Augmentation of Cognitive Training in Children With TBI With D-Cyloserine

Study Design/Procedure: The proposed study uses a double blind, parallel, placebo control design to test the hypotheses that augmentation of suppressed NMDA receptor function following pediatric msTBI with D-cycloserine (DCS) will increase neural activation, and when used in conjunction with cognitive training will enhance the effect of cognitive training on working memory (WM). Participants who show WM weaknesses within 12 to 24 months post-injury will be randomly assigned to one of two arms in the proposed study. Weakness in WM is operationally defined as a working memory index (WMI) standard score below 90 or evidence of at least a 10-point discrepancy between IQ and WMI. Given the purpose of the study (improving working memory), there is little utility in including children who do no demonstrate weaknesses in WM. Participants in both treatment arms will complete baseline evaluations on the WM and executive functioning (EF) tests that assess generalization, and parents will complete questionnaires that assess WM and attentional functioning. (Note: participants who completed their 12-month RAPBI visit within three months of enrollment in the current project will complete only novel measures). All participants will then receive their first Cogmed training session. During this first visit, participants will be also complete our MRI protocol immediately before and two hours after the first dose of DCS or placebo to measure the acute physiological response to DCS. Both groups will then complete six weeks of Cogmed training and in addition either DCS or placebo. Cogmed training will be completed in the home, with the parent/guardian supervising completion. During the six weeks of training, both you and your child will speak with a coach once a week, who will guide your child through the program and help to monitor his/her progress. Participants will travel to UCLA half-way through their training to consult with one of the medical personnel regarding the medication and to note any side effects. At the end of the sixth week, participants will be retested on our MRI protocol and non-trained measures of WM and EF. Parents will complete the questionnaires that assess WM and attention. Three months after the termination of treatment, participants will again return to UCLA to complete one session of Cogmed training and will be retested on the non-trained measures of WM and EF. Their parents will complete questionnaires to assess the maintenance of training.

Intercurrent events: Participants in the proposed project will be at least 12 months post-TBI. It is unlikely that new treatments will be initiated during the 4.5 months they are enrolled in the proposed project. Nevertheless we will monitor the medical and behavioral treatments outside of our study to ensure that they are not confounds.

Cogmed Training: Participants will perform the Cogmed WM training program via web-based software on a personal computer. If they do not have a personal computer, we will provide them with a laptop to borrow for the six weeks of training. Participants will train for 45 minutes per day, five days per week, for six weeks. Memory stimuli are presented in a computerized system in a total of eight visuospatial and verbal WM training exercises. Each training exercise consists of 15 trials. The exercises are in a video game format-with colorful graphics and crisp sound. In one spatial WM exercise the child remembers the sequence in which rows of lights turn on; in a verbal WM exercise the child recalls numbers in the reverse order in which they are given. The child uses a computer mouse to click the answers and earns points for performing well. The exercises train the child to attend to the screen and to visualize the location and remember the stimuli. For each of the eight WM training exercises difficulty is adjusted by changing the number of stimuli to be remembered. Training is performed close to the capacity of the individual by using an adaptive staircase method that adjusts difficulty on a trial-by-trial basis. At the end of each training day an Improvement index is calculated that measures improvement during the training period. The Improvement index is based on the person's results on three exercises.

On the first visit to UCLA, a coach will meet with the child and parent/guardian to teach them how to use the Cogmed program. The coach may encourage use a reward system to motivate and reinforce the child for training. The coach set up weekly times to contact the family. During these calls, the coach will review the child's progress, offer encouragement, and download performance data. The results of the improvement index will be shared with parents or adult participants, similar to how standardized paper and pencil neurocognitive test results are shared in clinical settings.

DCS treatment: DCS can have opposing effects at low dose vs. high dose. In mouse cerebellar tissue there is an inverted U-shaped dose-response relationship. At low DCS concentrations, agonist activity may reflect binding to NMDA receptor (NMDAR) subunits. In contrast, at higher DCS concentrations antagonist effects may become prominent. Consistent with the above research, in both animal models and clinical applications, isolated low dose DCS treatments appear to have significant advantages over chronic treatment at higher doses. In animal models, a single dose of DCS reversed cognitive impairment produced by hippocampal lesions, anticholinergic agents, and early social deprivation. In healthy animals, a single dose of DCS enhanced extinction of conditioned fear performance on maze tasks, and visual recognition memory. Mice treated with a single, low-dose of DCS 24 or 72 hours after TBI exhibited significantly more rapid and complete recovery of motor and memory function compared with untreated controls. Tachyphylaxis rapidly develops with repeated dosing of DCS. A single dose of DCS administered within 30 minutes of extinction training increases 24 hour retention of fear extinction approximately 3-fold, whereas this effect was completely attenuated by 5 doses of DCS administered over 10 days preceding the extinction training.