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The Cerebellum

ISSN 1473-4222
Volume 11
Number 4

Cerebellum (2012) 11:834-844
DOI 10.1007/s12311-012-0363-9
Cognition in Friedreich Ataxia
Antonieta Nieto, Rut Correia, Erika de
Nbrega, Fernando Montn, Stephany
Hess & Jose Barroso
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ORIGINAL PAPER
Cognition in Friedreich Ataxia
Antonieta Nieto & Rut Correia & Erika de Nbrega &
Fernando Montn & Stephany Hess & Jose Barroso
Published online: 16 February 2012
#Springer Science+Business Media, LLC 2012
Abstract Friedreich ataxia (FRDA) is the most frequent of
the inherited ataxias. However, very few studies have exam-
ined the cognitive status of patients with genetically defined
FRDA. Our aimwas to study cognitive performance of FRDA
patients taking into account the motor problems characteristic
of this clinical population. Thirty-six FRDA patients were
administered a comprehensive neuropsychological battery
measuring multiple domains: processing speed, attention,
working memory, executive functions, verbal and visual
memory, visuoperceptive and visuospatial skills, visuocon-
structive functions, and language. Thirty-one gender, age,
years of education, and estimated IQ-matched healthy partic-
ipants served as control subjects. All participants were native
Spanish speakers. Patients showed decreased motor and men-
tal speed, problems in conceptual thinking, a diminished
verbal fluency, deficits in acquisition of verbal information
and use of semantic strategies in retrieval, visuoperceptive and
visuoconstructive problems, and poor action naming. Scores
on the depression inventory were significantly higher in
patients than controls, but depression did not account for
group differences in cognitive performance. The observed
pattern of neuropsychological impairment is indicative of
executive problems and parieto-temporal dysfunction. Neuro-
pathological and neuroimaging studies with FRDA patients
have reported only mild anomalies in cerebral hemispheres.
Thus, cognitive impairment in FRDA is probably caused by
the interruption of the cerebro-cerebellar circuits that have
been proposed as the anatomical substrate of the cerebellar
involvement in cognition.
Keywords Cerebellum
.
Cognition
.
Friedreich ataxia
.
Neuropsychology
Introduction
Traditionally, the cerebellum has been regarded as a motor
mechanism, but this view of its function is being challenged
by observations from neuroanatomical, neuroimaging, and
neuropsychological studies, which suggest that it also plays
a role in cognitive activity [16]. Friedreich ataxia (FRDA) is
the most frequent syndrome of the cerebellar ataxias. It is
caused in more than 95% of cases by a homozygous triplet
GAA expansion in the first intron of the frataxin gene (FXN,
previously known as FRDA, X25) on chromosome 9q13,
while the remaining patients are compound heterozygotes
for a GAA expansion in the disease-causing range in one
FXN allele and another inactivating FXN point mutations in
the other allele [7]. Both types of mutations lead to a marked
deficiency of frataxin [8, 9]. Frataxin is a mitochondrial mem-
brane protein involved in iron distribution. Frataxin deficiency
causes iron accumulation in mitochondria, fundamentally in
cardiac muscle and in the cerebellar dentate nucleus [10],
which, in turn, produces mitochondrial dysfunction [11]. This
is probably what is responsible for the degenerative changes in
FRDA [9, 12, 13]. The neuropathological changes of FRDA
fundamentally involve the spinal cord, with degeneration of
posterior columns and spinocerebellar tracts, and the dentate
nucleus [13]. Pathological alteration of the cerebellum,
Electronic supplementary material The online version of this article
(doi:10.1007/s12311-012-0363-9) contains supplementary material,
which is available to authorized users.
A. Nieto (*)
:
R. Correia
:
E. de Nbrega
:
S. Hess
:
J. Barroso
School of Psychology, University of La Laguna,
38205, La Laguna, Tenerife, Spain
e-mail: anieto@ull.es
F. Montn
Department of Neurology, Hospital N.S. La Candelaria,
S/C de Tenerife, Spain
Cerebellum (2012) 11:834844
DOI 10.1007/s12311-012-0363-9
Author's personal copy
especially the dentate nucleus, could interfere with cognition,
affecting cerebellarthalamiccortical loops [14, 15].
Although established as the most common cerebellar atax-
ia, almost no attention has been paid to cognitive functions in
FRDA. Earlier studies in patients with clinical diagnosis of
FRDA have described deficits in several cognitive domains
such as information processing speed, executive and mnesic
functions, as well as some visuospatial and visuoconstructive
functions [3, 1619]. However, these studies were undertaken
prior to the identification of the FA mutations, or the clinical
diagnosis was not confirmed by genetic molecular analysis.
There are very fewstudies that examined the cognitive status
of patients with genetically defined FRDA and most of them
have investigated specific cognitive functions. Our group ex-
amined verbal fluency in genetically proven FRDA using
different word retrieval [20]. We observed phonemic and action
fluency impairments, suggesting a prefrontal dysfunction in
FRDA. Corben et al. described impairment in motor program-
ming [21] and Klopper et al. [22] reported deficits in sustained
volitional attention and working memory using the Test of
Everyday Attention [23]. To our knowledge, the only study
approaching a wide range of cognitive domains in FRDAis the
work published by Mantovan et al. [24]. In this study, 13
individuals with genetically proven FRDA were examined.
Patients showed slowed information processing, reduced verbal
span and visual memory, deficits in verbal fluency and alter-
ation in complex visuoperceptual and visuoconstructive abili-
ties. Nonetheless, the interpretation of these results might be
hampered by the fact that the FRDA group showed an average
IQ lower than controls and two patients had an IQ below
normal range. In addition, some conclusions reached by these
authors regarding specific cognitive functions (e.g., visual
memory, visuoconstructive abilities, concrete thinking, and
poor capacity in concept formation) are supported by data that
are not explicitly reported in their published manuscript.
