Biological Mechanisms of Enhanced Neuroplasticity in First-Episode Schizophrenia

描述（由申请人提供）：精神分裂症患者经历严重的认知功能障碍，但最普遍和功能衰弱的是言语情景记忆。神经影像学研究发现，海马体的异常生理活动有助于精神分裂症患者的情节记忆功能障碍。由于齿状回中发生的持续神经发生和突触可塑性，海马体被认为在成年后仍保持可塑性。精神分裂症患者的神经可塑性已被证明可以通过定期的身体活动和认知技能训练来增强。运动和认知训练对精神分裂症患者情景记忆系统中的神经活动有什么影响，以及什么神经化学机制促进了精神分裂症患者神经可塑性的增强，这些都有待于确定。与NIMH战略计划1.4一致，该K 01项目旨在“定义、测量和联系疾病状态下功能异常的基本生物和行为组成部分“，以澄清精神障碍的根本原因。“本研究将通过研究30名参加运动和认知训练干预的首发精神分裂症患者，与30名常规治疗对照组相比，试图确定有助于增加精神分裂症神经可塑性的神经生物学机制。措施将集中在一个情节记忆功能磁共振成像（fMRI）的范例和神经营养因子与神经可塑性。为了获得协助调查所需的培训，申请人必须 咨询了临床神经心理学家以及综合运动生理学家，翻译神经科学家，神经修复专家和具有纵向神经成像专业知识的生物统计学家，以制定创新的研究和培训计划。该计划将具有以下目的：1）应用高分辨率结构MRI测量齿状回中的皮质厚度，假设该厚度由于该干预而增加; 2）测量言语情景记忆fMRI任务期间的神经活动，假设干预组中的神经活动增加;和3）测量神经营养生长因子的血清水平，所述神经营养生长因子是神经化学机制，其被假设有助于增加干预组中齿状回的可塑性和改善情景记忆。总的来说，这些结果将阐明运动和认知训练干预影响首发精神分裂症患者情景记忆功能的神经生物学途径。这些经验将为申请人提供转化和基础神经科学的关键培训，沿着综合运动生理学和生物学，以联系疾病病理学中涉及的各种机制。拟议的研究将为申请人提供必要的培训，以便在精神病患者样本中进行随机临床试验，以检测分子和神经系统水平的变化，以帮助开发有效的精神分裂症认知增强治疗方法。 公共卫生相关性：除了个人，社会和医疗成本诊断为精神分裂症的个人，仅在美国治疗精神分裂症的经济成本估计为627亿美元;然而，这些标准治疗并不针对限制患者日常功能的衰弱性认知障碍。我们建议使用最先进的MRI和神经化学分析来阐明与接受常规治疗的患者相比，正在接受创新的运动和认知训练联合干预的首发精神分裂症患者的神经可塑性和认知增强的机制。这项多学科的研究将是至关重要的，以确定潜在的神经基板，有助于改善精神分裂症患者的认知，以帮助发展有效的认知增强治疗精神分裂症。

DESCRIPTION (provided by applicant): Schizophrenia patients experience severe cognitive dysfunctions but the most prevalent and functionally debilitating are those in verbal episodic memory. Neuroimaging studies have found that abnormal physiological activity in the hippocampus contributes to episodic memory dysfunctions in schizophrenia patients. The hippocampus is known to retain plasticity into adulthood, due to ongoing neurogenesis and synaptic plasticity occurring in the dentate gyrus. Neuroplasticity in schizophrenia patients has been shown to be enhanced with regular physical activity and also by cognitive skills training. What remains to be established is what effect exercise and cognitive training have on neural activity in the episodic memory system in schizophrenia patients and what neurochemical mechanisms are facilitating enhanced neuroplasticity in schizophrenia. Consistent with the NIMH Strategic Plan 1.4, this K01 project seeks to "define, measure, and link basic biological and behavioral components" of abnormal functioning in a diseased state "to clarify the underlying causes of mental disorders." The present study will seek to identify neurobiological mechanisms contributing to increased neuroplasticity in schizophrenia by studying 30 first-episode schizophrenia patients who are participating in an exercise and cognitive training intervention, as compared to 30 in a treatment as usual comparison group. Measures will focus on an episodic memory functional MRI (fMRI) paradigm and neurotrophic factors linked to neuroplasticity. To achieve the training needed to facilitate this investigation, the applicant has consulted with clinical neuropsychologists as well as an integrative exercise physiologist, a translational neuroscientist, an expert in neural repair, and a biostatistician with expertise in longitudinal neuroimaging to develop an innovative study and training plan. The plan will have the following Aims: 1) apply high-resolution structural MRI to measure cortical thickness in the dentate gyrus, which is hypothesized to increase as a result of this intervention; 2) measure neural activity during a verbal episodic memory fMRI task, which is hypothesized to increase in the intervention group; and 3) measure serum levels of neurotrophic growth factors which are neurochemical mechanisms hypothesized to contribute to increased plasticity in the dentate gyrus and improve episodic memory in the intervention group. Collectively, these results will elucidate the neurobiological pathways by which an exercise and cognitive training intervention impact episodic memory functioning in first- episode schizophrenia patients. These experiences will provide the applicant critical training in translational and basic neuroscience along with integrative exercise physiology and biology to link the various mechanisms implicated in the pathology in the disease. The proposed study will provide the applicant the necessary training needed to conduct randomized clinical trials in a psychosis patient sample to detect changes at molecular and neural systems levels to aid in the development of effective cognitive enhancement treatments in schizophrenia. PUBLIC HEALTH RELEVANCE: In addition to the personal, social and medical costs to an individual diagnosed with schizophrenia, the economic cost of treatment of schizophrenia in the U.S. alone is estimated to be $62.7 billion; however, these standard treatments do not target the debilitating cognitive impairments that limit everyday functioning of those with the illness. We propose to use cutting-edge MRI and neurochemical analyses to elucidate the mechanisms of enhanced neuroplasticity and cognition in first-episode schizophrenia patients who are undergoing an innovative combined exercise and cognitive training intervention, compared to patients receiving treatment-as-usual. This multi-disciplinary study will be crucial for identifyin underlying neural substrates that contribute to improved cognition in schizophrenia patients to aid in the development of effective cognitive enhancement treatments in schizophrenia.