Higher-order thalamic relays burst more than first-order relays.

There is a strong correlation between the behavior of an animal and the firing mode (burst or tonic) of thalamic relay neurons. Certain differences between first- and higher-order thalamic relays (which relay peripheral information to the cortex versus information from one cortical area to another, respectively) suggest that more bursting might occur in the higher-order relays. Accordingly, we recorded bursting behavior in single cells from awake, behaving rhesus monkeys in first-order (the lateral geniculate nucleus, the ventral posterior nucleus, and the ventral portion of the medial geniculate nucleus) and higher-order (pulvinar and the medial dorsal nucleus) thalamic relays. We found that the extent of bursting was dramatically greater in the higher-order than in the first-order relays, and this increased bursting correlated with lower spontaneous activity in the higher-order relays. If bursting effectively signals the introduction of new information to a cortical area, as suggested, this increased bursting may be more important in corticocortical transmission than in transmission of primary information to cortex.

Analysis of the frequency response of the saccadic circuit: system behavior.

To more thoroughly describe the system dynamics for the saccadic circuit in monkeys, we have determined the frequency response by applying a frequency modulated train of microstimulation pulses in the superior colliculus. The resulting eye movements reflect the transfer function of the saccadic circuit. Below input modulations of 5 cycles/s, the saccadic circuit increasingly oscillates with multiple high-frequency, low-amplitude movements reminiscent of the "staircase saccades" evoked during the sustained step response. Between 5 and 20 cycles/s, the circuit entrains well to the input, exhibiting one saccadic response to each sinusoidal input. Within this range there are systematic frequency-dependent changes in movement amplitudes, including super-normal saccades at some input frequencies. Above 20 cycles/s, the saccadic circuit increasingly exhibits periodic failures at rates of 1:2 or higher. In addition, the circuit exhibits predictable amplitude-modulated interference patterns in response to a combined step and frequency-modulated input. These experimental results provide insight into several biological mechanisms and serve as benchmark tests of viable models of the saccadic system. The data are consistent with negative feedback models of the saccadic system that operate as a displacement controller and inconsistent with theories that put the superior colliculus within the lowest-order, local feedback loop. The data support theories that the circuit feedback operates with dynamics that simulate a "leaky integrator." In addition, the results demonstrate how the temporal output of the superior colliculus interacts with recurrent inhibition to influence the eye movement dynamics.

The effects of saccadic eye movements on the activity of geniculate relay neurons in the monkey.

Saccadic suppression is the reduced visibility that occurs during saccadic eye movements. Recent psychophysical studies have suggested that this is due to a reduction in responsiveness of magnocellular (M), but not parvocellular (P), cells of the lateral geniculate nucleus. To address this and other phenomena of responsiveness during saccades, we recorded from geniculate neurons in the behaving monkey before, during, and after saccades. Specifically, we measured neuronal responses to a flashing, whole-field illumination. Contrary to the prediction, most M neurons showed pronounced enhancement of visual activity during saccades, whereas such responsiveness of parvocellular (P) neurons was not significantly affected by saccades. We also analyzed the extent to which saccades affected burst firing, which results from activation of a voltage-dependent Ca2+ conductance. We found that both M and P cells displayed a significant suppression of burst firing during saccades. These results do not support the idea that saccadic suppression has an obvious substrate in reduced responsiveness of geniculate cells, but this suppression may be related to an increased visual threshold for detection associated with reduced burst firing.

Analysis of the frequency response of the saccadic circuit: numerical simulations.

Fundamental mechanisms of a brain circuit's operation can be revealed by quantitative analysis of the system's dynamic behavior. This approach is particularly useful for investigation of motor circuits, which generate machine-like outputs and where systems control techniques can be applied to reveal the circuit behavior outside the dynamic range of volitional activation. As an extension of our previous study of the step response of the saccadic motor system, this paper presents analytical and numerical considerations for the frequency response of the saccadic circuit-the system response to a steady-state sinusoidal input. Consideration of these responses provides mechanistic explanation for several aspects of the biological circuit and formalizes constraints for viable models of the saccadic circuit. Most importantly, these studies provide quantitative predictions for comparison with experimental data in vivo and make explicit hypotheses about biological mechanisms for experimental verification.

