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Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the component neural circuitry giving rise to these signals remains unknown. Specifically, the functional architecture of cortical columns which results in attention-associated electric fields has not been explored. Here we detail the laminar cortical circuitry underlying an attention-associated electric field often measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Lastly, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field capable of being measured extracranially and the relative contribution of each column depends upon the underlying functional architecture.

Medial frontal cortex enables executive control by monitoring relevant information and using it to adapt behavior. In macaques performing a saccade countermanding (stop-signal) task, we recorded EEG over and neural spiking across all layers of the supplementary eye field (SEF). We report the laminar organization of concurrently activated neurons monitoring the conflict between incompatible responses and the timing of events serving goal maintenance and executive control. We also show their relation to coincident event-related potentials (ERP). Neurons signaling response conflict were largely broad-spiking found across all layers. Neurons signaling the interval until specific task events were largely broad-spiking neurons concentrated in L3 and L5. Neurons predicting the duration of control and sustaining the task goal until the release of operant control were a mix of narrow- and broad-spiking neurons confined to L2/3. We complement these results with the first report of a monkey homologue of the N2/P3 ERP complex associated with response inhibition. N2 polarization varied with error likelihood and P3 polarization varied with the duration of expected control. The amplitude of the N2 and P3 were predicted by the spike rate of different classes of neurons located in L2/3 but not L5/6. These findings reveal important, new features of the cortical microcircuitry supporting executive control and producing associated ERP.

The neural mechanisms of executive and motor control concern both basic researchers and clinicians. In human studies, preparation and cancellation of movements are accompanied by changes in the β-frequency band (15–29 Hz) of electroencephalogram (EEG). Previous studies with human participants performing stop signal (countermanding) tasks have described reduced frequency of transient β-bursts over sensorimotor cortical areas before movement initiation and increased β-bursting over medial frontal areas with movement cancellation. This modulation has been interpreted as contributing to the trial-by-trial control of behavior. We performed identical analyses of EEG recorded over the frontal lobe of macaque monkeys (one male, one female) performing a saccade countermanding task. While we replicate the occurrence and modulation of β-bursts associated with initiation and cancellation of saccades, we found that β-bursts occur too infrequently to account for the observed stopping behavior. We also found β-bursts were more common after errors, but their incidence was unrelated to response time (RT) adaptation. These results demonstrate the homology of this EEG signature between humans and macaques but raise questions about the current interpretation of β band functional significance.SIGNIFICANCE STATEMENTThe finding of increased β-bursting over medial frontal cortex with movement cancellation in humans is difficult to reconcile with the finding of modulation too late to contribute to movement cancellation in medial frontal cortex of macaque monkeys. To obtain comparable measurement scales, we recorded electroencephalogram (EEG) over medial frontal cortex of macaques performing a stop signal (countermanding) task. We replicated the occurrence and modulation of β-bursts associated with the cancellation of movements, but we found that β-bursts occur too infrequently to account for observed stopping behavior. Unfortunately, this finding raises doubts whether β-bursts can be a causal mechanism of response inhibition, which impacts future applications in devices such as brain-machine interfaces.

Ca2+spikes initiated in the distal trunk of layer 5 pyramidal cells (PCs) underlie nonlinear dynamic changes in the gain of cellular response, critical for top-down control of cortical processing. Detailed models with many compartments and dozens of ionic channels can account for this Ca2+spike-dependent gain and associated critical frequency. However, current models do not account for all known Ca2+-dependent features. Previous attempts to include more features have required increasing complexity, limiting their interpretability and utility for studying large population dynamics. We overcome these limitations in a minimal two-compartment biophysical model. In our model, a basal-dendrites/somatic compartment included fast-inactivating Na+and delayed-rectifier K+conductances, while an apical-dendrites/trunk compartment included persistent Na+, hyperpolarization-activated cation (Ih), slow-inactivating K+, muscarinic K+, and Ca2+L-type. The model replicated the Ca2+spike morphology and its critical frequency plus three other defining features of layer 5 PC synaptic integration: linear frequency-current relationships, back-propagation-activated Ca2+spike firing, and a shift in the critical frequency by blocking Ih. Simulating 1000 synchronized layer 5 PCs, we reproduced the current source density patterns evoked by Ca2+spikes and describe resulting medial-frontal EEG on a male macaque monkey. We reproduced changes in the current source density when Ihwas blocked. Thus, a two-compartment model with five crucial ionic currents in the apical dendrites reproduces all features of these neurons. We discuss the utility of this minimal model to study the microcircuitry of agranular areas of the frontal lobe involved in cognitive control and responsible for event-related potentials, such as the error-related negativity.SIGNIFICANCE STATEMENTA minimal model of layer 5 pyramidal cells replicates all known features crucial for distal synaptic integration in these neurons. By redistributing voltage-gated and returning transmembrane currents in the model, we establish a theoretical framework for the investigation of cortical microcircuit contribution to intracranial local field potentials and EEG. This tractable model will enable biophysical evaluation of multiscale electrophysiological signatures and computational investigation of cortical processing.

Patients with Parkinson’s disease (PD) often experience reductions in the proficiency to inhibit actions. The motor symptoms of PD can be effectively treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN), a key structure in the frontal–striatal network that may be directly involved in regulating inhibitory control. However, the precise role of the STN in stopping control is unclear. The STN consists of functional subterritories linked to dissociable cortical networks, although the boundaries of the subregions are still under debate. We investigated whether stimulating the dorsal and ventral subregions of the STN would show dissociable effects on ability to stop. We studied 12 PD patients with STN DBS. Patients with two adjacent contacts positioned within the bounds of the dorsal and ventral STN completed two testing sessions (OFF medication) with low amplitude stimulation (0.4 mA) at either the dorsal or ventral contacts bilaterally, while performing the stop task. Ventral, but not dorsal, DBS improved stopping latencies. Go reactions were similar between dorsal and ventral DBS STN. Stimulation in the ventral, but not dorsal, subregion of the STN improved stopping speed, confirming the involvement of the STN in stopping control and supporting the STN functional subregions.

SummaryModels of the cerebral cortex propose a canonical columnar architecture preserved across the brain. Evidence for this model primarily stems from observations in primary sensory areas, such as the visual cortex, where neurons in an anatomical column respond preferentially to the same stimulus features. Similar columnar feature selectivity has been described for visual area V2, visual area V3 [9, 10], the middle temporal visual area (area V5), and inferotemporal cortex. The fourth visual area (V4) features color selective neurons, organized in clusters across its surface. However, whether these color-sensitive neurons are organized in a columnar fashion is debated and uncertain due to technical limitations. Here, we utilize laminar multielectrode recordings along V4 columns to resolve rival hypotheses. Linear electrode arrays were introduced orthogonally into area V4, spanning all cortical layers. Monkeys viewed color stimuli presented to the visual receptive field of the column of neurons. We found that preference for a specific color was conserved along depth but varied across columns. Interestingly, while color preference (e.g. red or green) was consistent along depth, color selectivity was significantly greater in upper layers relative to the input layer and was weakest in the lower layers. These findings demonstrate that area V4 is organized in functional columns like other visual areas.

