Effects of repetitive transcranial magnetic stimulation over dorsolateral prefrontal and posterior parietal cortex on memory-guided saccades

We investigated the role of the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in a visuospatial delayed-response task in humans. Repetitive transcranial magnetic stimulation (20 Hz, 0.5 s) was used to interfere temporarily with cortical activity in the DLPFC and PPC during the delay period. Omnidirectional memory-guided saccades with a 3-s delay were used as a quantifiable motor response to a visuospatial cue. The question addressed was whether repetitive transcranial magnetic stimulation (rTMS) over the DLPFC or PPC during the sensory of memory phase affects accuracy of memory-guided saccades. Stimulation over the primary motor cortex served as control. Stimulation over the DLPFC significantly impaired accuracy of memory-guided saccades in amplitude and direction. Stimulation over the PPC impaired accuracy of memory-guided saccades only when applied within the sensory phase (50 ms after cue offset), but not during the memory phase (500 ms after cue offset). These results provide further evidence for a parieto-frontal network controlling performance of visuospatial delayed-response tasks in humans. It can be concluded that within this network the DLPFC is mainly concerned with the mnemonic respresentation and the PPC with the sensory representation of spatially defined perceptual information. Received: 22 April 1996/Accepted: 16 June 1997     

Effects of transcranial magnetic stimulation over the region of the supplementary motor area during sequences of memory-guided saccades

Transcranial magnetic stimulation (TMS) over the region of the supplementary motor area (SMA) was used to study the cortical control of sequences of memory-guided saccades. In ten healthy subjects, TMS was applied during (a) the target presentation (learning) phase, (b) the memorization phase, and (c) the execution phase of such saccade sequences. Stimulation during the presentation phase resulted in a significant increase in errors, compared to the results without stimulation. In contrast, stimulation during the memorization or execution phases had no significant influence on the performance of these sequences. The effect of TMS during the presentation phase seems to be specific for an interaction with the SMA function, since, in a control experiment with TMS of the occipital cortex during the same phase, the results were similar to those without stimulation. It is hypothesized that different cortical areas are involved in the learning, memorization and execution of sequences of memory-guided saccades. The SMA action could be crucial during the learning phase, but not during the memorization and execution phases of such sequences.     

Memory-guided saccades: what is memorized?

Summary In order to find out whether extraretinal (oculomotor, internal) input suffices to provide the oculomotor system with the information necessary for saccadic control, two subjects were asked to make memoryguided saccades in complete darkness, after three different location acquisition conditions. These conditions were visually-guided saccades (SA), providing retinal (external) and extraretinal input, visual peripheral target presentation during central target fixation (FI) (external input only), and smooth pursuit (PU) (internal input only). Either 2 or 12 s (delay) after locating the target, the subjects had to make a memory-guided saccade toward it in complete darkness. The results show that whereas these memory-guided saccades were quite accurate for trials with preceding external input, this was not the case with acquisition through internal input alone. Moreover, the accuracy of memory-guided saccades decreased when the delay increased from 2 to 12s for both conditions with retinal input, whereas the accuracy increased for the one condition without retinal input, i.e., the smooth pursuit location acquisition. Furthermore, when both retinal and oculomotor inputs were provided, better accuracy of the memory-guided saccades was observed than with single input.     

