Background and Purposes

Although improved medical treatment for children with brain tumors has dramatically increased five-year survival rates, this population is at increased risk for medical, behavioral, emotional, and cognitive late effects compared to children with other malignancies. Specifically, for average risk medulloblastoma, the most common type of posterior fossa brain tumor, relapse-free survival rates have increased to almost 90 percent. However, the "price of cure" for more than 50 percent of childhood posterior fossa tumor survivors includes long-term neurocognitive deficits, specifically in executive functions (Crawford et al., 2007).

Cardiovascular fitness has been associated with better performance on tests of executive function across the lifespan, including healthy adolescents, adults, and older adults (e.g. Smiley-Oyen et al. 2008). At a neural level, cardiovascular exercise has been linked with neurogenesis, angiogenesis, and increased synaptic plasticity in the brain (Van Praag, 2008). Translational research with brain-injured rats has found an association between voluntary exercise and cognitive recovery, attributable to up-regulation of brain-derived neurotrophic factor (BDNF; Griesbach et al., 2009). In addition, one study with adults with multiple sclerosis found a robust relationship between cardiovascular fitness and executive functions (Prakash et al., 2007). However, no study has investigated this relationship in childhood cancer survivors.

Finding innovative, cost-effective, and non-pharmacologic techniques to address executive deficits in surviving posterior fossa tumor patients is vital in improving their cognitive and behavioral functioning. The present study aims to establish rationale to explore cardiovascular exercise as a viable intervention for executive dysfunction in survivors of childhood posterior fossa tumor by demonstrating the relationships among executive functions, neural activation patterns, and cardiovascular fitness.

Methods Participants—Twenty pediatric posterior fossa tumor survivors will be recruited from the neuro-oncology clinic at Children's Hospital of Alabama. Inclusion criteria include: a) posterior fossa tumor survivors at least one year post-completion of medical therapy; b) received radiation therapy as part of treatment regimen; c) between the ages of 11-18 years; d) full-scale IQ>70; e) right-handed; f) English speaking; and g) modified Lansky or Karnofsky score of >70. This study has been approved by the University of Alabama at Birmingham Institutional Review Board.

Questionnaires

After completing informed consent and meeting inclusion criteria, a parent or caretaker of the participant will complete a demographic information questionnaire and the Behavior Rating Inventory of Executive Function (BRIEF), an ecologically valid parent-report measure of the participant's executive functions in everyday life. Participants themselves will complete the Physical Activity Questionnaire for Older Children (PAQC) or Physical Activity Questionnaire for Adolescents (PAQ-A), a valid and reliable self-report retrospective 7-day activity questionnaire.

Functional Magnetic Resonance Imaging (fMRI) Scan We plan to examine the brain activation and synchronization associated with executive functions, specifically sustained and divided attention, ininhibition, and working memory. The following tests will be utilized during the fMRI session: 1) a Go/no-go task (Mostofsky et al. 2003) to examine sustained attention and inhibition; and 2) an N-back task (Koshino et al., 2005), which will examine sustained and divided attention and working memory.

Cardiorespiratory Fitness

Participants' physical fitness will be measured using peak oxygen uptake, or VO2peak, testing. Participants will be asked to ride a cycle ergometer (stationary bicycle), with increasing intensity, while their heart rate, oxygen uptake, and carbon dioxide output are measured. This test yields a number that is considered one's "VO2peak score," typically a number between 20 and 50. Data Analysis

In order to investigate relationships between cardiorespiratory fitness and behavioral neurocognitive data, partial correlations will be computed for VO2peak scores and behavioral scores (i.e. accuracy and reaction time) from the Go/no-go and N-back tasks after accounting for age, race, and gender. Secondly, to examine the relationship between neural activation and cardiorespiratory fitness, partial correlations will be computed for average percent signal change in a priori regions of interest in the brain and VO2peak scores after accounting for age, race, and gender. Finally, subjects will be grouped into "high-fit" and "low-fit" groups by the median VO2peak score; groups will be compared on executive function scores and region of interest percent signal change using separate one-way ANOVAs after accounting for age, race, and gender.

Clinical and Research Implications

By investigating the relationship between cardiorespiratory fitness and executive functions through neuropsychological tests and neuroimaging, we hope to establish the significance of exercise for executive functions in childhood brain tumor survivors. Since executive abilities are crucial in many areas of functioning, ranging from social interactions to academic success, a low-cost, easily disseminable intervention could substantially improve the overall functioning of pediatric brain tumor survivors.

It is hoped that the present study will lay a foundation for an exercise intervention with pediatric brain tumor survivors and eventually other cancer diagnoses also known to suffer from executive function deficits in survivorship.

References

• Crawford, J.R., MacDonald, T.J., & Packer, R.J. (2007). Medulloblastoma in childhood: New biological advances. Lancet Neurology, 6(12), 1073-1085.

• Griesbach, G.S., Hovda, D.A., & Gomez-Pinilla, F. (2009). Exercise-induced improvement in cognitive performance of traumatic brain injury in rats is dependent on BDNF activation. Brain Research, 1288, 105-115.

• Prakash, R.S., Snook, E.M., Erickson, K.I., Colcombe, S.J., Voss, M.W., Motl, R.W., & Kramer, A.F. (2007). Cardiorespiratory fitness: A predictor of cortical plasticity in multiple sclerosis. NeuroImage, 34(3), 1238-1244.

• Smiley-Oyen, A.L., Lowry, K.A., Francois, S.J., Kohut, M.L., & Ekkekakis, P. (2008). Exercise, fitness, and neurocognitive function in older adults: The "selective improvement" and "cardiovascular fitness" hypotheses. Annals of Behavioral Medicine, 36(3), 280-291.

• Van Praag, H. (2008). Neurogenesis and exercise: Past and future directions. Neuromolecular Medicine, 10(2), 128-140.