Network Mechanisms of Flexible Cognitive Control

该独立之路奖（K99/R 00）申请的目标是从专家研究人员那里获得灵活认知控制和大脑网络分析的认知神经科学培训，为独立做准备，该培训将用于启动一个研究灵活控制网络机制的实验室。灵活的控制-一种支持适应性的能力，在日常生活中很重要的目标导向行为-在各种精神疾病中受到影响，显着降低生活质量。重要的是，灵活控制的机制在认知和神经水平上仍然知之甚少。大量的证据表明，灵活的控制是通过一组额顶叶脑区（有时被称为认知控制网络（CCN））在各种情况下实现的。我们最近发现，CCN区域在人类大脑中具有最高的全球大脑连通性（GBC），更重要的是，侧前额叶CCN区域的GBC强烈预测流体推理-这表明灵活的 控制与特定大脑区域的全局连通性有关。基于这些发现，我们假设灵活的枢纽假说：一些CCN区域能够利用其广泛的连接，灵活地重新配置当前活跃的连接（与任务相关的感觉，语义和运动区域）根据任务的需求。我们将研究的假设，灵活的枢纽是一个关键的神经机制，通过确定神经网络和认知属性之间的关系，灵活的枢纽和灵活的控制。在指导（K99）阶段，我将接受Steve Petersen博士（共同导师），Olaf Sporns博士（合作者）和Deanna Barch博士（合作者）的图论培训，以开发更精确的定量网络属性指标，这些指标可以识别和定义人类大脑中的灵活枢纽。此外，托德Braver博士（导师）和兰德尔恩格尔博士（合作者）的个体差异方法的培训将使灵活控制的定量更精确的认知措施的发展成为可能。在独立（R 00）阶段，我们将在此研究和培训的基础上，确定动态（跨任务）灵活的集线器连接变化如何与稳定的网络属性和灵活的控制能力相关。这种对灵活中枢和灵活控制之间联系的严格表征将使我们能够更全面地了解各种精神疾病中存在的灵活控制障碍。培训将在 圣路易斯的华盛顿大学拥有广泛的智力和设备资源，可以进行涉及个体差异和功能连接磁共振成像（fcMRI）的执行功能研究。Braver博士是认知控制研究领域的世界级专家，在使用功能性MRI的个体差异方法学方面拥有丰富的经验，这使他成为拟议培训计划的优秀导师。Petersen博士是开发图论fcMRI方法并将其应用于认知控制研究的世界专家，这使他成为拟议培训计划的优秀共同导师。重要的是，在K99阶段和过渡到独立R 00阶段期间，几个成熟的合作者也将补充我的培训和评估。自从我在加州大学伯克利分校的马克·德·埃斯波西托实验室读本科以来，我一直对研究执行功能的认知神经科学感兴趣。随后，我在匹兹堡大学沃尔特·施耐德的实验室读研究生，并获得了博士学位。神经科学我的研究生研究导致了多个第一作者的出版物，基于我强烈的独立研究兴趣驱动的创新研究方法。具体来说，这些兴趣使我主要关注两条研究路线：快速指令任务学习（RITL）和GBC。第一个，RITL，研究了灵活的，适应性的人类行为（即，灵活的认知控制）。这是一项重要而及时的研究，因为健康的个体如何能够迅速（即，在一个tril）学习几乎无限多种可能的任务（以及这种能力如何在精神疾病中受损）。例如，这种能力是在个人第一次使用手机（为了适应与“固定电话”的差异）或任何新技术时使用的。第二条研究线GBC专注于描述大脑最连接的区域。我在Braver博士的实验室做博士后的时间非常富有成效，因为我学习了新的先进的功能磁共振成像方法，如多变量模式分析（MVPA），开发了一种新的RITL认知范式，并发表了一篇研究精神分裂症中GBC缺陷的论文，以及其他成就。重要的是，拟议的研究计划将结合联合收割机-并受益于之间的协同作用-RITL和GBC的研究线，为形成自己的独立实验室做准备。我计划将我的实验室主要发展为这两条研究路线的交汇点：研究大脑网络连接指定灵活认知控制背后的动力学的方式。K99/R 00建议书中概述的培训和研究是我职业发展计划的重要组成部分，因为我正在成为一名成功的独立研究人员。

DESCRIPTION (provided by applicant): The goal of this Pathway to Independence Award (K99/R00) application is to obtain training in the cognitive neuroscience of flexible cognitive control and brain network analysis from expert researchers in preparation for independence, where this training will be used to start a laboratory that investigates the network mechanisms of flexible control. Flexible control - a capacity supporting adaptive, goal-directed behavior important in daily life - is affected in a variety of mental illnesses, markedly reducing quality o life. Critically, the mechanisms underlying flexible control remain poorly understood at both cognitive and neural levels. A large body of evidence suggests that flexible control is implemented across a variety of situations by a set of fronto-parietal brain regions sometimes referred to as the cognitive control network (CCN). We recently found that CCN regions have among the highest global brain connectivity (GBC) in the human brain and, more importantly, that GBC in a lateral prefrontal CCN region strongly predicts fluid reasoning - suggesting flexible control is linked to the global connectivity properties of specific brain regions. Based on these findings, we postulate the flexible hub hypothesis: that some CCN regions are able to use their extensive connectivity to flexibly reconfigure currently active connections (with task-relevant sensory, semantic, and motor regions) according to task demands. We will investigate the hypothesis that flexible hubs are a key neural mechanism underlying flexible control by determining the neural network and cognitive properties underlying the relationship between flexible hubs and flexible control. During the mentored (K99) phase I will receive training in graph theory from Dr. Steve Petersen (co-mentor), Dr. Olaf Sporns (collaborator), and Dr. Deanna Barch (collaborator) to enable the development of more quantitatively precise network property indicators that can identify and