Deficient Neural Plasticity and its Functional Consequences in Schizophrenia

虽然抗精神病药物可用于改善精神分裂症的精神症状，但它们 对认知功能障碍几乎没有影响，这是疾病的核心特征，也是疾病的主要决定因素。 功能性残疾和不良的社区结果。尽管最近的研究表明， 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，可能取决于完整的基本机制， neuroplasticity神经可塑性to achieve实现success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， 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）依赖的长时程增强（LTP），这是一种机制， 经验依赖性突触可塑性和学习和记忆的主要候选细胞机制， 基于精神分裂症的NMDAr功能减退模型，预测在精神分裂症中受损。 最近，已经开发了允许评估LTP样的感觉刺激范例。 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 在精神分裂症和情绪障碍中表现出LTP样视觉可塑性缺陷， 相对于健康个体，VEP的增强降低。然而，尽管这些初步发现令人鼓舞， 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 LTP样可塑性的研究进展 因此，这项职业发展奖研究旨在进一步优化和验证视觉 刺激范式作为LTP样视觉可塑性的探针，并检查临床和功能 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 通过以下定制组合发展主要研究者在精神病学神经影像学方面的专业知识： 课程作业，方法研讨会，并与具有专业知识的既定调查员合作， 精神分裂症和功能性神经影像学方法的整合。这项研究结合了神经影像学 模式（EEG和fMRI），以实现四个具体目标：1）确定何时何地LTP样视觉 可塑性效应，以及精神分裂症中的缺陷，发生在大脑中; 2）为了检验假设， LTP样视觉可塑性的变化与视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预测认知训练后的增益，以及4）探索 LTP样视觉可塑性的缺陷是否与更严重的症状和更差的视力相关。 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 认知训练不能改善某些患者的认知能力，或对其他患者产生有限的益处。这些 这些进展可能有助于1）开发个性化的医疗方法， 培训那些最有可能从中受益的人，2）识别新的神经生理学靶点， 干预措施专门针对改善神经可塑性不足，从而恢复能力， 精神分裂症退伍军人受益于依赖新学习的治疗。

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.