Interaction of the frontal eye field and superior colliculus for saccade generation.

Both the frontal eye field (FEF) in the prefrontal cortex and the superior colliculus (SC) on the roof of the midbrain participate in the generation of rapid or saccadic eye movements and both have projections to the premotor circuits of the brain stem where saccades are ultimately generated. In the present experiments, we tested the contributions of the pathway from the FEF to the premotor circuitry in the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying information to the brain stem, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF-brain stem pathway. If the contributions of the direct pathway were substantial, removal of the SC should have minimal effect on the FEF stimulation, whereas if the FEF stimulation were dependent on the SC, removal of the SC should alter the effect of FEF stimulation. By acutely inactivating the SC, instead of ablating it, we were able to test the efficiency of the direct FEF-brain stem pathway before substantial compensatory mechanisms could mask the effect of removing the SC. We found two striking effects of SC inactivation. In the first, we stimulated the FEF at a site that evoked saccades with vectors that were very close to those evoked at the site of the SC inactivation, and with such optimal alignment, we found that SC inactivation eliminated the saccades evoked by FEF stimulation. The second effect was evident when the FEF evoked saccades were disparate from those evoked in the SC, and in this case we observed a shift in the direction of the evoked saccade that was consistent with the SC inactivation removing a component of a vector average. Together these observations lead to the conclusion that in the nonablated monkey the direct FEF-brain stem pathway is not functionally sufficient to generate accurate saccades in the absence of the indirect pathway that courses from the FEF through the SC to the brain stem circuitry. We suggest that the recovery of function following SC ablation that has been seen in previous studies must result not from the use of an already functioning parallel pathway but from neural plasticity within the saccadic system.

Neural control of behavior: countermanding eye movements.

Understanding the self-control of action entails knowledge about how actions are initiated, how planned actions are canceled and how the consequences of actions are registered. We have investigated neural correlates of these processes using the countermanding paradigm--a task that required subjects to occasionally cancel a planned speeded response, and an analysis that provides an estimate of the time needed to cancel a planned movement. By monitoring the activity of single neurons in the frontal cortex of macaque monkeys performing this task we have distinguished signals responding to the visual stimuli, other signals that control the production of movements, and still other signals that seem to monitor behavior.

Countermanding saccades in humans.

We used a countermanding paradigm to investigate the relationship between conflicting cues for controlling human saccades. Subjects made a saccade to a target appearing suddenly in the periphery; but on some trials, after a delay, a stop-signal was presented that instructed subjects to inhibit the saccade. As we increased this delay, subjects increasingly failed to inhibit the movement. From measurements of this relationship, and of saccadic latency in control trials, we estimated the average time needed to inhibit the saccade (the stop-signal reaction time or SSRT). SSRTs were similar across subjects, between 125 and 145 ms, and did not vary with target luminance. We then investigated a race model in which the target initiates a response preparation signal rising linearly with a rate varying randomly from trial to trial, and racing against a similarly rising signal initiated by the cue to inhibit the saccade. The first process to cross a trigger threshold determines whether the saccade is initiated or not. In Monte Carlo simulations, this model correctly predicted the probability of successful saccade inhibition as a function of the stop-signal delay, and also the statistical distributions of saccadic latency during trials in which a stop-signal was presented but the subject failed to inhibit the saccade. These findings provide a comparison to results previously described in the monkey, and show that a simple race model with a linear rise to threshold may underlie behavioural performance in tasks of this kind.

Effects of low-dose isoflurane on saccadic eye movement generation.

The effects of 0.15% quasi-steady-state end-tidal isoflurane on two saccadic eye-movement tests were examined in five volunteers using a newly devised computer-based recording system. The tests were saccadic latency and a countermanding task, the latter being an indicator of the highest levels of conscious performance. A moving light-emitting diode target was displayed on a screen and in the saccadic-latency task the latency of eye movement to the target was measured. In all five subjects the latency increased with anaesthetic by an amount which varied from 8 to 45 ms. This result was significantly different (p < 0.05) from subjects without anaesthetic. In the countermanding task, the subject had to voluntarily inhibit movement to the target. Again anaesthetic increased the latency of response, which varied from 6 to 33 ms. This result was significantly different (p < 0.05) from subjects without anaesthetic. In these studies it appeared that two tasks, one a simple latency test and the other, the countermanding task, requiring higher cortical processing were equally impaired at subanaesthetic concentrations of isoflurane.

