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Department of Physiology, McGill University, Montreal, Quebec, Canada
Submitted 19 May 2008; accepted in final form 9 July 2008
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ABSTRACT |
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INTRODUCTION |
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; Mays 1984, 1998). Accordingly, the premotor circuitry involved in generating horizontal saccades (e.g., the saccadic burst neurons [SBNs] of the paramedian pontine reticular formation [PPRF]) was generally assumed to provide the command to drive the horizontal conjugate component of such movements, whereas a specific subpopulation of neurons in the mesencephalic reticular formation (MRF), which encode a signal proportional to viewing distance, were thought to produce the required vergence command (Busettini and Mays 2005b; Gamlin 2002; Gamlin et al. 1989; Mays et al. 1986; Zhang et al. 1992).
The summation of commands from two distinct premotor pathways, however, cannot account for a number of observations that have been made regarding disconjugate saccades. Notably, vergence velocities reach values greater during disconjugate saccades than would be predicted by the linear summation of commands from separate saccadic and vergence premotor pathways (Busettini and Mays 2005b; Collewijn et al. 1997; Enright 1984, 1992; Maxwell and King 1992; Ono et al. 1978; Oohira 1993; van Leeuwen et al. 1998; Zee et al. 1992). Thus it is now generally recognized that the commands driving conjugate saccades and vergence eye movements are not generated by strictly independent neural subsystems. To date, however, the mechanism responsible for the facilitation of vergence during disconjugate saccades remains controversial.
Two general classes of models have been proposed to account for the facilitation of vergence during disconjugate saccades (Busettini and Mays 2005b; Gamlin 2002; King and Zhou 2002; Kumar et al. 2006; Mays 1998; Mays and Gamlin 1995; Scudder et al. 2002; Van Horn et al. 2008; Zhou and King 1998). In one model, the premotor saccadic pathway drives the conjugate component of the saccade, whereas changes in vergence are exclusively driven by a premotor command from vergence neurons. In this view, projections from the "conjugate" saccadic pathway to the "vergence" pathway play a pivotal role in enhancing the premotor vergence command during disconjugate saccades (Busettini and Mays 2005b; Kumar et al. 2005). Alternatively, it has been proposed that classically assumed "conjugate" saccadic structures in the oculomotor brain stem underlie vergence facilitation by providing monocular saccade commands to the abducens nuclei during saccades (Cova and Galiana 1996; King and Zhou 2000, 2002). In this view, the vergence pathway is used to adjust ocular alignment following the saccadic component of the movement. Consistent with this latter proposal, we and others have reported that the premotor burst neurons in the PPRF that drive horizontal saccades do not encode conjugate commands (King and Zhou 2000; McConville et al. 1994; Sylvestre et al. 2003; Zhou and King 1996, 1998). Indeed, we have recently shown that the vergence-related information dynamically encoded by the premotor brain stem saccadic circuitry alone is sufficient to shape the activity of the abducens motoneurons during horizontal disconjugate saccades (Van Horn et al. 2008). In the present study we tested the proposal that vergence is facilitated by the classical horizontal saccadic pathway using a combination of complementary behavioral and recording approaches in rhesus monkeys. Although prior single-unit studies had exclusively focused on neural correlates during horizontal disconjugate saccades (Van Horn et al. 2008; Zhou and King 1998), there is evidence suggesting that vergence might be similarly facilitated during vertical saccades (Busettini and Mays 2005a; Enright 1984; Kumar et al. 2005; Maxwell and King 1992; van Leeuwen et al. 1998; Zee et al. 1992). Understanding how the brain drives vertical saccades between near and far targets is particularly interesting in terms of the current debate regarding the premotor control of vergence during saccades. Although these saccades require a vertical conjugate command, which would originate from the vertical burst neurons of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) (Büttner et al. 1977; Crawford and Vilis 1991, 1992; King and Fuchs 1979; Missal et al. 2000; Moschovakis et al. 1991a,b) they do not require the simultaneous production of a horizontal conjugate command. Instead, a command to generate horizontal movements of the two eyes in equal and opposite directions (i.e., vergence) is needed. Thus by recording the discharges of horizontal SBNs during this dissociation task, we were able to address whether neuronal commands from the horizontal saccadic pathway dynamically encode the movement of an individual eye even when no horizontal conjugate saccade command is required. Our results provide firm evidence that vergence is facilitated during vertical saccades and that integrated conjugate–vergence information encoded by the classical horizontal saccadic pathway is appropriate to drive the observed facilitation.
