Enhancing Cognitive Training Through Exercise Following a First Schizophrenia Episode

摘要 该R01申请涉及我们的创新治疗方法的确证性疗效临床试验， 改善精神分裂症的认知，使用NIMH倡导的实验性治疗设计。我们 干预方法结合神经营养素释放有氧运动训练与神经可塑性为基础的 认知训练，以增强认知训练对认知和功能结果的影响。两 认知训练和练习解决了NIMH战略研究的优先事项， 干预措施可以“广泛传播”和“容易地教给现有的劳动力， 成本。”认知补救和体育锻炼分别被证明有希望 改善精神分裂症的认知缺陷，但单独使用在慢性精神分裂症中产生中度效果。 精神分裂症患者我们将以脑源性神经营养因子（BDNF）为靶点， 功能结果作为我们的临床结果。我们假设，BDNF的增加与 定期的有氧运动提供了一个平台，允许基于神经可塑性的认知训练， 认知能力的提高程度要比单纯的认知训练研究中通常观察到的要高。我们假设 将体育锻炼与认知训练相结合， 相对于单独的认知训练，本确证性疗效临床试验以证据为指导 从我们目前的R34试点随机对照试验比较了认知训练的联合治疗， 没有体育锻炼。我们发现了令人信服的证据，BDNF靶点参与，差异改善， 在认知和功能结果方面，以及从最初BDNF获得的后期结果的预测， 支持向充分把握度的确证性疗效临床试验的转变。认知功能障碍 精神分裂症对成功恢复社区功能提出了巨大挑战。我们针对 精神分裂症第一次发作后不久的一段时间，以最大限度地概括认知 在确定慢性残疾之前，改善真实世界的功能结果。认知训练 加上有氧运动干预有可能检查假设的作用机制， 对患有严重精神疾病的人的生活产生有意义的影响。

ABSTRACT This R01 application involves a confirmatory efficacy clinical trial of our innovative treatment approach to improving cognition in schizophrenia, using an experimental therapeutic design that NIMH has advocated. Our intervention approach combines neurotrophin-releasing aerobic exercise training with neuroplasticity-based cognitive training to enhance the impact of cognitive training on cognition and functional outcome. Both cognitive training and exercise address the NIMH strategic research priorities for creating innovative interventions that can be “disseminated broadly” and “readily taught to the existing workforce with minimal cost.” Cognitive remediation and physical exercise have each been shown separately to have promise for improving cognitive deficits in schizophrenia, but used separately yield moderate effects in chronic schizophrenia patients. We will use brain-derived neurotrophic factor (BDNF) as our target and cognition and functional outcome as our clinical outcomes. We hypothesize that the increases in BDNF associated with regular aerobic exercise provide a platform which allows neuroplasticity-based cognitive training to enhance cognition to a greater degree than is typically observed in studies of cognitive training alone. We hypothesize that combining physical exercise with cognitive training will produce larger cognitive and functional improvements, relative to cognitive training alone. This confirmatory efficacy clinical trial is guided by evidence from our current R34 pilot randomized controlled trial comparing the combined treatment with cognitive training without physical exercise. We find compelling evidence of BDNF target engagement, differential improvement in cognition and functional outcome, and prediction of later outcome from initial BDNF gain that strongly supports the movement to a fully powered confirmatory efficacy clinical trial. Cognitive deficits in persons with schizophrenia present an enormous challenge to successful return to functioning in the community. We target the period shortly after a first episode of schizophrenia to maximize the generalization of cognitive improvement to real-world functional outcome, before chronic disability is established. The cognitive training plus aerobic exercise intervention has the potential to examine a hypothesized mechanism of action and to make a meaningful difference in the lives of individuals with severe mental illness.