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Part VII
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Functional Properties of the Cerebellum
Cerebro-Cerebellar Networks
https://t.me/medicina_free
IolandaPisotta andMarcoMolinari
55
Abstract
Considering the cerebellum an independent structure
devoted mainly to motor control functions, neuroscience
research has, until now, considerably neglected the
importance of the cerebellar’s contribution to non-motor
functions. In fact, as the cerebellar is anatomo-functionally connected to different large-scale networks in the
neocortex, including frontal and parietal regions typically involved in high-order cognitive processing, there
is strong evidence to suggest its primary role lay beyond
its motor control function. Histologically, the cerebellum
contains about 50 billion neurons—roughly half of the
total number of neurons in the whole brain, and this
impressive order of magnitude supports extremely powerful mechanisms for processing information. The denition of input–output organization between the cerebellum
and cerebral cortex helps to clarify the role of the cerebellum in higher cognitive functions. Indeed, these connections provide the means through which association
areas and the cerebellum may inuence each other’s
operations.
Keywords
Sequencing · Cognition · Cognitive affective syndrome
Functional connectivity
I. Pisotta (*)
IRCCS Fondazione Santa Lucia, Robotic Neurorehabilitation Lab,
Rome, Italy
e-mail: i.pisotta@hsantalucia.it
M. Molinari
IRCCS Santa Lucia Foundation, Neurorehabilitation 1 and Spinal
Center, Robotic Neurorehabilitation Lab, Rome, Italy
e-mail: m.molinari@hsantalucia.it
55.1 Neurophysiology ofCerebello-
Cortical Circuits
The cerebellum is traditionally considered an independent
structure devoted mainly to motor control functions.
Neuroscience research has, until now, considerably neglected
the importance of the cerebellar’s contribution to non-motor
functions. In fact, as the cerebellar is anatomo-functionally connected to different large-scale networks in the neocortex, including frontal and parietal regions typically involved in high-order
cognitive processing, there is strong evidence to suggest its primary role lay beyond its motor control function. Histologically,
the cerebellum contains about 50 billion neurons—roughly half
of the total number of neurons in the whole brain, and this
impressive order of magnitude supports extremely powerful
mechanisms for processing information (Ramnani 2006).
The denition of input–output organization between cerebellum and cerebral cortex helps to clarify the role of the cerebellum in higher cognitive functions because these connections
provide the means through which association areas and the cerebellum may inuence each other’s operations (Ramnani 2012).
Anatomical evidence, demonstrating the large connections through the dentate nuclei with the prefrontal, temporoparietal and limbic areas (D’Angelo and Casali 2013),
suggest that there is an high involvement of the cerebellum in
non-motor function. These wealth of studies have recently
lead to the general acceptance of the cerebellar role in modulating cognitive and emotional behavior (Schmahmann and
Sherman 1998). Each part of the cerebellar cortex has specic feedforward and feedback connections to the cerebral
cortex that go far beyond the long known connections to
motor and premotor cortical areas (Pisotta and Molinari
2014). Indeed, there are parallel connections to paralimbic
and association cortices. Based on these observations, it is
thought that the cerebellum performs a universal transform
that is applied to different domains, i.e., motor, cognitive,
and affective.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_55
359
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I. Pisotta and M. Molinari
In 1998, Schmahmann argued that the overshoot and the
inability of the motor system to check parameters of movements may be equated to the cognitive/affective realm with
“dysmetria of thought,” which leads to a mismatch between
reality and perceived reality, and erratic attempts to correct
errors of thought or behavior (Schmahmann and Sherman
1998). In the same vein, the involvement of the cerebellum in
cognitive functions has been supported by studies showing
that cerebellar lesions can produce cognitive decits (Tedesco
etal. 2011) in a variety of domains ranging from language,
working memory, special data elaborations, procedural learning as well as action inhibition (Koziol etal. 2014).
