Cerebellum and autism: Regional specialization for social and executive functions

项目总结 自闭症谱系障碍(Asd)是一种以社交缺陷为特征的神经发育疾病。 交流以及存在重复和僵化的行为。目前很少有生物学上的- ASD的靶向治疗选择，部分原因是潜在的神经生物学还没有被很好地理解。一 一直与ASD有关的大脑区域是小脑。然而，尽管广泛的 关于ASD小脑功能障碍的证据，小脑在ASD中的确切作用尚不清楚。 小脑与大脑的其他区域紧密相连，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亚区， 为理解小脑内的区域差异可能起到的作用提供了一个有用的框架 致ASD。具体地说，自闭症的两个小脑亚区显示出结构和功能上的差异 小脑小叶VII(Rvii)和小脑后部蠕虫。基于不同的解剖连通性 在这些区域中，我们假设RVII和后鞭毛调节ASD中不同的核心缺陷。我们的 先前的研究表明，RVII中的灰质与ASD的社交和沟通分数相关， 而后部蠕虫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绩效和 大脑的激活模式。我们发现，小脑神经调节改变了社交学习的表现 任务和与自闭症相关的大脑回路中功能连接的改变。此外，我们的合作者还展示了 抑制RVII导致了小鼠的社会缺陷，而RVII的兴奋挽救了小鼠模型中的社会缺陷 患有自闭症。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，小脑内的最佳调制靶点尚未确定，我们假设 这可能会在特定症状的方式上有所不同。在这里，我们将结合小脑神经调节和 功能神经成像来测试我们的假设，即针对RVII的神经调节将选择性地改变社会 学习和神经网络支持社会行为，而神经调节针对后部蠕虫 会影响认知灵活性和神经网络参与注意力的分配。神经型成人 患有自闭症的成年人在兴奋、抑制或伪装后会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部蠕虫的神经调节。我们将获得功能性脑成像 在小脑神经调节期间和之后的数据，这将使我们能够更好地通过 哪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 我们对自闭症的神经生物学的理解，以及产生关键证据的更广泛的意义- 概念数据，以评估小脑神经调节的临床翻译潜力。

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.