Full text of DOI:10.1016/S0022-510X(01)00683-9

Journal of the Neurological Sciences 195 (2002) 25–33
www.elsevier.com/locate/jns
Frontal lobe dysfunction in amyotrophic lateral sclerosis
*
I. Evdokimidis , T.S. Constantinidis, P. Gourtzelidis, N. Smyrnis, I. Zalonis,
P.V. Zis, E. Andreadou, C. Papageorgiou
ENG Lab of Neurology Clinic of Athens Medical School, Aeginitio Hospital, Vas. Sofias 72-74, Athens 11528, Greece
Received 2 March 2001; received in revised form 27 September 2001; accepted 26 November 2001
Abstract
The aim of the present study was to investigate the involvement of frontal lobe dysfunction in amyotrophic lateral sclerosis (ALS) using
ocular motor paradigms and neuropsychological testing. Fifty-one patients with ALS participated in the following ocular motor tasks: (1) a
three-choice task and (2) a remembered saccade task. The patients underwent a clinical and neuropsychological evaluation. One-third of ALS
patients presented with signs of frontal dysfunction, as determined by their high distractibility factors (DF) in the three-choice task and their
performances in both the Wisconsin and Stroop tests. ALS patients exhibited longer latencies to eye movement than controls in the
performance of the remembered saccade task, specifically in performance of both remembered and delayed saccades, but saccade accuracy
was not impaired. Finally, performance indices of the ocular motor tasks, in particular the DF, was correlated only with the degree of
dysarthria. D 2002 Elsevier Science B.V. All rights reserved.
Keywords: ALS; Motor neuron; Frontal lobe; Anti-saccade; Remembered saccade; Working memory
1. Introduction
ings have challenged this overly simplistic notion [5–9]. A
small minority of patients suffering from sporadic ALS
presented with memory and cognitive dysfunction, indicat-
ing a dementia of frontal lobe type [9]. Furthermore,
pathology studies as well as findings from PET, SPECT
and MRI investigations have already revealed that the
degenerative neuronal loss in ALS extends beyond the
primary motor cortex and includes other areas, mainly in
the prefrontal cortex [7–9]. In addition, evidence from
neuropsychological studies supports frontal lobe involve-
ment in sporadic ALS leading to significant impairment of
executive functions. More specifically, ALS patients repeat-
edly demonstrate decreased performance in the Wisconsin
Card Sorting Test, poor verbal fluency and difficulties in
problem solving, as well as increased latencies when per-
forming the random movement joystick test. However, they
perform normally in visuospatial, naming and memory tests
[10–13]. These findings are consistent with a frontal pattern
of impairment rather than, for example, the temporo-parietal
pattern found in Alzheimer’s disease.
The clinical spectrum of ALS that was described last
century by Charcot did not involve the ocular motor system.
In fact, the degenerative process occurring in ALS affects
mainly the corticospinal system and the anterior horn a-
motorneurons while sparing the brainstem ocular motor
circuitry, even in cases where the corticobulbar circuitry is
also affected. Although earlier studies reported several slight
oculographic abnormalities, including reduced saccadic eye
movement velocity and low smooth eye pursuit gain [1–3]
that were not apparent in the clinical evaluation of the
patients, these findings have not been replicated in the
recent literature [4,5]. Thus, it appears that the functional
integrity of the saccadic system at the brainstem level is
maintained. However, it is not known whether the ocular
motor circuitry used in higher cognitive functions is affected
by the disease.
Classically, cortical degeneration in ALS was believed to
be restricted to the primary motor areas. However, several
clinical, pathological, imaging and neuropsychological find-
The performance of a saccadic eye movement involves
the activation of cortical areas and the pattern of cortical
activation depends on the behavioral context in which the
saccade is elicited. In the case of an anti-saccadic eye
movement, the subject is instructed to perform an eye
movement in the opposite direction of a visual target with
*
Corresponding author. Tel.: +30-1-728-9115; fax: +30-1-721-6474.
E-mail addresses: ievdokim@cc.uoa.gr, tscon@otenet.gr
(I. Evdokimidis).
