that PATH training improves working memory, processing speed and attention more than Sham or N-Back WM training after a mTBI. Since PATH training must be followed by cognitive exercises to improve cognitive function, a complementary strategy consisting of 15 minutes of working memory practice, recalling the correct sequence of digits, each presented for 500 msec, from 5 digits up to 10 digits will be completed for 15 minutes following both PATH and Sham training. Three interventions (PATH, N-back WM, and Sham neurotraining) each 30 minutes, will be administered three times/week for 12 weeks.

The individuals entering into this study will come from general practice in Neurology, and may therefore include individuals involved in athletic injuries, motor vehicle accidents, and work-related injuries, as well as from the VA Hospital having a combat-related mTBI. As such the location and extent of brain trauma can be expected to be relatively heterogeneous. Inclusion/Exclusion criteria are described elsewhere. This study targets 80 mTBI adult subjects between the ages of 18-60 to conduct all three Specific Aims, using a single coordinated test site (UCSD-PDI). The experimental and control groups will be balanced in terms of age, sex, visual working memory, Montreal Cognitive Assessment (MoCA) scores, number of TBI incidents, duration of loss of consciousness, and locus and extent of the mTBI. Approximately 40 subjects, 13 subjects in each of three training groups will be studied each year for a total of 2 years. Half of the subjects in the experimental groups will have pre-post MEG exams to provide biomarkers of improvements in cognitive skills. There will be a rolling enrollment of subjects with at most 16 subjects at one time, enabling subjects to be monitored easily by UCSD staff. A key connecting actual subject name and ID number in stored data will be kept in a locked file cabinet and stored on a computer with password protection so subject confidentiality is preserved. Since patient burden is high by being trained 3 times a week for 12 weeks, subject compensation and desire for improved cognition should encourage mTBI subjects to remain in study. Less than a 5% drop-out rate is expected, since subjects will not be compensated for participating until they have completed this study. The statistician will randomly assign each subject to one of the three intervention training groups, controlling for all factors listed above. This study incorporates a parallel design to investigate which training group improves the most. Subjects will be studied over two time periods, 12 weeks apart (pre-post testing).

Intervention training will be implemented in a high-fidelity manner using: 1) a detailed written protocol that all Research Assistants (RAs) are trained to follow meticulously, 2) training videos, and 3) having all RAs complete PATH, N-Back WM, and Sham interventions before administering this training to subjects. To ensure all tests are administered the same way, written instructions are said verbatim, and all training is supervised by the PI and/or SRA. UCSD students will be recruited at UCSD under the co-sponsorship of Professor Rossano. Intervention training will be conducted at either PDI's office in Solana Beach or at the Atkinson Hall/Qualcomm Institute at UCSD, choosing the location that is more convenient for the subject. A second SRA will oversee all the MEG data collection at the Atkinson Hall/Qualcomm Institute at UCSD, coordinating activities with the behavioral SRA at PDI. Training will be done during the day at a convenient time for the subject to do for 30 minutes 3 days/week for 12 weeks for a total of 36 visits. New PATH training videos aimed at mTBI subjects have been developed, so are maximally relevant to adults with mTBI.

The RAs will: 1) follow the study protocol by making sure the subject is focused on task, 2) be trained extensively to administer the standardized tests, and 3) being blind to which mTBI subjects are in which group when administering standardized tests. Learning to administer the standardized tests and experimental and control interventions will be done with the PI and SRA supervising each team of new study RAs. Each subject will be trained one-on-one to ensure task is done correctly. RAs ensure the subject is on task by examining computer data, and provide more training when needed. All subjects must do supervised training to ensure training is done consistently, at same time of day, for 30 min 3 times/week for 12 weeks. Otherwise, completing this task in a timely manner is not likely to occur, especially since mTBI subjects are learning to pay attention and remember more easily. Text reminders will be sent to each subject, as well, to remind them to come in for the brain training. If a subject is experiencing some discomfort, they will be told to look away from screen, and take a short 1-2 minute break. These side effects are rarely experienced.

The PI, Dr. Teri Lawton, having extensive experience conducting controlled validation studies, and the 2 SRAs (one overseeing behavioral data and one MEG-based data) will be in charge of training all staff, running daily operations which requires scheduling and supervising: 1) pre-post neuropsychological testing, 2) pre-post MEG exams at UCSD, and 3) administering the experimental and control interventions. The PI cannot influence the results, since data is collected by the SRA or RA when neuropsychological tests are administered, or automatically by all intervention testing programs, and behavioral data will only be analyzed by statistician. PDI's SRA will enter all data into the REDCap database to be analyzed by statistician who will enter data into FITBIR database.

Studies with a biomarker component will be used for half subjects in each experimental group to determine the pre-post timing and functional capabilities of different cortical areas in the attention and executive control pathways, in conjunction with behavioral pre-post standardized tests of cognitive abilities. The interventions being examined promote sustained functional recovery from a mTBI, including interventions during the chronic phase of injury, when currently there are no proven solutions for mTBI (80% of TBIs).