In sum, given the current lack of results, more compre-
hensive neuropsychological explorations are needed to fur-
ther understand the cognitive impairment profile in FRDA.
Thus, our aim is to study these patients cognitive function-
ing in a wide range of cognitive domains, trying to mitigate
the possible effects of their motor disturbances on their
performance in neuropsychological tasks. In addition, we
examine a larger patient sample than that usually found in
FRDA studies, which might help to reduce inter-subject
variability in the neuropsychological data.
Methods
Participants
Thirty-six FRDA patients participated in this study. The
patients were consecutively recruited from the ataxia units
of three Spanish hospitals: Ntra. Sra. Candelaria Universi-
tary Hospital (S/C de Tenerife), Marqus de Valdecillas
Hospital (Cantabria), and La Paz Hospital (Madrid). All
patients fulfilled the diagnostic criteria of Friedreich ataxia
[25] and presented the molecular genotype of FRDA. They
presented a large homozygous GAA triplet-repeat expan-
sion in the first intron of the frataxin gene (X25, within the
critical region on chromosome 9). They showed progressive
ataxia of limbs and gait, nystagmus, and dysarthria. Twenty-
nine patients had typical FA (age of onset before 25 years
old) and seven cases had late onset FA. The mean duration
of illness was 15.89 (SD08.63), and the mean age at disease
onset was 18.06 years (SD09.40) (Table 1). All patients
underwent a neurological examination. The Rankin Incapac-
ity and the Nobile-Orazio Ataxia scales were used to quan-
tify disease severity (score from 0normal to 5most
impaired) [26, 27]. A Clinical Rating Scale modified from
Appollonio et al. [28] was used to quantify seven cerebellar
signs (dysarthria, limb tone, postural tremor, upper and
lower limb ataxia, standing balance, and gait ataxia). Each
of these was assigned a score from 0 (normal) to 4 (most
Table 1 Demographic characteristics and clinical features of patients
and normal controls
FA patients
(n036)
Controls
(n031)
p
Mean (SD) Mean (SD)
Age 33.94 (12.23) 30.35 (8.34) 0.172
Education (years) 12.39 (4.09) 13.55 (3.23) 0.208
Sex
a
20/16 17/14 0.953
Handedness
b
32/4 29/2 0.505
MMSE 28.81 (1.30) 29.23 (1.05) 0.157
Information subtest 9.31 (3.36) 10.42 (2.50) 0.134
BDI 12.47 (10.27) 6.03 (6.31) 0.003
c
Age at disease onset (years) 18.06 (9.40)
Disease duration (years) 15.89 (8.63)
Rankin Incapacity Scale 3.00 (0.89)
Nobile-Orazio Ataxia Scale 4.31 (1.01)
Appollonio CRS 13.47 (5.18)
A. CRS dysarthria 1.72 (0.81)
A. CRS limb tone 0.72 (0.75)
A. CRS postural tremor 0.32 (0.48)
A. CRS upper limb ataxia 1.96 (0.84)
A. CRS lower limb ataxia 2.26 (0.91)
A. CRS standing balance 2.76 (1.09)
A. CRS gait ataxia 3.08 (1.04)
A. CRS oculomotion 1.95 (1.59)
CRS clinical rating scale
a
Sex (men/women)
b
Handedness (right/left)
c
Significant differences
Cerebellum (2012) 11:834844 835
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impaired). In addition, the following abnormalities in ocular
movements were each scored as 1 when present: dysmetria,
nystagmus in the horizontal or vertical plane, slowed or
absent saccades, and saccadic breakdown of pursuit. Total
scores on this scale ranged from 0 to 32; the higher the
score, the worse the dysfunction. Magnetic resonance imag-
ing was performed on every patient. MR images were clin-
ically assessed by an experienced neuroradiologist. All
patients presented spinal cord atrophy, and two of them
presented mild cerebellar atrophy. Neither cerebral atrophy
nor focal lesions were observed.
The control group consisted of 31 subjects. Control par-
ticipants were free of neurological disease/injury, drug ad-
diction, and psychiatric illness histories. General cognition
was tested with a modified version of the Mini-Mental State
Examination [29]. The Information subtest of the Wechsler
Adult Intelligence Scale (WAIS)-III [30] was also adminis-
tered as a general intelligence estimation measure. Patient
and control groups did not differ with respect to age, level of
education, Mini-Mental State Examination (MMSE) score,
and Information score (WAIS-III). Depression was assessed
by the Beck Depression Inventory (BDI) [31].
Both groups of participants were informed about the aim of
the investigation and participated voluntarily. All subjects
gave their informed consent. The data included in the manu-
script were obtained in accordance with the regulations of the
ethics committees of the University of La Laguna and in
compliance with the Helsinki Declaration for human research.
Materials
Participants completed an extensive battery of neuropsycho-
logical tests administered by an experienced clinical neuro-
psychologist over two sessions. Every session consisted of
2 h of assessment with a 20-min break between the first and
the second hour. Tests were chosen to examine cognitive
functioning in various cognitive domains (Table 2). In ad-
dition, all the tests were selected in such a way that no or
only limited movements had to be carried out by the patient.
Additionally, motor baseline tasks and statistical methods
were used to control for the differences in motor coordination
deficits, psychomotor slowness, and dysarthria. Only
nonstandard procedures will be described here.
