Macaque Frontal Eye Field Research Articles

Neurons of Macaque Frontal Eye Field Signal Reward-Related Surprise.

The frontal eye field (FEF) plays a well-established role in the control of visual attention. The strength of an FEF neuron's response to a visual stimulus presented in its receptive field is enhanced if the stimulus captures spatial attention by virtue of its salience. A stimulus can be rendered salient by cognitive factors as well as by physical attributes. These include surprise. The aim of the present experiment was to determine whether surprise-induced salience would result in enhanced visual-response strength in the FEF. Toward this end, we monitored neuronal activity in two male monkeys while presenting first a visual cue predicting with high probability that the reward delivered at the end of the trial would be good or bad (large or small) and then a visual cue announcing the size of the impending reward with certainty. The second cue usually confirmed but occasionally violated the expectation set up by the first cue. Neurons responded more strongly to the second cue when it violated than when it confirmed expectation. The increase in the firing rate was accompanied by a decrease in spike-count correlation as expected from capture of attention. Although both good surprise and bad surprise induced enhanced firing, the effects appeared to arise from distinct mechanisms as indicated by the fact that the bad-surprise signal appeared at a longer latency than the good-surprise signal and by the fact that the strength of the two signals varied independently across neurons.

Conflict detection and resolution in macaque frontal eye fields

Stimulus-induced conflicts in decision-making tasks produce both behavioral and neuronal congruency effects. However, how and when conflicts are detected and resolved at the neuronal level remains largely unclear. To address these issues, we recorded from single neurons in the frontal eye fields of two macaques performing a conflict task. Although the temporal dynamics of the neuronal congruency effects are independent of the specific task rules, they are substantially different in target- and distractor-encoding neurons. Conflicts were detected ~100 ms after the conflict-inducing cue (20–30 ms after the visual response), which is much faster than predicted based on human EEG results. This suggests that conflict detection relies on a fast mechanism in frontal eye fields. Resolving the conflict at the neuronal level, however, requires between <400 ms to ~1000 ms, and shows profound interindividual differences and depends on task rules, indicating that it is a more complex and top-down driven process. Our findings illuminate the neuronal mechanisms underlying decision-making when a conflict is present, a crucial cognitive process playing a role in basic survival and high-level cognitive functions.

Orchestration of saccadic eye-movements by brain rhythms in macaque Frontal Eye Field

Visual perception has been suggested to operate on temporal ‘chunks’ of sensory input, rather than on a continuous stream of visual information. Saccadic eye movements impose a natural rhythm on the sensory input, as periods of steady fixation between these rapid eye movements provide distinct temporal segments of information. Ideally, the timing of saccades should be precisely locked to the brain’s rhythms of information processing. Here, we investigated such locking of saccades to rhythmic neural activity in rhesus monkeys performing a visual foraging task. We found that saccades are phase-locked to local field potential oscillations (especially, 9–22 Hz) in the Frontal Eye Field, with the phase of oscillations predictive of the saccade onset as early as 100 ms prior to these movements. Our data also indicate a functional role of this phase-locking in determining the direction of saccades. These findings show a tight—and likely important—link between oscillatory brain activity and rhythmic behavior that imposes a rhythmic temporal structure on sensory input, such as saccadic eye movements.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF+ or V1/V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF+ when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1/V2 or rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance [A. Fernández, M.Carrasco,Curr. Biol.30, 4078-4084 (2020)]. In experiment 2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor costs at the unattended location were significant. The frequency and directionality of microsaccades mimicked this pattern: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate directed toward the stimulated hemifield. These results provide causal evidence of the role of this frontal region for endogenous attention.

The interaction of saccadic and smooth pursuit eye movements signals in macaque frontal eye fields

The interaction of saccadic and smooth pursuit eye movements signals in macaque frontal eye fields

Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field.

Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

Visuomotor Transformations Are Modulated by Focused Ultrasound over Frontal Eye Field

Neuromodulation with focused ultrasound (FUS) is being widely explored as a non-invasive tool to stimulate focal brain regions because of its superior spatial resolution and coverage compared with other neuromodulation methods. The precise effects of FUS stimulation on specific regions of the brain are not yet fully understood. Here, we characterized the behavioral effects of FUS stimulation directly applied through a craniotomy over the macaque frontal eye field (FEF). In macaque monkeys making directed eye movements to perform visual search tasks with direct or arbitrary responses, focused ultrasound was applied through a craniotomy over the FEF. Saccade response times (RTs) and error rates were determined for trials without or with FUS stimulation with pulses at a peak negative pressure of either 250 or 425 kPa. Both RTs and error rates were affected by FUS. Responses toward a target located contralateral to the FUS stimulation were approximately 3 ms slower in the presence of FUS in both monkeys studied, while only one exhibited a slowing of responses for ipsilateral targets. Error rates were lower in one monkey in this study. In another search task requiring making eye movements toward a target (pro-saccades) or in the opposite direction (anti-saccades), the RT for pro-saccades increased in the presence of FUS stimulation. Our results indicate the effectiveness of FUS to modulate saccadic responses when stimulating FEF in awake, behaving non-human primates.

Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field.

Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.

Assessing within-trial and across-trial neural variability in macaque frontal eye fields and their relation to behaviour.

The conventional approach to understanding neural responses underlying complex computations is to study across-trial averages of repeatedly performed computations from single neurons. When neurons perform complex computations, such as processing stimulus-related information or movement planning, it has been repeatedly shown, through measures such as the Fano factor (FF), that neural variability across trials decreases. However, multiple neurons contribute to a common computation on a single trial, rather than a single neuron contributing to a computation across multiple trials. Therefore, at the level of a single trial, the concept of FF loses significance. Here, using a combination of simulations and empirical data, we show that changes in the spiking regularity on single trials produce changes in FF. Further, at the behavioural level, the reaction time of the animal was faster when the neural spiking regularity both within and across trials was lower. Taken together, our results provide further constraints on how changes in spiking statistics help neurons optimally encode visual and saccade-related information across multiple timescales and its implication on behaviour.

Parallel programming of saccades in the macaque frontal eye field: are sequential motor plans coactivated?

We use sequences of saccadic eye movements to continually explore our visual environments. Previous behavioral studies have established that saccades in a sequence may be programmed in parallel by the oculomotor system. In this study, we tested the neural correlates of parallel programming of saccade sequences in the frontal eye field (FEF), using single-unit electrophysiological recordings from macaques performing a sequential saccade task. It is known that FEF visual neurons instantiate target selection whereas FEF movement neurons undertake saccade preparation, where the activity corresponding to a saccade vector gradually ramps up. The question of whether FEF movement neurons are involved in concurrent processing of saccade plans is as yet unresolved. In the present study, we show that, when a peripheral target is foveated after a sequence of two saccades, presaccadic activity of FEF movement neurons for the second saccade can be activated while the first is still underway. Moreover, the onset of movement activity varied parametrically with the behaviorally measured time available for parallel programming. Although at central fixation coactivated FEF movement activity may vectorially encode the retinotopic location of the second target with respect to the fixation point or the remapped location of the second target, with respect to the first our evidence suggests the possibility of early encoding of the remapped second saccade vector. Taken together, the results indicate that movement neurons, although located terminally in the FEF visual-motor spectrum, can accomplish concurrent processing of multiple saccade plans, leading to rapid execution of saccade sequences.NEW & NOTEWORTHY The execution of purposeful sequences underlies much of goal-directed behavior. How different brain areas accomplish sequencing is poorly understood. Using a modified double-step task to generate a rapid sequence of two saccades, we demonstrate that downstream movement neurons in the frontal eye field (FEF), a prefrontal oculomotor area, allow for coactivation of the first and second movement plans that constitute the sequence. These results provide fundamental insights into the neural control of action sequencing.

Functional Localization of the Frontal Eye Fields in the Common Marmoset Using Microstimulation.