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-510X(01)00683-9

26
I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
respect to a central fixation point [14]. The suppression of
the reflexive saccadic eye movement, or the ‘‘ocular grasp-
ing reflex’’ [15], toward the visual target is considered to
require the intact functioning of frontal and prefrontal
cortices. Patients with frontal lobe lesions have great diffi-
culty in suppressing this reflex. The percentage of errors in
the anti-saccade task, i.e. the eye movements toward the
visual target, is called the distractibility factor (DF) and can
be considered a quantitative measure reflecting impairment
of frontal–prefrontal inhibitory functions. In schizophrenic
patients, the DF in the anti-saccadic eye movement task is
correlated with performance on specific neuropsychological
tests of frontal lobe function, i.e. the Wisconsin Card Sorting
Test [16].
important ways. First, we used a three-choice task instead of
the classical anti-saccade task. The three-choice task imposes
a greater attentional load, increases the degree of uncertainty
of the forthcoming eye movement and forces the subject to
perform more complicated visuomotor tasks (hence fronto-
parietal activation) for correct performance. Secondly, we
quantified the neurological deficit via the Appel test and sub-
sequently investigated correlations between Appel test para-
meters and ocular motor performance indices. Finally, the
present study employed a larger number of subjects (51 vs.
17).
2. Materials and methods
Remembered saccades, or saccades to a previously dis-
played target in visual space, can be considered to reflect
spatial working memory. Although the exact circuit for the
execution of a remembered saccadic eye movement re-
mains unclear, the participation of the frontal lobes and
especially of Brodman area 46 is well established [17,18].
Several studies in animals have already revealed that the
frontal lobes and especially dorsolateral prefrontal cortex
(DLPFC) are involved in working memory function. In part-
icular, during a delay response paradigm, neurons in these
areas encode both the target location in space and the
direction of the intended movement [19]. In addition, work-
ing memory performance is impaired when D1 antagonists
are injected into the prefrontal cortex (PFC), further sup-
porting the involvement of the PFC in working memory
mechanisms [20]. Thus, it was deduced that the PFC and
especially the DLPFC could be considered as a candidate
location for specific working memory functions [20]. Giv-
en that similar cortical areas have been implicated in the
performance of anti-saccadic and remembered saccadic eye
movements, a question arises concerning the possibility of
a dysfunction in both tasks in the case of frontal lobe
impairment.
2.1. Subjects
Fifty-one hospitalized ALS patients participated in the
experiments. The control group consisted of 28 subjects.
They were recruited from the patients’ spouses based on age
and educational level. All spouses that were selected par-
ticipated after giving their informed consent (Table 1).
Patients and control subjects with an IQ score below 70
were excluded, as were patients and controls with depres-
sion (Beck’s inventory). The diagnosis of ALS was based on
the criteria established by the World Federation of Neurol-
ogy [22]. Quantitative evaluation for disability was calcu-
lated according to the Appel procedure [23]. An overview of
the patient and control subjects data and related information
is presented in Table 1.
2.2. Stimulation procedure and eye movement recording
Subjects were seated comfortably with the head immobi-
lized by a headrest 120 cm in front of a gray monitor screen.
The monitor displayed the visual targets used as stimuli.
Horizontal (right eye) and vertical (left eye) eye movements
were recorded using the infrared method (IRIS, SKALARR).
The infrared-oculographic (IROG) data as well as data
concerning visual stimuli were sampled at 200 Hz and stored
The study of Shaunak et al. [5] is the only one, to date,
that focused on anti-saccades and remembered saccades in
relation to ALS. ALS patients showed increased error rates
and latencies in performance of both types of saccade. In
contrast, performance of reflexive saccades and smooth pur-
suit was normal. Thus, the pattern of eye movement disorder
in ALS is consistent with prefrontal dysfunction.