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METHODS |
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). Briefly, a stainless steel post was attached to the animal's skull with stainless steel screws and dental acrylic, permitting complete immobilization of the animal's head. Two stainless steel recording chambers, oriented stereotaxically toward the abducens nucleus on the right and left sides of the brain stem, were also secured to the implant. To record binocular eye position an eye coil (three loops of Teflon-coated stainless steel wire, 18- to 20-mm diameter) was implanted in each eye (Judge et al. 1980). All procedures were approved by the McGill University Animal Care Committee and complied with the guidelines of the Canadian Council on Animal Care. Behavioral paradigms
Monkeys were trained to fixate targets for a juice reward. The timing and location of target illumination, data acquisition, and on-line data displays were controlled using REX (real-time experimentation), a UNIX-based real-time acquisition system (Hays Jr et al. 1982). Neuronal responses were recorded during 1) horizontal and vertical conjugate saccades, 2) oblique saccades, 3) saccade-free symmetric vergence, 4) vertical saccades combined with vergence, and 5) horizontal saccades combined with vergence.
First, to elicit conjugate movements a red HeNe laser target was projected onto a cylindrical screen located 55 cm away from the monkey's eyes (isovergent, 
3.5° convergence). Ipsilaterally and contralaterally directed conjugate saccades were elicited by stepping the laser target between horizontal positions (±5–30°), in 5° increments, in predictable and unpredictable sequences and vertical saccades were elicited by stepping the laser target between vertical positions (±5–30°). Oblique saccades were generated by stepping the laser target between a central target to a sequence of targets that had varying vertical and horizontal components within this same range.
Next, to elicit changes in vergence a horizontal array of 16 red light-emitting diodes (LEDs), with intensities comparable to that of the laser target, was positioned between the screen and the monkey. Symmetric vergence was elicited by sequentially illuminating LEDs located along the midline (convergence angles: 17, 12, 8, and 6°). To generate vertical saccades with vergence, two specific paradigms were used, similar to those previously described in humans (Kumar et al. 2005; van Leeuwen et al. 1998).
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; Van Horn et al. 2008) neurons were also characterized during horizontal saccades combined with vergence (i.e., horizontal disconjugate saccades). The paradigms to elicit horizontal disconjugate saccades have been described previously (Sylvestre and Cullen 2002; Sylvestre et al. 2003; Van Horn et al. 2008). Briefly, an illuminated target changed from one of the close midsagittal LEDs to an eccentric (i.e., right or left of the midsagittal plane) laser target. During this paradigm, monkeys made saccades with horizontal components of 5–30° in amplitude in both directions and vergence components with amplitudes of approximately 4–13°. In addition, some LEDs were positioned in a configuration similar to the Müller paradigm (see Ramat et al. 1999 for examples) to elicit disconjugate saccades in which the movement of the right eye or left eye was minimized. Data acquisition procedures
During experiments monkeys were seated in primate chairs located within the center of a 1-m3 magnetic eye coil system (CNC Engineering). Horizontal and vertical eye position signals were measured using the magnetic search coil technique (Fuchs and Robinson 1966; Judge et al. 1980). Each eye coil signal was calibrated independently by having the monkey fixate, with one eye masked, a variety of targets at different horizontal and vertical eccentricities and different depths. Position signals were low-pass filtered at 250 Hz (analog eight-pole Bessel filter) and sampled at 1 kHz. Since ocular saccades include very little power at >50 Hz (Cullen et al. 1996; Van Opstal et al. 1985; Zuber et al. 1968) eye position signals were further digitally filtered (with a 51st-order finite-impulse-response filter with a Hamming window and a cutoff at 125 Hz), before being differentiated to obtain eye velocity signals (using zero-phase forward and reverse digital filtering to prevent phase distortion).