Cellular mechanisms underlying activity patterns in the monkey thalamus during visual behavior.

We show for the first time with in vitro recording that burst firing in thalamic relay cells of the monkey is evoked by activation of voltage-dependent, low threshold Ca(2+) spikes (LTSs), as has been described in other mammals. Due to variations in LTS amplitude, the number of action potentials evoked by an LTS could vary between 1 and 8. These data confirm the presence of two modes of firing in the monkey for thalamic relay cells, tonic and burst, the latter related to the activation of LTSs. With these details of the cellular processes underlying burst firing, we could account for many of the firing patterns we recorded from the lateral geniculate nucleus of the thalamus in behaving monkeys. In particular, we found clear evidence of burst firing during alert wakefulness, which had been thought to occur only during sleep or certain pathological states. This makes it likely that the burst firing seen in awake humans has the same cellular basis of LTSs, and this supports previous suggestions that burst firing represents an important relay mode for visual processing.

Burst and tonic firing in thalamic cells of unanesthetized, behaving monkeys.

Thalamic relay cells fire in two distinct modes, burst or tonic, and the operative mode is dictated by the inactivation state of low-threshold, voltage-gated, transient (or T-type) Ca2+ channels. Tonic firing is seen when the T channels are inactivated via membrane depolarization, and burst firing is seen when the T channels are activated from a hyperpolarized state. These response modes have very different effects on the relay of information to the cortex. It had been thought that only tonic firing is seen in the awake, alert animal, but recent evidence from several species suggests that bursting may also occur. We have begun to explore this issue in macaque monkeys by recording from thalamic relay cells of unanesthetized, behaving animals. In the lateral geniculate nucleus, the thalamic relay for retinal information, we found that tonic mode dominated responses both during alert behavior as well as during sleep. We nonetheless found burst firing present during the vigilant, waking state. There was, however, considerably more burst mode firing during sleep than wakefulness. Surprisingly, we did not find the bursting during sleep to be rhythmic. We also recorded from relay cells of the somatosensory thalamus. Interestingly, not only did these somatosensory neurons exhibit much more burst mode activity than did geniculate cells, but bursting during sleep was highly rhythmic. It thus appears that the level and nature of relay cell bursting may not be constant across all thalamic nuclei.

Numerical simulation of nonlinear feedback model of saccade generation circuit implemented in the LabView graphical programming language.

The object-oriented graphical programming language LabView was used to implement the numerical solution to a computational model of saccade generation in primates. The computational model simulates the activity and connectivity of anatomical strictures known to be involved in saccadic eye movements. The LabView program provides a graphical user interface to the model that makes it easy to observe and modify the behavior of each element of the model. Essential elements of the source code of the LabView program are presented and explained. A copy of the model is available for download from the internet.

Eye movements in depth: What does the monkey's parietal cortex tell the superior colliculus?

We have recorded identified cortico-tectal neurons from the primate parietal cortex to determine whether the depth-related activity in the intraparietal sulcus (area LIP) is transmitted to the superior colliculus. Traditional theory suggests that the superior colliculus is involved in the control of conjugate, saccadic eye movements and thus would not require inputs related to depth. We provide conclusive evidence that area LIP neurons in fact do transmit depth-related information to the superior colliculus.

Analysis of the step response of the saccadic feedback: computational models.