Table 1
In this study, as in the study of Shaunak et al. [5], we
evaluated the performance of ALS patients in the anti-
saccade and the remembered saccade tasks. In addition, the
patients performed an extensive battery of neuropsycholog-
ical tests. Our aim was twofold: (1) to investigate correlations
between frontal lobe dysfunction in ALS patients, as revealed
by ocular motor system function, and the results from the
neuropsychological testing; and (2) to investigate correla-
tions of the ocular motor and neuropsychological data with
clinical data to determine potential predictors of which non-
demented ALS patients have concurrent cognitive impair-
ment. Our study differs from the above mentioned in several
Demographic and clinical characteristics of ALS patients and control
subjects
ALS patients (n = 51)
Control subjects (n = 28)
mean F SD (min–max) mean F SD (min–max)
Age (years)
58.8 F 10.2 (36–74)
32
57.8 F 9.2 (44–70)
12
Male (number)
Female (number)
Education (years)
Time since
19
16
9.4 F 4.2 (0–18)
25.5 F 19.7 (6–84)
10 F 3.2 (6–16)
–
diagnosis (months)
Appel score
69.2 F 25.0 (30–123)
–
Eleven patients were diagnosed with the bulbar form of the disease whereas
40 were diagnosed with the distal form.

I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
27
to the hard drive for further analysis. The experimental
conditions are schematically depicted in Figs. 1 and 2.
location where the PT had previously appeared or a saccade
toward the PT which was still on, respectively. In the re-
membered saccade condition, a corrective target was turned
on at the remembered target location 1 s after the FP was
turned off. Subjects were allowed to perform a corrective
saccade, if necessary, and then fixate on the target until it was
turned off (Fig. 2).
2.2.1. The three-choice task
Subjects focused on a central fixation point (FP). A peri-
pheral target (PT) appeared randomly to the left or to the
right of the FP at a fixed eccentricity of 10ꢀ. The shape of the
peripheral target varied randomly indicating to the subject
the action to be taken: rectangle, saccade toward the target
(pro-target saccade); triangle, continued fixation at the center
(no move); circle, saccade in the opposite direction of the
target (anti-target saccade). After a saccadic eye movement,
the PT was extinguished, the FP was presented and a new
trial was initiated when the subjects’ IROG indicated that
eyes were fixated at the center (Fig. 1).
2.3. Analysis of eye movement data
For the three-choice task, we measured the mean latencies
for all types of saccades (correct pro- and correct anti-
saccades, error pro- and error anti-saccades), and calculated
the DF. Error pro-saccades were defined as pro-target errors,
i.e. inappropriate pro-saccades when an anti-saccade or no
saccade was indicated. Error pro-saccades in both anti-
saccade and no-move conditions were treated as one type
of error and pooled together in all subsequent calculations.
Error anti-saccades were defined as anti-target errors, i.e.
inappropriate anti-saccades performed in the saccade con-
dition. Latencies greater than 1000 ms or less than 80 ms
(anticipatory saccades) were excluded from the analysis. The
DF was defined as the percentage of errors (including both
pro- and anti-saccade) and was calculated for each subject
and across all subjects.
2.2.2. The remembered saccade task
Subjects focused on the FP. The PT appeared randomly to
the left or to the right at 8ꢀ or 16ꢀ. In the remembered saccade
task, the PT flashed for 200 ms, whereas in the delay task, it
remained on. Subjects were instructed to wait for a random-
ized delay period of 2 to 5 s until the FP was turned off (go
signal) to initiate action: a remembered saccade toward the
For the remembered saccade task, we calculated the mean
latency for both remembered and delay saccades as well as
the amplitude errors (dysmetria). The accuracy of remem-
bered and delayed saccades was calculated using the formula:
Accuracy =(expected amplitude À performed amplitude)/ex-
pected amplitude  100 [17].
2.4. Neuropsychological evaluation
Patients and controls were screened extensively using a
variety of neuropsychological tests. We present data from
the performance in tests specific to frontal lobe function
such as the Wisconsin Card Sorting Test (WCST) and the
Stroop Test (Stroop). In addition, we present results for the
Rey Complex Figure Recall (RCF), the Wechsler Adult
Intelligence Scale (WAIS) and the Verbal IQ (VIQ). Per-
formance IQ was not estimated in order to avoid bias due
to the motor deficit of ALS patients. Subjects with a VIQ
score of less than 70 were excluded from the study. In
order to avoid the interference of depression, Beck’s de-
pression inventory was administered and a cut-off point of 16
was used to exclude moderately and severely depressed
subjects [24].
