A tridimensional atlas of the developing human head.

The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis. We present detailed developmental series of diverse head tissues and cell types, including muscles, vasculature, cartilage, peripheral nerves, and exocrine glands. These datasets, accessible through a dedicated web interface, provide insights into human embryogenesis. We offer perspectives on the branching morphogenesis of human exocrine glands and unknown features of the development of neurovascular and skeletomuscular structures. These insights into human embryology have important implications for understanding craniofacial defects and neurological disorders and advancing diagnostic and therapeutic strategies.

VEGF, but Not BDNF, Prevents the Downregulation of KCC2 Induced by Axotomy in Extraocular Motoneurons.

The potassium-chloride cotransporter KCC2 is the main extruder of Cl- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl- accumulation, leading to the depolarizing activity of GABA and glycine. The downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain, and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, the KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons via the monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of choline acetyl-transferase (ChAT) and KCC2 was carried out in the brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and somata of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of the abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced the KCC2 levels following axotomy, suggesting that BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens up new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation.

Goal-directed and stimulus-driven selection of internal representations.

Adaptive behavior relies on the selection of relevant sensory information from both the external environment and internal memory representations. In understanding external selection, a classic distinction is made between voluntary (goal-directed) and involuntary (stimulus-driven) guidance of attention. We have developed a task-the anti-retrocue task-to separate and examine voluntary and involuntary guidance of attention to internal representations in visual working memory. We show that both voluntary and involuntary factors influence memory performance but do so in distinct ways. Moreover, by tracking gaze biases linked to attentional focusing in memory, we provide direct evidence for an involuntary "retro-capture" effect whereby external stimuli involuntarily trigger the selection of feature-matching internal representations. We show that stimulus-driven and goal-directed influences compete for selection in memory, and that the balance of this competition-as reflected in oculomotor signatures of internal attention-predicts the quality of ensuing memory-guided behavior. Thus, goal-directed and stimulus-driven factors together determine the fate not only of perception, but also of internal representations in working memory.

BDNF Influence on Adult Terminal Axon Sprouting after Partial Deafferentation.

BDNF is a neurotrophin family member implicated in many different neuronal functions, from neuronal survival during development to synaptic plasticity associated with processes of learning and memory. Its presence in the oculomotor system has previously been demonstrated, as it regulates afferent composition of extraocular motoneurons and their firing pattern. Moreover, BDNF expression increases after extraocular motoneuron partial deafferentation, in parallel with terminal axon sprouting from the remaining axons. To elucidate whether BDNF could play an active role in this process, we performed partial deafferentation of the medial rectus motoneurons through transection of one of the two main afferents, that is, the ascending tract of Deiters, and injected BDNF into the motoneuron target muscle, the medial rectus. Furthermore, to check whether BDNF could stimulate axon sprouting without lesions, we performed the same experiment without any lesions. Axon terminal sprouting was assessed by calretinin immunostaining, which specifically labels the remaining afferent system on medial rectus motoneurons, the abducens internuclear neurons. The results presented herein show that exogenous BDNF stimulated terminal axon growth, allowing the total recovery of synaptic coverage around the motoneuron somata. Moreover, calretinin staining in the neuropil exceeded that present in the control situation. Thus, BDNF could also stimulate axonal sprouting in the neuropil of intact animals. These results point to an active role of BDNF in plastic adaptations that take place after partial deafferentation.

MIF versus SIF Motoneurons, What Are Their Respective Contribution in the Oculomotor Medial Rectus Pool?

