Offline memory processing in schizophrenia

记忆障碍是精神分裂症的核心和致残特征，但我们缺乏有效的治疗方法。一个主要 理解和治疗记忆损伤的努力的局限性在于，记忆通常在治疗期间评估。 单次会话。这种方法忽略了记忆的关键，也可以说是最重要的方面， 离线，在清醒和睡眠期间，在有意识的意识之外。在过去的20年里， 的研究已经产生了大量的证据，证明了离线过程的进化保守功能， 巩固多种形式的记忆，清醒的休息和睡眠发挥互补作用。这一基本 这项工作揭示了离线记忆巩固对整个生命周期认知的重要性， 机制，尤其是海马体的中心作用。然而，这种机械知识并没有被 转化为临床：海马生理学作为治疗靶点在很大程度上被忽视。这是 目前的医疗需求尚未得到满足。我们的实验室已经证实， 精神分裂症显示睡眠依赖性记忆巩固缺陷。初步数据显示 清醒时离线学习的相关缺陷。来自人类和啮齿动物研究的证据表明， 这两种离线学习都依赖于海马体的锐波波纹和相关的记忆重放。 精神分裂症的特征是海马结构和功能异常， 来破坏涟漪拟议研究的主要目标是测试的假设， 精神分裂症中的海马波纹损害离线学习，可以使用闭环听觉治疗 睡眠时的刺激（CLASS）。CLASS是一种新型无创神经刺激技术， 在家里实施。首先，使用档案数据，我们将建立精神分裂症患者与 在清醒和睡眠期间离线记忆的缺陷，与共同的潜在机制一致。接着在 CLASS的机械试验，我们将确定是否通过重复同步睡眠振荡超过一个 CLASS可以加强前额叶-前额叶的相互作用， 改善精神分裂症患者离线记忆最后，通过研究癫痫患者的直接海马 录音，我们将明确链接涟漪离线学习。在尾流期间，我们将显示涟漪增加 在学习后的休息时间，与绩效提高相关。在睡眠中，我们将证明， CLASS增加了缓慢振荡和纺锤波的纹波耦合，这对睡眠依赖性 记忆巩固。通过研究清醒和睡眠时的记忆，这项研究计划将揭示 在这些不同的国家的平行巩固机制。它既能增进我们对 海马体在离线记忆中的作用，并将这种机械知识转化为记忆， 精神分裂症由于缺乏有效的治疗方法来治疗精神分裂症中的致残性认知缺陷， CLASS作为一种可扩展的，机械引导的，有效的记忆丧失治疗方法将是巨大的。

Memory impairment is a core, disabling feature of schizophrenia, yet we lack effective treatments. A major limitation of efforts to understand and treat memory impairment is that memory is generally assessed during a single session. This approach misses the critical, and arguably most important, aspects of memory that happen offline, outside of conscious awareness, during both wake and sleep. Over the past 20 years, a virtual explosion of research has produced a wealth of evidence of an evolutionary conserved function of offline processes in the consolidation of multiple forms of memory, with wakeful rest and sleep playing complementary roles. This basic work has revealed the importance of off-line memory consolidation to cognition across the lifespan and its mechanisms, most notably the central role of the hippocampus. Yet this mechanistic knowledge has not been translated to the clinic: hippocampal physiology has largely been neglected as a treatment target. This is the unmet medical need that the present proposal addresses. Our laboratory has established that people with schizophrenia show a deficit in sleep-dependent memory consolidation. And our preliminary data show a correlated deficit in offline learning during wake. Converging evidence from human and rodent studies show that both types of offline learning depend on hippocampal sharp-wave ripples and associated memory replay. Schizophrenia is characterized by structural and functional hippocampal abnormalities that would be expected to disrupt ripples. The primary goals of the proposed research are test the hypotheses that disrupted hippocampal ripples in schizophrenia impair offline learning and can be treated using closed-loop auditory stimulation during sleep (CLASS). CLASS is a novel noninvasive neurostimulation technique that can be implemented at home. First, using archival data, we will establish that schizophrenia patients have correlated deficits in offline memory during wake and sleep, consistent with a common underlying mechanism. Next, in a mechanistic trial of CLASS, we will determine whether by repeatedly synchronizing sleep oscillations over a hippocampal-prefrontal cortical network, CLASS can strengthen hippocampal-prefrontal interactions and improve offline memory in schizophrenia. Finally, by studying epilepsy patients with direct hippocampal recordings, we will definitively link ripples to offline learning. During wake, we will show that ripples increase during the rest breaks that follow learning and correlate with performance gains. During sleep, we will show that CLASS increases the ripple coupling with slow oscillations and spindles that is critical for sleep-dependent memory consolidation. By studying memory during both wake and sleep, this research program will reveal parallel mechanisms of consolidation in these distinct states. It will both augment our basic understanding of the role of the hippocampus in offline memory and translate this mechanistic knowledge to improve memory in schizophrenia. Given the lack of effective treatments for disabling cognitive deficits in schizophrenia, the impact of CLASS as a scalable, mechanistically guided, effective treatment for memory loss would be substantial.