1Institut National de la Santé et de la Recherche Médicale U. 289 and Service de Neurologie, Hôpital de la Salpêtrière, F-75651 Paris Cedex 13, France; and 2Klinik für Neurologie, Charité, D-10117 Berlin, Germany
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ABSTRACT |
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Ploner, Christoph J., Sophie Rivaud-Péchoux, Bertrand M. Gaymard, Yves Agid, and Charles Pierrot-Deseilligny. Errors of Memory-Guided Saccades in Humans With Lesions of the Frontal Eye Field and the Dorsolateral Prefrontal Cortex. J. Neurophysiol. 82: 1086-1090, 1999. Behavioral studies in monkeys and humans suggest that systematic and variable errors of memory-guided saccades reflect distinct neuronal computations in primate spatial memory. We recorded memory-guided saccades with a 2-s delay in three patients with unilateral ischemic lesions of the frontal eye field and in three patients with unilateral ischemic lesions of the frontal eye field and the dorsolateral prefrontal cortex. Results suggest that systematic errors of memory-guided saccades originate in the frontal eye field and variable errors in the dorsolateral prefrontal cortex. These data are the first human lesion data to support the hypothesis that these regions provide functionally distinct contributions to spatial short-term memory.
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INTRODUCTION |
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The memory-guided saccade (MGS) paradigm requires
execution of an eye movement to the memorized position of a visual cue. This paradigm represents a delayed oculomotor response task and has
been applied widely in the study of primate spatial short-term memory
(see Goldman-Rakic 1996; Pierrot-Deseilligny et
al. 1995
for reviews). An impairment in spatial short-term
memory causes inaccuracy of MGS with two possible and qualitatively
different error types: errors may be systematic, i.e., MGS may
systematically over- or undershoot the memorized cue position, pointing
to a biased but stable relationship between spatial cue and oculomotor response and/or errors may be variable, i.e., MGS may show an increased
scatter around the memorized cue position, thus revealing a weakened
and unstable relationship between spatial cue and oculomotor response.
Behavioral studies suggest that the neuronal computations underlying
these error types are distinct (Ploner et al. 1998
; White et al. 1994
).
In the frontal cortex, two regions appear to be essential for the task:
the frontal eye field (FEF) and the dorsolateral prefrontal cortex
(DLPFC). Single neuron recordings in monkeys have revealed spatially
selective neuronal activity during the memory delay of a MGS-task both
in the DLPFC (Funahashi et al. 1989, 1990
, 1993b
) and
FEF (Bruce and Goldberg 1985
; Funahashi et al.
1989
). Although it is probable that the FEF rather than the
DLPFC participates in the initiation of MGS (Bruce and Goldberg
1985
; Bruce et al. 1985
, Deng et al.
1986
; Dias et al. 1995
; Funahashi et al.
1989
, 1993a
, Rivaud et al. 1994
; Sommer
and Tehovnik 1997
), the respective roles of delay-period
activity in DLPFC and FEF for spatial short-term memory are less clear.
It may be proposed that DLPFC and FEF provide similar contributions to
a common spatial representation. Alternatively, both regions may
support distinct spatial representations, with the DLPFC subserving a
spatial representation in perceptual coordinates and the FEF providing
a spatial representation of the forthcoming MGS in oculomotor
coordinates (Funahashi et al. 1989
, 1993b
).
Various MGS-parameters already have been studied in monkeys and humans
with lesions or inactivations of FEF (Deng et al. 1986; Dias et al. 1995
; Rivaud et al. 1994
;
Sommer and Tehovnik 1997
) and/or DLPFC (Funahashi
et al. 1993a
; Pierrot-Deseilligny et al. 1991
,
1993
; Sawaguchi and Goldman-Rakic 1991
).
However, no direct quantitative comparison of the effects of FEF and
DLPFC lesions on systematic and variable errors of MGS has been carried
out so far. Here we studied systematic and variable errors of MGS in
patients with unilateral ischemic lesions including the FEF but sparing
the DLPFC in patients with unilateral ischemic lesions of FEF and DLPFC
and in controls. We aimed to infer from MGS error patterns whether or
not FEF and DLPFC make different contributions to spatial short-term memory.
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METHODS |
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Subjects
For reconstruction of the patient's lesions, we used two brain
sections +50 mm and +28 mm parallel above the anterior
commissure-posterior commissure line taken from the atlas of
Talairach and Tournoux (1988) (Fig.
1A). The +50-mm section was chosen
to show the FEF in the precentral gyrus as defined by recent functional
imaging studies (Darby et al. 1996
; Paus
1996
). The +28-mm section was chosen to show the invariable
portion of Brodmann's area 46 in the DLPFC in the middle portion of
the middle frontal gyrus (+28-mm section) as defined by
cytoarchitectonic criteria (Rajkowska and Goldman-Rakic
1995
). This region also shows activation during functional
imaging of normal subjects performing MGS (O'Sullivan et al.
1995
; Sweeney et al. 1996
) and nonoculomotor
spatial working memory tasks (McCarthy et al. 1994
;
Owen et al. 1998
). The patient's lesions were
identified on transverse computer tomography (CT) and/or magnetic
resonance imaging (MRI) scans and transposed on both sections.