Multiply-innervated muscle fibers (MIFs) are peculiar to the extraocular muscles as they are non-twitch but produce a slow build up in tension on repetitive stimulation. The motoneurons innervating MIFs establish en grappe terminals along the entire length of the fiber, instead of the typical en plaque terminals that singly-innervated muscle fibers (SIFs) motoneurons establish around the muscle belly. MIF motoneurons have been proposed to participate only in gaze holding and slow eye movements. We aimed to discern the function of MIF motoneurons by recording medial rectus motoneurons of the oculomotor nucleus. Single-unit recordings in awake cats demonstrated that electrophysiologically-identified medial rectus MIF motoneurons participated in different types of eye movements, including fixations, rapid eye movements or saccades, convergences, and the slow and fast phases of the vestibulo-ocular nystagmus, the same as SIF motoneurons did. However, MIF medial rectus motoneurons presented lower firing frequencies, were recruited earlier and showed lower eye position (EP) and eye velocity (EV) sensitivities than SIF motoneurons. MIF medial rectus motoneurons were also smaller, had longer antidromic latencies and a lower synaptic coverage than SIF motoneurons. Peristimulus time histograms (PSTHs) revealed that electrical stimulation to the myotendinous junction, where palisade endings are located, did not recurrently affect the firing probability of medial rectus motoneurons. Therefore, we conclude there is no division of labor between MIF and SIF motoneurons based on the type of eye movement they subserve.SIGNIFICANCE STATEMENT In addition to the common singly-innervated muscle fiber (SIF), extraocular muscles also contain multiply-innervated muscle fibers (MIFs), which are non-twitch and slow in contraction. MIF motoneurons have been proposed to participate only in gaze holding and slow eye movements. In the present work, by single-unit extracellular recordings in awake cats, we demonstrate, however, that both SIF and MIF motoneurons, electrophysiologically-identified, participate in the different types of eye movements. However, MIF motoneurons showed lower firing rates (FRs), recruitment thresholds, and eye-related sensitivities, and could thus contribute to the fine adjustment of eye movements. Electrical stimulation of the myotendinous junction activates antidromically MIF motoneurons but neither MIF nor SIF motoneurons receive a synaptic reafferentation that modifies their discharge probability.

Unrestricted eye movements strengthen effective connectivity from hippocampal to oculomotor regions during scene construction.

Scene construction is a key component of memory recall, navigation, and future imagining, and relies on the medial temporal lobes (MTL). A parallel body of work suggests that eye movements may enable the imagination and construction of scenes, even in the absence of external visual input. There are vast structural and functional connections between regions of the MTL and those of the oculomotor system. However, the directionality of connections between the MTL and oculomotor control regions, and how it relates to scene construction, has not been studied directly in human neuroimaging. In the current study, we used dynamic causal modeling (DCM) to interrogate effective connectivity between the MTL and oculomotor regions using a scene construction task in which participants' eye movements were either restricted (fixed-viewing) or unrestricted (free-viewing). By omitting external visual input, and by contrasting free- versus fixed- viewing, the directionality of neural connectivity during scene construction could be determined. As opposed to when eye movements were restricted, allowing free-viewing during construction of scenes strengthened top-down connections from the MTL to the frontal eye fields, and to lower-level cortical visual processing regions, suppressed bottom-up connections along the visual stream, and enhanced vividness of the constructed scenes. Taken together, these findings provide novel, non-invasive evidence for the underlying, directional, connectivity between the MTL memory system and oculomotor system associated with constructing vivid mental representations of scenes.

The effect of amblyopia on saccadic eye movements.

The effect of amblyopia on several sensory and perceptual functions has been widely studied. However, relatively fewer studies have evaluated the influence of amblyopia on visuomotor aspects. This concise but comprehensive collection of materials is to show how saccadic eye movements are severely affected by amblyopia and therefore spatiotemporal coordination between the visual and motor systems is distorted. The author hopes that recognition of these saccade deficits in amblyopia can help all eye professionals and neurologists to consider validated clinical tests related to saccadic eye movements in patients with amblyopia as these tests are not presently performed in routine clinical eye examinations.

Frontal eye field inactivation alters the readout of superior colliculus activity for saccade generation in a task-dependent manner.

Saccades require a spatiotemporal transformation of activity between the intermediate layers of the superior colliculus (iSC) and downstream brainstem burst generator. The dynamic linear ensemble-coding model (Goossens and Van Opstal 2006) proposes that each iSC spike contributes a fixed mini-vector to saccade displacement. Although biologically-plausible, this model assumes cortical areas like the frontal eye fields (FEF) simply provide the saccadic goal to be executed by the iSC and brainstem burst generator. However, the FEF and iSC operate in unison during saccades, and a pathway from the FEF to the brainstem burst generator that bypasses the iSC exists. Here, we investigate the impact of large yet reversible inactivation of the FEF on iSC activity in the context of the model across four saccade tasks. We exploit the overlap of saccade vectors generated when the FEF is inactivated or not, comparing the number of iSC spikes for metrically-matched saccades. We found that the iSC emits fewer spikes for metrically-matched saccades during FEF inactivation. The decrease in spike count is task-dependent, with a greater decrease accompanying more cognitively-demanding saccades. Our results show that FEF integrity influences the readout of iSC activity in a task-dependent manner. We propose that the dynamic linear ensemble-coding model be modified so that FEF inactivation increases the gain of a readout parameter, effectively increasing the influence of a single iSC spike. We speculate that this modification could be instantiated by FEF and iSC pathways to the cerebellum that could modulate the excitability of the brainstem burst generator.

