Deficient Neural Plasticity and its Functional Consequences in Schizophrenia

虽然抗精神病药物可有效改善精神分裂症的精神病症状，但它们 对认知功能障碍影响不大，而认知功能障碍是疾病的核心特征，也是疾病的主要决定因素 功能障碍和不良的社区结果。尽管最近的研究显示出一些希望 使用认知训练和认知行为技术来针对认知和临床症状， 对这些干预措施的反应差异很大，并且可能取决于完整的基本机制 神经可塑性以取得成功。最近的一些理论观点和观察表明 精神分裂症病理生理学中神经可塑性基本机制的异常，导致 认知缺陷并可能干扰基于认知的干预措施的有效性。具体来说，N- 甲基-D-天冬氨酸受体（NMDAr）依赖性长时程增强（LTP），这是一种机制 经验依赖的突触可塑性和学习和记忆的主要候选细胞机制， 根据该疾病的 NMDAR 功能减退模型，预计该功能在精神分裂症中会受到损害。 最近，已经开发出感觉刺激范式，可以评估类似 LTP 的能力 人体内的可塑性。类似于动物的电刺激，重复的视觉刺激可以 诱导重复的同步传入活动，导致 LTP 样效应，包括持续增强 头皮记录的视觉诱发电位（VEP）。一些使用这种范式变体的研究现在已经 研究表明，精神分裂症和情绪障碍患者缺乏类似 LTP 的视觉可塑性，反映在 相对于健康个体，VEP 的效力降低。然而，尽管初步发现有这些希望， 需要进一步的工作来优化和验证视觉刺激范式作为完整性的探针 精神分裂症中类似 LTP 的可塑性。 因此，这项职业发展奖研究旨在进一步优化和验证视觉效果 刺激范式作为 LTP 样视觉可塑性的探针，并检查临床和功能 患有精神分裂症的退伍军人中缺乏 LTP 样可塑性的后果。培训计划将进一步 通过量身定制的组合来发展首席研究员在精神科神经影像学方面的专业知识 课程作业、方法研讨会以及与具有以下专业知识的知名研究人员的合作 精神分裂症和功能神经影像学方法的整合。这项研究结合了神经影像学 模态（脑电图和功能磁共振成像）来实现四个具体目标：1）确定何时何地出现类似 LTP 的视觉 可塑性效应及其在精神分裂症中的缺陷发生在大脑中； 2）检验假设 LTP 样视觉可塑性的变化与视觉感知学习的变化相关； 3）检查 类似 LTP 的视觉可塑性的完整性是否可以预测认知训练后的收益，以及 4) 探索 LTP 样视觉可塑性的更大缺陷是否与更严重的症状和更差的症状相关 精神分裂症的功能结果。这项研究有可能提供一个机制解释为什么 认知训练无法改善某些患者的认知能力，或者对另一些患者的认知效果有限。这些 进步可能会促进 1) 个性化医疗方法的发展，这些方法可以规定认知能力 对那些最有可能从中受益的人进行培训，以及2）识别新的神经生理学目标 专门针对改善神经可塑性缺陷的干预措施，从而恢复神经可塑性的能力 患有精神分裂症的退伍军人可以从依赖新学习的治疗中受益。

While antipsychotic medications are useful for ameliorating psychotic symptoms of schizophrenia, they have little effect on cognitive dysfunction, which is a core feature of the illness and a major determinant of functional disability and poor community outcomes. Although recent research has shown some promise in using cognitive training and cognitive-behavioral techniques to target cognition and clinical symptoms, responses to these interventions are highly variable and likely depend on intact basic mechanisms of neuroplasticity to achieve success. Several recent theoretical perspectives and observations implicate abnormalities in basic mechanisms of neuroplasticity in the pathophysiology of schizophrenia, contributing to cognitive deficits and potentially interfering with the efficacy of cognition-based interventions. Specifically, N- methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP), which is a mechanism of experience-dependent synaptic plasticity and a leading candidate cellular mechanism of learning and memory, is predicted to be compromised in schizophrenia based on NMDAr hypofunction models of the disorder. Recently, sensory stimulation paradigms have been developed that allow for the assessment of LTP-like plasticity in humans in vivo. Analogous to electrical stimulation in animals, repeated visual stimulation can induce repetitive synchronous afferent activity that results in LTP-like effects, including persistent potentiation of scalp-recorded visual evoked potentials (VEPs). A few studies using variants of this paradigm have now demonstrated deficient LTP-like visual plasticity in schizophrenia as well as mood disorders, reflected by reduced potentiation of VEPs relative to healthy individuals. Despite these promising initial findings, however, further work is needed to both optimize and validate the visual stimulation paradigm as a probe of the integrity of LTP-like plasticity in schizophrenia. Accordingly, this Career Development Award study aims to further optimize and validate the visual stimulation paradigm as a probe of LTP-like visual plasticity and examine the clinical and functional consequences of deficient LTP-like plasticity in Veterans with schizophrenia. The training plan will further develop the Principal Investigator's expertise in psychiatric neuroimaging through a tailored combination of coursework, methodological workshops, and collaboration with established investigators with expertise in schizophrenia and the integration of functional neuroimaging methods. This study combines neuroimaging modalities (EEG and fMRI) to achieve four specific aims: 1) to identify when and where LTP-like visual plasticity effects, and their deficiencies in schizophrenia, occur in the brain; 2) to test the hypothesis that variation in LTP-like visual plasticity is associated with variation in visual perceptual learning; 3) to examine whether the integrity of LTP-like visual plasticity predicts gains following cognitive training, and 4) to explore whether greater deficits in LTP-like visual plasticity are correlated with more severe symptoms and poorer functional outcomes in schizophrenia. This study has the potential to provide a mechanistic account for why cognitive training fails to improve cognition in some patients or produces limited gains in others. These advances may facilitate 1) the development of personalized medicine approaches that prescribe cognitive training to those most likely to benefit from it, and 2) the identification of neurophysiological targets for novel interventions specifically aimed at ameliorating deficient neuroplasticity, thereby restoring the capacity of Veterans with schizophrenia to benefit from treatments that rely on new learning.