Content uploaded by Marco Molinari
Author content
All content in this area was uploaded by Marco Molinari on Jan 28, 2014
Content may be subject to copyright.
Cognitive sequencing impairment in patients with
focal or atrophic cerebellar damage
M. G. Leggio,
1, 2
A. M . Tedesco,
1, 2
F. R. Chiricoz zi,
1, 2
S. Clausi,
1, 2
A. O rs i n i
1
and M. M o li nari
2
1
Department of Psychology, University of Rome ‘La Sapienza’ and
2
Ataxia Lab, I.R.C.C.S. Santa Lucia Foundation, Rome, Italy
Correspondence to: Maria G. Leggio, MD, PhD, Associate Professor of Psychophysiology, Head Ataxia Lab Santa Lucia
Foundat ion, De part ment of Psy chol ogy, U ni ve rs ity of Rome ‘ La Sapie nza’, V ia dei Marsi 78, 00185 Roma, Ital y
E-mail: maria.leggio@uniroma1.it
Al though cogniti ve im pai rment after cerebel l ar damage has been widel y reported, the mechani sms of cerebro-
cerebellar interactions are still a matter of debate. The cerebellum is involved in sequence detection and
production in both motor and sensory domains, and sequencing has been proposed as the basic mechanism of
cerebellar functioning. Furthermore, it has been sug gested that knowledge of sequencing mechanisms may help
to define cerebellar predictive control processes. In spite of its recognized importance, cerebellar sequencing
has sel dom been i nves tigated in cogniti ve domains. Cogni tive sequenci ng functi ons are often analysed by means
of action/ scri pt elabo rati on. Lesi on and activation stud ies ha ve l ocal ized this functi on i n frontal cortex and basal
ganglia circuits.The present study is the first to report deficits in script sequencing after cerebellar damage.We
emp lo yed a card-sequenci ng test, developed ad hoc, to evaluate the influence of the content to be sequenced.
Stimuli consisted of sets of sentences that described actions with a precise logical and temporal sequence
(Verbal Factor), sets of cartoon-like drawings that reproduced behavioural sequences (Behavioural Factor) or
abstract figures (Spatial Factor). The influence of the lesion characteristics was analysed by grouping patients
accordi ng to les ion-type ( focal or atrophi c ) and lesion-si de (right or left). The resul ts indi cated that patients with
cerebellar damage present a cognitive sequencing impairment independently of lesion type or localization.
A correlation was also shown betwe en lesion side and characteristics of the material to be sequenced. Namely,
patients with left lesions perform defectively only on script sequences based on pictorial material and patients
with right lesions only on script sequences requiring verbal elaboration.The present data support the hypothesis
that sequence processing is the cerebellar mode of operati on also in the cognitive domain. I n addition, the pre -
sence of right/left and pictorial/verbal differences is in agreement with the idea that cerebro-cerebellar interac-
tions are organized in segregated cortico-cerebellar loops in which specificity is not related to the mode of
functioning, but to the characteristics of the information processed.
Keywords: ce rebel l um ; execut i ve funct ion; pictu re arrange ment; script
Abbrev iations: MRI = magnetic resonance imaging; TIQ = total inte lli gence quotient; WAIS-r = Wechsler Adult Intel ligence
Scal e Rev ised
Recei ved July 24, 2007. Rev ised and Accepted February 14 , 2008. Adv ance Access publ i cation Mar ch 11, 2008
Introduction
Anatomical, experimental and functional neuroimaging and
clinical data stress the importance of cortico-cerebellar
interactions in a variety of non-motor functions such as
cognition, emotion and affective processing (Timmann and
Daum, 2007). This cerebellar revolution makes a complete
reconsideration of cortico-cerebellar interrelationships man-
datory in order to discover the mechanisms through which
the cerebellum exerts its influence on the cerebral cortex.
Among the different theories on cerebellar functions (Bower
and Parsons, 2003; Ito, 2006), a cerebellar role in sequencing
incoming sensory patterns and outgoing responses has been
proposed (Braitenberg et al., 1997; Ivry, 1997; Mauk, et al.,
2000). Visuo-spatial implicit learning of sequences in patients
with cerebellar lesions has been analysed in different
experimental paradigms and cerebellar patients have been
consistently reported impaired (Pascual-Leone et al., 1993;
Molinari et al., 1997; Doyon et al., 1998; Gomez-Beldarrain
et al., 1998). Functional magnetic resonance data in healthy
subjects are controversial in discriminating the cerebellar
involvement in sequence learning or in motor adaptation
(Doyon et al., 1998; Seidler et al., 2002; Parsons et al., 2005).
doi :10 .1093/ brain /a wn040 Bra in (200 8), 131,1332^1343
ß The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
Conversely, neurophysiological studies in healthy volunteers
or in patients with focal cerebellar damage indicated a role of
the cerebellum in sequence acquisition/detection (Molinari
et al., 1997; Restuccia et al., 2007).
Acquiring and acting upon a serial order of events is a
fundamental ability that can lead to sequence structure
knowledge either incidentally through experience (implicit
learning) or intentionally through explicit effort (declar-
ative learning). To recognize that stimuli are presented in
a given order, the sensory information pertaining to one
stimulus must be kept active in a working memory
system and compared with subsequent stimuli. Procedural
learning can be achieved only if the correct sequence of
events (sensory or motor) is acquired implicitly or
explicitly. Thus, a disruption of ‘sequence in’ processing
of stimuli could be responsible for the implicit learning
impairment.
The severity of cerebellar patients’ difficulty in the serial
reaction time task in detecting a visuo-spatial sequence,
indicates a prevalent role of cerebellar circuitry in
recognizing event sequences, rather than in planning and
executing them (Molinari et al., 1997). Tesche and Karhu
(2000), with a somatosensory evoked paradigm, analysed
the neural signal generated in the cortex and in the
cerebellum during the presentation of somatosensory
sequences perturbed by random stimulus omissions.
While the response in the somatosensory cortex was closely
linked to the actual presentation of the stimulus, cerebellar
activity was particularly evident when the expected stimulus
was omitted (Tesche and Karhu, 2000). As stated by Ivry
(2000), this finding provides experimental evidence of a
cerebellar role ‘as detector of change or deviation in the
sequence of sensory events’.
To verify whether cerebellar processing affects the ability
to recognize the similarity/diversity of incoming sequence
inputs, the somatosensory mismatch negativity (S-MMN)
component of event-related potentials (ERPs) was recently
analysed in six patients with unilateral cerebellar lesions
(Restuccia et al., 2007). In all subjects analysed, MMN was
clearly abnormal in the cerebral hemisphere contralateral to
the cerebellar damage. This evidence identifies the cerebel-
lum as the ideal structure for detecting discordances
between the input from the deviant event and the sensory
memory representation of the regular aspects of sequence
stimulation.
Support for a cerebellar role in the acquisition of
procedural sequences also derives from animal data. In a
series of studies based on surgical lesions it was shown that
cerebellar damage impairs the acquisition of the spatial
procedural sequences required for Morris water maze test
in rats (Petrosini et al., 1998). The good performances of
animals, that have acquired the correct competence before
the lesion, underline the specificity of the cerebellum in
acquisition rather than execution (Leggio et al ., 1999).
