Evidence of the role of the cerebellum in EES functions from healthy volunteer and patient studiesStudies in healthy volunteers

In healthy children, they are few task-based imaging studies related to EES functions [5, 42]. They are different from the adult studies (see above) in that, they do not only report activation clusters for a specific task, but they aimed to explore the relationship between cerebellar grey matter (GM) volume of a specific cerebellar region and performance of specific cognitive tasks. Moreover, the specific cerebellar regions explored are a priori chosen, based on the adult data. Therefore, the entire cerebellum is not explored for each task which limits the generalization of these results. Bernard et al. reported that larger GM volume of left Crus I and posterior cerebellum was correlated with lower working memory performance. This effect was not found for the right Crus I and posterior cerebellum [5]. Moore et al. reported an association between increased GM in bilateral lobule VIIB/VIIIA and left Crus II with higher scores on EF tasks as well as higher scores on a working memory task and GM in right lobule VII (Crus I/II). They noted that some GM activation clusters’ overlap between different cognitive tasks such as general intelligence ability [42]. Increased cerebellar GM volume and higher general intelligence ability were reported in children and young adults [17].

One study compared children and adult brain and cerebellar activation, using fMRI during a working memory task [9]. They reported that children and adults engaged different neural networks. Adults were engaging the prefrontal, the inferior temporal cortex, the posterior cingulate and the precuneus. Limited activation of the cerebellum was observed. On the other hand, children were engaging the premotor, superior/inferior parietal and middle temporal cortex, anterior insula, caudate/putamen, and the cerebellum. Cerebellar activations were stronger and more diffuse in children compared to adults [9]. Thus, there was a shift of the activation pattern, from children to adults, of areas closely related to sensory-motor and dorsal visual pathways associated with visual–spatial or action-related behaviors in children to complex cognitive processing in adults [13].

Studies in cerebellar patients

Since the latter part of the last century, cognitive deficits including EES functions were described following cerebellar injuries in children, leading to the launch of the Cerebellar Cognitive Affective Syndrome (CCAS) [35], and the Cerebellar Mutism Syndrome (CMS) [55]. In children, contrary to adults (see below), very few inconsistencies are reported [18].

The CCAS is characterized by impairments in EF (planning, set-shifting, abstract reasoning, verbal fluency, working memory), often with perseveration, distractibility or inattention; visual–spatial disorganization and impaired visual–spatial memory; personality change with blunting of affect or disinhibited and inappropriate behavior; and by impairments in language production such as dysprosody, agrammatism and mild anomia. The CMS is a condition that encompasses speech and language dysfunction (from complete mutism to mild dysfunction), behavioral/emotional changes with cerebellar motor signs (e.g., ataxia and gait disturbance), cognitive (including EF), and sometimes brainstem dysfunction including long tract signs and cranial nerve impairment. This syndrome has been extensively studied in children [55] especially after posterior fossa surgery but has also been described in a non-surgical context (cerebellitis) [38]. It has also been described in adults [56]. However, compared to children, different cerebellar sub-divisions were found to be responsible for CCAS onset (hemispheric lobules VI, VII and possibly lobule IX) with no involvement of the vermis [54].

The pathophysiology of CMS is unclear [4]. It occurs very rarely in adults [66]. However, in children, increasing evidence has shown an association between the CMS/CCAS and damage to cerebellothalamic-cerebral connections [3, 4, 56, 62] and to the deep cerebellar nuclei (DCN) [3, 32]. Also, bilateral DCN damage is likely to lead to greater deficits [3, 32]. Moreover, lesion mapping studies in children have found that damage to the vermis was associated with CMS/CCAS occurrence. Lobule IX and X of the vermis were identified as the sub-division responsible for the CMS/CCAS [3].