Tedesco etal. (2011) examined the expression of cerebellar cognitive affective syndrome with regard to lesion topography in a large group of subjects with cerebellar damage, by
analyzing the neuropsychological assessment compared with
the topography of the lesion. Based on the data collected, the
authors concluded that the location of a lesion provides an
understanding of the connectivity between cerebellum and
cortical areas involved in each cognitive domain. Of the various cognitive domains, the ability to sequence was the most
adversely affected in nearly all subjects, supporting the
hypothesis that sequencing is a basic cerebellar operation.
Traditionally, sequencing has not been recognized as a discrete cognitive function and can be dened as a “supramodal
function,” but the relationship with other cortical functions,
such as working memory and timing, is still unknown.
Molinari et al. (2008) proposed that sequencing be considered as the basic mechanism that allows cerebellar prediction
ability in all functional domains (Molinari etal. 2008) (see
Chap. 54 on sequencing by Molinari M. in this book).
Also, Lupo etal. (2018) in a single-case study described a
patient with a cerebellum arteriovenous malformation and history of behavioral dysregulation. After the rupture of the cerebellar malformation, the patient’s behavior morphed into
specic psychiatric symptoms and cognitive decits occurred.
The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language
domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules and in
the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The patient suffered from cognitive and behavioral symptoms that are part of the cerebellar
cognitive affective syndrome. This case supports the hypothesis
of a cerebellar role in personality disorders emphasizing the
importance of also examining the cerebellum in the presence of
behavioral disturbances in children and adults. A considerable
amount of new and more recent data are leading to profound
changes on the views on the cerebrocerebellar circuits, so much
they may be now considered to be essential for the functional
regulation of many neocortex areas, perhaps all, as well as of the
hypothalamus and of the limbic system. Accordingly, clinical
studies have pointed out an involvement of the cerebrocerebel-
lar circuits in the pathophysiology of an increasing number of
neuropsychiatric disorders (Benagiano etal. 2018).
Although these evidences support the proposal that functional connectivity is a key determinant of cerebellar functions,
little is known about the precise mechanisms through which the
cerebellum exerts its inuence upon the cerebral cortex. In spite
of all the advances in the framework of cerebellar research and
the enormous amount of data available on cerebral cortex physiology (Manto etal. 2006; Manto and Haines 2012), the functional electrophysiology of the human cerebellum remains
poorly characterized according to (Dalal etal. 2013).
By applying neurophysiological techniques to subjects
suffering from focal unilateral cerebellar damage, it has been
possible to address the role of cerebellar input on motor (Di
Lazzaro et al. 1995; Di Lazzaro et al. 1994a; Di Lazzaro
et al. 1994b) and somatosensory cortices in humans
(Restuccia etal. 2001; Restuccia etal. 2007). In a rst study,
Di Lazzaro etal. tested the effects of electrical stimuli over
the base of the skull on the motor responses evoked by cortical magnetic stimulation in two patients with unilateral cerebellar lesions. In both patients, no inhibition of motor
responses was present in the muscles ipsilateral to the lesion,
whereas an inhibition, similar to the one observed on controls, was evident on the opposite side. The ndings suggest
that the cerebellar origin of the motor effects seen after electrical stimulation of the base of the skull is further clarication of the physiological cerebro-cerebellar interactions in
humans. Di Lazzaro etal. (1994a) evaluated also the excitability of the motor cortex to magnetic stimulation in seven
patients with cerebellar lesions and 20 control subjects. In all
but one of the patients with a hemicerebellar lesion, the
threshold was higher in the motor cortex contralateral to the
impaired hemicerebellum and the right/left threshold asymmetry was greater than normal. This suggests the existence
of a facilitating tonic action of the cerebellum on central
motor circuits that might be acting at either the cortical, or
spinal level, or perhaps both.