Furthermore, evidence that the cerebellar lesioned rats were
impaired not only in learning through direct execution but
also in learning through observation of conspecific
behaviour, provides additional proof of the importance of
the cerebellum in sensory processing (Leggio et al., 2000a;
Graziano et al., 2002).
Thus, detecting and generating sequences might be a key
for understanding the basic cerebellar function in different
domains. If so, the ability to detect and generate sequences
should represent an operational mode also in the cognitive
domain. To investigate this topic (Experiment 1) we first
retrospectively investigated the performances of patients
with cerebellar lesions on the Picture Arrangement subtest
(PAs) of the Italian version of the Wechsler Adult
Intelligence Scale Revised (WAIS-r) (Orsini and Laicardi,
1997); and second (Experiment 2) we analysed whether the
characteristics of the material processed influenced
sequence detection performances of cerebellar-damaged
subjects.
Experiment 1çW AIS -r Picture
A rrangement subtest
The PAs of the WAIS-r mainly investigates sequential
thinking. To solve the task correctly visual material has to
be analysed, understood and integrated (Lezak, 1995). The
correct logical sequence is reconstructed by identifying
relations between events, deciding priority and ordering
these events in chronological order (Orsini and Laicardi,
1997). In Experiment 1, PAs subtest performances of
patients affected by pathologies exclusively confined to the
cerebellar structures, who were admitted to the IRCCS
Santa Lucia Foundation rehabilitation hospital between
2003 and 2006, were retrospectively reviewed.
Su bj ects
Based on lesion lateralization and focal or degenerative
aetiology, 77 right-handed patients, i.e. 44 males and 33
females were divided into the following groups: patients
affected by focal cerebellar lesions on the right side (Table 1:
RCb—n.21); patients affected by focal cerebellar lesions on
the left side (Table 1: LCb—n.21); and patients affected by
cerebellar atrophy. These latter patients were grouped either
considering all subjects independently from aetiologies
(CA—n.35 Experiment 1 Supplementary Material Table 1)
or considering only subjects with idiopathic cerebellar ataxia
(Table 1: ICA—n.18). Therefore according to the grouping
methods the total number of cerebellar subjects was 77
(Cbt group Experiment 1 Supplementary Material Table 1) or
60 (Cb group Table 1).
Focal cerebellar lesions consisted of ischemic or haemor-
rhagic stroke or surgical ablation due to arteriovenous
malformations or tumours. Lesion characteristics were
reconstructed from the written reports of the charts. No
clinical or radiological evidence of extracerebellar patholo-
gies were reported, with the exception of one subject that
presented an involvement of the brainstem. One subject
Cere be ll ar cogn iti ve sequencin g i mpai rment Bra in (2008), 131, 133 2 ^ 13 43 133 3
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
had a temporary, moderate, increase of the volume of the
ventricles not requiring surgical derivation and not
associated with comatose conditions.
Of the patients with cerebellar atrophy 12 had a genet-
ically determined diagnosis (2: ataxia-oculomotor apraxia
type 2, 5: Friedreich ataxia, 2: spino-cerebellar ataxia type 2,
and 3: spino-cerebellar ataxia type 1), 1 presented atrophy
as sequaele of a cerebellitis and 22 presented idiopathic
forms. Of the idiopathic forms, 17 subjects presented pure
cerebellar syndromes, four subjects presented additional
extracerebellar atrophy (3: brainstem atrophy and 1:
bilateral posterior parietal atrophy), one subject presented
spastic paraparesis beside cerebellar deficits. The diagnosis
of ICA was based on clinical indications of a purely
cerebellar syndrome and on magnetic resonance imaging
(MRI) evidence of atrophic pathology restricted to the
cerebellum.
Differences in the grouping of atrophic subjects might
influence the results; therefore we run statistics following
both grouping methods. Since no differences were evi-
denced, in the results section only data from the more
selective series of patients with ICA will be presented. Data
on the statistical comparisons considering the entire group
of subjects with degenerative pathologies (CA) are reported
in Supplementary Material (Filename: Experiment 1—Test
with CA group).
Some of these patients had already participated in
previous studies (Leggio et al., 2000b; Molinari et al.,
2004, 2005; Restuccia et al., 2007). All patients underwent a
neurological examination and their motor impairment was
quantified using a modified version of the cerebellar motor
deficit scale, proposed by Appollonio et al. (1993), which
ranges from 0 (absence of any deficit) to 42 (presence of all
deficits to the highest degree) and evaluates eight cerebellar
signs (dysarthria, limb tone, postural tremor, upper and
lower limb ataxia, standing balance, gait ataxia and ocular
movements). See Table 1 for group characteristics. The
control group consisted of 69 subjects who had no history
of neurological or psychiatric illness (Table 1: C—n.69).
Mean age and education of control subjects is reported in
Table 1. t-Test for independent samples confirmed that
cerebellar patients and control subjects were well-matched
for age (P = n.s.) and education (P = n.s.). Furthermore a
one-way ANOVA failed to reveal any differences in
age [F(3,125) = 2.59, P = n.s.] or years of education
[F(3,125) = 0.58, P = n.s.] among C group and cerebellar
subgroups. Experimental procedures were approved by the
ethical committee of the IRCCS Santa Lucia Foundation;
written consent for anonymous use of clinical data was
obtained from each subject.
N europsychol ogical assessment
The patients’ general cognitive profile was assessed
from data available on their charts. In particular, we
considered the following data: WAIS-r total intelligence
quotient (TIQ) values, immediate and delayed recall of
Rey’s 15 words (Rey, 1958), immediate visual memory
(Carlesimo et al., 1996), forward and backward digit span
and forward and backward Corsi Test (Corsi, 1972),
Raven’s 47 progressive matrices (Raven, 1949), freehand
copying of drawings (Gainotti et al., 1977), copying
drawings with landmarks (Gainotti et al., 1977), temporal
rules induction (Villa et al., 1990) and word fluency
(Borkowsky et al., 1967). The same Italian version of the
WAIS-r reported in the charts was employed to test control
subjects.
The p i cture arrangemen t subtest
of the WA IS-r
The PAs consists of 10 sets of cartoon pictures that tell
stories. Each set, comprised of three to six pictures, is
presented to the subject in scrambled order with instruc-
tions to rearrange the pictures to make the most sensible
story. The PAs was administered and scored according to
the Italian version of the WAIS-r (Wechsler, 1981; Orsini
and Laicardi, 1997, 2003).
Statistical analysis
Student’s t-test for independent samples was used to detect
differences between cerebellar patients and control subjects.
Metric units were compared by one-way ANOVA. When
significant differences were found, post-hoc comparisons
Ta b l e 1 Experiment 1: Demographic, motor and cognitive data
Group No M/F Age Ed u cat i on Mot o r score
a
TI Q WAIS-R
Cb 60 36/24 48.93 (17.04) 10.68 (4.27) 9.07 (5.33) 96.45 (14.56)
RCb 21 15/6 53.29 (18.44) 10.71 (4.55) 8.19 (5.54) 100.71 (14.47)
LCb 21 12/9 49.76 (17.98) 11.19 (4.32) 7.48 (6.75) 97.57 (9.88)
ICA 18 9/9 42.8 8 (12.81) 10.05 (4.04) 12.06 (4.74) 90.17 (17.58)
C 69 23/46 43.78(15.96) 11.39(4.07) ^ 106.17(12.45)
Mean values and standard deviations.
