Response properties of saccade-related neurons of the post-arcuate premotor cortex.

We studied the phasic saccade-related discharges of single neurons (S neurons) of the premotor cortex of female rhesus monkeys, mostly in the caudal bank of the arcuate sulcus. As described in previous work from our laboratory (Neromyliotis E, Moschovakis AK. Front Behav Neurosci 11: 1-21, 2017), some of these cells emitted phasic discharges for coordinated movements of the eyes and hand as well as for movements of either effector executed in isolation (motor equivalence, Meq). Other cells (S) did not emit phasic discharges for hand movements unaccompanied by saccades. In contrast to frontal eye field (FEF) neurons, but similar to forelimb-related neurons (H neurons) and Meq cells, the discharges of S cells did not display contralateral bias; their on-directions were as likely to be ipsiversive as contraversive. Because the onset of their discharge preceded that of FEF neurons, S cells are unlikely to convey to their targets corollary discharges of the FEF. We also encountered a small number of neurons that could function as logic gates: cells that discharged for saccades if they were not accompanied by hand movements, cells that discharged for saccades or movements of the hand but not for coordinated movements of both effectors, and cells that discharged only for coordinated movements of the eyes and the hand but not when one of the effectors moved unaccompanied by the other. Our findings are discussed in terms of sequences of decision processes stitching effector-specific motor plans onto effector-invariant movement primitives. NEW & NOTEWORTHY The premotor cortex, traditionally associated with skeletomotor control, is shown to contain cells that emit strong discharges time-linked to saccades but not for hand movements unaccompanied by saccades (S cells). Unlike frontal eye field (FEF) neurons, the S cells of the premotor cortex did not display contralateral bias, and because their presaccadic discharges preceded those of FEF neurons, they are unlikely to serve as conveyors of FEF efferent discharges.

Saccades evoked in response to electrical stimulation of the posterior bank of the arcuate sulcus.

To test the hypothesis that the premotor cortex in and behind the caudal bank of the arcuate sulcus can generate saccades, we stimulated electrically the periarcuate region of alert rhesus monkeys. We were able to produce saccades from sites of the premotor cortex that were contiguous with the frontal eye fields and extended up to 2 mm behind the smooth pursuit area. However, premotor sites often elicited saccades with ipsiversive characteristic vectors, lower peak velocities, and flatter velocity profiles when compared to saccades evoked from the frontal eye field.

Response Properties of Motor Equivalence Neurons of the Primate Premotor Cortex.

To study the response properties of cells that could participate in eye-hand coordination we trained two macaque monkeys to perform center-out saccades and pointing movements with their right or left forelimb toward visual targets presented on a video display. We analyzed the phasic movement related discharges of neurons of the periarcuate cortex that fire before and during saccades and movements of the hand whether accompanied by movements of the other effector or not. Because such cells could encode an abstract form of the desired displacement vector without regard to the effector that would execute the movement we refer to such cells as motor equivalence neurons (Meq). Most of them (75%) were found in or near the smooth pursuit region and the grasp related region in the caudal bank of the arcuate sulcus. The onset of their phasic discharges preceded saccades by about 70 ms and hand movements by about 150 ms and was often correlated to both the onset of saccades and the onset of hand movements. The on-direction of Meq cells was uniformly distributed without preference for ipsiversive or contraversive movements. In about half of the Meq cells the preferred direction for saccades was the preferred direction for hand movements as well. In the remaining cells the difference was considerable (>90 deg), and the on-direction for eye-hand movements resembled that for isolated saccades in some cells and for isolated hand movements in others. A three layer neural network model that used Meq cells as its input layer showed that the combination of effector invariant discharges with non-invariant discharges could help reduce the number of decoding errors when the network attempts to compute the correct movement metrics of the right effector.

Neural network simulations of the primate oculomotor system. V. Eye-head gaze shifts.

We examined the performance of a dynamic neural network that replicates much of the psychophysics and neurophysiology of eye-head gaze shifts without relying on gaze feedback control. For example, our model generates gaze shifts with ocular components that do not exceed 35 degrees in amplitude, whatever the size of the gaze shifts (up to 75 degrees in our simulations), without relying on a saturating nonlinearity to accomplish this. It reproduces the natural patterns of eye-head coordination in that head contributions increase and ocular contributions decrease together with the size of gaze shifts and this without compromising the accuracy of gaze realignment. It also accounts for the dependence of the relative contributions of the eyes and the head on the initial positions of the eyes, as well as for the position sensitivity of saccades evoked by electrical stimulation of the superior colliculus. Finally, it shows why units of the saccadic system could appear to carry gaze-related signals even if they do not operate within a gaze control loop and do not receive head-related information.

