Neuroimaging Of Frontal Lobe In Neuropsychiatric Disease

我们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。利用双背连续工作记忆任务的n背版本，我们再次证实了先前的发现（来自一个更复杂的任务，威斯康星卡片分类测试（WCST））前额皮质功能障碍。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的几个时间点认知诱发激活的变化，并确定生理变化与伴随的症状学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索了工作记忆系统各节点之间的功能连通性，并表明超过一半的组间差异（在对照组和患者之间）可以用单一模式解释，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20%方差的模式表明，与对照受试者相比，工作记忆相关网络的表达变化明显更大，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和海马体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。此外，精神分裂症患者在WCST表现上与健康的老年人相比，前额叶皮层的激活程度仍然较低。在这个精神分裂症组中，背外侧前额叶皮层（DLPFC）激活的降低与WCST期间更强的持续性相关。相比之下，在老年受试者中，DLPFC的激活被保留下来，与表现无关，这表明其他机制可能解释了他们在这项任务中的认知障碍。我们已经启动了许多精神分裂症的跨模式神经成像研究。我们发现，前额叶n -乙酰-天冬氨酸磁共振波谱信号不仅可以预测患者前额叶皮层的WCS rCBF激活受损，还可以预测工作记忆系统的其他节点。这种关系在患者中发现，但在对照组中没有发现，在其他脑区也没有发现NAA （n -乙酰天冬氨酸）。最后，我们发现患者前额皮质功能失调的程度预示着他们皮层下多巴胺储存异常升高的程度。

We use 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. Using a 2-back version of an N-back continuous working memory task, we have re-confirmed previous findings (derived with a more complex task, the Wisconsin Card Sorting Test (WCST)) of dysfunction of prefrontal cortex. As in those previous studies, the aberrant activation pattern appears to occur even in patients who perform relatively well on the task. We also examined changes in cognitively-evoked activation across several time points during a medication-free period in individual patients and determining the relationship between the physiological changes and concomitant changes in symptomatology 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 and have shown that more than half the intergroup variance (across controls and patients) was explained by a single pattern showing inferotemporal-hippocampal-cerebellar 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 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 a specific abnormality in the functional relationship between the dorsolateral prefrontal cortex 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 dorsolateral prefrontal cortex (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 have found that prefrontal N-acetyl-aspartate magnetic resonance spectroscopy signal predicts impaired WCS rCBF activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship is found in patients, but not in control subjects, and not with NAA (N-acetylaspartate) in other brain regions. Finally, we have found that the degree to which patients' prefrontal cortices are dysfunctional predicts the degree to which their subcortical dopamine stores are aberrantly elevated.