The cerebellum modulates the cortical excitability. In 2005,
in studies using rats, Oulad Ben Taib and colleagues, demonstrated that motor cortex excitability can be modulated largely
by Transcranial Direct Current Stimulation (tDCS) of cerebellar cortex or deep cerebellar nuclei, which corroborates the
importance of cerebellar processing for sensory modulation of
cortical excitability (Oulad Ben Taib etal. 2005). In humans,
Oulad Ben Taib and Manto (2013) argued that tDCS of the
cerebellum modulates the excitability of both the motor cortex
and the spinal cord. The authors also examined the effects of
anodal/cathodal direct current stimulation (DCS) applied epidurally over the cerebellum. The anodal tDCS decreased the
excitability of the motor cortex, reduced the excitability of F
waves, exerted a “smoothing effect” on corticomotor maps,
reshaping the representation of muscles on the motor cortex,
and enhanced the afferent inhibition of conditioned motor
evoked responses. Cathodal tDCS in the cerebellum exerted
55 Cerebro-Cerebellar Networks
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361
partially reverse effects. This study is the rst demonstration
that cerebellar tDCS tunes the shape of corticomotor maps,
providing a mechanism by which tDCS of the cerebellum
exerts a remote neuromodulatory effect upon motor cortex and
opening up possible clinical applications for improving
impairments in social and affective skills associated with cerebellar abnormalities (Cattaneo etal. 2022).
Diffusion Tensor Imaging (DTI) permits researchers to use
Magnetic Resonance Imaging (MRI) to study the trajectories
of ber pathways in the living brain (Le Bihan 2003). Ramnani
et al. (2006) used this approach to compare the anatomical
organization of cortico-pontine bers in primate and human
brains. The results showed that the bers were topographically
arranged in both humans and monkeys but the proportion of
the cerebral peduncle occupied by bers from the prefrontal
cortex was much larger in humans than in macaque monkeys.
The roles of the cerebellum and motor cortex during
adaptive learning are dissociated: the motor cortex retains
what the cerebellum learns. Jayaram et al. (2012) showed
that increasing neural activity of the cerebellum by means of
anodal tDCS applied during adaptation accelerated the learning process in a visuo-motor adaptation task (VAT), while
cathodal cerebellar tDCS slowed it down. Moreover, the neural activity of the cerebellum can also be strongly modulated
by means of theta burst stimulation (TBS) (Huang et al.
2005) a form of repetitive transcranial magnetic stimulation
(rTMS) that mimics protocols inducing long-term potentiation (LTP) or long-term depression (LTD) in animal models.
In the study of Bonnì etal. (2020), the authors investigated
the effects of cerebellar intermittent theta burst stimulation
(c-iTBS), a high-frequency rTMS protocol, on visuo- motor
learning in a sample of hemiparetic patients due to recent
stroke in the territory of the contralateral middle cerebral
artery. Eight stroke patients were enrolled and c-iTBS was
applied immediately before the learning phase of a visuomotor adaptation task. Real, but not sham, c-iTBS improved
visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation
task. Moreover, the authors also found that real but not sham
c-iTBS induced a sustained improvement in the re- adaptation
of the recently learned skill (i.e., when patients were retested after 30 min). Taken together, these data point to
c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.
In line with the cerebellar’s involvement in cortical processing, Tesche and Karhu (2000) and Ivry (2000) suggested
that the cerebellum evaluates the predictability of incoming
somatosensory stimuli and, accordingly, modulates the activity of the somatosensory cerebral cortex (Tesche and Karhu
2000; Ivry 2000). By analyzing early latency somatosensory
evoked potentials (SEPs) in patients with lateralized cerebellar
lesions, Restuccia et al. (2001) demonstrated that inhibitory
circuitries, whose activation follows the primary depolarization of granular layer cells, are low-functioning in cerebellar
patients (Restuccia etal. 2001). These ndings conrm that
the cerebellum inuences the activity of inhibitory circuitries
in the primary somatosensory cortex and that the cerebellum
tunes the excitability of the primary sensory cortex at very
early stages of somatosensory input processing.
