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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要自闭症谱系障碍 (ASD) 是一种普遍存在的神经发育疾病，其特征是社交能力缺陷沟通以及重复和僵化行为的存在。目前生物学上很少有自闭症谱系障碍（ASD）的针对性治疗方案，部分原因是其潜在的神经生物学尚不清楚。一一直与自闭症谱系障碍相关的大脑区域是小脑。然而，尽管广泛虽然自闭症谱系障碍（ASD）存在小脑功能障碍的证据，但小脑对自闭症谱系障碍（ASD）的确切贡献仍不清楚。小脑与大脑的其他区域有着丰富的相互联系，这些区域支持运动、认知和情感功能，我们之前的工作已经在小脑内建立了功能分区，为理解小脑内的区域差异如何发挥作用提供了一个有用的框架到自闭症谱系障碍。具体来说，两个小脑亚区域在自闭症中表现出结构和功能差异：右小脑小叶 VII (RVII) 和小脑后蚓部。基于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。我们的之前的研究表明，RVII 中的灰质与 ASD 中的社交和沟通得分相关，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交任务表现的影响，以及大脑激活模式。我们发现小脑神经调节改变了社交学习的表现任务和改变与自闭症相关的大脑回路的功能连接。此外，我们的合作者还展示了 RVII 抑制会导致小鼠的社交缺陷，而 RVII 兴奋则可以挽救小鼠模型中的社交缺陷自闭症。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，小脑内的最佳调节目标尚未确定，我们假设这可能会因特定症状而有所不同。在这里，我们将小脑神经调节与功能神经影像来检验我们的假设，即针对 RVII 的神经调节将选择性地改变社交支持社会行为的学习和神经网络，同时针对后蚓部的神经调节将影响认知灵活性和参与注意力分配的神经网络。神经正常的成年人患有自闭症谱系障碍的成年人将在兴奋性、抑制性或假性刺激后完成社交和认知灵活性任务受试者内设计中的神经调节。一些参与者将接受针对 RVII 的神经调节其他人将接受针对后蚓部的神经调节。我们将获得功能性脑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理解其机制非侵入性调节可能会影响临床疾病的行为。这项工作将进一步有助于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评估小脑神经调节的临床转化潜力的概念数据。