High-resolution Functional Imaging of Hippocampal Subfields in Schizophrenia

描述(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。通过将基本的认知神经科学记忆范式转化为临床研究，它们在表征方面的改进有望成为高危青少年向精神病转化的更好预测指标，更好地预测功能结果，更好地作为全基因组关联研究的目标，以及更好地测试治疗效果的生物标志物。推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的神经基础和精神病症状之间的关系的理解。Tamminga，Stan和Wagner(2010)最近提出了一种基于海马区的精神病模型，该模型表现为齿状回(DG)谷氨酸能低减，并减少了向Amonis角(CA3)的苔藓纤维输入。该模型预测，精神分裂症患者在依赖DG的模式分离(形成非重叠记忆表征所需的)方面存在缺陷，而依赖CA3/CA1的模式完成(基于部分信息的关联检索所需的)增加。这两个过程对于形成和提取陈述性情景记忆至关重要，当受到干扰时，可能会导致精神联想。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)来测试该模型。这种结合是由斯塔克等人首创的。(2008)，他执行了一项连续的附带编码任务，其中显示了对象：对象、对象的重复和与对象相似的诱饵。他们表明，基于大脑激活的偏向分数，表示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(偏向分数接近1；诱饵被视为重复)或模式分离(偏向分数接近0；诱饵被视为第一次呈现)。本研究首次提供了DG/CA3参与人类模式分离的证据。此外，斯塔克和他的同事在老年人和年轻人以及轻度认知障碍患者和对照组中显示出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，血氧水平依赖的信号是体素大小的函数，尽管存在校正心脏和呼吸相关噪声的方法，但还没有研究将它们与hr-fMRI结合使用，其中它们可能是最有益的。我们建议用hr-fMRI研究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组的客体和空间模式分离和完成相关的生理激活，包括心脏和呼吸相关噪声校正和不校正，以表征海马区对精神分裂症患者的陈述性记忆缺陷、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.