To verify whether the cerebellum participates in somatosensory input processing and, more specically, whether the
presence/absence of cerebellar processing affects the
somatosensory cortex’s ability to recognize the similarity/
diversity of incoming inputs, Restuccia etal. (2007) investigated the somatosensory mismatch negativity (S-MMN), a
component of event-related potentials (ERPs), in six patients
with unilateral cerebellar lesions. When unattended, deviant
acoustic stimuli are interspersed between regular, frequent
acoustic stimuli; however, the deviant ones usually elicit a
frontotemporal negative response (in the 120–180ms latency
range) labelled MMN (see Näätänen and Escera (2000) for
review). MMN was clearly abnormal in the cerebellar
patients (Restuccia etal. 2007). This is a strong indication
that the cerebellum plays a role in mechanisms generating
the S-MMN and that subjects with cerebellar damage may
experience an alteration in their capacity to correctly process
somatosensory information at cortical level.
55.2 Conclusions
The cerebellum receives massive higher-order input via the
cortico-ponto-cerebellar pathway. It sends projections back to
the associative cerebral cortical areas via the thalamus (cerebello-thalamo-cortical pathway). Therefore, the cerebellocortical network allows the cerebellum not only to contribute to
the coordination of movements, as once thought, but also to the
modulation and integration of all higher cortical functions.
There is an increasing interest in the scientic community to
increase our understanding of cortico-cerebellar interactions,
and of the cerebellar which is thought to be involved in the
pathophysiology of behavioral disturbances of high incidences,
such as schizophrenia, autism, and manic disorder (Sudarov
2013; Shakiba 2014; Van Overwalle etal. 2020).
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Clinical Functional Topography
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inCognition
MariaLeggio
56
Abstract
In 1998, Schmahmann and Sherman dened the new clinical entity “cerebellar cognitive affective syndrome”
(CCAS), which refers to the behavioral and cognitive
symptoms that can be encountered in patients affected by
cerebellar pathologies.
In the last 15 years, increasing evidence has been
obtained on nonmotor cerebellar functions, and in 2011,
Tedesco etal. characterized the cognitive prole of subjects affected by focal cerebellar lesions.
Focal cerebellar lesions consist of ischemic or hemorrhagic stroke or surgical ablation due to arteriovenous
malformations or tumors, and they involve discrete portions of cerebellar lobules. Thus, subjects with focal damage represent an optimal model to analyze cerebellar
functional topography.
Furthermore, since the cerebellum is known to modulate supratentorial activity and contribute to distinct functional networks related to higher-level functions, it is
conceivable that one or more networks rather than isolated regions may be dysfunctional. This is particularly
true when dealing with cerebellar degenerative diseases,
in which abnormal connectivity within specic cerebellocortical regions might explain the widespread decits
typically observed in patients.
Keywords
Cerebellum · Laterality effect · SCA · PICA · Deep
cerebellar nuclei · Posterior lobe · Cerebello-cerebral
network · Functional connectivity
M. Leggio (*)
Department of Psychology, Sapienza University of Rome,
Rome, Italy
Ataxia Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
e-mail: maria.leggio@uniroma1.it
In 1998, Schmahmann and Sherman dened the new clinical
entity “cerebellar cognitive affective syndrome” (CCAS),
which refers to the behavioral and cognitive symptoms that
can be encountered in patients affected by cerebellar
pathologies.
In the last 15years, increasing evidence has been obtained
on nonmotor cerebellar functions, and in Tedesco etal. 2011,
Tedesco etal. characterized the cognitive prole of subjects
affected by focal cerebellar lesions.
56.1 The Cerebellar Cognitive Prole
Subjects with cerebellar damage have a preserved intellectual level with poor performance with regard to denite cognitive abilities. All major cognitive domains can be affected
by cerebellar damage, although cognitive scores generally
result in a lower range of normal limits (Schmahmann and
Sherman 1998; Tedesco etal. 2011). This evidence is consistent with the hypothesis that cerebellar injury does not abolish specic cognitive functions but rather renders them less
efcient (Courchesne and Allen 1997; Hokkanen etal. 2006).
It has been proposed that “cerebellar cognitive affective syndrome” (CCAS) represents the clinical manifestation of dysmetria of thought (Schmahmann 2000).
