Cerebellum and Development

Many of these observations come from the following paper: Sathyanesan et al. 2019

Introduction

  • Subdivisions of the cerebellum have distinctive developmental trajectories with more phylogenetically recent regions maturing later (Tiemeier et al. 2010)
  • Why should we study the cerebellum during development: unique protracted developmental trajectories, sexual dimorphism, preferential vulnerability to environmental influences, implication in neurodevelopmental disorders.
  • Because the cerebellum reaches its peak volume later than the cerebrum [suggesting prolonged developmental course], it may be especially interesting to investigate differences in grey matter volume between cerebellum and cortex during this developmental window (across males + females too).
  • The larger size of the cerebellum in males and differences between sexes in longitudinal development may reflect sex-specific factors related to the higher risk for these disorders in males (Tiemeier et al. 2010)
  • Different cerebellar regions have distinct growth patterns with varying degrees of sexual dimorphism. Cerebellum is at adult volume in females during 7-11 years but not males (Caviness et al. 1996).
  • Males are particularly vulnerable to neurodevelopmental disorders (diagnosed at a higher rate with adhd, dyslexia etc).

Cerebellum and vulnerability

  • risk factors that impair cerebellar growth (e.g. neonatal brain injury) are correlated with poor overall developmental outcomes at later stages Sathyanesan et al. 2019
  • cerebellum is especially suspectible and vulnerability to insult is due to its protracted developmental trajectory.
  • the cerebellum is among the first brain structures to begin cellular differentiation and one of the last to fully mature, therefore, the cerebellum is vulnerable to dysfunction due to genetic and epigenetic factors, a toxic in utero environment, focal or global neonatal brain injury
  • the complexity of risk factors acting over the course of development results in a broad range of cellular, morphological, and circuit abormalities.
  • whereas much of neocortical neurogenesis occurs prenatally Silbereis et al. 2016 , cerebellar neurogenesis continues until the 11th postnatal month Abraham et al. 2001
  • 85% of granule cells are generated after birth Kiessling et al. 2013
  • the cerebellum quadruples in volume between the 24th and the 38th gestational weeks, and its cortical surface increases 30 times Volpe et al. 2009
  • the cerebellum effectively doubles in size (increase in 108%) in the first 90 days after birth. this increase in size is underscored by an increase in cell density.
  • the external granule layer disappears by the end of the 18th postnatal month Rauf & Kernohan, 1944. The authors hypothesize that the persistence of the external granule layer past 20 postnatal months lead to the development of medulloblastomas (tumors that affect the cerebellum in children). Typically the EGL disappears first in the vermis and then later in the hemispheres.
  • Early postnatal development is also characterized by massive outgrowth of dendrites and axons, followed by synaptogenesis, glial proliferation, and myelination, predominately in the forebrain and cerebellum.
  • developmental disruption resulting in cerebellar atrophy could affect cerebello-cortical connectivity.
  • the synapse is an effective point of functional comparison between neocortex and cerebellum. many neurodevelopmental disorders involve deficits in synapse formation, maturation, and function.
    • a typical pyramidal cell in the neocortex has approx 8,000 synapses, whereas a single Purkinje cell may have 200,000 synapses.
    • reduced number of synapses are characteristic of many neurodevelopmental disorders
    • we now know that granule cells encode rich sensory information, therefore, synaptic deficits in PCs likely correlate with sensory processing deficits in neurodevelopmental disorders.

Cerebellar dysfunction

  • Evidence from Neuroimaging
    • structural and functional abnormalities are commonly reported. specific regions (e.g., vermis) seem to be more prone to ASD-like structural abnormalities.
    • within the non-motor domain, children and adults with ASD have been reported to show atypical fMRI activation of cortico-cerebellar networks during biological motion perception Jack et al. 2017 and perception fo social interaction Kana et al. 2015.
    • Limperopoulos et al. (2014) have shown that perinatal cerebellar injury leads to volume reduction not only in cerebellar grey matter but also in cerebellar white matter and remote neocortical regions. These results suggest that changes in early cerebellar activity affect both cerebellar development and activity of neocortex.
    • It’s also possible that coordinated deficits in the cerebellum and cortex could arise due to a common molecular and/or environmental insult rather than co-dependence between structures.
    • the cerebellum is also implicated in downs syndrome - which is the most prevelent developmental disability with a known genetic origin. People with DS have smaller total cerebellar volumes, smaller frontal and temporal lobes and smaller hippocampal volumes. Similar to ASD, white matter structural changes are also observed in the adult DS brain.
  • Evidence from Behavior
    • in people with obvious ‘non-motor’ behavioral abnormalities, do ‘pure’ motor cerebellar abnormalities exist? For example, Tran et al. 2017 tested delayed eyeblink conditioning, a task which is depenedent on the cerebellum, on a group of very preterm children and adults. They found that in this group, there were significant deficits in the acquisition of conditioned responses, therefore suggesting that ‘motor’ cerebellar behavioral abnormalities coexist with non-motor abnormalities.
    • children with ASD also display abnormal conditioned responses in the eyeblink conditioning paradigm
    • it has been suggested that the language and social deficits observed in children with complex disorders are a consequence of deficits in multi-sensory integration.
    • one particular process that could be implicated in multisensory integration in children with ASD is timing. For example, this process may be impacted by a deficit in perceiving the temporal relationship between distinct sensory components of complex audio-visual stimuli such as language, and this deficit could also compound in social cognitive processes like theory of mind Stevenensen et al. 2014
  • Inter-regional morphogenesis
    • interestingly, the cerebellum and the thalamus initiate neuronal differentiation at about the same time - E10.5 Wong et al. 2018
    • given their common neurogenic timetables, one could speculate that extensive connectivity and matching of developmental trajectories could indicate that early defects in the cerebellum might lead to structural and wiring alterations in the thalamus.
    • it has been suggested that the cerebellum could interact its cortical targets using developmental cues that ‘match up’ regions of connectivity: with the goal of establishing a precise topography between subregions of the cerebellar nuclei and subnuclei of the thalamus.

Methods

Questions:

To what extent are disorders characterized by Healthy Brains accompanied by RDoC-like constructs and domains? How is cognitive function measured? [behavioral tasks or questionnaires]. * Do cerebellar anatomical differences reflect a generic developmental vulnerability or disorder-specific characteristics? * Are different cerebellar regions affected in neurodevelopmental disorders? And do these regions align with functional networks that are consistent with the characteristic symptoms of each disorder. * Are there differences in brain age across regions (functional, anatomical, network) of the cerebellum, and how does this differ across disorders? * The brain age paper provided some key insights across whole-brain regions but treated subcortical-cerebellum as one region, therefore, obscuring any within-cerebellum heterogeneity