Neuronal activity in the caudal frontal eye fields of monkeys during memory-based smooth pursuit eye movements: comparison with the supplementary eye fields

Recently, we examined the neuronal substrate of predictive pursuit during memory-based smooth pursuit and found that supplementary eye fields (SEFs) contain signals coding assessment and memory of visual motion direction, decision not-to-pursue ("no-go"), and preparation for pursuit. To determine whether these signals were unique to the SEF, we examined the discharge of 185 task-related neurons in the caudal frontal eye fields (FEFs) in 2 macaques. Visual motion memory and no-go signals were also present in the caudal FEF but compared with those in the SEF, the percentage of neurons coding these signals was significantly lower. In particular, unlike SEF neurons, directional visual motion responses of caudal FEF neurons decayed exponentially. In contrast, the percentage of neurons coding directional pursuit eye movements was significantly higher in the caudal FEF than in the SEF. Unlike SEF inactivation, muscimol injection into the caudal FEF did not induce direction errors or no-go errors but decreased eye velocity during pursuit causing an inability to compensate for the response delays during sinusoidal pursuit. These results indicate significant differences between the 2 regions in the signals represented and in the effects of chemical inactivation suggesting that the caudal FEF is primarily involved in generating motor commands for smooth-pursuit eye movements.     

The contribution of the human FEF and SEF to smooth pursuit initiation

Smooth pursuit eye movements function to keep moving targets foveated. Behavioral studies have shown that pursuit is particularly effective for predictable target motion. There is evidence that both the frontal eye field (FEF) and supplementary eye field (SEF) (also known as the dorsomedial frontal cortex) contribute to pursuit control. The goal of the current experiment was to determine whether these 2 areas made different contributions to the initiation of pursuit in response to predictable compared with unpredictable target motion. Transcranial magnetic stimulation (TMS) was used in 5 healthy human participants to temporarily disrupt each area around the time of target motion onset. TMS over the FEF delayed contraversive pursuit markedly more than ipsiversive pursuit and this direction-dependent difference was more deeply modulated during pursuit of unpredictable than predictable target motion. By contrast, TMS over the SEF resulted in a much more muted modulation of pursuit latency that was similar across both predictable and unpredictable conditions. Taken together, we conclude that the human FEF, but not the SEF, makes a significant contribution to the processing required during the preparation of contraversive pursuit responses to unpredictable target motion and this contribution is less vital during pursuit to predictable target motion.     

Smooth pursuit-related information processing in frontal eye field neurons that project to the NRTP

The cortical pursuit system begins the process of transforming visual signals into commands for smooth pursuit (SP) eye movements. The frontal eye field (FEF), located in the fundus of arcuate sulcus, is known to play a role in SP and gaze pursuit movements. This role is supported, at least in part, by FEF projections to the rostral nucleus reticularis tegmenti pontis (rNRTP), which in turn projects heavily to the cerebellar vermis. However, the functional characteristics of SP-related FEF neurons that project to rNRTP have never been described. Therefore, we used microelectrical stimulation (ES) to deliver single pulses (50-200 microA, 200-micros duration) in rNRTP to antidromically activate FEF neurons. We estimated the eye or retinal error motion sensitivity (position, velocity, and acceleration) of FEF neurons during SP using multiple linear regression modeling. FEF neurons that projected to rNRTP were most sensitive to eye acceleration. In contrast, FEF neurons not activated following ES of rNRTP were often most sensitive to eye velocity. In similar modeling studies, we found that rNRTP neurons were also biased toward eye acceleration. Therefore, our results suggest that neurons in the FEF-rNRTP pathway carry signals that could play a primary role in initiation of SP.     