Extracellular single-unit activity was recorded using enamel-insulated tungsten microelectrodes (2- to 10-MÙ impedance, FHC; for details, see Sylvestre and Cullen 1999). Saccadic burst neurons (n = 57) were identified on-line by their stereotypical discharge properties during eye movements (Cullen and Guitton 1997). Excitatory and inhibitory burst neurons (EBNs and IBNs, respectively) were distinguished based on their recording location relative to the abducens nucleus. EBNs were recorded in a small region extending 1–2 mm rostral to the abducens nucleus and 0.5–1.5 mm from the midline. IBNs were recorded in a region extending 0–2 mm caudal to the abducens nucleus and 0.5–1.5 mm from the midline. Both areas correspond to previous anatomical characterizations (Strassman et al. 1986a,b). When a neuron was isolated, unit activity, horizontal and vertical positions of the right and left eyes, and target position were recorded on a digital audio tape. The isolation of each neuron was reassessed off-line during playback. A burst neuron was considered to be adequately isolated only when individual action potential waveforms could be discriminated using a windowing circuit (BAK Industries) during saccades (e.g., see Fig. 1 in Sylvestre and Cullen 1999) and during fixation. Subsequent analysis was performed using custom algorithms (Matlab, The MathWorks).
Definitions and conventions
Eye movements are described in terms of conjugate [conjugate = (left eye + right eye)/2] and vergence [vergence = (left eye – right eye)] coordinates (where the left eye and right eye inputs could be either position or velocity signals), such that positive and negative vergence velocity signals denote convergence and divergence, respectively. In addition, we report the movements of each eye as either ipsilateral or contralateral based on their location relative to the recording site. Note, positive and negative values indicate eye positions that are to the right and left or up and down of the central position (i.e., straight ahead), respectively.
Data analysis
The onset and offset of all saccades was determined using a 20°/s saccade velocity (i.e., horizontal or vertical) criterion. Horizontal saccades were defined as movements for which changes in vertical eye position were <10% of the change in horizontal position; vertical saccades were defined as movements for which changes in horizontal eye position were <10% of the change in vertical position. Saccades were categorized as conjugate if the change in vergence angle was <3.0° and further categorized as vertical, horizontal, or oblique. The onset and offset of slow, saccade-free vergence were determined using 10°/s vergence velocity criteria. Symmetrical vergence was defined as movements with a change in vergence >2.5° that were not accompanied by saccades.
The preferred direction for each neuron was determined by fitting a Gaussian function to the relationship between the number of spikes in a unit's discharge and saccade direction for saccades ranging in amplitude from 20 to 25°. A spike density function, in which a Gaussian function was convolved with the spike train (SD of 5 ms), was used to estimate neuronal firing rate (Cullen and Guitton 1996; Sylvestre and Cullen 1999). Linear optimization techniques were used to quantify each neuron's dynamic sensitivity to eye movements, during conjugate (Cullen and Guitton 1996, 1997; Sylvestre and Cullen 1999) and disconjugate saccades (Sylvestre et al. 2002, 2003; Van Horn et al. 2008), as described previously. Briefly, for each neuron we estimated the sensitivity to ipsilaterally directed conjugate saccades using the following dynamic model, which we have previously shown is an accurate description of both EBNs and IBNs (Cullen and Guitton 1997; Sylvestre and Cullen 2006; Van Horn et al. 2008).
 | (1) |
(t) refers to the instantaneous horizontal conjugate eye velocity.
The specific linear regression models used for the analysis of neural responses during disconjugate saccades are elaborated in RESULTS. The goodness of fit of a given model to neuronal data was quantified using the variance-accounted-for value {VAF = 1 – [var (mod – fr)/var (fr)]}, where mod represents the modeled firing rate and fr represents the actual firing rate. Note, that when estimating linear models, the VAF is mathematically equivalent to the correlation coefficient R2. Accordingly, a VAF value of 1 indicates a perfect fit to the data, whereas a value of 0 indicates a fit that is equivalent to the mean value of the firing rate models. The dynamic lead time of individual neurons (td) was computed during conjugate saccades as previously described by Sylvestre and Cullen (1999).