Eye position modulates the electromyographic responses of neck muscles to electrical stimulation of the superior colliculus in the alert cat.

Rapid gaze shifts are often accomplished with coordinated movements of the eyes and head, the relative amplitude of which depends on the starting position of the eyes. The size of gaze shifts is determined by the superior colliculus (SC) but additional processing in the lower brain stem is needed to determine the relative contributions of eye and head components. Models of eye-head coordination often assume that the strength of the command sent to the head controllers is modified by a signal indicative of the eye position. Evidence in favor of this hypothesis has been recently obtained in a study of phasic electromyographic (EMG) responses to stimulation of the SC in head-restrained monkeys (Corneil et al. in J Neurophysiol 88:2000-2018, 2002b). Bearing in mind that the patterns of eye-head coordination are not the same in all species and because the eye position sensitivity of phasic EMG responses has not been systematically investigated in cats, in the present study we used cats to address this issue. We stimulated electrically the intermediate and deep layers of the caudal SC in alert cats and recorded the EMG responses of neck muscles with horizontal and vertical pulling directions. Our data demonstrate that phasic, short latency EMG responses can be modulated by the eye position such that they increase as the eye occupies more and more eccentric positions in the pulling direction of the muscle tested. However, the influence of the eye position is rather modest, typically accounting for only 10-50% of the variance of EMG response amplitude. Responses evoked from several SC sites were not modulated by the eye position.

The local loop of the saccadic system closes downstream of the superior colliculus.

Models of the saccadic system differ in several respects including the signals fed back to their comparators, as well as the location and identity of the units that could serve as comparators. Some models place the comparator in the superior colliculus while others assign this role to the reticular formation. To test the plausibility of reticular models we stimulated electrically efferent fibers of the superior colliculus (SC) of alert cats along their course through the pons, in the predorsal bundle (PDB). Our data demonstrate that electrical stimulation of the PDB evokes saccades, even with stimuli of relatively low frequency (100 Hz), which are often accompanied by slow drifts. The velocity and latency of saccades are influenced by the intensity and frequency of stimulation while their amplitude depends on the intensity of stimulation and the initial position of the eyes. The dynamics of evoked saccades are comparable to those of natural, self-generated saccades of the cat and to those evoked in response to the electrical stimulation of the SC. We also show that PDB-evoked saccades are not abolished by lesions of the SC and that therefore antidromic activation of the SC is not needed for their generation. Our data clearly demonstrate that the burst generator of the horizontal saccadic system is located downstream of the SC. If it is configured as a local loop controller, as assumed by most models of the saccadic system, our data also demonstrate that its comparator is located beyond the decussation of SC efferent fibers, in the pons.

Implications of interrupted eye-head gaze shifts for resettable integrator reset.

The neural circuit responsible for saccadic eye movements is generally thought to resemble a closed loop controller. Several models of the saccadic system assume that the feedback signal of such a controller is an efference copy of "eye displacement", a neural estimate of the distance already travelled by the eyes, provided by the so-called "resettable integrator" (RI). The speed, with which the RI is reset, is thought to be fast or instantaneous by some authors and gradual by others. To examine this issue, psychophysicists have taken advantage of the target-distractor paradigm. Subjects engaged in it, are asked to look to only one of two stimuli (the "target") and not to a distractor presented in the diametrically opposite location and they often generate movement sequences in which a gaze shift towards the "distractor" is followed by a second gaze shift to the "target". The fact that the second movement is not systematically erroneous even when very short time intervals (about 5 ms) separate it from the first movement has been used to question the verisimilitude of gradual RI reset. To explore this matter we used a saccade-generating network that relies on a RI coupled to a head controller and a model of the rotational vestibulo-ocular reflex. An analysis of the activation functions of model units provides disproof by counterexample: "targets" can be accurately acquired even when the RI of the saccadic burst generator is not reset at all after the end of the first, interrupted eye-head gaze shift to the distractor and prior to the second, complete eye-head gaze shift to the "target".

Functional imaging of the intraparietal cortex during saccades to visual and memorized targets.