Cb = patients affected by cerebellar pathologies considered as a whole group; RCb = patients affected by focal cerebellar lesions on the
right side; LCb = patients affected by focal cerebellar lesions on the left side; ICA = patients affected by idiopathic cerebellar ataxia;
C = control subjects; TIQ = to tal intelligence quotient. Standard deviation in brackets.
a
0 ^ 42 cere be l lar motor sco re mod ified from (Ap pol lon io et a l ., 1993): h igher scor e in dicat es higher moto r im pairment.
133 4 Bra in (2008), 131,1332^1343 M.G.Leggio et al .
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
among groups were assessed with the Bonferroni post hoc
test; Bonferroni adjusted P-values (P
Bonf
) are reported.
Pearson correlations among motor scores and PAs scores
were calculate to verify possible relations between motor
performances and cognitive performances.
Results
Cerebellar patients showed no obvious deficits in the
general neuropsychological assessment. The TIQ values of
cerebellar patients and control subjects (Table 1) as well as
the scores of the neuropsychological assessment of cere-
bellar patients (Table 2) were within the normal range
except for the forward Corsi test, which was just above the
cut-off. TIQ scores were employed to compare cognitive
levels among groups; significant differences were present
among the control subjects and the three subgroups of
cerebellar patients [One-way ANOVA: F(3,125) = 7.89,
P = 0.001]; Bonferroni post hoc comparisons showed that
ICA group had scores significantly lower than controls
(P
Bonf
= 0.000).
Regarding the PAs, all experimental groups scored within
the normal range (10 3) (Wechsler, 1981; Orsini and
Laicardi, 1997, 2003). However, all cerebellar group scores
were lower than C group scores (Fig. 1). An independent
samples t-test demonstrated that the difference between the
performances of Cb and C groups was significant
(P50.001). This finding was further confirmed by a
multiple comparison among the three subgroups of
cerebellar patients and the C group [One-way Anova:
F(3,125) = 10.97, P50.001]. Post hoc analyses (Bonferroni
Test) demonstrated that all patient subgroups performed
worse than control subjects (RCb: P
Bonf
= 0.011; LCb:
P
Bonf
= 0.002; ICA: P
Bonf
= 0.000), while no difference was
detected between subgroups of cerebellar patients. Pearson
correlation results did not highlight any relation between
ataxia and PAs scores (Table 3).
Cerebellar subjects as a group and considering type and
side of lesion presented a preserved general cognitive
pattern. The lack of deficits of clinical relevance is not
completely surprising. In different domains such as
language, working memory and visuo-spatial abilities, just
to name a few, cerebellar deficits have been evidenced only
in ad hoc testing conditions (Silveri et al., 1998; Leggio
et al., 2000b ; Molinari et al., 2004; Justus, 2004; Restuccia
et al., 2007). Although on the PAs cerebellar patients’
performances were within the normal range, they were
clearly defective when compared to control group perfor-
mances. As stated in the ‘Introduction’ section, different
lines of reasoning prompted us to hypothesize a sequencing
deficit after cerebellar damage.
Ta b l e 2 Experiment 1: Neuropsychological assessment
Group IR D R IVM PM WF CD CDL FDS BDS FC BC T R I
Cb 40.15(8.84) 8.37(2.76) 19.30(2.16) 26.57(5.73) 28.84(12.02) 8.84(1.72) 66.80(6.03) 5.76(1.01) 3.93(1.10) 4.88(0.90) 4.42(1.30) 10.76(7.06)
RCb 37.98 (9.88) 8.24 (3.08) 19.57 (2.11) 28.07 (3.63) 27.33 (15.07) 9.27 (1.57) 67.54 (3.0 4) 5.52 (0.93) 4.00 (1.22) 4.75 (0.85) 4.48 (1.40) 11.07 (7.21)
LCb 41.74 (8.31) 8.61 (2.76) 19.27 (2 .60) 27.11 (5.05) 33.99 (11.34) 9.01 (2.05) 65.71 (9.67) 6.15 (0.81) 4.10 (1.02) 5.00 (0.89) 4.52 (1.47) 9.18 (5.74)
ICA 40.69 (8.28) 8.23 (2.53) 18.99 (1.89) 24.43 (7.59) 25.15 (5.83) 7.96 (1.24) 67.07 (3.08) 5.61 (1.20) 3.67 (1.03) 4.88 (0.99) 4.24 (0.97) 12.16 (8.21)
CUT
OFF
a
28.53 4. 69 13.85 18 .93 17.35 7.18 61.85 5.00 3.00 5.00 3.00 15.00
Mean data and standard deviations.
IR = Rey’s 15 mots short term (immediate recall); DR = Rey’s 15 mots long term (delayed recall); IVM = immediate visual memory;
PM = Raven’s 47 (progressive matrices); WF = word fluency; CD = copying drawings; CDL = copying drawings with landmarks;
FDS = forward digit span; BDS = Backward digit span; FC = forward Corsi; BC = backward Corsi; TRI = temporal rules induction; group
abbreviations as in Table 1. Standard deviation in brackets.
a
Pathological values are inferior to cut off levels in all tests with the exception of TRI in which pathological values are superior to cut off
leve l .
Fig . 1 Experiment 1. Picture Arrangement subtest mean data and
standard deviations. Dashed line indicates cut-off value.
Abbrev iations as in Table 1. Stat istical si gnifican ce versus C group:
P50.05,
P50.0 05,
P50.0 01 .
Ta b l e 3 Experiment 1: Pearson Correlation
Ataxia score PAs
Tota l atax i a Pearson co rre l ation 0 .142
Significance (two-tailed) 0.279
Upperlimb Pearson corre lation 0. 1 67
Significance (two-tailed) 0.203
Ocular Pearson corre lation 0.047
Significance (two-tailed) 0.720
Dys arthr ia Pearson corre lation 0.088
Significance (two-tailed) 0.505
Cere be ll ar cogn iti ve sequencin g i mpai rment Bra in (200 8), 131,1332^1343 1335
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
Exper i ment 2
In order to solve the PAs of the WAIS-r correctly, various
aspects of the material to be sequenced have to be taken
into account at the same time. To analyse whether
cerebellar influences on sequential processing are material
related, we tested cerebellar patients with new, specifically
developed sets of cartoon-like drawings/texts.
Su bj ects
Forty-five right-handed patients (25 males and 20 females)
with cerebellar lesions were recruited from those admitted
to the IRCCS Santa Lucia Foundation rehabilitation
hospital. Some of these subjects were already included in
Experiment 1 since they had previous admissions to the
hospital. According to the focal or diffuse localization of
the cerebellar damage, the total group of patients was
divided into subgroups: subjects with right cerebellar
lesions (RCb: n.11), subjects with left cerebellar lesions
(LCb: n.9) and subjects affected by cerebellar atrophy.
These latter patients were grouped either considering all
subjects independently from aetiologies (CA—n.25
Experiment 2 Supplementary Material Table 1) or con-
sidering only subjects with idiopathic cerebellar ataxia
(ICA—n.14). Therefore according to the grouping methods
the total number of cerebellar subjects was 45 (Cbt group
Experiment 2 Supplementary Material Table 1) or 34 (Cb
group Table 1).