Cerebellar cognitive impairment is not linked to motor
decits, as demonstrated by the lack of correlations between
cognitive and motor scores (Tedesco etal. 2011) and by the
evidence of better cognitive performance in patients with
higher motor impairment, i.e., patients with cerebellar atrophy (Leggio etal. 2000).
Manto and Mariën conceptualized CCAS as the third cornerstone of ataxiology along with motor and vestibular disorders (Manto and Mariën 2015), and a specic cerebellar
topography was identied. Indeed, while the sensorimotor
cerebellum has a primary representation in the anterior lobe
bordering lobule VI and a second representation in lobule
VIII, the cognitive–limbic cerebellum has three representa-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_56
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M. Leggio
tions in the posterior lobe, i.e., lobules VI/Crus I, Crus II/
VIIB, and IX/X, and a high degree of functional topography
is observed within the individual lobules (Stoodley and
Schmahmann 2009; Buckner etal. 2011; Guell etal. 2018).
56.2 Laterality Eects
Consistent with the discovery of segregated parallel
cerebello- cortico-cerebellar loops (Schmahmann and Pandya
1997; Middleton and Strick 1998), several groups have dem-
onstrated the importance of the topography of cerebellar
lesions in cognition (Tavano et al. 2007; Stoodley and
Schmahmann 2010), suggesting differences in cognitive
impairments between right and left focal cerebellar damage
(Fiez et al. 1992; Gottwald et al. 2004; Gross-Tsur et al.
2006; Hokkanen et al. 2006; Riva and Giorgi 2000; Scott
etal. 2001).
However, this laterality effect is not clearly dened
(Molinari etal. 1997; Leggio etal. 2000; Chiricozzi et al.
2008; Tedesco etal. 2011).
The cerebellum acts within complex cortical-subcortical
networks that mediate cognitive functions (Schmahmann
and Pandya 1997; Middleton and Strick 1998). Based on the
functional lateralization of the cerebral cortex and the
crossing of cerebello-cortico-cerebellar connections, the
right cerebellar hemisphere should be involved in verbal performance and the left hemisphere should be critical for spatial performance (Baillieux et al. 2010). Cerebral cortex
functions are not completely lateralized; however, bilateral
cortical activation during linguistic and spatial tasks has
been reported in fMRI studies (Knecht et al. 2000; van
Ettinger-Veenstra etal. 2010).
Consistent with this evidence of bilateral activation, studies on lesions have observed decits in language after right
and left cerebellar damage (Leggio etal. 2000; Fabbro etal.
2004; Fabbro 2000). Furthermore, specic language-related
impairments have been demonstrated after the development
of left cerebellar lesions (Cook etal. 2004).
How is this possible? It has been suggested that cerebellar processing is not linked to a specic subcomponent of a
given function but instead provides support to all components, particularly in smoothing their interplay (Leggio
et al. 2011). Thus, a function whose subcomponents are
distributed bilaterally, such as language, should be affected
by right and left lesions. However, despite bilateral impairment, in- depth analyses have often demonstrated right–left
specicity (Molinari etal. 2004; Leggio etal. 2008). For
example, visuospatial abilities can be affected in the presence of left or right cerebellar damage. However, differences are evidenced by comparing the performance of
patients with left or right lesions, with subjects presenting
left lesions showing very slow but correct spatial process-
ing and subjects presenting right lesions showing quicker
but inaccurate processing (Molinari etal. 2004).
These differences have been interpreted to mean that
within a distributed function, modules can be differentially
affected by cerebellar damage (Molinari and Leggio 2007).
