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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral “nodes” in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.
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Accepted Manuscript
Neural substrates of motor and cognitive dysfunctions in SCA2
patients: A network based statistics analysis
G. Olivito, M. Cercignani, M. Lupo, C. Iacobacci, S. Clausi, S.
Romano, M. Masciullo, M. Molinari, M. Bozzali, M. Leggio
PII: S2213-1582(17)30069-4
DOI: doi: 10.1016/j.nicl.2017.03.009
Reference: YNICL 978
To appear in: NeuroImage: Clinical
Received date: 12 January 2017
Revised date: 7 March 2017
Accepted date: 24 March 2017
Please cite this article as: G. Olivito, M. Cercignani, M. Lupo, C. Iacobacci, S. Clausi,
S. Romano, M. Masciullo, M. Molinari, M. Bozzali, M. Leggio , Neural substrates of
motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis.
The address for the corresponding author was captured as affiliation for all authors. Please
check if appropriate. Ynicl(2017), doi: 10.1016/j.nicl.2017.03.009
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Title Page
Neural substrates of motor and cognitive dysfunctions in SCA2 patients:
a network based statistics analysis.
G. Olivito1,2 , M. Cercignani2,3, M. Lupo1 , C. Iacobacci1,4, S. Clausi1,4, S. Romano5, M. Masciullo6,
M. Molinari7, M. Bozzali2, M. Leggio1,4
1. Ataxia Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy;
2. Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy;
3.Clinical Imaging Science Center, Brighton and Sussex Medical School, Brighton, UK;
4. Department of Psychology, Faculty of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy;
5. Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), “Sapienza” University of Rome -
Sant'Andrea Hospital - Rome, Italy ;
6. SPInal REhabilitation Lab, IRCCS Fondazione Santa Lucia,Rome, Italy
7. Neurorehabilitation 1 and Spinal Center, Robotic Neurorehabilitation Lab, IRCCS Santa Lucia Foundation, Rome,
Funding: This work was supported by the Ministry of Education, Universities and Research
(MIUR)- (Grant Number C26A1329A).
Corresponding author:
Dr. Giusy Olivito, PhD
Ataxia Laborarory, IRCCS Santa Lucia Foundation, Via Ardeatina, 306, 00179, Rome, Italy.
Telephone number: #39-06-51501547
Fax number: #39-06-51501213
E-mail address:
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease
characterized by a progressive cerebellar syndrome, which can be isolated or associated with
extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive
impairments and psychiatric symptoms.
The cerebellum is known to modulate cortical activity and to contribute to distinct functional
networks related to higher-level functions beyond motor control. It is therefore conceivable that one
or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative
diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain
the widespread deficits typically observed in patients.
In the present study, the network-based statistics (NBS) approach was used to assess differences in
functional connectivity between specific cerebellar and cerebral “nodes” in SCA2 patients. Altered
inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in
the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar
lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions.
The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral
regions and that the clinical symptoms may be specifically related with connectivity changes
between motor and non-motor cerebello-cortical nodes.
Cerebellum, cerebral cortex, resting-state fMRI, functional connectivity, nodes
1. Introduction
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease
involving the cerebellum. Neuropathological studies confirmed a pattern of grey matter (GM) loss
to affect the cerebellar vermis and hemispheres with sparing of the vermian lobules I,II (lingula)
and X (nodulus) and of the hemispheric lobules I,II (lingula) and Crus II (Della Nave et al., 2008a)
as well as a diffuse damage of the brainstem and cerebellar white matter (WM) (Durr et al., 1995,
Gilman et al., 1996, Estrada et al., 1999).
In addition to typical motor deficits (Takahashi et al., 2010), the presence of cognitive impairments
in subjects with degenerative ataxia has long been debated (Fehrenbach et al., 1984). Recently, the
cognitive performances of SCA 2 patients have been exhaustively investigated showing that the
patients may present with impairment in several cognitive and emotional domains (Klinke et al.,
2010; Sokolovsky et al., 2010, D’Agata et al., 2011; Fancellu et al., 2013; Moriarty et al., 2016).
The evidence of motor, cognitive, and emotional impairments in presence of cerebellar damage has
been linked to alterations of cerebro-cerebellar networks (Broich et al., 1987; Clausi et al., 2009;
Komaba et al., 2000; Baillieux et al., 2010).
Indeed, the cerebellum has extensive projections to and from cortical regions by means of middle
and superior cerebellar peduncles, the main afferent and efferent cerebellar white matter (WM)
tracts. These connections are known to be strictly controlateral and to be spatially and functionally
organized in distinct parallel loops (Middleton and Strick, 1994; Ramnani, 2006), thus contributing
to distinct functional networks (Allen et al., 2005; Habas et al., 2009; De Vico Fallani et al., 2006)
clearly related to different functional processes. Within this complex neural system the role of the
cerebellum is to integrate multisensory information and then send them back to cerebral cortex
(Leggio and Molinari, 2015). More specifically, it has been proposed that the cerebellum modulates
the cortical activity (Di Lazzaro et al., 1994; Middleton and Strick, 2000) by detecting predictable
sequences and allowing an optimized feedforward control that is necessary to accomplish the
different functions successfully (Leggio et al., 2011).
Therefore, it is conceivable that an abnormal connectivity within specific cerebello-cortical circuits
might explain the widespread deficits typically observed in SCA2 patients and that one or more
networks, rather than isolated regions, might be dysfunctional.
Consistent with this hypothesis, a reduction of brain size has been reported in patients with SCA2,
involving not only cerebellum and brainstem, but also other cortical and subcortical areas, such as
frontal regions, primary sensorimotor cortex, temporo-mesial and parahyppocampal regions,
substantia nigra, middle striatum, and thalamus (Estrada et al.,1999; Brenneis et al., 2003; Fancellu
et al., 2013, Mercadillo et al., 2014). All these regions are known to be reciprocally connected with
the cerebellum (Schmahmann, 1991; Schmahmann and Pandya, 1997; Middleton and Strick, 2001),
indicating that several targets of cerebellar projections, including both motor and non-motor areas,
are affected in patients with SCA2.