However, the impairment of a function after cerebellar damage may also reflect the remote effect of the cerebellar malfunction to the cerebral cortex. Perfusion Imaging studies are helpful to explore the distant consequence (s) of a cerebellar injury and therefore in understanding the role of the cerebellum in children [62]. In children with cerebellar pathologies, cerebellar perfusion deficits are reported [51, 65]. Supratentorial hypoperfusion was also reported which usually normalizes when cerebellar symptoms were resolved [41, 51, 65]. The hypoperfusion spreads to several cortical (e.g., frontal, parietal, temporal cortices) and subcortical (e.g., thalamus) regions with the frontal regions [from the PFC to the primary motor cortex (M1)] being the most consistently reported. One study found a global cortical hypoperfusion with a pronounced effect on the frontal lobes [41]. The mechanism of the distant cortical hypoperfusion is theoretically similar to the adult crossed cerebellar diaschisis initially described after a cortical stroke [8], however, for the cerebellum, cortical hypoperfusion is contralateral to the cerebellar affected hemisphere [41, 51, 65]. Furthermore, Wang et al. proposed the same diaschisis in ASD patients, in which disruption of the cerebello-thalamo-cortico pathways would lead to a developmental disorder leading to the appearance of ASD [64]. The diaschisis we refer here to is the connectional as opposed to the focal diaschisis in which changes of structural and functional connectivity between brain areas appear distant to the focal lesion. Connectional diaschisis explains the role of the cerebellum in the broad spectrum of high order functions due to its multiple and complex connections to distant cerebral cortical areas.

Up until recently, it was debatable whether a younger age at the time of a cerebellar injury predicted worse motor and cognitive outcomes. Does a cerebellar injury impair EES function in the same way across development? It has been shown that complex congenital cerebellar anomalies such as cerebellar agenesis may be linked to developmental diaschisis [64]. Others studies reported that cerebellar acquired damage at a young age contributed to more severe, and prolonged impairment [12, 50]. Some investigators argued that it was not due to the cerebellar injury but to the post-operative radiotherapy [44]. In non-irradiated children, no effect [27] or positive effect [35] of young age was reported. Only, Aarsen et al. described a negative effect [1]. However, multiple caveats limited those studies [6]. Beuriat et al. in a study of patients who were treated for a posterior fossa tumor, controlled all the major confounders (namely radiotherapy, tumor characteristics, damages to the deep cerebellar nuclei and delay between surgery and assessment time) and reported that early cerebellar damage (≤ 7 years old) is an independent factor for poor long-term functional (cognitive and motor) outcome [6].This suggests that the cerebellum is a sort of “broad learning machine”, and that during critical periods of development, the cerebellum, as part of a distributed neural network, is the foundation for future motor and cognitive learning.

This concept has been previously suggested by some authors. In a consensus paper on the role of the cerebellum in movement and cognition, most of the authors described the cerebellum as a structure that acquires internal models that govern both movement and thinking [29]. Schmahmann defined it as a Universal Cerebellar Transformation [53] while Riva and colleagues characterized the cerebellum as a “homeo-static orchestrator” [49] and Parker and Andreasen's described the concept of “synchrony” as the coordination of sequences of both action (movement) and thought [45]. This is also consistent with the view that the cerebellum is critical to motor and cognitive automation and adaptation as supported by others [43]. It was also proposed that the cerebellum operates as a general-purpose co-processor, whose effects depend on the specific brain centers to which individual modules are connected [11]. The idea of these authors is that the cerebellum act as a “timing and learning machine” for cognitive/emotional and mental processes.

Cerebellar anatomy and EES networks in children

Structurally, the cerebellum and the cerebrum undergo major changes during human development, as a consequence of brain maturation and adaptation. Functionally, networks evolve from spatially close anatomical hubs to large-scale but integrated network communities [15].