One of the strongest pieces of evidence in favor of this
hypothesis is derived from the theory that “sequence detection” is the operational mode of the cerebellum (Leggio and
Molinari 2015). Sequence processing is a supramodal function crucial for driving motor, cognitive, and behavioral abilities. Damage to the cerebellum affects the ability to detect
sequences and thus to make predictions in several domains,
both with and without laterality effects according to the performance required. Several examples will be provided. In a
serial reaction time task, the ability to recognize visuomotor
sequences is impaired independently from left or right cerebellar lesions (Molinari et al. 1997). Otherwise, in a cardsequencing test, cerebellar patients present with clear
cognitive sequencing impairments independent of the material that is processed (i.e., verbal, spatial, or behavioral)
(Leggio etal. 2008). However, when comparing the patients
based on the cerebellar lesion side, material-related laterality
was detected. Namely, patients with left lesions perform
defectively only on sequences based on pictorial material,
and patients with right lesions perform defectively only on
sequences requiring verbal elaboration (Leggio etal. 2008).
56.3 Vascular Territory Eects
Anatomical, developmental, and neuropsychological data
indicate the existence of cerebellar motor functions in the
anterior lobe and cognitive functions in the posterior lobe
(Stoodley and Schmahmann 2010; Timmann et al. 2008).
The vascular territory of the superior cerebellar artery (SCA)
primarily involves the anterior lobe and that of the posterior
inferior cerebellar artery (PICA) mostly involves the posterior lobe (Schmahmann 2000). Thus, a comparison between
patients with stroke lesions in the SCA or PICA territory
allows us to evaluate anterior versus posterior cerebellar
lesions.
Indeed, literature data indicate that PICA subjects perform worse than SCA patients in all cognitive domains, particularly with regard to sequencing ability and verbal
memory, language, visuospatial, and executive functions
(Tedesco etal. 2011).
Leiner etal. (1986) emphasized the contribution to “mental skills” of phylogenetically new posterior components of
the cerebellum. Their hypothesis was based on the observation that the dentate nucleus enlarges in parallel with the
frontal cortex during phylogenetic and ontogenetic development. This model was proposed by several groups and implicated the cerebellar posterior lobe and dentate nucleus in
56 Clinical Functional Topography inCognition
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various cognitive domains (Schmahmann and Sherman
1998; Krienen and Buckner 2009).
In a series of studies, Strick and colleagues (Middleton
and Strick 1998; Strick etal. 2009) observed that the output
channels to the prefrontal and posterior parietal areas are
clustered in the ventral and caudal regions of the dentate
nucleus. These output channels are segregated from those in
the dorsal dentate that target motor areas of the cortex (Habas
2010). Current evidence supports a model of a motor anterior
lobe versus a “cognitive” posterior lobe, thus providing clinical indications consistent with reports (Grimaldi and Manto
2012; Tedesco etal. 2011) showing that SCA and PICA ter-
ritory lesions can be differentiated based on motor or cognitive symptoms.
Overall, evidence from the cerebellar stroke literature
identies a specic cognitive topography, and the reconstruction of the lobules that are affected by focal lesions conrms the general pattern of the involvement of posterior
lobules in various cognitive functions (Stoodley and
Schmahmann 2009; Tedesco etal. 2011).
56.4 Deep Cerebellar Nuclei Eects
Deep cerebellar nuclei (DCN) effects facilitate cerebellothalamo- cortical projections, and the cerebellar cortex inhibits the activity of the nuclei, thereby blocking cerebellar
activation of the cerebral cortex (Tarnecki 2003). Thus, cortical cerebellar lesions should affect disparate symptoms than
lesions that involve the DCN. In addition to animal models,
this pattern has been observed in cerebellar patients (Di
Lazzaro etal. 1994).
Recently, in addition to its relevance in motor recovery
(Schoch etal. 2006), the importance of the DCN in cognition
has been demonstrated by anatomical (Strick etal. 2009) and
fMRI data (Habas 2010).
Clinical studies have demonstrated that patients with or
without damage to the DCN present differences in performance in cognitive tasks (Tedesco etal. 2011; Brunamonti
etal. 2014). Indeed, subjects with spared DCN have better
scores than those with damage to the DCN. Note that among
the various cognitive domains, sequencing ability is the most
adversely affected when the lesion involves the DNC
(Tedesco etal. 2011).
56.5 Lobular Distribution ofImpairments
inPerformance
Functional distribution in cerebellar lobules has been
addressed by several neuroimaging and lesion studies (for
reviews, see Timmann et al. 2008; Stoodley and
Schmahmann 2009).