We present results of theoretical analysis and computational simulations of two models of the saccadic burst generator: the Scudder model and the Jurgens model. We used the experimental paradigm of prolonged stimulation in monkey superior colliculus (SC) to compare the performance of the two models. We excluded the Scudder model since it was not capable of reproducing the experimentally observed staircase movements. We modified the Jurgens model by replacing the originally proposed feedback integrator with an active reset mechanism by a leaky integrator. With this modification we have shown that the staircase movement elicited by prolonged stimulation in the SC can be modeled as a damped oscillatory step response of this model. Furthermore, to replicate the changes in the kinetic profiles of the staircase movements with increased stimulation we modified the functionality of the model. Our results suggest that prolonged stimulation of the SC dynamically changes the gains and time constant of the saccadic feedback.

Influence of the superior colliculus on the primate blink reflex.

In this study we used microstimulation to investigate the influence of the superior colliculus on the trigeminal blink reflex. We report that stimulation in the intermediate to deep layers of the tectum produced inhibition of reflex blinks at a latency of approximately 26 ms. We considered the hypothesis that the blink inhibition was mediated via the omnipause neurons (OPNs) of the eye movement control system in the brainstem. Our results show that the least effective sites for suppression were in the rostral colliculus. This is inconsistent with the prediction that OPNs should be maximally recruited from the rostral tectum near the "fixation zone." From these points and other considerations, we conclude that the reflex blink suppression from the superior colliculus is not directly mediated by the OPNs or the saccadic eye movement circuits.

Statistical analysis of the information content in the activity of cortical neurons.

We sought to quantify the information in the activity of posterior parietal neurons in behaving Rhesus monkeys. We found several models that were adequate to represent the neurons' response fields. We used a gaussian model to construct a signal/noise ratio, which provided an estimate of the number of distinguishable levels (NDL) of activity within the response field. For the typical neuron, an unbiased ideal observer could reliably discriminate 3.4 levels of activity. At change levels of detectability, the threshold limit of reliable discrimination, there was an average of 5.8 NDL. We then used the NDL to divide the response field into regions of spatial ambiguity. For an individual neuron, we suggest that firing rate is a measure of the probability that the target is at the center of the neuron's response field.

Analysis of the step response of the saccadic feedback: system behavior.

We used prolonged stimulation of the monkey superior colliculus to elicit staircase eye movements. By changing the parameters of the stimulating current we were able to obtain movements with different dynamics. An increase in the current frequency resulted in the shortening of the intersaccadic interval and a decrease of the amplitudes in the staircase. In cases of high stimulation, after an initial saccade of fixed metrics, the eyes moved in an apparently smooth fashion. The movement was conjugate and in the same direction as the first saccade. By analyzing the velocity trace we found that the movement consisted of a chain of small saccades, each of which started before the previous one ended. We conducted a quantitative analysis of the staircase movements including the cases of apparently smooth movement of the eyes. We conclude that all of the movements elicited by prolonged SC stimulation were generated by the saccadic feedback circuitry. The dynamic profiles of the elicited movements changed continuously with the stimulating current parameters. On one end of the continuum we observed the classically, described staircase movements with individual movements separated in time. On the other end of the continuum we saw the apparent smooth movement as the limit case produced by high stimulation of the SC.

Neurons in monkey parietal area LIP are tuned for eye-movement parameters in three-dimensional space.

