A Neural Basis for Cognitive Decline Following Deep Brain Stimulation

深部脑刺激后认知能力下降的神经基础

• 批准号: 10642226
• 负责人: Daniel Lench
• 金额: $ 12.74万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642226
• 关键词: Acceleration; Acetylcholine; Affect; Anatomy; Anterior; Attention; Attentional deficit; Award; Basal Nucleus of Meynert; Behavioral; Brain; Brain region; Cerebral cortex; Clinical; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Deep Brain Stimulation; Diffusion; Diffusion Magnetic Resonance Imaging; Dopamine; Dorsal; Dose; Dyskinetic syndrome; Evaluation; Faculty; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Image; Impaired cognition; Individual; Interruption; K-Series Research Career Programs; Knowledge; Language; Language Disorders; Lead; Lesion; Measures; Medial; Memory; Mentors; Mission; Motor; Movement Disorders; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurobehavioral Manifestations; Neurocognitive; Neurologist; Neuropsychology; Neurotransmitters; Operative Surgical Procedures; Parkinson Disease; Participant; Pathway interactions; Patient Selection; Patients; Phase; Positioning Attribute; Postoperative Period; Prefrontal Cortex; Quality of life; Research; STN stimulation; Scanning; Schedule; Secure; Source; Specificity; Structure; Structure of subthalamic nucleus; System; Tissues; Training; United States National Institutes of Health; Visuospatial; career; cholinergic; cingulate cortex; cognitive performance; cognitive reserve; disability; effective therapy; executive function; experience; illness length; imaging study; improved; motor symptom; nerve supply; nervous system disorder; neural; neural network; neurocognitive test; neuroimaging marker; neuroregulation; patient subsets; programs; recruit; side effect; skills; tenure track; tool

Project Summary/Abstract Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) is an established therapy for PD patients with motor fluctuations and dyskinesias. While STN DBS is an effective treatment for motor symptoms, it can produce unintended side effects cognition including executive function, language and attention deficits which affect quality of life and independence. Developing an individualized STN DBS approach which optimizes patient selection prior to surgery and enhances specificity when targeting neural networks is significant because it has the potential to reduce DBS induced cognitive decline. The research proposed in this K99/R00 Pathway to Independence Award will lay the groundwork needed to establish this approach by determining 1) how limited cognitive reserve prior to surgery and 2) how direct DBS interference with cognitive networks contribute to cognitive decline. Cholinergic and dopaminergic network hubs (i.e., the Nucleus Basalis of Meynert; NBM, and striatum) support cognition, however, these regions degenerate in PD and may be indirectly modulated by STN stimulation. Thus, the central objective of this proposal is to determine how vulnerability (K99) and the direct modulation (R00) of the NBM, and striatal networks contribute to cognitive decline in individuals with STN DBS. NBM/striatal vulnerability will be measured using diffusion kurtosis imaging (DKI) which reflects microstructural changes associated with the progressive degeneration of neuronal tissue. Network interference will be measured by assessing the change in NBM/striatal connectivity using combined DBS-fMRI which allows functional MRI data to be collected while simultaneously cycling stimulation. The central hypothesis of this proposal is that pre-surgical microstructural integrity (K99) and DBS induced interference (R00) of the NBM, and striatal networks will be associated with greater cognitive decline. Preliminarily data demonstrates that reduced mean kurtosis of diffusion within the NBM and striatum are associated with reduced executive function and language deficits in those with PD. In the 2-year mentored K99 phase of this proposal, I will establish the relationship between NBM/striatal microstructure and cognition (Aim 1) and cognitive decline 1-year following STN-DBS surgery (Aim 2). To accomplish these aims I will collect DKI and longitudinal neurocognitive data from 50 participants with PD planning to undergo clinical STN-DBS treatment. Additionally, I will receive training in DBS as a research tool, neurocognitive testing, combined DBS-fMRI and DKI analysis/interpretation. This will be facilitated by my mentoring team which includes DKI co-developer Dr. Jens Jensen (Primary Mentor) and DBS neurologist Dr. Gonzalo Revuelta (Co-mentor). After securing a tenure track faculty position, I will transition into the R00 phase of the award to investigate the relationship between STN-DBS modulation of the NBM/striatal networks and cognitive decline (Aim 3). This independent R00 phase will build upon my technical training and mentoring skills established during the K99 phase. Ultimately, this award will generate the pilot data necessary to apply for a R01 and establish a research program in individualized neuromodulation therapies for movement disorders.

项目摘要/摘要 以丘脑底核(STN)为靶点的深部脑刺激(DBS)是帕金森病的一种公认的治疗方法 有运动波动和运动障碍的患者。虽然STN DBS是治疗运动症状的有效方法， 它会产生意想不到的副作用认知，包括执行功能、语言和注意力缺陷 这会影响生活质量和独立性。开发个性化的STN DBS方法，优化 在手术前选择患者，并在定位神经网络时提高特异性是重要的，因为 它有可能减少DBS引起的认知功能下降。K99/R00途径中提出的研究 独立奖将为建立这种方法奠定必要的基础，方法是确定1)如何限制 手术前的认知储备和2)DBS对认知网络的直接干预如何有助于 认知能力下降。胆碱能和多巴胺能网络中枢(即Meynert基底核、NBM和 纹状体)支持认知，然而，这些区域在帕金森病中退化，并可能受到STN间接调节 刺激。因此，本提案的中心目标是确定脆弱性(K99)和直接 NBM的调制(R00)和纹状体网络导致STN DBS患者的认知能力下降。 NBM/纹状体脆弱性将使用反映微结构的扩散峰度成像(DKI)进行测量 与神经元组织进行性退化相关的变化。将测量网络干扰 通过使用联合DBS-fMRI来评估NBM/纹状体连接性的变化，这使得功能MRI能够 在骑行刺激的同时收集数据。这项提议的中心假设是 术前微结构完整性(K99)和DBS诱导的NBM和纹状体网络的干扰(R00) 将与更大的认知衰退有关。数据初步表明，折合后的平均峰度 NBM和纹状体内的扩散与执行功能降低和语言障碍有关 那些警局的人。在此建议书的两年指导K99阶段中，我将在 NBM/纹状体微结构和认知(目标1)与STN-DBS手术后1年认知功能下降(目标1 2)。为了实现这些目标，我将收集50名帕金森病患者的DKI和纵向神经认知数据 计划进行临床STN-DBS治疗。此外，我将接受星展银行作为研究工具的培训， 神经认知测试，结合DBS-fMRI和DKI分析/解释。这将由我的 指导团队包括DKI联合开发人员Jens Jensen博士(主要导师)和星展银行神经科医生Dr。 Gonzalo Revuelta(共同导师)。在获得终身教职后，我将过渡到R00阶段 研究STN-DBS对NBM/纹状体网络的调制与 认知衰退(目标3)。这个独立的R00阶段将建立在我的技术培训和指导技能的基础上 在K99阶段建立。最终，这项奖励将产生申请R01所需的试点数据 并建立针对运动障碍的个体化神经调节疗法的研究计划。