Reducing Hippocampal Hyperactivity and Improving Cognition in Schizophrenia

减少海马过度活跃并改善精神分裂症患者的认知

• 批准号: 10671447
• 负责人: JASON R TREGELLAS
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671447
• 关键词: Alzheimer' s disease model; Animal Model; Antiepileptic Agents; Antipsychotic Agents; Attention; Behavioral; Binding Proteins; Biological; Biological Markers; Characteristics; Clinical; Cognition; Cognitive; Cognitive deficits; Crossover Design; Data; Disease; Dose; Double-Blind Method; Epilepsy; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Goals; Hippocampus; Human; Hyperactivity; Impaired cognition; Investigation; Knowledge; Levetiracetam; Memory; Metabolism; Monitor; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Neurological status; Neurons; Neuropsychology; Occupations; Outcome; Outcome Measure; Pathology; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Population; Prediction of Response to Therapy; Publishing; Quality of life; Randomized; Research; Rest; Rodent Model; Schizophrenia; Symptoms; Testing; Veterans; Work; clinical efficacy; cognitive enhancement; cognitive function; cognitive load; cognitive performance; cognitive testing; design; disability; effective therapy; experimental study; gray matter; improved; interest; mild cognitive impairment; mouse model; novel; novel strategies; novel therapeutics; open label; pharmacologic; prevent; processing speed; psychosocial; recruit; response; targeted biomarker; therapeutic development; treatment strategy

Schizophrenia is a leading cause of disability for Veterans. Due to the lack of an effective treatment, Veterans with schizophrenia suffer a myriad of cognitive impairments, including deficits in attention, memory, and processing speed. As a result, patients struggle on the job, in relationships, and in day-to-day activities, contributing to an overall poor quality of life. New treatments for cognitive dysfunction in schizophrenia clearly are needed. A potentially powerful approach for developing and evaluating novel therapeutics is to combine behavioral/neurocognitive outcome measures with functional imaging of a drug's effects on a neurobiological marker. A topic of current great interest in schizophrenia research is the finding that patients show increased activity of the hippocampus, particularly at “rest” or in other similar conditions of low cognitive load. This increased activity has been hypothesized to prevent further recruitment of the region as task demands increase, contributing to cognitive dysfunction. Furthermore, recently published work has demonstrated that cognitive performance in schizophrenia is negatively correlated with resting hippocampal activity. It follows that a drug treatment capable of reducing resting hippocampal activity may improve cognition in patients. Recent findings have demonstrated that low doses of the anti-epileptic drug levetiracetam (LEV) reduce hippocampal hyperactivity and improve performance on a memory task in patients with mild cognitive impairment. LEV also reduces hippocampal hyperactivity in mouse models of Alzheimer's disease, an effect also recently shown in a mouse model of schizophrenia. Unlike other anti-epileptics, LEV improves cognition in epilepsy patients. The drug is well tolerated at doses several fold higher than that used to demonstrate its effects on the hippocampus. As such, it is possible that low-dose LEV may be a useful strategy for reducing hippocampal hyperactivity and improving cognition in schizophrenia. A thorough investigation of the hypothesis that LEV will reduce hippocampal hyperactivity and improve cognition in Veterans with schizophrenia is proposed. In the first Aim, functional magnetic resonance imaging will be used to determine the lowest dose at which LEV engages the biological target of interest, hippocampal hyperactivity. This Aim will use a 2-week open-label crossover design to examine the effects of two low doses of LEV (125 mg b.i.d. and [62.5] mg b.i.d.) on resting hippocampal activity in schizophrenia. The second Aim will then use the dose optimized in Aim 1 in a 4-week placebo-controlled, double-blind, randomized, parallel design to assess the cognitive effects of LEV, utilizing the Repeatable Battery for the Assessment of Neurological Status (RBANS). The relationship between LEV effects on hippocampal activity and its effects on cognitive performance also will be examined. This project will use a novel approach to investigate the efficacy of a potential new pharmacologic target in schizophrenia. The project also will evaluate hippocampal hyperactivity as a biomarker in schizophrenia by examining its ability to predict treatment response. Understanding the cognitive and neurobiological effects of LEV will provide an early indication of whether LEV can be repurposed to enhance cognitive function in Veterans with schizophrenia.