All subjects with focal lesions did not present any clinical
or radiological evidence of extracerebellar involvement or
increased intracranial pressure at the time of testing. Three
subjects had positive history of moderate increase of the
volume of the ventricles in the very acute phase. None of
them received surgical derivation or intracranial pressure
direct measurement. In all cases, the ventricular dilatation
was not accompanied by comatose conditions and was
resolved in few days. Lesion characteristics of RCb and LCb
groups according to the MRI images are described in
Table 4 and in Fig. 2. Table 4 reports vascular and gross
anatomical subdivisions touched by the lesion, while Fig. 2
depicts two selected coronal sections involving the core of
the lesion.
Of the patients with cerebellar atrophy 1 presented
atrophy as sequaele of a cerebellitis, 1 had a paraneoplastic
atrophy, 11 had a genetically determined diagnosis
(2: ataxia-oculomotor apraxia type 2, 6; Friedreich ataxia,
2: spino-cerebellar ataxia type 2, and 1: spino-cerebellar
ataxia type 1), and 12 presented idiopathic forms. Of the
idiopathic forms, seven subjects presented pure cerebellar
syndromes and five, beside cerebellar deficits, presented
additional extracerebellar signs (three peripheral neuropa-
thy, one spastic paraparesis and one spastic paraparesis and
convergence insufficiency). The diagnosis of ICA was based
on clinical indications of a purely cerebellar syndrome and
on MRI evidence of atrophic pathology restricted to the
cerebellum. As in Experiment 1, differences in the grouping
of atrophic subjects, considering CA or ICA groups, might
influence the results; therefore we run statistics following
both grouping methods.
Since no differences were evidenced, in the results section
only data from the more selective series of patients with
ICA will be presented. Data on the statistical comparisons
considering the entire group of subjects with degenerative
pathologies (CA) are reported in Supplementary Material
(Filename: Experiment 2—Test with CA group).
The patients’ motor impairment was quantified using the
same motor scale employed in Experiment 1 (Appollonio
et al., 1993). See Table 5 for patients’ characteristics. A
random sample of 132 healthy subjects, matched for age
and education with the cerebellar group and with no
history of neurological disease, comprised the control group
(C group). Mean age and education of control subjects is
reported in Table 5. An independent samples t-test
confirmed that the C group was well-matched with the
Cb group for age (P = n.s.) and years of education (P = n.s.).
Furthermore, a one-way ANOVA among the C group and
the subgroups of cerebellar patients failed to reveal any
differences in age [F(3,159) = 1.85, P = n.s.] or years of
education [F(3,159) = 1.47, P = n.s.).
Experimental procedures were approved by the ethical
committee of the IRCCS Santa Lucia Foundation; written
consent was obtained from each subject according to the
Declaration of Helsinki.
Ta b l e 4 Experiment 2: lesion characteristics in subjects
with focal cerebellar lesions
Case
Code
Side Lesion PICA AICA SCA DCN ANT POST Hem Vermis
Cb1 R ischemic x x x
Cb2 L ischemic x x x
Cb3 L ischemic x x x x
Cb4 R sur gical x x x
Cb5 R sur gical x x
Cb6 R sur gical x x
Cb7 R ischem i c X x
Cb8 L su r gical x x x x x
Cb9 R ischem i c x x x x x x
Cb10 R he morrhagic x x x x
Cb11 R he morrhagic x x x
Cb12 L sur gical x x
Cb13 L ischemic x x x x x x x
Cb14 R s u r gical x x x x
Cb15 R ische mic x x x x x x
Cb16 L hemor rhagic x x x
Cb17 L hemor rhagic x x x
Cb18 L ische mic x x
Cb19 R ische mic x x x
Cb20 R su rg i cal x x
PICA = postero inferior cerebellar artery; AICA = antero inferior
cere bell ar artery; SCA = supe ri or cerebel lar arte ry; DCN = deep
cerebelar nuclei; ANT = anterior cerebellar lobe; POST = posterior
cerebellar lobe; Hem = cerebellar hemisphere; R = right; L = Left.
133 6 Bra in (2008), 131,1332^1343 M.G.Leggio et al .
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
Fig . 2 Experiment 2. Subjects with focal lesions: lesion extent in two representative coronal sections for each individual. Lesion is
presented as overlaid on coronal T1-weighted template from (Schmahmann et al., 2000). Lesion extensions were assessed on the
3D-T1-MPRAGEs after spatial normalization. Case codes as in Table 4.
Ta b l e 5 Experiment 2: Demographic, motor and cognitive data
Group N o M/F AG E Ed u cat i on Mot o r sco r e
a
Raven’s 47
Cb 34 18/16 51.94 (14.7 7 ) 1 1.32 (4.41) 10.3 8 ( 7 .32) 27 .05 (6.32)
RCb 11 6/5 48.18 (20.72) 13.73 (4.41) 7.89 (7.14) 28.50 (3.52)
LCb 9 2/7 60.63 (7.42) 10.75 (4.20) 7.66 (6.80) 29.60 (3.56)
ICA 1 4 5/9 49.36 ( 11.08) 1 0. 00 (4.1 4) 1 4.37 (6.85) 24.7 4 (8.23)
C 132 57/ 75 47.02 (17.33) 12.80 ( 4 . 41) ^ 29.50 (2.5 2)
Mean values and standard deviations.
Abbrev iations as in table 1. Standard dev iation in brack ets.
a
0 ^ 42 cere be l lar motor sco re mod ified from (Ap pol lon io et a l .,1993).
Cere be ll ar cogn iti ve sequencin g i mpai rment Bra in (2008), 131, 133 2 ^ 13 43 133 7
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
Methods
The same battery described in Experiment 1 was used to assess the
general cognitive profile of the cerebellar patients in Experiment 2
(Table 6). In the present experiment, a test specifically developed
to differentiate content-related effects on sequential information
processing was administered. The test consisted of 16 sets of cards;
each set was comprised of six cartoon-like drawings or six
sentences to be ordered in a logical sequence. The cartoon-like
drawings depicted behavioural sequences or abstract figures. The
former were correctly sequenced by taking into account time and
semantic and spatial coding; the latter were ordered exclusively
according to spatial cues. The sentences had to be ordered to form
logically consistent short narratives. Out of the 16 sets of cards, 4
reconstructed abstract figures, 4 short narratives, 8 reproduced
behavioural sequences; of these last sets, 4 were based on human
figurines and 4 on object disposition.
Scoring was based on entirely correct sequences and correct
fragments. Calculation was performed using the ‘Ratio of
repetition’ (RR) proposed by Cofer (1966). Thus, two cartoon-
like drawings in correct succession were considered the shortest
fragment of a sequence to be evaluated. Each correct fragment was
computed independently of its right or wrong position in the
whole sequence (for instance, if the correct answer was 1
23456
and the subject’s answer was:
234615,thesequence 234
represented a correct fragment). The RR was obtained using the
following formula:
RR ¼
ðCorrectly sequenced cardsÞðCorrect sequence fragmentsÞ
Total number of cards 1
Thus, RR values run from zero to one. The task was administered
without a time limit.
Data from the 132 healthy subjects were pre-processed for item
analysis. This analysis excluded 5 out of the 16 sets of cards. To
analyse whether the performances on the remaining 11 sets
clustered, a factor analysis was performed. Analysis of the principal
component, with extraction of the three factors and an oblique
rotation of the axis, was carried out. Since the intercorrelation
among factors resulted lower than 0.18, confirming the hypothesis of
the independence among factors, we executed an analysis of the
principal component with an orthogonal rotation of the axis
(Varimax). The factorial saturation of the rotated solution is
reported in Table 7.