We hypothesize that cerebellar dysfunctions affect long- distance regions of the brain and clinical
symptoms are related with changes in functional connectivity (FC) within specific cerebello-cortical
The investigation of FC may provide important information to further characterize the neural basis
and examine the integrity of cerebellar and cerebral networks in SCA2 patients. Indeed FC allows
the relationship between the neuronal activation patterns of anatomically separated brain regions to
be described (van den Heuvel and Hulshoff Pol, 2010). Amongst the available methods to
investigate the brain functional connectivity, resting-state fMRI (RS-fMRI) has been proven reliable
and easy to implement (Biswal et al., 1997) and it is particularly suitable for the study of a complex
structure like the cerebellum is, in which the function of each subregion is defined by its connection
with specific brain areas (Schmahmann and Pandya, 1997; Middleton and Strick, 2001).
While structural patterns associated with cerebellum and cerebral cortex have been largely
investigated in SCA2, the few studies, that addressed FC, have used resting-state fMRI approaches
limited to investigate specific structures using regions chosen a priori through seed-based analysis
(HernandezCastillo et al., 2015a) or meaningful functional networks through independent
component analysis (ICA) (HernandezCastillo et al., 2015a; Cocozza et al., 2015). Indeed, the
analysis of pre-defined seed regions or specific networks only represents a small proportion of the
brain, thus they may not be able to provide a complete picture of how the connectome is affected in
by SCA2. Taking into account these limits, in the present study we aimed to investigate the whole-
brain functional organization associated with cerebellar structural degeneration in SCA2 by
applying the whole-brain analysis driven by graph theory, a mathematical approach that describes
complex systems as networks (Bullmore and Sporns, 2009; Rubinov and Sporn, 2010). In essence,
the brain is represented by a graph, composed by number of regions (nodes) that are functionally
connected to each other by the edges. The nodes can be defined anatomically or functionally, and
edges can be computed from RS-fMRI data. A graph can be represented mathematically by a matrix
(connectivity matrix), with each row/column identifying node, and the corresponding value
indicating the edge weight. Connectivity matrices can be compared using appropriate statistical
tools. Specifically, the Network Based Statistics (NBS) (Zalensky et al., 2010; Han et al., 2013), is
a validated statistical method to deal with the multiple comparisons problem when analyzing
connectivity matrices (or graphs). NBS can be used to identify connections and sub-networks
associated with an experimental effect or showing a between-group difference. (Zalenski et al.,
2010; Wen and Hsieh, 2016).
2. Materials and Methods
2.1 Subjects
Nine patients with SCA2 [F/M=6/3; mean age ± SD = 47.6± 10.2 years], were recruited from the
Ataxia Lab of Foundation Santa Lucia Hospital. Both in-patients (admitted for rehabilitation) and
out-patients (followed up at the clinic) were included. At the time of assessment, all patients had
more than 6 months of illness from the genetically confirmed diagnosis. The absence of any extra-
cerebellar lesion was investigated by an expert neuroradiologist and performed by visual inspection
of the T2-weighted MRI scans acquired as part of this research study.
All patients underwent a comprehensive neurological examination. They showed a pure cerebellar
syndrome. Only CA-2 presented a Babinski sign. Cerebellar motor deficits were assessed using the
International Cooperative Ataxia Rating Scale (ICARS, Trouillas et al., 1997). ICARS global score
ranges from 0 (absence of any motor deficit) to 100 (presence of motor deficits at the highest
degree). Demographic characteristics and total motor scores of the patients are reported in Table 1.
A group of 33 healthy subjects (HS) [F/M=21/12] ranging from 40 to 60 years of age [mean age ±
SD = 50.8 ± 8.8 years] with no history of neurological or psychiatric illness were also recruited as
control group. A T-test analysis ensured that there was no significant difference in the mean age
between the two groups (p=0.34).
All patients were examined extensively through a neuropsychological protocol, covering all
cognitive domains, including : a) verbal long-term memory: 15-Word List (Immediate and Delayed
recall) (Carlesimo et al., 1996); b) verbal and visuospatial short-term memory: Digit span and the
Corsi Block Tapping task (Monaco et al., 2013); c) executive functions: Phonological Word Fluency
(Carlesimo et al., 1996) and Modified Card Sorting Test (Heaton et al., 2000); d) Reasoning:
Raven’s Coloured Progressive Matrices (Carlesimo et al., 1996); e) constructional praxis: copy of
Complex Rey’s Figure (Carlesimo et al., 2002); f) language: Naming objects subtest of the BADA
(‘‘Batteria per l’Analisi dei Deficit Afasici’’, Italian for ‘‘Battery for the analysis of aphasic
deficits’’) (Miceli et al., 1991).
The results of the neuropsychological assessment are reported in Table 2.
This research study was approved by the Ethics Committee of Santa Lucia Foundation, according to
the principles expressed in the Declaration of Helsinki. Written informed consent was obtained
from each subject.
2.2 MRI acquisition protocol
All subjects underwent an MRI examination at 3T (Magnetom Allegra, Siemens, Erlangen,
Germany) that included the following acquisitions: 1) dual-echo turbo spin echo [TSE] (TR = 6190
ms, TE = 12/109 ms); 2) fast-FLAIR (TR = 8170 ms, 204TE = 96 ms, TI = 2100 ms); 3) 3D
Modified Driven Equilibrium Fourier Transform (MDEFT) scan (TR = 1338 ms, TE = 2.4 ms,
Matrix = 256 × 224 × 176, in-plane FOV = 250 × 250 mm2, slice thickness = 1 mm); 3) T2*
weighted echo planar imaging (EPI) sensitized to blood oxygenation level dependent imaging
(BOLD) contrast (TR: 2080 ms, TE: 30 ms, 32 axial slices parallel to AC-PC line, matrix: 64×64,
pixel size: 3×3 mm2, slice thickness: 2.5 mm, flip angle: 70°) for resting state fMRI. BOLD echo
planar images were collected during rest for a 7 min and 20 s period, resulting in a total of 220
volumes. During this acquisition, subjects were instructed to keep their eyes closed, not to think of
anything in particular, and not to fall asleep. The TSE scans of patients, acquired as part of this
research study, were reviewed by an expert neuroradiologist in order to characterize the brain
anatomy and determine the presence of macroscopic structural abnormalities involving
extracerebellar structures. For the control group, conventional MRI scans were inspected in order to
exclude any pathological conditions according to the inclusion criteria.