For each model parameter, which was estimated in our analysis of neuronal firing rates during disconjugate saccades, we computed 95% confidence intervals using a nonparametric bootstrap approach (Carpenter and Bithell 2000) and used these confidence intervals to identify nonsignificant or identical model parameters (Sylvestre and Cullen 2002; Sylvestre et al. 2003; Van Horn et al. 2008). Notably, equal numbers of converging and diverging saccades were included in the disconjugate data set to prevent biasing the parameter estimates. If a confidence interval overlapped with zero the model was rerun with the nonsignificant term removed. The Bayesian information criterion (BIC), which served as a "cost index," was calculated for each model estimation to quantitatively determine whether removing the term was justified (Schwartz 1978).
Quantification of ocular preference
The ocular preference of each neuron was quantified as previously described (Sylvestre and Cullen 2002; Sylvestre et al. 2003; Van Horn et al. 2008). Briefly, for a given neuron the velocity sensitivity of each eye was used to compute a Ratio index
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for specific criteria for each category].
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Data presented in the RESULTS are described as means ± SDs. A one-way ANOVA followed by a Tukey–Kramer multiple-comparison test was used to compare results across behavior and neuron types.
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RESULTS |
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Characterization of vergence facilitated by vertical saccades
Figure 2 shows average traces of the four vertical–vergence movements studied. Position and velocity traces are shown for monkey D making saccades from a central near target to a higher far target (A: Diverge-Up), from the higher far target to the lower central near target (B: Converge-Down), from a lower far target to the higher near target (C: Converge-Up), and from the near target to a lower far target (D: Diverge-Down). In each example, fixation of the LED that was positioned 8 cm from the monkey's nose required a vergence angle of about 10°. Note that since the velocities of the two eyes were equal and opposite in all four conditions, the horizontal conjugate velocity associated with each eye movement was virtually zero. During each of the four paradigms vergence velocities were 1) substantially greater than expected for saccade-free vergence movements and 2) peak vergence velocities were relatively synchronized with peak vertical velocities (see arrows in Fig. 2). In the following text, we further quantify each of these findings.
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Next, we evaluated the temporal alignment of peak vertical and vergence velocities. Figure 4, A1 and A2 illustrates typical examples of eye movements in which vertical and convergence movements were combined (Converge-Down and Converge-Up, respectively). As shown for these example movements, vergence and vertical velocities peaked at approximately the same time. This result was typical for all four behavioral conditions with only small differences in temporal dissociation between monkeys (see Table 1). On average, vergence velocities peaked approximately 3–4 ms after peak vertical velocity. Recently, Kumar et al. (2005) observed that significant temporal dissociations (
320 ms) could occur when humans made self-paced shifts between far targets and higher near targets (i.e., Converge-Up). A similar dissociation pattern was not observed in the monkeys evaluated in this study. As illustrated in Fig. 4B1, during the Converge-Up condition the temporal dissociation was <40 ms in the majority of trials (>95%). On the very rare occasion that peak vergence velocity was markedly delayed compared with peak vertical velocity in this condition (closed star in Fig. 4B1) the peak vergence velocity associated with the overall eye movement was relatively small (
50°/s). Indeed, the dynamics of the vergence components of these eye movements were similar to those of saccade-free vergence. As illustrated in Fig. 4B2 peak vergence velocities were generally >100°/s when combined with a vertical saccade (Fig. 4B2, black bars). However, when peak vergence velocity was delayed, the resulting vergence velocity was in the range of vergence velocities observed during symmetric vergence (Fig. 4B2, dark gray vs. light gray, respectively).
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Test of the hypothesis: vergence is facilitated by the classical saccadic pathway during disconjugate saccades
The second goal of this study was to determine whether the premotor burst neurons, which drive horizontal saccades, discharge in a manner appropriate to facilitate vergence velocities during vertical saccades between near and far targets. To address this question, we characterized the command signal that was dynamically encoded by the horizontal SBNs during vertical saccade-facilitated vergence. Notably, these saccades would also require a vertical conjugate command, which would originate from the vertical burst neurons of the riMLF (Büttner et al. 1977; Crawford and Vilis 1991, 1992; King and Fuchs 1979; Missal et al. 2000; Moschovakis et al. 1991a,b).