Head and eye movements are each facilitated by the offset of a central fixation point in a virtual gap paradigm.

Eye movements exhibit reduced latencies when the point of fixation is extinguished prior to, or coincident with, the appearance of a peripheral target. Two independent components are responsible for this facilitation. If the offset occurs before target onset, it presents a warning which stimulates response preparation and execution. If offset occurs prior to or coincident with target onset, it triggers the release of fixation-maintenance neurons in the superior colliculus that can delay saccadic responses. While the warning effect facilitates responses regardless of effector, the fixation release effect is thought to be specific to the oculomotor system. Head movements, like saccades, contribute significantly to gaze shifts and may be generated directly by the SC. While head movements have been shown to benefit from the warning effect, it is unknown if, and to what degree, they are affected by the release of fixation-maintenance neurons responsible for inhibiting saccades. To address this issue, we measured head and eye response latencies in a virtual reality-based gap paradigm, turning off the fixation point either 200 ms before (temporal gap condition), coincident with (step condition), or 1000 ms after (temporal overlap/baseline condition) target onset. Our results indicate that head movements, like saccades, are facilitated by both the warning and release components of the gap paradigm. Further, rotational kinematics during gap trials differed significantly from those observed in step and overlap trials (higher, earlier peak velocities). These results are discussed with respect to the theorized structure and organisation of the superior colliculus in humans.

Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System.

Vascular endothelial growth factor (VEGF) was initially characterized as a potent angiogenic factor based on its activity on the vascular system. However, it is now well established that VEGF also plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons. These motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem pools. That higher VEGF level could be due to an enhanced retrograde input from their target muscles, but it can also be produced by the motoneurons themselves and act in an autocrine way. By contrast, VEGF's paracrine supply from the vicinity cells, such as glial cells, seems to represent a minor source of VEGF for brainstem motoneurons. In addition, ocular motoneurons experiment an increase in VEGF and Flk-1 level in response to axotomy, not observed in facial or hypoglossal motoneurons. Therefore, in this review, we summarize the differences in VEGF availability that could contribute to the higher resistance of extraocular motoneurons to injury and neurodegenerative diseases.

Impairment but not abolishment of express saccades after unilateral or bilateral inactivation of the frontal eye fields.

Express saccades are a manifestation of a visual grasp reflex triggered when visual information arrives in the intermediate layers of the superior colliculus (SCi), which in turn orchestrates the lower level brainstem saccade generator to evoke a saccade with a very short latency (~100 ms or less). A prominent theory regarding express saccades generation is that they are facilitated by preparatory signals, presumably from cortical areas, which prime the SCi before the arrival of visual information. Here, we test this theory by reversibly inactivating a key cortical input to the SCi, the frontal eye fields (FEF), while monkeys perform an oculomotor task that promotes express saccades. Across three tasks with a different combination of potential target locations and unilateral or bilateral FEF inactivation, we found a spared ability for monkeys to generate express saccades, despite decreases in express saccade frequency during FEF inactivation. This result is consistent with the FEF having a facilitatory but not critical role in express saccade generation, likely because other cortical areas compensate for the loss of preparatory input to the SCi. However, we also found decreases in the accuracy and peak velocity of express saccades generated during FEF inactivation, which argues for an influence of the FEF on the saccadic burst generator even during express saccades. Overall, our results shed further light on the role of the FEF in the shortest-latency visually-guided eye movements.NEW & NOTEWORTHY Express saccades are the shortest-latency saccade. The frontal eye fields (FEF) are thought to promote express saccades by presetting the superior colliculus. Here, by reversibly inactivating the FEF either unilaterally or bilaterally via cortical cooling, we support this by showing that the FEF plays a facilitative but not critical role in express saccade generation. We also found that FEF inactivation lowered express saccade peak velocity, emphasizing a contribution of the FEF to express saccade kinematics.

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 architecture underlying binocular coordination of eye position and velocity in the larval zebrafish hindbrain.

