Limbic pallidal circuits linked to apathy in Parkinson’s disease during subthalamic deep brain stimulation
边缘苍白球回路与丘脑深部脑刺激期间帕金森病的冷漠有关
基本信息
- 批准号:10592985
- 负责人:
- 金额:$ 43.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAffectAmygdaloid structureAnatomyBehaviorBehavior assessmentBehavioralBiological MarkersBrainBrain DiseasesBrain regionChronicClinicalCognitionCognitiveDeep Brain StimulationDevelopmentDisease modelElectric StimulationElectricityElectrodesElectrophysiology (science)FDA approvedFOS geneFundingFutureGlobus PallidusGlutamatesGoalsGrantGrowthHumanHyperactivityImpairmentImplanted ElectrodesInjectionsInvestigationKnowledgeLaboratoriesLeadLesionLightLinkMaintenanceMeasuresMediatingModelingModernizationMood DisordersMoodsMotivationMotorMovementNeurodegenerative DisordersNeuronal PlasticityNeuronsOpsinOutcomeOutcome StudyOutputParkinson DiseasePathogenicityPatientsPharmaceutical PreparationsProtocols documentationQuality of lifeRattusResearchResearch Project GrantsRodentRoleSTN stimulationSleepStructureStructure of subthalamic nucleusSymptomsTechniquesTechnologyTestingThinkingTimeTissuesUnited States National Institutes of HealthWorkbehavior testclinical careclinically relevantdesigneffective therapyimprovedimproved outcomeinnovationmotor behaviormotor symptomnon-motor symptomnoveloptogeneticsparkinsonian rodentprogramsside effecttransmission process
项目摘要
PROJECT SUMMARY/ABSTARCT
Parkinson’s disease (PD) is a neurodegenerative disease that presents both motor and non-motor
disturbances. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficacious in treating cardinal
motor features of PD. In contrast, non-motor symptoms typically do not improve and may even worsen with
DBS. Electrode placement in the STN is targeted to the motor subregion, but off-target activation of limbic and
associative circuits, and the resultant adaptations in circuit activity after DBS, likely lead to non-motor adverse
effects. The long-term goals of our Research Program are to i) identify biomarkers that can be used to predict
when DBS may result in disorders of mood and cognition, and ii) improve DBS stimulation paradigms to reduce
non-motor adverse effects. Apathy is a prevalent non-motor symptom of PD that frequently worsens after STN-
DBS to significantly impair quality of life. Thus, the current R21 Study will focus on apathy. Accordingly, the
overall objective of the Study is to determine the mechanism(s) and anatomical substrate(s) of apathy after
STN-DBS in a rat model of PD. Highly selective optogenetic stimulation approaches will be used to isolate the
contribution of STN outputs known to regulate apathy; i.e., STN glutamatergic efferents to the ventral pallidum
(VP). The Study central hypotheses are that i) apathy-like behaviors during STN-DBS treatments in a rat model
of PD reflect neuroplasticity in downstream limbic structures that regulate motivation, and ii) activation of STN-
VP glutamatergic efferents in a rat model of PD is sufficient to mediate apathy-like behaviors and circuit
changes. Specific Aim 1 will assess the temporal development and persistence of apathy-like and motor
behaviors in chronic optogenetic STN-DBS. Specific Aim 2 will assess whether selective activation of
glutamatergic STN-VP projections during STN-DBS is sufficient to produce apathy-like behaviors.
Comprehensive behavioral assessments will include PD-like motor and apathy profiles. Circuit consequences
will be revealed by measuring post mortem markers of neuronal activity. The proposed research is innovative
as these studies will combine established techniques to decipher a currently undescribed pathogenic circuit
that likely underpins non-motor behaviors associated with STN-DBS. The research is significant for outcomes
are expected to i) determine the role of specific STN glutamatergic projections to the VP in PD-like behaviors,
ii) indicate the potential of STN-VP circuits to serve as biomarkers for apathy during DBS, and iii) form the
basis for future NIH-funded projects that will lead to the design of novel DBS protocols that improve outcomes.
项目概要/摘要
帕金森病(Parkinson's disease,PD)是一种神经退行性疾病,表现为运动性和非运动性
干扰.丘脑底核深部脑刺激术(DBS)是治疗心脏病的有效方法。
PD的运动特征。相比之下,非运动症状通常不会改善,甚至可能恶化,
DBS电极放置在小脑的运动亚区,但脱靶激活边缘和
关联电路,以及DBS后电路活动的适应性变化,可能导致非运动不良反应。
方面的影响.我们的研究计划的长期目标是i)确定可用于预测的生物标志物
当DBS可能导致情绪和认知障碍时,以及ii)改善DBS刺激范例以减少
非运动副作用。冷漠是PD的一种普遍的非运动症状,经常在治疗后出现。
DBS严重损害生活质量。因此,目前的R21研究将集中在冷漠。因此
研究的总体目标是确定冷漠的机制和解剖学基础,
PD大鼠模型中的STN-DBS。高选择性光遗传学刺激方法将用于分离
已知调节冷漠的情感输出的贡献;即,腹侧苍白球的多巴胺能传出神经
(副总统)。本研究的中心假设是:i)在大鼠模型中,STN-DBS治疗期间的冷漠样行为
反映了下游边缘结构的神经可塑性,调节动机,和ii)激活的神经元,
在PD大鼠模型中,VP能传出足以介导冷漠样行为和回路
变化具体目标1将评估类失语症和运动性失语症的时间发展和持续性。
慢性光遗传STN-DBS中的行为。具体目标2将评估是否选择性激活
在STN-DBS期间,脑电刺激性STN-VP投射足以产生冷漠样行为。
综合行为评估将包括PD样运动和冷漠特征。电路后果
将通过测量死后神经元活动的标记来揭示。该研究具有创新性
因为这些研究将结合联合收割机已建立的技术来破译一种目前尚未描述的致病回路
这可能是与STN-DBS相关的非运动行为的基础。该研究对结果具有重要意义
i)确定特定的神经元投射到VP在PD样行为中的作用,
ii)表明STN-VP回路作为DBS期间冷漠的生物标志物的潜力,以及iii)形成
为未来NIH资助的项目奠定了基础,这些项目将导致设计新的DBS协议,以改善结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alana E. Kirby其他文献
Cognitive Decline in a Case of Poorly Controlled Bipolar Disorder: A Diagnostic and Therapeutic Challenge.
控制不良的双相情感障碍病例中的认知下降:诊断和治疗的挑战。
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:3.8
- 作者:
R. Thom;Polina Teslyar;Alana E. Kirby;T. Fong;R. Friedman;R. Brady;K. Bloomingdale - 通讯作者:
K. Bloomingdale
TABLE 1. CHARACTERISTICS OF PATIENTS WITH ABRUPT ONSET TIC-LIKE MOVEMENTS VS TIC-LIKE MOVEMENTS OF TIKTOK “TIC-” RELATED CONTENT
表 1. 突发性抽动样运动患者的特征与 TikTok“TIC-”相关内容的抽动样运动患者的特征
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
C. Olvera;Alana E. Kirby - 通讯作者:
Alana E. Kirby
Transmission of Temporal Information Through the Auditory Pathway Measured with Cochlear-Implant Stimulation
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
Alana E. Kirby - 通讯作者:
Alana E. Kirby
Level of Satisfaction with the Intervention
对干预的满意度
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
R. Thom;Polina Teslyar;Alana E. Kirby;T. Fong;R. Friedman;R. Brady;K. Bloomingdale - 通讯作者:
K. Bloomingdale
Alana E. Kirby的其他文献
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