Reaction Times Simple and choice reaction time tasks of the
Reaction Unit/Vienna System (RT) were used [32]. This
system permits the dissociation of the cognitive component
[decision time (DT)] and the motor component [motor time
(MT)]. Simple reaction time: A yellow light appeared ran-
domly, at which time the subject was instructed to remove
his/her index finger of the dominant hand from a rest button
and press another key as quickly as possible. Choice reac-
tion time: A red light appeared randomly in a background of
distractor stimuli. DT is the time interval between the ap-
pearance of the stimuli and release of the finger. MT is the
time interval between release of the finger and depression of
the second key. DT is a cognitive measure of information
processing speed. Motor time reflects motor and coordination
deficit [18]. Total reaction time is the sum of both components
(DT and MT).
Attention A computerized version of the Continuous Perfor-
mance Test-Identical pairs (CPT-IP) paradigm [33] was
administered in order to measure sustained attention. One
hundred fifty digits were auditory presented with an inter-
stimulus interval of 1 s. The subjects were instructed to
press the response button every time two identical letters
appeared consecutively (15% target stimuli). The total num-
ber of correct responses and omission and commission
errors were obtained. Selective attention was assessed with
the Stroop Color and Word Test [34]. This Stroop Test
version includes an index to assess the interference related
to the wordcolor conflict by comparing the subjects per-
formance in the third sheet (WordColor), with the same
Table 2 Neuropsychological test administered grouped by cognitive
domains
Global screening
Mini-Mental State Examination (MMSE)
Information Subtest (WAIS-III)
Becks Depression Inventory (BDI)
Reaction Time, Attention, and Working Memory (WM)
Simple Reaction Time (Pc-Vienna System)
Choice Reaction Time (Pc-Vienna System)
Continuous Performance Test (CPT-IP)
Stroop Word and Color Test
Digit Span (WMS-III)
Spatial Span (WMS-III)
Executive functions
Wisconsin Card Sorting Test (WCST)
Similarities Subtest (WAIS-III)
Verbal fluency (FAS, animals, and actions)
Memory and learning
Logical Memory (WMS-III)
California Verbal Learning Test (CVLT)
10/36 Spatial Recall Test (10/36 SRT)
Visuoperceptive, visuospatial, and visuoconstructive abilities
Judgment Line Orientation Test (JLOT)
Facial Recognition Test (FRT)
Minnesota Test
Block Design (WAIS-III)
Language
Noun and action naming
Anaphora comprehension
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subjects performance in the other two neutral conditions
(Word and Color sheets). To calculate the interference index
(I), it is first required to calculate an expected score (ES)
from subjects performance in the word and the color con-
ditions [ES 0 (word color)/(word + color)] and then to
calculate the interference index by subtracting the expected
score from number of corrected responses emitted in the
third condition (I 0 wordcolor ES).
Working memory was tested with digit span and spatial
span [forward and backwards; Wechsler Memory Scale
(WMS-III)] [35].
Executive functions were tested with the Wisconsin Card
Sorting Test (WCST) [36], Similarities subtest of the WAIS-
III [30], and Verbal fluency tasks. These tasks consist of
asking the participants to rapidly generate words beginning
by a given letter (phonemic fluency FAS) [37], to generate
only animals (semantic fluency), and to rapidly generate verbs
(action fluency) [38].
Verbal memory was tested with the Logical Memory
subtest (immediate and delayed free recall and recognition
of two prose passages) of the WMS-III [35] and the Spanish
adaptation of the California Verbal Learning Test (learning
over five-trial presentation of a 16-word list, free and cued
delayed recall, recognition) [39, 40]. Visual memory was
tested with a modified 10/36 Spatial Recall Test (10/36)
[41], a spatial memory test that does not require good motor
control. A ten-dot pattern was displayed on a 66 grid.
Participants studied this arrangement for 10 s. Afterwards,
the pattern was removed and the participants reproduced it
from memory on an empty grid using poker chips. This
learning task continued over five trials and delayed visual
recall was assessed at 30 min. Visual recognition was mea-
sured employing a forced choice procedure in which four
grids with ten-dot patterns were presented. The participants
attempted to pick the grid with the correct pattern. This
forced choice procedure was given twice.
Visuoperceptive skills were tested with the Facial Recog-
nition Test (FRT) [42]. Abbreviated versions of the Judg-
ment of Line Orientation Test (JLOT15 items) [42] and a
task of mental spatial rotation, the Minnesota Paper Form
Board Test [43], were used to assess visuospatial function-
ing. Finally, for the assessment of visuoconstructive skills, a
Modified Block Design subtest of the WAIS-III was select-
ed. This subtest was administered as described in the manual
[30] except that if the design was not correctly completed
within the standard administration time, we allowed the
subject to work on the problem for one extra minute. The
number of correct blocks was recorded without any kind of
speed credits in order to take into account the motor deficits
of patients. A motor baseline task was also administered and
execution time was recorded. This task was equivalent to the
original Block Design Test in motor demand but had mini-
mal perceptive and planning requirements. It consisted of
making two designs, one four-block design and one nine-
block design, with all the red faces of the blocks at the top.
Language was assessed with a naming task by visual
confrontation of pictorial stimuli and an anaphora comprehen-
sion task. These tasks were designed by our group with the aim
of measuring both language production and comprehension.
The naming task consists of 40 stimuli representing elements
(noun naming) and 20 stimuli depicting action scenes (action
naming). Nouns and actions were paired in those variables
known to affect naming: every action item was paired with
two noun items in word frequency [44] and nominal agreement
[45]. Stimuli are line drawings of objects in black and white,
taken from the work of Cuetos et al. [46], from the Interna-
tional Picture Naming Project [47] and the materials of Druks
and Masterson [48]. Stimuli presentation was computerized
using E-Prime v1.1 [49]. The participants were instructed to
recall the name of the concept represented (either the noun
corresponding to the element drawn or the verb corresponding
to the action depicted). Hits were recorded.
