AMYGDALA CONNECTIVITY MAP IN 'IN VIVO' HUMAN BRAINS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 在过去的15年里，我们已经看到了越来越多的兴趣，了解杏仁核的作用，一个复杂的结构，涉及广泛的正常行为功能和精神疾病。杏仁核所在的颞叶受损，会导致原始行为（恐惧、进食和性行为）的深刻变化。几项功能性神经影像学研究探索了杏仁核在情绪处理和调节中的作用，更广泛地说，在人类社会行为（奖励，动机和学习）中的作用，建立在先前死后人类和动物研究的细胞结构发现的假设基础上。然而，由于缺乏对杏仁核组织及其与其他大脑区域的连接的了解，以及通过行为任务测量的情感功能的复杂性，限制了我们的理解，并需要对“体内”人类受试者进行进一步研究。在我们的初步数据中，我们已经能够重建连接种子区，杏仁核，同侧皮质（额叶，颞叶，顶叶，岛叶，枕叶皮质）的纤维。有趣的是，尽管目标区域范围很广，但我们发现杏仁核连接到这些皮质的高度功能化的子域，对情绪过程和调节很重要。此外，通过重建杏仁核与皮质下核（杏仁核、基底神经节、丘脑）之间的连接纤维，我们已经能够在人类受试者中确定杏仁核是否直接或间接通过杏仁核-皮质下-皮质回路与同侧皮质连接，这与动物研究中的组织学标志物的发现平行并远远超出。此外，从个体皮质表面播种为我们提供了值得注意的优势，即考虑到大的主体间解剖变异性，最大限度地减少假阳性连接，例如当采用几何或模板衍生的掩模（MNI，Talairach等）时发生的穿过种子/目标位置附近的脑回的连接。这个项目的规模远远超过了我们目前管理/处理数据的能力。事实上，我们的硬件无法支持这些分析。然而，我们可以完成我们的项目的速度可以大大提高额外的计算能力和并行处理器。在过去的一年中，我们已经能够完成对35名已经收集的健康受试者中的18名的分析。此外，在50名健康对照者中探索杏仁核连接图将只是该项目的第一阶段。事实上，目前正在收集50名双相抑郁症患者、50名缓解型双相抑郁症患者和50名单相抑郁症患者的神经影像学数据（大约50名患者已经收集并等待分析）。支持我们的初步观察，我们假设，我们的多模式神经影像学方法，如果促进足够的计算能力，将同意映射正常的杏仁核连接在健康的个人，更广泛的异常杏仁核连接在情感障碍，在体内。因此，为了验证我们的假设，我们提出了以下具体目标。具体目标1：在50名健康受试者中，将高分辨率MPWE采集与68个方向的弥散加权成像序列相结合。在这一目标中，我们建议映射杏仁核解剖连接的第一次在体内。首先（i）我们将采用基于处理流的大脑皮层和皮层下体积的自动重建，由外壳脚本（recon-all）控制，在FREESURFER中实现。第二，（ii）这些皮质和皮质下掩模，在个人的解剖空间中定义，然后将作为种子/目标区域运行概率纤维束成像（bedpostx和probtrackx，在FSL中实现）。具体目标2：确定情感障碍的潜在神经解剖学标志物。在这个目标中，我们建议比较杏仁核连接在50个健康的人，并在这样一个大的和代表性的样本的广泛的情绪障碍。该项目的成功不仅取决于解决刚刚列出的研究挑战的能力，而且还取决于实现研究进展和直接用于神经成像研究的高性能计算的能力。这个项目是雄心勃勃的，计算要求很高，但它将是情感文献中的一个里程碑，通过澄清人类大脑的杏仁核连接图，在健康个体和情感障碍的大样本中。这些神经解剖学证据将为杏仁核功能作用的现代和整体理论的发展奠定基础，并随后开发出更协调的行为功能磁共振成像任务。限速步骤：首先（i），为了自动重建大脑的皮质和皮质下区域，recon_all（FREESURFER）大约需要2 ½天/受试者。第二（ii），bedpostx（FSL），代表使用采样技术获得的扩散参数的贝叶斯估计，运行马尔可夫链蒙特卡罗采样以建立每个体素的扩散参数分布，并且需要大约3天的处理时间/对象（64个切片）。这个脚本允许并行作业;实际上，每个切片都可以独立地进行预处理。第三（iii），为了重建我们目前正在探索的30个概率轨迹并最终绘制杏仁核，probtackx（FSL）大约需要24小时/受试者。同样，每个概率轨迹可以独立地进行预处理。我们的招募率约为1名受试者/周。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the last 15 years, we have seen an increasing interest in understanding the role of the amygdala, a complex structure involved in a wide range of normal behavioral functions and psychiatric conditions. Damage to the temporal lobe, where the amygdala is located, results in profound changes in primordial behaviors (fear, feeding and sexuality). Several functional neuroimaging studies have explored the role that the amygdala plays in emotional processing and regulation and, more broadly, in human social behavior (reward, motivation and learning), building upon hypotheses of previous cytoarchitectural findings of post-mortem human and animal studies. However, the lack of knowledge of amygdala organization and its connections to other brain areas and the complexity of emotional functions measured by behavioral tasks limits our understanding and require further investigation in "in vivo" human subjects. In our preliminary data we have been able to reconstruct fibers connecting the seed region, amygdala, to the ipsilateral cortices (frontal, temporal, parietal, insular, occipital cortices). Interestingly, despite the fact that the targets regions are wide-ranging, we found that the amygdala connects to highly functionally specialized sub-domains of these cortices, salient to the emotional process and regulation. Additionally, reconstructing the fibers connecting the amygdala to subcortical nuclei (nucleus accumbens, basal ganglia, thalamus), we have been able to identify in human subjects whether the amygdala connects to the ipsilateral cortices directly or indirectly via amygdala-subcortical-cortical circuits, paralleling and going far beyond findings of histological markers in animal studies. Moreover, seeding from individual cortical surface provided us with the noteworthy advantage of taking into account the large intersubjective anatomical