The representation of perceived space and intended actions in the primate parietal cortex has been the subject of considerable debate. To address this issue, we used the quantitative 14C-deoxyglucose method to obtain maps of the activity pattern in the intraparietal cortex of rhesus monkeys executing saccades to visual and memorized targets. The principal effect induced by memory-guided saccades was found more caudally in the deepest part of the middle third of the lateral bank (within area LIPv) whereas that induced by visually guided saccades extended more rostrally and superficially in the anterior third of the bank (within area LIPd). The memory-saccade-related and the visual-saccade-related regions of activation overlapped only within area LIPv. Besides saccade execution, maximal activity in area LIPd required a visual stimulus. The region activated by visual fixation was located at the border of LIPv and LIPd, extending mainly within area LIPd, and occupying about one third of the neural space of the region activated for visual-saccades. We suggest that the lateral intraparietal cortex represents visual and motor space in segregated, albeit partially overlapping, regions.

Oculomotor areas of the primate frontal lobes: a transneuronal transfer of rabies virus and [14C]-2-deoxyglucose functional imaging study.

We used the [14C]-2-deoxyglucose method to study the location and extent of primate frontal lobe areas activated for saccades and fixation and the retrograde transneuronal transfer of rabies virus to determine whether these regions are oligosynaptically connected with extraocular motoneurons. Fixation-related increases of local cerebral glucose utilization (LCGU) values were found around the fundus of the inferior limb of the arcuate sulcus (AS) just ventral to its genu, in the dorsomedial frontal cortex (DMFC), cingulate cortex, and orbitofrontal cortex. Significant increases of LCGU values were found in and around both banks of the AS, DMFC, and caudal principal, cingulate, and orbitofrontal cortices of monkeys executing visually guided saccades. All of these areas are oligosynaptically connected to extraocular motoneurons, as shown by the presence of retrogradely transneuronally labeled cells after injection of rabies virus in the lateral rectus muscle. Our data demonstrate that the arcuate oculomotor cortex occupies a region considerably larger than the classic, electrical stimulation-defined, frontal eye field. Besides a large part of the anterior bank of the AS, it includes the caudal prearcuate convexity and part of the premotor cortex in the posterior bank of the AS. They also demonstrate that the oculomotor DMFC occupies a small area straddling the ridge of the brain medial to the superior ramus of the AS. Our results support the notion that a network of several interconnected frontal lobe regions is activated during rapid, visually guided eye movements and that their output is conveyed in parallel to subcortical structures projecting to extraocular motoneurons.

Neural network simulations of the primate oculomotor system IV. A distributed bilateral stochastic model of the neural integrator of the vertical saccadic system.

The present report examines the performance of a distributed bi-directional neural network that simulates the vertical velocity to position integrator of the primate brain. Consistent with anatomy and physiology, its units receive stochastically weighted input from vertical medium-lead burst neurons. Also consistent with anatomy, units belonging to integrators with opposite on-directions (up or down) are interconnected via the posterior commissure (again in a stochastically weighted manner) and they can be excitatory or inhibitory. To demonstrate that integration can be a one-step process, the output of model units was routed directly to vertical motoneurons. Model units replicate the wide range of saccade-related discharge patterns encountered in the portion of the primate brain that is thought to house the vertical neural integrator (the interstitial nucleus of Cajal) while "lesions" of model units and/or their interconnections replicate the symptoms which follow insults to this brain area.

Functional imaging of the primate superior colliculus during saccades to visual targets.

The primate superior colliculus (SC) is a midbrain nucleus crucial for the control of rapid eye movements (saccades). Its neurons are topographically arranged over the rostrocaudal and mediolateral extent of its deeper layers so that saccade metrics (amplitude and direction) are coded in terms of the location of active neurons. We used the quantitative [14C]-deoxyglucose method to obtain a map of the two-dimensional pattern of activity throughout the SC of rhesus monkeys repeatedly executing visually guided saccades of the same amplitude and direction for the duration of the experiment. Increased metabolic activity was confined to a circumscribed region of the two-dimensional reconstructed map of the SC contralateral to the direction of the movement. The precise rostrocaudal and mediolateral location of the area activated depended on saccade metrics. Our data support the notion that the population of active SC cells remains stationary in collicular space during saccades.

Anatomy and physiology of the primate interstitial nucleus of Cajal. II. Discharge pattern of single efferent fibers.

Anatomy and physiology of the primate interstitial nucleus of Cajal. II. Discharge pattern of single efferent fibers. J. Neurophysiol. 80: 3100-3111, 1998. Single efferent fibers of the interstitial nucleus of Cajal (NIC) were characterized physiologically and injected with biocytin in alert behaving monkeys. Quantitative analysis demonstrated that their discharge encodes a constellation of oculomotor variables. Tonic and phasic signals were related to vertical (up or down) eye position and saccades, respectively. Depending on how they encoded eye position, saccade velocity, saccade size, saccade duration, and smooth-pursuit eye velocity, fibers were characterized as regular or irregular, bi- or unidirectionally modulated, more or less sensitive, and reliable or unreliable. Further, fibers that did not burst for saccades (tonic) and fibers the eye-position and saccade-related signals of which increased in the same (in-phase) or in the opposite (anti-phase) directions were encountered. A continuum of discharge properties was the rule. We conclude that NIC efferent fibers send a combination of eye-position, saccade-, and smooth-pursuit-related signals, mixed in proportions that differ for different fibers, to targets of the vertical neural integrator such as extraocular motoneurons.