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The first patient group consisted of three men with a mean age of 48 yr (34, 51, and 59 yr) with unilateral ischemic infarctions including the FEF [2 left, 1 right; mean time since lesion 25 ± 22 (SD) days]. In this group, lesions of the FEF were highly selective and remote from the DLPFC and its connections, in particular the superior and inferior occipitofrontal fascicles (Fig. 1B). The second patient group consisted of one woman and two men with a mean age of 56 yr (38, 52, and 77 yr) with unilateral ischemic infarctions including the FEF and DLPFC (3 right; mean time since lesion 44 ± 32 days). In this group, lesions always included the invariable portion of area 46 (Fig. 1C). In both patient groups, lesions were well demarcated and spared the basal ganglia, the internal capsule, and cortical oculomotor areas outside the FEF and DLPFC. No additional lesions were visible on the patient's scans. Neurological examination revealed full visual fields and full-range conjugate ocular motility in all patients. Horizontal smooth pursuit directed toward the lesion side was saccadic in all patients. Paresis of the contralateral upper limb was found in all patients with interindividually varying additional motor deficits.
The control group consisted of 10 normal subjects (mean age 50 ± 14 yr) and was tested under the same conditions as the patient group. All subjects gave informed consent before participation in the study which was approved by the local ethics committee and conducted in conformity with the Declaration of Helsinki.
Eye movement recordings
Eye movements were recorded using horizontal DC electrooculography with bitemporal electrodes. Data were sampled at a frequency of 200 Hz. The system had a bandwith of 0-100 Hz and a spatial resolution of 0.5°. Subjects were seated in complete darkness with the head fixed at the temples. Visual cues were presented at a distance of 95 cm with red light-emitting diodes (LEDs) forming a curved horizontal array. LEDs were 0.15° in size and 5 cd/m2 in luminance. Each recording session was preceded by 10 min of dark adaptation. Then calibration of the system was performed with two lateral LEDs at 30° eccentricity and regularly repeated during the recording session.
Memory-guided saccades
A visual cue was presented for 50 ms in one of five pseudorandomly varied horizontal positions (10, 15, 20, 25, and 30°) either in the right or left visual hemifield, while the subject fixated on a central fixation point (Fig. 2). After a delay of 2 s, during which fixation was maintained, the central fixation point was switched off and the subject moved the eyes as precisely as possible to the remembered cue position (memory-guided saccade). Two seconds after central fixation point offset, a control target was presented for 1 s in the same position as the visual cue to allow for a corrective saccade.
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Data analysis
Data were analyzed off-line. Trials with premature saccades were
excluded from analysis. At least 12-15 trials in each direction entered analysis in each subject. The first saccade after central fixation offset was studied (Pierrot-Deseilligny et al.
1991). Targeting error of MGS was expressed as gain, i.e., the
ratio saccade amplitude/target eccentricity (Fig.
3). Additional saccades just after
initial saccades and before presentation of the control target were
rare and did not decrease MGS errors. Therefore data from final eye
positions are similar to those of initial saccades and not presented.
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Statistics were done with reference to Altman (1991).
Medians were used to describe a subject's average gain (systematic
error) and interquartile ranges to describe a subject's gain
variability (variable error). In the control group, no significant
right-left differences between systematic errors and variable errors
were found (P = 0.26 and P = 0.26 respectively, two-tailed Wilcoxon signed-rank test). Thus these
variables were averaged in controls and compared with patient values
ipsi- and contralateral to the lesion side using Kruskal-Wallis ANOVA
and Bonferroni-corrected two-tailed Mann-Whitney U tests.
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RESULTS |
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Exemplary results from a control subject and two patients showing individual distributions of MGS targeting errors are shown in Fig. 3. Note increase in scatter of MGS targeting errors in the patient with a combined lesion of FEF and DLPFC. Group results of the two patient groups and controls are summarized in Fig. 4. No significant group differences between MGS systematic errors of patients ipsilateral to the lesion side and controls were found (df = 2, H = 1.42, P = 0.49). By contrast, MGS systematic errors of patients contralateral to the lesion side and controls differed significantly (df = 2, H = 10.6, P = 0.005). These systematic errors consisted of a significant decrease in average gain, i.e., MGS hypometria, contralateral to the lesion side in both patient groups (P = 0.014 and P = 0.014, respectively, see also example in Fig. 3). For variable errors, no significant differences between MGS of patients ipsilateral to the lesion side and controls were found (df = 2, H = 1.2, P = 0.54). However, when MGS variable errors of patients contralateral to the lesion side and controls were compared, significant differences were found (df = 2, H = 7.0, P = 0.03). These differences were entirely due to a significant increase in MGS variable errors contralateral to the lesion side in patients with combined lesions of FEF and DLPFC (P = 0.014, see also example in Fig. 3). Contralateral variable errors in patients with selective FEF lesions were nearly identical to control values (P > 0.81).