Context-dependent effects of substantia nigra stimulation on eye movements

In a series of now classic experiments, an output structure of the basal ganglia (BG)--the substantia nigra pars reticulata (SNr)--was shown to be involved in the generation of saccades made in particular behavioral contexts, such as when memory was required for guidance. Recent electrophysiological experiments, however, call this original hypothesis into question. Here we test the hypothesis that the SNr is involved preferentially in nonvisually guided saccades using electrical stimulation. Monkeys performed visually guided and memory-guided saccades to locations throughout the visual field. On 50% of the trials, electrical stimulation of the SNr occurred. Stimulation of the SNr altered the direction, amplitude, latency, and probability of saccades. Visually guided saccades tended to be rotated toward the field contralateral to the side of stimulation, whereas memory-guided saccades tended to be rotated toward the hemifield ipsilateral to the side of stimulation. Overall, the changes in saccade vector direction were larger for memory-guided than for visually guided saccades. Both memory- and visually guided saccades were hypometric during stimulation trials, but the stimulation preferentially affected the length of memory-guided saccades. Electrical stimulation of the SNr produced decreases in visually guided saccades bilaterally. In contrast, memory-guided saccades often had increases in saccade latency bilaterally. Finally, we found approximately 10% reduction in the probability of memory-guided saccades bilaterally. Visually guided saccade probability was unaltered. Taken together the results are consistent with the hypothesis that SNr primarily influences nonvisually guided saccades. The pattern of stimulation effects suggests that SNr influence is widespread, altering the pattern of activity bilaterally across the superior colliculus map of saccades.     

Neuronal activity throughout the primate mediodorsal nucleus of the thalamus during oculomotor delayed-responses. II. Activity encoding visual versus motor signal

We collected single-neuron activity from the mediodorsal (MD) nucleus of the thalamus, examined the information that was represented by task-related activity during performance of a spatial working memory task, and compared the present results with those obtained in the dorsolateral prefrontal cortex (DLPFC). We used two oculomotor delayed-response (ODR) tasks. In the ordinary ODR task, monkeys were required to make a memory-guided saccade to the location where a visual cue had been presented 3 s previously, whereas in the rotatory ODR task, they were required to make a memory-guided saccade 90 degrees clockwise from the cue direction. By comparing the best directions of the same task-related activity between the two tasks, we could determine whether this activity represented the cue location or the saccade direction. All cue-period activity represented the cue location. In contrast, 56% of delay-period activity represented the cue location and 41% represented the saccade direction. Almost all response-period activity represented the saccade direction. These results indicate that task-related MD activity represents either visual or motor information, suggesting that the MD participates in sensory-to-motor information processing. However, a greater proportion of delay- and response-period activities represented the saccade direction in the MD than in the DLPFC, indicating that more MD neurons participate in prospective information processing than DLPFC neurons. These results suggest that although functional interactions between the MD and DLPFC are crucial to cognitive functions such as working memory, there is a difference in how the MD and DLPFC participate in these functions.     

The effect of transcranial magnetic stimulation on the latencies of vertical saccades

In this study, we investigated the effect of transcranial magnetic stimulation (TMS) over the right posterior parietal cortex (PPC) on the latency of two different types of visually-guided vertical saccades: reflexive saccades triggered by the sudden onset of a target, and saccades towards target locations known in advance. For this reason, we used two oculomotor tasks: a gap and a delay task, respectively. Nine normal subjects performed vertical saccades at ±7.5 and ±15°. TMS was applied at 80 and 100 ms after target onset in the gap task, and after fixation offset in the delay task. Without TMS, we confirmed a latency asymmetry in the gap task favouring upward saccades at the lower eccentricity (7.5°), and a latency symmetry in the delay task. TMS increased the latencies of all saccades in the delay task, when delivered at 100 ms. This effect was mostly pronounced for downward saccades at 7.5°. As a result, saccade latencies showed an asymmetry in this condition, similar to the one observed in the gap task without TMS. The gap task with TMS resulted in a variable latency distribution and no significant overall effect on saccade latency. Our results indicate that the right PPC is involved in the initiation of vertical saccades in the delay task, and that this involvement appears to be enhanced for downward saccades. A conclusion for the involvement of this area in the gap task could not be drawn from this study.     