1. A functional class of neurons in area LIP on the lateral bank of the intraparietal sulcus were shown previously (Gnadt and Andersen 1988) to be related to the metrics of saccadic eye movements. In this study, we tested LIP neurons at different depths with respect to the plane of fixation. 2. Sixty-one neurons were identified for their increased activity before saccadic eye movements. While holding the location of the target constant at the center of the frontoparallel (saccadic) response field, the neurons were tested systematically during eye movements to target positions proximal (near) to the plane of fixation, at the plane of fixation, and distal (far) to the plane of fixation. By necessity, the movements of these targets required a combination of saccadic and vergence movements. 3. Seventy-two percent of the neurons were found to change their activity as a function of target depth relative to the plane of fixation. The neurons had broad tuning curves for depth. Some cells preferred "near" target positions, some preferred "far" positions, and others responded best in the frontoparallel plane of fixation. 4. The location of a neuron's response field in the frontoparallel plane remained constant regardless of target depth. However, the magnitude of the neuron's response increased when the target was positioned at the preferred depth and it decreased for targets positioned at nonpreferred depths. This indicated that the neurons always were related to the same frontoparallel coordinates, but responded more vigorously when the target was positioned at its preferred depth. 5. The visual display apparatus allowed independent presentation of two stimulus cues for depth: binocular disparity and accommodative demand whereas other cues were held constant. For many neurons, either cue was sufficient to tune the activity in depth, though most neurons responded best for the geometrically appropriate combination of the two cues. 6. Comparison of the binocular tuning for depth with the individual monocular responses showed that the tuning for depth was not produced by simple linear combination of two monocular response fields. 7. We tested a subset of the neurons in a double-movement task that dissociated the retinal coordinates of the visual stimuli from the eye-movement coordinates of the second movement. These tests confirmed earlier findings that this functional class of neurons are active when the eye-movement coordinates matched the neurons' response field. It was not necessary for a visual stimulus to fall within the neurons' response field for them to become active.(ABSTRACT TRUNCATED AT 400 WORDS)

Saccade-related activity in the lateral intraparietal area. I. Temporal properties; comparison with area 7a.

1. The cortex of the inferior parietal lobule (IPL) contains neurons whose activity is related to saccadic eye movements. The exact role of the IPL in relation to saccades remains, however, unclear. In this and the companion paper, we approach this problem by quantifying many of the spatial and temporal parameters of the saccade-related (S) activity. These parameters have hitherto been largely unstudied. 2. The activity of single neurons was recorded from Macaca mulatta monkeys while they were performing a delayed-saccade task. The analysis presented here is based on 161 neurons recorded from the lateral intraparietal area (LIP), a recently defined subdivision of the IPL; and 54 neurons recorded from the neighboring part of the IPL, area 7a. Overall, 409 IPL neurons were isolated in this study. 3. The typical activity of IPL neurons during the delayed-saccade task has three basic phases: light sensitive (LS), memory (M), and S. These basic phases are common to neurons of both areas LIP and 7a. In each phase (LS, M, and S), individual neurons may or may not be active. Most LIP neurons, however, are active in more than one phase. 4. To compare the activity levels of different neurons, the actual firing rate was weighted by each neuron's background level, yielding an "activity index" for each neuron, in each phase of the task. We calculated the activity index for the LS and M phases and for three phases related to the saccade: a presaccadic (Pre-S), a saccade-coincident (S-Co), and a postsaccadic (Post-S) phase. For area LIP neurons the median values of the activity index were high for the LS, M, Pre-S, and S-Co activities, and slightly lower in the Post-S period. In area 7a the median values were low for the LS phase and, in particular, for the M and Pre-S phases, somewhat higher coincident with the saccade, and high post-saccadically. 5. In area LIP, in each phase, 49-63% of the neurons had excitatory activity, and 10-17% had inhibitory responses. 6. In contrast, in area 7a excitatory responses were most frequent in the Post-S phase (56%). Excitation was particularly infrequent during M (28%) and Pre-S (22%). The incidence of inhibitory responses varied too (4-18%). The time course of inhibition was roughly opposite that of excitation; the highest frequency of inhibitory responses occurred during the saccade.(ABSTRACT TRUNCATED AT 400 WORDS)

Saccade-related activity in the lateral intraparietal area. II. Spatial properties.