TMS evidence for smooth pursuit gain control by the frontal eye fields

Smooth pursuit eye movements are used to continuously track slowly moving visual objects. A peculiar property of the smooth pursuit system is the nonlinear increase in sensitivity to changes in target motion with increasing pursuit velocities. We investigated the role of the frontal eye fields (FEFs) in this dynamic gain control mechanism by application of transcranial magnetic stimulation. Subjects were required to pursue a slowly moving visual target whose motion consisted of 2 components: a constant velocity component at 4 different velocities (0, 8, 16, and 24 deg/s) and a superimposed high-frequency sinusoidal oscillation (4 Hz, +/-8 deg/s). Magnetic stimulation of the FEFs reduced not only the overall gain of the system, but also the efficacy of the dynamic gain control. We thus provide the first direct evidence that the FEF population is significantly involved in the nonlinear computation necessary for continuously adjusting the feedforward gain of the pursuit system. We discuss this with relation to current models of smooth pursuit.     

Smooth-pursuit eye movement representation in the primate frontal eye field.

Physiological and behavioral data reported here show an involvement of the primate frontal eye field (FEF) cortex in smooth-pursuit eye movements, in addition to its well-established role in saccadic eye movements. Microstimulation just ventral to the small saccade representation of the FEF elicits eye movements that, in contrast to elicited saccades, have low velocities, continue smoothly without interruption during prolonged stimulation, and are usually directed ipsilaterally to the stimulated hemisphere. Neurons in this region respond in association with smooth-pursuit eye movements and visual motion. Tracking deficits following experimental lesions of the FEF depend critically upon the status of this ventral region: superficial lesions sparing it leave smooth-pursuit eye movements intact, whereas lesions removing it produce substantial deficits in the anticipatory initiation, motion-induced acceleration, asymptotic velocity, and predictive continuation of ipsilateral smooth pursuit.     

MEG tomography of human cortex and brainstem activity in waking and REM sleep saccades

We recorded the magnetoencephalographic (MEG) signal from three subjects before, during and after eye movements cued to a tone, self-paced, awake and during rapid eye movement (REM) sleep. During sleep we recorded the MEG signal throughout the night together with electroencephalographic (EEG) and electromyographic (EMG) channels to construct a hypnogram. While awake, just prior to and during eye movements, the expected well time-locked physiological activations were imaged in pontine regions, with early 3 s priming. Activity in the frontal eye fields (FEF) was identified in the 300 ms before the saccade onset. Visual cortex activation occurred 200 ms after saccades. During REM, compared to the eyes closed awake condition, activity was higher in supplementary motor area (SMA) and lower in inferior parietal and precuneus cortex. Electro-occulographic (EOG) activity just prior to REM saccades correlated with bilateral pontine and FEF activity some 250-400 ms before REM saccade onset, which in turn was preceded 200 ms earlier by reciprocal activation of the pons and FEF. An orbitofrontal-amygdalo-parahippocampal-pontine sequence, possibly related to emotional activation during REM sleep, was identified in the last 100 ms leading to the REM saccade, but not linked to saccade initiation.     

Brain and behavior: a task-dependent eye movement study

Recent electrophysiological and behavioral studies have found similarities in the neurology of pursuit and saccadic eye movements. In a previous study on eye movements using closely matched paradigms for pursuit and saccades, we revealed that both exhibit bimodal distributions of latency to predictable (PRD) and randomized (RND) stimuli; however, the latency to each type of stimulus was different, and there was more segregation of latencies in saccades than pursuit (Burke MR, Barnes GR. 2006. Quantitative differences in smooth pursuit and saccadic eye movements in humans. Exp Brain Res. 175(4):596-608). To investigate the brain areas involved in these tasks, and to search for correlates of behavior, we used functional magnetic resonance imaging during equivalent PRD and RND target presentations. In the contrast pursuit > saccades, which reflects velocity-dependent versus position-dependent activities, respectively, we found higher activation in the dorsolateral prefrontal cortex (DLPFC) for pursuit and in the frontopolar region for saccades. In the contrast RND > PRD, which principally reflects activation related to visually driven versus memory-driven responses, respectively, we found a higher sustained level of activation in the frontal eye fields during visually guided eye movements. The reverse contrast revealed higher activity for the memory-guided responses in the supplementary eye fields and the superior parietal lobe. In addition, we found learning-related activation during the PRD condition in visual area V5, the DLPFC, and the cerebellum.     