In all, 57 SBNs were recorded in the paramedian pontine reticular formation (PPRF), the majority of which (n = 38) were recorded with sufficient behavior during vertical-facilitated vergence to determine the neuron's ocular sensitivity (see METHODS). Neurons were classified as excitatory (EBNs; n = 22) or inhibitory (IBNs; n = 35) based on their anatomical location (see METHODS) and further categorized as short- or long-lead neurons depending on whether the mean period between the onset of the first spike and the onset of eye velocity was 15 or >15 ms, respectively, during conjugate saccades (25 long-lead IBNs; 10 short-lead IBNs; 9 long-lead EBNs; 13 short-lead EBNs) (Cullen and Guitton 1997; Scudder et al. 1988). As shown in a recent comparison of short- and long-lead EBNs and IBNs during disconjugate saccades (Van Horn et al. 2008), we found no major differences (with the obvious exception of the burst lead times) between the two groups of neurons. Thus for simplicity, short- and long-lead EBNs and IBNs are discussed as a pooled population and are referred to as SBNs.
We first tested whether the command signal encoded by SBN correlates to the increase in vergence velocity that is observed when vertical saccades are made between far and near targets (i.e., Fig. 3). Our logic was the following: if SBNs provide a saccadic monocular command to the extraocular motoneurons, their responses should preferentially encode the movement of an individual eye during vertical as well as horizontal disconjugate saccades. Alternatively, if SBNs provide only a conjugate command to the extraocular motoneurons, then their firing patterns should be unaffected when compared with that generated when vertical saccades are made between two far targets. Overall, our results support the former proposal. Specifically, the movement of an individual eye was required to accurately describe the burst activity of the majority (84%) of the SBNs when vertical saccades were made between near and far targets. An example SBN illustrating this main finding is presented in Figs. 5 and 6.
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We next tested whether we could predict the firing rate of the neuron based on its sensitivity to eye movements during horizontal conjugate saccades using the following dynamic model.
Horizontal-prediction model
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(t) represents either 1) conjugate velocity (), 2) ipsilateral eye velocity (
), or 3) contralateral eye velocity (
) (for a comparable approach in the analysis of horizontal disconjugate saccades, also see Van Horn et al. 2008). The distribution of horizontal velocity sensitivities for the population of SBNs is shown in Fig. 7 A and average parameters estimated during conjugate saccades are provided in Supplemental Table S1.1 For the example neuron illustrated in Fig. 6, we found that neuronal discharge dynamics were most accurately predicted when we used the movement of the ipsilateral eye to estimate firing rate (Fig. 6, blue trace superimposed on firing rate). When conjugate or contralateral eye velocity was used in the estimation, we obtained much poorer predictions of neuronal firing (black and red traces superimposed on the firing rate, respectively).
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; Hepp and Henn 1983; Kaneko 2006; Scudder et al. 1988; Strassman et al. 1986a,b), approximately half of the SBNs in our population were not completely silent during vertical saccades made between two far targets but instead produced a small discharge of action potentials. For these neurons (n = 22/38) we also characterized the firing rates during vertical saccades using a vertical-eye velocity–based version of Eq. 1 and found that they were dynamically related to vertical eye velocity (mean VAF = 0.39 ± 0.15 and 0.28 ± 0.25 obtained for vertical up and down saccades, respectively; see Supplemental Table S1 for average parameters estimated during vertical saccades). Furthermore, we could well predict the firing rate of a given neuron in this subpopulation during oblique saccades by simply accounting for its sensitivity to horizontal and vertical velocity during horizontal and vertical saccades, respectively (mean VAF = 0.51 ± 0.17). Note this quality of fit is comparable to that obtained during conjugate saccades (see Supplemental Table S1). The tuning and discharge of an example neuron during oblique saccades are shown in Supplemental Figs. S1 and S2, respectively. Thus to fully describe the discharge dynamics of these neurons when vertical saccades were made between near and far targets (i.e., vertical saccades combined with vergence) we used a model that also accounted for each neuron's sensitivity both to horizontal and to vertical eye velocity during saccades. (Supplemental Fig. S3 shows this approach applied to the same example neuron that was shown in Supplemental Figs. S1 and S2.)
