This application is in response to RFA DA05-007. Clinical and preclinical observations suggest that prenatal methamphetamine (METH) exposure may lead to abnormal brain structures and neurochemistry. Little is known about how these brain changes (structural and chemical) relate to cognitive development. Our preliminary cross-sectional studies in children exposed to METH prenatally provide strong evidence that these children have smaller subcortical brain structures and brain metabolite abnormalities on proton MR spectroscopy (1H MRS), along with decreased performance on neuropsychological tests. Our preliminary data also suggest that these children do not show appropriate age-related increases in some subcortical structures (putamen, globus pallidus, and hippocampi). High resolution MRI, coupled with novel image processing technques, can precisely quantify volumes of brain structures while 1H MRS can reliably and non-invasively quantify neurochemicals that reflect neuronal density (N-acetyl aspartate or NAA) and other cellular markers (choline-compounds, total creatine, myoinositol, glutamate plus glutamine) in selected brain regions. Our primary Specific Aims are: 1) To assess changes in brain structure (on MRI) and brain metabolite concentrations (on 1H MRS) in young children (age 3 years) who were exposed to METH in utero, and to follow these changes longitudinally and annually until age 7 years. 2) To evaluate neuropsychological performance in these children on a yearly basis over the same time period (ages 3-7 years). 3) To evaluate how structural and chemical brain abnormalities (on MRI and 1H MRS) are related to cognitive development in children exposed to METH prenatally. We will follow 120 children (60 with and 60 without prenatal METH exposure) over the course of 5 years, to determine temporal changes in brain metabolite levels, morphometry and neuropsychological performance during early childhood development. Most of these children will be co-enrolled and have been followed since birth in the NIDA-funded Infant Development, Environment and Lifestyle (""""""""IDEAL"""""""") study, which assesses infant neurobehavioral development. Detailed maternal drug use, psychosocial and mood evaluations will be performed and correlated with biological brain changes in these children.
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