The following WCST parameters were scored: number of
categories, perseverative and non-perseverative errors, total
number of errors, perseverative responses, correct trials,
percentage of perseverative errors and responses, and per-
centage of conceptual level of responses [25].
Fig. 1. The behavioral stimuli and sample IROG recordings for the three-
choice anti-saccade task. (A) The central fixation point (FP) was extinguished
simultaneously with peripheral target (PT) presentation. (B) Typical eye
movement responses according to the type of target (square = pro-target
move, triangle = no move, circle = anti-saccade move). The dotted lines
represent the common types of errors, namely pro-target moves in the ‘‘no
move’’, and anti-saccade conditions.
The Stroop was used to estimate the ability to suppress
interfering information. We recorded the total number of
correct responses during a constant period of time [26].

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I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
Fig. 2. The behavioral stimuli and sample IROG recordings for the remembered saccade task. After a variable period of 2–5 s, the central fixation is turned off
corresponding to the go signal. (A) The remembered saccade condition. The peripheral target flashes for 200 ms during central fixation. The subject initiates a
saccade to the remembered target (performed amplitude) followed by a correction movement based on presentation of a corrective target (thin line under the eye
movement record). (B) The delay saccade condition. The peripheral target remains on until after the go signal. The subject initiates a saccade to the target after a
variable delay of 2 to 5 s.
Finally, visual memory was assessed by the RCF 15 min
after its presentation [27]. Patients with severe motor deficit
were not given this test.
after logarithmic transformation of data. Statistical analyses
were performed using Statisticak for Windows 95k
(1997).
2.5. Statistical analysis
3. Results
A normality test (Kolmogorov–Smirnov for one sam-
ple) was first performed for all variables under consider-
ation. The Mann–Whitney U-test and the Students’ t-test
were used as indicated for comparisons between patients
and controls. Spearman rank order correlations were cal-
culated for the correlations among the different variables.
Chi-square and Fisher’s exact test were also performed.
ANOVA, Pearson’s correlations (values of R were calcu-
lated) and multiple regression analyses were performed
3.1. Clinical data
The clinical characteristics of ALS patients and controls
are presented in Table 1. The majority of patients (n = 40,
78%) presented with the distal form of the disease whereas
the remainder (n = 11, 22%) showed signs of bulbar onset.
There were no significant differences between ALS patients
and controls in terms of gender (v2 = 3.14, p > 0.07).

I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
29
Table 2A
Measures from the three-choice task
Control subjects
ALS patients
Controls vs. ALS
Latencies for correct pro-saccades (ms)
Latencies for correct anti-saccades (ms)
Latencies for error pro-saccades (ms)
Latencies for error anti-saccades (ms)
DF (%)
477 F 163
575 F 164
333 F 181
595 F 188
16.1 F 9
403 F 173
565 F 167
284 F 165
440 F 209
32 F 19
p < 0.01 (U = 229505, z = À 8.07)
n.s. (U = 146222, z = À 0.55)
p < 0.01 (U = 113217, z = À 4.69)
p < 0.01 (U = 3190, z = À 4.98)
p < 0.01 (U = 341, z = 3.81)
Experimental measures are listed in column 1. Means and standard deviations are shown for control subjects (column 2) and ALS patients (column 3).
Statistical analysis comparing the two groups (Mann–Whitney U-test) are shown in column 4. Statistically significant differences are marked in bold.
3.2. Eye movements
and delay saccade latencies in either the control group or
the ALS patient group. However, the ALS patient group
latencies were significantly longer than those for the control
group both for remembered and delay saccades.
Tables 2A and 2B present measurements and statistical
analyses regarding the ocular motor tasks.
3.2.1. The three-choice task
3.2.2.2. Dysmetria. There were no differences in dysmetria
between ALS patients and controls for either remembered or
delay saccades. However, the remembered saccades were
more dysmetric than the delay ones for both groups.