Signicant neuroimaging activation during cognitive
tasks is mainly observed in lobules VI and VII (Crus I and II)
(see Ale values in Table 3 of Stoodley and Schmahmann
2009). Clinical lesion overlap data indicate a more wide-
spread distribution of cognition-relevant lobules (Tedesco
etal. 2011). The lesion cognition map involves lobules VII
(Crus I and II), VIIB, and VIIIA, with only partial involvement of lobule VI.
Further insights are derived from correlations between the
quantitative mapping of the lobular pattern of cerebellar grey
matter (GM) atrophy and cognitive decits in patients
affected by cerebellar degenerative diseases.
A detailed mapping of motor and cognitive dysfunctions
linked to specic cerebellar lobules has been proposed in a
large cohort of patients with mixed subtypes of cerebellar
neurodegenerative disease (Kansal etal. 2017). While motor
dysfunctions were associated with the anterior lobe and posterior lobule VI, cognitive dysfunctions (specically involving verb and phonemic uency, working memory, cognitive
exibility, immediate and delayed recall, verbal learning,
and visuomotor coordination) were associated with lobules
VI, Crus I, Crus II, VII B, and IX (Kansal etal. 2017).
The study of a more homogeneous patient population
made an additional step in the characterization of the structural/functional correlation of the impairments in patients
affected by cerebellar damage. In spinocerebellar ataxia type
2 (SCA2), GM loss in cognitive posterior lobules VI, Crus I,
Crus II, VIIB, and IX correlates with visuospatial, verbal
memory, and executive tasks, while additional correlations
with motor anterior lobule V and posterior lobules VIIIA and
VIIIB are found for tasks that engage motor and planning
components (Olivito etal. 2017a). Interestingly, correlations
between cerebellar volumes and visuospatial and verbal
scores did not show a specic pattern of lateralization, which
is consistent both with anatomical and functional studies that
have also shown ipsilateral connections between the cerebellum and cerebral cortex (Middleton and Strick 2001; Allen
etal. 2005; Milardi etal. 2016) and with evidence showing
that left- or right-damaged cerebellar patients have a similar
cognitive prole (Tedesco etal. 2011) (see the “Laterality
effects” section for details on this issue).
Within this framework, analyzing specic functional
domains allows us to further detail the mapping of clinical
dysfunctions to the cerebellar lobules. For instance, the study
of attention subcomponents in SCA2 patients evidenced a
specic altered pattern with affected performances in selective attention, divided attention, and sustained attention.
Interestingly, specic posterior cerebellar regions, mainly
lobules VIIb/VIIIa, correlate with specic attention tasks
(i.e., divided attention and sustained attention tasks) (Lupo
etal. 2018a). These results are in line both with the functional connectivity of lobules VIIb/VIIIa and with the cognitive processing required by the altered tasks.
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M. Leggio
Intriguing data are also derived from the social cognitive
domain, indicating that both structural damage to specic
cerebellar lobules and microstructural alterations in the cerebellar peduncles are responsible for social cognition
impairment (Clausi etal. 2021). SCA2 patients showed a
pattern of GM atrophy localized in specic areas of the
anterior (lobules I-IV), intermediate (lobule VI), and posterior cerebellum (lobules VIIIb, Crus I, and Crus II) and in
paravermal regions (lobule IX). Some of these lobules (i.e.,
IX, VIIIb, and Crus II) are known to be involved in cerebral
networks that subserve specic subcomponents of social
cognition (Baumann and Mattingley 2012). The patients
also presented with reduced microstructural integrity in the
cerebellar peduncles. Interestingly, altered social cognition
performances of SCA2 patients correlated with the degree
of cerebellar GM reduction and with the presence of microstructural abnormalities in the cerebellar peduncles (Clausi
etal. 2021; for a deeper discussion of this issue, see “Theory
of Mind and Cerebellum” chapter by Olivito, Siciliano,
Leggio in this volume).