Structural modifications

Most of the brain’s macroscopic changes (cortical folding and increase volume) are completed by the age of 2 [46]. Nevertheless, the course of maturation of the cortex is different from one region to another with a later maturation of cortices processing high-order functions compared to those processing somatosensory ones. For example, somatosensory, visual, auditory, and motor cortices mature earlier than the PFC. One the other hand, microstructural (sub-cortical areas/white matter of the brain and cerebellum) architecture continues to mature from gestational age to far beyond 2 years of age. These changes are supported by the myelinization process that continues into young adulthood [19]. EES and complex sensorimotor behavioral development are more limited before 2 years old with later development [46] including myelinization, leading to an increased efficiency of the connectivity of these large-scale integrated networks [16].

Cerebellar macroscopic changes reaches peak later in development [61]. Interestingly, the cerebellar vermis, has an almost stable volume from 8 to 20 years old. Most of the later growth of the cerebellum is due to the increased volume of the cerebellar hemispheres [61].

Brain and cerebellar functional connectivity and EES network modifications

Using resting-state functional magnetic resonance image (rs-fMRI), it was reported that functional connectivity (FC) is already present in utero from 24 weeks gestation age and increases with full-term age [60]. However, this connectivity between brain regions is immature (weak FC) compared to adults, even at full term, especially antero-posterior networks compared to inter-hemispheric ones [60]. Using diffusion magnetic resonance image (dMRI), Huang et al. showed that the number of connections (nodes) within the functional networks was lower in neonates compared to toddlers and preadolescents [23].

It had been thought that long-range network connections between the cerebellum and cortical areas developed only after birth [67]. Yet, the cortical volume of prefrontal, sensorimotor and temporal regions is decreased after preterm cerebellar injury [37]. Contrasting results were published regarding the FC of the cerebellum with other cortical regions in children. Doria et al. found FC between the cerebellum and cortical regions such as the PFC, cingulum and parietal lobe in full term infants at birth. The connectivity in this network was not present in the early preterm infant [14]. In contrast, Kipping et al. showed that in the infant (6 months of age), the cerebellum connection to the sensorimotor cortex was present, but that connections to other cortical regions only appeared later in childhood. In his study, the sensorimotor cortex was connected to lobule I–IV and to lobule VIII. This is remarkable because, in the adult humans, lobule VIII is said be part of the cognitive part of the cerebellum. The strength of cortico-cerebellar FC was greater in middle childhood compared to infant or late childhood and even to the adult. The coherence (maturity), of the cortico-cortical FC was stronger in adults. Therefore, they described the development of Cerebellar, Cerebello-Cortical, and Cortico-Cortical Functional Networks in Infancy, Childhood, and Adulthood as “asynchronous” [25] (Fig. 3).

Fig. 3

Cerebello-cortical functional networks from early childhood to adulthood: this figure illustrates the cerebello-cortical functional networks according to the functional connectivity of the cerebellar networks as proposed by Yeo et al. [68]. For each cerebellar lobules, the cerebello-cortical connectivity strengh at each age (early childhood, middle childhood, late childhood, adulthood) is represented from low (+) to high (++++). Note that the maturity of the cerebello-cortical functional networks dysplayed here increases from early childhood to adulthood. Maps are overlaid on anatomical surface maps. A anterior; P posterior; L left; R right; lat lateral; med medial

Moreover, Kipping et al. assessed cerebellar GM volume and white matter (WM) tract integrity [Fractional Anisotropy (FA)] in children from 6 to 10 years of age. First, they showed that there was an evolution across development of both parameters. Compared to older children, younger children had lower GM volumes and higher WM FA of the anterior cerebellum, while compared to younger children, older children had higher GM volumes and lower WM FA in the posterior cerebellum. Moreover, they correlated these findings with increasing cognitive planning capacity [26].

The evidence reviewed above indicates significant morphological, microstructural and functional reorganization of human cortical and cerebellar structural networks from infancy to adulthood. As this occurred, EES functional processing became more efficient and organized indicating that the relevance of each component of the network to EES changes over development. We will address later in this article the implication of these changes for the shifting role of the cerebellum in EES functions.