2.3 Resting state fMRI data preprocessing
Data were pre-processed using Statistical Parametric Mapping [Wellcome Department of Imaging
Neuroscience; SPM8 (], and in-house software implemented in
Matlab (The Mathworks Inc, Natick, Massachussetts, USA). For each subject, the first four
volumes of the fMRI series were discarded to allow for T1 equilibration effects. The pre-
processing steps included correction for head motion, compensation for slice-dependent time shifts,
normalization to the EPI template in MNI coordinates provided with SPM8, and smoothing with a
3D Gaussian Kernel with 8mm3 full-width at half maximum. For each data set the motion
parameters estimated during correction were checked to ensure that the maximum absolute shift did
not exceed 2 mm and the maximum absolute rotation did not exceed 1.5°. The global temporal drift
was removed using a 3rd order polynomial fit and the signal was regressed against the realignment
parameters, and the signal averaged over whole brain voxels, to remove other potential sources of
bias. Then, all images were filtered by a phase-insensitive band-pass filter (pass band 0.01-0.08
Hz) to reduce the effect of low frequency drift and high frequency physiological noise. Every
participant’s MDEFT was segmented in SPM in order to estimate the total grey matter (GM)
volume. This quantity was compared (using a two-sample T-test) between patients and controls to
exclude the presence of macroscopic atrophy in patients.
3. Statistical Analysis
3.1 Network Based Statistics
In order to obtain a connectivity matrix for each participant, we first identified a set of 116 nodes
defined by the automated anatomical labelling (AAL) atlas. Each node’s mean time course was
calculated as the average of the fMRI time series from all voxels within a given region. Correlation
matrices were then obtained calculating the correlation between all pairs of nodes’ mean signals as
described by Serra and colleagues (2016). In this way, we were able to assess differences in
functional connectivity (FC) between specific cerebellar and cerebral “nodes”. The “Networks-
based statistics” (NBS) tool developed by Zalesky and co-authors (2010) was used for statistical
comparison. A two-sample t-test was used to compare FC matrices between patients and controls,
with 5000 permutations and setting the significant p-value at 0.05 corrected for multiple
comparisons by using NBS correction (Zalesky et al., 2010).
4. Results
4.1 Neuropsychological assessment
The neuropsychological assessment revealed the presence of selective and very slight impairments
in some patients but did not show clear evidence of general cognitive impairment. Indeed, some
patients displayed values below the cut-off in word fluency test and backward digit span (CA5),
forward digit span (CA7), and Wisconsin Card Sorting Test (CA6) (see Table 2). These results are
consistent with findings that patients who are affected by cerebellar damage do not present with
marked cognitive deficits.
4.2 Resting-state fMRI data results
No significant differences were found between total GM volumes of patients [mean ± SD = 655.7
± 51.5] and controls [mean ± SD = 644.2 ± 49.1] as assessed by the T-test analysis (p=0.26).
NBS analysis showed altered inter-nodal connectivity between cerebellum and several cerebral
regions throughout the whole brain. Overall, 62 nodes and 110 edges showed differences in SCA2
brains compared to control ones while 57 edges and 35 nodes survived after Bonferroni correction
for multiple comparisons (FWE= .05) (Fig 1a). According to the cerebellar functional topography,
cerebellar nodes in the posterior cerebellum, such as Crus I and Crus II, showed reduced FC with
nodes in cortical regions implicated in cognition and emotion, such as superior (SFg) and middle
(MFg) frontal gyrus. Similarly, cerebellar nodes in the motor anterior cerebellum, such as lobule
III, IV, V, and vermis IV-V, showed reduced FC with nodes in the cortical regions related to motor
control, such as precentral (PrG) and postcentral (PcG) gyrus, Rolandic Operculum (RO),
supplementary motor area (SMA) (Fig.1b).
Finally, reduced inter-nodal FC was found between cerebellar lobule VI and both cognitive and
motor regions in the cerebral cortex, including supramarginal gyrus and supplementary motor area.
A similar pattern was found in the vermis lobule VI, showing decreased functional connectivity
with regions in the rolandic and frontal operculum as well as the supramarginal area. Detailed
results of NBS analysis are reported in table 3 that shows the cerebello-cortical edges of significant
FC decrease in SCA2 patients.
Figure1. a) Network of significantly decreased functional connectivity in SCA2 patients as assessed by NBS analysis
(FWE= .05). The regions of the cerebello-cortical (red) and cortico-cortical (blue) modules are shown in different
colors. Bigger nodes correspond to cerebellar and cortical regions relevant to cognition and emotion; smaller nodes
correspond to cerebellar and cortical regions relevant to motor control. The brain network is visualized using the
BrainNet Viewer ( (Xia et al., 2013). b) Anatomical representations of cognitive
(violet) and motor (green) nodes in the cerebellum and cerebral cortex showing underconnectivity between each other.
5. Discussion
Despite the advancing knowledge of cerebellar functions, the specific role that the cerebellum plays
in concert with other brain regions in SCA2 patients remains unclear. RS-fMRI is an ideal method
for investigating functional interactions between cerebellum and cerebral cortex in the human brain
and it may prove a useful tool for interpreting motor and non-motor impairment driven by the
cerebellar damage.
A growing body of studies explored the use of RS-fMRI in functional disconnection in
neurological and psychiatric disorders (Greicius and Menon, 2004; Greicius et al., 2007; Rombouts
et al., 2005, 2009; Liu et al., 2008; Bluhm et al., 2009; Whitfield-Gabrieli et al., 2009). Disrupted
functional cerebellar connectivity has been demonstrated in patients with schizophrenia (Liu et al.,
2008; Collin et al., 2011;), Parkinson’s Disease (Liu et al., 2013), and major depressive disorder
(Ma et al., 2013). Disruption of visual and motor connectivity has also been demonstrated in
spinocerebellar ataxia type 7 (SCA 7) supporting the theory that neurodegenerative diseases target
specific regions in large-scale networks (Seeley et al., 2007). Further, typical connectivity patterns
have been characterized in patients with autosomal dominant spinocerebellar ataxia 17 (SCA17)
(Reetz et al., 2012) suggesting that the broad range of symptoms observed in SCA17 patients may
primarily reflect the involvement of distinct functional networks affected by the cerebellar atrophy.
A disconnection syndrome has been suggested in spinocerebellar ataxia type 1 (SCA 1) by means
of intrinsic functional analysis and diffusion tensor imaging (Solodkin et al., 2011).
Accordingly, RS-fMRI studies in healthy subjects provided a detailed mapping of resting state
networks of the human cerebellum revealing that distinct networks are associated with each single
lobule (Bernard et al., 2012). van den Heuvel and Hulshoff Pol (2010) suggested that there is a
more general link between structural and functional connectivity. Indeed, it has been shown that
almost all functionally linked regions of the most often reported resting-state networks are
structurally interconnected by known white matter tracts (van den Heuvel et al., 2009). This
suggests the existence of a general structural core of resting-state networks, supporting the notion
of an overall link between structural and functional connectivity on a whole-brain scale
(Damoiseaux and Greicius, 2009; Hagmann et al., 2008). These assumptions support the idea that
the functional heterogeneity of the cerebellum is reflected in its connectional heterogeneity and
give rise to the hypothesis that different cerebello-cortical projections and distinct functional
modules can be selectively impaired by cerebellar disorders.