SUMMARYThe balance of speed with accuracy requires error detection and performance adaptation. To date, neural concomitants of these processes have been investigated only with noninvasive measures. To provide the first neurophysiological description, macaque monkeys performed visual search under cued speed accuracy tradeoff (SAT). Monkeys changed SAT emphasis immediately after a cued switch while neuron discharges were sampled in medial frontal cortex area supplementary eye field (SEF). A multiplicity of SEF neurons signaled production of choice errors and timing errors. Modulation of SEF activity after choice errors predicted production of un-rewarded corrective saccades. Modulation of activity after timing errors signaled reward prediction error. Adaptation of performance during SAT of visual search was accomplished through pronounced changes in neural state from before search array presentation until after reward delivery. These results contextualize previous findings using noninvasive measures, complement neurophysiological findings in visuomotor structures, endorse the role of medial frontal cortex as a critic relative to the actor instantiated in visuomotor structures, and extend our understanding of the distributed neural mechanisms of SAT.HIGHLIGHTSMedial frontal cortex enables post-error adjustment during SATChoice and timing errors were signaled by partially overlapping neural poolsMedial frontal cortex can proactively modulate visuomotor processesMedial frontal cortex is to visuomotor circuits as critic to actor

We investigated the chronometry of neural processes in frontal eye fields of macaques performing double-step saccade visual search in which a conspicuous target changes location in the array on a random fraction of trials. Durations of computational processes producing a saccade to original and final target locations (GO1 and GO2, respectively) are derived from response times (RT) on different types of trials. In these data, GO2 tended to be faster than GO1, demonstrating that inhibition of the initial saccade did not delay production of the compensated saccade. Here, we measured the dynamics of visual, visuomovement, and movement neuron activity in relation to these processes by examining trials when neurons instantiated either process. First, we verified that saccades were initiated when the discharge rate of movement neurons reached a threshold that was invariant across RT and trial type. Second, the time when visual and visuomovement neurons selected the target and when movement neuron activity began to accumulate were not significantly different across trial type. Third, the interval from the beginning of accumulation to threshold of movement-related activity was significantly shorter when instantiating the GO2 relative to the GO1 process. Differences observed between monkeys are discussed. Fourth, random variation of RT was accounted for to some extent by random variation in both the onset and duration of selective activity of each neuron type but mostly by variation of movement neuron accumulation duration. These findings offer new insights into the sources of control of target selection and saccade production in dynamic environments.

Visual search performance varies with stimulus and response history. Priming of pop-out refers to increased accuracy and reduced response time with repeated presentation of particular singleton and distractor features (e.g., a red target among green distractor stimuli), which are abruptly impaired when singleton and distractor features swap (e.g., green target among red distractors). Meanwhile, inhibition of return refers to the slowing of response time when target location repeats. Neurophysiological correlates of both these phenomena have been reported in the frontal eye field (FEF), an area in the frontal lobe contributing to attentional selection and eye movement planning. To understand the mechanistic origin of these adaptive behaviors, we investigated visual cortical area V4, an area providing input to and receiving feedback from FEF, during feature-based priming of pop-out and location-based inhibition of return. Performing a color pop-out task, monkeys exhibited pronounced priming of pop-out and inhibition of return. Neural spiking from V4 revealed earlier target selection associated with priming of pop-out and delayed selection associated with inhibition of return. These results demonstrate substantial involvement of extrastriate visual cortex in behavioral priming and inhibition of return.

The medial frontal cortex enables performance monitoring, indexed by the error-related negativity (ERN) and manifested by performance adaptations. We recorded electroencephalogram over and neural spiking across all layers of the supplementary eye field, an agranular cortical area, in monkeys performing a saccade-countermanding (stop signal) task. Neurons signaling error production, feedback predicting reward gain or loss, and delivery of fluid reward had different spike widths and were concentrated differently across layers. Neurons signaling error or loss of reward were more common in layers 2 and 3 (L2/3), whereas neurons signaling gain of reward were more common in layers 5 and 6 (L5/6). Variation of error- and reinforcement-related spike rates in L2/3 but not L5/6 predicted response time adaptation. Variation in error-related spike rate in L2/3 but not L5/6 predicted ERN magnitude. These findings reveal novel features of cortical microcircuitry supporting performance monitoring and confirm one cortical source of the ERN.

Impairments in cognitive control-the ability to exert control over thoughts and actions and respond flexibly to the environment-are well-documented in schizophrenia. However, the degree to which experimental task performance reflects true cognitive control impairments or more general alterations in effort, arousal and/or task preparedness is unclear. Pupillary responses can provide insight into these latter factors, as the pupil dilates with degree of cognitive effort and response preparation. In the current study, 16 medicated outpatients with schizophrenia (SZP) and 18 healthy controls performed a task that measures the ability to reactively inhibit and modify a planned action-the double-step task. In this task, participants were required to make a saccade to a visual target. Infrequently, the target jumped to a new location and participants were instructed to rapidly inhibit and change their eye movement plan. Applying a race model of performance, we have previously shown that SZP require more time to inhibit a planned action. In the current analysis, we measured pupil dilation associated with task preparation and found that SZP had a shallower increase in pupil size prior to the onset of the trial. Additionally, reduced magnitude of the pupil response was associated with negative symptom severity in patients. Based on primate neurophysiology and cognitive neuroscience work, we suggest that this blunted pupillary response may reflect abnormalities in a general orienting response or reduced motivational significance of a cue signifying the onset of a preparatory period and that these abnormalities might share an autonomic basis with negative symptoms.

Neocortex is striking in its laminar architecture. Tracer studies have uncovered anatomical connectivity among laminae, but the functional connectivity between laminar compartments is still largely unknown. Such functional connectivity can be discerned through spontaneous neural correlations during rest. Previous work demonstrated a robust pattern of mesoscopic resting-state connectivity in macaque primary visual cortex (V1) through interlaminar cross-frequency coupling. Here we investigated whether this pattern generalizes to other cortical areas by comparing resting-state laminar connectivity between V1 and the supplementary eye field (SEF), a frontal area lacking a granular layer 4 (L4). Local field potentials (LFPs) were recorded with linear microelectrode arrays from all laminae of granular V1 and agranular SEF while monkeys rested in darkness. We found substantial differences in the relationship between the amplitude of gamma-band (>30 Hz) LFP and the phase of alpha-band (7–14 Hz) LFP between these areas. In V1, gamma amplitudes in L2/3 and L5 were coupled with alpha-band LFP phase in L5, as previously described. In contrast, in SEF phase-amplitude coupling was prominent within L3 and much weaker across layers. These results suggest that laminar interactions in agranular SEF are unlike those in granular V1. Thus the intrinsic functional connectivity of the cortical microcircuit does not seem to generalize across cortical areas.

