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

Hrishikesh Suresh; Benjamin R Morgan; Karim Mithani; Nebras M Warsi; Han Yan; Jürgen Germann; Alexandre Boutet; Aaron Loh; Flavia Venetucci Gouveia; Julia Young; Jennifer Quon; Felipe Morgado; Jason Lerch; Andres M Lozano; Bassam Al-Fatly; Andrea Kühn; Suzanne Laughlin; Michael C Dewan; Donald Mabbot; Carolina Gorodetsky; Ute Bartels; Annie Huang; Uri Tabori; James T Rutka; James M Drake; Abhaya V Kulkarni; Peter Dirks; Michael D Taylor; Vijay Ramaswamy; George M Ibrahim

doi:10.1093/neuonc/noad230

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

Neuro Oncol. 2023 Dec 11:noad230. doi: 10.1093/neuonc/noad230. Online ahead of print.

Authors

Hrishikesh Suresh^{1

2

3}, Benjamin R Morgan⁴, Karim Mithani³, Nebras M Warsi^{1

2

3}, Han Yan^{2

3}, Jürgen Germann⁴, Alexandre Boutet^{4

5}, Aaron Loh³, Flavia Venetucci Gouveia², Julia Young⁶, Jennifer Quon³, Felipe Morgado⁷, Jason Lerch⁸, Andres M Lozano^{9

10}, Bassam Al-Fatly¹¹, Andrea Kühn^{11

12}, Suzanne Laughlin⁴, Michael C Dewan¹³, Donald Mabbot¹⁴, Carolina Gorodetsky¹⁵, Ute Bartels¹⁶, Annie Huang¹⁶, Uri Tabori¹⁶, James T Rutka³, James M Drake³, Abhaya V Kulkarni³, Peter Dirks³, Michael D Taylor³, Vijay Ramaswamy¹⁶, George M Ibrahim^{1

2

3

10}

Affiliations

¹ Institute of Biomedical Engineering, University of Toronto, Toronto ON, Canada.
² Program in Neuroscience and Mental Health, The Hospital for Sick Children Research Institute, Toronto ON, Canada.
³ Division of Neurosurgery, The Hospital for Sick Children, Department of Surgery, University of Toronto, Toronto ON, Canada.
⁴ Department of Medical Imaging, University of Toronto, Toronto, Canada.
⁵ Joint Department of Medical Imaging, University of Toronto, Toronto, Canada.
⁶ Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Temerty Faculty of Medicine, University of Toronto, Toronto ON, Canada.
⁸ Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom.
⁹ Division of Neurosurgery, University Health Network, Department of Surgery, University of Toronto, Toronto ON Canada.
¹⁰ Institute of Medical Science, University of Toronto, Toronto ON Canada.
¹¹ Department of Neurology and Experimental Neurology, Movement Disorders and Neuromodulation Unit, Charité, Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health.
¹² Exzellenzcluster NeuroCure, Charité, Universitätsmedizin Berlin.
¹³ Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN USA.
¹⁴ Department of Psychology, University of Toronto, Toronto ON, Canada.
¹⁵ Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto ON, Canada.
¹⁶ Division of Neuro-Oncology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto ON, Canada.

PMID: 38079480
DOI: 10.1093/neuonc/noad230

Abstract

Background: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour 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 post-operative 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 paediatric 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 paediatric 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 prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours.

Conclusions: Our findings indicate that CMS-associated lesions 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: Autism spectrum disorder; Cerebellar cognitive affective syndrome; Cerebellar mutism; Connectomics; PFS; Posterior fossa syndrome; medulloblastoma; posterior fossa tumour.