1. Single-neuron activity was recorded from the inferior parietal lobule (IPL) of Macaca mulatta monkeys while they were performing delayed saccades and related tasks. Temporal characteristics of this activity were presented in the companion paper. Here we focus on the spatial characteristics of the activity. The analysis was based on recordings from 145 neurons. All these neurons were from the lateral intraparietal area (LIP), a recently defined subdivision of the IPL. 2. Delayed saccades were made in eight directions. Direction-tuning curves were calculated for each neuron, during each of the following activity phases that were described in the companion paper: light sensitive (LS), delay-period memory (M), and saccade related (S); the latter further partitioned into presaccadic (Pre-S), saccade coincident (S-Co), and postsaccadic (Post-S). 3. Width and preferred direction were calculated for each direction-tuning curve. We studied the distributions of widths and preferred directions in LIP's neuronal population. In each case we included only neurons that showed clear excitatory activity in the phases in question. 4. Width was defined as the angle over which the response was higher than 50% of its maximal net value. Width distributions were similar for all phases studied. Widths varied widely from neuron to neuron, from very narrow (less than 45 degrees) to very wide (close to 360 degrees). Median widths were approximately 90 degrees in all phases. 5. Preferred-direction distributions were also similar for various phases. All directions were represented in each distribution, but contralateral directions were more frequent (e.g., 69% for S-Co). 6. For each neuron the alignment of the preferred directions of its various phases was determined. Distributions of alignments were calculated (again, phases that were not clearly excitatory were disregarded). On the level of the neuronal population LS, M, and Pre-S were well aligned with each other. S-Co was also aligned with these phases, but less precisely. 7. A set of "narrowly tuned" neurons was selected by imposing a constraint of narrow (width, less than 90 degrees) LS and S-Co direction tuning. In this set of neurons, the LS and S-Co preferred directions were very well aligned (median, 12 degrees). The fraction of narrowly tuned neurons in the population was 40% (25/63). Thus, in a large subpopulation of area LIP, a fairly precise alignment exists between sensory and motor fields. 8. An additional set of 82 area LIP neurons were recorded while the monkey performed delayed saccades to 32 targets located on small, medium, and large imaginary circles.(ABSTRACT TRUNCATED AT 400 WORDS)

Sensorimotor transformation during eye movements to remembered visual targets.

For eye movements made to visual targets, the brain must transform the retinotopic coordinate frame of the visual system to that of the oculomotor plant. Ideally, responses should exactly match target demands. However, during eye movements to remembered targets, responses are spatially distorted. The transformation does not retain accurate retinotopic registration, having both constant and variable components of error. Generally, the constant pattern of distortion appears as a hypermetria for upward saccades and a hypometria for downward movements. Most of the error accumulates during the first 800 msec of memory-contingent delay. The results are interpreted with respect to theories of how spatial information may be coded and transformed.

Eye position effects on visual, memory, and saccade-related activity in areas LIP and 7a of macaque.

We studied the effect of eye position on the light-sensitive, memory, and saccade-related activities of neurons of the lateral intraparietal area and area 7a in the posterior parietal cortex of rhesus monkeys. A majority of the cells showed significant effects of eye position, for each of the 3 types of response. The direction tuning of the light-sensitive, memory and saccade responses did not change with eye position but the magnitude of the response did. Since previous work showed a similar effect for the light-sensitive response of area 7a neurons (Andersen and Mountcastle, 1983; Andersen et al., 1985b), the present results indicate that this modulating effect of eye position may be a general one, as it is found in 3 types of responses in 2 cortical areas. Gain fields were mapped by measuring the effect of eye position on the magnitude of the response at 9 different eye positions for each neuron. The gain fields were usually planar or largely planar for all 3 types of response in both areas, indicating that the magnitude of the response usually varies linearly with both horizontal and vertical eye position. A similar observation was made previously for the gain fields of the light-sensitive response of area 7a neurons (Andersen et al., 1985b). Although gain fields sloped in all directions for the population of cells, the gain field slopes of the light-sensitive, memory and saccade responses for individual cells were usually similar. It is proposed that these eye position effects play an important role in making coordinate transformations for visually guided movement.

Abducens internuclear neurons carry an inappropriate signal for ocular convergence.