The frontal eye field (FEF) is a critical region for the deployment of overt and covert spatial attention. Although investigations in the macaque continue to provide insight into the neural underpinnings of the FEF, due to its location within a sulcus, the macaque FEF is virtually inaccessible to electrophysiological techniques such as high-density and laminar recordings. With a largely lissencephalic cortex, the common marmoset (Callithrix jacchus) is a promising alternative primate model for studying FEF microcircuitry. Putative homologies have been established with the macaque FEF on the basis of cytoarchitecture and connectivity; however, physiological investigation in awake, behaving marmosets is necessary to physiologically locate this area. Here, we addressed this gap using intracortical microstimulation in a broad range of frontal cortical areas in three adult marmosets (two males, one female). We implanted marmosets with 96-channel Utah arrays and applied microstimulation trains while they freely viewed video clips. We evoked short-latency fixed vector saccades at low currents (<50 μA) in areas 45, 8aV, 8C, and 6DR. We observed a topography of saccade direction and amplitude consistent with findings in macaques and humans: small saccades in ventrolateral FEF and large saccades combined with contralateral neck and shoulder movements encoded in dorsomedial FEF. Our data provide compelling evidence supporting homology between marmoset and macaque FEF and suggest that the marmoset is a useful primate model for investigating FEF microcircuitry and its contributions to oculomotor and cognitive functions.SIGNIFICANCE STATEMENT The frontal eye field (FEF) is a critical cortical region for overt and covert spatial attention. The microcircuitry of this area remains poorly understood because in the macaque, the most commonly used model, it is embedded within a sulcus and is inaccessible to modern electrophysiological and imaging techniques. The common marmoset is a promising alternative primate model due to its lissencephalic cortex and potential for genetic manipulation. However, evidence for homologous cortical areas in this model remains limited and unclear. Here, we applied microstimulation in frontal cortical areas in marmosets to physiologically identify FEF. Our results provide compelling evidence for an FEF in the marmoset and suggest that the marmoset is a useful model for investigating FEF microcircuitry.

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field

Attention is critical to high-level cognition, and attentional deficits are a hallmark of cognitive dysfunction. A key transmitter for attentional control is acetylcholine, but its cellular actions in attention-controlling areas remain poorly understood. Here we delineate how muscarinic and nicotinic receptors affect basic neuronal excitability and attentional control signals in different cell types in macaque frontal eye field. We found that broad spiking and narrow spiking cells both require muscarinic and nicotinic receptors for normal excitability, thereby affecting ongoing or stimulus-driven activity. Attentional control signals depended on muscarinic, not nicotinic receptors in broad spiking cells, while they depended on both muscarinic and nicotinic receptors in narrow spiking cells. Cluster analysis revealed that muscarinic and nicotinic effects on attentional control signals were highly selective even for different subclasses of narrow spiking cells and of broad spiking cells. These results demonstrate that cholinergic receptors are critical to establish attentional control signals in the frontal eye field in a cell type-specific manner.

Induction of Shape Selectivity in Macaque Frontal Eye Field Dissociates Perceptual and Motor Processing Stages of Visual Search

Neurons in frontal eye field (FEF) respond to visual stimulation, before eye movements, and both. These responses differentiate whether or not a stimulus is a saccade target. This differentiation, or target selection, is stimulus-locked for many neurons. Importantly, this target selection does not usually depend on the features that define a target as such, because most neurons in FEF do not exhibit intrinsic feature selectivity. However, consistent mapping of a stimulus feature and reward can elicit feature selectivity. Whether this feature selectivity is similarly stimulus-locked or if it is related to the selection of a saccade endpoint is unknown. We developed a search pro-/anti-saccade task in which shape varies among stimuli but does not define the saccade target. One monkey tested in this task developed a strategy that exploits an incidental shape-response association as opposed to the intended rule. We identified visual neurons in FEF that exhibited shape selectivity. The timing of this selectivity followed visual onset but was coincident with saccade target selection. Further, we found that these neurons showed an additional increase in firing rate when a stimulus of the preferred shape was also chosen via saccade. This occurred after feature selection and was coincident with additional temporal measures of saccade endpoint selection. These findings together suggest that feature selectivity, when induced, is tantamount to target selection which is then followed by saccade endpoint selection. In this way, we can exploit feature selectivity in FEF neurons to dissociate the perceptual and motor stages of a complex visual search task.

