Sensory and motor electrophysiological mapping of the cerebellum in humans

Cerebellar damage during posterior fossa surgery in children can lead to ataxia and risk of cerebellar mutism syndrome. Compartmentalisation of sensorimotor and cognitive functions within the cerebellum have been demonstrated in animal electrophysiology and human imaging studies. Electrophysiological monitoring was carried out under general anaesthesia to assess the limb sensorimotor representation within the human cerebellum for assessment of neurophysiological integrity to reduce the incidence of surgical morbidities. Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. Sensory evoked field potentials were recorded in response to mapping (n = 8) to electrical stimulation of limb nerves or muscles. For motor mapping (n = 5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles. Sensory evoked potentials were found in two patients (25%). Responses were located on the surface of the right inferior posterior cerebellum to stimulation of the right leg in one patient, and on the left inferior posterior lobe in another patient to stimulation of left forearm. No evoked EMG responses were found for the motor mapping. The present study identifies challenges with using neurophysiological methods to map functional organization within the human cerebellum and considers ways to improve success.

Functional Subdivisions of the Cerebellum in Naturalistic Paradigm Functional Magnetic Resonance Imaging

Compelling evidence has suggested that the human cerebellum is engaged in a wide range of cognitive tasks besides traditional opinions of motor control, and it is organized into a set of distinct functional subregions. The existing model-driven cerebellum parcellations through resting-state functional MRI (rsfMRI) and task-fMRI are relatively coarse, introducing challenges in resolving the functions of the cerebellum especially when the brain is exposed to naturalistic environments. The current study took the advantages of the naturalistic paradigm (i.e., movie viewing) fMRI (nfMRI) to derive fine parcellations via a data-driven dual-regression-like sparse representation framework. The parcellations were quantitatively evaluated by functional homogeneity, and global and local boundary confidence. In addition, the differences of cerebellum–cerebrum functional connectivities between rsfMRI and nfMRI for some exemplar parcellations were compared to provide qualitatively functional validations. Our experimental results demonstrated that the proposed study successfully identified distinct subregions of the cerebellum. This fine parcellation may serve as a complementary solution to existing cerebellum parcellations, providing an alternative template for exploring neural activities of the cerebellum in naturalistic environments.

Altered temporal sequence of transcriptional regulators in the generation of human cerebellar granule cells

Brain development is regulated by conserved transcriptional programs across species, but little is known about divergent mechanisms that create species-specific characteristics. Among brain regions, human cerebellar histogenesis differs in complexity compared with non-human primates and rodents, making it important to develop methods to generate human cerebellar neurons that closely resemble those in the developing human cerebellum. We report a rapid protocol for the derivation of the human ATOH1 lineage, the precursor of excitatory cerebellar neurons, from human pluripotent stem cells (hPSC). Upon transplantation into juvenile mice, hPSC-derived cerebellar granule cells migrated along glial fibers and integrated into the cerebellar cortex. By Translational Ribosome Affinity Purification-seq, we identified an unexpected temporal shift in the expression of RBFOX3 (NeuN) and NEUROD1, which are classically associated with differentiated neurons, in the human outer external granule layer. This molecular divergence may enable the protracted development of the human cerebellum compared to mice.

The Human Cerebellum as a Hub of the Predictive Brain

Although the cerebellum has long been believed to be involved uniquely in sensorimotor processes, recent research works pointed to its participation in a wide range of cognitive predictive functions. Here, we review the available evidence supporting a generalized role of the cerebellum in predictive computation. We then discuss the anatomo-physiological properties that make the cerebellum the ideal hub of the predictive brain. We further argue that cerebellar involvement in cognition may follow a continuous gradient, with higher cerebellar activity occurring for tasks relying more on predictive processes, and outline the empirical scenarios to probe this hypothesis.

Single-nucleus transcriptomic analyses reveal microglial activation underlying cerebellar degeneration in Ataxia Telangiectasia

While ATM loss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (AT), how this genetic mutation leads to selective and progressive cerebellar degeneration of Purkinje and granule cells remains unknown. We performed single-nucleus RNA-sequencing of the human cerebellum and prefrontal cortex from individuals with AT and matched unaffected controls to identify AT-associated transcriptomic changes in a cell-type- and brain-region-specific manner. We provide the largest single-nucleus transcriptomic atlas of the adult human cerebellum to-date (126,356 nuclei), identify upregulation of apoptotic and ER stress pathways in Purkinje and granule neurons, and uncover strong downregulation of calcium ion homeostasis genes in Purkinje neurons. Our analysis reveals prominent inflammation of microglia in AT cerebellum with transcriptional signatures similar to aging and neurodegenerative microglia, and suggests that microglia activation precedes Purkinje and granule neuron death in disease progression. Our data implicates a novel role of microglial activation underlying cerebellar degeneration in AT.