The objective of the present study was to compare two components of executive functioning, response monitoring and inhibition, in bipolar disorder (BP) and schizophrenia (SZ). The saccadic countermanding task is a translational paradigm optimized for detecting subtle abnormalities in response monitoring and response inhibition. We have previously reported countermanding performance abnormalities in SZ, but the degree to which these impairments are shared by other psychotic disorders is unknown. 18 BP, 17 SZ, and 16 demographically matched healthy controls (HC) participated in a saccadic countermanding task. Performance on the countermanding task is approximated as a race between movement generation and inhibition processes; this model provides an estimate of the time needed to cancel a planned movement. Response monitoring was assessed by the reaction time (RT) adjustments based on trial history. Like SZ patients, BP patients needed more time to cancel a planned movement. The two patient groups had equivalent inhibition efficiency. On trial history-based RT adjustments, however, we found a trend towards exaggerated trial history-based slowing in SZ compared to BP. Findings have implications for understanding the neurobiology of cognitive control, for defining the etiological overlap between schizophrenia and bipolar disorder, and for developing pharmacological treatments of cognitive impairments.

SummaryAvoiding distraction by salient irrelevant stimuli is critical to accomplishing daily tasks. Regions of prefrontal cortex control attention by enhancing the representation of task-relevant information in sensory cortex, which can be measured directly in modulation of both single neurons and averaging of the scalp-recorded electroencephalogram [1,2]. However, when irrelevant information is particularly conspicuous, it may distract attention and interfere with the selection of behaviorally relevant information. Many studies have shown that that distraction can be minimized via top-down control [3–5], but the cognitive and neural mechanisms giving rise to this control over distraction remain uncertain and vigorously debated [6–8]. Bridging neurophysiology to electrophysiology, we simultaneously recorded neurons in prefrontal cortex and event-related potentials (ERPs) over extrastriate visual cortex to track the processing of salient distractors during a visual search task. Critically, we observed robust suppression of salient distractor representations in both cortical areas, with suppression arising in prefrontal cortex before being manifest in the ERP signal over extrastriate cortex. Furthermore, only prefrontal neurons that participated in selecting the task-relevant target also showed suppression of the task-irrelevant distractor. This suggests a common prefrontal mechanism for target selection and distractor suppression, with input from prefrontal cortex being responsible for both selecting task-relevant and suppressing task-irrelevant information in sensory cortex. Taken together, our results resolve a long-standing debate over the mechanisms that prevent distraction, and provide the first evidence directly linking suppressed neural firing in prefrontal cortex with surface ERP measures of distractor suppression.

This review surveys how vision becomes action through the frontal lobe. Signals from extrastriate areas create maps in frontal areas. These maps are shaped by visual features and shaded by goals, values, and experience, and they guide contingent activation of motor circuits to execute coordinated gaze, head, and limb movements. Frontal circuits also support the visual perception of learned objects, events, and actions. Other frontal circuits monitor consequences and exert executive control to improve the effectiveness of visually guided behavior.

Primate vision is served by rapid shifts of gaze called saccades. This review will survey current knowledge and particular problems concerning the neural control and guidance of gaze shifts.

This chapter compares the location, extent, and boundaries of the frontal eye field (FEF) in prosimians, New World monkeys, Old World monkeys, apes, and humans. We are particularly interested in understanding how the location of FEF in humans relates to that in other primate species. We consider whether FEF should be understood as a collection of distinct areas or as a single area with multiple modules that can be of different sizes (and locations) in different species according to lifestyle and habitat. We also consider how the size and location of FEF is a matter of operational definition with resolution specified by the various techniques applied, making comparison across species, especially humans, challenging. Locating FEF is challenged further by the variation of sulcal morphology across species and individuals. Nevertheless, in all investigated primate species FEF appears to be located at the transition zone between premotor area 6 and prefrontal area 8 in a cortical region with significant sulcal variation where it is bordered caudally (in premotor cortex) and rostrally (in prefrontal cortex) by areas also contributing to visually guided gaze behavior. We highlight current areas of uncertainty. In particular, lacking information about precise boundaries, we do not know whether the size and modularity of FEF scales across species with overall neocortical area, or with the complexity of visual and other sensory systems, or with changes in associated subcortical circuits, or with the complexity of the musculature used for visually guided behaviors, or with the complexity of cognitive control over gaze behavior.

How supplementary eye field (SEF) contributes to visual search is unknown. Inputs from cortical and subcortical structures known to represent visual salience suggest that SEF may serve as an additional node in this network. This hypothesis was tested by recording action potentials and local field potentials (LFPs) in two monkeys performing an efficient pop-out visual search task. Target selection modulation, tuning width, and response magnitude of spikes and LFP in SEF were compared with those in frontal eye field. Surprisingly, only ∼2% of SEF neurons and ∼8% of SEF LFP sites selected the location of the search target. The absence of salience in SEF may be due to an absence of appropriate visual afferents, which suggests that these inputs are a necessary anatomical feature of areas representing salience. We also tested whether SEF contributes to overcoming the automatic tendency to respond to a primed color when the target identity switches during priming of pop-out. Very few SEF neurons or LFP sites modulated in association with performance deficits following target switches. However, a subset of SEF neurons and LFPs exhibited strong modulation following erroneous saccades to a distractor. Altogether, these results suggest that SEF plays a limited role in controlling ongoing visual search behavior, but may play a larger role in monitoring search performance.

We describe a stochastic accumulator model demonstrating that visual search performance can be understood as a gated feedforward cascade from a salience map to multiple competing accumulators. The model quantitatively accounts for behavior and predicts neural dynamics of macaque monkeys performing visual search for a target stimulus among different numbers of distractors. The salience accumulated in the model is equated with the spike trains recorded from visually responsive neurons in the frontal eye field. Accumulated variability in the firing rates of these neurons explains choice probabilities and the distributions of correct and error response times with search arrays of different set sizes if the accumulators are mutually inhibitory. The dynamics of the stochastic accumulators quantitatively predict the activity of presaccadic movement neurons that initiate eye movements if gating inhibition prevents accumulation before the representation of stimulus salience emerges. Adjustments in the level of gating inhibition can control trade-offs in speed and accuracy that optimize visual search performance.