A neuron-by-neuron comparison of horizontal and vertical sensitivities estimated during ipsilateral versus vertical saccades is shown in Fig. 7B. Because we found no major differences (other than obvious exception of their tuning to saccade direction) between neurons with or without vertical sensitivities, they are discussed as a pooled population in the following text. Overall, we found that the discharges of the majority of the neurons in our population (27/38) were best predicted by the horizontal velocity of an individual eye, rather than the conjugate velocity, during vertical-facilitated vergence (25% average relative improvement in VAF). Table 2 summarizes the average VAFs for conjugate versus individual eye predictions for the population of SBNs.
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We next investigated whether estimating a more complex model, specifically a binocular expansion of the conjugate model, might provide an improved description of neuronal discharges during vertical saccades that are made between near and far targets using the following model.
Binocular-estimation model
 | (3) |
(t) and (t) refer to the instantaneous velocity of the ipsilateral and contralateral eye, respectively. Note that for neurons that were not completely silent during vertical saccades made between two far targets, an addition term was included in Eq. 2 to account for their sensitivity to vertical saccadic eye motion. Model fits using this expanded binocular model (Eq. 2) for the example neuron are shown in the second row of Fig. 6 (black trace superimposed on firing rate). To determine whether both eye velocity parameters in the binocular model (i.e., rIE + rCE) were necessary to describe the firing rate of this neuron, we estimated the 95% confidence intervals using a bootstrapping technique described in METHODS and in previous studies (Sylvestre and Cullen 2002; Sylvestre et al. 2003; Van Horn et al. 2008). Figure 6B shows the values of the original parameter estimates (vertical arrows) as well as the distributions of the estimates obtained using the bootstrapping approach (histograms). For each of the two parameter estimates, the 95% confidence interval is denoted by the heavy horizontal line below the distribution. Two important observations can be made from this figure: 1) the confidence intervals of the two eyes were statistically different (i.e., they do not overlap with each other and could therefore not be replaced with a single term proportional to conjugate eye velocity) and 2) the confidence interval for the sensitivity of the contralateral eye velocity was not statistically different from zero (i.e., the confidence interval overlaps with zero). Accordingly, we removed the contralateral eye velocity term from the estimation model such that only ipsilateral eye velocity was used to estimate the firing rate using the following model.
Ipsilateral-estimation model
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BIC = 0), confirming that the contralateral eye velocity parameter played no significant role in describing the discharge of this neuron. Similar results were obtained for the majority of neurons in our population of SBNs. Overall, the 95% confidence intervals for most neurons (n = 34/38) did not overlap with each other, confirming that individual eye velocity terms should not be replaced with a single conjugate term. Moreover, in about two thirds (n = 24/38) of the neurons the 95% confidence interval for one eye velocity parameter overlapped with zero and the fits resulting from the full binocular model (Eq. 3) were nearly identical to the fits using the preferred individual eye (Eq. 4) (i.e., the eye for which the eye velocity parameter did not overlap with zero, mean population VAFbinocular = 0.47 ± 0.07 vs. VAFreduced = 0.44 ± 0.07). Thus these results suggest that horizontal SBNs facilitate vergence during vertical saccades between near and far targets by preferentially encoding the horizontal movement of an individual eye.
Ocular sensitivities across of the population of SBNs
For each SBN, a Ratiodyn index was computed based on the parameters estimated for the binocular model to objectively assign each neuron to one of five ocular categories (for details, see METHODS and Van Horn et al. 2008). The distributions obtained for Ratiodyn during vertical saccades between near and far targets for all SBNs (n = 38) are shown in Fig. 8. We found that the majority of the SBNs could preferentially encode the movement of either eye (e.g., monocular ipsilateral, n = 15; monocular contralateral, n = 9). Table 2 summarizes the average VAFs and changes in BIC provided by the complete binocular versus reduced models for each of the five categories during vertical-facilitated vergence. This distribution is comparable to that previously described for a separate population of SBNs during horizontal disconjugate saccades (Van Horn et al. 2008).