Involvement of the cerebellar dorsal vermis in vergence eye movements in monkeys

Frontal-eyed primates use both smooth pursuit in frontoparallel planes (frontal pursuit) and pursuit-in-depth (vergence pursuit) to track objects moving slowly in 3-dimensional (3D) space. To understand how 3D-pursuit signals represented in frontal eye fields are processed further by downstream pathways, monkeys were trained to pursue a spot moving in 3D virtual space. We characterized pursuit signals in Purkinje (P) cells in the cerebellar dorsal vermis and their discharge during vergence pursuit. In 41% of pursuit P-cells, 3D-pursuit signals were observed. However, the majority of vermal-pursuit P-cells (59%) discharged either for vergence pursuit (43%) or for frontal pursuit (16%). Moreover, the majority (74%) of vergence-related P-cells carried convergence signals, displaying both vergence eye position and velocity sensitivity during sinusoidal and step vergence eye movements. Preferred frontal-pursuit directions of vergence + frontal-pursuit P-cells were distributed in all directions. Most pursuit P-cells (73%) discharged before the onset of vergence eye movements; the median lead time was 16 ms. Muscimol infusion into the sites where convergence P-cells were recorded resulted in a reduction of peak convergence eye velocity, of initial convergence eye acceleration, and of frontal-pursuit eye velocity. These results suggest involvement of the dorsal vermis in conversion of 3D-pursuit signals and in convergence eye movements.     

The location probability effects of saccade reaction times are modulated in the frontal eye fields but not in the supplementary eye field

The visual system constantly utilizes regularities that are embedded in the environment and by doing so reduces the computational burden of processing visual information. Recent findings have demonstrated that probabilistic information can override attentional effects, such as the cost of making an eye movement away from a visual target (antisaccade cost). The neural substrates of such probability effects have been associated with activity in the superior colliculus (SC). Given the immense reciprocal connections to SC, it is plausible that this modulation originates from higher oculomotor regions, such as the frontal eye field (FEF) and the supplementary eye field (SEF). To test this possibility, the present study employed theta burst transcranial magnetic stimulation (TMS) to selectively interfere with FEF and SEF activity. We found that TMS disrupted the effect of location probability when TMS was applied over FEF. This was not observed in the SEF TMS condition. Together, these 2 experiments suggest that the FEF plays a critical role not only in initiating saccades but also in modulating the effects of location probability on saccade production.     

Representing Spatial Information for Limb Movement: Role of Area 5 in the Monkey

How is spatial information for limb movement encoded in thebrain? Computational and psychophysical studies suggest thatbeginning hand position, via-points, and target are specifiedrelative to the body to afford a comparison between the sensory(e. g., kinesthetic) reaf-ferences and the commands that generatelimb movement Here we propose that the superior parietal lobule(Brodmann area 5) might represent a substrata for a body-centeredpositional code. Monkeys made arm movements in different partsof 3D space in a reaction-time task. We found that the activityof area 5 neurons can be related to either the starting pointor the final point or combinations of the two. Neural activityis monotonicalty tuned in a body-centered frame of reference,whose coordinates define the azimuth, elevation, and distanceof the hand. Each spatial coordinate tends to be encoded ina different sub-population of neurons. This parcellation couldbe a neural correlate of the psychophysical observation thatthese spatial parameters are processed in parallel and largelyindependent of each other in man.     