Thus, 11 out of the 16 sequences clustered around three factors.
All four sentence sequences, three out of the four abstract
sequences and four out of the eight behavioural sequences
clustered. Thus, only these clustering sequences were considered
for further analyses. The full set of used stimuli is available as
Supplementary Material (Figs 1–3).
The three factors that resulted from the factor analysis were
indicated as:
– VERBAL FACTOR (Ve) script sequences n. 4. (Fig. 3A).
– SPATIAL FACTOR (Sp) abstract sequences n. 3. (Fig. 3B).
– BEHAVIOURAL FACTOR (Be) behavioural sequences n. 4.
(Fig. 3C).
To detail the relations between verbal versus non-verbal factors
we calculated verbal/behavioural (Ve/Be) and verbal/spatial
(Ve/Sp) indexes for each subject. These indexes were calculated
by subtracting the Sp mean score from the Ve mean score
and the Be mean score from the Ve mean score, respectively.
Ta b l e 6 Experiment 2: Neuropsychological assessment
Group IR DR IV M PM WF CD C D L FDS BDS FC BC T R I TQI
Cb 43.37(7.07) 9.14(2.38) 19.47(1.99) 27.05(6.32) 27.93(12.57) 8.36(2.18) 65.01(7.62) 5.59(1.13) 3.91(1.38) 4.97(1.00) 4.68(0.98) 9.08(7.33)96.18(15.93)
RCb 44.33 (7.24) 9.37 (2.50) 19.28 (1.95) 28.50 (3.52) 30.81 (17.77) 9.15 (1.37) 67.13 (2.70) 5.82 (0.60) 4.36 (1.12) 4.91 (0.83) 4.64 (1.12) 12.59 (11.01) 99.6 ( 1 6.5)
LCb 43.33 (7.87) 8.95 (3.25) 20.46 (1.30) 29.60 (3.56) 29.28 (3.52) 9.19 (2.10) 62.73 (13.07) 5.78 (0.67) 4.11 (1.17) 5.11 (1.36) 5.22 (0.97) 6.28 (3.22) 1 03 .8 (9.3)
ICA 42.74 (6.84) 9.07 (1.52) 18.98 (2.27) 24.74 (8.23) 22.78 (6.83) 7.16 (2.35) 64.77 (5.54) 5.29 (1.59) 3.43 (1.60) 4.93 (0.92) 4.36 (0.74) 7.86 (3.11)89.21(17.36)
CUT
OFF
a
28.53 4. 6 9 13 .8 5 18.93 17.3 5 7.18 61.85 5.00 3.00 5.00 3.00 15.00 70.00
Means and standard deviations.
Abbreviations as in tables 1 and 2. Standard deviation in brackets.
a
Patholog ical val ues are inferio r to cut off le ve ls in all tests with t he ex ception of TRI in which patholog ical values are supe rio r to cut off leve l .
133 8 Bra in (2008), 131,1332^1343 M.G.Leggio et al .
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
In this analysis, positive values indicate better performances in the
verbal factor.
Statistical analysis
Student’s t-test for independent samples was used to detect
differences between the two groups. To identify among-
group differences metric units of the results of each group
were compared by one-way ANOVA. When significant
differences were found, post hoc comparisons among groups
were assessed with the Bonferroni post hoc test; Bonferroni
adjusted P-values (P
Bonf
) are reported. To assess whether
the patients exhibited significantly different performances in
the three factors a repeated measures ANOVA was
performed (within-subjects factor: Ve, Sp, Be; between-
subjects factor: group).
Pearson correlations among motor scores and sequencing
factors scores were calculated to verify possible relations
between motor performances and sequence results.
Results
As in Experiment 1, in this experiment cerebellar patients
did not present any clear deficits in the general
neuropsychological assessment except in the forward Corsi
test (Table 6).
Raven’s 47 progressive matrices (PM) results were
employed (Raven, 1949) to compare cognitive levels
among groups (Table 5). An independent samples t-test
demonstrated a significant difference between C and Cb
groups (P50.001). Significant differences were also present
among the control subjects and the three subgroups of
cerebellar patients [one-way ANOVA: F(3,159) = 12.36;
P50.001]. However, Bonferroni post hoc comparisons
showed that ICA group had scores significantly lower
than each other groups (versus C group: P
Bonf
= 0.000;
versus RCb: P
Bonf
= 0.001; versus LCb: P
Bonf
= 0.000).
The Cb group’s RR scores were clearly lower than those
of the C group on all tasks (Fig. 4). Independent samples
t-test demonstrated these significant differences (Ve:
P50.001; Sp: P50.001; Be: P5 0.001). Moreover, when
cerebellar patients’ performances were considered taking
into account type and side of damage, performances of all
groups on all tasks were lower than those of controls
(Fig. 4). The ICA group’s performances were very similar
on Ve and Be tasks; conversely, LCb and RCb performances
varied according to the factor considered with a specular
profile. LCb patients had low Be scores and better Ve
performances. On the contrary, RCb patients presented low
Ve scores and better Be performances (Fig. 4). One-way
Anovas showed significant differences among groups
for each task [Ve: F(3,159) = 11.56; P50.001; Sp:
F(3,159) = 7.77; P50.001; Be: F(3,159) = 8.02; P50.001].
Bonferroni post hoc test confirmed lesion-side differences.
The RCb group scored significantly lower than the C group
on the Ve factor (P
Bonf
= 0.002), while the LCb group
scored significantly lower than the C group on the Be
(P
Bonf
= 0.013) and Sp factors (P
Bonf
= 0.019). The ICA
group’s scores were significantly lower than the C group’s
scores on all factors (Ve Factor: P
Bonf
= 0.000; Be Factor:
P
Bonf
= 0.001; Sp Factor: P
Bonf
= 0.006). A repeated measures
Anova confirmed the differences among groups [between-
subjects effect: F(3,159) = 2191.185; P50.001] and also
Fig . 3 Experiment 2. Set of cards representative of the three factors. (A) V erbal factor . Michel fell while playing/and he bruised his
knee:/he went back home crying/and his mother comforted him,/she medicated him/and he went back to play. (B) Spatial factor.
(C) Behavioural factor.
Ta b l e 7 Experiment 2: Factorial saturation of the rotated
solution
Be Ve Sp
Be 1 0.69 0.2 2 0. 1 8
Be 2 0.66 0 .29 0 .20
Be 3 0.54 0.21 0.33
Be 4 0.69 0.23 0.0 6
Ve 1 0.07 0.58 0.07
Ve 2 0. 1 6 0.77 0.03
Ve 3 0.35 0.50 0.01
Ve 4 0.27 0.44 0.25
Sp 1 0.1 4 0.08 0.69
Sp 2 0.32 0.24 0.66
Sp 3 0. 42 0. 12 0.54
Ve = verbal Factor; Be = behavioral factor; Sp = spatial factor.
Cere be ll ar cogn iti ve sequencin g i mpai rment Br ain (20 08), 131,1332^1343 1339
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
highlighted that groups presented factor dependent perfor-
mances [within-subjects effect: F(2,318) = 4.35; P50.05].
Pearson correlation results highlighted relations between
ataxia and sequencing (Table 8). Ocular subscore did not
correlate with performances in any of the three sequencing
factors. Total cerebellar deficit score and dysarthria sub-
score significantly correlated with the performances in Be
and Ve factors while upper limb subscore significantly
correlated with the performances in Ve factor.