Signal timing across the macaque visual system.

The onset latencies of single-unit responses evoked by flashing visual stimuli were measured in the parvocellular (P) and magnocellular (M) layers of the dorsal lateral geniculate nucleus (LGNd) and in cortical visual areas V1, V2, V3, V4, middle temporal area (MT), medial superior temporal area (MST), and in the frontal eye field (FEF) in individual anesthetized monkeys. Identical procedures were carried out to assess latencies in each area, often in the same monkey, thereby permitting direct comparisons of timing across areas. This study presents the visual flash-evoked latencies for cells in areas where such data are common (V1 and V2), and are therefore a good standard, and also in areas where such data are sparse (LGNd M and P layers, MT, V4) or entirely lacking (V3, MST, and FEF in anesthetized preparation). Visual-evoked onset latencies were, on average, 17 ms shorter in the LGNd M layers than in the LGNd P layers. Visual responses occurred in V1 before any other cortical area. The next wave of activation occurred concurrently in areas V3, MT, MST, and FEF. Visual response latencies in areas V2 and V4 were progressively later and more broadly distributed. These differences in the time course of activation across the dorsal and ventral streams provide important temporal constraints on theories of visual processing.

Role of frontal eye fields in countermanding saccades: visual, movement, and fixation activity.

A new approach was developed to investigate the role of visual-, movement-, and fixation-related neural activity in gaze control. We recorded unit activity in the frontal eye fields (FEF), an area in frontal cortex that plays a central role in the production of purposeful eye movements, of monkeys (Macaca mulatta) performing visually and memory-guided saccades. The countermanding paradigm was employed to assess whether single cells generate signals sufficient to control movement production. The countermanding paradigm consists of a task that manipulates the monkeys' ability to withhold planned saccades combined with an analysis based on a race model that provides an estimate of the time needed to cancel the movement that is being prepared. We obtained clear evidence that FEF neurons with eye movement-related activity generate signals sufficient to control the production of gaze shifts. Movement-related activity, which was growing toward a trigger threshold as the saccades were prepared, decayed in response to the stop signal within the time required to cancel the saccade. Neurons with fixation-related activity were less common, but during the countermanding paradigm, these neurons exhibited an equally clear gaze-control signal. Fixation cells that had a pause in firing before a saccade exhibited elevated activity in response to the stop signal within the time that the saccade was cancelled. In contrast to cells with movement or fixation activity, neurons with only visually evoked activity exhibited no evidence of signals sufficient to control the production of gaze shifts. However, a fraction of tonic visual cells exhibited a reduction of activity once a saccade command had been cancelled even though the visual target was still present in the receptive field. These findings demonstrate the use of the countermanding paradigm in identifying neural signatures of motor control and provide new information about the fine balance between gaze shifting and gaze holding mechanisms.

Neural mechanisms of selection and control of visually guided eye movements.

The selection and control of action is a critical problem for both biological and machine animated systems that must operate in complex real world situations. Visually guided eye movements provide a fruitful and important domain in which to investigate mechanisms of selection and control. Our work has focused on the neural processes that select the target for an eye movement and the neural processes that regulate the production of eye movements. We have investigated primarily an area in the frontal cortex that plays a central role in the production of purposive eye movements which is called the frontal eye field. A fundamental property of biological nervous systems is variability in the time to respond to stimuli. Thus, we have been particularly interested in examining whether the time occupied by perceptual and motor decisions explains the duration and variability of behavioral reaction times. Current evidence indicates that salient visual targets are located through a temporal evolution of retinotopically mapped visually evoked activation. The responses to non-target stimuli become suppressed, leaving the activation representing the target maximal. The selection of the target leads to growth of movement-related activity at a stochastic rate toward a fixed threshold to generate the gaze shift. For a given image, the neural concomitants of perceptual processing occupy a relatively constant interval so that stochastic variability in response preparation introduces additional variability in reaction times. Neural processes in another cortical area, the supplementary eye field, do not participate in the control of eye movements but seem to monitor performance. The signals and processes that have been observed in the cerebral cortex of behaving monkeys may provide useful examples for the engineering problems of robotics.

Perceptual and motor processing stages identified in the activity of macaque frontal eye field neurons during visual search.

