Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

我们的研究小组使用功能神经成像来确定精神分裂症和其他神经精神疾病患者在执行工作记忆和抽象推理任务以及执行匹配的感觉运动控制测试和其他对比任务期间的局部神经元活动。本研究采用N-back连续工作记忆任务的2-back版本，再次证实了威斯康星州卡片分类测验（WCST）对前额叶皮层功能障碍的研究结果。与先前的研究一样，异常激活模式似乎发生在那些在任务中表现相对较好的患者中。我们还检查了个体患者在停药期间几个时间点的认知激活变化。这确定了生理变化与伴随的症状和认知表现变化之间的关系。目前正在进一步分析这些变化的时间进程。我们还探讨了工作记忆系统的各个节点之间的功能连接使用本征图像分析。这表明，超过一半的组间方差（对照组和患者）是由一个单一的模式，显示颞下-海马-脑负荷的患者与背外侧-前额叶-扣带活动的控制。这种模式的表达完美地将所有患者扫描与对照组分开，这一发现在两个新的数据集中得到了前瞻性验证，表明它可能是一个性状标记。另一种模式占20%的方差表明，工作记忆相关网络的表达在患者中比在对照组中的变量显着更多，这表明一个系统水平的解释功能减退的结果。我们进一步证明了这种模式的一个重要组成部分在于 背外侧前额叶皮层（DLPFC）和海马之间的功能关系的特定异常。我们还发现，即使将精神分裂症患者与表现同样糟糕的年轻正常受试者进行比较，他们在执行具有强烈工作记忆成分的任务时，前额叶皮层反应仍然减弱。此外，精神分裂症患者与健康老年人相比，在WCST表现上仍然表现出前额叶皮层的激活减少。在这组精神分裂症患者中，DLPFC的激活减少与WCST期间更多的持续相关。相反，在老年受试者中，DLPFC激活被保留，并且与性能无关，这表明其他机制可能导致他们在这项任务上的认知障碍。 我们已经开始了一些精神分裂症的跨模态神经影像学研究。我们以前发现，前额叶N-乙酰天冬氨酸磁共振波谱信号预测受损的WCST rCBF激活不仅在我们的患者的前额叶皮质，而且在工作记忆系统的其他节点。在患者中发现了这种关系，但在对照组中没有发现这种关系，并且在其他脑区中也没有发现NAA（N-乙酰天冬氨酸）。此外，为了验证这一假设，即夸大纹状体多巴胺能神经传递在精神分裂症是DLPFC功能障碍的后果，我们使用正电子发射断层扫描（PET），以确定是否以及如何异常纹状体突触前多巴胺能神经传递和干扰前额叶皮质功能在精神分裂症中相互作用。 在一次PET检查中，我们测定了停药四周的患者和匹配对照组在WCST期间的前额叶活动（用局部脑血流量测量）和突触前多巴胺能功能（用PET示踪剂6- 18 F-DOPA FDOPA测量，FDOPA的摄取取决于多巴胺生物合成的速率）。患者纹状体FDOPA摄取显著高于正常对照组，而前额叶皮层WCST相关活性降低。 最重要的是，在患者中，任务相关的前额叶和纹状体多巴胺摄取之间存在高度显着的负相关，而对照组中则不存在。 这项研究为精神分裂症两个关键的病理生理学标志的共存提供了一个机制性的解释。

Our group used functional neuroimaging to determine local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests and other contrast tasks. By using a 2-back version of an N-back continuous working memory task, we have re-confirmed previous findings derived from the Wisconsin Card Sorting Test (WCST) of dysfunction of prefrontal cortex. As in previous studies, the aberrant activation pattern appears to occur even in patients who perform relatively well on the task. We also examined changes in cognitive activation across several time points during a medication-free period in individual patients. This determined the relationship between the physiological changes and concomitant changes in symptoms and cognitive performance. Further analyses of the time course of these changes are ongoing. We have also explored the functional connectivity among various nodes of the working memory system using eigenimage analysis. This has shown that more than half the intergroup variance (across controls and patients) was explained by a single pattern showing inferotemporal-hippocampal-cereballar loading for patients versus dorsolateral-prefrontal-cingulate activity for controls. Expression of this pattern perfectly separated all patient scans from the control group, a finding prospectively validated in two new data sets, suggesting that it may be a trait marker. Another pattern accounting for 20% of the variance demonstrated that expression of the working-memory-related network was significantly more variable in patients than that in control subjects, suggesting a systems-level explanation for the findings of hypofunction. We have further demonstrated that an important component of this pattern lies in specific abnormality in the functional relationship between the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they still have diminished prefrontal cortical response while performing tasks with a strong working memory component. Moreover, patients with schizophrenia still show reduced activation of the prefrontal cortex when compared with healthy, elderly subjects matched with them on a one-to-one basis for WCST performance. In this schizophrenic group, reduced activation in the DLPFC correlated with more perseveration during the WCST. In contrast, in the elderly subjects DLPFC activation is preserved and does not correlate with performance, suggesting that other mechanisms may account for their cognitive impairment on this task. We have initiated a number of cross-modal neuroimaging studies in schizophrenia. We previously found that prefrontal N-acetyl-aspartate magnetic resonance spectroscopy signal predicts impaired WCST rCBF activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship was found in patients, but not in control subjects, and not with NAA (N-acetylaspartate) in other brain regions. Additionally, to test the hypothesis that exaggerated striatal dopaminergic neurotransmission in schizophrenia is a consequence of DLPFC dysfunction, we used positron emission tomography (PET) to determine whether and how abnormal striatal presynaptic dopaminergic neurotransmission and disturbed prefrontal cortical function interact in schizophrenia. In a single PET session we determined both prefrontal activity (measured with regional cerebral blood flow) during the WCST and presynaptic dopaminergic function (measured with the PET tracer 6-18F-DOPA FDOPA, uptake of which depends on the rate of dopamine biosynthesis), in patients withdrawn from medication for four weeks and matched controls. Striatal FDOPA uptake in patients was significantly higher than in normal controls, while WCST-related activity in prefrontal cortex was decreased. Most importantly, in patients there was a highly significant negative correlation between task-related prefrontal and striatal dopamine uptake which was absent in controls. This study provided a mechanistic explanation for the coexistence of two key pathophysiological hallmarks of schizophrenia.