Background: A subjective sense of agency over actions is thought to arise from a match between the predicted and actual sensory consequences of a movement command. A failure to appropriately generate or utilize such predictions is argued to give rise to the agency disturbances that characterize psychosis. A likely mechanism of such predictions are corollary discharge (CD) signals—“copies” of motor signals that, rather than being sent to the muscles, are sent to sensory areas. The most robust behavioral paradigms for studying CD as well as the only neurophysiological evidence for CD signals in primates have come from the oculomotor system, making it an ideal translational framework in which to investigate CD and, in turn, the mechanisms of agency disturbances in psychosis.

Background Cognitive control deficits are pervasive in individuals with schizophrenia (SZ) and are reliable predictors of functional outcome, but the specificity of these deficits and their underlying neural mechanisms have not been fully elucidated. The objective of the present study was to determine the nature of response inhibition and response monitoring deficits in SZ and their relationship to symptoms and social and occupational functioning with a behavioral paradigm that provides a translational approach to investigating cognitive control. Methods Seventeen patients with SZ and 16 demographically matched healthy control subjects participated in a saccadic countermanding task. Performance on this task is approximated as a race between movement generation and inhibition processes; this race model provides an estimate of the time needed to cancel a planned movement. Response monitoring can be assessed by reaction time adjustments on the basis of trial history. Results Saccadic reaction time was normal, but patients required more time to inhibit a planned saccade. The latency of the inhibitory process was associated with the severity of negative symptoms and poorer occupational functioning. Both groups slowed down significantly after correctly cancelled and erroneously noncancelled stop signal trials, but patients slowed down more than control subjects after correctly inhibited saccades. Conclusions These results suggest that SZ is associated with a difficulty in inhibiting planned movements and an inflated response adjustment effect after inhibiting a saccade. Furthermore, behavioral results are consistent with potential abnormalities in frontal and supplementary eye fields in patients with SZ.

The goal of this study was to obtain a better understanding of the physiological basis of errors of visual search. Previous research has shown that search errors occur when visual neurons in the frontal eye field (FEF) treat distractors as if they were targets. We replicated this finding during an inefficient form search and extended it by measuring simultaneously a macaque homologue of an event-related potential indexing the allocation of covert attention known as the m-N2pc. Based on recent work, we expected errors of selection in FEF to propagate to areas of extrastriate cortex responsible for allocating attention and implicated in the generation of the m-N2pc. Consistent with this prediction, we discovered that when FEF neurons selected a distractor instead of the search target, the m-N2pc shifted in the same, incorrect direction prior to the erroneous saccade. This suggests that such errors are due to a systematic misorienting of attention from the initial stages of visual processing. Our analyses also revealed distinct neural correlates of false alarms and guesses. These results demonstrate that errant gaze shifts during visual search arise from errant attentional processing.

We describe intracranial local field potentials (LFP) recorded in the anterior cingulate cortex (ACC) of macaque monkeys performing a saccade countermanding task. The most prominent feature at ∼70% of sites was greater negative polarity after errors than after rewarded correct trials. This negative polarity was also evoked in unrewarded correct trials. The LFP evoked by the visual target was much less polarized, and the weak presaccadic modulation was insufficient to control the initiation of saccades. When saccades were cancelled, LFP modulation decreased slightly with the magnitude of response conflict that corresponds to the coactivation of gaze-shifting and -holding neurons estimated from the probability of canceling. However, response time adjustments on subsequent trials were not correlated with LFP polarity on individual trials. The results provide clear evidence that error- and feedback-related, but not conflict-related, signals are carried by the LFP in the macaque ACC. Finding performance monitoring field potentials in the ACC of macaque monkeys establishes a bridge between event-related potential and functional brain-imaging studies in humans and neurophysiology studies in non-human primates.

A half-century's worth of research has established the existence of numerous event-related potential components measuring different cognitive operations in humans including the selection of stimuli by covert attention mechanisms. Surprisingly, it is unknown whether nonhuman primates exhibit homologous electrophysiological signatures of selective visual processing while viewing complex scenes. We used an electrophysiological technique with macaque monkeys analogous to procedures for recording scalp event-related potentials from humans and found that monkeys exhibit short-latency visual components sensitive to sensory processing demands and lateralizations related to shifting of covert attention similar to the human N2pc component. These findings begin to bridge the gap between the disparate literatures by using electrophysiological measurements to study the deployment of visual attention in the brains of humans and nonhuman primates.

To explore how eye and hand movements are controlled in a stop task, we introduced effector uncertainty by instructing subjects to initiate and occasionally inhibit eye, hand, or eye + hand movements in response to a color-coded foveal or tone-coded auditory stop signal. Regardless of stop signal modality, stop signal reaction time was shorter for eye movements than for hand movements, but notably did not vary with knowledge about which movement to cancel. Most errors on eye + hand stopping trials were combined eye + hand movements. The probability and latency of signal respond eye and hand movements corresponded to predictions of Logan and Cowan's (1984) race model applied to each effector independently.

Disruptions in corollary discharge (CD), motor signals that send information to sensory areas and allow for prediction of sensory states, are argued to underlie the perceived loss of agency in schizophrenia. Behavioral and neurophysiological evidence for CD in primates comes largely from the saccadic double-step task, which requires participants to make two visually triggered saccadic eye movements in brief succession. Healthy individuals use CD to anticipate the change in eye position resulting from the first saccade when preparing the second saccade. In the current study with human participants, schizophrenia patients and healthy controls of both sexes performed a modified double-step task. Most trials required a saccade to a single visual target (T1). On a subset of trials, a second target (T2) was flashed shortly following T1. Subjects were instructed to look directly at T2. Healthy individuals also use CD to make rapid, corrective responses following erroneous saccades to T1. To assess CD in schizophrenia, we examined the following on error trials: (1) frequency and latency of corrective saccades, and (2) mislocalization of the corrective (second) saccade in the direction predicted by a failure to use CD to account for the first eye movement. Consistent with disrupted CD, patients made fewer and slower error corrections. Importantly, the corrective saccade vector angle was biased in a manner consistent with disrupted CD. These results provide novel and clear evidence for dysfunctional CD in the oculomotor system in patients with schizophrenia. Based on neurophysiology work, these disturbances might have their basis in medial thalamus dysfunction. SIGNIFICANCE STATEMENT According to the World Health Organization, acute schizophrenia carries more disability weight than any other disease, but its etiology remains unknown. One promising theory of schizophrenia highlights alterations in a sense of self, in which self-generated thoughts or actions are attributed externally. Disruptions in corollary discharge (CD), motor signals sent to sensory areas that allow for the prediction of impending sensations, are proposed to underlie these symptoms. Direct physiological evidence, however, is limited. In nonhuman primates, inactivation of mediodorsal thalamic neurons disrupts CD associated with eye movements. Using the same task, we show similar impairments in schizophrenia patients, consistent with disrupted CD. These findings allow us to link clinical phenomenology to primate neurophysiology and interpret findings within a biological framework.