In the present study the pattern of FC alterations between regions in the cerebellum and cerebral
cortex has been extensively characterized in SCA2 patients using the NBS approach, that is based
on the whole-brain analysis allowing complex systems to be described as networks (Bullmore and
Sporns, 2009; Rubinov and Sporn, 2010). We found nodes in the posterior cerebellum to show
reduced functional connectivity with nodes in cortical regions related to cognition and emotion and
nodes in the anterior cerebellum to show reduced functional connectivity with nodes in the cortical
regions related to motor control. This result is, at least in part, in line with a previous FC study in
SCA2 patients using a seed-based approach (Hernandez-Castillo et al., 2015a) and showing FC
decrease between the right posterior cerebellum and the left superior frontal gyrus, which could
impact different cognitive operations such as self-monitoring and verbal/visuospatial working
memory (Cao et al., 1998; O’Reilly et al., 2010).
Additionally, we found that in both hemispheres and vermis, lobule VI shows decreased FC with
regions related to motor control as well as to cognition and emotion (i.e. supplementary motor area,
rolandic opercula, cingulum and supramarginal gyrus). It is worth noting that the right
supramarginal gyrus is considered a region strongly implicated in emotional processing related to
social judgements and empathy (Silani et al., 2013; Hoffman et al., 2016). This finding is in line
with the evidence suggesting that SCA 2 patients are impaired in emotional behaviour (D’Agata et
al., 2011; Sokolovsky et al., 2010). The hypothesis is that cerebellar cortical neurodegeneration
associated with SCA2 may impact spatially segregated cortical regions that are functionally
connected to the cerebellum thus affecting cerebello-cortical functional networks relevant for both
motor and non-motor functions. With respect to the latter ones, cumulative evidences have been
collected suggesting that connections between posterior cerebellum and cerebral cortex are related
to cognitive functions (Stoodley and Schmahmann 2009, 2010; Strick et al., 2009; Stoodley et al.,
2012). In our SCA2 patients, within the posterior cerebellum the prominent finding was an
impaired connectivity towards medial and superior frontal regions. These prefrontal areas have
been consistently implicated in different aspects of executive functions using both verbal and
visuospatial tasks (Reverberi et al., 2005; Crescentini et al., 2011; Langdon and Warrington, 2000).
In spite of this, in the present study only 3 patients presented impaired performances in executive
processing and verbal working memory. This datum can be explained by the fact that most
standard norms of testing do not detect cognitive impairments in cerebellar cohorts because
cerebellar patients’ symptoms are present in selective domains and very often, they can be detected
only when the patients are compared to matched healthy controls (Tedesco et al., 2011).
An important issue that needs to be discussed is that the pattern of decreased cerebello-cerebral
functional connectivity may be at least in part explained by damage of the cortical GM in SCA2.
Indeed, cerebellar atrophy has been also reported to reduce GM volume in several supratentorial
areas (Brenneis et al., 2003; Della Nave et al., 2008a). Thus, even if in the present study the total
GM volume was not significantly different between SCA2 patients and controls, the possibility of
local GM loss cannot be ruled out. An alternative explanation for the absence of significant whole
brain GM loss in patients might be that the pattern of ponto-cerebellar atrophy associated with
SCA2 pathology predominantly entails a WM damage (Della Nave et al., 2008b).
Overall, the observed pattern of inter-nodal underconnectivity is consistent with previous studies
using different RS-fMRI approaches (O’Reilly et al., 2010; Bernard et al., 2012) demonstrating in
healthy subjects the functional segregation of the cerebellum in sensorimotor and supramodal
zones, the former containing overlapping functional connectivity maps for domain-specific motor
and somatosensory cortices, the latter for prefrontal and posterior-parietal cortex, and provides
important insight into understanding the neural circuit abnormalities in SCA2. In light of the
general link between structural and functional connectivity (van den Heuvel et al., 2009) a
comprehensive understanding of neural connectivity may require clear evidence as to whether
structural connectivity is affected in SCA2. In SCA2 patients microstructural alterations of the
cerebellar WM have been reported by Diffusion Tensor Imaging (DTI) studies, showing the
prevalent involvement of the main afferent and efferent tracts (i.e. Middle and Superior Cerebellar
Peduncle), connecting the cerebellum with both motor and non-motor cortical regions (Mandelli et
al., 2007; Della Nave et al., 2008b; Hernandez-Castillo et al., 2015b). Although in the present study
structural connectivity has not been specifically investigated, it has to be considered that
microstructural abnormalities of the cerebellar WM tracts, typically reported in SCA2 patients,
may underlie a deficient structural connectivity that impacts the cerebello-cerebral interplay and
results in a lack of functional connectivity.
Cerebellar clusters of significantly reduced functional connectivity have been recently reported by
Cocozza and colleagues (2015) only in the default mode network, executive control network and
right fronto-parietal network in patients with SCA2. However, this study used a different resting-
state approach (i.e. ICA) limited to investigate connectivity within specific functional networks
(Cocozza et al., 2015). In the present study, by using a whole-brain approach, we provide
additional evidence that extensive and segregated functional brain changes may occur as the result
of the SCA2 degenerative process.
Indeed, cerebello-cerebral functional disconnections are observed in this patient population
throughout the brain and they are consistent with the pattern of cerebellar structural alterations
mainly involving vermis and cerebellar hemispheres reported by Della Nave and colleagues (2008)
In particular, connectivity reduction involved segregated motor and cognitive cerebello-cortical
networks with the only exception of lobule VI involvement, not by chance a region in which both
motor, cognitive, and emotional functions are localized.
It has to be underlined that we also found crus II e lobule VII to show a functional disconnection
with nodes in superior and middle frontal regions. This evidence is partially inconsistent with
previous VBM studies that have shown cerebellar grey matter reduction to spare both Crus II and
lobule VII in SCA2 patients (Brenneis et al., 2003; Ying et al., 2006; Della Nave et al., 2008).
Nevertheless, it has to be considered that a functional coherence between the two cerebellar
hemispheres has been widely demonstrated by RS-fMRI studies (Habas et al., 2009; O’Reilly et al.,
2009; Buckner et al., 2011). Thus, it is reasonable to hypothesize that the cerebellar regions that are
not directly affected by the degenerative process could suffer from the functional release of the
affected cerebellar regions and result functionally impaired.