Effects of anterior cingulate cortex lesions on ocular saccades in humans

Cerebral blood flow studies in humans suggest that the anterior cingulate cortex (ACC) could be involved in eye movement control. In two patients with a small infarction affecting the posterior part of this area (on the right side) and in ten control subjects, we studied several paradigms of saccadic eye movements: gap task, overlap task, antisaccades (using either a 5° or 25° lateral target), memory-guided saccades with a short (1 s) or long (7 s) delay, and sequences of memory-guided saccades. Compared with controls, patients had normal latency in the gap task but increased latency in the other tasks. The gain of memory-guided saccades was markedly decreased, bilaterally, whatever the duration of the delay. Patients made more errors than controls in the antisaccade task when the 5° lateral target was used, and a higher percentage of chronological errors in the sequences of saccades. These results show that the posterior part of the right ACC plays an important role in eye movement control and suggest that this area could correspond to a “cingulate eye field” (CEF). The role of this hypothetical CEF could be an early activation exerted on the frontal ocular motor areas involved in intentional saccades and also a direct action on brainstem ocular premotor structures. Received: 8 November 1996 / Accepted: 14 October 1997     

Disconjugate memory-guided saccades to disparate targets: temporal aspects

Memory-guided saccades to disparate targets (i.e., more eccentric for one eye) flashed 1 s earlier become disconjugate (i.e., of different amplitude for the two eyes) after only about 30 trials. After about 225 trials the disconjugacy persists even when the target to remember is no longer disparate. This suggests fast learning based on short-term memorization of disparity. Learning, however, fails to occur if during the training the memory delay for each trial is increased to 2 s. The purpose of the present study was to test the importance of the frequency of stimulus presentation and thereby the rate of saccades. The same memory-guided saccade paradigm was used as in the prior study and a short training period of 225 trials was applied. For each training trial, the memory delay was again 2 s, but the time allocated for fixation of the central dot and the time allocated for fixation of the remembered target in the dark was reduced to increase the frequency of saccades made. Saccades became rapidly disconjugate and their disconjugacy was retained in a subsequent neutral condition using non-disparate targets. These findings indicate that stimulus frequency and thereby saccade frequency is important for disconjugate oculomotor learning based on disparity memorization. Nevertheless, additional experiments using longer memory delays of 3 s or 4 s show a definite failure of memorization and disconjugate learning.     

The role of the right medial temporal lobe in the control of memory-guided saccades

The role of the hippocampal formation in the control of memory-guided saccades is unclear. We tested two types of memory-guided saccades with short memorization delay in three patients with a lesion affecting the right medial temporal lobe and involving the hippocampal formation. In single memory-guided saccades, testing spatial working memory, the gain of the patient group did not differ from that of an age-matched control group. In contrast, in sequences of memory guided saccades, testing chronological working memory, there was a marked and significant increase in the percentage of erroneous sequences in patients, compared to controls. These results suggest an important role of the hippocampal formation in the memorization of the chronological order of saccade sequences. In contrast, this structure does not appear to be crucial for spatial working memory, used in single memory-guided saccades.     

Cortical Potentials Evoked in Humans by Signals to Perform Memory-Guided Saccades

Increases in the latent periods of memory-guided saccades as compared with those of visually guided saccades were observed, providing evidence of slowing in saccade programming based on extraction of information from working memory. Comparison of the parameters and topography of the N1 and P1 components of evoked potentials induced by a signal to perform a memory-guided saccade and a visual stimulus-guided saccade suggested that the early stages of saccade programming, associated with the processing of spatial information, are mediated mainly by the descending mechanism of attention for memory-guided saccades and the ascending mechanism for saccades in response to a visual stimulus. These data may indicate that the increase in the latent period of memory-guided saccades is associated with lengthening of the central stage of saccade programming – the decision-taking stage, a correlate of which is the N2 wave developing in the middle of the latent period of the memory-guided saccade. The temporospatial dynamics of the N1, P1, and N2 components provide evidence that memory-guided saccade programming is controlled by the fronto-medio-thalamic system of selective attention, as well as by left-hemisphere motor attention mechanisms.     

