Secondary cerebro-cerebellar and intra-cerebellar dysfunction in cerebellar mutism syndrome

Abstract

Background: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology.

Methods: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury.

Results: CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere.

Conclusions: The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal gray and other critical midbrain targets.

Keywords: Cerebellar mutism syndrome; cerebellum; functional magnetic resonance imaging; medulloblastoma; posterior fossa syndrome.

Figure 1.

Summary of data used for connectivity analyses. (A) Illustration of diagnostic makeup and exclusion processes for participants enrolled in the study. (B) Ages of participants within the test and control group of the study. After exclusions, there was no age difference between the 2 groups. (C) Functional nodes used in connectivity analyses are projected onto a standard 3D SPM 152 brain. Only projections onto the left cerebral/subcortical hemisphere are shown; node locations on the right side were comparable.

Figure 2.

Cerebellar connectivity. Left: Cerebellar cortical connectivity with functional nodes throughout the brain. Colors indicate the putative resting state network association of the node. Activity of the VM-PFC has the strongest positive correlation with the cerebellar cortex. Right: Mean cerebello-cerebral connectivity in asymptomatic MB and cerebellar mutism syndrome (CMS) participants (not inclusive of Putamen, PAG, RN, and Dentate nodes). Connectivity was significantly increased between the left cerebral cortex and the right cerebellar cortex in participants with CMS.

Figure 3.

Evaluation of Cortico-cerebello-cortical loop involving VM-PFC, and dependence of cerebellar outflow on cerebello-cortical functional connectivity. (A) Violin plots showing functional connectivity between VM-PFC and functional nodes along its putative cortico-cerebellar loop. Heightened influence of VM-PFC in the cerebellar cortex is not conveyed to the right dentate nucleus or the left red nucleus. (B): Heat map of surgical resections in study participants with cerebellar mutism syndrome. As in more focused studies of this cohort, complete transection of SCP or dentate nucleus was not the norm. (C) Analysis of the relationship between right SCP integrity (Per T1 imaging) and right cerebellar connectivity with nodes of interest. Damage of 0 indicates no detectable injury while 1 indicates complete transection. Notably, VM-PFC connectivity with the cerebellum does not show a dependence on SCP integrity, which might indicate a directional influence predominantly from the VM-PFC to the right cerebellar hemisphere. Other nodes implicated in speech disruption in a prior study did show varying degrees of dependence on SCP integrity, suggesting a directionality from cerebellum to cerebrum, based on dependence on cerebellar output.

Figure 4.

Functional changes within the cerebellum. (A) Connectivity of cerebellar cortical clusters with the ipsilateral dentate nucleus. Areas that exhibit a greater functional association with ipsilateral dentate in asymptomatic patients are largely unaffected, while areas with a lesser connection have a diminished or inverse relationship. Colors indicate the putative resting state network association of the cluster, based on a canonical parcellation. (B) Flattened statistical map of the cerebellar cortex showing areas with significant changes in cortico-dentato connectivity.