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To more directly relate our present results with those previously described (Van Horn et al. 2008) a subset of SBNs (n = 16) were also recorded during horizontal disconjugate saccades. Approximately an equal number of SBNs with and without vertical sensitivities (n = 9 and 7, respectively) were tested. An analysis comparable to that described earlier was then used to determine whether, on a neuron-by-neuron basis, SBNs had similar ocular preferences when vergence was facilitated by either horizontal or vertical saccades. Figure 9 illustrates the neuronal discharge of the same example neuron shown in Figs. 5 and 6 during four example horizontal disconjugate saccades (converging and diverging are shown in Fig. 9, A1 and A2, respectively). Note the large differences in dynamics for the two eyes during these movements: in the converging case (Fig. 9A1) the contralateral eye moved, whereas the ipsilateral eye was relatively stationary; in the diverging case (Fig. 9A2) the ipsilateral eye moved, whereas the contralateral eye was relatively stationary. The conjugate component of the movements was comparable in the two conditions. Consistent with the results found during vertical-facilitated vergence, we found that the neuron's activity preferentially encoded the velocity of the ipsilateral eye (Fig. 9, blue trace superimposed on firing rate). In particular, an ipsilateral-based prediction most accurately predicted the firing rate (blue trace superimposed on firing rate), whereas conjugate- and contralateral-based predictions tended to overshoot the firing rate when the ipsilateral eye moved less (i.e., during the diverging movements for this example neuron; Fig. 9A1) and to undershoot when the ipsilateral eye moved more (Fig. 9A2; black and red traces superimposed on the firing rate). Confidence intervals obtained using the bootstrapping technique further confirmed that the neuron's sensitivity to contralateral eye velocity was not statistically different from zero (Fig. 9B). Furthermore, when we removed the contralateral eye velocity term from our dynamic model such that only ipsilateral eye velocity was used to estimate the firing rate, the resulting fit was nearly identical to that of the full binocular model (Fig. 9, second row, dotted blue trace superimposed on firing rate, BIC = 0).
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75%), ocular sensitivities were identical during horizontal and vertical disconjugate saccades (black, red, and blue columns). Taken together, our analyses of vertical and horizontal disconjugate saccades suggest that the premotor burst neurons of the brain stem saccade burst generator functions to facilitate vergence when saccades are made between near and far targets by preferentially encoding the horizontal movement of a specific eye. The implications of this finding are further explored in the DISCUSSION.
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DISCUSSION |
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; McConville et al. 1994; Sylvestre et al. 2003; Zhou and King 1996, 1998), thereby mediating the facilitation of vergence as well as horizontal conjugate velocity during horizontal disconjugate saccades (Van Horn et al. 2008). Here we investigated whether the monocular commands coded by SBNs are suitable for facilitating vergence when vertical saccades are made between near and far targets. Notably, such saccades require the generation of commands to make a vertical conjugate saccade, which would originate from vertical SBNs in the riMLF (Büttner et al. 1977; Crawford and Vilis 1991, 1992; King and Fuchs 1979; Missal et al. 2000; Moschovakis et al. 1991a,b) and vergence (but not horizontal conjugate) eye movements. Thus we could more directly test the hypothesis that the vergence information encoded by the classical horizontal saccadic pathway is consistent with the vergence facilitation that occurs during saccades. We first established that vergence velocities are significantly facilitated when vertical saccades are made between targets located at different distances. Next, we tested whether horizontal SBNs encode monocular commands that are appropriate to account for the facilitation of vergence during these vertical saccades, even though the commanded saccade had no significant horizontal conjugate component. We find that the majority of the SBNs preferentially encode the movement of a specific eye during both vertical and horizontal saccades that are made in depth. Thus our results are consistent with the proposal that the monocular command generated by the brain stem saccadic burst generator is for facilitating all shifts of vergence.