The anaphora comprehension task consisted of 20 senten-
ces with anaphoric expressions, ten non-ambiguous and ten
ambiguous. Ambiguity is defined in terms of gender, thus
when it is possible to discriminate the antecedent based solely
on its gender, the anaphora resolution is easier than when there
is more than one word in the sentence which agrees in gender
with the anaphoric pronoun. Thus, in our design, we consider
two types of pronominal anaphora: (1) non-ambiguous, in
which the anaphora is resolved by the gender key (e.g., Alba
gave a painkiller to Eduardo as he had a headache) and (2)
ambiguous, where gender does not solve the ambiguity, re-
quiring a semantic interpretation of the sentence to solve
it (e.g., Alba gave a painkiller to Mercedes as she had a
headache). Since pronominal anaphors are very common lin-
guistic expressions that give coherence and continuity to
speech, the aim of this task is to assess the ability to make
the necessary inferences to comprehend sentences involving
anaphora. All sentences were presented in auditory format by
E-Prime computer software. Participants were instructed to
listen to a series of sentences and to look at the computer
screen where two words would appear during each sentence
auditory presentation. These words correspond to the charac-
ters in the opening sentence, that is, the subject (Alba) and the
object (Eduardo) of the sentence. After each sentence presen-
tation, the participants were asked to answer a question re-
garding either the subject (Who gave a painkiller?) or the
object (Who had a headache?) of the sentence. Responses
were registered by means of a two-button panel and partic-
ipants were instructed to press the button corresponding to the
correct answer (either right button if the correct answer is the
word present at the right side of the screen or left button for the
word at the left side). In some cases, due to motor impairment,
the patients responded orally and the tester registered the
response. We recorded the number of hits and errors.
Cerebellum (2012) 11:834844 837
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Data Analysis
All the statistical analyses were performed with Statistical
Package for Social Sciences (SPSS, Chicago, IL) version
15.0 for Windows. Groups were compared using univariate
and repeated measures analysis of variance (ANOVA), or t
test where appropriate. Violations of equality of variance
between groups were established using Levenes test, and
thus, Welch correction was used when necessary. Statistical
significance was taken as p0.05 and Bonferroni test cor-
rection was applied to account for multiple comparisons
among means within each task, adjusting the to /n,
where n is the number or comparisons performed [50].
Analysis has been performed to account for the effect of
possible covariables. Correlations between variables were
determined by Pearsons coefficient r.
Results
Reaction Time, Attention, and Working Memory
As Table 3 shows, significant differences were found in both
decision and motor reaction times. In contrast, there were no
significant differences in any of the CPTaccuracy measures,
Digit, and Spatial Span Tests.
With regard to subjects performance in the Stroop Test,
FRDA patients significantly differed from the controls in the
three task trials (word, F(1, 62)073.25, p<0.0001; color, F
(1, 62)053.82, p<0.0001; and wordcolor, F(1, 62)035.48,
p<0.0001). However, there were no significant differences
when their scores in the Stroop Interference Index were
compared (Table 3).
Regarding CPT measures, we also analyzed performance
differences between the two halves of the task in order to
explore a differential effect on the second half associated
with its greater demand of sustained attention. With this
purpose, we conducted a two-way ANOVA including the
within-subjects factor CPT (first half vs. second half) and
the between-subjects factor group (FRDA patients vs. con-
trols). The interaction between these two factor was not
significant [F(1, 32)00.006, p00.937]. There were no sig-
nificant differences between FRDA patients and controls [F
(1, 32)00.301, p00.587], and both groups performance
was significantly higher in the first half [(Sd) 010.74
(1.50)] than in the second half [(Sd)09.97 (1.88)] of the
CPT [F(1, 32)04.639, p00.039].
Executive Functions
Table 4 shows that FRDA patients showed significantly
poorer performance than controls in the Similarities subtest,
but did not significant differ in any of the WCST measures
included in our analysis. FRDA patients showed significant-
ly poorer performance than the controls in all verbal fluency
measures (Table 4). In order to control for the possible
effects of articulatory deficits, we followed two procedures.