The mediodorsal pulvinar coordinates the macaque fronto-parietal network during rhythmic spatial attention

Spatial attention is discontinuous, sampling behaviorally relevant locations in theta-rhythmic cycles (3–6 Hz). Underlying this rhythmic sampling are intrinsic theta oscillations in frontal and parietal cortices that provide a clocking mechanism for two alternating attentional states that are associated with either engagement at the presently attended location (and enhanced perceptual sensitivity) or disengagement (and diminished perceptual sensitivity). It has remained unclear, however, how these theta-dependent states are coordinated across the large-scale network that directs spatial attention. The pulvinar is a candidate for such coordination, having been previously shown to regulate cortical activity. Here, we examined pulvino-cortical interactions during theta-rhythmic sampling by simultaneously recording from macaque frontal eye fields (FEF), lateral intraparietal area (LIP), and pulvinar. Neural activity propagated from pulvinar to cortex during periods of engagement, and from cortex to pulvinar during periods of disengagement. A rhythmic reweighting of pulvino-cortical interactions thus defines functional dissociations in the attention network.

Differential Expression of Dopamine D5 Receptors across Neuronal Subtypes in Macaque Frontal Eye Field.

Dopamine signaling in the prefrontal cortex (PFC) is important for cognitive functions, yet very little is known about the expression of the D5 class of dopamine receptors (D5Rs) in this region. To address this, we co-stained for D5Rs, pyramidal neurons (neurogranin+), putative long-range projection pyramidal neurons (SMI-32+), and several classes of inhibitory interneuron (parvalbumin+, calbindin+, calretinin+, somatostatin+) within the frontal eye field (FEF): an area within the PFC involved in the control of visual spatial attention. We then quantified the co-expression of D5Rs with markers of different cell types across different layers of the FEF. We show that: (1) D5Rs are more prevalent on pyramidal neurons than on inhibitory interneurons. (2) D5Rs are disproportionately expressed on putative long-range projecting pyramidal neurons. The disproportionately high expression of D5Rs on long-range projecting pyramidals, compared to interneurons, was particularly pronounced in layers II–III. Together these results indicate that the engagement of D5R-dependent mechanisms in the FEF varies depending on cell type and cortical layer, and suggests that non-locally projecting neurons contribute disproportionately to functions involving the D5R subtype.

Renewed Attention on the Pupil Light Reflex

In a recent study, Ebitz and Moore described how subthreshold electrical microstimulation of the macaque frontal eye fields (FEF) modulates the pupillary light reflex. This elegant study suggests that the influence of the FEF and prefrontal cortex on attentional modulation of cortical visual processing extends to the subcortical circuit that mediates a very basic reflex, the pupillary light reflex.

Selective Modulation of the Pupil Light Reflex by Microstimulation of Prefrontal Cortex

The prefrontal cortex (PFC) is thought to flexibly regulate sensorimotor responses, perhaps through modulating activity in other circuits. However, the scope of that control remains unknown: it remains unclear whether the PFC can modulate basic reflexes. One canonical example of a central reflex is the pupil light reflex (PLR): the automatic constriction of the pupil in response to luminance increments. Unlike pupil size, which depends on the interaction of multiple physiological and neuromodulatory influences, the PLR reflects the action of a simple brainstem circuit. However, emerging behavioral evidence suggests that the PLR may be modulated by cognitive processes. Although the neural basis of these modulations remains unknown, one possible source is the PFC, particularly the frontal eye field (FEF), an area of the PFC implicated in the control of attention. We show that microstimulation of the rhesus macaque FEF alters the magnitude of the PLR in a spatially specific manner. FEF microstimulation enhanced the PLR to probes presented within the stimulated visual field, but suppressed the PLR to probes at nonoverlapping locations. The spatial specificity of this effect parallels the effect of FEF stimulation on attention and suggests that FEF is capable of modulating visuomotor transformations performed at a lower level than was previously known. These results provide evidence of the selective regulation of a basic brainstem reflex by the PFC.SIGNIFICANCE STATEMENT The pupil light reflex (PLR) is our brain's first and most fundamental mechanism for light adaptation. Although it is often described in textbooks as being an immutable reflex, converging evidence suggests that the magnitude of the PLR is modulated by cognitive factors. The neural bases of these modulations are unknown. Here, we report that microstimulation in the prefrontal cortex (PFC) modulates the gain of the PLR, changing how a simple reflex circuit responds to physically identical stimuli. These results suggest that control structures such as the PFC can add complexity and flexibility to even a basic brainstem circuit.