It has been proposed that low-threshold Ca2+ (LT)-associated bursts in the lateral geniculate nucleus (LGN) of awake animals communicate significant or unexpected visual events to cortex. The present study investigated this hypothesis by examining the incidence of LT bursts in 146 cells recorded from the LGN of three macaque monkeys. Bursts were defined as clusters of two or more action potentials separated by not more than 4 ms and preceded by a ≥100-ms quiescent interval. The incidence of bursts was examined in several intensive-training Go-NoGo and target selection tasks as well as in training-free tasks where natural scenes with both familiar and novel contents were shown. Our chief findings were as follows. 1) Bursts occur in the majority of cells under every condition tested, 2) burst incidence is very low (

Success requires deciding among alternatives, controlling the initiation of movements, and judging the consequences of actions. When alternatives are difficult to distinguish, habitual responses must be overcome, or consequences are uncertain, deliberation is necessary and a supervisory system exerts control over the processes that produce sensory-guided movements. We have investigated these processes by recording neural activity in the frontal lobe of macaque monkeys performing a countermanding task. Distinct neurons in the frontal eye field respond to visual stimuli or control the production of the movements. In the supplementary eye field and anterior cingulate cortex, neurons appear not to control directly movement initiation but instead signal the production of errors, the anticipation and delivery of reinforcement, and the presence of processing conflict. These signals form the core of current models of supervisory control of sensorimotor processes.

Background: Cognitive control impairments are linked to functional outcome in schizophrenia. The goal of the current study was to investigate precise abnormalities in two aspects of cognitive control: reactively changing a prepared response, and monitoring performance and adjusting behavior accordingly. We adapted an oculomotor task from neurophysiological studies of the cellular basis of cognitive control in nonhuman primates. Methods: 16 medicated outpatients with schizophrenia (SZ) and 18 demographically-matched healthy controls performed the modified double-step task. In this task, participants were required to make a saccade to a visual target. Infrequently, the target jumped to a new location and participants were instructed to rapidly inhibit and change their response. A race model provided an estimate of the time needed to cancel a planned movement. Response monitoring was assessed by measuring reaction time (RT) adjustments based on trial history. Results: SZ patients had normal visually-guided saccadic RTs but required more time to switch the response to the new target location. Additionally, the estimated latency of inhibition was longer in patients and related to employment. Finally, although both groups slowed down on trials that required inhibiting and changing a response, patients showed exaggerated performance-based adjustments in RTs, which was correlated with positive symptom severity. Conclusions: SZ patients have impairments in rapidly inhibiting eye movements and show idiosyncratic response monitoring. These results are consistent with functional abnormalities in a network involving cortical oculomotor regions, the superior colliculus, and basal ganglia, as described in neurophysiological studies of non-human primates using an identical paradigm, and provide a translational bridge for understanding cognitive symptoms of SZ.

We investigated whether a frontal area that lacks granular layer IV, supplementary eye field, exhibits features of laminar circuitry similar to those observed in primary sensory areas. We report, for the first time, visually evoked local field potentials (LFPs) and spiking activity recorded simultaneously across all layers of agranular frontal cortex using linear electrode arrays. We calculated current source density from the LFPs and compared the laminar organization of evolving sinks to those reported in sensory areas. Simultaneous, transient synaptic current sinks appeared first in layers III and V followed by more prolonged current sinks in layers I/II and VI. We also found no variation of single- or multi-unit visual response latency across layers, and putative pyramidal neurons and interneurons displayed similar response latencies. Many units exhibited pronounced discharge suppression that was strongest in superficial relative to deep layers. Maximum discharge suppression also occurred later in superficial than in deep layers. These results are discussed in the context of the canonical cortical microcircuit model originally formulated to describe early sensory cortex. The data indicate that agranular cortex resembles sensory areas in certain respects, but the cortical microcircuit is modified in nontrivial ways.

Although many studies have explored the neural correlates of visual attention and selection, few have examined the reliability with which neurons represent relevant information. We monitored activity in the frontal eye field (FEF) of monkeys trained to make a saccade to a target defined by the conjunction of color and shape or to a target defined by color differences. The difficulty of conjunction search was manipulated by varying the number of distractors, and the difficulty of feature search was manipulated by varying the similarity in color between target and distractors. The reliability of individual neurons in signaling the target location in correct trials was determined using a neuron—anti-neuron approach within a winner-take-all architecture. On average, approximately seven trials of the activity of single neurons were sufficient to match near-perfect behavioral performance in the easiest search, and ∼14 trials were sufficient in the most difficult search. We also determined how many neurons recorded separately need to be evaluated within a trial to match behavioral performance. Results were quantitatively similar to those of the single neuron analysis. We also found that signal reliability in the FEF did not change with task demands, and overall, behavioral accuracy across the search tasks was approximated when only six trials or neurons were combined. Furthermore, whether combining trials or neurons, the increase in time of target discrimination corresponded to the increase in mean saccade latency across visual search difficulty levels. Finally, the variance of spike counts in the FEF increased as a function of the mean spike count, and the parameters of this relationship did not change with attentional selection.

It is known that the prestriate cortical regions that project to area LIP in parietal cortex and to areas TEO and TE in temporal cortex are mostly separated. Two separate streams of information transfer from occipital cortex can thus be distinguished. We wished to determine whether the parietal and temporal streams remain segregated in their projections to frontal cortex. Paired injections of retrograde fluorescent tracers were placed in parietal and temporal cortex, or in the lateral and medial parts of the frontal eye field (FEF). The cortical regions containing retrogradely labeled cells were reconstructed in two-dimensional maps. The results show that temporal cortex mainly projects to lateral FEF (area 45). Parietal cortex sends projections to medial FEF (area 8a) and to lateral FEF, as well as to area 46. Thus, the parietal and temporal streams converge in lateral FEF. Most of the occipital regions projecting to medial FEF are the same as those projecting to parietal cortex, whereas lateral FEF receives afferents from the same occipital regions as those sending projections to temporal cortex. Thus, one can distinguish two interconnected networks. One is associated with the inferotemporal cortex and includes areas of the ventral bank and fundus of the superior temporal sulcus (STS), lateral FEF and ventral prestriate cortex. This network emphasizes central vision, small saccades and form recognition. The other network is linked to cortex of the intraparietal sulcus. It consists of areas of the upper bank and fundus of STS, medial FEF and dorsal prestriate cortex. These areas encode peripheral visual field and are active during large saccades.