On one hand, we analyzed the correlation between the
Table 3 Performance by FRDA patients and normal controls in meas-
ures of attention, reaction time, and WM
FRDA
(n036)
Controls
(n031)
Mean (SD) Mean (SD) p
Simple decision time (ms) 426.14
(109.92)
308.37
(50.15)
0.0001
ac
Simple motor time (ms) 362.31
(145.37)
170.10
(55.71)
0.0001
ac
Choice decision time (ms) 956.41
(225.37)
632.07
(11.35)
0.0001
ac
Choice motor time (ms) 548.48
(107.94)
454.97
(68.07)
0.0001
ac
CPT right responses 21.07 (1.91) 20.47 (3.22) 0.533
b
CPT omission errors 1.80 (1.86) 2.47 (3.22) 0.477
b
CPT commission errors 0.27 (0.46) 0.05 (0.23) 0.085
b
Stroop interference index 1.71 (6.83) 0.94 (8.52) 0.686
a
Digit Span Forward 5.36 (1.20) 5.90 (1.11) 0.060
a
Digit Span Backward 4.28 (1.14) 4.71 (1.32) 0.155
a
Spatial Span Forward 5.50 (1.03) 6.00 (1.12) 0.145
a
Spatial Span Backward 5.50 (1.5) 5.61 (0.80) 0.697
a
CPT Continuous Performance Test
a
Significance level of /400.0125
b
Significance level of /300.016
c
Significant differences according to Bonferroni adjusted values
(/n)
Table 4 Performance by FRDA patients and normal controls in exec-
utive functions
FRDA
(n036)
Controls
(n028)
Mean (SD) Mean (SD) p
Similarities subtest 9.00 (3.00) 11.06 (2.94) 0.026
d
WCST right responses
a
68.82 (8.56) 73.11 (10.48) 0.236
c
WCST categories achieved
a
4.91 (1.92) 5.50 (1.23) 0.260
c
WCST perseveration index
a
14.29 (6.31) 11.33 (6.40) 0.200
c
FAS 26.89 (8.73) 37.87 (7.71) 0.0001
cd
Animal
b
18.92 (4.59) 23.77 (4.18) 0.0001
cd
Action 13.42 (4.96) 20.23 (5.45) 0.0001
cd
WCST Wisconsin Card Sorting Test
a
Results from 11 patients
b
Results from 35 patients
c
Significance level of /300.0160
d
Significant differences according to Bonferroni-adjusted values
(/n)
838 Cerebellum (2012) 11:834844
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dysarthria score from the Appollonio Clinical Rating Scale
and the patients performance on every verbal fluency task.
Only action fluency showed a significant correlation (FAS,
r00.219, p00.206; animal, r00.294, p00.087; action,
r00.333, p00.050). However, it did not show a significant
effect as a covariable when the subsequent analysis of
covariance (ANCOVA) was performed [F(1, 63)03.168,
p00.080]. On the other hand, we decided also to divide
the FRDA group into patients without dysarthria or with
only mild dysarthria (non-dysarthric patients) and patients
with moderate or severe dysarthria according to the dysar-
thria item of the Appollonio Clinical Rating Scale. Perform-
ances on fluency measures were reanalyzed for control
participants and non-dysarthric FRDA. These two groups
did not significant differ in age, education, and MMSE.
Non-dysarthric FRDA patients also performed significantly
worse than controls in the three verbal fluency measures
(Table 5).
In addition, although moderate and significant correla-
tions were found between total reaction time and each of the
verbal fluency measures (FAS, r00.463, p00.001; animal,
r00.330, p00.020; action, r00.430, p00.002), total re-
action time did not show a significant effect when subse-
quent ANCOVA was performed [FAS, F(1, 46)01.327, p0
0.255; animal, F(1, 46)00.790, p00.379; action, F(1, 46)0
1.541, p00.221]. Thus, reaction time does not explain
between-groups differences in verbal fluency measures.
Memory and Learning
Patients scored significantly worse than controls on imme-
diate in the Logical Memory subtest. Although they also
scored worse on the delayed recall, there were no significant
differences between groups on the retention percentage and
the recognition trial of this subtest. Significant differences
between patients and controls were also found on cued short
delay recall in California Verbal Learning Test (CVLT). No
significant differences were found between groups on visual
memory measures (Table 6).
Visuoperceptual, Visuospatial, and Visuoconstructive
Abilities
As shown in Table 7, FRDA patient scores were significantly
lower than the controls only in FRT. In addition, there was no
significant correlation between the FRTscore and the presence
of oculomotor disturbances assessed by the Appollonio
Clinical Rating Scale (r00.128, p00.838).
In the Block Design subtest, we found significant
between-groups differences on both standard and extended
time conditions (Table 8). As suggested by Lezak et al. [51],
we grouped trials in easy and complex designs and found
that FRDA patients had significantly poorer performance
than controls in the complex but not the easy designs
(Table 8). Significant between-groups differences were
also found on the baseline motor task administered.
Moreover, performance in this control task correlated
with accuracy in total (r00.568, p<0.0001) and complex
designs (r00.573, p<0.0001). Therefore, we performed
subsequent ANCOVA analyses. Nonetheless, participants
performance in control designs was not a significant covariant
in the analyses performed [total extended time, F(1, 49)0
0.766, p00.386; complex extended time, F(1, 49)00.858,
p00.359]. Neither was FRDA patients performance in
the complex designs correlated with their performance
in FRT (total, r00.498, p00.070; complex designs, r00.509,
p00.063).
Language
We conducted a repeated measures analysis in order to
analyze both differences between groups and the effect of
the naming category (noun vs. action) on participants per-
formance in naming tasks. There was a significant effect of
the between-subjects variable group [F(1, 57)06.930, p0
0.011)]. We did not find a significant effect of the within-
subjects variable naming category [F(1, 57) 03.943, p0
0.052] but the interaction between both independent varia-
bles was significant [F(1, 57)04.901, p00.031]. As shown
in Fig. 1, the controls performed similarly in every naming
task but patients showed a significantly higher performance
in noun compared to action naming. In addition, FRDA
patients and controls did not significantly differ in noun
naming, but in action naming, the controls exhibited a
superior performance to that of the patients (Fig. 1).
Since the participants had a lower performance than the
controls in FRT, we studied the relationship between partic-
ipants performances on FRTand both naming tasks. We did
not find a significant relationship between FRT and these
naming tasks (nouns, r00.226, p00.094; actions, r00.229,
p00.089).
