Cerebellum and autism: Regional specialization for social and executive functions

小脑和自闭症：社会和执行功能的区域专业化

• 批准号: 10359882
• 负责人: Kathleen C Gunthert
• 金额: $ 44.52万
• 依托单位: AMERICAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359882
• 关键词: Adult; Affective; American; Anatomy; Attention; Award; Behavior; Brain; Brain imaging; Brain region; Cerebellar Diseases; Cerebellar vermis structure; Cerebellum; Cerebrum; Clinic; Clinical; Cognitive; Data; Development; Disease; Dissociation; Etiology; Functional Imaging; Future; Goals; Human; International; Learning; Lobule; Location; Longevity; Medial; Methods; Mind; Modeling; Modification; Motor; Mus; Neurobiology; Participant; Pattern; Performance; Prefrontal Cortex; Publications; Regulation; Reporting; Research; Role; Route; Social Behavior; Social Functioning; Social support; Students; Symptoms; Task Performances; Testing; Therapeutic; Translating; Translations; Universities; Work; adult with autism spectrum disorder; attentional modulation; autism spectrum disorder; autistic children; base; cognitive function; cohort; design; executive function; experience; flexibility; graduate student; gray matter; improved; information model; interest; learning network; mouse model; neural network; neuroimaging; neuromechanism; neuroregulation; novel; novel therapeutics; regional difference; relating to nervous system; repetitive behavior; social; social cognition; social communication; social deficits; social learning; symposium; targeted treatment; theories; translational potential; undergraduate student

PROJECT SUMMARY Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition characterized by deficits in social communication and the presence of repetitive and inflexible behaviors. There are currently few biologically- targeted treatment options for ASD, in part because the underlying neurobiology is not well understood. One region of the brain that is consistently implicated in ASD is the cerebellum. However, despite extensive evidence of cerebellar dysfunction in ASD, the exact contribution of the cerebellum to ASD remains unclear. The cerebellum is richly interconnected with other regions of the brain that support motor, cognitive, and affective functions, and our previous work has established functional subregions within the cerebellum, providing a useful framework for understanding how regional differences within the cerebellum might contribute to ASD. Specifically, two cerebellar subregions show structural and functional differences in autism: right cerebellar lobule VII (RVII) and the posterior cerebellar vermis. Based on the different anatomical connectivity of these regions, we hypothesize that RVII and the posterior vermis regulate different core deficits in ASD. Our previous work has shown that grey matter in RVII correlates with social and communication scores in ASD, whereas the volume of the posterior vermis is associated with repetitive behaviors. In a previous R15 award, we determined the impact of non-invasive neuromodulation of cerebellar RVII on social task performance and brain activation patterns. We found that cerebellar neuromodulation changed performance on a social learning task and altered functional connectivity in brain circuits relevant to autism. Further, our collaborators showed that RVII inhibition led to social deficits in mice, while RVII excitation rescued social deficits in a mouse model of autism. These findings suggest that cerebellar neuromodulation could be a novel therapeutic option in ASD. However, the optimal modulation target within the cerebellum has yet to be established, and we hypothesize that this could differ in a symptom-specific way. Here we will combine cerebellar neuromodulation with functional neuroimaging to test our hypothesis that neuromodulation targeting RVII will selectively alter social learning and neural networks supporting social behavior, while neuromodulation targeting the posterior vermis will impact cognitive flexibility and neural networks involved in the allocation of attention. Neurotypical adults and adults with ASD will complete social and cognitive flexibility tasks after excitatory, inhibitory, or sham neuromodulation in a within-subjects design. Some participants will receive neuromodulation targeting RVII and others will receive neuromodulation targeting the posterior vermis. We will acquire functional brain imaging data during and after cerebellar neuromodulation, which will allow us to better understand the mechanisms by which non-invasive modulation might impact behavior in clinical disorders. This work will further contribute to our understanding of the neurobiology of autism, with the broader significance of generating critical proof-of- concept data to evaluate the clinical translational potential of cerebellar neuromodulation.

项目摘要 自闭症谱系障碍（ASD）是一种普遍存在的神经发育状况，其特征在于社交能力的缺陷。 沟通和重复和不灵活的行为的存在。在生物学上，目前很少有- ASD的靶向治疗选择，部分原因是对潜在的神经生物学还没有很好的了解。一 与ASD相关的大脑区域是小脑。尽管广泛 尽管ASD患者小脑功能障碍的证据很多，但小脑对ASD的确切作用仍不清楚。 小脑与大脑的其他区域密切相关，这些区域支持运动，认知和运动。 情感功能，我们以前的工作已经在小脑内建立了功能分区， 这为理解小脑内的区域差异如何影响大脑提供了一个有用的框架， 到ASD。具体来说，两个小脑亚区显示自闭症的结构和功能差异：对 小脑小叶VII（RVII）和小脑后蚓部。根据不同的解剖连接 在这些区域中，我们假设RVII和后蚓部调节ASD中不同的核心缺陷。我们 先前的工作已经表明RVII中的灰质与ASD中的社交和交流分数相关， 而后蚓部的体积与重复行为有关。在之前的R15奖项中， 我们确定了小脑RVII的非侵入性神经调节对社会任务表现的影响， 大脑激活模式我们发现，小脑神经调节改变了社会学习的表现， 与自闭症相关的脑回路中的任务和改变的功能连接。此外，我们的合作者表明， RVII抑制导致小鼠的社会缺陷，而RVII兴奋则挽救了小鼠模型中的社会缺陷。 自闭症的症状这些发现表明小脑神经调节可能是ASD的一种新的治疗选择。 然而，小脑内的最佳调节靶点尚未确定，我们假设 这可能会以一种特定的方式有所不同。在这里，我们将联合收割机小脑神经调节与 功能性神经影像学来验证我们的假设，即以RVII为靶点的神经调节将选择性地改变社交功能。 学习和神经网络支持社会行为，而神经调节针对后蚓部 将影响认知灵活性和参与注意力分配的神经网络。神经质的成年人 而患有ASD的成年人将在兴奋性、抑制性或假刺激后完成社交和认知灵活性任务。 神经调节在受试者内设计。一些参与者将接受针对RVII的神经调节 而其他人将接受针对后蚓部的神经调节。我们将获取大脑功能成像 小脑神经调节期间和之后的数据，这将使我们能够更好地了解机制， 这种非侵入性调节可能会影响临床疾病的行为。这项工作将进一步促进 我们对自闭症神经生物学的理解，具有产生关键证据的更广泛意义， 概念数据，以评估小脑神经调节的临床转化潜力。