Transcranial magnetic stimulation disrupts eye-hand interactions in the posterior parietal cortex

Recent neurophysiological studies have started to shed some light on the cortical areas that contribute to eye-hand coordination. In the present study we investigated the role of the posterior parietal cortex (PPC) in this process in normal, healthy subjects. This was accomplished by delivering single pulses of transcranial magnetic stimulation (TMS) over the PPC to transiently disrupt the putative contribution of this area to the processing of information related to eye-hand coordination. Subjects made open-loop pointing movements accompanied by saccades of the same required amplitude or by saccades that were substantially larger. Without TMS the hand movement amplitude was influenced by the amplitude of the corresponding saccade; hand movements accompanied by larger saccades were larger than those accompanied by smaller saccades. When TMS was applied over the left PPC just prior to the onset of the saccade, a marked reduction in the saccadic influence on manual motor output was observed. TMS delivered at earlier or later periods during the response had no effect. Taken together, these data suggest that the PPC integrates signals related to saccade amplitude with limb movement information just prior to the onset of the saccade.     

Prefrontal cortical representation of visuospatial working memory in monkeys examined by local inactivation with muscimol

In primates, dorsolateral areas of the prefrontal cortex (PFC) play a major role in visuospatial working memory. To examine the functional organization of the PFC for representing visuospatial working memory, we produced reversible local inactivation, with the local injection of muscimol (5 microg, 1 microl), at various sites (n = 100) in the dorsolateral PFC of monkeys and observed the behavioral consequences in an oculomotor delayed-response task that required memory-guided saccades for locations throughout both visual fields. At 82 sites, the local injection of muscimol induced deficits in memory-guided saccades to a few specific, usually contralateral, target locations that varied with the location of the injection site. Such deficits depended on the delay length, and longer delays were associated with larger deficits in memory-guided saccades. The injection sites and affected spatial locations of the target showed a gross topographical relationship. No deficits appeared for a control task in which the subject was required to make a visually guided saccade to a visible target. These findings suggest that a specific site in the dorsolateral PFC is responsible for the working memory process for a specific visuospatial coordinate to guide goal-directed behavior. Further, memoranda for specific visuospatial coordinates appear to be represented in a topographical memory map within the dorsolateral PFC to represent visuospatial working memory processes.     

Influence of reward expectation on visuospatial processing in macaque lateral prefrontal cortex

The lateral prefrontal cortex (LPFC) has been implicated in visuospatial processing, especially when it is required to hold spatial information during a delay period. It has also been reported that the LPFC receives information about expected reward outcome. However, the interaction between visuospatial processing and reward processing is still unclear because the two types of processing could not be dissociated in conventional delayed response tasks. To examine this, we used a memory-guided saccade task with an asymmetric reward schedule and recorded 228 LPFC neurons. The position of the target cue indicated the spatial location for the following saccade and the color of the target cue indicated the reward outcome for a correct saccade. Activity of LPFC was classified into three main types: S-type activity carried only spatial signals, R-type activity carried only reward signals, and SR-type activity carried both. Therefore only SR-type cells were potentially involved in both visuospatial processing and reward processing. SR-type activity was enhanced (SR+) or depressed (SR-) by the reward expectation. The spatial discriminability as expressed by the transmitted information was improved by reward expectation in SR+ type. In contrast, when reward information was coded by an increase of activity in the reward-absent condition (SR- type), it did not improve the spatial representation. This activity appeared to be involved in gaze fixation. These results extend previous findings suggesting that the LPFC exerts dual influences based on predicted reward outcome: improvement of memory-guided saccades (when reward is expected) and suppression of inappropriate behavior (when reward is not expected).     

Burst discharges of fastigial neurons in macaque monkeys are driven by vision- and memory-guided saccades but not by spontaneous saccades.