BACKGROUND: The oculomotor integrator (OI) in the vertebrate hindbrain transforms eye velocity input into persistent position coding output, which plays a crucial role in retinal image stability. For a mechanistic understanding of the integrator function and eye position control, knowledge about the tuning of the OI and other oculomotor nuclei is needed. Zebrafish are increasingly used to study integrator function and sensorimotor circuits, yet the precise neuronal tuning to motor variables remains uncharacterized. RESULTS: Here, we recorded cellular calcium signals while evoking monocular and binocular optokinetic eye movements at different slow-phase eye velocities. Our analysis reveals the anatomical distributions of motoneurons and internuclear neurons in the nucleus abducens as well as those of oculomotor neurons in caudally adjacent hindbrain volumes. Each neuron is tuned to eye position and/or velocity to variable extents and is only activated after surpassing particular eye position and velocity thresholds. While the abducens (rhombomeres 5/6) mainly codes for eye position, in rhombomeres 7/8, a velocity-to-position coding gradient exists along the rostro-caudal axis, which likely corresponds to the oculomotor structures storing velocity and position, and is in agreement with a feedforward mechanism of persistent activity generation. Position encoding neurons are recruited at eye position thresholds distributed across the behaviourally relevant dynamic range, while velocity-encoding neurons have more centred firing thresholds for velocity. In the abducens, neurons coding exclusively for one eye intermingle with neurons coding for both eyes. Many of these binocular neurons are preferentially active during conjugate eye movements and less active during monocular eye movements. This differential recruitment during monocular versus conjugate tasks represents a functional diversification in the final common motor pathway. CONCLUSIONS: We localized and functionally characterized the repertoire of oculomotor neurons in the zebrafish hindbrain. Our findings provide evidence for a mixed but task-specific binocular code and suggest that generation of persistent activity is organized along the rostro-caudal axis in the hindbrain.

Effects of Selective Deafferentation on the Discharge Characteristics of Medial Rectus Motoneurons.

Medial rectus motoneurons receive two main pontine inputs: abducens internuclear neurons, whose axons course through the medial longitudinal fasciculus (MLF), and neurons in the lateral vestibular nucleus, whose axons project through the ascending tract of Deiters (ATD). Abducens internuclear neurons are responsible for conjugate gaze in the horizontal plane, whereas ATD neurons provide medial rectus motoneurons with a vestibular input comprising mainly head velocity. To reveal the relative contribution of each input to the oculomotor physiology, single-unit recordings from medial rectus motoneurons were obtained in the control situation and after selective deafferentation from cats with unilateral transection of either the MLF or the ATD. Both MLF and ATD transection produced similar short-term alterations in medial rectus motoneuron firing pattern, which were more drastic in MLF of animals. However, long-term recordings revealed important differences between the two types of lesion. Thus, while the effects of the MLF section were permanent, 2 months after ATD lesioning all motoneuronal firing parameters were similar to the control. These findings indicated a more relevant role of the MLF pathway in driving motoneuronal firing and evidenced compensatory mechanisms following the ATD lesion. Confocal immunocytochemistry revealed that MLF transection produced also a higher loss of synaptic boutons, mainly at the dendritic level. Moreover, 2 months after ATD transection, we observed an increase in synaptic coverage around motoneuron cell bodies compared with short-term data, which is indicative of a synaptogenic compensatory mechanism of the abducens internuclear pathway that could lead to the observed firing and morphological recovery.SIGNIFICANCE STATEMENT Eye movements rely on multiple neuronal circuits for appropriate performance. The abducens internuclear pathway through the medial longitudinal fascicle (MLF) and the vestibular neurons through the ascending tract of Deiters (ATD) are a dual system that supports the firing of medial rectus motoneurons. We report the effect of sectioning the MLF or the ATD pathway on the firing of medial rectus motoneurons, as well as the plastic mechanisms by which one input compensates for the lack of the other. This work shows that while the effects of MLF transection are permanent, the ATD section produces transitory effects. A mechanism based on axonal sprouting and occupancy of the vacant synaptic space due to deafferentation is the base for the mechanism of compensation on the medial rectus motoneuron.

Visual Sampling Predicts Hippocampal Activity.