Brain activation related to combinations of gaze position, visual input, and goal-directed hand movements

Humans reach to and acquire objects by transforming visual targets into action commands. How the brain integrates goals specified in a visual framework to signals into a suitable framework for an action plan requires clarification whether visual input, per se, interacts with gaze position to formulate action plans. To further evaluate brain control of visual-motor integration, we assessed brain activation, using functional magnetic resonance imaging. Humans performed goal-directed movements toward visible or remembered targets while fixating gaze left or right from center. We dissociated movement planning from performance using a delayed-response task and manipulated target visibility by its availability throughout the delay or blanking it 500 ms after onset. We found strong effects of gaze orientation on brain activation during planning and interactive effects of target visibility and gaze orientation on movement-related activation during performance in parietal and premotor cortices (PM), cerebellum, and basal ganglia, with more activation for rightward gaze at a visible target and no gaze modulation for movements directed toward remembered targets. These results demonstrate effects of gaze position on PM and movement-related processes and provide new information how visual signals interact with gaze position in transforming visual inputs into motor goals.     

Theta-burst stimulation over human frontal cortex distorts perceptual stability across eye movements

We perceive a stable outside world despite the constant changes of visual input induced by our eye movements. Internal monitoring of a corollary discharge associated with oculomotor commands may help to anticipate the perceptual consequences of impending eye movements. The primate frontal eye fields have repeatedly been presumed to participate in the maintenance of perceptual stability across eye movements. However, a direct link between integrity of frontal oculomotor areas and perceptual stability is missing so far. Here, we show that transcranial magnetic stimulation (TMS) over the right human frontal cortex impairs the integration of visual space across eye movements. We asked 9 healthy subjects to report the direction of transsaccadic stimulus displacements and applied TMS before the actual experiment in a novel offline stimulation protocol, continuous theta-burst stimulation (cTBS). A systematic perceptual distortion was observed after stimulation over the right frontal cortex that was best explained by an internal underestimation of executed eye movement amplitudes. cTBS apparently disturbed an internal prediction process for contraversive saccades, while the metrics of associated oculomotor actions remained unchanged. Our findings suggest an important role of the frontal cortex in the internal monitoring of oculomotor actions for the perceptual integration of space across eye movements.     

Modulation of visual responses in macaque frontal eye field during covert tracking of invisible targets

The purpose of this study was to investigate the interaction between internal representations of invisible moving targets and visual responses of neurons in frontal eye fields (FEFs). Monkeys were trained to make saccades to the extrapolated position of a target that was temporarily rendered invisible for variable durations as if it had passed behind an occluder. Flashed, task-irrelevant visual probe stimuli were used to study the visual responsiveness of FEF neurons during this task. Probes were flashed at various times and locations during the occlusion interval. Net changes in neuronal activity were obtained by comparing the activity on trials with probes with randomly interleaved trials without any probe. Most neurons showed an increase in firing rate in response to the probe, but some showed a decrease. Both types of responses were enhanced when the invisible target moved toward the receptive field (RF) as compared with trials on which the target moved away from the RF. Some neurons showed a spatial shift in the visual response during the occlusion interval. For cells that were excited by the probe, the shift tended to be correlated with the direction of motion of the target, whereas for cells that were inhibited the shift tended to be in the opposite direction. These results suggest that the role of FEF in predicting invisible target motion includes a sensory/perceptual component.     

The ability of bispectral index to detect intra‐operative wakefulness during total intravenous anaesthesia compared with the isolated forearm technique

It has been suggested that monitoring during total intravenous anaesthesia should include aspects of brain function. The current study used a manually adjusted target‐controlled infusion of propofol for anaesthesia, guided to a bispectral index range of 55–60. Intra‐operative responsiveness, as assessed by the isolated forearm technique, was compared with whether the bispectral index predicted/identified a patient's appropriate hand movements in responses to commands. Twenty‐two women underwent major gynaecological surgery with total intravenous anaesthesia, propofol, remifentanil and atracurium. Sixteen women responded, on 80 occasions, with appropriate hand movements to commands during surgery, of which the bispectral index detected 47 (sensitivity 59%). The bispectral index suggested consciousness 220 times in the absence of movement responses (specificity 85%). The positive predictive value of a bispectral index response was 18%. While two women had vague recall about squeezing fingers, none had recall of surgery. For patients who responded more than once during surgery the bispectral index value associated with a response was not constant. Although there was no difference in the median (IQR [range]) effect site propofol concentration between intra‐operative responses (2.0 (1.5–2.3 [1.2–4.0]) μg.ml^?1) and eye opening after surgery (2.1 (1.7–2.8 [1.5–3.9]) μg.ml^?1), the median (IQR [range]) bispectral index value at eye opening after surgery was significantly higher than that associated with responses during surgery: 75 (70–78 [51–93]) vs 61 (52–67 [37–80]) respectively, (p < 0.001). The manual control of propofol intravenous anaesthesia to target a bispectral index range of 55–60 may result in an unacceptable number of patients who are conscious during surgery (albeit without recall).     