A limitation of this study is that, due to the small number of patients, the cognitive performance has
not been directly correlated with functional connectivity alterations observed. Further
investigations are needed to support our interpretation with greater patient population.
5. Conclusion
To our knowledge this is the first study using a whole-brain approach to investigate functional
organization in SCA2 patients and to detect cerebello-cerebral inter-nodal connectivity changes
that can be associated with cerebellar structural abnormalities of SCA2.
Altogether, the present findings show that a cerebellar dysfunction may affect long-distance
regions in the cerebral cortex targeted by cerebellar projections and that specific cerebral functional
alterations derive from cerebellar structural degeneration typically associated with SCA2
pathology, thus resulting into the multifarious motor, cognitive, and emotional deficits evidenced
in patients.
Conflict of Interest
The authors declare that they have no conflict of interest.
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Table 1. Demographic and clinical characteristics of the patients.
Case code
Years of Illness
ICARS = International Cooperative Ataxia Rating Scale
Table 2. Patients’ Neuropsychological assessment.
Cut-off values refer to published normative data. Scores below the cut-off are marked in bold.
IR: Rey’s 15 mots short term (immediate recall); DR: Rey’s 15 mots long term (delayed recall); PM:
Progressive Matrices; WF: word fluency; fREY: Complex Rey’s Figure-copy; FDS: forward digit span;
BDS: backward digit span; FC: forward Corsi; BC: backwords Corsi; WISC: Wisconsin Card Sorting Test:
PErr (perseverative errors), TErr:total errors; NamOb(err): Naming objects (errors).
PErr TErr
Table 3
Table 3. Cerebello-cerebral nodes of functional underconnectivity
Pairwise brain regions
R-Crus I
L-temporal inferior
L-frontal medial
L-Crus I
R-frontal superior
R-frontal medial
L-Crus II
R-frontal superior
R-Frontal medial
L-frontal superior
L-frontal medial
L-temporal inferior
L-frontal medial
R-frontal medial
R-supplementary motor
L-supplementary motor
L-supplementary motor
R-supplementary motor
R-frontal inferior operculum
L-frontal inferior operculum
L-frontal inferior operculum
L-rolandic operculum
R-rolandic operculum
L-postcentral gyrus
L-frontal inferior operculum
L-frontal inferior operculum
R-frontal inferior operculum
L-frontal inferior,pars triangularis
R-rolandic operculum
L-postcentral gyrus
L-precentral gyrus
R-precentral gyrus
L-frontal inferior operculum
L-rolandic operculum
R-rolandic operculum
L-supplementary motor
R-supplementary motor
L-postcentral gyrus
R-postcentral gyrus
L-frontal inferior operculum
L-rolandic operculum
R-rolandic operculum
Table 3. Difference of functional connectivity into pairwise brain regions in patients with SCA2 compared to controls (p-
value <0.05 in the whole-network comparison using Network Based statistics)
*t-values are reported; R=right; L=left
1) A cerebellar dysfunction affects long-distance cerebral regions in SCA2 patients
2) Connectivity changes affect sensorimotor and cognitive cerebello-cortical nodes
3) Cerebellar symptoms may be related to altered cerebello-cerebral connectivity
... Conventional MRI scans were inspected by an expert neuroradiologist confirming the absence of macroscopic extra-cerebellar brain abnormalities and revealing the presence of diffuse cerebellar gray matter atrophy as showed in Fig. 1. The patients in the present study correspond to a previous study that investigated motor reserve in SCA2 [24] and partially overlapped with the samples of other studies [22,23,30]. ...
... Cognitive functions in SCA2 patients were underrated until several years ago but have now been widely evaluated, some of whom have been recognized to be deficient in this population [9,30,47]. However, cognitive reserve has been largely ignored. ...
... L left; R right correlated with the degree of gray matter reduction in cerebellar lobules that modulate cognitive processes, such as lobules VII and VIII [47]. Studies on SCA2 patient morphological alterations typically report cerebellar degeneration in anterior (I-II, IV-V) and posterior (VI, VII and VIII) lobules [30,47,49,50]. On the contrary, disease progression spares degeneration in lobule X [49][50][51]. ...
Full-text available
Pre-existing or enhanced cognitive abilities influence symptom onset and severity in neurodegenerative diseases, which improve an individual’s ability to deal with neurodegeneration. This process is named cognitive reserve (CR), and it has acquired high visibility in the field of neurodegeneration. However, the investigation of CR has been neglected in the context of cerebellar neurodegenerative disorders. The present study assessed CR and its impact on cognitive abilities in spinocerebellar ataxia type 2 (SCA2), which is a rare cerebellar neurodegenerative disease. We investigated the existence of CR networks in terms of compensatory mechanisms and neural reserve driven by increased cerebello-cerebral functional connectivity. The CR of 12 SCA2 patients was assessed using the Cognitive Reserve Index Questionnaire (CRIq), which was developed for appraising life-span CR. Patients underwent several neuropsychological tests to evaluate cognitive functioning and a functional MRI examination. Network based statistics analysis was used to assess functional brain networks. The results revealed significant correlations of CRIq measures with cognitive domains and patterns of increased connectivity in specific cerebellar and cerebral regions, which likely indicated CR networks. This study showed that CR may influence disease-related cognitive deficits, and it was related to the effective use of specific cerebello-cerebral networks that reflect a CR biomarker. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-023-11855-3.
... 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 et al. 2017a). Interestingly, correlations between cerebellar volumes and visuospatial and verbal scores did not show a specific 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 et al. 2005;Milardi et al. 2016) and with evidence showing that left-or right-damaged cerebellar patients have a similar cognitive profile ) (see the "Laterality effects" section for details on this issue). ...
... 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 et al. 2017a). The NBS approach allows complex systems to be described as networks (Zalensky et al. 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 finding was impaired connectivity toward medial and superior frontal regions that have been consistently implicated in different aspects of executive functions (Olivito et al. 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 et al. 2015). ...
In 1998, Schmahmann and Sherman defined 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 et al. characterized the cognitive profile 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 specific cerebello-cortical regions might explain the widespread deficits typically observed in patients.KeywordsCerebellumLaterality effectSCAPICADeep cerebellar nucleiPosterior lobeCerebello-cerebral networkFunctional connectivity
... Motor networks have been studied in other neurodegenerative diseases comprising the precentral cortex, basal ganglia, thalamus, ventral diencephalon, and cerebellum. 17,[20][21][22][23] We used network-based statistics (NBS), 24 a statistical approach that identifies connections in a graph that may be relevant to diagnostic status, 25 to find different subnetworks in preclinical and ataxic SCA3/MJD patients. Given that previous imaging studies have shown that morphological changes already occur in the cerebellum at the preataxic stage, we hypothesized that motor network abnormalities are already detectible before the onset of ataxia, and motor network alterations are associated with disease severity in SCA3/MJD. ...
