Neuroimaging Of Frontal Lobe Function During Cognition

使用功能神经成像来确定局部神经元的活动，我们发现正常受试者在执行涉及工作记忆的任务时使用皮质网络，包括背外侧前额叶、顶下小叶和颞枕叶下部。在其他与前额叶皮质相关的任务中，我们已经表明，通过单词生成(词汇流畅性)任务，语义和语音线索激活了类似的大脑区域，包括前扣带回、左额叶皮质、丘脑和小脑，但它们之间存在细微差异，这与病变文献一致。在一项关于正常衰老过程中认知激活的研究中，我们发现神经生理学的变化与环境有关。也就是说，在不同的任务中，生命周期的明显变化是不同的，这取决于特定神经系统在特定任务中的作用。在年轻受试者执行任务时生理活动通常受到抑制的区域，年长受试者激活得越多，他们激活(或抑制失败)的程度越高，他们在任务中的表现就越差。在执行任务的年轻人通常会增加生理活动的其他区域，年龄较大的受试者活动较少；这些区域激活得越少，他们的表现就越受损。我们还证实，系统水平上的大脑活动的大规模变化(伴随着行为的非线性变化)遵循非线性动力学理论的预测，我们定义了可区分的额叶区域(外侧前额叶皮质和前扣带回皮质)，这些区域在任务之间的切换(分别克服先前任务需求的残余抑制和启动新任务)中辅助不同的认知成分。我们还表明，健康个体被激活的神经系统模式反映了他们在工作记忆任务中的表现和认知策略(语言和空间)的水平，认知控制过程中的额叶功能可以用功能成像和任务转换范式进行剖析。 在这些发现的基础上，我们使用神经成像来探索儿茶酚-O-甲基转移酶基因(COMT)在大脑中的影响，该基因已被确定为精神分裂症的易感基因。众所周知，COMT主要参与影响皮质多巴胺水平的多巴胺分解代谢(COMT基因敲除小鼠的多巴胺水平增加就是证据)，尤其是在前额叶皮质。COMT基因的一种常见多态(val108/158met)导致前额叶皮质(PFC)蛋氨酸编码等位基因酶活性显著降低。尸检研究表明，Valine编码的等位基因与中脑中多巴胺合成的增加直接相关，这表明这种功能性的单核苷酸多态性(SNP)可以调节PFC和中脑之间的相互作用。以前的工作已经显示了PFC神经元的激活和多巴胺能受体之间的关系，因为它们与工作记忆过程有关。这意味着COMT基因影响前额叶活动和中脑多巴胺能功能的相互作用。基于这些发现，我们小组参与了一项研究，以证明在正常健康生活的人中，PFC和中脑多巴胺合成之间的特定相互作用是COMT基因的函数。在相同的个体中，我们测量了工作记忆中的局部脑血流量(RCBF)和[F-18]氟多巴摄取(以测量多巴胺合成和突触前储存)。以前的研究已经将多巴胺描述为决定任务相关的神经放电与任务无关的神经放电或调谐的比率的关键。前额叶皮质神经元。我们的研究发现，Valine携带者增加了中脑FDOPA的摄取，COMT基因决定了工作记忆中中脑FDOPA和前额叶rCBF之间关系的方向，证实了PFC和多巴胺之间的强烈相互作用以及PFC-中脑调节机制的基因控制。这些数据首次在人类身上提供了重要的佐证证据，支持目前关于多巴胺能调节PFC功能的概念。

Using functional neuroimaging to determine local neuronal activity, we have found that normal subjects performing tasks involving working memory use a cortical network including dorsolateral prefrontal cortex, inferior parietal lobule, and inferior temporo-occipital cortex. In other tasks related to prefrontal cortex, we have shown, with word generation (verbal fluency) tasks that semantic and phonologic cues activate similar brain regions including anterior cingulate, left frontal cortex, thalamus and cerebellum, but subtle differences exist between them that are consistent with the lesion literature. In a study of cognitive activation in normal aging we found that neurophysiological changes were context dependent. That is, apparent changes over the life span differed in different tasks, depending on the role of the particular neural system for the particular task. In regions where physiological activity is normally suppressed when young subjects perform the tasks older subjects activate more, and the more they activate (or fail to suppress), the worse they perform on the tasks. In other areas, where physiological activity is normally increased in young people performing the tasks, older subjects activate less; and the less they activate these regions, the more impaired their performance. We have also confirmed that large-scale changes in brain activity at the systems level (accompanying nonlinear changes in behavior) follow predictions from nonlinear dynamical theory, and we have defined discriminable frontal lobe regions (lateral prefrontal cortex and anterior cingulate cortex) that subserve different cognitive components in switching between tasks (overcoming the residual inhibition of previous task demands and initiating a new task, respectively). We have also shown that the neural system patterns activated in individual healthy subjects reflect their levels of performance and cognitive strategies (verbal versus spatial) on a working memory task and that frontal lobe functions during cognitive control can be dissected with functional imaging and task-switching paradigms. Building upon these findings, we have used neuroimaging to explore the effects in the brain of the Catechol-O-methyltransferase gene (COMT), which has been identified as a susceptibility gene for schizophrenia. It is well known that, particularly in prefrontal cortex, COMT is primarily involved in dopamine catabolism which influences cortical dopamine levels (as evidenced by the increase in dopamine in COMT knock-out mice). A common polymorphism in the COMT gene (val108/158met) leads to a significant reduction in methionine-coding allele enzyme activity in the prefrontal cortex (PFC). Postmortem studies have shown a direct correlation between valine-encoding alleles and increases in dopamine synthesis in the midbrain, which suggested that this functional single nucleotide polymorphism (SNP) can modulate the interaction between the PFC and the midbrain. Previous work has shown a relationship between activation of PFC neurons and dopaminergic receptors as they relate to working memory processes. The implication is that the COMT genotype effects the interaction of prefrontal activity and midbrain dopaminergic function. Based upon these findings, our group engaged in a study to demonstrate the specific interactions between PFC and midbrain dopamine synthesis in normal healthy living people as a function of COMT genotype. In the same individuals we measured both regional cerebral blood flow (rCBF) during working memory and [F-18] Fluoro-dopa uptake (to measure dopamine synthesis and presynaptic stores). Previous studies have described dopamine as being critical to determine the ratio of task-related to task-unrelated neural firing or ?tuning? of PFC neurons. Our findings that valine carriers have increased midbrain FDOPA uptake and that the COMT genotype determines the direction of the relationship between midbrain FDOPA and prefrontal rCBF during working memory substantiate the idea of strong interactions between PFC and dopamine and of genetic control of the PFC-midbrain tuning mechanism. These data provide for the first time important corroborative evidence in humans that supports current concepts about dopaminergic modulation of PFC function.