The primate visual system consists of at least two processing streams, one passing ventrally into temporal cortex that is responsible for object vision, and the other running dorsally into parietal cortex that is responsible for spatial vision. How information from these two streams is combined for perception and action is not understood. Visually guided eye movements require information about both feature identity and location, so we investigated the topographic organization of visual cortex connections with frontal eye field (FEF), the final stage of cortical processing for saccadic eye movements. Multiple anatomical tracers were placed either in parietal and temporal cortex or in different parts of FEF in individual macaque monkeys. Convergence from the dorsal and ventral processing streams occurred in lateral FEF but not in medial FEF. Certain extrastriate areas with retinotopic visual field organizations projected topographically onto FEF. The dorsal bank of the superior temporal sulcus projected to medial FEF; the ventral bank, to lateral FEF, and the fundus, throughout FEF. Thus, lateral FEF, which is responsible for generating short saccades, receives visual afferents from the foveal representation in retinotopically organized areas, from areas that represent central vision in inferotemporal cortex and from other areas having no retinotopic order. In contrast, medial FEF, which is responsible for generating longer saccades, is innervated by the peripheral representation of retinotopically organized areas, from areas that emphasize peripheral vision or are multimodal and from other areas that have no retinotopic order or are auditory.

Consensus is emerging that the medial frontal lobe of the brain is involved in monitoring performance, but precisely what is monitored remains unclear. A saccade-countermanding task affords an experimental dissociation of neural signals of error, reinforcement, and conflict. Single-unit activity was monitored in the anterior cingulate cortex of monkeys performing this task. Neurons that signaled errors were found, half of which responded to the omission of earned reinforcement. A further diversity of neurons signaled earned or unexpected reinforcement. No neurons signaled the form of conflict engendered by interruption of saccade preparation produced in this task. These results are consistent with the hypothesis that the anterior cingulate cortex monitors the consequences of actions.

Although areas of frontal cortex are thought to be critical for maintaining information in visuospatial working memory, the event-related potential (ERP) index of maintenance is found over posterior cortex in humans. In the present study, we reconcile these seemingly contradictory findings. Here, we show that macaque monkeys and humans exhibit the same posterior ERP signature of working memory maintenance that predicts the precision of the memory-based behavioral responses. In addition, we show that the specific pattern of rhythmic oscillations in the alpha band, recently demonstrated to underlie the human visual working memory ERP component, is also present in monkeys. Next, we concurrently recorded intracranial local field potentials from two prefrontal and another frontal cortical area to determine their contribution to the surface potential indexing maintenance. The local fields in the two prefrontal areas, but not the cortex immediately posterior, exhibited amplitude modulations, timing, and relationships to behavior indicating that they contribute to the generation of the surface ERP component measured from the distal posterior electrodes. Rhythmic neural activity in the theta and gamma bands during maintenance provided converging support for the engagement of the same brain regions. These findings demonstrate that nonhuman primates have homologous electrophysiological signatures of visuospatial working memory to those of humans and that a distributed neural network, including frontal areas, underlies the posterior ERP index of visuospatial working memory maintenance.

The error-related negativity (ERN) and positivity (Pe) are components of event-related potential (ERP) waveforms recorded from humans and are thought to reflect performance monitoring. Error-related signals have also been found in single-neuron responses and local-field potentials recorded in supplementary eye field and anterior cingulate cortex of macaque monkeys. However, the homology of these neural signals across species remains controversial. Here, we show that monkeys exhibit ERN and Pe components when they commit errors during a saccadic stop-signal task. The voltage distributions and current densities of these components were similar to those found in humans performing the same task. Subsequent analyses show that neither stimulus- nor response-related artifacts accounted for the error-ERPs. This demonstration of macaque homologues of the ERN and Pe forms a keystone in the bridge linking human and nonhuman primate studies on the neural basis of performance monitoring.

The stop signal task is used to investigate motor inhibition. Several groups have reported partial electromyogram (EMG) activation when subjects successfully withhold manual responses and have used this finding to define the nature of response inhibition properties in the spinal motor system. It is unknown whether subthreshold EMG activation from extraocular muscles can be detected in the saccadic response version of the stop signal task. The saccadic spike potential provides a way to examine extraocular EMG activation associated with eye movements in electroencephalogram (EEG) recordings. We used several techniques to isolate extraocular EMG activation from anterior electrode locations of EEG recorded from macaque monkeys. Robust EMG activation was present when eye movements were made, but no activation was detected when saccades were deemed canceled. This work highlights a key difference between the spinal motor system and the saccade system.

