Neural Bases of Eyeblink Conditioning in FASD

FASD 眨眼条件反射的神经基础

• 批准号: 8100119
• 负责人: SANDRA W. JACOBSON
• 金额: $ 49.34万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100119
• 关键词: 11 year old; 5 year old; Affect; Age; Age-Years; Alcohol abuse; Alcohol dependence; Alcohol-Related Neurodevelopmental Disorder; Alcohols; Algorithms; Animal Model; Area; Atlases; Back; Behavioral; Biological Assay; Biological Markers; Blinking; Brain; Cell Nucleus; Cerebellar Nuclei; Cerebellum; Characteristics; Child; Childhood; Cognitive; Cognitive deficits; Cohort Studies; Collaborations; Color; Communities; Conditioned Stimulus; Consultations; Corpus Callosum; Data; Data Reporting; Development; Diagnosis; Diagnostic; Differential Diagnosis; Diffusion Magnetic Resonance Imaging; Discrimination; Disease; Dysmorphology; Early Diagnosis; Early identification; Early treatment; Effect Modifiers (Epidemiology); Elements; Esters; Etiology; Exhibits; Exposure to; Face; Fatty Acids; Female of child bearing age; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fingers; Functional Magnetic Resonance Imaging; Functional disorder; Genetic Polymorphism; Goals; Gold; Growth; Head circumference; Human; Image; Impaired cognition; Impairment; Incidence; Individual; Infant; Inferior; Institutes; International; Intervention; Interview; Laboratory Animals; Lead; Learning; Life; Link; Lip structure; Lobe; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maternal Age; Meconium; Mediating; Movement; Neuraxis; Neurosciences; Outcome; Parietal; Parietal Lobe; Pathway interactions; Pattern; Performance; Phenotype; Pilot Projects; Postpartum Period; Pregnancy; Process; Psychological reinforcement; Recording of previous events; Recruitment Activity; Research; Research Personnel; Resolution; Rodent; Sampling; Science; South Africa; Specialist; Specificity; Specimen; Stimulus; Structure; Symptoms; Techniques; Testing; Time; TimeLine; Universities; Variant; Visual Acuity; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; base; brain morphology; caudate nucleus; cohort; conditioning; craniofacial; design; drinking; efficacy evaluation; follow-up; improved; infancy; innovation; interest; intrapartum; meetings; neural circuit; neurobehavioral; neuroimaging; neuropathology; neuropsychological; prenatal exposure; processing speed; prospective; public health relevance; relating to nervous system; response; tool; white matter

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：胎儿酒精谱系障碍 (FASD) 的诊断很困难，因为通常缺乏有关产前暴露的信息，许多受影响的儿童没有表现出特征性的面部异常，也没有发现独特的行为表型。对 FASD 病理生理学的了解有限，阻碍了适当治疗的发展。自 1999 年以来，我们一直在南非开普敦的开普有色人种（混血）社区进行一项前瞻性纵向研究，该地区胎儿酒精综合症 (FAS) 的发病率极高。在对该队列进行为期 5 年的随访中，我们发现胎儿酒精暴露对眨眼条件反射的影响非常一致，眨眼条件反射是一种依赖小脑的学习形式，其神经回路和酒精影响已在实验动物身上得到详细记录。与 75% 的非暴露对照组相比，没有一个患有完全 FAS 的儿童符合调节标准。因此，我们已经确定了酒精相关中枢神经系统损伤的潜在生物标志物。此外，由于它在婴儿早期就已经很成熟，短延迟 EBC 可能为 FASD 的早期诊断以及评估产时和产后早期干预的效果提供重要工具。在这项研究中，我们将对开普敦的 165 名 8.5 岁儿童队列进行随访，并从同一社区招募 60 名婴儿（30 名重度暴露者，30 名对照者）组成的新前瞻性队列。主要目的是描述 EBC 中酒精相关障碍的发展过程；使用选定的神经影像技术来检查胎儿酒精暴露对介导 EBC 的神经回路的影响；并使用神经行为和功能 MRI 任务来评估对小脑介导的计时（EBC 的核心要素）的影响。先进的神经影像学将包括用于检查大脑发育不全的区域模式的高分辨率结构 MRI，以及用于 FASD 儿童的首个全脑扩散张量成像 (DTI)，以评估白质束的完整性。还将检查母亲年龄、酗酒史和 ADH1B 多态性变异对儿童 FASD 易感性的调节作用。公共健康相关性：更好地了解胎儿酒精暴露对儿童期和婴儿期 EBC 小脑回路的影响，有可能增进我们对 FASD 神经病理学的理解，改善这种疾病的诊断和治疗，并能够更早识别受影响的儿童。