define flexible hubs in the human brain. Further, trainin in individual differences approaches from Dr. Todd Braver (mentor) and Dr. Randall Engle (collaborator) will enable the development of more quantitatively precise cognitive measures of flexible control. During the independent (R00) phase we will then build upon this research and training to determine how dynamic (across-task) flexible hub connectivity changes are related to stable network properties and flexible control abilities. This rigorous characterization of the lin between flexible hubs and flexible control will enable a more comprehensive understanding of the flexible control impairments present in a variety of mental illnesses. Training will take place at Washington University in St. Louis, which has extensive intellectual and equipment resources for conducting studies of executive functions involving individual differences and functional connectivity magnetic resonance imaging (fcMRI). Dr. Braver is a world expert in cognitive control research and has extensive experience using individual differences methodology with functional MRI, which makes him an excellent mentor for the proposed training plan. Dr. Petersen is a world expert in developing graph theory fcMRI methods and applying them to cognitive control research, makes him an excellent co-mentor for the proposed training plan. Importantly, several well-established collaborators will also supplement my training and evaluation during the K99 phase and the transition into the independent R00 phase. I have pursued my interest in researching the cognitive neuroscience of executive functions since I was an undergraduate in Mark D'Esposito's laboratory at UC Berkeley. I subsequently went to graduate school in Walter Schneider's laboratory at the University of Pittsburgh and received a Ph.D. in Neuroscience. My graduate research led to multiple first-authored publications based on innovative research approaches driven by my strong independent research interests. Specifically, these interests led me to focus primarily on two lines of research: rapid instructed task learning (RITL) and GBC. The first, RITL, investigates the executive functions underlying flexible, adaptive human behavior (i.e., flexible cognitive control). This is important and timely research as it remains a mystery how healthy individuals are able to rapidly (i.e., in a single tril) learn a virtually infinite variety of possible tasks (and how this ability can become impaired in mental illnesses). For instance, this ability is used the first time an individual uses a cell phon (in order to adapt to differences from 'landline' phones), or any new technology. The second line of research, GBC, is focused on characterizing the brain's most connected regions. My time as a postdoctoral fellow in Dr. Braver's lab has been highly productive, as I have learned new advanced fMRI methods such as multivariate pattern analysis (MVPA), developed a new RITL cognitive paradigm, and published a paper investigating GBC deficits in schizophrenia, among other accomplishment. Critically, the proposed research plan will combine - and benefit from synergy between - the RITL and GBC lines of research in preparation for forming my own independent laboratory. I plan to develop my laboratory primarily at the confluence of these two lines of research: investigating the ways in which brain network connectivity specifies the dynamics underlying flexible cognitive control. The training and research outlined in this K99/R00 proposal are essential components of my career development plans as I transition to becoming a successful independent researcher.