56.6 Cerebello-Cerebral Network-Based
Impairments inPerformance
fMRI studies have shown that cerebellar functions are topographically arranged in function-specic cerebellar networks
connected to function-specic networks in the cerebrum
(Buckner et al. 2011). Thus, a network-based approach is
essential for understanding cerebellar functions across
domains. The cerebellum is known to modulate supratentorial activity and contribute to distinct functional networks
related to higher-level functions. It is therefore conceivable
that one or more networks rather than isolated regions may
be dysfunctional, especially in cerebellar degenerative diseases and that abnormal connectivity within specic
cerebello- cortical regions might explain the widespread decits typically observed in patients.
The investigation of functional connectivity (FC) may
provide important information to characterize the neural
basis and examine the integrity of cerebellar and cerebral
networks. Indeed, FC allows us to describe the relationship
between the neuronal activation patterns of anatomically
separated brain regions (van den Heuvel et al. 2009).
Among the available methods to investigate brain FC, resting-state fMRI has been proven reliable, easy to implement, and particularly suitable for the study of a complex
structure such as the cerebellum, in which the function of
each subregion is dened by its connection with specic
brain areas (Schmahmann and Pandya 1997; Middleton and
Strick 1998).
In SCA2 patients, the pattern of FC alterations between
regions in the cerebellum and cerebral cortex has been exten-
sively characterized using network-based statistics (NBS)
(Olivito etal. 2017a). The NBS approach allows complex
systems to be described as networks (Zalensky etal. 2010;
Han et al. 2013). Nodes in the posterior cerebellum have
been found to show reduced FC with nodes in cortical
regions related to cognition and emotion and nodes in the
anterior cerebellum to show reduced FC with nodes in the
cortical regions related to motor control. Within the posterior
cerebellum, the prominent nding was impaired connectivity
toward medial and superior frontal regions that have been
consistently implicated in different aspects of executive
functions (Olivito etal. 2017a). These data are in line with a
previous FC study in SCA2 patients using a seed-based
approach and showing FC decreases between the right posterior cerebellum and the left superior frontal gyms, which has
been proposed to impact different executive operations, such
as self-monitoring and verbal/visuospatial working memory
(Hernandez-Castillo etal. 2015).
A novel contribution to understanding the relationship
between cerebello-cerebral disconnection and the specic
cognitive symptomatology associated with cerebellar neurodegenerative processes is obtained from the investigation of
the microstructural organization of middle cerebellar peduncles (MCPs) and superior cerebellar peduncles (SCPs),
which were reconstructed by means of diffusion tensor
imaging (DTI) (Olivito etal. 2017b). The MCP and SCP are
the feedback and feedforward limbs of the cerebello-cortical
system, respectively, and through these limbs, the cerebellum receives information from cerebral regions and then
sends back the cerebellar-processed information to accomplish functions successfully. DTI has proven to be a valuable
tool for investigating brain white matter (WM) (Basser etal.
1994). In SCA2 patients, WM diffusivity was altered bilater-
ally in the MCP and SCP.Interestingly, executive and visuospatial functions, typically altered in SCA2, signicantly
correlate with damage to the right and left SCP, respectively.
The signicant correlations of visuospatial functions with
altered right SCP diffusivity and executive functions with
altered left SCP diffusivity indicate a precise lateralization of
cognitive functions and structural alterations (Olivito et al.
2017b). These data demonstrate that WM diffusivity is
altered in the presence of cerebellar cortical degeneration,
thus resulting in cerebello-cerebral dysregulation that may
account for the specicity of cognitive symptomatology
observed in patients.
A growing body of studies has shown that cerebellocerebral functional disconnection occurs in several neurological and psychiatric conditions, such as schizophrenia
(see Ding etal. 2019 for a meta-analysis), Parkinson’s disease (Mijalkov et al. 2021), Alzheimer’s disease (Olivito
etal. 2020), and major depressive disorder (see Helm etal.
2018 for a systematic review). Of particular interest is a sub-
ject who developed a manic state after an acute cerebellar
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