A repeated measures analysis of variance was also per-
formed to analyze participant performance in the anaphora
Table 5 Performance by non-dysarthric patients and normal controls
in verbal fluency measures
FRDA (n021) Controls (n031)
Mean (SD) Mean (SD) p
FAS 26.24 (8.92) 37.87 (7.71) 0.0001
ab
Animal 19.95 (5.14) 23.77 (4.18) 0.005
ab
Action 14.14 (4.28) 20.23 (5.45) 0.0001
ab
a
Significance level of /300.0160
b
Significant differences according to Bonferroni-adjusted values
(/n)
Cerebellum (2012) 11:834844 839
Author's personal copy
comprehension task. There was a significant effect of the
within-subjects variable anaphora ambiguity [F(1, 56) 0
30.908, p<0.0001], so non-ambiguous anaphora is easier
to understand than ambiguous ones, but we did not find a
significant effect of the between-subjects variable group [F
(1, 56)01.338, p00.252]. The interaction between the two
independent variables was not significant [F(1, 56)00.080,
p00.778].
Cognitive Performance and Depression
Patients reported a significantly higher BDI score than con-
trols (Table 1). In order to statistically control for the effect
of depression on cognitive performance, we conducted
ANCOVA. Including participants scores on the BDI as a
covariate, we reanalyzed group differences in all the tasks
where significant between-groups differences have been
reported in the above paragraphs.
Depression had a significant effect as a covariate only on
the immediate recall of logical memory [F(1, 54)011.749,
p00.001] and cued short delay in CVLT [F(1, 43)06.406,
p00.015]. Nonetheless, depression did not account for all
the variance on these measures and significant between-
groups difference remained [logical memory, F(1, 54)0
4.676, p00.035; CVLT, F(1, 43)07.036, p00.011].
Discussion
This study examined neuropsychological performance of
FRDA patients with genetic confirmation of diagnosis in a
wide range of cognitive domains. Results demonstrated
impairments in several of these domains.
Patients exhibited slowing in simple and choice reaction
time tasks, not only in motor time but also in decision time,
suggesting a reduction of the speed of cognitive information
processing in addition to motor slowing. No attentional
dysfunction was observed. As expected, patients and con-
trols showed a lower number of correct responses in the
second half of CPT-IP, with this poorer performance similar
between both groups, which suggests that sustained atten-
tion is preserved. FRDA patients produced less correct
responses in the Stroop Test not only in the interference
condition (where participants are required to name the ink
Table 6 Performance by FRDA
patients and normal controls in
memory and learning measures
CVLT California Verbal
Learning Test
a
10/36: 10/36 Spatial Recall Test
b
Significance level of
/400.0125
c
Significance level of
/600.0083
d
Significance level of
/200.025
e
Significant differences
according to
Bonferroni-adjusted
values (/n)
FRDA (n026) Controls (n031) p
Mean (SD) Mean (SD)
Logical memory (immediate recall) 37.19 (12.77) 46.87 (9.45) 0.002
be
Logical memory (delayed recall) 24.00 (9.57) 29.94 (7.66) 0.012
be
Logical memory (retention percentage) 83.37 (14.53) 87.49 (12.38) 0.253
b
Logical memory (recognition) 24.65 (4.80) 27.10 (2.43) 0.024
b
CVLT (total learning score) 56.35 (9.55) 61.48 (7.51) 0.068
c
CVLT (free short delay) 11.88 (3.62) 13.90 (1.95) 0.046
c
CVLT (cued short delay) 12.35 (2.69) 14.48 (1.40) 0.006
ce
CVLT (free long delay) 12.59 (3.92) 14.55 (1.66) 0.064
c
CVLT (cued long delay) 13.06 (3.29) 14.72 (1.53) 0.063
c
CVLT (recognition) 15.35 (1.06) 15.66 (0.67) 0.300
c
10/36 (total learning score)
a
37.45 (6.84) 41.73 (6.20) 0.041
d
10/36 (delayed recall)
a
8.45 (1.70) 9.41 (1.05) 0.038
d
Table 7 Performance by FRDA patients and normal controls on
visuperceptual and visuospatial tasks
FRDA (n026) Controls (n031) p
Mean (SD) Mean (SD)
FRT (total score) 22.15 (2.44) 24.10 (1.83) 0.001
a
JLOT (total score) 13.23 (1.94) 14.03 (1.14) 0.058
Minnesota Test (total score) 7.94 (2.64) 9.33 (2.01) 0.051
FRT facial recognition test, JLOT Judgment of Line Orientation Test
a
Significant differences
Table 8 Performance (accuracy) by FRDA patients and normal con-
trols on block design WAIS subtest
FRDA
(n022)
Controls
(n031)
p
Mean (SD) Mean (SD)
Block design test (total on st) 43.18 (9.45) 52.55 (4.20) 0.0001
ac
Block design test (total on et) 47.18 (8.99) 54.19 (3.48) 0.002
ac
Easy designs (on st) 16.30 (1.66) 17.00 (0.00) 0.057
ab
Easy designs (on et) 16.78 (0.74) 17.00 (0.00) 0.171
ab
Complex designs (on st) 32.65 (8.80) 41.90 (5.82) 0.0001
ac
Complex designs (on et) 38.00 (7.18) 44.30 (5.57) 0.002
ac
Control designs (time in seconds) 42.26 (15.48) 14.59 (3.62) 0.0001
ac
st standard time, et extended time
a
Significance level of /700.0071
b
t test
c
Significant differences according to Bonferroni-adjusted values
(/n)
840 Cerebellum (2012) 11:834844
Author's personal copy
color instead of reading the word printed) but also in the
reading and color naming conditions. Moreover, when in-
terference indices were calculated and groups were compared,
no significant differences were found between them. Thus,
impaired performance on Stroop trials might be interpreted as
the result of reduced processing speed or dysarthric speech
rather than due to a selective attention deficit.
