Effects of Psychopathology on Prefrontal Cortical Functioning During Goal-Directe

描述（由申请人提供）：对前额皮质（PFC）功能的基础研究已经建立了该区域病变患者的特定认知和行为特征，其特征是在需要集中注意力、抑制或目标实现的行动顺序的任务中表现下降。临床心理学的研究表明，大多数被诊断为抑郁症的患者也有类似的次优认知风格，这表现在决策方面的明显困难、对生活事件的执着（尤其是消极的）解释以及完成任务的效率低下。临床神经科学的最新进展表明，前额叶区域的神经发育异常与重度抑郁症密切相关。具体来说，背外侧前额叶（DLPFC）和眶额叶（OBC）皮质、前扣带皮层（ACC）和基底神经节的不同类型异常被假设为与该疾病相关的脑回路病理生理学的基础。尽管最近对PFC异常的识别进行了研究，但很少有研究调查了这些区域异常如何影响患者在各种认知任务中的表现以及它们如何与治疗效果和治疗结果相关的个体差异。本项目的主要目的是在宾夕法尼亚大学的临床和神经科学界之间建立强有力的伙伴关系，将重点放在PFC功能的基本行为/神经科学研究与抑郁症的临床研究之间的转化研究的发展。我们的目标是启动一项研究计划，探索抑郁症的认知缺陷（即正常认知和运动抑制的中断，注意力障碍和冲动）与以pfc边缘系统异常为特征的某种生理特征之间的关系。这个项目的重点是开发一套新的方法，这些方法将提供更详细的抑郁症下额叶功能的神经认知评估，从而可以更好地描述不同患者亚组。目前的研究项目结合了多种新颖的方法，包括行为学、灌注功能磁共振成像（fMRI）、经颅磁刺激（TMS）和神经心理学/临床研究，并引入了一组新的任务，这些任务将允许更好地表征正常受试者的额下认知特征，以及它在不同抑郁患者群体中的表现。通过一套全面的神经认知评估程序的发展，我们将能够更好地描述基于侧PFC功能低下诊断为抑郁症的不同患者群体，并对不同治疗方案的有效性和结果做出具体的预测。最后，我们的目标是收集探索性数据，以支持更大规模的长期研究计划的发展，促进基于PFC功能与不同患者亚组特定认知和情绪特征之间关系的抑郁症诊断和治疗的跨学科研究，这些研究可用于指导最佳临床实践。对额叶的研究已经建立了该区域病变患者的特定认知和行为特征，其特征是在需要集中注意力和记忆力的任务中表现下降。临床心理学的研究表明，抑郁症患者也存在类似的问题，这表现在他们决策困难和对生活事件的消极解读上。前额皮质区域的不同类型的异常被假设为与这种疾病相关的行为和认知问题的基础。尽管最近对抑郁症的脑部病理进行了研究，但很少有研究调查患者之间的个体差异，即这种病理如何影响各种认知任务的表现，以及它如何与治疗效果和治疗结果相关联。该项目的目标是提高我们对抑郁症的基本行为过程和大脑参与认知任务的理解，这将导致更准确的诊断，并为个体患者选择最合适的治疗方法。

DESCRIPTION (provided by applicant): Basic research on prefrontal cortex (PFC) functioning has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, that is characterized by a decline in performance in tasks that require focused attention, inhibition, or action sequencing in goal achievement. Research in clinical psychology has revealed a similarly suboptimal cognitive style in the majority of patients diagnosed with depression, as indicated by pronounced difficulties in decision-making, perseverations on, particularly negative, interpretations of life events, and ineffectiveness in task completion. Recent developments in clinical neuroscience have suggested that neurodevelopmental abnormalities in prefrontal regions are critically associated with major depression. Specifically, different types of abnormalities in the dorsolateral prefrontal (DLPFC) and orbitofrontal (OBC) cortices, anterior cingulate cortex (ACC), and basal ganglia are hypothesized to underlie the brain circuit pathophysiology linked to the disorder. Despite recent research on the identification of such PFC anomalies, few studies have investigated individual differences among patients on how abnormalities in these areas affect performance on a variety of cognitive tasks and how they are associated with treatment effectiveness and therapeutic outcomes. The primary aim of the present project is to establish a strong partnership between the clinical and neuroscience communities of the University of Pennsylvania that will focus on the development of translational research between basic behavioral/neuroscience research on PFC function and clinical research on depression. We aim to initiate a research program that will explore the relationships between the deficient cognitive profile in depression (i.e., disruptions in normal cognitive and motor inhibition, attentional disturbances, and impulsivity) and a certain physiological profile as characterized by PFC-limbic system abnormalities. The focus of this project is to develop a set of new methodologies that will provide more detailed neurocognitive assessments of hypofrontal functioning in depression that will allow for better characterization of different patient subgroups. The present research program incorporates diverse and novel methodologies including behavioral, perfusion fMRI, transcranial magnetic stimulation (TMS), and neuropsychological/clinical studies, and introduces a novel set of tasks that will allow for a better characterization of hypofrontal cognitive profile in normal subjects, as well as its manifestation in different populations of depressed patients. Through the development of a comprehensive set of neurocognitive assessment procedures we will be able to better characterize different populations of patients diagnosed with depression based on lateral PFC hypo- functioning and to make specific predictions on the effectiveness and outcome of different treatment plans. Finally, we aim to collect exploratory data in support of the development of a larger-scale, long-term research plan promoting interdisciplinary research on the diagnosis and treatment of depression based on the relationship between PFC functioning and specific cognitive and mood profiles of different patient subgroups that can be used to guide optimal clinical practice. Research on the frontal lobes has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, which is characterized by a decline in performance in tasks that require focused attention and memory. Research in clinical psychology has revealed similar problems in patients diagnosed with depression, as indicated by their difficulties in decision-making and their negative interpretations of life events. Different types of abnormalities in regions of the prefrontal cortex are hypothesized to underlie the behavioral and cognitive problems linked to this disorder. Despite recent research on the brain pathology of depression, few studies have investigated individual differences among patients on how this pathology affects performance on a variety of cognitive tasks and how it is associated with treatment effectiveness and therapeutic outcomes. The goal of this project is to improve our understanding of basic behavioral processes and brain involvement in cognitive tasks in depression, which will lead to more accurate diagnoses and to the selection of the most suitable treatment approaches for individual patients. RELEVANCE: Research on the frontal lobes has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, which is characterized by a decline in performance in tasks that require focused attention and memory. Research in clinical psychology has revealed similar problems in patients diagnosed with depression, as indicated by their difficulties in decision-making and their negative interpretations of life events. Different types of abnormalities in regions of the prefrontal cortex are hypothesized to underlie the behavioral and cognitive problems linked to this disorder. Despite recent research on the brain pathology of depression, few studies have investigated individual differences among patients on how this pathology affects performance on a variety of cognitive tasks and how it is associated with treatment effectiveness and therapeutic outcomes. The goal of this project is to improve our understanding of basic behavioral processes and brain involvement in cognitive tasks in depression, which will lead to more accurate diagnoses and to the selection of the most suitable treatment approaches for individual patients.