Eye movements serve to accumulate information from the visual world, contributing to the formation of coherent memory representations that support cognition and behavior. The hippocampus and the oculomotor network are well connected anatomically through an extensive set of polysynaptic pathways. However, the extent to which visual sampling behavior is related to functional responses in the hippocampus during encoding has not been studied directly in human neuroimaging. In the current study, participants engaged in a face processing task while brain responses were recorded with fMRI and eye movements were monitored simultaneously. The number of gaze fixations that a participant made on a given trial was correlated significantly with hippocampal activation such that more fixations were associated with stronger hippocampal activation. Similar results were also found in the fusiform face area, a face-selective perceptual processing region. Notably, the number of fixations was associated with stronger hippocampal activation when the presented faces were novel, but not when the faces were repeated. Increases in fixations during viewing of novel faces also led to larger repetition-related suppression in the hippocampus, indicating that this fixation-hippocampal relationship may reflect the ongoing development of lasting representations. Together, these results provide novel empirical support for the idea that visual exploration and hippocampal binding processes are inherently linked. SIGNIFICANCE STATEMENT: The hippocampal and oculomotor networks have each been studied extensively for their roles in the binding of information and gaze function, respectively. Despite the evidence that individuals with amnesia whose damage includes the hippocampus show alterations in their eye movement patterns and recent findings that the two systems are anatomically connected, it has not been demonstrated whether visual exploration is related to hippocampal activity in neurologically intact adults. In this combined fMRI-eye-tracking study, we show how hippocampal responses scale with the number of gaze fixations made during viewing of novel, but not repeated, faces. These findings provide new evidence suggesting that the hippocampus plays an important role in the binding of information, as sampled by gaze fixations, during visual exploration.

Frontoparietal Functional Connectivity in the Common Marmoset.

In contrast to the well established macaque monkey, little is known about functional connectivity patterns of common marmoset monkey (Callithrix jacchus) that is poised to become the leading transgenic primate model. Here, we used resting-state ultra-high-field fMRI data collected from anesthetized marmosets and macaques along with awake human subjects, to examine and compare the brain's functional organization, with emphasis on the saccade system. Exploratory independent component analysis revealed eight resting-state networks in marmosets that greatly overlapped with corresponding macaque and human networks including a distributed frontoparietal network. Seed-region analyses of the superior colliculus (SC) showed homolog areas in macaques and marmosets. The marmoset SC displayed the strongest frontal functional connectivity with area 8aD at the border to area 6DR. Functional connectivity of this frontal region revealed a similar functional connectivity pattern as the frontal eye fields in macaques and humans. Furthermore, areas 8aD, 8aV, PG,TPO, TE2, and TE3 were identified as major hubs based on region-wise evaluation of betweeness centrality, suggesting that these cortical regions make up the functional core of the marmoset brain. The results support an evolutionarily preserved frontoparietal system and provide a starting point for invasive neurophysiological studies in the marmoset saccade and visual systems.

Shared sensory estimates for human motion perception and pursuit eye movements.

Are sensory estimates formed centrally in the brain and then shared between perceptual and motor pathways or is centrally represented sensory activity decoded independently to drive awareness and action? Questions about the brain's information flow pose a challenge because systems-level estimates of environmental signals are only accessible indirectly as behavior. Assessing whether sensory estimates are shared between perceptual and motor circuits requires comparing perceptual reports with motor behavior arising from the same sensory activity. Extrastriate visual cortex both mediates the perception of visual motion and provides the visual inputs for behaviors such as smooth pursuit eye movements. Pursuit has been a valuable testing ground for theories of sensory information processing because the neural circuits and physiological response properties of motion-responsive cortical areas are well studied, sensory estimates of visual motion signals are formed quickly, and the initiation of pursuit is closely coupled to sensory estimates of target motion. Here, we analyzed variability in visually driven smooth pursuit and perceptual reports of target direction and speed in human subjects while we manipulated the signal-to-noise level of motion estimates. Comparable levels of variability throughout viewing time and across conditions provide evidence for shared noise sources in the perception and action pathways arising from a common sensory estimate. We found that conditions that create poor, low-gain pursuit create a discrepancy between the precision of perception and that of pursuit. Differences in pursuit gain arising from differences in optic flow strength in the stimulus reconcile much of the controversy on this topic.

Visual sensitivity of frontal eye field neurons during the preparation of saccadic eye movements.