1. Single-unit recording studies in alert Rhesus monkeys characterized the vergence signal carried by abducens internuclear neurons. These cells were identified by antidromic activation and the collision of spontaneous with antidromic action potentials. The behavior of abducens internuclear neurons during vergence was compared with that of horizontal burst-tonic fibers in the medial longitudinal fasciculus (MLF) and to that of a large sample of unidentified abducens cells (presumably both motoneurons and internuclear neurons). 2. The results indicate that abducens internuclear neurons and lateral rectus motoneurons behave similarly during vergence eye movements: the majority of both groups of cells decrease their firing rate for convergence eye movements: a minority show no change for vergence. This finding is strongly supported by recordings of horizontal burst-tonic fibers in the MLF, the majority of which decrease their activity significantly for convergence eye movements. 3. These findings indicate that a net inappropriate vergence signal is sent to medial rectus motoneurons via the abducens internuclear pathway. Because medial rectus motoneurons increase their activity appropriately during symmetrical convergence, this inappropriate MLF signal must be overcome by a more potent direct vergence input. 4. Overall, both abducens internuclear neurons and lateral rectus motoneurons decrease their activity for convergence less than would be expected based on their conjugate gain. This implies that some degree of co-contraction of the lateral and medial rectus muscles occurs during convergence eye movements. 5. Some horizontal burst-tonic MLF fibers decrease their activity more for convergence than any recorded abducens neuron. These fibers may arise from cells in the nucleus prepositus hypoglossi or vestibular nuclei.

Lidocaine-induced unilateral internuclear ophthalmoplegia: effects on convergence and conjugate eye movements.

1. To characterize the vergence signal carried by the medial longitudinal fasciculus (MLF), it was subjected to reversible blockade by small injections of 10% lidocaine hydrochloride. The effects of these blockades on both conjugate and vergence eye movements were studied. 2. With this procedure, experimentally induced internuclear ophthalmoplegia (INO) and its effects on conjugate eye movements could be studied acutely, without possible contamination from long-term oculomotor adaptation. In the eye contralateral to the MLF blockade, saccadic and horizontal smooth-pursuit eye movements were normal. Horizontal abducting nystagmus, often seen in patients with INO, was not observed in this eye. 3. As previously reported for INO, profound oculomotor deficits were seen in the eye ipsilateral to the MLF blockade. During maximal blockade, adducting saccades and horizontal smooth-pursuit movements in this eye did not cross the midline. Adducting saccades were reduced in amplitude and peak velocity and showed significantly increased durations. Abducting saccades, which were slightly hypometric, displayed a marked postsaccadic centripetal drift. 4. The eye ipsilateral to the blockade displayed a pronounced, upward, slow drift, whereas the eye contralateral to the blockade showed virtually no drift. Furthermore, although vertical saccades to visual targets remained essentially conjugate, the size of the resetting quick phases in each eye was related to the amplitude of the slow phase movement in that eye. Thus the eye on the affected side displayed large quick phases, whereas the eye on the unaffected side showed only slight movements. On occasion, unilateral downbeating nystagmus was seen. This strongly suggests that the vertical saccade generators for the two eyes can act independently. 5. The effect of MLF blockade on the vergence gain of the eye on the affected side was investigated. As a measure of open-loop vergence gain, the relationship of accommodative convergence to accommodation (AC/A) was measured before, during, and after reversible lidocaine block of the MLF. After taking conjugate deficits into account, the net vergence signal to the eye ipsilateral to the injection was found to increase significantly during the reversible blockade. 6. The most parsimonious explanation for this increased vergence signal is suggested by the accompanying single-unit study. This study showed that abducens internuclear neurons, whose axons course in the MLF, provide medial rectus motoneurons with an appropriate horizontal conjugate eye position signal but an inappropriate vergence signal. Ordinarily, this incorrect vergence signal is overcome by another, more potent, v