3.2.1.1. Latencies. In the three-choice task, for both controls
and ALS patients (Table 2A), the shortest latencies were
observed for error pro-saccades whereas the longest were
observed for error anti-saccades. Error pro-saccade latencies
were significantly shorter than those in correct pro-saccades,
which in turn were significantly shorter than correct anti-
saccades. Latencies for error anti-saccades did not differ
from those in correct anti-saccades for either controls or
ALS patients. The comparison of latencies between the two
subject groups showed shorter latencies of correct and error
pro-saccades and error anti-saccades in the ALS patient
group.
3.2.3. Summary of the ocular motor results
In the three-choice anti-saccade task, the ALS group ex-
hibited shorter latencies for correct pro-saccades, error pro-
saccades, and error anti-saccades as well as higher DF com-
pared to the control group. As for the remembered saccade
task, although ALS patients had longer latencies in both
remembered and delay conditions, their accuracy (as meas-
ured by dysmetria) was similar to that of control subjects.
3.3. Neuropsychological data
3.2.1.2. Distractibility factor. ALS patients exhibited a sig-
nificantly higher average DF than the control group. In
addition, more than 90% of their error saccades were pro-
target errors. Seventeen ALS patients (33%) had DF higher
than the 99th percentile of DF values of the control group.
The distributions of DF in ALS patients and controls are
depicted in Figs. 3 and 4, respectively.
The results of the neuropsychological tests are given in
Table 3. ALS patients differed from controls in 8 of the 11
categories of the WCST, whereas they did not differ in VIQ,
Stroop and RCF scores.
3.4. Correlations
3.2.2. The remembered saccade task
The results of correlation analyses between DF and,
successively, clinical data, ocular motor data and neuropsy-
chological test scores are presented in Table 4. We consid-
ered the DF to be the dependent variable indicative of frontal
lobe dysfunction.
3.2.2.1. Latencies. Ocular motor data from the remembered
saccade task are presented in Table 2B. There were no
statistically significant differences between remembered
Table 2B
Measures from the remembered saccade task
Control subjects
ALS patients
Controls. vs. ALS
Latencies for remembered saccades (ms)
Latencies for delay saccades (ms)
294 F 122
310 F 152
16.5 F 23
3.9 F 13
322 F 139
335 F 139
19.3 F 22
4.8 F 13
p < 0.01 (U = 308978, z = 4.68)
p < 0.01 (U = 283723, z = 6.71)
n.s. (U = 316490, z = 3.91)
n.s. (U = 339687, z = 1.60)
Dysmetria for remembered saccades (%)
Dysmetria for delay saccades (%)
Column 1 presents the types of data measured in this task which were the latency and dysmetria for the remembered saccades and the delay saccades. The other
columns correspond to those for Table 2A.

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I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
Table 3
Neuropsychological tests
Control
subjects
ALS
Controls vs. ALS
patients
VIQ
103.12 F 10.56 97.96 F 13
78.7 F 23.2 63.15 F 25.7
13 F 5.34 12.55 F 6.75
n.s.
(U = 374, z=-1.09)
n.s.
Stroop
RCF
U = 310, z = À 2.49)
n.s.
(U = 244, z = À 0.44)
WCST
Categories
5.28 F 0.89
3.35 F 1.79 p < 0.01
(U = 244, z = À 4.46)
Trials
111.57 F 15.9 117.8 F 20.2
n.s.
U = 480, z = À 1.83)
Correct resp.
Errors
75.0 F 3.69 63.78 F 16.08 p < 0.01
(U = 334, z = À 3.45)
36.57 F 15.38 53.97 F 22.36 p < 0.01
(U = 354, z = À 3.23)
24 F 12.5 39.48 F 24.64 p < 0.01
(U = 422, z = À 2.47)
20.14 F 8.68 31.58 F 19.61 p < 0.05
(U = 446, z = À 2.2)
n.s.
(U = 480, z = À 1.83)
56.42 F 15.69 39.47 F 21.65 p < 0.01
(U = 306, z = À 3.76)
Pers. resp.
Percentage
of pers. resp.
Non-pers. resp.
