Neuroimaging Of Frontal Lobe In Neuropsychiatric Disease

我们使用功能神经成像来确定精神分裂症和其他神经精神障碍患者在工作记忆和抽象推理任务执行期间以及在匹配的感觉运动控制测试和其他对比任务执行期间的局部神经元活动。使用2-back版本的N-back连续工作记忆任务，我们再次确认了先前关于前额叶皮质功能障碍的发现(源自更复杂的任务，威斯康星卡片分类测试(WCST))。与以前的研究一样，异常激活模式似乎甚至发生在执行任务相对较好的患者身上。我们还检查了个体患者在停药期间的几个时间点上认知诱发激活的变化，并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。对这些变化的时间进程的进一步分析正在进行中。我们还使用特征图像分析探索了工作记忆系统不同节点之间的功能连接，并表明超过一半的组间差异(跨对照组和患者)可由单一模式解释，即患者的下颞叶-海马体-小脑负荷与对照组的背外侧-前额叶扣带活动。这种模式的表达完美地将所有患者的扫描从对照组中分离出来，这一发现在两个新的数据集中得到了前瞻性的验证，表明它可能是一个特征标记。另一种解释20%的差异的模式表明，与工作记忆相关的网络的表达比对照组的表达更具变异性，这表明对功能低下的发现有系统水平的解释。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质和海马体之间的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差的年轻正常受试者进行比较，他们在执行具有强大工作记忆成分的任务时，前额叶皮质反应仍然减弱。此外，与一对一的WCST表现相匹配的健康老年受试者相比，精神分裂症患者前额叶皮质的激活仍然减少。在这组精神分裂症患者中，背外侧前额叶皮质(DLPFC)的激活减少与WCST期间更多的坚持有关。相比之下，在老年受试者中，DLPFC的激活被保留下来，并且与表现无关，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。我们已经启动了一些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-天冬氨酸磁共振信号不仅在患者的前额叶皮质，而且在工作记忆系统的其他节点预测WCS rCBF激活受损。这种关系在患者身上发现，但在对照组中没有，也与其他大脑区域的NAA(N-乙酰天冬氨酸)无关。最后，我们发现，患者前额叶皮质功能障碍的程度可以预测他们皮质下多巴胺存储异常升高的程度。

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.