Primate vision is continuously disrupted by saccadic eye movements, and yet this disruption goes unperceived. One mechanism thought to reduce perception of this self-generated movement is saccadic suppression, a global loss of visual sensitivity just before, during, and after saccadic eye movements. The frontal eye field (FEF) is a candidate source of neural correlates of saccadic suppression previously observed in visual cortex, because it contributes to the generation of visually guided saccades and modulates visual cortical responses. However, whether the FEF exhibits a perisaccadic reduction in visual sensitivity that could be transmitted to visual cortex is unknown. To determine whether the FEF exhibits a signature of saccadic suppression, we recorded the visual responses of FEF neurons to brief, full-field visual probe stimuli presented during fixation and before onset of saccades directed away from the receptive field in rhesus macaques (Macaca mulatta) We measured visual sensitivity during both epochs and found that it declines before saccade onset. Visual sensitivity was significantly reduced in visual but not visuomotor neurons. This reduced sensitivity was also present in visual neurons with no movement-related modulation during visually guided saccades and thus occurred independently from movement-related activity. Across the population of visual neurons, sensitivity began declining ∼80 ms before saccade onset. We also observed a similar presaccadic reduction in sensitivity to isoluminant, chromatic stimuli. Our results demonstrate that the signaling of visual information by FEF neurons is reduced during saccade preparation, and thus these neurons exhibit a signature of saccadic suppression.

Distracted by danger: Temporal and spatial dynamics of visual selection in the presence of threat.

Threatening stimuli are known to influence attentional and visual processes in order to prioritize selection. For example, previous research showed faster detection of threatening relative to nonthreatening stimuli. This has led to the proposal that threatening stimuli are prioritized automatically via a rapid subcortical route. However, in most studies, the threatening stimulus is always to some extent task relevant. Therefore, it is still unclear if threatening stimuli are automatically prioritized by the visual system. We used the additional singleton paradigm with task-irrelevant fear-conditioned distractors (CS+ and CS-) and indexed the time course of eye movement behavior. The results demonstrate automatic prioritization of threat. First, mean latency of saccades directed to the neutral target was increased in the presence of a threatening (CS+) relative to a nonthreatening distractor (CS-), indicating exogenous attentional capture and delayed disengagement of covert attention. Second, more error saccades were directed to the threatening than to the nonthreatening distractor, indicating a modulation of automatically driven saccades. Nevertheless, cumulative distributions of the saccade latencies showed no modulation of threat for the fastest goal-driven saccades, and threat did not affect the latency of the error saccades to the distractors. Together these results suggest that threatening stimuli are automatically prioritized in attentional and visual selection but not via faster processing. Rather, we suggest that prioritization results from an enhanced representation of the threatening stimulus in the oculomotor system, which drives attentional and visual selection. The current findings are interpreted in terms of a neurobiological model of saccade programming.

Transcranial magnetic stimulation of the prefrontal cortex in awake nonhuman primates evokes a polysynaptic neck muscle response that reflects oculomotor activity at the time of stimulation.

Transcranial magnetic stimulation (TMS) has emerged as an important technique in cognitive neuroscience, permitting causal inferences about the contribution of a given brain area to behavior. Despite widespread use, exactly how TMS influences neural activity throughout an interconnected network, and how such influences ultimately change behavior, remain unclear. The oculomotor system of nonhuman primates (NHPs) offers a potential animal model to bridge this gap. Here, based on results suggesting that neck muscle activity provides a sensitive indicator of oculomotor activation, we show that single pulses of TMS over the frontal eye fields (FEFs) in awake NHPs evoked rapid (within ∼25 ms) and fairly consistent (∼50-75% of all trials) expression of a contralateral head-turning synergy. This neck muscle response resembled that evoked by subsaccadic electrical microstimulation of the FEF. Systematic variation in TMS location revealed that this response could also be evoked from the dorsolateral prefrontal cortex (dlPFC). Combining TMS with an oculomotor task revealed state dependency, with TMS evoking larger neck muscle responses when the stimulated area was actively engaged. Together, these results advance the suitability of the NHP oculomotor system as an animal model for TMS. The polysynaptic neck muscle response evoked by TMS of the prefrontal cortex is a quantifiable trial-by-trial reflection of oculomotor activation, comparable to the monosynaptic motor-evoked potential evoked by TMS of primary motor cortex. Our results also speak to a role for both the FEF and dlPFC in head orienting, presumably via subcortical connections with the superior colliculus.