1. The latency between the appearance of a popout search display and the eye movement to the oddball target of the display varies from trial to trial in both humans and monkeys. The source of the delay and variability of reaction time is unknown but has been attributed to as yet poorly defined decision processes. 2. We recorded neural activity in the frontal eye field (FEF), an area regarded as playing a central role in producing purposeful eye movements, of monkeys (Macaca mulatta) performing a popout visual search task. Eighty-four neurons with visually evoked activity were analyzed. Twelve of these neurons had a phasic response associated with the presentation of the visual stimulus. The remaining neurons had more tonic responses that persisted through the saccade. Many of the neurons with more tonic responses resembled visuomovement cells in that they had activity that increased before a saccade into their response field. 3. The visual response latencies of FEF neurons were determined with the use of a Poisson spike train analysis. The mean visual latency was 67 ms (minimum = 35 ms, maximum = 138 ms). The visual response latencies to the target presented alone, to the target presented with distractors, or to the distractors did not differ significantly. 4. The initial visual activation of FEF neurons does not discriminate the target from the distractors of a popout visual search stimulus array, but the activity evolves to a state that discriminates whether the target of the search display is within the receptive field. We tested the hypothesis that the source of variability of saccade latency is the time taken by neurons involved in saccade programming to select the target for the gaze shift. 5. With the use of an analysis adapted from signal detection theory, we determined when the activity of single FEF neurons can reliably indicate whether the target or distractors are present within their response fields. The time of target discrimination partitions the reaction time into a perceptual stage in which target discrimination takes place, and a motor stage in which saccade programming and generation take place. The time of target discrimination occurred most often between 120 and 150 ms after stimulus presentation. 6. We analyzed the time course of target discrimination in the activity of single cells after separating trials into short, medium, and long saccade latency groups. Saccade latency was not correlated with the duration of the perceptual stage but was correlated with the duration of the motor stage. This result is inconsistent with the hypothesis that the time taken for target discrimination, as indexed by FEF neurons, accounts for the wide variability in the time of movement initiation. 7. We conclude that the variability observed in saccade latencies during a simple visual search task is largely due to postperceptual motor processing following target discrimination. Signatures of both perceptual and postperceptual processing are evident in FEF. Procrastination in the output stage may prevent stereotypical behavior that would be maladaptive in a changing environment.

Neural control of voluntary movement initiation.

When humans respond to sensory stimulation, their reaction times tend to be long and variable relative to neural transduction and transmission times. The neural processes responsible for the duration and variability of reaction times are not understood. Single-cell recordings in a motor area of the cerebral cortex in behaving rhesus monkeys (Macaca mulatta) were used to evaluate two alternative mathematical models of the processes that underlie reaction times. Movements were initiated if and only if the neural activity reached a specific and constant threshold activation level. Stochastic variability in the rate at which neural activity grew toward that threshold resulted in the distribution of reaction times. This finding elucidates a specific link between motor behavior and activation of neurons in the cerebral cortex.

Saccade target selection in frontal eye field of macaque. I. Visual and premovement activation.

We investigated how the brain selects the targets for eye movements, a process in which the outcome of visual processing is converted into guided action. Macaque monkeys were trained to make a saccade to fixate a salient target presented either alone or with multiple distractors during visual search. Neural activity was recorded in the frontal eye field, a cortical area at the interface of visual processing and eye movement production. Neurons discharging after stimulus presentation and before saccade initiation were analyzed. The initial visual response of frontal eye field neurons was modulated by the presence of multiple stimuli and by whether a saccade was going to be produced, but the initial visual response did not discriminate the target of the search array from the distractors. In the latent period before saccade initiation, the activity of most visually responsive cells evolved to signal the location of the target. Target selection occurred through suppression of distractor evoked activity contingent on the location of the target relative to the receptive field. The evolution of a signal specifying the location of the salient target could be dissociated from saccade initiation in some cells and could occur even when fixation was maintained. Neural activity in the frontal eye fields may participate in or be the product of the decision process guiding eye movements.

Countermanding saccades in macaque.

