Abnormal Functional Connectivity in Brain Regions of Cerebellar Mutism Syndrome Patients After Chemotherapy
Pediatric brainstem glioblastoma is the most common malignant brain tumor in children, and surgical resection is the primary treatment method. However, posterior fossa surgery may lead to a complication known as “Pediatric Cerebellar Mutism Syndrome (CMS).” CMS is primarily characterized by temporary mutism, motor disorders, and emotional abnormalities, which have a severe impact on the affected children. Previous studies suggested that CMS may result from the disruption of connections between the cerebellum and other brain regions, but its precise pathophysiological mechanism remains unclear.
Source of the Paper: This study was conducted by Samuel S. McAfee et al. from St. Jude Children’s Research Hospital in the United States and published in the journal Neuro-Oncology in 2024. The researchers employed functional magnetic resonance imaging (fMRI) to analyze the functional brain connectivity in 70 children with brainstem glioblastoma after surgery, aiming to investigate the mechanism underlying CMS.
Research Process:
a) The study subjects were 70 children with brainstem glioblastoma, divided into a CMS group (32 children) and an asymptomatic control group (38 children). All patients underwent fMRI scans immediately after surgery.
b) The researchers used independent component analysis (ICA) to extract 33 functional nodes from the whole-brain fMRI data, including the cerebellar cortex, thalamus, red nucleus, and other brain regions. By calculating the temporal correlation between nodes, the strength of functional connectivity between them could be assessed.
c) Using structural images, the researchers mapped the surgical resection area for each patient and calculated the extent of damage to the superior cerebellar peduncle (SCP), which is an important pathway connecting the cerebellar cortex to the cerebral cortex.
Main Results:
Compared to the control group, CMS patients exhibited significantly enhanced functional connectivity between the right cerebellar cortex and the left cerebral cortex, especially between the right cerebellar cortex and the left ventromedial prefrontal cortex (VM-PFC).
The strength of the functional connectivity between the right cerebellar cortex and the VM-PFC was unrelated to the extent of SCP damage, suggesting that this abnormal connectivity may arise from increased input to the cerebellum from the VM-PFC, rather than damage to the cerebellar output pathway. In contrast, the connectivity between the cerebellum and language-related areas, such as Broca’s area, depended on the integrity of the SCP.
In CMS patients, the connectivity between the posterior cerebellar cortex and the ipsilateral cerebellar nuclei was altered, with some regions exhibiting abnormal anti-correlations, suggesting abnormal signal transmission within the cerebellum.
Research Significance:
Scientific Significance: This study is the first to reveal functional connectivity abnormalities between the cerebellum and the cerebrum, as well as within the cerebellum itself, in living CMS patients, providing new clues for elucidating the disease mechanism.
Clinical Significance: The observed abnormal functional connectivity between the cerebellum and the VM-PFC may be related to the emotional control deficits and motor learning impairments commonly seen in CMS patients. Additionally, the aberrant connectivity between the cerebellar cortex and nuclei could potentially impact cognitive function. These findings help explain the complexity of clinical symptoms in CMS and provide insights for future targeted therapies.
Research Highlights:
This study is the first to discover functional abnormalities in the cerebellar input pathway in CMS, proposing a novel pathophysiological explanation.
The use of a data-driven method to extract functional nodes ensures the applicability of the analysis approach to developmental and pathological states.
By incorporating pathological imaging analysis, the study distinguishes the relationship between functional connectivity abnormalities and damage to the cerebellar output pathway.
This research provides a new perspective for unraveling the long-standing neurological mystery of CMS, suggesting that CMS may originate from a cascading reaction involving the loss of normal cerebellar input and aberrant intrinsic neuronal activity, leading to disrupted brain function. Future studies investigating the role of the cerebellum-VM-PFC circuit in emotional processing and motor control may uncover new therapeutic targets for CMS.