EARLY ABUSE AND CORTICOLIMBIC DEVELOPMENT

早期滥用和皮质边缘发育

• 批准号: 2675299
• 负责人: MARTIN H TEICHER
• 金额: $ 42.32万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2675299
• 关键词: adolescence (12-20); alpha adrenergic receptor; behavioral /social science research tag; blood volume; brain electrical activity; brain interhemispheric activity; cerebral cortex; child abuse; child physical development; child psychology; clinical research; corticosteroid receptors; developmental neurobiology; evoked potentials; human subject; hypothalamic pituitary adrenal axis; immunocytochemistry; limbic system; magnetic resonance imaging; neuropsychological tests; neuropsychology; psychobiology; psychological shock; sex abuse; young adult human (21-34)

The overall aim of this application is to systematically evaluate the hypothesis that early traumatic experience, in the form of childhood abuse, affects the development of the cerebral cortex and limbic system. This hypothesis endeavors to explain the psychiatric sequela of childhood traumatic experience using an integrative biopsychosocial model, that focuses on the possible biological consequences of adverse early social experience, and the subsequent psychological and behavioral ramifications of stress-induced corticolimbic abnormalities. A two pronged approach will be used, in which clinical studies exploring the association between early abuse and corticolimbic development, will be bolstered by preclinical studies in rodents focusing on the effects of early separation stress on the development of cortical connectivity, corticosteroid regulation, and monoaminergic innervation. In the clinical studies, two groups of unmedicated young adults (18 - 22 years of age) will be compared. The first group will consist of normal controls who have never been abused, or psychologically traumatized. They will be compared to a second group who have experienced forced sexual abuse accompanied by intense fear. Electrophysiological measures of coherence will be used, as a primary measure, to test whether early abuse is associated with an abnormal pattern of right vs left hemisphere interconnection, and attenuated frontal cortex development. The clinical sample will also be assessed using magnetic resonance imaging for abuse related alterations in hippocampal and corpus collosum volume. Dynamic Susceptibility Contrast MRI will be performed to calculate regional cerebral blood volume in the basal state, to test the hypothesis that abuse alters the normal pattern of laterality. Probe evoked potential studies will be used to assess shifts in cortical activity during recall of abuse. Neuropsychological tests will assess for left vs right hemisphere functional impairment. Measures of lymphocyte glucocorticoid receptors, and platelet alpha-2 receptors will provide covariate data on alterations in HPA axis and catecholamine function. In the preclinical component, repeated maternal isolation at cool temperature will be used as an intense life-threatening species relevant stressor, that elevates corticosteroid levels throughout development, and affects HPA axis regulation. The effects of acute and continuous stress on monoamine release in left and right hippocampus will be assessed using in vivo microdialysis in 10 day old rats. Measures will also be made of corticosteroid response. Enduring effects of chronic stress will be evaluated in measures of glucocorticoid receptors density in hippocampus and on lymphocytes, and alpha2 receptors density in locus coeruleus and platelets. Measures will be made of synaptic density in hippocampus, prefrontal cortex in striatum using synaptophysin immunocytochemistry, and the effects of early stress on the pattern of synaptic overproduction and elimination will be ascertained. Functional effects of early stress on hippocampus will be evaluated using radial arm maze. Effects of severe early stress on laterality of cortical and hippocampal function will be assessed under both basal and stressed states, using 2-deoxy-D-glucose as a measure of brain metabolism, and using measures of serotonin, dopamine and norepinephrine turnover. In tandem, the proposed clinical and preclinical investigations will provide urgently needed information on the effects of early trauma on the development of cortical and limbic system function, that may underlie the psychiatric sequelae observed in persons who were victims of early violence and trauma.

该应用的总体目的是系统地评估 假设早期创伤经历，以童年的形式 滥用，影响大脑皮层和边缘系统的发展。 这一假设努力解释儿童精神续集 使用综合性生物心理社会模型的创伤经验， 重点关注不利早期社会的生物学后果 经验以及随后的心理和行为后果 压力诱导的皮质脂质异常。两个李子的方法将 使用，其中临床研究探讨了早期之间的关联 滥用和皮质临床的发展将由临床前促成 研究啮齿动物的研究，重点是早期分离应力对 皮质连通性，皮质类固醇调节和 单胺能神经。在临床研究中，两组 将比较未经药物的年轻人（18-22岁）。这 第一组将包括从未被虐待的正常对照组成，或者 心理创伤。他们将与第二组进行比较 经历了强迫性虐待，并伴随着强烈的恐惧。 将使用电生理的一致性测量，作为主要的 测量，测试早期滥用是否与异常有关 右与左半球互连的模式，并减弱 额叶皮层开发。还将评估临床样本 使用磁共振成像进行滥用相关的更改 海马和collosum体积。动态敏感性对比 将进行MRI以计算区域脑血体积 基础状态，以检验滥用改变正常模式的假设 横向。探测诱发的潜在研究将用于评估 在虐待召回期间皮质活动的转变。神经心理学 测试将评估左半球功能障碍。 淋巴细胞糖皮质激素受体和血小板α-2的度量 受体将提供有关HPA轴改变的协变数据和 儿茶酚胺功能。在临床前成分中，重复的母体 在凉爽温度下的隔离将被用作强烈的威胁生命 物种相关的应激源，可以提高整个整个皮质类固醇水平 开发并影响HPA轴调节。急性和 左右海马中单胺释放的持续应力将 在10天大的大鼠中使用体内微透析进行评估。措施将 也是由皮质类固醇反应制成的。慢性的持久影响 将在糖皮质激素受体密度的度量中评估应力 在海马和淋巴细胞中，以及基因座中的α2受体密度 凝结和血小板。措施将是针对突触密度的 海马，纹状体中的前额叶皮质使用突触 免疫细胞化学以及早期压力对模式的影响 突触过量生产和消除将得到确定。功能 将使用径向臂评估早期应力对海马的影响 迷宫。严重的早期压力对皮质和皮质侧向的影响 海马功能将在基础和应力下评估 状态，使用2-脱氧-D-葡萄糖作为脑代谢的量度，并 使用5-羟色胺，多巴胺和去甲肾上腺素的度量。在 串联，拟议的临床和临床前研究将提供 迫切需要有关早期创伤对影响的影响的信息 皮质和边缘系统功能的发展，这可能是 在早期受害者中观察到的精神后遗症 暴力和创伤。