A countermanding paradigm was utilized to investigate the regulation of saccade initiation. Two rhesus monkeys were instructed to generate a saccade to a peripheral target; however, on a fraction of trials after a delay, the monkeys were signaled to inhibit saccade initiation. With short delays between the presentation of the target and the signal to inhibit saccade generation, monkeys withheld saccades to the peripheral target. As the delay of the stop signal increased, monkeys increasingly failed to withhold the saccade. The hypothesis that the generation of the saccade is determined by a race between a go and a stop process provides three explicit means of estimating the covert latency of response to the stop signal. This latency, known as stop signal reaction time, was estimated to be on average 82 ms for both monkeys. Because the stop signal latency represents the time required to exert inhibitory control over saccade production, the countermanding paradigm will be useful for studying neural mechanisms that regulate saccade initiation.

Relationship of presaccadic activity in frontal eye field and supplementary eye field to saccade initiation in macaque: Poisson spike train analysis.

The purpose of this study was to investigate the temporal relationship between presaccadic neuronal discharges in the frontal eye fields (FEF) and supplementary eye fields (SEF) and the initiation of saccadic eye movements in macaque. We utilized an analytical technique that could reliably identify periods of neuronal modulation in individual spike trains. By comparing the observed activity of neurons with the random Poisson distribution generated from the mean discharge rate during the trial period, the period during which neural activity was significantly elevated with a predetermined confidence level was identified in each spike train. In certain neurons, bursts of action potentials were identified by determining the period in each spike train in which the activation deviated most from the expected Poisson distribution. Using this method, we related these defined periods of modulation to saccade initiation in specific cell types recorded in FEF and SEF. Cells were recorded in SEF while monkeys made saccades to targets presented alone. Cells were recorded in FEF while monkeys made saccades to targets presented alone or with surrounding distractors. There were no significant differences in the time-course of activity of the population of FEF presaccadic movement cells prior to saccades generated to singly presented or distractor-embedded targets. The discharge of presaccadic movement cells in FEF and SEF could be subdivided quantitatively into an early prelude followed by a high-rate burst of activity that occurred at a consistent interval before saccade initiation. The time of burst onset relative to saccade onset in SEF presaccadic movement cells was earlier and more variable than in FEF presaccadic movement cells. The termination of activity of another population of SEF neurons, known as preparatory set cells, was time-locked to saccade initiation. In addition, the cessation of SEF preparatory set cell activity coincided precisely with the beginning of the burst of SEF presaccadic movement cells. This finding raises the possibility that SEF preparatory set cells may be involved in saccade initiation by regulating the activation of SEF presaccadic movement cells. These results demonstrate the utility of the Poisson spike train analysis to relate periods of neuronal modulation to behavior.

Pattern of peripheral deafferentation predicts reorganizational limits in adult primate somatosensory cortex.

Previous experiments have shown that the reorganization of the hand representations in areas 3b and 1 of somatosensory cortex of monkeys can be extensive or limited, depending on the pattern of peripheral sensory loss. After the loss of two or more digits, the deprived zones of cortex are not fully reactivated by remaining inputs from the hand (Merzenich et al., 1984). In contrast, after deafferentation of the entire glabrous surface of the hand, the deprived cortex becomes responsive throughout its extent to cutaneous stimulation of the dorsal hairy surface of the hand (Garraghty and Kaas, 1991). To test the hypothesis that it is the pattern of sensory loss and not the deprivation procedure that results in these differences, we mimicked multiple-digit amputation by deafferenting corresponding parts of the dorsal and ventral hand. We then recorded from areas 3b and 1 of 3 squirrel monkeys 3-11 months after the deafferentation. In each case, much of the cortex normally activated by the removed inputs remained unresponsive to cutaneous stimulation of skin surfaces of the hand with intact innervation. Thus, the reorganization that can occur in somatosensory cortex following peripheral sensory loss is constrained by the precise content of the stimulus deprivation; that is, there is a limit to the set of new receptive fields cortical neurons can acquire.

Neural basis of saccade target selection in frontal eye field during visual search.

Conspicuous visual features commonly attract gaze, but how the brain selects targets for eye movements is not known. We investigated target selection in rhesus monkeys performing a visual search task by recording neurons in the frontal eye field, an area known to be responsible for generating purposive eye movements. Neurons with combined visual- and eye movement-related activity were analysed. We found that the initial visual responses to search stimulus arrays were the same whether the target or a distractor was in the response field. We also found that the neural activity evolved to specify target location before the execution of eye movements, ultimately peaking when the target was in the response field and being suppressed when the target was beside but not distant from the response field. These results demonstrate a possible mechanism by which a desired target is fixated and inappropriate eye movements are prevented.