A recent review in Trends in Neuroscience by Cole, Yeung, Freiwald and Botvinick identified a potential fundamental difference in functional properties of the anterior cingulate cortex (ACC) of humans and macaque monkeys [Cole et al., 2009]. The key function in question is monitoring of conflict in response preparation. The conflict hypothesis, defended by the senior authors of the review as a general theory of ACC function, states that when a task calls for multiple competing responses, then executive control is required to resolve the conflict. It is supposed to explain the origin and purpose of event-related potential components such as the error-related negativity (ERN) that occurs after response errors [reviewed by Taylor et al., 2007] and a body of functional brain imaging data. The ERN can be generated by a dipole in the ACC; however, uncertainties in the localization of this dipole as well as other neuroimaging and lesion data demonstrate that more dorsal areas of medial frontal cortex including preSMA also contribute to performance monitoring [e.g. Garavan et al., 2003]. The ERN can also be identified with a reward prediction error originating from the dopamine system [Taylor et al., 2007]. An active literature has developed evaluating these and other alternative hypotheses using human subjects. The relative merits of these alternative hypotheses are not the focus of this commentary. Over the last decade this literature derived from human studies has been supplemented by neurophysiological data from macaque monkeys. In monkeys performing an eye movement stop signal task, neurons are found in the supplementary eye field that signal when errors are produced, when reward is delivered and when conflict occurs [Stuphorn et al., 2000]. In contrast, multiple neurophysiological studies of the macaque monkey ACC have reported error and reward signals but an absence of a conflict signal in tasks that should engender such response conflict [Ito et al., 2003; Nakamura et al., 2005; Emeric et al., 2008]. Cole et al. [2009] argue that the lack of a single neuron conflict signal in macaque monkeys in contrast to humans is a manifestation of a fundamental species difference and a greater sensitivity of functional brain imaging methods to weak conflict signals. We will argue that simpler alternative interpretations have not been ruled out. To account for the apparent incommensurability of results in monkeys and humans, Cole et al. [2009] emphasize species differences. We suggest that effector differences should be considered first. The monkey studies that sparked their review were based on data obtained in tasks requiring monkeys to produce or inhibit saccadic eye movements. The human studies used to describe conflict (as well as error and feedback) signals typically employ forelimb movements. Although the motor control of the eyes and of the hands may share common features centrally, they are substantially different peripherally. Eye movements entail fewer degrees of freedom (basically just 2) and need not be concerned about gravity. Natural arm movements entail more degrees of freedom (as many as 7 not counting the fingers) and usually must contend with gravity. Furthermore, and possibly crucially for this review, being an extension of the body, the limbs can get into kinds of trouble that the eyes cannot, e.g. colliding with other objects in the world. Specific neuroanatomical differences should also be highlighted. First, the neurons in the cortex that contribute to eye movement generation do not form synapses on the motor neurons innervating the muscles of the eyes, but the neurons in the cortex that contribute to forelimb movement generation form synapses directly on the motor neurons innervating the muscles of the limbs. Second, parts of cingulate cortex project to motor cortex and the spinal cord [Dum and Strick 2002], and body movements can be evoked by electrical stimulation of these regions, but such connectivity and excitability for saccades is considerably weaker. Indeed, eye movements are evoked only rarely by stimulation of the ACC of most monkeys. Finally, in many of the studies that report conflict signals with manual movements the alternative responses could be generated together, e.g. press buttons with both hands. In contrast, only one saccadic eye movement can be produced at a time. Why are neuronal responses related to error and reward but not response conflict consistently observed in the ACC? We suggest that conflict signals may not be observed because the oculomotor representation of the macaque ACC does not support enough connections to influence gaze. However, the presence of a conflict signal in supplementary eye fields can perform the same function for the eyes that such a signal in the ACC can perform for the limbs. Cole et al. [2009] also suggest that the conflict-sensitive portion of the human ACC has no homologue in macaque monkeys. However, it is not clear that this view is consistent with the most current anatomical descriptions. While the sulcal pattern in humans with the parasplenial lobules is more complex than that in macaques, the cytoarchitecture of the cingulofrontal transitional cortex identified as area 32 is shared by humans and macaques [Vogt et al., 1995, 2005]. In other words, cortex with cytoarchitecture of area 32 is not absent in macaques, just smaller area. In fact, the caudal part of human area 32ac has been identified as a homolog of macaque area 24c, making it part of the cingulate motor areas [Ongur et al., 2003]. The cingulate motor areas in the caudal anterior cingulate are in a unique position to monitor response conflict and exert control on the skeletal motor system through connections with motor cortical areas and the spinal cord [Dum and Strick 2002]. Meta-analyses of cingulate activation have demonstrated that a somatotopic map corresponding to the cingu- late motor areas in monkeys [Picard and Strick, 2001] overlaps with the foci of conflict-related activation across studies within the region labeled area 32′ [e.g. Hester et al., 2004]. Although we heartily endorse distinguishing illusory from actual cross-species differences, drawing categorical conclusions from nuanced and often ambiguous data is premature. Fundamentally, it is not clear why the general conflict model should not apply to macaques who exhibit complex, extended responses to ambiguous stimuli with uncertain payoffs. If macaque monkeys are not equipped to monitor conflict, then specifically what should they not be able to do?

The role of spike rate versus timing codes in visual target selection is unclear. We simultaneously recorded activity from multiple frontal eye field neurons and asked whether they interacted to select targets from distractors during visual search. When both neurons in a pair selected the target and had overlapping receptive fields (RFs), they cooperated more than when one or neither neuron in the pair selected the target, measured by positive spike timing correlations using joint peristimulus time histogram analysis. The amount of cooperation depended on the location of the search target: it was higher when the target was inside both neurons' RFs than when it was inside one RF but not the other, or outside both RFs. Elevated spike timing coincidences occurred at the time of attentional selection of the target as measured by average modulation of discharge rates. We observed competition among neurons with spatially non-overlapping RFs, measured by negative spike timing correlations. Thus, we provide evidence for dynamic and task-dependent cooperation and competition among frontal eye field neurons during visual target selection.

The goal of this study was to determine whether the activity of neurons in the supplementary eye field (SEF) is sufficient to control saccade initiation in macaque monkeys performing a saccade countermanding (stop signal) task. As previously observed, many neurons in the SEF increase the discharge rate before saccade initiation. However, when saccades are canceled in response to a stop signal, effectively no neurons with presaccadic activity display discharge rate modulation early enough to contribute to saccade cancellation. Moreover, SEF neurons do not exhibit a specific threshold discharge rate that could trigger saccade initiation. Yet, we observed more subtle relations between SEF activation and saccade production. The activity of numerous SEF neurons was correlated with response time and varied with sequential adjustments in response latency. Trials in which monkeys canceled or produced a saccade in a stop signal trial were distinguished by a modest difference in discharge rate of these SEF neurons before stop signal or target presentation. These findings indicate that neurons in the SEF, in contrast to counterparts in the frontal eye field and superior colliculus, do not contribute directly and immediately to the initiation of visually guided saccades. However the SEF may proactively regulate saccade production by biasing the balance between gaze-holding and gaze-shifting based on prior performance and anticipated task requirements.

Despite nearly a century of electrophysiological studies recording extracranially from humans and intracranially from monkeys, the neural generators of nearly all human event-related potentials (ERPs) have not been definitively localized. We recorded an attention-related ERP component, known as the N2pc, simultaneously with intracranial spikes and local field potentials (LFPs) in macaques to test the hypothesis that an attentional-control structure, the frontal eye field (FEF), contributed to the generation of the macaque homologue of the N2pc (m-N2pc). While macaques performed a difficult visual search task, the search target was selected earliest by spikes from single FEF neurons, later by FEF LFPs, and latest by the m-N2pc. This neurochronometric comparison provides an empirical bridge connecting macaque and human experiments and a step toward localizing the neural generator of this important attention-related ERP component.

The frontal eye field (FEF) contributes to directing visual attention and saccadic eye movement through intrinsic processing, interactions with extrastriate visual cortical areas (e.g. V4), and projections to subcortical structures (e.g. superior colliculus; SC). Several models have been proposed to describe the relationship between the allocation of visual attention and the production of saccades. We obtained anatomical information that might provide useful constraints on these models by evaluating two characteristics of FEF. First, we investigated the laminar distribution of efferent connections from FEF to visual areas V4 + TEO and to SC. Second, we examined the laminar distribution of different populations of GABAergic neurons in FEF. We found that the neurons in FEF that project to V4 + TEO are located predominantly in the supragranular layers, colocalized with the highest density of calbindin- and calretinin-immunoreactive inhibitory interneurons. In contrast, the cell bodies of neurons that project to SC are found only in layer 5 of FEF, colocalized primarily with parvalbumin inhibitory interneurons. None of the neurons in layer 5 that project to V4 + TEO also project to SC. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that different populations of neurons project to extrastriate visual cortical areas and to SC. This finding also suggests that FEF neurons projecting to visual cortex and superior colliculus are embedded in different patterns of intracortical circuitry.

