Corticosteroids are widely used in treatment of pediatric illness, most notably for controlling inflammation. Cytokines are released during active disease in a range of inflammatory and autoimmune conditions. Both have the potential to disrupt brain systems critical for memory and executive control processes (ECP), however, little is known about these effects, especially in developing populations. Crohn's disease (CD), a main type of inflammatory bowel disease, was chosen as model disease. The long-term goal of this K23 award is for the candidate, a pediatric neuropsychologist, to become an independent clinical investigator in developmental neuroscience and neuroimaging of children with chronic illness, with emphasis on endocrine and immune influences on the developing brain. The primary training objective is to acquire expertise in the use of functional magnetic neuroimaging (fMRI) for use in future studies. Secondary objectives include to gain an appreciation of the pathophysiology of CD with emphasis on neuroendocrine and -immune factors affecting behavior and to further skills for conducting longitudinal clinical studies. These will be accomplished through: 1) mentorship in a clinical/research environment;2) hands-on training in fMRI by the candidate's sponsor and co-sponsors complemented by didactics in fMRI, neuroendocrinology, neuroimmunology, and advanced statistics;3) execution of the proposed research plan with focus on memory, ECP, and mood in children with CD age 8-16 years.
The specific aims of the project are based on the candidate's preliminary work and will examine: 1) the effects of corticosteroids on memory/ECP acutely and 6-months post treatment;2) the association between pro-inflammatory cytokines and memory/ECP;3) differences in frontal and hippocampal activation in steroid-treated vs. healthy control children. A longitudinal group- comparison design will be employed. Children with CD on high-dose steroids will be compared to 3 control groups at baseline and 6-month follow-up on neurobehavioral testing and event-related potentials (ERP). A pilot cross-sectional fMRI study will be conducted in a subgroup of the study population. The proposed research will yield important information about the link between steroids, inflammation, and brain impact in pediatric CD with implications not only for the safety of steroid therapy, but also for other autoimmune disorders, informing future prevention, intervention, and in-depth fMRI studies.
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|Mrakotsky, Christine; Forbes, Peter W; Bernstein, Jane Holmes et al. (2013) Acute cognitive and behavioral effects of systemic corticosteroids in children treated for inflammatory bowel disease. J Int Neuropsychol Soc 19:96-109|
|Mrakotsky, Christine M; Silverman, Lewis B; Dahlberg, Suzanne E et al. (2011) Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. Pediatr Blood Cancer 57:492-8|