Deficient Neural Plasticity and its Functional Consequences in Schizophrenia

虽然抗精神病药物对改善精神分裂症的精神症状很有用，但它们 对认知功能障碍几乎没有影响，认知功能障碍是这种疾病的核心特征，也是 功能残疾和社区结果不佳。尽管最近的研究表明在 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是高度可变的，可能取决于完整的 神经可塑性才能取得成功。最近的几个理论观点和观察结果表明 精神分裂症病理生理学中神经可塑性的基本机制异常，导致 认知缺陷并可能干扰以认知为基础的干预措施的效果。具体来说，N- 甲基-D-天冬氨酸受体(NMDAR)依赖的长时程增强(LTP)，这是 依赖经验的突触可塑性和领先的学习和记忆候选细胞机制， 根据精神分裂症的NMDAR功能低下模型预测会出现妥协。 最近，已经开发了允许评估类LTP的感觉刺激范例 活体内人类的可塑性。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 在精神分裂症和情绪障碍中表现出LTP样视觉可塑性缺陷，反映在 与健康人相比，视觉诱发电位的增强作用减弱。然而，尽管有这些有希望的初步发现， 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索者 精神分裂症患者的LTP样可塑性。 因此，本职业发展奖研究旨在进一步优化和验证视觉 LTP样视可塑性的刺激范式及其临床和功能研究 退伍军人精神分裂症患者LTP样可塑性缺陷的后果。培训计划将进一步 通过量身定做的组合发展首席调查员在精神神经成像方面的专业知识 课程工作、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 精神分裂症与神经功能成像方法的整合。这项研究结合了神经成像 实现四个具体目标的模式(EEG和fMRI)：1)识别LTP样视觉的时间和地点 可塑性效应及其在精神分裂症中的缺陷发生在大脑中；2)检验以下假设 LTP样视觉可塑性的变化与视觉知觉学习的变化有关；3)检查 LTP样视觉可塑性的完整性是否可以预测认知训练后的获得，以及4)探索 LTP样视觉可塑性缺陷是否与更严重的症状和更差的症状相关 精神分裂症患者的功能结局。这项研究有可能提供一个机械性的解释 认知训练不能改善一些患者的认知，或者对另一些患者产生有限的收益。这些 进展可能会促进1)个性化医学方法的发展，这些方法规定了认知 对那些最有可能从中受益的人进行培训，以及2)确定新颖的神经生理目标 专门针对改善神经可塑性缺陷的干预措施，从而恢复 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.