Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

我们的研究小组使用功能性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在执行匹配的感觉运动控制测试和其他对比任务时的局部神经元活动。通过使用双背连续工作记忆任务，我们再次证实了威斯康星卡片分类测试（WCST）对前额皮质功能障碍的研究结果。与之前的研究一样，这种异常的激活模式甚至出现在那些在任务中表现相对较好的患者身上。我们还检查了个体患者在无药期间几个时间点的认知激活变化。这决定了生理变化与伴随的症状和认知表现变化之间的关系。对这些变化的时间进程的进一步分析正在进行中。我们还利用特征图像分析探讨了工作记忆系统各节点之间的功能连通性。这表明，超过一半的组间差异（在对照组和患者之间）可以用一个单一的模式来解释，即患者的颞下-海马-小脑负荷与对照组的背外侧-前额叶-扣带活动。这种模式的表达完全将所有患者的扫描结果与对照组区分开来，这一发现在两个新的数据集中得到了前瞻性的验证，表明它可能是一种特征标记。另一种占差异20%的模式表明，与对照组相比，患者工作记忆相关网络的表达变化明显更多，这表明对功能减退的发现有系统层面的解释。我们进一步证明，这种模式的一个重要组成部分在于背外侧前额叶皮层（DLPFC）和海马之间功能关系的特定异常。我们还表明，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，前额叶皮层的反应仍然减少。

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. We have now initiated a number of cross-modal neuroimaging studies in schizophrenia. We previously found that prefrontal N-acetylaspartate magnetic resonance spectroscopy signal predicts impaired WCST regional cerebral blood flow (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 rCBF) during the WCST and presynaptic dopaminergic function (measured with the PET tracer 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.