Temporal evolution and strength of neural activity in parietal cortex during eye and hand movements

The role of area 7a in eye-hand movement was studied by recording from individual neurons while monkeys performed 7 different tasks, aimed at assessing the relative influence of retinal, eye, and hand information on neural activity. Parietal cell activity was modulated by visuospatial signals about target location, as well as by information concerning eye and/or hand movement, and position. The highest activity was elicited when the hand moved to the fixation point. The population activities across different memory tasks showed common temporal peaks when aligned to the visual instruction (visuospatial peak) or Go signal (motor peak) for eye, hand, and coordinated eye-hand movement. The motor peak was higher for coordinated eye-hand movement, and it was absent in a No-Go task. Two activation maxima were also observed during visual reaching. They had the same latency of the visuospatial and motor peaks seen in the memory tasks. Therefore, area 7a seems to operate through a common neural mechanism underlying eye, hand, or combined eye-hand movement. This mechanism is revealed by invariant temporal activity profiles and is independent from the effector selected and from the presence or absence of a visible target during movement. For comparative purposes, we have studied the temporal evolution of the population activity in the superior parietal lobule (SPL) during the same reaching tasks and during a saccade task. In SPL, the population activity was characterized by a single peak, time locked to the Go signal for eye, hand, or combined eye-hand movement. As in IPL, the time of occurrence of this peak was effector independent. The population activity remained unchanged when the position of the eye changed, suggesting that SPL is mostly devoted to the hand motor behavior.     

Neural activity in primate parietal area 7a related to spatial analysis of visual mazes

Cognitive psychological studies of humans and monkeys solving visual mazes have provided evidence that a covert analysis of the maze takes place during periods of eye fixation interspersed between saccades, or when mazes are solved without eye movements. We investigated the neural basis of this process in posterior parietal cortex by recording the activity of single neurons in area 7a during maze solution. Monkeys were required to determine from a single point of fixation whether a critical path through the maze reached an exit or a blind ending. We found that during this process the activity of approximately one in four neurons in area 7a was spatially tuned to maze path direction. We obtained evidence that path tuning did not reflect a covert saccade plan insofar as the majority of neurons active during maze solution were not active on a delayed-saccade control task, and the minority that were active on both tasks did not exhibit congruent spatial tuning in the two conditions. We also obtained evidence that path tuning during maze solution was not due to the locations of visual receptive fields mapped outside the behavioral context of maze solution, in that receptive field centers and preferred path directions were not spatially aligned. Finally, neurons tuned to path direction were not present in area 7a when a na?ve animal viewed the same visual maze stimuli but did not solve them. These data support the hypothesis that path tuning in parietal cortex is not due to the lower level visual features of the maze stimulus, but rather is associated with maze solution, and as such, reflects a cognitive process applied to a complex visual stimulus.     

