High-resolution Functional Imaging of Hippocampal Subfields in Schizophrenia

描述（由申请人提供）：精神分裂症患者陈述性记忆缺陷的确切性质和神经基础仍有待确定。通过将基本认知神经科学记忆范式转化为临床研究，这些特征的改进有望更好地预测高危青少年转化为精神病，更好地预测功能结果，更好地进行全基因组关联研究的目标，以及更好地检测治疗效果的生物标志物。促进我们对精神病的理解的一个关键障碍是我们缺乏对认知缺陷和精神病症状的神经基础之间关系的理解。taminga， Stan和Wagner（2010）最近提出了一种基于海马的齿状回（DG）低谷氨酸能功能障碍和苔藓纤维输入减少的精神病模型（CA3）。该模型预测，精神分裂症患者表现出dg依赖性模式分离（形成非重叠记忆表征所需）的缺陷，以及CA3/ ca1依赖性模式完成（基于部分信息的联想检索所需）的增加。这两个过程对于陈述性情景记忆的形成和恢复至关重要，当受到干扰时可能导致精神病联想。该模型可以使用对模式分离和模式完成敏感的记忆范式，结合海马体的高分辨率功能磁共振成像（hr-fMRI）进行测试。这种组合是由Stark等人（2008）首创的，他们执行了一个连续的附带编码任务，在这个任务中，受试者被展示：物体，重复的物体，以及与物体相似的诱饵。他们发现，基于大脑激活的偏差分数，表达了诱饵活动与重复刺激活动之间的相似性，可以评估大脑区域参与模式完成（偏差分数接近1；诱饵被视为重复）或模式分离（偏差分数接近0；诱饵被视为第一次呈现）。这项研究提供了DG/CA3参与人类模式分离的第一个证据。此外，Stark和他的同事们还发现，老年人与年轻人、轻度认知障碍患者与对照组相比，物体和空间模式分离能力受损（以及相关的结构和生理异常）。在hr-fMRI的背景下，血氧水平依赖信号是体素大小的函数，尽管存在纠正心脏和呼吸相关噪声的方法，但没有研究将它们与hr-fMRI结合使用，其中它们可能是最有益的。我们拟利用hr-fMRI对30名慢性精神分裂症患者和30名年龄和性别匹配的健康对照进行对象和空间模式分离和完成相关的生理激活研究，并对心脏和呼吸相关噪音进行校正和不校正，以表征海马亚区对精神分裂症患者陈述性记忆缺陷、神经心理记忆缺陷、症状严重程度和功能结果水平的贡献。

DESCRIPTION (provided by applicant): The precise nature and neural underpinnings of schizophrenia patients' declarative memory deficits remain to be determined. Improvements in their characterization, through translation of basic cognitive neuroscience memory paradigms into clinical research, hold promise as better predictors of conversion to psychosis in adolescents at risk, better predictors of functional outcome, better targets for genome-wide association studies, and better biomarkers for testing treatment effectiveness. A critical barrier to advancing our understanding of psychosis is the lack in our understanding of the relationship between the neural underpinnings of cognitive deficits and psychotic symptoms. Tamminga, Stan, and Wagner (2010) recently proposed a hippocampus- based psychosis model of dentate gyrus (DG) hypoglutamatergic dysfunction and reduced mossy fiber input to Cornu Amonis region 3 (CA3). The model predicts that schizophrenia patients show a deficit in DG-dependent pattern separation (required for forming non-overlapping memory representations) and an increase in CA3/CA1-dependent pattern completion (required for associative retrieval based on partial information). These two processes are critically important for forming and retrieving declarative episodic memories and when disturbed may result in psychotic associations. The model can be tested using a memory paradigm sensitive to pattern separation and pattern completion, combined with high-resolution functional magnetic resonance imaging (hr-fMRI) of the hippocampus. This combination was pioneered by Stark et al. (2008), who performed a continuous incidental encoding task in which subjects were shown: objects, repeats of the objects, and lures similar to the objects. They showed that a brain activation-based bias score, which expresses similarity between lure activity as compared to repeat stimulus activity, can assess a brain region's involvement in pattern completion (bias score approaching 1; lure treated as a repetition) or pattern separation (bias score approaching 0; lure treated as first presentation). This study provided the first evidence that DG/CA3 is involved in pattern separation in humans. Moreover, Stark and colleagues have shown impaired object and spatial pattern separation performance (and associated structural and physiological abnormalities) in old versus young adults and in patients with mild cognitive impairment versus controls. In the context of hr-fMRI, the blood oxygenation level dependent signal is a function of voxel size, and although methods to correct for cardiac and respiration-associated noise exist, no study has employed them in concert with hr-fMRI, in which they may be most beneficial. We propose to investigate object and spatial pattern separation and completion- associated physiological activations with hr-fMRI in 30 chronic schizophrenia patients and 30 age- and sex- matched healthy controls, with and without corrections for cardiac and respiration-associated noise, in order to characterize the contributions of hippocampal subfields to schizophrenia patients' declarative memory deficits, neuropsychological memory deficits, symptom severity, and functional outcome levels. PUBLIC HEALTH RELEVANCE: The study findings will help to clarify the nature of hippocampal subfield contributions to declarative memory deficits in schizophrenia, and whether behavioral and physiological deficits are diferentialy predictive of clinically observed memory deficits, symptomatolgy, and functional outcome. The findings may be used to identify predictors of conversion to psychosis or functional outcome, predisposing genes, or biomarkers.