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致残的主要原因。由于缺乏有效的

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