... The network-based statistics (NBS) toolbox introduced by Zalesky et al. 24 was utilized for performing edge-wise analyses to identify subnetworks (clusters of nodes and edges) comprising connections with reduced connectivity strength in preclinical and ataxia SCA3/MJD patients. In brief, a two-sample t-test was independently performed at each edge to test the null hypothesis of equality in mean connectivity strength, with age as a nuisance variable, between patients and controls. ...
... This result reflects cerebral-cerebellar connectivity disruption, which is also found in other types of ataxia. 24,48,49 A recent neuroimage study 12,50 in preclinical SCA3/MJD patients reported white matter fiber damage in the bilateral cerebellar peduncles and cerebellum. As a bridge between the cerebellum and other brain areas, the WM fiber damage in cerebellum peduncles decreases the structural connectivity between the cerebellum, thalamus, and base ganglia, which may lead to a change in the motor network of patients with preclinical SCA3/MJD. ...
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Objectives: Spinocerebellar ataxia type 3 is a disorder within the brain network. However, the relationship between the brain network and disease severity is still unclear. This study aims to investigate changes in the white matter (WM) structural motor network, both in preclinical and ataxic stages, and its relationship with disease severity. Methods: For this study, 20 ataxic, 20 preclinical SCA3 patients, and 20 healthy controls were recruited and received MRI scans. Disease severity was quantified using the SARA and ICARS scores. The WM motor structural network was created using probabilistic fiber tracking and was analyzed using graph theory and network-based statistics at global, nodal, and edge levels. In addition, the correlations between network topological measures and disease duration or clinical scores were analyzed. Results: Preclinical patients showed increasing assortativity of the motor network, altered subnetwork including 12 edges of 11 nodes, and 5 brain regions presenting reduced nodal strength. In ataxic patients assortativity of the motor network also increased, but global efficiency, global strength, and transitivity decreased. Ataxic patients showed a wider altered subnetwork and a higher number of reduced nodal strengths. A negative correlation between the transitivity of the motor network and SARA and ICARS scores was observed in ataxic patients. Interpretation: Changes to the WM motor network in SCA3 start before ataxia onset, and WM motor network involvement increases with disease progression. Global network topological measures of the WM motor network appear to be a promising image biomarker for disease severity. This study provides new insights into the pathophysiology of disease in SCA3/MJD.
... Apart from CB11, who presented with a coronary stent incompatible with MRI scanning, all other patients underwent an MRI examination, and had no macroscopic extracerebellar brain abnormalities, as assessed by an expert neuroradiologist by visual inspection of the T2-weighted MRI scans. Some of these patients had participated in previous studies [15,16,23]. The demographic and clinical characteristics of the patients are reported in Table 1. ...
... Indeed, the NBS analysis revealed patterns of increased internodal connectivity between specific cerebral and cerebellar areas. Abnormal connectivity within cerebello-cortical regions has been consistently described in SCA2 patients, suggesting that the impaired cerebello-cerebral interaction may explain the widespread deficits typically observed in such patients [15,16,23]. However, while patterns of decreased FC are typically explored and described as representative of deteriorated pathways associated with affected functions, increased FC is described in the literature in terms of both degenerative and compensatory modifications [9,51]. ...
... The present study revealed SCA2 patients' patterns of increased internodal cerebralcerebellar FC that do not correlate with MRIq measures (see Table 5). Interestingly, alterations in these areas are associated with patients' deficits in motor, sensorimotor, and cognitive functions [15,23], and have been explained in terms of pathological functional mechanisms related to cerebellar alterations [52]. ...
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The ability to resiliently cope with neuropathological lesions is a key scientific concern. Accordingly, this study aims to investigate whether motor reserve (MR), likely to be boosted by exercise engagement in a lifetime, affects motor symptom severity, cognitive functioning, and functional brain networks in spinocerebellar ataxia type 2 (SCA2)—a cerebellar neurodegenerative disease. The MR of 12 SCA2 patients was assessed using the Motor Reserve Index Questionnaire (MRIq), developed ad hoc for estimating lifespan MR. The International Cooperative Ataxia Rating Scale was used to assess clinical motor features, and neuropsychological tests were used to evaluate cognitive functioning. Patients underwent an MRI examination, and network-based statistics (NBS) analysis was carried out to detect patterns of functional connectivity (FC). Significant correlations were found between MRIq measures and the severity of motor symptoms, educational and intellectual levels, executive function, and processing speed. NBS analysis revealed a higher FC within subnetworks consisting of specific cerebellar and cerebral areas. FC patterns were positively correlated with MRIq measures, likely indicating the identification of an MR network. The identified network might reflect a biomarker likely to underlie MR, influenced by education and cognitive functioning, and impacting the severity of motor symptoms.
... When compared to controls, the CD group showed a diffuse pattern of GM loss throughout the cerebellar cortex. In line with the presence of typical cerebellar motor syndrome [19,55,69], an extensive pattern of GM loss involved motor anterior (i.e., I−IV, V) and posterior cerebellar regions (i.e., VIIIA and VIIIB). On the other hand, a pattern of GM loss was also found to extensively affect cognitive posterior cerebellar lobules, specifically crus I, crus II and lobe VI, in line with the presence of cognitive and emotional alterations as reported in CCAS [46,54,55,[69][70][71][72]. ...
... In line with the presence of typical cerebellar motor syndrome [19,55,69], an extensive pattern of GM loss involved motor anterior (i.e., I−IV, V) and posterior cerebellar regions (i.e., VIIIA and VIIIB). On the other hand, a pattern of GM loss was also found to extensively affect cognitive posterior cerebellar lobules, specifically crus I, crus II and lobe VI, in line with the presence of cognitive and emotional alterations as reported in CCAS [46,54,55,[69][70][71][72]. Finally, when directly comparing BD and CD patients, significantly reduced cerebellar GM was found in the CD compared to the BD patients, only involving motor anterior cerebellar regions. ...
