Biological Mechanisms of Enhanced Neuroplasticity in First-Episode Schizophrenia

描述(申请人提供)：精神分裂症患者经历严重的认知功能障碍，但最普遍和功能削弱的是那些在言语情景记忆方面的功能障碍。神经成像研究发现，海马体的异常生理活动与精神分裂症患者的情景记忆功能障碍有关。众所周知，由于齿状回中正在进行的神经发生和突触可塑性，海马体在成年后仍具有可塑性。精神分裂症患者的神经可塑性已被证明通过定期的体力活动和认知技能训练而增强。尚待确定的是，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。与NIMH战略计划1.4一致，这个K01项目寻求“定义、测量和连接疾病状态下异常功能的基本生物和行为成分，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，与常规治疗对照组的30名患者相比，试图确定导致精神分裂症神经可塑性增加的神经生物学机制。措施将集中在情节记忆功能磁共振(FMRI)范例和与神经可塑性有关的神经营养因子上。为达到协助调查所需的训练，申请人须 咨询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、神经修复专家和在纵向神经成像方面有专长的生物统计师，以制定创新的研究和培训计划。该计划将有以下目标：1)应用高分辨率结构MRI来测量齿状回的皮质厚度，假设由于这种干预而增加；2)测量在言语情景记忆功能磁共振任务中的神经活动，假设在干预组增加；以及3)测量血清神经营养生长因子的水平，这是神经化学机制，假设有助于增加齿状回的可塑性和改善干预组的情景记忆。总而言之，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。这些经验将为申请者提供翻译和基础神经科学方面的关键培训，以及综合运动生理学和生物学，以将疾病病理中涉及的各种机制联系起来。拟议的研究将为申请者提供必要的培训，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。

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.