The ability of bispectral index to detect intra‐operative wakefulness during isoflurane/air anaesthesia,compared with the isolated forearm technique

Clinical signs are unreliable for guiding anaesthetic administration and it is suggested that using the bispectral index can improve anaesthetic delivery. In the current study, isoflurane administration was guided to a bispectral index range of 55–60. Intra‐operative responsiveness, as assessed by the isolated forearm technique, was compared with whether the bispectral index predicted/identified a patient's appropriate hand movements in response to commands. Thirty‐four women underwent major gynaecological surgery with isoflurane/air and atracurium. Eleven women responded on 32 occasions with appropriate hand movements to commands given during surgery, of which the bispectral index detected 17 (sensitivity 53%). The bispectral index suggested consciousness 660 times in the absence of any movement responses (specificity 69%). The positive predictive value of the bispectral index was 3%. The median (IQR [range]) bispectral index value associated with an intra‐operative response was significantly lower than that associated with eye opening after surgery: 60 (50–68 [36–83]) vs 77 (75–84 [59–90]), respectively (p = 2.25 × 10^?8). Conversely, end‐tidal isoflurane concentration was significantly higher at intra‐operative response than at eye opening: 0.3 (0.3–0.4 [0.2–0.9]) vs 0.2 (0.1–0.2 [0.1–0.3]), respectively (p = 7.36 × 10^?8). For patients who responded more than once during surgery, the bispectral index value associated with a response was not constant. No patient had recall for surgery or the taped commands, and only one could remember dreaming (a good dream). Titrating isoflurane to target a bispectral index range of 55–60 may result in an unacceptable number of patients who are conscious during surgery (albeit without recall).     

Behavioral influences on cortical neuronal responses to optic flow

Optic flow selectively activates neurons in medial superior temporal (MST) cortex. We find that many MST neurons yield larger and more selective responses when the optic flow guides a subsequent eye movement. Smaller, less selective responses are seen when optic flow is preceded by a flashed precue that guides eye movements. Selectivity can decrease by a third (32%) after a flashed precue is presented at a peripheral location as a small spot specifying the target location of the eye movement. Smaller decreases in selectivity (18%) occur when the precue is presented centrally with its shape specifying the target location. Shape precues presented centrally, but not linked to specific target locations, do not appear to alter optic flow selectivity. The effects of spatial precueing can be reversed so that the precue leads to larger and more selective optic flow responses: A flashed precue presented as a distracter before behaviorally relevant optic flow is associated with larger optic flow responses and a 45% increase in selectivity. Together, these findings show that spatial precues can decrease or increase the size and selectivity of optic flow responses depending on the associated behavioral contingencies.     

Multiple levels of representation of reaching in the parieto-frontal network

In daily life, hand and eye movements occur in different contexts. Hand movements can be made to a visual target shortly after its presentation, or after a longer delay; alternatively, they can be made to a memorized target location. In both instances, the hand can move in a visually structured scene under normal illumination, which allows visual monitoring of its trajectory, or in darkness. Across these conditions, movement can be directed to points in space already foveated, or to extrafoveal ones, thus requiring different forms of eye-hand coordination. The ability to adapt to these different contexts by providing successful answers to their demands probably resides in the high degree of flexibility of the operations that govern cognitive visuomotor behavior. The neurophysiological substrates of these processes include, among others, the context-dependent nature of neural activity, and a transitory, or task-dependent, affiliation of neurons to the assemblies underlying different forms of sensorimotor behavior. Moreover, the ability to make independent or combined eye and hand movements in the appropriate order and time sequence must reside in a process that encodes retinal-, eye- and hand-related inputs in a spatially congruent fashion. This process, in fact, requires exact knowledge of where the eye and the hand are at any given time, although we have no or little conscious experience of where they stay at any instant. How this information is reflected in the activity of cortical neurons remains a central question to understanding the mechanisms underlying the planning of eye-hand movement in the cerebral cortex. In the last 10 years, psychophysical analyses in humans, as well as neurophysiological studies in monkeys, have provided new insights on the mechanisms of different forms of oculo-manual actions. These studies have also offered preliminary hints as to the cortical substrates of eye-hand coordination. In this review, we will highlight some of the results obtained as well as some of the questions raised, focusing on the role of eye- and hand-tuning signals in cortical neural activity. This choice rests on the crucial role this information exerts in the specification of movement, and coordinate transformation.