Errors of Memory-Guided Saccades in Humans With Lesions of the Frontal Eye Field and the Dorsolateral Prefrontal Cortex

Christoph J. Ploner,1,2 Sophie Rivaud-Péchoux,1 Bertrand M. Gaymard,1 Yves Agid,1 and Charles Pierrot-Deseilligny1

 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


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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.



View larger version (38K):
[in this window]
[in a new window]
 
Fig. 1. A: anatomy of the frontal cortex. Two transverse brain sections parallel above the anterior commissure-posterior commissure (AC-PC) line with Talairach coordinate frame show the location of the frontal eye field (FEF, left) and the invariable portion of Brodmann's area 46 in the dorsolateral prefrontal cortex (DLPFC, right) as gray-shaded areas. X, distance from the sagittal plane; Y, distance from the coronal plane through the anterior commissure; Z, distance from the AC-PC line; VCA, vertical anterior commissure line; VCP, vertical posterior commissure line; R, right; L, left; F1, superior frontal gyrus; F2, middle frontal gyrus; F3, inferior frontal gyrus; PRC, precentral gyrus; *, precentral "knob." B: lesion drawings of patients with selective lesions of the FEF (1 right, 2 left) with VCA and VCP line. C: lesion drawings of patients with combined lesions of FEF and DLPFC (3 right) with VCA and VCP line. Note involvement of the invariable portion of Brodmann's area 46 in all 3 patients.

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.



View larger version (10K):
[in this window]
[in a new window]
 
Fig. 2. The memory-guided saccade paradigm with electrooculographic recording trace. C, cue (duration: 50 ms); FP, fixation point; E, eye; MGS, memory-guided saccade.

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.



View larger version (10K):
[in this window]
[in a new window]
 
Fig. 3. Examplary results. Targeting errors (gain) of leftward memory-guided saccades of a control subject (Cont), a patient with a selective lesion of the right FEF and a patient with a lesion of right FEF and DLPFC. Note a systematic reduction of memory-guided saccade gain (hypometria) in the patient with a selective FEF lesion, while gain variability is similar to the control subject. Note both systematic reduction of MGS gain and an increase in gain variability in the patient with a lesion of FEF and DLPFC.

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.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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).



View larger version (34K):
[in this window]
[in a new window]
 
Fig. 4. Group results. A: systematic targeting errors (average gain). B: variable targeting errors (gain variability) of memory-guided saccades. White bars: group means of controls (Cont); light gray bars: group means of patients with selective lesions of the FEF; dark gray bars: group means of patients with combined lesions of FEF and DLPFC. Dots represent individual results. I, values of memory-guided saccades ipsilateral to the lesion side; C, values of memory-guided saccades contralateral to the lesion side; *, P = 0.014 difference with controls.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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.


    ACKNOWLEDGMENTS

We are grateful to M. Ploner, S. A. Brandt, F. Ostendorf, and the referees for helpful comments on the manuscript.


    FOOTNOTES

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.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

0022-3077/99 $5.00 Copyright © 1999 The American Physiological Society