Postoperative cerebellar mutism syndrome is an acquired autism-like network disturbance

Abstract

Background: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumor surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates.

Methods: In this study, we analyzed postoperative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and pediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n = 427).

Results: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the pediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to the prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviors.

Conclusions: Our findings indicate that CMS-associated lesions may result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

Keywords: PFS; autism spectrum disorder; cerebellar cognitive affective syndrome; cerebellar mutism; connectomics; medulloblastoma; posterior fossa syndrome; posterior fossa tumor.

Figure 1.

Lesion localization. (A) Segmentation and registration of postoperative cerebellar lesions to MNI space. (B) Lesion voxels are common in children who developed CMS. The map on the left denotes the regional differences between CMS+ Lesions and CMS– lesions, with red-yellow indicating a higher presence of CMS+ lesions and blue indicating a higher presence of CMS– lesions. CMS+ lesions had greater odds of involving the vermis and paramidline cerebellar lobules. (C) CMS+ lesions showed a higher degree of overlap with each other than CMS– lesions

Figure 2.

Connectivity of CMS+ lesions in adults and children. (A) Regions of the brain correlating to the location of the cerebellar lesion were seeded in adult and pediatric connectomes. In children, prefrontal connectivity was predominant, whereas parietal connectivity was predominant in adults. (B) CMS– regions were preferentially connected to widespread cortical regions related to thalamic and limbic brain regions

Figure 3.

Connectivity of CMS+ lesions in children with ASD and matched controls. (A) Children with ASD show weaker connectivity from the regions of the brain involved by the CMS+ Lesion volume to the anterior and posterior cingulate cortices. (B) With increasing age, there is stronger connectivity of the CMS+ Lesion volume to the brainstem, including the red nucleus, bilateral thalami, PCC and the precuneus. Increasing age is also associated with decreasing connectivity to widespread cortical areas including the inferior frontal lobe and motor areas

Figure 4.

Associations between ASD-related scores and CMS+ lesional volume connectivity. (A–C) Whole-brain voxel-wise connectivity of the CMS+ lesion volume is associated with communication, social deficits and repetitive behaviors in individuals with ASD. communication (A) and social deficits (B) show a decrease in connectivity in association with greater deficits whereas repetitive behaviors (C) show an increase in connectivity. (D) Multidimensional associations between ASD scores and imaging data reveal a significant latent variable with associations between communication deficits and CMS+ lesion volume connectivity to the prefrontal and parietal cortices.