Feature-Selective Attentional Modulations in Human Frontoparietal Cortex

Control over visual selection has long been framed in terms of a dichotomy between "source" and "site," where top-down feedback signals originating in frontoparietal cortical areas modulate or bias sensory processing in posterior visual areas. This distinction is motivated in part by observations that frontoparietal cortical areas encode task-level variables (e.g., what stimulus is currently relevant or what motor outputs are appropriate), while posterior sensory areas encode continuous or analog feature representations. Here, we present evidence that challenges this distinction. We used fMRI, a roving searchlight analysis, and an inverted encoding model to examine representations of an elementary feature property (orientation) across the entire human cortical sheet while participants attended either the orientation or luminance of a peripheral grating. Orientation-selective representations were present in a multitude of visual, parietal, and prefrontal cortical areas, including portions of the medial occipital cortex, the lateral parietal cortex, and the superior precentral sulcus (thought to contain the human homolog of the macaque frontal eye fields). Additionally, representations in many-but not all-of these regions were stronger when participants were instructed to attend orientation relative to luminance. Collectively, these findings challenge models that posit a strict segregation between sources and sites of attentional control on the basis of representational properties by demonstrating that simple feature values are encoded by cortical regions throughout the visual processing hierarchy, and that representations in many of these areas are modulated by attention. Influential models of visual attention posit a distinction between top-down control and bottom-up sensory processing networks. These models are motivated in part by demonstrations showing that frontoparietal cortical areas associated with top-down control represent abstract or categorical stimulus information, while visual areas encode parametric feature information. Here, we show that multivariate activity in human visual, parietal, and frontal cortical areas encode representations of a simple feature property (orientation). Moreover, representations in several (though not all) of these areas were modulated by feature-based attention in a similar fashion. These results provide an important challenge to models that posit dissociable top-down control and sensory processing networks on the basis of representational properties.

Dynamics of visual receptive fields in the macaque frontal eye field.

Neuronal receptive fields (RFs) provide the foundation for understanding systems-level sensory processing. In early visual areas, investigators have mapped RFs in detail using stochastic stimuli and sophisticated analytical approaches. Much less is known about RFs in prefrontal cortex. Visual stimuli used for mapping RFs in prefrontal cortex tend to cover a small range of spatial and temporal parameters, making it difficult to understand their role in visual processing. To address these shortcomings, we implemented a generalized linear model to measure the RFs of neurons in the macaque frontal eye field (FEF) in response to sparse, full-field stimuli. Our high-resolution, probabilistic approach tracked the evolution of RFs during passive fixation, and we validated our results against conventional measures. We found that FEF neurons exhibited a surprising level of sensitivity to stimuli presented as briefly as 10 ms or to multiple dots presented simultaneously, suggesting that FEF visual responses are more precise than previously appreciated. FEF RF spatial structures were largely maintained over time and between stimulus conditions. Our results demonstrate that the application of probabilistic RF mapping to FEF and similar association areas is an important tool for clarifying the neuronal mechanisms of cognition.

Performance Monitoring in Monkey Frontal Eye Field

The frontal eye fields (FEF) are thought to mediate response selection during oculomotor decision tasks. In addition, many FEF neurons have robust postsaccadic responses, but their role in postchoice evaluative processes (online performance monitoring) is only beginning to become apparent. Here we report error-related neural activity in FEF while monkeys performed a biased speed-categorization task that enticed the animals to make impulsive errors. Twenty-three percent of cells in macaque FEF coded an internally generated error-related signal, and many of the same cells also coded task difficulty. The observed responses are primarily consistent with three related concepts that have been associated with performance monitoring: (1) response conflict; (2) uncertainty; and (3) reward prediction. Overall, our findings suggest a novel role for the FEF as part of the neural network that evaluates the preceding choice to optimize behavior in the future.