14.57 F 5.9
18.19 F 9.38
Fig. 3. The distribution of DF in ALS patients. The x-axis represents DF
values and y-axis the number of patients. The dotted line separates two
distinct areas of accumulation of DF values.
Percentage
of level
of resp.
Percentage
of errors
31.42 F 9.87
44.3 F 16.54 p < 0.01
(U = 336, z = À 3.43)
21.57 F 10.18 34.87 F 20.57 p < 0.01
(U = 412, z = À 2.58)
18.28 F 7.02 28.41 F17.61 n.s.
(U = 442, z = À 2.25)
Pers. errors
3.4.1. Correlations between DF and clinical data
A forward stepwise multiple regression was performed
after the normalization of the demographic and clinical data.
The following independent variables were used: age, educa-
tion, time since diagnosis, and Appel score. The DF showed a
statistically significant partial correlation with the Appel
score, R = 0.310, p = 0.04 (DF = À 1.5 + 0.3 Â Appel score,
F to enter = 3) but was not correlated with age, educational
level or time since diagnosis. In a second multiple regression,
Percentage
of pers. errors
Means and standard deviations are presented. The between group
comparisons were conducted using the Mann–Whitney U-test. Resp. = res-
ponses, pers. = perseverative. Cells with statistically significant values of
the U statistic are marked in bold.
the Appel score was replaced by the subscores in the follow-
ing measures: dysarthria (speech), swallowing, respiration,
upper muscle strength, lower muscle strength. The DF was
significantly correlated only with the speech score, R = 0.38,
p = 0.03 (DF = 25.3 + 0.36 Â speech score, F to enter = 3).
3.4.2. Correlations between DF and ocular motor data
(latencies and dysmetria)
The DF was significantly correlated with all the ocular
motor parameters measured except the latency of delay
saccades. The correlation coefficients (values of R) and the
p value for the R between DF and each of the ocular motor
parameters are presented in Table 4.
3.4.3. Correlations between DF and neuropsychological test
results
We performed Spearman rank order correlations between
the DF and each of the WCST, Stroop and RCF parameters. In
the ALS patient group, DF was significantly correlated with
10 out of 14 test parameters. Specifically, significant corre-
lations were found with the Stroop test and 9 of the 11
Fig. 4. The distribution of DF in control subjects. Axes as in Fig. 3.

I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
31
Table 4
The correlation coefficients, R and partial correlation coefficients, pR, of the DF with clinical parameters (see columns 1 and 2), ocular motor task performance
parameters (see columns 3 and 4) and neuropsychological testing parameters (see columns 5 and 6)
Clinical
Ocular motor
Neuropsychological
Age
pR = 0.17, p = 0.26
pR = 0.01, p = 0.95
pR = 0.31, p = 0.04
pR = 0.38, p = 0.03
pR = 0.01, p = 0.97
Latency pro-saccade
Latency anti-saccade
Latency error pro-saccade
Latency error anti-saccade
Latency
R = À 0.40, p < 0.01
R = À 0.13, p < 0.01
R = À 0.32, p < 0.01
R = À 0.46, p < 0.01
R = 0.17, p < 0.01
VIQ
R = À 0.18, p = 0.21
R = À 0.35, p < 0.05
R = 0.23, p = 0.29
R = À 0.34, p < 0.01
R = 0.04, p = 0.74
Education
Appel
Stroop
RCF
Dysarthria
Swallowing
WCST categories
WCST trials
remembered saccade
Latency delay saccade
Respiration
pR = 0.06, p = 0.75
pR = 0.02, p = 0.92
pR = 0.07, p = 0.71
R = 0.02, p = 0.53
R = 0.17, p < 0.01
R = 0.12, p < 0.01
WCST correct
responses
R = À 0.43, p < 0.01
R = 0.39, p < 0.01
R = 0.35, p < 0.01
R = 0.36, p = 0.01
R = À 0.05, p = 0.70
R = À 0.43, p < 0.01
Upper muscle
strength
Dysmetria
WCST errors
remembered saccade
Dysmetria delay saccade
Lower muscle
strength
WCST perseverative
responses
WCST percentage of
perseverative responses
WCST non-perseverative
responses
WCST percentage of level
of responses
WCST percentage of errors
WCST perseverative errors
WCST percentage of
perseverative errors
R = 0.42, p < 0.01
R = 0.36, p < 0.01
R = 0.38, p < 0.01
Cells with statistically significant values are marked in bold.
parameters of the WCST. DF was not correlated with per-
formance of the trials and the non-perseverative responses of
the WCST or with the VIQ and the RCF test scores.
