The Effect of Electrical Stimulation on Cognitive Control Networks in Treatment-Resistant Depression

严重抑郁障碍(MDD)是一种普遍存在的令人衰弱的疾病，其中三分之一的患者 人口对治疗具有抵抗力。抑郁症的特征是认知功能障碍，包括 认知控制，定义为对认知和行为的灵活适应，与一个人的当前状态相称 目标。脑深部刺激(DBS)在难治性抑郁症治疗中的应用 (TRD)，以前在实验任务中显示出认知控制的增强，但在治疗方面 结果喜忧参半，以及我们对DBS对大脑网络中神经动力学的影响的理解 神经精神障碍与认知功能障碍和控制力受损的关系尚不为人所知。在……里面 此外，我们对神经刺激频率如何在调节神经活动中发挥作用的理解 抑郁症患者认知控制网络中的交流是有限的。 为了解决这些未知问题，在F99阶段，阿努沙将收集颅内局部场势 通过植入穿过前额叶皮质、眶前叶皮质、 通过母公司UH3研究招募的TRD患者的杏仁核和前扣带回皮质 (UH3-NS103549)。受试者在高频率之前和期间执行认知控制行为任务 通过植入腹侧被膜/腹侧纹状体的DBS电极进行电刺激 胼胝体下扣带状。此外，阿努沙将在刺激实验期间收集LFP记录 在静息状态期间系统地施加电刺激频率范围(6，50,130赫兹) DBS电极。使用收集的数据，阿努沙将描述行为定义的认知控制 在患有TRD的参与者中建立子网络，并探索已知的 与健康受试者的冲突处理和认知控制有关。她将把这项工作扩大到 在行为任务期间执行功能连通性分析。阿努沙还将把这些技术应用于 对静息状态下刺激实验采集的数据进行分析。理解认知控制是 迫切需要不仅提高我们对抑郁症认知功能障碍的理解，而且是朝着 围绕与行为相关的电生理标记物进行个体化和优化治疗 神经精神障碍中的损害，代替症状的临床评估或除了症状评估之外。 在K00阶段，阿努莎将把她的研究扩展到使用啮齿动物进行更多颗粒状的电路解剖 精神疾病模型，并利用她在统计和计算神经科学方面的博士培训 分析这类研究的数据，同时继续在人类受试者中进行研究，以研究认知 控制力。F99和K00阶段的拟议培训将确保向HER提供多学科培训 作为一名独立研究调查员的职业目标，专注于使用多学科方法来帮助 全面了解神经精神障碍中的认知功能障碍。

Major Depressive Disorder (MDD) is a prevalent and debilitating disorder, where one-third of this population is treatment-resistant. Depression is characterized by cognitive dysfunction, including deficits in cognitive control, defined as flexible adaptation of cognitive and behavior commensurate with one’s current goals. Application of deep brain stimulation (DBS), a common therapy used for treatment-resistant depression (TRD), has previously shown enhancement in cognitive control during experimental tasks, but therapeutically shown mixed results, and our understanding of the effect of DBS on neural dynamics in brain networks associated with impaired cognitive dysfunction and control in neuropsychiatric disorders is not well-known. In addition, our understanding of how the frequency of neurostimulation plays a role in modulating neural activity and communication in cognitive control networks in depression is limited. To tackle these unknowns, in the F99 phase, Anusha will collect intracranial local field potential recordings (LFP) through depth electrodes implanted across the prefrontal cortex, orbitofrontal cortex, amygdala and anterior cingulate cortex in patients with TRD, recruited through a parent UH3 study (UH3-NS103549). Participants perform a cognitive control behavioral task before, and during high-frequency electrical stimulation delivered through DBS electrodes implanted in the ventral capsule/ventral striatum and subcallosal cingulate. Additionally, Anusha will collect LFP recordings during stimulation experiments where a range of electrical stimulation frequencies (6,50,130 Hz) are applied systematically during resting state through DBS electrodes. Using the collected data, Anusha will characterize behaviorally defined cognitive control subnetworks in participants with TRD, and explore the effect of low-frequency oscillations that are known to be associated with conflict processing and cognitive control in healthy subjects. She will expand this work to perform functional connectivity analysis during the behavioral task. Anusha will also apply these techniques for analysis of data collected in stimulation experiments during resting state. Understanding cognitive control is imperative to not only improving our understanding of cognitive dysfunction in depression, but is a step towards individualizing and optimizing therapy around electrophysiological markers associated with behavioral impairment in neuropsychiatric disorders, in lieu of or in addition to clinical evaluation of symptoms. In the K00 phase, Anusha will extend her research to more granular circuit dissection using rodent models of psychiatric disease, and leverage her doctoral training in statistical and computational neuroscience to analyze data from such studies, while continuing to perform research in human subjects to study cognitive control. The proposed training during the F99 and K00 phases will ensure multidisciplinary training to reach her career goal as an independent research investigator focused on using a multidisciplinary approach to help achieve a comprehensive understanding of cognitive dysfunction in neuropsychiatric disorders.