Discharges from 61 saccadic burst neurons in the fastigial oculomotor region were recorded for two trained macaque monkeys during vision-guided or memory-guided saccades or spontaneous saccades in the dark. Although these neurons exhibited vigorous, burst discharges during both vision-guided and memory-guided saccades, only weak bursts were observed during spontaneous saccades in the dark. Especially in 10 of the 61 neurons, saccadic burst discharge was almost completely absent during spontaneous saccades in the dark. These findings suggest that the cerebellum plays an important role in the control of vision-guided saccades as well as memory-guided saccades, but not of spontaneous saccades in the dark.     

The frontal eye field is involved in spatial short-term memory but not in reflexive saccade inhibition

Physiological studies in monkeys have shown that the frontal eye field (FEF) is involved in the preparation and triggering of purposive saccades. However, several questions of FEF function remain unclear: the role of the FEF in visual short-term memory, its ability to update its spatial map and its role in reflexive saccade inhibition. We have addressed these issues in a patient with a small acute ischemic lesion whose location corresponded very accurately to the region of the left FEF according to the most recent cerebral blood flow studies. An initial study was conducted on days 7 and 8 after the stroke, i.e., before substantial recovery. A first group of paradigms (smooth pursuit, simple saccade tasks) was performed to assess FEF dysfunction. In a second group of paradigms, (1) visual short-term memory was tested by means of memory-guided saccade paradigms with short and long delays (1 and 7 s), (2) spatial updating abilities were tested by a double-step saccade task and two memory-guided saccade tasks in which the central fixation point was displaced during the memorization delay, and (3) reflexive saccade inhibition was tested by the antisaccade task. Results show that the FEF is involved in short-term memorization of the parameters of the forthcoming memory-guided saccade encoded in oculocentric coordinates. Normal results in the antisaccade task suggest that the FEF is not involved in reflexive saccade inhibition. Received: 26 January 1999 / Accepted: 3 June 1999     

Inhibition of visual discrimination during a memory-guided saccade task

Voluntary behavior critically depends on attentional selection and short-term maintenance of perceptual information. Recent research suggests a tight coupling of both cognitive functions with visual processing being selectively enhanced by working memory representations. Here, we combined a memory-guided saccade paradigm (6-s delay) with a visual discrimination task, performed either 1,500, 2,500, or 3,500 ms after presentation of the memory cue. Contrary to what can be expected from previous studies, our results show that memory of spatial cues can transiently delay speeded discrimination of stimuli presented at remembered locations. This effect was not observed in a control experiment without memory requirements. Furthermore, delayed discrimination was dependent on the strength of actual memory representations as reflected by accuracy of memory-guided saccades. We propose an active inhibitory mechanism that counteracts facilitating effects of spatial working memory, promoting flexible orienting to novel information during maintenance of spatial memoranda for intended actions. Inhibitory delay-period activity in prefrontal cortex is a likely source for this mechanism which may be mediated by prefronto-tectal projections.     

Effects of age on latency and error generation in internally mediated saccades

Most studies on the effects of ageing on saccades have examined reflexive saccades; the only commonly studied volitional task has been the antisaccade task, with contradictory results. We examined in both young and elderly normal subjects the latency of anti-, memory-guided, and predictable saccades and the timing of self-paced saccades; we also evaluated errors made on the first two tasks. We expected errors to be correlated between tasks; we also expected antisaccade latencies and errors to be inversely correlated. We also expected antisaccade and memory-guided saccade latencies to be longer in individuals with a high self-paced rate. Except for predictable saccades, mean latencies were significantly higher in the elderly. However, their performance was more variable. Errors were also significantly more frequent on anti- and memory-guided saccade tasks. Most of the hypothesised correlations were not observed. Analysis of error latencies showed that whilst most antisaccade errors were reflexive, for memory-guided saccades both express errors and errors with latencies between 0.4 and 2.5 s were observed. The latter appeared to be a premature release of what would otherwise have been a properly planned response. Age thus impaired all but the predictable saccade task; nevertheless, there were few relationships between measures across tasks. This suggests that a range of processes mediate peoples' performance on these saccade paradigms.     