... Finally, when directly comparing BD and CD patients, significantly reduced cerebellar GM was found in the CD compared to the BD patients, only involving motor anterior cerebellar regions. This is in line with the presence of the cerebellar motor syndrome that is specific of CD patients and was not detected in our BD patients [19,55,69]. As previously stated, structural alterations in anterior cerebellar regions are also found in BD but they may be more related to the psychomotor agitation that typically accompanies the affective episodes. ...
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The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I−IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder.
... However, an ongoing follow-up study in a larger cohort of Cuban SCA2 patients and preclinical carriers scanned with higher-resolution imaging will have studied in depth, to clarify the present data. In addition, our correlation analyses also corroborated the role of the cerebellum for the control of cognition in SCA2 [18,19], but this was true only for the verbal memory test and not for the Stroop test, as we had previously observed [13]. ...
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Background. The influence of brain atrophy on sleep microstructure impairments in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. Objective. To explore the relationship between sleep microstructure and the brain atrophy in SCA2 and its role on the clinical phenotype Methods. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. Results. The sleep spindle activity was directly correlated with the cerebellar volume and the anteroposterior diameter of the pons. Sleep spindles significantly mediated the effect of the cerebellar atrophy on verbal memory test performance. In REM sleep, Phasic EMG activity and REM sleep without atonia were both directly associated with pontine atrophy but showed no causal mediation effect between the atrophy measures and disease severity markers. Conclusions. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindles activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as useful disease biomarkers. Clinical trial registration number (TRN): No applicable
... Differential changes in functional connectivity have been established for different SCA subtypes based on resting-state fMRI [25,26,40]. We did not deem it appropriate to discuss the differential pattern of volumetric changes in comparison to fMRI findings in distinct SCA aetiologies due to the differences in the group composition and the methodological differences. ...
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Objective We aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex. Methods We recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular–motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry. Results Patients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular–motor representations in lobules IX, X and V–VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition. Conclusion Functional disability in multiple domains was associated with structural changes in the cerebral cortex.
... Cognitive speed, verbal and executive disturbances reported in specific SCA subtypes also vary according to clinical variables and in particular illness onset and duration. In SCA2 patients for instance no or slight impairments of word fluency and executive function were observed after one to three years of illness 12 , verbal memory and fluency impairments after 6 years of illness 29 . A follow-up study reported some impairments in SCA2 patients on tasks of speed, attention and executive function after ten to fifteen years of illness and relatively little change over an additional 7-year period suggesting a rather stable neuropsychological profile in SCA2 patients 8 , also reported by Le Pira et al's study after 8.5 years of follow-up in SCA2 patients. ...
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Over the last decade a number of studies have demonstrated the implication of the cerebellum in cognition, including verbal memory, executive function, and language. Social cognition abilities like emotion attribution and theory of mind are essential in social interaction and rely on verbal abilities and executive functions. Involvement in social cognition has been explored in the most common forms of Spinocerebellar Ataxia (SCA), but several aspects remain unclear. The present study tested whether socio-affective impairments are observed in SCA patients by using different tasks and to determine whether these impairments were associated with reduced verbal processing and/or processing speed. 13 patients (SCA1, n=1; SC2, n=5; SCA3, n=7) were matched with 13 controls for gender, age and education. Verbal and non-verbal theory of mind abilities were tested (validated French versions of an attribution of intention test, faux-pas test), and emotion attribution. Language efficacy was explored in a word fluency test and processing speed in two non-motor tasks. Results revealed no difference between SCA2 and SCA3 patients in neither socio-affective or cognitive test. Performance on all tests was on contrary significantly reduced in the SCA patient group compared to controls. SCA patients' performance was positively correlated between the three social cognition tests, indicating a somewhat generalized impairment. Their performance rate in each of three social cognition tests was further correlated with processing speed but not with word fluency. In the verbal theory of mind task they displayed however comprehension deficits of the faux-pas and of general control questions. Taken together the data suggest that processing speed and comprehension difficulties might account, partly at least, for socio-affective and cognitive deficits in both genotypes. This conclusion was modulated by the observation that the neuropsychological features did not correspond well with age of illness diagnosis and illness duration, indicating that there is a degree of heterogeneity in the cognitive profiles and social cognitive impairments in SCA patients.
... Here, previous MRI studies have revealed comparable volume reductions in both anterior and posterior regions of the cerebellum in patients with SCA2 [44], which has been supported by neuropathological analyses [45]. In addition, the selective decrease of the functional connectivity between these regions with the somatosensory cortex and the cognition-related cortical regions, respectively, occurs in similar extent [46,47]. Moreover, the comparable extent of cerebellar atrophy with the degeneration of the basal forebrain nuclei [48] and the thalamic nuclei [49] also could underlie the parallelism between motor and cognitive severity in SCA2. ...
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The cerebellar cognitive affective syndrome scale (CCAS-S) was designed to detect specific cognitive dysfunctions in cerebellar patients but is scarcely validated in spinocerebellar ataxias (SCA). The objective of this study is to determine the usefulness of the CCAS-S in a Cuban cohort of SCA2 patients and the relationship of its scores with disease severity. The original scale underwent a forward and backward translation into Spanish language, followed by a pilot study to evaluate its comprehensibility. Reliability, discriminant, and convergent validity assessments were conducted in 64 SCA2 patients and 64 healthy controls matched for sex, age, and education. Fifty patients completed the Montreal Cognitive Assessment (MoCA) test. The CCAS-S showed an acceptable internal consistency (Cronbach’s alpha = 0.74) while its total raw score and the number of failed tests showed excellent (ICC = 0.94) and good (ICC = 0.89) test–retest reliability, respectively. Based on original cut-offs, the sensitivity of CCAS-S to detect possible/probable/definite CCAS was notably high (100%/100%/91%), but specificities were low (6%/30/64%) because the decreased specificity observed in four items. CCAS-S performance was significantly influenced by ataxia severity in patients and by education in both groups. CCAS-S scores correlated with MoCA scores, but showed higher sensitivity than MoCA to detect cognitive impairments in patients. The CCAS-S is particularly useful to detect cognitive impairments in SCA2 but some transcultural and/or age and education-dependent adaptations could be necessary to improve its diagnostic properties. Furthermore, this scale confirmed the parallelism between cognitive and motor deficits in SCA2, giving better insights into the disease pathophysiology and identifying novel outcomes for clinical trials.
The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative, and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher-order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies have demonstrated the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of cerebellar incorporation into circuits that subserve cognition and emotion mandates a deeper understanding of the cerebellum by practitioners in behavioral neurology and neuropsychiatry because it impacts the understanding and diagnosis of disorders of emotion and intellect and has potential for novel cerebellar-based approaches to therapy.
