Neurodevelopmental Assessment of Children in Uganda and Malawi Using a Software Package

University of Michigan, Johns Hopkins University, MU-JHU CARE, Kamuzu University of Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The investigators will use Brain Power Games or Village Builder, two different MSU-developed computer-based learning games for children on Tablets, as a neurocognitive "stress test" or medical "challenge" test, in order to evaluate brain/behavior functional integrity in HIV-affected children. This dual use of BPG is a key innovative feature. Each of the 5 core BPG games lasts 10 minutes and trains fine motor, monitoring/attention, visual/auditory working memory, spatial navigational learning. Village Builder (VB) uses similar graphics as BPG, but is a pro-social "world-building" game where children gather and protect resources to build a village. thus VB emphasizes planning/reasoning (executive function or EF) neurocognitive abilities, while BPG emphasizes attention, memory, and learning tasks. In As an African child plays with BPG or VB on a touch-screen tablet, we will use games as a dynamic window into the child's developing brain and EF-based frontal lobe development Aim 1. Evaluate concurrent and predictive validity of BPG static (baseline) and dynamic (during 12 training sessions) cognitive assessments Aim 2. Compare the validity of BPG static and dynamic assessments Aim 3. Test the sensitivity of dynamic assessment to learning loss over time by evaluating how much BPG and/or VB performance gains diminish during a 6-month absence of training The investigator's central hypothesis is that the BPG and VB performance gains (dynamic assessment) will explain the additional variation in the gold-standard measures at time points after static (baseline) assessment, and more effectively capture the effects of HIV/ARV exposure and treatment across HIV affected cohorts (HIV, HEU, HUU) of children in Uganda and Malawi.

In Phase I of the study we randomize equal numbers of each of three exposure groups of children (perinatally HIV infected, perinatally HIV-exposed but not infected, and unexposed/uninfected children) to one of two intervention arms. They are randomized to either the Brain Powered Games (BPG) intervention arm of 12 sessions of hour-long training (twice a day for several days weekly at the study clinic), or to the "wait-listed" arm of no BPG training sessions. In phase II of the protocol (after pretesting, 2 months of waiting followed by post-training testing and then 6-month follow-up testing for both immediate and wait-listed BPG training arms - the wait-listed children will all undergo 12 sessions of village Builder which is a pro-social reasoning/planning strategy game newly developed by our Games for Entertainment and Learning (GEL) lab at Michigan State University (MSU). In Phase II for the Village Builder children, all children will also undergo neuropsychological testing before and after the 12 training sessions, as well as neuropsychological assessment at six-month follow-up post training.

The subject population for this proposal will consist of 600 children roughly equally divided between males and females and between HIV exposed uninfected and HIV unexposed and uninfected. These are Ugandan and Malawian children 5-12 years of age at study initiation who live in Uganda or Malawi.

Brain Powered Games (BPG) uses games for neurocognitive assessment and training, using images and sounds more familiar to African children. As a computerized cognitive rehabilitation training (CCRT) program designed for Sub-Saharan African school-age children, it can help children infected affected directly or indirectly by HIV. BPG consists of 5 core games evaluating different cognitive abilities (learning, memory, language, attention). Each game includes a visual tutorial, several adjustable settings on the administrative side (Admin), and records game play data for research purposes. Village Builder (VB) is a pro-social reasoning/planning world building strategy type game intended to evaluate frontal lobe executive functions in a culture-friendly and enjoyable game manner. It consists of many of the village artistic components as used in BPG but orchestrated into a village setting where children must gather resources and protect them in order to expand the capacity of the village.

the KABC-II will be the principal test for cognitive ability.47 It is validated in sub-Saharan Africa48-51 and has been adapted for pediatric HIV research.1,18,46,52-55 Using the Luria model for neuropsychological assessment within KABC-II, the primary outcome variables are the global scores of Sequential Processing (memory), Simultaneous Processing (visual-spatial processing and problem solving), Learning (immediate and delayed memory), Planning (executive reasoning), Delayed Recall, Nonverbal Index (NVI) subtests not dependent on understanding instructions in English, and Mental Processing Index (MPI), a composite of all the cognitive performance areas.

TOVA is a computerized visual continuous performance test used in to screen, diagnose and monitor children and adults at risk for ADHD.56 TOVA consists of the rapid (tachistoscopic) presentation of a large geometric square on the computer screen with a smaller dark box either in the upper position (signal) or lower position (non-signal). The child is asked to press a switch held in the preferred hand as fast as possible in response to the signal (measuring vigilance attention), but to withhold responding to the non-signal (measuring impulsivity).

CogState presents a 30-min session that includes playing cards in a game-like manner to assess memory, attention, discrimination learning, and executive function that is non-language dependent. CogState tests include Card Detection (simple reaction time), Identification (choice reaction time), One-Back Working Memory, and One-Card Learning. CogState also includes the Groton Maze Task, which can measure visual-motor tracking (Maze Chase) and executive functioning/planning (Maze Learning).

Parent-based screening tool for emotional and behavioral problems observed in the child. CBCL is important to assess when a child's social environment is enriched by adult oversight in game assessment and training, reflecting a collateral training benefit

We will use the middle childhood version of the Caldwell Home Observation for the Measurement of the Environment (HOME) validated for use as an important distal measure predictive of our gold standard assessments.The HOME assesses the stimulation and learning opportunities offered by the child's home environment.

As part of their standard of care (HIV cohort only), CD4 measures will be available from a blood draw taken within a week from the time of neuropsychological assessment as a more proximal predictor of disease effects on assessment performance

As part of their standard of care (HIV cohort only), viral load will be available from a blood draw taken within a week from the time of neuropsychological assessment as a more proximal predictor of disease effects on assessment performance

As part of their standard of care (HIV cohort only), CD8 measures will be available from a blood draw taken within a week from the time of neuropsychological assessment as a more proximal predictor of disease effects on assessment performance

Inclusion Criteria: HEU and HUU children at least 5 yrs of age and older from the PROMISE ND study (Uganda and Malawi) HIV+ children from P1104s (Uganda and Malawi) HUU children age-matched from PROMISE ND and P1104s study cohorts (Uganda and Malawi) Exclusion Criteria: Medical history of serious birth complications Severe malnutrition Bacterial meningitis Encephalitis Cerebral malaria Other known brain injury or disorder requiring hospitalization Seizures or other neurological disabilities