Further investigation of the relations between lesion side
and content to be sequenced was made by analysing the
verbal/behavioural (Ve/Be) and verbal/spatial (Ve/Sp)
indexes (Fig. 5). According to these analyses, especially
for the Ve–Be data, all non-lateralized groups (C, Cb, CA)
tended toward a balance in the two parameters with values
around 0. Conversely, in the two groups with lateralized
lesions a clear prevalence was present with positive values in
the LCb group and negative values in the RCb group. The
one-way ANOVA revealed significant differences for both
Ve/Be index [F(3,159) = 2.67, P50.05] and Ve/Sp index
[F(3,159) = 2.68, P50.05]. Bonferroni post hoc test reveals
that the only significant difference was between RCb and
LCb patients (Ve/Be index: P
Bonf
= 0.035; Ve/Sp index:
P
Bonf
= 0.035).
Discussion
The present data indicate that subjects affected by cerebellar
pathologies are impaired on card-sequencing tests in which
scrambled cards have to be arranged in a logical order
independently from the material processed. Impairment was
present in the PAs of the WAIS-r as well as in the different
tasks of Experiment 2, regardless of the nature of the
cerebellar lesion (atrophic or focal) and the lesion side
(right or left).
Picture Arrangement, as analysed by the WAIS, has been
considered to evaluate the capacity to process behavioural
sequences and different terms, such as action script or
semantic sequencing, have been used more or less
indifferently to refer to such a function. In the present
study, we referred to script sequencing as the process that
allows recognizing correct spatial and temporal relations
among behaviourally relevant actions. Script sequencing has
been considered to be sustained by frontal lobe and basal
ganglia circuits (Tinaz et al., 2006). Regardless of whether
script-sequencing presentation is verbal or pictorial, deficits
have been reported in subjects with frontal cortex (Sirigu
et al., 1998; Zanini et al., 2002) or basal ganglia lesions
(Zalla et al., 1998; Tinaz et al., 2008). Although the
cerebellum has been considered to be highly involved in
sequence processing (Braitenberg et al., 1997) and sequen-
cing deficits in processing sensory and motor information
are widely reported in subjects with cerebellar damage
(Molinari et al., 1997; Timmann et al., 2004), the cerebellar
role in script sequencing has never been addressed. One
aspect of sequencing functions often highlighted is the
ability to plan ahead and order meaningful events
chronologically (Tinaz et al., 2006). Neurophysiological
data in healthy subjects (Tesche and Karhu, 2000), lesion
Ta b l e 8 Experiment 2: Pearson correlation
Ataxia score Be Ve Sp
Tota l atax i a Pearson corre lation 0 .420
0.423
0.224
Significance (two-tailed) 0.019 0.018 0.225
Upperlimb Pearson co rre l ation 0.299 0.375
0.22 1
Significance (two-tailed) 0.102 0.038 0.232
Ocula r Pearson corre lation 0.258 0.3 03 0.101
Significance (two-tailed) 0.162 0.097 0.587
Dy s arth ri a Pearson corre lation 0.474
0.405
0. 1 89
Significance (two-tailed) 0.007 0.024 0.308
Si gnificant at the 0 . 05 level (two-tailed) ;
significant at the 0. 0 1
le ve l (two-tailed) .
Fig . 4 Experiment 2. Histograms of mean RR scores in patient and control groups.Ve = verbal factor; Be = behavioural factor;
Sp = spat ial factor; group abbrev iation as in Table 1.
P50.05,
P50.0 05,
P50.001 .
13 4 0 Brain (20 0 8), 131,1332^1343 M.G.Leggio et al .
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
studies after cerebellar damage (Restuccia et al., 2007) and
experimental evidence of focal lesions in animal models
(Nixon, 2003) all point to the cerebellum as the key structure
for preparing responses to predictable sensory events.
Card-sequencing tasks require examining visual or verbal
material in order to understand spatial, temporal and/or
semantic relationships and correctly reconstructing the
strings in logical sequences. In other words, subjects have to
extract elements that will allow predicting the next card in
the sequence out of the complex array of sensory information.
Patients with cerebellar damage were able to rearrange
only small fragments of whole strings. This deficit was not
related to deficits at the level of perception since, when
requested to analyse cartoon-like drawings individually, they
were extremely competent in verbally describing the content.
As regards to possible influences of the motor ataxia
impairment on the sequence performances it must be said
that no time limit was applied and no fine movement was
associated with the cart-sorting responses. Thus, motor
impairment per se cannot be considered a determinant factor
of the lower sequencing score of the cerebellar patients.
Nevertheless, correlations were found between behavioural
and verbal factors and motor ataxia and dysarthria scores,
as well as between verbal factor and upper limb score
(Table 8). This evidence might support interesting specula-
tions on the importance of impaired sequencing for motor
and cognitive functions (Ackermann et al., 2004).
Furthermore, general cognitive deterioration cannot
explain the specificity of the script sequencing deficits
observed. All groups of cerebellar patients presented normal
IQ values (Experiment 1) and their scores on Raven’s 47
progressive matrices were within the cut-off (Experiment 2).
In a direct comparison with the control group, ICA subjects
presented significantly lower values than controls. Never-
theless, ICA scores were still within the normal range
(Table 5). In detail IQ values of ICA subjects were sparse
with different subjects in the pathological range.
Finally, defects in elementary perceptual or verbal analyses
are not a conceivable explanation. Cerebellar patients were
able to solve correctly the visuo-spatial and verbal tasks of
the WAIS-r and the BDM battery that clearly cannot
be solved in the presence of significant defects in perceptual
or verbal analysis.
These findings constitute the first report of a script
sequencing impairment after cerebellar damage.
Timmann and colleagues (Timmann et al., 2004; Frings
et al., 2004, 2006) analysed the ability of patients with
cerebellar dysfunction to acquire sequence information
from sensory inputs of different modalities and found
conflicting results. These authors related discrepancies in
their findings regarding differences in the motor character-
istics of the different tasks employed and hypothesized that
the cerebellar role in sensory sequence learning ‘may
become evident only if the sequence information has to
be connected with a significant motor response’ (Frings
et al., 2006).
Richter et al. (2004) tested subjects affected by degen-
erative cerebellar disease using different experimental
paradigms of visuomotor associative learning. In one
condition, they had to learn to associate one colour with
a motor response. In another condition, they had to learn
to associate two colours with a motor response. In both the
conditions motor response was a right or a left key press.
Cerebellar patients learned considerably less in the stimu-
lus–stimulus-response condition than in the stimulus-
response condition. Furthermore, when the sequence of
colours was the reverse of that in the previous and
following blocks, only the control subjects showed an
increase in reaction time, suggesting that cerebellar patients
did not use the sequence information to reduce reaction
time across tasks (Richter et al., 2004). Thus, also in this
case the key aspect is the impaired processing of sequence
information present in cerebellar patients. Support for the
hypothesis of a cerebellar role in processing script sequence
information derives from an fMRI study that demonstrated
increased activity in the right dentate nucleus correlating to
sequence length and complexity but not to motor
parameters (Boecker et al., 2002). Deficits in processing
Fig . 5 Experiment 2. Histograms of Ve ^Be and Ve ^Sp mean indexes in patient and control groups.Ve ^Be = Verbal minus Behavioural
scores, Ve ^Sp = Verbal minus Spatial scores; group abbreviations as inTable 1.