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The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.
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Although cerebellar-cortical interactions have been studied extensively in animal models and humans using modern neuroimaging techniques, the effects of cerebellar stroke and focal lesions on cerebral cortical processing remain unknown. In the present study, we analyzed the large-scale functional connectivity at the cortical level by combining high-density electroencephalography (EEG) and source imaging techniques to evaluate and quantify the compensatory reorganization of brain networks after cerebellar damage. The experimental protocol comprised a repetitive finger extension task by 10 patients with unilateral focal cerebellar lesions and 10 matched healthy controls. A graph theoretical approach was used to investigate the functional reorganization of cortical networks. Our patients, compared with controls, exhibited significant differences at global and local topological level of their brain networks. An abnormal rise in small-world network efficiency was observed in the gamma band (30–40 Hz) during execution of the task, paralleled by increased long-range connectivity between cortical hemispheres. Our findings show that a pervasive reorganization of the brain network is associated with cerebellar focal damage and support the idea that the cerebellum boosts or refines cortical functions. Clinically, these results suggest that cortical changes after cerebellar damage are achieved through an increase in the interactions between remote cortical areas and that rehabilitation should aim to reshape functional activation patterns. Future studies should determine whether these hypotheses are limited to motor tasks or if they also apply to cerebro-cerebellar dysfunction in general.
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Background: The natural history of clinical symptoms in the spinocerebellar ataxias (SCA)s has been well characterised. However there is little longitudinal data comparing cognitive changes in the most common SCA subtypes over time. The present study provides a preliminary longitudinal characterisation of the clinical and cognitive profiles in patients with SCA1, SCA2, SCA3, SCA6 and SCA7, with the aim of elucidating the role of the cerebellum in cognition. Methods: 13 patients with different SCAs all caused by CAG repeat expansion (SCA1, n = 2; SCA2, n = 2; SCA3, n = 2; SCA6, n = 4; and SCA7, n = 3) completed a comprehensive battery of cognitive and mood assessments at two time points, a mean of 7.35 years apart. All patients were evaluated clinically using the Scale for the Rating and Assessment of Ataxia (SARA) and the Inventory of Non-Ataxia Signs (INAS). Patients underwent structural MRI imaging at follow-up. Results: Clinical scale scores increased in all patients over time, most prominently in the SCA1 (SARA) and SCA3 (INAS) groups. New impairments on neuropsychological tests were most commonly observed with executive functions, speed, attention, visual memory and Theory of Mind. Results suggest possible differences in cognitive decline in SCA subtypes, with the most rapid cognitive decline observed in the SCA1 patients, and the least in the SCA6 patients, congruent with observed patterns of motor deterioration. Minimal changes in mood were observed, and MRI measures of atrophy did not correlate with cognitive decline. Conclusion: As well as increasing physical impairment, cognitive decline over time appears to be a distinct aspect of the SCA phenotype, in keeping with the cerebellar cognitive-affective syndrome. Our data suggest a trend of cognitive decline that is different for each SCA subtype, and for the majority is related to the severity of cerebellar motor impairment.
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Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients’ dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the “Reading the Mind in the Eyes” and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients’ “Theory of Mind-network”, which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients’ success in life.
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Introduction Preoccupation and compulsive use of the internet can have negative psychological effects, such that it is increasingly being recognized as a mental disorder. The present study employed network-based statistics to explore how whole-brain functional connections at rest is related to the extent of individual’s level of internet addiction, indexed by a self-rated questionnaire. We identified two topologically significant networks, one with connections that are positively correlated with internet addiction tendency, and one with connections negatively correlated with internet addiction tendency. The two networks are interconnected mostly at frontal regions, which might reflect alterations in the frontal region for different aspects of cognitive control (i.e., for control of internet usage and gaming skills). Next, we categorized the brain into several large regional subgroupings, and found that the majority of proportions of connections in the two networks correspond to the cerebellar model of addiction which encompasses the four-circuit model. Lastly, we observed that the brain regions with the most inter-regional connections associated with internet addiction tendency replicate those often seen in addiction literature, and is corroborated by our meta-analysis of internet addiction studies. This research provides a better understanding of large-scale networks involved in internet addiction tendency and shows that pre-clinical levels of internet addiction are associated with similar regions and connections as clinical cases of addiction.
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Autism spectrum disorder (ASD) shows deficits in self-other distinction during theory of mind (ToM). Here we investigated whether ASD patients also show difficulties in self-other distinction during empathy and if potential deficits are linked to dysfunctional resting-state connectivity patterns. In a first study, ASD patients and controls performed an emotional egocentricity paradigm and a ToM task. In the second study, resting-state connectivity of right temporo-parietal junction and right supramarginal gyrus (rSMG) were analysed using a large-scale fMRI data set. ASD patients exhibited deficient ToM but normal emotional egocentricity, which was paralleled by reduced connectivity of regions of the ToM network and unimpaired rSMG network connectivity. These results suggest spared self-other distinction during empathy and an intact rSMG network in ASD.
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Background: Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. Methods: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. Results: Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. Conclusion: Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.
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Background: Several neuropathological studies in spinocerebellar ataxia type 2 (SCA2) have revealed significant atrophy of the cerebellum, brainstem, sensorimotor cortex, and several regions in the frontal lobe. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is unknown. To analyze the clinical impact of these functional changes, we correlated the abnormal functional connectivity found in SCA2 patients with their scores in clinical scales. To obtain the functional connectivity changes, we followed two approaches. In one we used areas with significant cerebellar gray matter atrophy as anchor seeds, and in the other we performed a whole-brain data-driven analysis. Methods: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Voxel-based morphometry and resting-state functional magnetic resonance imaging (fMRI) were done to analyze structural and functional brain changes. Independent component analysis and dual regression were used for intrinsic network comparison. Significant functional connectivity differences were correlated with the behavioral scores. Results: Seed-based analysis found reduced functional connectivity within the cerebellum and between the cerebellum and frontal/parietal cortices. Cerebellar functional connectivity increases were found with parietal, frontal, and temporal areas. Intrinsic network analysis found a functional decrease in the cerebellar network, and increase in the default-mode and fronto-parietal networks. Further analysis showed significant correlations between clinical scores and the abnormal functional connectivity strength. Conclusion: Our findings show significant correlations between functional connectivity changes in key areas affected in SCA2 and these patients' motor and neuropsychological impairments, adding an important insight to our understanding of the pathophysiology of SCA2. © 2015 International Parkinson and Movement Disorder Society.