New mechanism that accounts for position sensitivity of saccades evoked in response to stimulation of superior colliculus.

New mechanism that accounts for position sensitivity of saccades evoked in response to stimulation of superior colliculus. J. Neurophysiol. 80: 3373-3379, 1998. Electrical stimulation of the feline superior colliculus (SC) is known to evoke saccades whose size depends on the site stimulated (the "characteristic vector" of evoked saccades) and the initial position of the eyes. Similar stimuli were recently shown to produce slow drifts that are presumably caused by relatively direct projections of the SC onto extraocular motoneurons. Both slow and fast evoked eye movements are similarly affected by the initial position of the eyes, despite their dissimilar metrics, kinematics, and anatomic substrates. We tested the hypothesis that the position sensitivity of evoked saccades is due to the superposition of largely position-invariant saccades and position-dependent slow drifts. We show that such a mechanism can account for the fact that the position sensitivity of evoked saccades increases together with the size of their characteristic vector. Consistent with it, the position sensitivity of saccades drops considerably when the contribution of slow drifts is minimal as, for example, when there is no overlap between evoked saccades and short-duration trains of high-frequency stimuli.

An anatomical substrate for the spatiotemporal transformation.

The purpose of the present experiments was to test the hypothesis that the metrics of saccades caused by the activation of distinct collicular sites depend on the strength of their projections onto the burst generators. This study of morphofunctional correlations was limited to the horizontal components of saccades. We evoked saccades by stimulation of the deeper layers of the superior colliculus (SC) in alert, head-fixed cats. We used standard stimulus trains of 350 msec duration, 200 Hz pulse rate, and intensity set at two times saccade threshold in all experiments. Evoked saccades were analyzed quantitatively to determine the amplitude of the horizontal component of their "characteristic vectors". This parameter is independent of eye position and was used as the physiological, saccade-related metric of the stimulation sites. Anatomical connections arising from these sites were visualized after anterograde transport of biocytin injected through a micropipette adjoining the stimulation electrode. The stimulation and injection sites were, therefore, practically identical. We counted boutons deployed in regions of the paramedian pontine reticular formation reported to contain long-lead and medium-lead burst neurons of the horizontal burst generator. Regression analysis of the normalized bouton counts revealed a significant positive correlation with the size of the horizontal component of the characteristic vectors. This data supports a frequent modelling assumption that the spatiotemporal transformation in the saccadic system relies on the graded strength of anatomical projections of distinct SC sites onto the burst generators.

Neural network simulations of the primate oculomotor system. III. An one-dimensional, one-directional model of the superior colliculus.

This report evaluates the performance of a biologically motivated neural network model of the primate superior colliculus (SC). Consistent with known anatomy and physiology, its major features include excitatory connections between its output elements, nigral gating mechanisms, and an eye displacement feedback of reticular origin to recalculate the metrics of saccades to memorized targets in retinotopic coordinates. Despite the fact that it makes no use of eye position or eye velocity information, the model can account for the accuracy of saccades in double step stimulation experiments. Further, the model accounts for the effects of focal SC lesions. Finally, it accounts for the properties of saccades evoked in response to the electrical stimulation of the SC. These include the approximate size constancy of evoked saccades despite increases of stimulus intensity, the fact that the size of evoked saccades depends on the time that has elapsed from a previous saccade, the fact that staircases of saccades are evoked in response to prolonged stimuli, and the fact that the size of saccades evoked in response to the simultaneous stimulation of two SC sites is the average of the saccades that are evoked when the two sites are separately stimulated.

The neural integrators of the mammalian saccadic system.

