Diagnosis of fetal alcohol spectrum disorder (FASD) is difficult because information regarding prenatal exposure is often lacking, many affected children do not exhibit the characteristic facial anomalies, and no distinctive behavioral phenotype has been identified. Development of appropriate treatments has been hampered by limited understanding of the pathophysiology of FASD. Since 1999, we have been conducting a prospective, longitudinal study in the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where there is an exceptionally high incidence of fetal alcohol syndrome (FAS). In a 5-year follow-up of this cohort, we found a remarkably consistent effect of fetal alcohol exposure on eyeblink conditioning, a cerebellar-dependent form of learning whose neural circuitry and alcohol effects have been documented in detail in laboratory animals;not a single child with full FAS met criterion for conditioning, compared with 75% of the non-exposed controls. Thus, we have identified a potential biomarker of alcohol-related CNS impairment. Moreover, because it is well established in early infancy, short-delay EBC may provide an important tool in the early diagnosis of FASD and in the evaluation of the efficacy of intrapartum and early postpartum interventions. In this study we will follow-up our Cape Town cohort of 165 children at 8.5 years and recruit a new prospective cohort of 60 infants (30 heavy exposed, 30 controls) from the same community. The principal aims are to characterize the developmental course of alcohol-related impairment in EBC;to use selected neuroimaging techniques to examine the impact of fetal alcohol exposure on the neural circuitry mediating EBC;and to use neurobehavioral and functional MRI tasks to assess effects on cerebellar- mediated timing, a central element of EBC. Advanced neuroimaging will include high resolution structural MRI to examine the regional pattern of brain hypoplasia and the first whole brain diffusion tensor imaging (DTI) in children with FASD to assess the integrity of white matter tracts. The moderating effects of maternal age, alcohol abuse history, and variants of the ADH1B polymorphism on the child's vulnerability to FASD will also be examined. Public Health Relevance: A better understanding of the effects of fetal alcohol exposure on the EBC cerebellar circuit in childhood and infancy has the potential to advance our understanding of the neuropathology of FASD, to improve the diagnosis and treatment of this disorder, and to enable earlier identification of affected children.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016781-04
Application #
8100119
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Matochik, John A
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$493,402
Indirect Cost
Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Warton, Fleur L; Taylor, Paul A; Warton, Christopher M R et al. (2017) Prenatal methamphetamine exposure is associated with corticostriatal white matter changes in neonates. Metab Brain Dis :
Jacobson, Sandra W; Jacobson, Joseph L (2017) Cardiac Orienting Response as an Early Indicator of Impairment in Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 41:262-265
Warton, Fleur L; Meintjes, Ernesta M; Warton, Christopher M R et al. (2017) Prenatal methamphetamine exposure is associated with reduced subcortical volumes in neonates. Neurotoxicol Teratol :
Kodali, Vikas N; Jacobson, Joseph L; Lindinger, Nadine M et al. (2017) Differential Recruitment of Brain Regions During Response Inhibition in Children Prenatally Exposed to Alcohol. Alcohol Clin Exp Res 41:334-344
Jacobson, Sandra W; Jacobson, Joseph L; Molteno, Christopher D et al. (2017) Heavy Prenatal Alcohol Exposure is Related to Smaller Corpus Callosum in Newborn MRI Scans. Alcohol Clin Exp Res 41:965-975
Suttie, Michael; Wetherill, Leah; Jacobson, Sandra W et al. (2017) Facial Curvature Detects and Explicates Ethnic Differences in Effects of Prenatal Alcohol Exposure. Alcohol Clin Exp Res 41:1471-1483
Lindinger, Nadine M; Malcolm-Smith, Susan; Dodge, Neil C et al. (2016) Theory of Mind in Children with Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 40:367-76
Fan, Jia; Jacobson, Sandra W; Taylor, Paul A et al. (2016) White matter deficits mediate effects of prenatal alcohol exposure on cognitive development in childhood. Hum Brain Mapp 37:2943-58
Carter, R Colin; Jacobson, Joseph L; Molteno, Christopher D et al. (2016) Fetal Alcohol Growth Restriction and Cognitive Impairment. Pediatrics 138:
Lewis, Catherine E; Thomas, Kevin G F; Molteno, Christopher D et al. (2016) Prospective Memory Impairment in Children with Prenatal Alcohol Exposure. Alcohol Clin Exp Res 40:969-78

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