P50.05.
Cere be ll ar cogn iti ve sequencin g i mpai rment Brain (2008), 131,1332^1343 1341
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
sequential information have also been reported in different
experimental models in rats. Gaytan-Tocaven and Olvera-
Cortes reported that bilateral lesions of the dentate nucleus
impair the acquisition of a ‘new’ sequential egocentric-
based task (Gaytan-Tocaven and Olvera-Cortes, 2004); in a
series of studies, Petrosini and co-workers demonstrated
deficits in the acquisition of sequential procedures after
hemicerebellectomy (Petrosini et al., 1998; Leggio et al.,
1999, 2000a).
Shin and Ivry (2003) investigated the role of the
cerebellum and the basal ganglia in learning spatial and
temporal sequences and in integrating them when they were
simultaneously present. Unlike Parkinson’s disease patients,
who were unable to learn the relationship between the two
sequences but acquired the spatial and temporal sequences
individually, cerebellar patients failed to show any evidence
of sequence detection and acquisition, indicating that the
cerebellum plays a central role in sequence learning in
general (Shin and Ivry, 2003).
In the present work we specifically analysed the perfor-
mances of cerebellar patients in script sequencing and in
sequencing non-behaviourally relevant abstract figures.
Script sequencing requires using both spatial and temporal
information while abstract figure sequencing can rely
exclusively on spatial information. Subjects with cerebellar
lesions were impaired in both conditions. These data
indicate that cerebellar processing is required in both script
and spatial sequencing and, together with previous data on
cerebellar sequencing functions, support the hypothesis of a
central role of cerebellar circuits in sequence processing
regardless of whether the material processed is sensory
(Bower, 1997), motor (Thach et al., 1992) or behavioural
(present work).
Within this general framework supporting the wide-
spread influence of the cerebellum on sequencing, indica-
tions of a more selective role emerged from the present data
on patients with unilateral cerebellar damage. Statistical
evaluation of performances on the different card-sequen-
cing tasks demonstrated significant differences between
subjects with right and left focal lesions. Indeed, patients
with lesions of the left hemicerebellum performed defec-
tively on script sequences based on pictorial material.
Conversely, patients with lesions of the right hemicerebel-
lum were impaired, exclusively on script sequences requir-
ing verbal elaboration. The relation between right cerebellar
hemisphere and verbal processing appears stronger than the
relation between left hemisphere and non-verbal processing.
Specificity of the cortico-cerebellar interactions or differ-
ences in the two patient groups’ characteristics might
explain the observed variability. These data not only
demonstrate that the cerebellum has a specific role in
elaborating sequential information pertaining to cognitive
domains, but also that the ability to integrate different
information in correct logical sequences is linked to the
specific characteristic of the material to be processed. Thus,
sequencing in general requires cerebellar processing and
different cerebro-cerebellar circuits might be engaged
depending on the material to be sequenced. This hypothesis
is in agreement with the existence of a crossed cerebello-
cortical loop organized in segregated channels that reach
specific cortical zones (Schmahmann and Pandya, 1997;
Middleton and Strick, 2000; Giannetti and Molinari, 2002).
Different authors have stressed that this precise topography
could represent the hardware that allows the cerebellum to
intervene in many functions pertaining to motor control as
well as to cognition (Molinari et al., 2002; Schmahmann,
2004; Ito, 2005, 2006).
Supplementary material
Supplementary material is available at Brain online.
Acknowledgements
The continuous encouragement and support of Professor
Carlo Caltagirone is gratefully acknowledged. The profes-
sional English style editing of Claire Montagna and the
statistical expert support of Alessia Mammone are also
gratefully acknowledged. The present work was in part
supported by MURST, and Italian Ministry of Health grants
to M.M. and M.G.L.
References
Ackermann H, Mathiak K, Ivry RB. Temporal organization of ‘‘internal
speech’’ as a basis for cerebellar modulation of cognitive functions.
Behav Cogn Neurosci Rev 2004; 3: 14–22.
Appollonio IM, Grafman J, Schwartz V, Massaquoi S, Hallett M. Memory
in patients with cerebellar degeneration. Neurology 1993; 43: 1536–44.
Boecker H, Ceballos AO, Bartenstein P, et al. A H
215O
positron emission
tomography study on mental imagery of movement sequences – the
effect of modulating sequence length and direction. NeuroImage 2002;
17: 999–1009.
Borkowsky JG, Benton AL, Spreen O. Word fluency and brain-damage.
Neuropsychologia 1967; 5: 135–40.
Bower JM. Control of sensory data acquisition. Int Rev Neurobiol 1997;
41: 489–513.
Bower JM, Parsons LM. Rethinking the ‘‘lesser brain’’. Sci Am 2003; 289:
50–7.
Braitenberg V, Heck D, Sultan F. The detection and generation of
sequences as a key to cerebellar function: experiments and theory. Behav
Brain Sci 1997; 20: 229–77.
Carlesimo GA, Caltagirone C, Gainotti G. The mental deterioration
battery: Normative data, diagnostic reliability and qualitative analyses of
cognitive impairment. Eur Neurol 1996; 36: 378–84.
Cofer CN, Bruce DR, Reicher GM. Clustering in free recall as a function of
certain methodological variations. J Exp Psychol 1966; 71: 858–66.
Corsi PM. Human memory and the medial temporal regions of the brain.
Dissertation Abstracts International, 34 (02), 891B. (University
Microfilms No. AAI05-77717). Mc Gill University; 1972.
Doyon J, Laforce R, Bouchard G, et al. Role of the striatum, cerebellum
and frontal lobes in the automatization of a repeated visuomotor
sequence of movements. Neuropsychologia 1998; 36: 625–41.
Frings M, Boenisch R, Gerwig M, Diener HC, Timmann D. Learning of
sensory sequences in cerebellar patients. Learn Mem 2004; 11: 347–55.
Frings M, Maschke M, Gerwig M, Diener HC, Timmann D. Acquisition of
simple auditory and visual sequences in cerebellar patients. Cerebellum
2006; 5: 206–11.
13 4 2 Brai n (2008), 131,1332^1343 M.G.Leggio et al.
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
Gainotti G, Miceli G, Caltagirone C. Constructional apraxia in left brain-
damage patients: a planning disorder? Cortex 1977; 13: 109–18.
Gaytan-Tocaven L, Olvera-Cortes ME. Bilateral lesion of the cerebellar-
dentate nucleus impairs egocentric sequential learning but not
egocentric navigation in the rat. Neurobiol Learn Mem 2004; 82: 120–7.
Giannetti S, Molinari M. Cerebellar input to the posterior parietal cortex
in the rat. Brain Res Bull 2002; 58: 481–9.
Gomez-Beldarrain XXXX, Garcia-Monco JC, Rubio B, Pascual-Leone A.
Effect of focal cerebellar lesions on procedural learning in the serial
reaction time task. Exp Brain Res 1998; 120: 25–30.
Graziano A, Leggio MG, Mandolesi L, Neri P, Molinari M, Petrosini L.
Learning power of single behavioral units in acquisition of a complex
spatial behavior: an observational learning study in cerebellar-lesioned
rats. Behav Neurosci 2002; 116: 116–25.