We conducted a large number of separate correlations
between DF and ocular motor and neuropsychological var-
iables. While this increases the probability of type I error, the
correlations follow the between groups comparisons, rein-
forcing these findings and the large number of significant
correlations suggest that the majority have not occurred by
chance.
4.1. Anti-saccades in ALS
The performance of an anti-saccade [14] is a complex task
since it demands the inhibition of the unwanted reflexive
saccade. It involves the activation of posterior parietal cort-
ical (PPC) areas for target localization and eye movement
triggering [28] as well as the frontal motor areas (frontal eye
field). In addition, it requires integrative function [29] of
prefrontal areas.
In this study, ALS patients showed a high distractibility
in the anti-saccadic eye movement task. The fact that the
error saccadic eye movements were almost exclusive due to
ineffective suppression of unwanted saccades toward the
target, and that the errors were followed by correction,
suggests that although the subjects understood the instruc-
tion, they could not avoid inhibit a saccade to the target
when it appeared. Similar results have already been reported
in a study on eye movements in ALS, although the exper-
imental conditions differed slightly [5].
4. Discussion
The main findings of our study may be summarized as
follows. First, one-third of the ALS patients showed great
difficulties when they had to suppress unwanted saccades, as
reflected in the particularly high DF of this group. In addition,
the ALS patient DF was correlated with abnormal scores in
several categories of the WCST and with low performance in
the Stroop test. These results suggest frontal lobe impairment
in ALS patients. Second, ALS patients exhibited longer
latencies than controls in both remembered and delay sac-
cades without any difference in the accuracy of either sac-
cade. No affect on remembered saccades suggests no deficit
in the memorization of spatial information regarding the
visual stimulus and thus no effect on spatial working memory
as measured in this task. Third, the cognitive impairment was
independent of many clinical parameters but significantly
correlated with dysarthria as measured by the Appel test.
While the elevated DF seems to be related to a frontal
lobe dysfunction, the precise localization of the suppression
mechanisms in the frontal–prefrontal areas remains unclear
[15,17,30,31]. The hypothesis of a frontal and/or prefrontal
lesion in ALS revealed by the high DF in the anti-saccadic
eye movement task is additionally supported by the results
of neuropsychological testing. Specifically, the DF is stat-
istically significantly correlated with the WCST results. A
high correlation between errors in the anti-saccade task and
WCST has also been found in schizophrenic patients and
was considered a sign of frontal lobe dysfunction [16,32].

32
I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
There was also a significant correlation between DF and low
performance on the Stroop test, although there is no evi-
dence of an impairment in the ALS patients on this test. In
the present study, the latencies for both error anti-saccades
(but not correct anti-saccades) and correct and error pro-
saccades for the ALS patient group were shorter than those
of the control subjects, whereas in the study of Shaunak et
al. [5], these latencies were found to be longer than the
control. The much more difficult three-choice paradigm we
used requires longer overall processing time (inherently
with greater variability) and may explain the discrepancy
of our findings with that of Shaunak et al. [5].
patients presented a slight but significant increase in remem-
bered and delay saccade latencies similar to that reported
previously under slightly different experimental conditions
[5]. Lesions at several sites including the frontal, prefrontal
and parietal cortices can affect remembered saccade latency
[17]. The possibility of frontal involvement is supported by
neuropsychological test results, but the possibility of pari-
etal impairment cannot be excluded. Some evidence for
parietal cortical involvement in ALS comes from PET
studies [37] and frontal (dorsolateral prefrontal) and parietal
lesions, showing an increase in both the latency of saccades
and the degree of dysmetria [17]. Several findings implicate
the DLPFC as the candidate location for working memory
dysfunction [21].
