CEREBRAL BLOOD FLOW PATTERN INDUCED BY KETAMINE

氯胺酮引起的脑血流模式

• 批准号: 2122753
• 负责人: HENRY HILLIARD HOLCOMB
• 金额: $ 23.06万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2122753
• 关键词: antipsychotic agents; anxiety; brain mapping; cerebral cortex; cingulate gyrus; corpus striatum; delusions; hallucinations; haloperidol; hippocampus; human subject; intravenous administration; ketamine; magnetic resonance imaging; neurochemistry; perceptual distortions; phencyclidine; positron emission tomography; psychosis; psychotomimetic drug; schizophrenia; social psychology; thalamus

The overall objective of this proposal is to define the functional neuroanatomy of ketamine (an NMDA receptor antagonist) induced psychosis. Within this general objective are 3 specific aims. 1) We will compare and contrast regional cerebral blood flow (rCBF) time activity curves in normal volunteers and unmedicated schizophrenic (SZ) patients given an acute intravenous dose of ketamine. We expect ketamine to effect larger limbic regions for longer time periods in schizophrenics than normals. 2) We will compare and contrast time activity rCBF changes in neuroleptic medicated and unmedicated SZ patients given acute ketamine to assess the role of dopaminergic blockade in ketamine induced limbic rCBF changes. Haloperidol is expected to reduce regional activity changes and the duration of activation in limbic areas (cingulate, hippocampus, anterior thalamus, striatum). 3) In these three groups, neuroleptic treated and neuroleptic withdrawn SZ and normal volunteers we will assess the correlation between psychosis ratings, using the Brief Psychiatric Rating Scale, and rCBF at peak drug effect measurements. These goals will be accomplished using serial 15-oxygen labeled water rCBF positron emission tomography (PET) studies. By acquiring three studies prior to drug administration and seven studies, at ten minute intervals, after the drug is given we will be able to determine the correlation between a subject's mental status change and his rCBF pattern. Hallucinations, perceptual distortions, delusions, social withdrawal, and anxiety will be assessed. Subjects will be studied at rest, with their eyes open. Within and between group statistical analyses of time activity curves at each brain image pixel will be facilitated by two preprocessing steps. First, within each subject all PET scans will be aligned with one another and these will in turn be aligned with each subject's MRI. Second, using each subject's MRI all data sets will be elastically warped to fit a common template in "Talairach space." Within and between group time activity curve patterns will be assessed using the Statistical Parametric Mapping program (Friston, et al, 1991). Preliminary data have established ketamine elicits, in dose dependent fashion, psychotic exacerbations congruent with their endogenous symptoms. Normal volunteers receiving ketamine also exhibit a wide range of behavioral changes similar to those observed with PCP toxicity. In these studies we will use time activity measures of rCBF in the cingulate cortex and other limbic regions to assess the anatomical substrate of ketamine induced behavioral changes.

本提案的总体目标是确定 氯胺酮（一种NMDA受体拮抗剂）诱发精神病的神经解剖学研究。 在这个总目标中有三个具体目标。 1)我们会比较， 对比局部脑血流（rCBF）时间活动曲线， 正常志愿者和未服药的精神分裂症（SZ）患者给予 急性静脉注射氯胺酮我们预计克他命的作用 精神分裂症患者的边缘区域比正常人的时间更长。（二） 我们将比较和对比抗精神病药物治疗后的时间活动rCBF变化， 接受急性氯胺酮给药和未给药的SZ患者，以评估 多巴胺能阻滞剂在氯胺酮诱导的边缘脑血流变化中的作用 预计氟哌啶醇可减少区域活动变化， 边缘区（扣带、海马、前额叶）激活的持续时间 丘脑、纹状体）。 3)在这三组中，神经阻滞剂治疗， 我们将评估停用抗精神病药的SZ和正常志愿者 精神病评定之间的相关性，使用简明精神病评定 量表和峰值药物效应测量时的rCBF。这些目标将是 使用连续的15-氧标记水rCBF正电子发射 断层扫描（PET）研究。 通过在给药前获得三项研究， 给药后10分钟间隔， 我们将能够确定受试者的 精神状态变化和脑血流图 幻觉，知觉 将评估扭曲、妄想、社交退缩和焦虑。 受试者将在睁眼休息时接受研究。内和之间 对每个脑图像的时间活动曲线进行分组统计分析 像素将通过两个预处理步骤来促进。首先，在每个 受试者所有PET扫描将彼此对齐， 与每个受试者的MRI对齐。第二，利用每个受试者的核磁共振成像 所有数据集将被弹性扭曲以适应通用模板 “塔拉拉赫空间。“组内和组间时间活动曲线 将使用统计参数映射程序进行评估 （Friston等人，1991）。初步数据表明氯胺酮 以剂量依赖性方式，精神病加重与 内源性症状。接受氯胺酮的正常志愿者也 表现出广泛的行为变化，类似于观察到的 五氯苯酚毒性。在这些研究中，我们将使用rCBF的时间活动测量 在扣带皮层和其他边缘区域，以评估解剖 氯胺酮的底物诱导的行为改变。