Ito M. Bases and implications of learning in the cerebellum–adaptive
control and internal model mechanism. Prog Brain Res 2005; 148:
95–109.
Ito M. Cerebellar circuitry as a neuronal machine. Prog Neurobiol 2006;
78: 272–303.
Ivry R. Cerebellar timing systems. Int Rev Neurobiol 1997; 41: 555–73.
Ivry R. Exploring the role of the cerebellum in sensory anticipation and
timing: commentary on Tesche and Karhu. Hum Brain Mapp 2000; 9:
115–8.
Justus T. The cerebellum and English grammatical morphology: evidence
from production, comprehension, and grammaticality judgments.
J Cogn Neurosci 2004; 16: 1115–30.
Leggio MG, Molinari M, Neri P, Graziano A, Mandolesi L, Petrosini L.
Representation of actions in rats: the role of cerebellum in learning
spatial performances by observation. Proc Natl Acad Sci USA 2000a; 29:
5–2320.
Leggio MG, Neri P, Graziano A, Mandolesi L, Molinari M, Petrosini L.
Cerebellar contribution to spatial event processing: characterization of
procedural learning. Exp Brain Res 1999; 127: 1–11.
Leggio MG, Silveri MC, Petrosini L, Molinari M. Phonological grouping
is specifically affected in cerebellar patients: a verbal fluency study.
J Neurol Neurosurg Psychiatry 2000b; 69: 102–6.
Lezak MD. Neuropychological assessment. New York: Oxford University
Press; 1995.
Mauk MD, Medina JF, Nores WL, Ohyama T. Cerebellar function:
coordination, learning or timing? Curr Biol 2000; 10: 522–5.
Middleton FA, Strick PL. Basal ganglia output and cognition: evidence
from anatomical, behavioral, and clinical studies. Brain Cogn 2000; 42:
183–200.
Molinari M, Filippini V, Leggio MG. Neuronal plasticity of interrelated
cerebellar and cortical networks. Neuroscience 2002; 111: 863–70.
Molinari M, Leggio MG, Filippini V, Gioia MC, Cerasa A, Thaut MH.
Sensorimotor transduction of time information is preserved in subjects
with cerebellar damage. Brain Res Bull 2005; 67: 448–58.
Molinari M, Leggio MG, Solida A, et al. Cerebellum and procedural
learning: evidence from focal cerebellar lesions. Brain 1997; 120:
1753–62.
Molinari M, Petrosini L, Misciagna S, Leggio MG. Visuospatial abilities in
cerebellar disorders. J Neurol Neurosurg Psychiatry 2004; 75: 235–40.
Nixon PD. The role of the cerebellum in preparing responses to
predictable sensory events. Cerebellum 2003; 2: 114–22.
Orsini A, Laicardi C. Wais-r. Contributo alla taratura italiana. Firenze:
Organizzazioni Speciali; 1997.
Orsini A, Laicardi C. Wais-r e terza eta
`
. Firenze: Organizzazioni Speciali;
2003.
Parsons MW, Harrington DL, Rao SM. Distinct neural system underline
learning visuomtor and spatial representations of motor skills. Hum
Brain Mapp 2005; 24: 229–47.
Pascual-Leone A, Grafman J, Clark K, et al. Procedural learning in
Parkinson’s disease and cerebellar degeneration. Ann Neurol 1993; 34:
594–602.
Petrosini L, Leggio MG, Molinari M. The cerebellum in the spatial
problem solving: a co-star or a guest star? Prog Neurobiol 1998; 56:
191–210.
Raven JC. Progressive matrices (1947). Set A, Ab, B: board and book form.
London: H.K. Lewis; 1949.
Restuccia D, Della MG, Valeriani M, Leggio MG, Molinari M. Cerebellar
damage impairs detection of somatosensory input changes. A somato-
sensory mismatch-negativity study. Brain 2007; 130: 276–87.
Rey A. Memorisation d’une se
´
rie de 15 mots en 5 re
´
pe
´
titions. In: Rey A,
editor. L’examen clinique en psychologie. Paris: Presses Universiteries de
France; 1958.
Richter S, Matthies K, Ohede T, et al. Stimulus-response versus stimulus-
stimulus-response learning in cerebellar patients. Exp Brain Res 2004;
158: 438–49.
Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of
thought, and the cerebellar cognitive affective syndrome.
J Neuropsychiatry Clin Neurosci 2004; 16: 367–78.
Schmahmann JD, Pandya DN. The cerebrocerebellar system. Int Rev
Neurobiol 1997; 41: 31–60.
Schmahmann JD, Doyon J, Toga AW, Petrides M, Evans AC. MRI Atlas of
the human cerebellum. San Diego: Academic Press; 2000.
Seidler RD, Purushotham A, Kim SG, Ugurbil K, Willingham D, Ashe J.
Cerebellum activation associated with performance change but not
motor learning. Science 2002; 296: 2043–6.
Shin JC, Ivry RB. Spatial and temporal sequence learning in patients with
Parkinson’s disease or cerebellar lesions. J Cogn Neurosci 2003; 15:
1232–43.
Silveri MC, Di Betta AM, Filippini V, Leggio MG, Molinari M. Verbal
short-term store-rehearsal system and the cerebellum. Evidence from a
patient with a right cerebellar lesion. Brain 1998; 121 (Pt 11): 2175–87.
Sirigu A, Cohen L, Zalla T, et al. Distinct frontal regions
for processing sentence syntax and story grammar. Cortex 1998; 34:
771–8.
Tesche CD, Karhu JT. Anticipatory cerebellar responses during somato-
sensory omission in man. Hum Brain Mapp 2000; 9: 119–42.
Thach WT, Goodkin HP, Keating JG. The cerebellum and the
adaptive coordination of movement. Annu Rev Neurosci 1992; 15:
403–42.
Timmann D, Drepper J, Calabrese S, et al. Use of sequence information in
associative learning in control subjects and cerebellar patients.
Cerebellum 2004; 3: 75–82.
Timmann D, Daum I. Cerebellar contributions to cognitive functions: a
progress report after two decades of research. Cerebellum 2007; 6:
159–62.
Tinaz S, Schendan HE, Schon K, Stern CE. Evidence for the importance of
basal ganglia output nuclei in semantic event sequencing: an fMRI
study. Brain Res 2006; 1067: 239–49.
Tinaz S, Schendan HE, Stern CE. Fronto-striatal deficit in Parkinson’s
disease during semantic event sequencing. Neurobiol Aging 2008; 29:
397–407.
Villa G, Gainotti G, De Bonis C, Marra C. Double dissociation between
temporal and spatial pattern processing in patients with frontal and
parietal damage. Cortex 1990; 26: 399–407.
Wechsler D. Wais-r. Wechsler Adult Intelligence Scale Revised. Firenze:
Organizzazioni Speciali; 1981.
Zalla T, Sirigu A, Pillon B, Dubois B, Grafman J, Agid Y. Deficit in
evaluating pre-determined sequences of script events in patients with
Parkinson’s disease. Cortex 1998; 34: 621–7.
Zanini S, Rumiati RI, Shallice T. Action sequencing deficit following
frontal lobe lesion. Neurocase 2002; 8: 88–99.
Cere be ll ar cogn iti ve sequencin g i mpai rment Bra in (2008), 131,1332^1343 1343
by guest on June 2, 2013http://brain.oxfordjournals.org/Downloaded from