The neural velocity to position integrators transform the saccade related signal of the burst generators into an eye position related tonic signal they convey to motoneurons. They are largely confined to three heavily interconnected midbrain structures: 1) The interstitial nucleus of Cajal (NIC), 2) The nucleus prepositus hypoglossi (NPH), 3) The vestibular nuclei (VN). Integration in the horizontal and vertical planes is accomplished largely independently by the NPH-VN and the NIC-VN complexes, respectively. Cells in these regions carry a more or less intense phasic signal related to saccades and a tonic signal related to eye position. Depending on the relationship between the rate of their discharge and the position of the eyes, these cells have been further subdivided into regular or irregular, more or less sensitive, and bi-directionally or uni-directionally modulated. The present review provides a brief description of their discharge pattern and that of burst neurons and extraocular motoneurons. Then, evidence concerning the input-output connections of relevant cell classes is summarized. Finally, several modelling attempts to simulate the neural velocity-to-position integrators are presented and their verisimilitude is evaluated in the light of psychophysical, anatomical, physiological and neurological evidence.

The superior colliculus and eye movement control.

Saccade metrics are largely determined by command signals generated in the superior colliculus. Recent work has improved our knowledge of the highly complex axonal trees that disseminate these signals. It has also demonstrated that electrical stimulation of the superior colliculus evokes slow (drifts) as well as fast (saccades) eye movements and has provided detailed quantitative descriptions of their metrical properties. New biologically influenced models of the superior colliculus provide a detailed and realistic account of the discharge of tectal pre-saccadic neurons, the properties of evoked saccades and the ability of subjects to execute correct saccades in a variety of circumstances.

The microscopic anatomy and physiology of the mammalian saccadic system.

A central goal of the Neurosciences is to provide an account of how the brain works in terms of cell groups organised into pattern generating networks. This review focuses on the neural network that generates the rapid movements of the eyes that are called saccades. A brief description of the metrical and dynamical properties of saccades is provided first. Data obtained from lesion and electrical stimulation experiments are then described; these indicate that the relevant neural machinery spreads over at least 10 distinct cortical and subcortical regions of the brain. Each one of these regions harbors several distinct classes of saccade related cells (i.e. cells whose discharge encodes the metrical and often dynamical properties of saccades). The morphological and physiological properties of about 30 saccade related cell classes are described. To generate the signals they carry, and therefore saccades, distinct classes of cells influence each other in a non-random manner. Anatomical evidence is provided that indicates the existence of about 100 distinct connections established between saccade related neurons. The overall picture of the saccadic system that emerges from these studies is one of intricate complexity. In part this is due to the presence of at least 3, multiply interconnected negative feedback loops. Several computational models of the saccadic system have been proposed in an attempt to understand the functional significance of the simultaneous operation of these loops. An evaluation of these models demonstrates that besides providing a coherent summary of the data that concern it, successful models of the saccadic system generate realistic saccades (in precise quantitative psychophysical terms) when their elements are stimulated, produce abnormal saccades, reminiscent of those encountered in the clinic, when their elements are disabled, while their constituent units display realistic discharge patterns and are connected in a manner that respects anatomy.

Anatomy and physiology of saccadic long-lead burst neurons recorded in the alert squirrel monkey. II. Pontine neurons.

1. The discharge patterns and axonal projections of saccadic long-lead burst neurons (LLBNs) with somata in the pontine reticular formation were studied in alert squirrel monkeys with the use of the method of intraaxonal recording and horseradish peroxidase injection. 2. The largest population of stained neurons were afferents to the cerebellum. They originated in the dorsomedial nucleus reticularis tegmenti pontis (NRTP) including its dorsal cell group (N = 5), the preabducens intrafascicular nucleus (N = 5), and the raphe pontis (N = 1). Axons of all neurons coursed under NRTP and entered brachium pontis without having synapsed in the brain stem. Three axons sent collaterals to the floccular lobe, but other more distant targets of these and the other cerebellar afferents could not be determined. Movement fields of these neurons were intermediate between vectorial and directional types. 3. Four neurons had their somata in nucleus reticularis pontis oralis and terminations in the brain stem reticular formation. Each neuron was different, but all terminated in the region containing excitatory burst neurons, and most terminated in the region containing inhibitory burst neurons. Other targets include nucleus reticularis pontis oralis and caudalis, NRTP, raphe interpositus, and the spinal cord. Discharge patterns included both vectorial and directional types. 4. Two reticulospinal neurons had large multipolar somata either just rostral or ventral to the abducens nucleus. These neurons also projected to the medullary reticular formation, caudal nucleus prepositus hypoglossi, and dorsal and ventral paramedian reticular nucleus. 5. The functional implications of the connections of these LLBNs and those reported in the companion paper are extensively discussed. The fact that the efferents of the superior colliculus target the regions containing medium-lead saccadic burst neurons confirms the role of the colliculus in saccade generation. However, the finding that many other neurons project to these regions and the finding that superior colliculus efferents project more heavily to areas containing reticulospinal neurons argue for a diminished role of the superior colliculus in saccade generation but an augmented role in head movement control.