Impairment of extraretinal eye position signals after central thalamic lesions in humans

Accuracy of four different types of memory-guided saccades was studied in two patients with a small central thalamic lesion, probably involving the region of the internal medullary lamina (IML), and in a control group. In the first paradigm, the eyes and head remained immobile between the time of the presentation of the visual target to be remembered and the memory-guided saccade. In the other three paradigms, the eyes were displaced during the same period (before the memory-guided saccade) by either visually-guided saccades, a smooth pursuit eye movement or a body movement (with vestibulo-ocular reflex suppression). Therefore, in these three paradigms, the initial eye displacement required the use of extraretinal eye position to produce accurate memory-guided saccades. Compared with the control group, the two patients had normal accuracy in the first memory-guided saccade paradigm, in which there was no initial eye displacement, but markedly impaired saccade accuracy in the other three paradigms. These results suggest that the cortical areas triggering saccades did not receive correct extraretinal eye position signals. They are consistent with an impairment of the efference copy, which could be distributed to the cortical ocular motor areas by the IML.     

Neuronal activity representing temporal prediction of reward in the primate prefrontal cortex

Temporal prediction of future events, especially regarding reward delivery, is critical for controlling/learning purposeful behavior. The dorsolateral prefrontal cortex (DLPFC) has been considered to be involved in behavioral control based on prospective coding for future events, including reward. Thus this area is likely to have a neuronal mechanism responsible for temporal prediction of forthcoming reward. To address this hypothesis, we recorded the neuronal activity from the DLPFC of macaque monkeys while they performed an oculomotor delayed-response task under two conditions regarding the time of reward delivery. In this task, when the subjects made a correct response, the reward was delivered after a reward-delay period of 0.5 or 2 s. At the behavioral level, the onset latency for saccades was significantly faster in the shorter reward-delay trials (0.5 s) than in longer reward-delay trials (2 s), indicating that our subjects actually predicted the time of reward delivery. At the neuronal level, we found that many DLPFC neurons showed differential activity depending on the predicted time of reward delivery during the cue and/or delay periods. These results suggest that a fraction of neurons in the DLPFC represent the temporal prediction of reward and probably a variety of other future events.     

Suppression of visually and memory-guided saccades induced by electrical stimulation of the monkey frontal eye field. II. Suppression of bilateral saccades

To understand the neural mechanism of fixation, we investigated effects of electrical stimulation of the frontal eye field (FEF) and its vicinity on visually guided (Vsacs) and memory-guided saccades (Msacs) in trained monkeys and found that there were two types of suppression induced by the electrical stimulation: suppression of ipsilateral saccades and suppression of bilateral saccades. In this report, we characterized the properties of the suppression of bilateral Vsacs and Msacs. Stimulation of the bilateral suppression sites suppressed the initiation of both Vsacs and Msacs in all directions during and approximately 50 ms after stimulation but did not affect the vector of these saccades. The suppression was stronger for ipsiversive larger saccades and contraversive smaller saccades, and saccades with initial eye positions shifted more in the saccadic direction. The most effective stimulation timing for the suppression of ipsilateral and contralateral Vsacs was approximately 40-50 ms before saccade onset, indicating that the suppression occurred most likely in the superior colliculus and/or the paramedian pontine reticular formation. Suppression sites of bilateral saccades were located in the prearcuate gyrus facing the inferior arcuate sulcus where stimulation induced suppression at < or =40 microA but usually did not evoke any saccades at 80 microA and were different from those of ipsilateral saccades where stimulation evoked saccades at < or =50 microA. The bilateral suppression sites contained fixation neurons. The results suggest that fixation neurons in the bilateral suppression area of the FEF may play roles in maintaining fixation by suppressing saccades in all directions.