FRDA patients and controls performed similarly in
WCST. However, patients showed poor performance in the
similarities test, indicating verbal concept formation prob-
lems. Although this result could be attributed to a global
intellectual deficit, FRDA patients did not differ from the
controls in their IQ estimated from the Information subtest
scores. Therefore, this result seems to be a deficit circumscribed
to verbal conceptual thinking.
Patients showed a diminished verbal fluency perfor-
mance at the three modalities assessed. Although verbal
fluency tasks are good measures of executive functioning,
performance can also be affected by articulatory problems
and slowed processing speed. Regarding the first confound-
ing factor, the two different approaches followed converged
in showing significant differences between FRDA patients
and controls, even after dysarthria effects were controlled.
Regarding the second one, processing speed was not a
significant covariant when ANCOVA analyses were per-
formed. Taking into account these results, it could be con-
sidered that FRDA patients showed a primary verbal fluency
deficit that could not be explained by either dysarthria or a
generalized slowing.
In regards to memory, FRDA patients showed poor per-
formance on immediate and delayed recall of prose texts.
However, since nonsignificant differences were found be-
tween patients and controls in the retention percentage,
differences observed in delayed recall seem to be better
explained by previous poor acquisition. The results on
CVLT showed that patients preserved the ability to learn
lists of words but presented difficulties in cued delayed
recall. In this last trial, the examiner asks the subject to
recall items by each of the categories of the word list (tools,
fruits, spices, and clothes). The impaired performance on
cued recall suggests that patients failed to benefit from this
cueing, indicating difficulties in the use of semantic associ-
ations as a strategy to retrieve stored information. Visual
learning and memory, as assessed by 10/36 Spatial Recall
test, is preserved in FRDA patients.
Comparable performances of patients and normal con-
trols on JLOTand Minnesota Test were obtained, suggesting
unimpaired visuospatial functioning in FRDA. On the con-
trary, patients showed poorer performance than controls on
FRT. The lack of a significant correlation between FRT and
ocular motor scores and the fact that other tasks involving
visual analysis are correctly performed, suggest that ocular
motion impairment is not playing a determinant role in FRT
impairment. Patients also showed a poor performance on
block design. The interpretation of block design results in
cerebellar ataxia (as in any other movement disorder) is
always complicated. We have designed an assessment pro-
cedure (including baseline motor trials, softening time
restrictions, and eliminating time credits) and performed
different statistical analysis to address this issue and to try
to clarify the interpretation of results. So, although we did
not give time credits and increased the time for the task
execution by an extra minute, FRDA patients showed im-
paired performance in the block design. Therefore, FRDA
deficits in this task cannot be solely explained by the speed
requirements. In addition, administering a baseline motor/
manipulative task allowed us to show that the motor/manip-
ulative component does not account for the poorer perfor-
mance of patients in the block design. Thirdly, we
distinguished between easy and complex design in terms
of their visuoperceptivevisuoconstructive complexity, and
patients and controls only differed significantly in those
more complex designs. Finally, given the visuoperceptive
difficulties assessed with FRT, we studied the possible rela-
tionship between this impairment and performance in the
block design task. There was no significant relationship
between both variables. Therefore, after following the pro-
cedure depicted above, it seems that the impaired FRDA
patient performance in block design is not due to motor
slowness, coordination, nor visuoperceptive deficits. More-
over, the fact that significant differences appear only in
complex designs suggests an impairment of the components
related to structuring and organizing the materials and planning
the visuoconstructive task.
With respect to language, our assessment protocol includes
a naming task where participants are required to name both
nouns and actions and an anaphora comprehension task.
FRDA patients and controls did not differ significantly in
nouns but they did in action naming. In addition, while the
performance of the control group is comparable between both
naming conditions, patients showed a significantly lower per-
formance in action compared to noun naming. These FRDA
patients difficulties in naming by visual confrontation of
pictorial stimuli are not related to visuoperceptive deficits.
Fig. 1 Performance by FRDA patients and normal controls on nouns
and actions naming tasks
Cerebellum (2012) 11:834844 841
Author's personal copy
Regarding the comprehension task, patients solved correctly
both non-ambiguous and ambiguous anaphora to comprehend
the meaning of the sentences presented.
In sum, FRDA patients showed slowed processing speed,
impaired concept formation and verbal fluency, deficits in
acquisition of verbal information and use of semantic strate-
gies in retrieval, visuoperceptive and visuoconstructive prob-
lems, and poor action naming. Attentional functions, working
memory, visual memory, and language comprehension are
preserved.
In general, the cognitive deficits observed in the present
study are in line with those observed in previous studies about
cognitive performance in genetically confirmed FRDA
patients. Impaired information processing speed is a consis-
tent result in the scarce cognitive research on FRDA [20, 21,
24]. Our results are also concordant with reports regarding
impairment in concept formation, verbal fluency, and visuo-
perceptive and visuoconstructive functions [20, 24]. In addi-
tion, the procedures followed in our study allowed us to
explore more deeply explanations for task results with a
difficult interpretation such as verbal fluency or visuocon-
structive skills. Regarding declarative memory, the only study
that has examined memory performance in FRDA reported a
poorer overall performance (memory quotient) but did not
report differences between FRDA patients and control partic-
ipants in specific memory tasks [24]. Action naming has not
been studied to date, but the preservation of noun naming is in
line with results obtained by Mantovan et al. [24].
On the other hand, the preservation of working memory
and attention is partially discrepant with results obtained in
previous studies. Impairment in verbal working memory, as
assessed by digit tasks, was reported by Mantovan et al. [24],
but in that study, patients presented an average IQ lower than
controls and 2 of 13 patients had an IQ below normal average.