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DISCUSSION |
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Our study complements previous lesion studies in monkeys
(Deng et al. 1986; Funahashi et al.
1993a
) and humans (Pierrot-Deseilligny et al. 1991
,
1993
; Rivaud et al. 1994
) showing that lesions
of the frontal cortex impair accuracy of MGS. In addition, our results suggest that the pattern of MGS errors depends critically on the frontal subregions involved: Selective lesions of the FEF caused systematic errors of MGS, i.e., hypometria, contralateral to the lesion
side, whereas variable errors remained normal. By contrast, lesions
with involvement of the DLPFC led to an additional increase of variable
errors of MGS contralateral to the lesion side.
A differential involvement of premotor processes is unlikely to
account for this dissociation, as the DLPFC is largely devoid of
premotor functions (Funahashi et al. 1993a). Moreover,
the FEF, i.e., the premotor region for voluntary saccades (Bruce
and Goldberg 1985
; Bruce et al. 1985
), was
lesioned in both patient groups. Another explanation is a difference in
lesion size between the two patient groups. There are nevertheless
arguments against this interpretation: Lesion size may influence
cognitive deficits through increasing involvement of functionally
homologous areas. However, the pattern of MGS targeting errors was
qualitatively, not quantitatively, different between the two patient
groups. Likewise, compression of surrounding cerebral tissue appears
unlikely, as the lesions were not space-occupying. We are therefore
confident that the observed group differences in the pattern of MGS
errors are attributable to differential involvement of frontal
subregions performing distinct computations in spatial short-term memory.
Parallel findings to our patients with selective FEF lesions have been
reported in a study with monkeys receiving chronic unilateral lesions
of the FEF performing MGS (Deng et al. 1986). The
plotted MGS endpoints 3 months after the lesion reveal MGS hypometria
with, however, no clear information on their variability. Recent
studies using acute pharmacological inactivation of the monkey FEF
yielded more substantial effects, with near-to-complete abolition of
MGS contralateral to the lesion side (Dias et al. 1995
;
Sommer and Tehovnik 1997
). These results therefore
suggest partial recovery of MGS accuracy with chronic FEF lesions, as has previously been shown with other saccade paradigms and for other
saccade parameters (Schiller et al. 1980
, 1987
). The
findings in our patients with selective FEF lesions, like those from an earlier study (Rivaud et al. 1994
), likewise probably
reflect partial recovery of MGS in the hemifield contralateral to the lesion side. The new finding, here, is that MGS were performed with
normal variable errors, i.e., that there was a stable and predictable
albeit biased relationship between spatial cue and oculomotor response.
Therefore neural computations underlying variable errors of MGS are
likely to be performed outside the FEF. A functional independence of
both error types already has been suggested by the different delay
dependency of MGS errors both in monkeys (White et al.
1994
) and humans (Ploner et al. 1998
). In these
studies, lengthening of the memorization delay from some hundred
milliseconds to several seconds caused an increase in variable errors
of MGS, whereas systematic errors remained fairly constant. In humans,
the time course of variable errors closely parallels the presumed upper
temporal limits for spatial memory storage in the DLPFC
(Goldman-Rakic 1996
; Ploner et al. 1998
).
Indeed, MGS errors after inactivation or lesion of the monkey DLPFC
have been shown to be variable not systematic (Funahashi et al.
1993a
; Sawaguchi and Goldman-Rakic 1991
).
Likewise, our patients with DLPFC involvement showed a weakened (i.e.,
less predictable) relationship between cue and oculomotor response.
In our patients with selective FEF lesions, variable errors
contralateral to the lesion side were normal. This suggests that the
intact DLPFC ipsilateral to the lesioned FEF still exerted control on
MGS directed toward the lesion side. Although our data provide no
information on the cortical areas participating in compensatory
processes after unilateral FEF lesions, the intact contralateral FEF
appears as a likely candidate region. Previous research supports this
hypothesis, as each FEF is principally capable to trigger ipsiversive
saccades (Schlag and Schlag-Rey 1990) and interacts with
its contralateral counterpart (Schlag et al. 1998
).
Transcallosal connections between right and left DLPFC
(Goldman-Rakic and Schwartz 1982
; Schwartz and
Goldman-Rakic 1984
) provide pathways by which spatial
representations in the DLPFC ipsilateral to a lesioned FEF could
maintain control of MGS directed in the hemifield ipsilateral to the
lesion side and triggered by the intact contralateral FEF.
In summary, our results suggest, not only that systematic and variable errors of MGS are functionally independent but also that they have distinct neuronal substrates. It appears therefore likely that delay-period activity in the human FEF and DLPFC provides distinct contributions to spatial short-term memory rather than forming the substrate of a common spatial representation.
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ACKNOWLEDGMENTS |
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We are grateful to M. Ploner, S. A. Brandt, F. Ostendorf, and the referees for helpful comments on the manuscript.
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FOOTNOTES |
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Address reprint requests to: C. J. Ploner, Klinik für Neurologie, Charité, Schumannstr. 20/21, D-10117 Berlin, Germany.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 March 1999; accepted in final form 8 April 1999.
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REFERENCES |
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