Understanding Hippocampal Neuroplasticity in Schizophrenia by Targeting Molecular Pathways Through Physical Exercise Training (PsychTrain)

通过体育运动训练靶向分子途径了解精神分裂症的海马神经可塑性 (PsychTrain)

• 批准号: 515976200
• 负责人: Professorin Dr. Heike Bickeböller
• 金额: --
• 依托单位: Klinik für Psychiatrie und Psychotherapie (Campus Innenstadt)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515976200?language=en
• 关键词: Understanding; Hippocampal; Neuroplasticity; Schizophrenia; Targeting

Aerobic exercise has been shown to improve cognition, hippocampal volume, and functional outcomes in individuals with schizophrenia. Research indicates that improvements may be mediated by neuroplastic brain regeneration moderated by genetic risk factors. However, a limitation of prior research is that it did not identify the molecular pathways linking exercise with genes and specific neuroplastic mechanisms. We will address this research gap by investigating the impact of genetics-related moderators of aerobic exercise. The primary outcome of our study will be the correlation of a schizophrenia polygenic risk score (PRS), assessed by genome-wide association studies, with the change in volume of the hippocampal subfield cornu ammonis 4 (CA4)/dentate gyrus (DG) after a 3-month aerobic exercise intervention compared with balance and tone training, the control condition. Previously, we found preliminary evidence for effects of PRS on volume change in the CA4/DG subregion after aerobic exercise training. Secondary outcomes will be synapse-related pathways, brain structural and resting-state functional alterations, symptoms, cognition, and epigenetic parameters. We will investigate a sample of 142 patients with schizophrenia. A total of 65 patients with schizophrenia have already completed the 3-month training in our aerobic exercise study of the BMBF-funded “Enhancing Schizophrenia Prevention and Recovery through Innovative Treatments” (ESPRIT) consortium. Of these patients, 34 underwent 3-Tesla multimodal magnetic resonance imaging (MRI) scans and provided blood for genetic and molecular biomarker investigations and will be included in this study. In addition, for additional assessment of secondary outcomes, blood has been collected from 31 patients of the ESPRIT study with only clinical phenotyping. According to our power calculation, assuming a drop-out rate of 30% we additionally need to enroll a further 156 patients in the planned study. We will construct PRSs and include molecular pathways that mediate synaptic plasticity, as indicated by our recent aerobic exercise studies, including Synapse Part (GO: 0045202) and Chemical Synaptic Transmission (GO: 0007268), and compare them with pathways not related to synaptic processes. We will use machine learning to stratify patients according to CA4/DG volume and thus approach the complex construct of neuroplasticity. Furthermore, we will determine the influence of PRS on structural MRI, diffusion tensor imaging, resting-state functional MRI, and electroencephalography parameters. Rich, multimodal longitudinal imaging data will be analyzed by multivariate techniques, including independent component analyses and advanced longitudinal modeling techniques. We will harness genetic, epigenetic, neuroimaging, clinical, and cognitive data acquired before and after the intervention to identify predictive multimodal signatures.

有氧运动已被证明可以改善精神分裂症患者的认知、海马体体积和功能结果。研究表明，这种改善可能是通过遗传风险因素减缓的神经再生脑再生来实现的。然而，先前研究的局限性在于，它没有确定将运动与基因和特定的神经再生机制联系起来的分子途径。我们将通过调查有氧运动的遗传学相关调节因子的影响来解决这一研究差距。我们研究的主要结果将是通过全基因组关联研究评估的精神分裂症多基因风险评分(PRS)与3个月有氧运动干预后与平衡和音调训练(对照条件)相比，海马区AM4角(CA4)/齿状回(DG)体积变化的相关性。以前，我们发现了初步证据表明，在有氧运动训练后，PRS对CA4/DG亚区的容量变化有影响。次要结果将是与突触相关的通路、大脑结构和静息状态功能改变、症状、认知和表观遗传参数。我们将对142名精神分裂症患者进行抽样调查。共有65名精神分裂症患者已完成为期3个月的有氧运动研究，该研究是由BMBF资助的“通过创新治疗促进精神分裂症的预防和康复”(ESPRIT)财团进行的。在这些患者中，34人接受了3-特斯拉多模式磁共振成像(MRI)扫描，并为遗传和分子生物标记物研究提供了血液，并将纳入这项研究。此外，为了进一步评估二次结局，ESPRIT研究的31名患者的血液仅进行了临床表型分析。根据我们的能力计算，假设辍学率为30%，我们还需要在计划的研究中再招募156名患者。我们将构建PRS，并包括介导突触可塑性的分子途径，最近的有氧运动研究表明，包括突触部分(GO：0045202)和化学突触传递(GO：0007268)，并将它们与与突触过程无关的途径进行比较。我们将使用机器学习根据CA4/DG体积对患者进行分层，从而探讨神经可塑性的复杂结构。此外，我们还将确定PrS对结构MRI、扩散张量成像、静息状态功能MRI和脑电参数的影响。丰富的多模式纵向成像数据将通过多变量技术进行分析，包括独立分量分析和先进的纵向建模技术。我们将利用干预前后获得的遗传、表观遗传学、神经成像、临床和认知数据来识别预测性多模式特征。