Attention is a complex function that consists of different
subsystems that perform different but interrelated functions
[52]. In the present study, we focused on two of these sub-
systems: selective attention and sustained attention. Selective
attention, conceptualized as the capacity to select relevant
stimuli and inhibit irrelevant ones, was assessed with the
Stroop Test. In agreement with Corben et al. [21], FRDA
patients were not impaired. Mantovan et al. [24] reported a
different result. However, they used a modification of the
Stroop paradigm that does not actually examine selective
attention but the perception of the consistency or inconsisten-
cy between stimuli features. Sustained attention, the ability to
self-sustain attention in the absence of external manipulators
of attention such as novelty, was assessed with a paradigm of
CPT-IP. FRDA patients showed a preserved performance in
this task. To our knowledge, no other study has used a CPT
paradigm to assess sustained attention in FRDA before.
Klopper et al. [22] reported sustained attention deficit in
this clinical population based on their impaired performance
in the Test of Everyday Attention [23]. Nonetheless, the tasks
included in Kloppers work have an important switching
attention component [53, 54] or a considerable working mem-
ory load. In fact, the only task included considered to be a pure
sustained attention measure is the elevator counting condition
[5356] where FRDA patients had a preserved performance.
Therefore, in our opinion, the ability to self-sustain attention is
not a characteristic deficit of FRDAbut difficulties might arise
in more complex tasks where other cognitive processes (work-
ing memory, flexibility, switching, etc.) are also involved.
Impairment observed in conceptual thinking and verbal
fluency is indicative of deficits in prefrontal functions, at least
in its executive component. The characteristics of other deficits
showed by FRDApatients, in the present study, also suggest an
interpretation in terms of executive dysfunction. Whereas
patients showed a good performance in immediate recall of
the words list of the CVLT, they were impaired on the imme-
diate recall of texts. This suggests that difficulties in text recall
may be due to an inappropriate use of organizing strategies for
encoding the abundant information contained in the texts. In
addition, problems with the proper use of semantic strategies to
retrieve a list of words seem also to be the cause of the poor
performance in CVLT delayed cued recall. On the other hand,
visuoperceptive and visuoconstructional impairments are in-
dicative of a dysfunction in right temporo-parietal systems [42,
51]. In addition, the fact that poor performance in block
designs was observed only in more complex designs points
to a difficulty in self-generating strategies for problem solving
and a lack of the flexibility needed to perceive components of a
gestalt and then integrate them as a particular block arrange-
ment. All these results are indicative of impairments in the
more executive components of these different tasks. In agree-
ment with this, results in naming tasks indicate that patients
have difficulties only in action naming, a task that has been
especially associated with frontal lobe functioning [5759].
There is converging evidence from anatomical, physio-
logical, and clinical approaches to recognize the cerebellum
as a critical component of the distributed neural circuits
subserving cognition [60]. Inputs to the cerebellum arise
from multiple cortical areas, such as the frontal, parietal,
and temporal lobes. Outputs from the deep cerebellar nuclei
project to a diverse set of thalamic nuclei and, in turn, these
nuclei project to cortical areas other than the motor cortex
[1, 61, 62]. Particularly, prefrontal and parietal areas are
cortical targets of cerebellothalamocortical pathway from
the dentate nucleus [6365]. This deep cerebellar nucleus is,
precisely, the one especially affected in FRDA, showing
increased iron and severe neuronal degeneration. Thus, the
deficits shown by FRDApatients may relate to the disruption of
cerebro-cerebellar circuits, especially those linking cerebellum
with prefrontal and parieto-temporal cortex.
Another explanation for these deficits is that they are
caused by a primary cerebral damage. Similarly to the neurons
842 Cerebellum (2012) 11:834844
Author's personal copy
of the dorsal root ganglia, spinal cord, or dentate nucleus,
other neural systems may be affected by the frataxin deficien-
cy, although in a subtler way [24]. There are some neuropath-
ological reports of atrophy of cerebral gyri, but these changes
were considered as secondary to hypoxia resulting from epi-
sodes of heart failure [66, 67]. Lamarche [68] examined
postmortem material from six FRDA cases and he found no
neuropathological changes in cerebral cortex. Neuroimaging
studies of FRDA with genetic diagnosis have reported mild
white matter anomalies in cerebral hemispheres, but volume
loss in gray matter has not been observed [6971]. Thus, while
the possibility of a primary cortical dysfunction is interesting,
further studies are needed to support this interpretation.
Conclusions
The findings of the present study demonstrate mild cognitive
impairments in a large sample (n036) of patients with FRDA
genetically confirmed. Impairments were observed in process-
ing speed, conceptual thinking, verbal fluency, acquisition of
verbal information, use of semantic strategies in retrieval,
visuoperceptive and visuoconstructive functions, and action
naming. These deficits cannot be attributed to motor impair-
ment or depressed mood. Taken together, these results point to
a dysfunction of prefrontal and temporo-parietal systems that
may be caused by the affectation of the cerebro-cerebellar
circuits proposed as the anatomical substrate of the
cerebellums involvement in cognition.
Acknowledgments The authors thank Dr. Berciano (Hospital Marques
de Valdecillas, Santander) and Dr. Arpa (Hospital La Paz, Madrid) for
providing access to patients and for their helpful assistance. They also
thank Margaret Guillon for linguistic review of the manuscript. This
research has been partially supported by a research grant from Ministerio
de Ciencia e Innovacion (PSI2011-24665) and Proyecto Estructurante
Neurocog, financed by the ACIISI and cofinanced by FEDER funds and
the University of La Laguna.
Conflict of Interest The authors declare that they have no competing
personal or financial interests.
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