The mystery of the cerebellum: clues from experimental and clinical observations

Abstract

The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders.

Heterozygous mutation of Sonic Hedgehog receptor (Ptch) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice

“…The cerebellum is divided into functionally specific regions with lobules I-V and IX often associated with motor function and working memory in rodents and humans (D’Mello et al, 2015; Guell et al; Lawrenson et al, 2018). Reductions in volume of lobules IV/V and IX are also associated with social impairments in patients with autism (D’Mello et al, 2015).…”

Lobule-specific dosage considerations for cerebellar transcranial direct current stimulation during healthy aging – a computational modeling study using age-specific MRI templates

“…The electric field dispersion outside of the targeted brain region during aging (Mahdavi and Towhidkhah, 2018) require dosage considerations in older adults. Here, an age-specific head model for FEA is needed to optimize ctDCS in the older adults due age-related cerebellar volume loss to address different cerebellar syndromes (Lawrenson et al, 2018), e.g., the vestibulocerebellar syndrome, the cerebellar motor syndrome, and the cerebellar cognitive affective syndrome (Koziol et al, 2014). For example, the motor performance is associated with the volume of the anterior lobe and top part of the superior posterior lobe, and the cognitive performance is related to the volume of the bottom part of the superior posterior lobe and the inferior posterior lobe (Koppelmans et al, 2017).…”

“…Hence, there is significant inter-subject variability in the impact of age on the shrinkage of the cerebellar lobules that may be associated with the decline in motor and cognitive behavior. There is a dichotomy between the sensorimotor cerebellum and the lateral portions of the cerebellum (cognitive cerebellum) (Lawrenson et al, 2018) that needs to be accounted for in optimizing ctDCS dose to address the decline in motor and cognitive behavior during aging. For example, lobules IV, V, VI, and VIII were shown related to motor functions while lobules VI and VII were involved in non-motor functions (van Dun et al, 2018).…”

“…Here, lobule-specific dosage considerations for ctDCS in older adults can be based on computational modeling of electrical fields, e.g., one performed in children that advised caution (Kessler et al, 2013). However, a lobule-specific electrical field distribution was not presented by the computational modeling study by Rampersad and colleagues (Rampersad et al, 2014) that is postulated to be crucial for ctDCS due to the dichotomy between the sensorimotor cerebellum and the cognitive cerebellum (Lawrenson et al, 2018). Moreover, since cerebellar cortex has a very high concentration of neurons with highly organized distribution, therefore, computation of lobule-specific electric field distribution can be very effective for ctDCS dosage considerations to address different cerebellar syndromes (Lawrenson et al, 2018), e.g., the vestibulocerebellar syndrome, the cerebellar motor syndrome, and the cerebellar cognitive affective syndrome (Koziol et al, 2014).…”

“…Here, one-size-fits-all ctDCS approach (called "Celnik montage" henceforth (Galea et al, 2009)) is postulated to be inadequate in ensuring comparable lobule-specific dosing across subjects due to inter-subject variability of the complex cerebellar structure with distinct motor and non-motor regions related to distinct motor, language, social, working memory, and emotional functions (van Dun et al, 2018). This is crucial since cerebellar cortex is organized into a myriad of functional units called microzones with segregated loops between the cerebellum and prefrontal cortex, parietal cortex, paralimbic cortex and superior temporal sulcus (Lawrenson et al, 2018). Table 1 lists the cerebellar region, the associated area in the brain, and the behavioral task from literature.…”