The dynamics of visual selection and saccade preparation by the frontal eye field was investigated in macaque monkeys performing a search-step task combining the classic double-step saccade task with visual search. Reward was earned for producing a saccade to a color singleton. On random trials the target and one distractor swapped locations before the saccade and monkeys were rewarded for shifting gaze to the new singleton location. A race model accounts for the probabilities and latencies of saccades to the initial and final singleton locations and provides a measure of the duration of a covert compensation process—target-step reaction time. When the target stepped out of a movement field, noncompensated saccades to the original location were produced when movement-related activity grew rapidly to a threshold. Compensated saccades to the final location were produced when the growth of the original movement-related activity was interrupted within target-step reaction time and was replaced by activation of other neurons producing the compensated saccade. When the target stepped into a receptive field, visual neurons selected the new target location regardless of the monkeys’ response. When the target stepped out of a receptive field most visual neurons maintained the representation of the original target location, but a minority of visual neurons showed reduced activity. Chronometric analyses of the neural responses to the target step revealed that the modulation of visually responsive neurons and movement-related neurons occurred early enough to shift attention and saccade preparation from the old to the new target location. These findings indicate that visual activity in the frontal eye field signals the location of targets for orienting, whereas movement-related activity instantiates saccade preparation.

1. The purpose of this study was to describe the response properties of neurons in the supplementary motor area (SMA), including the supplementary eye fields (SEF) of three rhesus monkeys (Macaca mulatta) performing visually guided eye and forelimb movements. Seven hundred thirty single units were recorded in the dorsomedial agranular cortex while monkeys performed a go/no-go visual tracking task. The unit activity associated with rewarded, task-related movements was compared with that associated with unrewarded, spontaneous movements executed in the intertrial interval or when the task was not running. A number of neuronal response types were identified. 2. Sensory cells were characterized by their response to the visual and/or auditory target stimuli combined with no discharge associated with eye or forelimb movements. New information was provided about the receptive fields of the visual cells; they varied in size and, although many included the ipsilateral hemifield, they tended to emphasize the contralateral. A significant proportion of the visually responsive cells had receptive fields restricted to within 8 degrees of the fovea. The response latency was relatively long (greater than 90 ms) and variable. 3. Preparatory set cells were activated from the appearance of the target until the presentation of the go/no-go cue. This subpopulation ceased firing 50-100 ms before the movement was initiated. These cells tended to respond best in relation to contralateral movements. The response latency was similar to that of the sensory cells, although some of these units began to discharge in anticipation of predictable target presentations. These neurons were not active before unrewarded, spontaneous saccades. 4. Sensory-movement cells comprised the largest population of neurons identified in SMA. They were active from the appearance of the target until after the execution of the saccade. These neurons tended to respond preferentially in association with contraversive saccades. The latency of response to the target was significantly longer than that of the sensory cells. There was a large amount of variability in the time to reach the peak level of activation, and this population of units generally became inactivated shortly after the saccade was initiated. Although there were counterexamples, most sensory-movement cells responded equally in association with visually and auditory guided movements. In addition, these neurons were not active in relation to self-generated eye movements made during the intertrial intervals. 5. Pause-rebound cells were identified by their suppression at the appearance of the target and subsequent discharge associated with the saccade. These units tended to respond preferentially to contralateral targets.(ABSTRACT TRUNCATED AT 400 WORDS)

The countermanding (or stop signal) task probes the control of the initiation of a movement by measuring subjects' ability to withhold a movement in various degrees of preparation in response to an infrequent stop signal. Previous research found that saccades are initiated when the activity of movement-related neurons reaches a threshold, and saccades are withheld if the growth of activity is interrupted. To extend and evaluate this relationship of frontal eye field (FEF) activity to saccade initiation, two new analyses were performed. First, we fit a neurometric function that describes the proportion of trials with a stop signal in which neural activity exceeded a criterion discharge rate as a function of stop signal delay, to the inhibition function that describes the probability of producing a saccade as a function of stop signal delay. The activity of movement-related but not visual neurons provided the best correspondence between neurometric and inhibition functions. Second, we determined the criterion discharge rate that optimally discriminated between the distributions of discharge rates measured on trials when saccades were produced or withheld. Differential activity of movement-related but not visual neurons could distinguish whether a saccade occurred. The threshold discharge rates determined for individual neurons through these two methods agreed. To investigate how reliably movement-related activity predicted movement initiation; the analyses were carried out with samples of activity from increasing numbers of trials from the same or from different neurons. The reliability of both measures of initiation threshold improved with number of trials and neurons to an asymptote of between 10 and 20 movement-related neurons. Combining the activity of visual neurons did not improve the reliability of predicting saccade initiation. These results demonstrate how the activity of a population of movement-related but not visual neurons in the FEF contributes to the control of saccade initiation. The results also validate these analytical procedures for identifying signals that control saccade initiation in other brain structures.

Executive control requires controlling the initiation of movements, judging the consequences of actions, and adjusting performance accordingly. We have investigated the role of different areas in the frontal lobe in executive control expressed by macaque monkeys performing a saccade stop signal task. Certain neurons in the frontal eye field respond to visual stimuli, and others control the production of saccadic eye movements. Neurons in the supplementary eye field do not control directly the initiation of saccades but, instead, signal the production of errors, the anticipation and delivery of reinforcement, and the presence of response conflict. Neurons in the anterior cingulate cortex signal the production of errors and the anticipation and delivery of reinforcement, but not the presence of response conflict. Intracranial local field potentials in the anterior cingulate cortex of monkeys indicate that these medial frontal signals can contribute to event-related potentials related to performance monitoring. Electrical stimulation of the supplementary eye field improves performance in the task by elevating saccade latency. An interactive race model shows how interacting units produce behavior that can be described as the outcome of a race between independent processes and how conflict between gaze-holding and gaze-shifting neurons can be used to adjust performance.

The stop-signal or countermanding task probes the ability to control action by requiring subjects to withhold a planned movement in response to an infrequent stop signal which they do with variable success depending on the delay of the stop signal. We investigated whether performance of humans and macaque monkeys in a saccade countermanding task was influenced by stimulus and performance history. In spite of idiosyncrasies across subjects several trends were evident in both humans and monkeys. Response time decreased after successive trials with no stop signal. Response time increased after successive trials with a stop signal. However, post-error slowing was not observed. Increased response time was observed mainly or only after cancelled (signal inhibit) trials and not after noncancelled (signal respond) trials. These global trends were based on rapid adjustments of response time in response to momentary fluctuations in the fraction of stop signal trials. The effects of trial sequence on the probability of responding were weaker and more idiosyncratic across subjects when stop signal fraction was fixed. However, both response time and probability of responding were influenced strongly by variations in the fraction of stop signal trials. These results indicate that the race model of countermanding performance requires extension to account for these sequential dependencies and provide a basis for physiological studies of executive control of countermanding saccade performance.