MEG recordings before and after training will provide a neural correlate biomarker to determine whether PATH training improves the function of the dorsal, attention, and working memory networks more than found after a sham intervention and after a N-Back WM intervention. MEG recordings will also be used to determine whether PATH training strengthens coupled theta/ gamma activity, and/or alpha/ gamma activity. To increase its commercialization ability, PATH neurotraining must be shown to improve brain function using a biomarker, as stated by neurologists and therapists in letters of support. A structural MRI used for superimposing the functional activity on top of the brain anatomy will be collected before initial MEG recording. To evaluate effectiveness of PATH, and WM neurotraining, the magnitude of improvements in MEG physiological recordings in the first 100-200 msec interval will be used to examine the functional changes in the visual system, and the 200-1000 msec interval will be used to study the changes in the later responses of the WM network. Professor Huang and his staff will record voxel-wise MEG source magnitude images, physiological recordings from half of the mTBI subjects in the experiental groups (using a neural correlate biomarker to show feasibility of interventions to improve cognitive ability). MEG images covering the whole brain, and each frequency band, following the Fast-VESTAL procedure to measure time-locked signals during an N-back WM task, will be used to evaluate improvements in brain function, as done in a pilot study. Three interventions (PATH, N-back WM, and Sham neurotraining) each 30 minutes, will be administered three times/week for 12 weeks.

The investigators will examine moderators that may determine training outcome. Individual differences at initial assessment will be evaluated to determine whether they predict improvements following training for different subpopulations: 1) Veteran mTBI subjects vs. civilian mTBI subjects, 2) different age groups (18-28, 29-41, 42-60), and 3) different loci and extent of the mTBI deficit. Whether these timing-based deficits predict cognitive skill deficits that are moderated by individual factors such as number of concussions, duration of loss of consciousness (LOC), nature and extent of cognitive deficits, cause of mTBI (blast or car accident or fall, for example), and age will be examined. These assessments will help to better understand the effects of a mTBI on different loci of mTBI deficit. Studies with a biomarker component will be used to determine the pre-post timing and functional capabilities of different cortical areas in the attention and executive control pathways, in conjunction with behavioral pre-post standardized tests of cognitive abilities. This exploratory aim will be used to determine whether different interventions should be explored during Phase II for different types of mTBI and different ages.

The purpose of this study is to test the feasibility of PATH training to improve neural timing and cognitive skills after a mTBI. We use the most precise methods to measure improvements in cognitive skills for mTBI subjects pre- and post- training by using established standardized tests of cognitive skills that will be analyzed by the statistician using mixed-factors Multiple Analysis of CoVariance (MANCOVA) and Multi Level Modeling (MLM) statistics. The proposed statistical analyses are more than sufficient to answer the questions being examined using a well-planned statistical design.

Meetings of our team will be conducted as needed on zoom to ensure this rigorous study is on track, and to prepare results for scientific meetings and publishing in high-impact scientific journals. Whether cognitive improvements are sustained over time will be evaluated during Phase II.

Eligibility Criteria:
A patient with a mTBI who has had a traumatically induced physiologic disruption of brain function will be referred by neurologist Dr. Ahmed who has made a diagnosis of mTBI, which includes one or more of the following (Marshall et al., 2012):

1. any loss of consciousness from 5- 30 min (not longer than 30 min),
2. any loss of memory for events immediately before or after the accident for as much as 24 hours,
3. any alteration of mental state at the time of the accident (e.g. feeling dazed, disoriented, or confused),
4. after 30 minutes, Glasgow Coma Scale of 13-15 (not lower or is considered more severe than a mild TBI),
5. post-traumatic amnesia less than 24 hours,
6. a score of 19-25 on the Montreal Cognitive Assessment (MoCA) screening test,
7. focal neurologic deficits that might/might not be transient,
8. one or multiple concussions.

For this study, the following criteria will be utilized:

Inclusion Criteria:

1. Diagnosis of mTBI (scoring between 19-25 on MoCA screening test),
2. between the ages of 18 to 60 years, when development and aging are not factors,
3. agrees to complete the study after hearing the time commitment involved,
4. has corrected 20/20 visual acuity, so can do PATH training (dim gray stripes),
5. reads English fluently, so can follow instructions, and
6. can complete the PATH neurotraining task, by pushing the left or right arrow key on the computer.
7. can sign and understand the informed consent form themself,
8. can drive to test sites or capable of using public transportation (bus or train) to test site.

Exclusion Criteria:

1. mTBI occurred less than 3 months earlier,
2. post-traumatic amnesia longer than 24 hours,
3. diagnosis of epilepsy or seizure disorder in last 12 months,
4. diagnosis of major depressive disorder or severe anxiety,
5. answers 'Yes' to any of the questions on the Columbia Suicide Severity Rating Scale,
6. had a stroke or metabolic derangements causing cognitive impairments, ie. alcohol or substance abuse,
7. cannot sign and understand the informed consent form themself,
8. cannot drive or use public transportation to arrive at PDI 3 times/week (MWF) for 30 minutes for 12 weeks,

   And for those chosen to undergo MEG/MRI exams:
9. has extensive metal dental hardware (e.g., braces and large metal dentures; fillings are acceptable) or other metal objects in head, neck, or face areas that cause artifacts in MEG data and health concerns in MRI data, and are not removable during pre-processing, and
10. has claustrophobia since MRI scanner is in small enclosed space, or
11. has a cardiac pacemaker.