Neural networks underlying impaired information gating in major depression

描述（由申请人提供）：重度抑郁症（MDD）的一个行为特征是消极的、与任务无关的信息的门控受损。在之前的研究中，我们记录了重度抑郁症患者在控制不相关的负面信息进入工作记忆（WM）和从WM中删除不再相关的信息方面表现出障碍。鉴于重度抑郁症的高患病率和巨大的成本，我们有必要更好地了解这些认知困难背后的神经机制。尽管研究者已经开始研究MDD中受损信息门控过程的神经相关性，但我们还不了解这些激活的功能意义或它们与抑郁症关系的本质，也不知道如何利用这些知识来开发和评估针对这种异质性疾病的个性化治疗。我们建议使用尖端的神经成像技术来阐明MDD中负面信息门控受损的神经机制，并对fMRI数据进行创新分析（多体素模式分析[MVPA]和功能连接），以便在每一刻的基础上量化消极无关信息在WM中的表现程度。这种方法将允许我们测试以下假设：(a)特定的大规模网络被假定为MDD中信息门控缺陷的基础；(b)这些网络对重度抑郁症各种临床特征的贡献。具体来说，在两个实验中，我们将阐明在消极刺激进入WM和从WM中去除消极信息期间，MDD的门控受损的认知和神经机制。此外，鉴于在非抑郁人群中发现，与任务无关的信息门控能力的个体差异与目标导向行为的差异有关，我们进一步建议评估信息门控的个体差异与抑郁症状的特定方面的关系。我们假设，在消极信息输入WM和从WM中删除消极信息的过程中，MDD中消极无关信息的门控受损与背额顶叶（自上而下的注意控制）和皮层下（情绪评价）网络的异常功能有关。我们进一步假设这些异常与情绪失调、反刍和消极情绪等特定抑郁特征以及抑郁症状的严重程度有关。重要的是，我们对负面信息的神经表征的新量化将超越粗糙的群体水平分析，更细致地了解重度抑郁症背后神经认知机制的动态本质。总之，拟议的研究有望：(1)促进对重度抑郁症中情感信息控制机制的理解；2)告知注意与情绪相互作用的理论模型；3)促进最终发展更有效的、针对患者的干预措施（例如，认知或神经训练），以治疗重度抑郁症。

DESCRIPTION (provided by applicant): A behavioral hallmark of Major Depressive Disorder (MDD) is impaired gating of negative, task-irrelevant information. In previous work we documented that people with MDD exhibit impairments in controlling the entry of irrelevant negative information into working memory (WM) and in removing no-longer-relevant information from WM. Given the high prevalence and enormous costs of MDD, it is critical that we gain a better under- standing of the neural mechanisms that underlie these cognitive difficulties. Although investigators have begun to examine neural correlates of impaired information-gating processes in MDD, we do not yet understand the functional significance of these activations or the nature of their relation to depression, or consequently, how to leverage this knowledge to develop and evaluate individualized treatments for this heterogeneous disorder. We propose to use cutting-edge neuroimaging techniques to elucidate the neural mechanisms that underlie impaired gating of negative information in MDD, conducting innovative analyses of fMRI data (multi-voxel pattern analyses [MVPA] and functional connectivity) in order to quantify on a moment-to-moment basis the degree to which negative irrelevant information is represented in WM. This approach will allow us to test hypotheses about (a) specific large-scale networks that are posited to underlie information-gating deficits in MDD; and (b) the contribution of these networks to various clinical characteristics of MDD. Specifically, in two experiments we will elucidate the cognitive and neural mechanisms that underlie impaired gating in MDD during the entry of negative stimuli into WM, and during the removal of negative information from WM. Moreover, given findings in nondepressed populations that individual differences in the ability to gate task- irrelevant information are related to variations in goal-directed behavior, we further propose to assess the relation of individual differences in information gating to specific aspects of depressive symptomatology. We hypothesize that impaired gating of negative irrelevant information in MDD is associated with anomalous functioning of dorsal frontoparietal (top-down attentional control) and subcortical (emotional appraisal) networks during both the entry of negative information into WM and the removal of negative information from WM. We further hypothesize that these abnormalities are related to the specific depressive characteristics of emotion dysregulation, rumination, and negative affect, and to the severity of depressive symptoms. Importantly, our novel quantification of neural representations of negative information will move beyond coarse group-level assays to a more fine-grained individual-subject and trial-level understanding of the dynamic nature of the neurocognitive mechanisms that underlie MDD. Together, the proposed studies promise to 1) advance understanding of mechanisms that underlie the control of affective information in MDD; 2) inform theoretical models of the interaction of attention and emotion; and 3) facilitate the ultimate development of more effective, patient-specific interventions (e.g., cognitive or neural training) for major depression.