Lesions of the human frontal lobes produce slight and
usually transient ocular motor dysfunction. Aside from the
well-established higher saccadic error rate, the effect of
prefrontal lesions on saccade reaction time is still unclear.
In the study of Guitton et al. [15], frontal patients exhibited
latencies similar to those of control subjects, both for pro-
saccades and anti-saccades. In addition, the study of Pierrot-
Deseilligny et al. [17] failed to reveal any statistically
significant difference of latencies among PFC, frontal eye
field (FEF) and supplementary motor area (SMA) patients
when comparing them to the control group. In contrast, the
study of Braun et al. [33] showed a significant increase in
express saccade latencies (in the range of 80–150 ms) when
frontal patients performed a visually guided saccade in a gap
ocular motor paradigm. Patients with small ischemic lesions
affecting one FEF exhibited longer anti-saccade latencies
when performing an overlap ocular motor task [34]. In a
recent study of lesions affecting the FEF and/or the DLPFC,
it was shown that FEF lesions were followed by an increase
in the latency of short latency reflexive saccades [35]. These
findings are contradictory and suggest that the FEF either
plays a rather minor role in the preparation of saccades (as
revealed by latency studies) [15,17], or contributes to the
voluntary shiftings of attention [33] and underlines the
volitional characteristics of a saccadic eye movement.
Nevertheless, the results of our study and one of the above
mentioned [35] allow us to assume that the shorter latencies
of reflexive saccades may be attributed to an inactivation of
the FEF-collicular inhibitory pathway. We might hypothe-
size that, in frontal patients, the signal for saccadic eye
movement onset bypasses the FEF and reaches the disinhi-
bited colliculi directly. In other words, the slow voluntary
controlled system is substituted by the fast reflexive one for
triggering an eye movement and this ‘‘hyperactive visual
grasp reflex’’ can be attributed to the frontal lobe impair-
ment.
4.3. Cognitive deficits and clinical correlates
The association of motor neuron disease with cognitive
dysfunction has been described [6,38,39]. In our study,
frontal lobe dysfunction was found in 30% of a large number
of patients screened with WCST, Stroop, RCF and WAIS-
VIQ. The present study is in agreement with one of the
previous studies [39] in that one-third of our non-demented
patients showed suppression difficulties indicating frontal
lobe deficit.
More interestingly, the DF was correlated with only one
subcategory of the Appel score, namely dysarthria. In spite
of the purely clinical rating of speech and deglutition in the
Appel procedure, which might be inappropriate for precise
detection of bulbar symptoms, the selective correlation of
dysarthria with frontal dysfunction is interesting in the light
of recent findings. In particular, the presence of pseudobul-
bar palsy in ALS is associated with frontal lobe impairment
[10]. It has recently been suggested that cognitive impair-
ment and dysarthria could be considered as a single under-
lying process based on the absence of the calcium-binding
proteins [40,41].
Our findings shows that a subgroup of ALS patients
present clear and subclinical frontal deficits. The question
remains as to whether the ALS subgroup shares a common
pathology with the rest of the ALS patients reflecting a
unique disease with quantitatively different expression, or
whether the ALS population could be divided in two
distinct and qualitatively different diseases according to
the presence or absence of the frontal deficit. Several
studies have proposed that the phenotypic expression of
ALS varies between different forms. Thus, the disease has
been described as sporadic without cognitive impairment,
sporadic with cognitive deficits and coexistent ALS with
frontal dementia [9,10,42], raising the question of whether
the clinical spectrum of ALS is a continuum or discrete
entities.
4.2. Remembered saccades in ALS
The frontal lobes are involved in the performance of
memory-guided or remembered saccades. Studies with
regional cerebral blood flow during a remembered saccade
task showed an activation of several areas such as the FEF,
SMA, DLPFC and PPC [35,36]. In the present study, ALS
In conclusion, it seems that ALS is a disease that affects
higher cognitive frontal functions such as suppression of
unwanted saccadic responses and preparation of remem-
bered saccades.

I. Evdokimidis et al. / Journal of the Neurological Sciences 195 (2002) 25–33
33
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