variability, minimizing false positive connections such as those crossing a gyrus near the seed/target location that occurs when geometrical or template-derived masks (MNI, Talairach, etc ) are employed. The scale of this project far outpaces our current ability to manage/process data. Our hardware, in fact, is unable to support these analyses. However, the speed at which we could complete our projects could be greatly improved with additional computational power and parallel processors. In the past year, we have been able to finalize the analyses of only 18 healthy subjects out of the 35 already collected. Furthermore, exploring the amygdala connectivity map in 50 healthy controls will be just a first stage of this project. In fact, neuroimaging data are currently being collected in 50 depressed bipolar, 50 remitted bipolar, and 50 depressed unipolar individuals (about 50 have already been collected and are waiting to be analyzed). Supported by our initial observation we hypothesize that our multimodal neuroimaging approach, if facilitated by adequate computational power, will consent the mapping of the normative amygdala connectivity in healthy individuals and, more broadly of the abnormal amygdala connectivity in affective disorders, in vivo. Hence, to test our hypothesis we propose the following specific aims. Specific Aim 1: To combine a high-resolution MPRAGE acquisition with a 68-directions diffusion-weighted imaging sequence in 50 living healthy subjects. In this aim we propose to map the amygdala anatomical connectivity for the first time in vivo. First (i) we will employ an automated reconstruction of the brain's cortical and subcortical volumes based on a processing stream, controlled by a shell script (recon-all), implemented in FREESURFER. Second, (ii) these cortical and subcortical masks, defined in individual anatomical space, will then serve as seed/target regions to run probabilistic tractography (bedpostx and probtrackx, implemented in FSL). Specific Aim 2: To identify potential neuroanatomical marker of affective disorders. In this aim we propose to compare the amygdala connectivity in 50 healthy individuals and in such a large and representative sample of the wide spectrum of mood disorders. The success of this project depends on the ability not only to address the research challenges just listed but also to implement research advances and high performance computing of direct utility to the neuroimaging research. This project is ambitious and computationally-demanding, but it will be a milestone in the literature of emotion by clarifying the amygdala connectivity map of the human brain, in a large sample of healthy individuals and affective disorders. Such neuro-anatomical evidence will serve as groundwork to develop modern and holistic theories of the functional role of the amygdala and subsequent development of more tuned behavioral fMRI tasks. Rate-limiting-steps: First (i), to automatically reconstruct brain's cortical and subcortical regions, recon_all (FREESURFER) takes about 2 ¿ days/subject. Second (ii), bedpostx (FSL), which stand for Bayesian Estimation of Diffusion Parameters Obtained using Sampling Techniques, runs Markov Chain Monte Carlo sampling to build up distributions on diffusion parameters at each voxel and requires about 3 days processing time/subject (64 slices). This script allows parallel jobs; indeed, each slice could be preprocessed independently. Third (iii), to reconstruct the 30 probability tracks that we are currently exploring and ultimately map the amygdala, probtackx (FSL) takes about 24 hours/subject. Again, each probability tracks could be preprocessed independently. Our recruitment rate is about 1 subject/week.