Error Processing in Depressive States: A Translational Opportunity?
Error Processing in Depressive States: A Translational Opportunity?
复制标题
抑郁状态下的错误处理：转化机会？
DOI：
10.1038/npp.2016.183
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Carlezon,WilliamA
中科院分区：
文献类型：
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作者：
Pizzagalli,DiegoA;Carlezon,WilliamA
认知缺陷是抑郁症的一个核心特征，与日常功能受损、临床结果恶化和治疗抵抗有关。特别是，认知控制障碍（即，根据内部目标和环境需求自适应调节行动和思想的能力）先于抑郁发作，缓解后持续存在，并预测抗抑郁反应不良（Pizzagalli，2011）。此外，在健康的参与者中，（如情绪Stroop任务所探测的）预测了对压力的反应中促炎细胞因子的较低水平;因此，当受到情绪信息的挑战时，更好的调节行为的能力与降低的炎症应激反应有关（Shields et al，2016），强调了认知控制和免疫功能可能直接相互影响的途径。这些发现表明，认知控制缺陷可能构成抑郁症脆弱性的标志，因此代表了新的治疗目标。正如最近强调的那样，尽管改善了情绪，但目前的药理学，心理学和心身治疗往往无法改善认知缺陷（美国国家科学院，工程，2015）。因此，具有前认知效应的新型干预措施可能会提供一种创新策略，以更有效地治疗一些最衰弱但往往被忽视的抑郁症症状。开发针对认知功能的治疗方法的挑战由于在抑郁症的临床前和临床研究中使用不同的方法而变得更加复杂，这并不令人惊讶地产生了很差的翻译。临床前检测经常涉及终点，例如在应对压力或延迟吃新食物时挣扎的时间，这两者都不符合人类的实际状况或挖掘高级认知功能。在临床上，认知控制缺陷往往出现时，探测错误处理。具体来说，抑郁症患者表现出恐怖后行为调整受损（即，在错误与正确反应之后立即降低准确性）-这是一种与认知控制相关的额扣带通路内的激活中断相关的模式（Pizzagalli，2011）。基于这些临床发现，我们报告说，给予大鼠促肾上腺皮质激素释放因子，一种在人类和实验室动物中引起无数压力和抑郁症状的肽，在注意力任务中表现出类似的恐怖后准确性降低。JDTic（一种具有抗抑郁样作用的κ阿片受体拮抗剂）可减弱该作用（Beard et al，2015）。这些发现表明，认知控制中的抑郁样损害可以在啮齿动物中重现，并且对正在研究的治疗抑郁症的药物类别敏感，从而打开了令人兴奋的转化途径。新出现的证据表明，在啮齿动物和人类中可以观察到相同的认知控制神经标志物，包括强化的恐怖后θ振荡（Laubach et al，2015）和不成功试验后的反馈相关消极性（Warren et al，2015），这为跨物种对齐终点提供了额外的机会。这些类型的客观神经生理学标志物可用于筛选新化合物，并优先考虑那些使认知控制的行为和EEG标志物正常化的化合物。创建一个框架来研究实验室动物和人类的同源终点应该提供更快和更准确地预测人类临床结果的方法，并且与NIMH的努力一致（例如，“快速失败”试验：http：//www. nimh。nih。gov/research-prio rities/research-initiatives/fast-fast.
Cognitive deficits are a core feature of depressive disorders, and have been linked to impaired daily functioning, worse clinical outcome, and treatment resistance. In particular, impairments in cognitive control (ie, the ability to adaptively modulate action and thoughts based on internal goals and environmental demands) precede depression onset, persist after remission, and predict poor antidepressant responses (Pizzagalli, 2011). Moreover, among healthy participants, better cognitive control (as probed by an emotional Stroop task) predicted lower levels of pro-inflammatory cytokines in response to stress; thus, a better ability to modulate behavior when challenged by emotional information was associated with reduced inflammatory stress reactivity (Shields et al, 2016), highlighting a pathway by which cognitive control and immune function may directly influence one another. These findings suggest that cognitive control deficits might constitute markers of depression vulnerability and thus represent targets for new treatments. As recently emphasized, current pharmacological, psychological, and psychosomatic treatments often fail to ameliorate cognitive deficits despite improving mood(National Academies of Sciences, Engineering, 2015). Accordingly, novel interventions with procognitive effects may offer an innovative strategy to more effectively treat some of the most debilitating—yet often overlooked—symptoms of depression. Challenges in developing treatments that target cognitive function are compounded by the use of different approaches in preclinical and clinical studies of depression, which unsurprisingly yields poor translation. Preclinical assays frequently involve end points such as time spent struggling in response to stress or latency to eat a novel food, neither of which matches the reality of the human condition or tap into high-level cognitive function. Clinically, cognitive control deficits often emerge when probing error processing. Specifically, individuals with depression show impaired posterror behavioral adjustments (ie, lower accuracy immediately following an incorrect vs correct response)—a pattern associated with disrupted activation within frontocingulate pathways implicated in cognitive control (Pizzagalli, 2011). Building on these clinical findings, we reported that rats given corticotropin-releasing factor, a peptide that causes myriad signs of stress and depression in humans and laboratory animals, in an attention task showed similar reductions in posterror accuracy. This effect was attenuated by JDTic, a kappa-opioid receptor antagonist with antidepressant-like effects (Beard et al, 2015). These findings indicate that depression-like impairments in cognitive control can be recapitulated in rodents and are sensitive to classes of drugs under investigation for treating depression, opening exciting translational avenues. Emerging evidence indicates that the same neural markers of cognitive control can be observed in rodents and humans, including potentiated posterror theta oscillations (Laubach et al, 2015) and feedback-related negativity after unsuccessful trials (Warren et al, 2015), which offer additional opportunities to align end points across species. These types of objective neurophysiological markers could be used to screen novel compounds, and prioritize those that normalize behavioral and EEG markers of cognitive control. Creating a framework to study homologous end points in laboratory animals and humans should offer ways to more quickly and accurately predict clinical outcomes in humans, and is consistent with efforts at NIMH (eg,‘Fast-Fail’trials: http://www. nimh. nih. gov/research-prio rities/research-initiatives/fast-fast …