精神分裂症是退伍军人残疾的主要原因。由于缺乏有效的 在治疗过程中，患有精神分裂症的退伍军人遭受多种认知障碍，包括认知能力缺陷 注意力、记忆力和处理速度。结果，患者在工作、人际关系和生活中陷入困境。 日常活动，导致整体生活质量下降。 显然需要针对精神分裂症认知功能障碍的新疗法。一个潜在的 开发和评估新疗法的有效方法是将 通过药物作用的功能成像来测量行为/神经认知结果 神经生物学标记。当前精神分裂症研究中最受关注的一个主题是以下发现： 患者表现出海马体活动增加，特别是在“休息”或其他类似条件下 认知负荷低。假设这种增加的活动是为了防止进一步招募 随着任务要求的增加，该区域会增加，从而导致认知功能障碍。此外，最近发表 研究表明，精神分裂症患者的认知表现与休息时间呈负相关。 海马体活动。由此可见，能够减少静息海马活动的药物治疗可能 提高患者的认知能力。 最近的研究结果表明，低剂量的抗癫痫药物左乙拉西坦 (LEV) 减少海马过度活跃并提高轻度患者的记忆任务表现 认知障碍。 LEV 还可以降低阿尔茨海默病小鼠模型中海马的过度活跃程度 最近在精神分裂症小鼠模型中也显示出这种效应。与其他抗癫痫药不同的是， LEV 可改善癫痫患者的认知能力。该药物在剂量高几倍时具有良好的耐受性 用来证明它对海马体的影响。因此，低剂量 LEV 可能 减少海马过度活跃和改善精神分裂症认知的有用策略。 对 LEV 会减少海马过度活跃这一假设的彻底调查 建议改善患有精神分裂症的退伍军人的认知能力。第一个目标是功能性磁性 共振成像将用于确定 LEV 与生物靶标结合的最低剂量 有趣的是，海马过度活跃。该目标将使用为期 2 周的开放标签交叉设计来检验 两种低剂量 LEV（125 mg b.i.d. 和 [62.5] mg b.i.d.）对静息海马活动的影响 精神分裂症。然后，第二个目标将在为期 4 周的安慰剂对照中使用目标 1 中优化的剂量， 双盲、随机、平行设计，利用可重复性评估 LEV 的认知效果 用于神经状态评估（RBANS）的电池。 LEV 影响之间的关系 海马体活动及其对认知表现的影响也将被检查。 该项目将使用一种新方法来研究潜在新药理学的功效 精神分裂症的目标。该项目还将评估海马过度活跃作为生物标志物 通过检查其预测治疗反应的能力来诊断精神分裂症。了解认知和 LEV 的神经生物学效应将提供 LEV 是否可以重新用于 增强患有精神分裂症的退伍军人的认知功能。

项目成果

Spike-associated networks and intracranial electrographic findings.

尖峰相关网络和颅内电图发现。

• DOI: 10.1684/epd.2020.1163
• 发表时间: 2020
• 期刊: Epileptic disorders : international epilepsy journal with videotape
• 作者: Bear,JoshuaJ;Kirsch,HeidiE;Berman,BrianD;Chapman,KevinE;Tregellas,JasonR
• 通讯作者: Tregellas,JasonR

Rapid Early Brain Development Highlights a Critical Period and Possible Intervention Window.

早期大脑的快速发育凸显了一个关键时期和可能的干预窗口。

• DOI: 10.1016/j.bpsc.2020.08.007
• 发表时间: 2020
• 期刊: Biological psychiatry. Cognitive neuroscience and neuroimaging
• 作者: Tregellas,JasonR;Legget,KristinaT
• 通讯作者: Legget,KristinaT

Beyond the AJR: Should Patients With First-Episode Psychosis Undergo Brain MRI?

AJR 之外：首发精神病患者是否应该接受脑部 MRI 检查？

• DOI: 10.2214/ajr.23.30338
• 发表时间: 2023
• 期刊: AJR. American journal of roentgenology
• 作者: Tanabe,Jody;Tregellas,JasonR
• 通讯作者: Tregellas,JasonR

In Utero Exposure to Maternal Overweight or Obesity is Associated with Altered Offspring Brain Function in Middle Childhood.

在子宫内，母亲超重或肥胖与后代中期大脑功能的改变有关。

• DOI: 10.1002/oby.22908
• 发表时间: 2020
• 期刊: Obesity (Silver Spring, Md.)
• 作者: Shapiro,AllisonLB;Moore,BriannaF;Sutton,Brianne;Wilkening,Greta;Stence,Nicholas;Dabelea,Dana;Tregellas,JasonR
• 通讯作者: Tregellas,JasonR