Vergence velocity is facilitated during vertical disconjugate saccades
In everyday life, we typically combine saccades and vergence to look between near and distant objects in three-dimensional space. During these orienting eye movements, there is general agreement that vergence velocity is facilitated (i.e., vergence velocities are greater than expected relative to saccade-free vergence of comparable amplitudes), whereas conjugate saccade velocities are slowed. Although most previous studies have focused on the facilitation that occurs when vergence movements are made in combination with horizontal saccades (Busettini and Mays 2005a; Collewijn et al. 1997; Enright 1984, 1992; Maxwell and King 1992; Ono et al. 1978; Oohira 1993; Van Horn et al. 2008; van Leeuwen et al. 1998; Zee et al. 1992), there had been some evidence for the facilitation vergence velocity during vertical saccades (Busettini and Mays 2005a; Enright 1984; Kumar et al. 2005; Maxwell and King 1992; van Leeuwen et al. 1998). However, because these studies characterized vertical saccades with nonnegligible horizontal components (Busettini and Mays 2005a) or did not methodically examine changes in horizontal conjugate position (Enright 1984; Ono et al. 1978; van Leeuwen et al. 1998), the possibility that the observed facilitation might be, at least in part, due to horizontal saccadic interactions, had been left open.
In the present study we limited our analysis to saccades for which vertical component of the movement was 
90% of total movement amplitude and found that during vertical saccades vergence velocities reached values as large as 300°/s compared with saccade-free movements where velocities were generally <100°/s. Our findings were consistent with those of prior reports, although in our study downward convergence was slower than upward convergence, whereas van Leeuwen et al. (1998) found the opposite tendency in humans.
Vergence and vertical velocities are temporally aligned during vertical saccades in monkeys
Horizontal gaze shifts between targets located at different depths are characterized by the synchronized occurrence of saccadic and vergence movements (Busettini and Mays 2005a; Enright 1984; Kumar et al. 2005; Maxwell and King 1992; van Leeuwen et al. 1998; Zee et al. 1992). This finding has been used as evidence for the proposal that the neural circuitries commanding horizontal saccades and vergence interact (Collewijn et al. 1997). In the present study we further show that when vertical saccades are made between far and near targets, the peak vergence and vertical velocities are generally temporally aligned in monkey. Specifically, peak vergence velocity peaked roughly 3–4 ms after peak vertical velocity. This finding was consistent regardless of whether gaze was shifted to/or from a lower or higher more distant target.
Similar temporal alignments have also been recently reported for humans during comparable tasks (Kumar et al. 2005; van Leeuwen et al. 1998; Zee et al. 1992). For example, most recently, Kumar et al. (2005) reported dissociation intervals that were on the order of about 4–20 ms for the majority of the trials. Notably, however, Kumar and colleagues (2005) did observe that in trials where human subjects shifted their gaze from a lower distant target to a near higher target (i.e., Converge-Up), the occurrence of peak convergence velocity could be considerably delayed relative to peak vertical velocity (delays generally >40 and as large as 320 ms). In the present study, we rarely (e.g., <5%) observed such delays. Moreover, the few trials that had larger dissociation intervals were characterized by vergence movements that began after the onset of the vertical saccade and had velocity profiles resembling those of saccade-free vergence velocity (50°/s). Thus the results indicate that the synchronized occurrence of a saccade is important for the facilitation of vergence velocities in monkey.
Dynamics of SBNs during horizontal and vertical conjugate saccades
Previous studies, which have used system identification techniques to characterize SBN discharge during horizontal conjugate and disconjugate saccades, have demonstrated that SBNs encode saccade trajectories in their spike trains. In particular, a clear relationship between EBN and IBN firing rates and eye movement dynamics has been described (Cullen and Guitton 1997; Sylvestre and Cullen 2006; Van Horn et al. 2008). Here, we demonstrate that this approach can be extended to describe the responses of SBNs during vertical and oblique saccades.
Although all neurons recorded in this study discharged primarily for ipsilaterally directed saccades the directional tuning differed between neurons. In particular, approximately half of the neurons in our sample were broadly tuned and were not completely silent during vertical saccades. This result is in agreement with many previous studies that have also reported SBNs with broad tuning curves (Cullen and Guitton 1997; Hepp and Henn 1983; Kaneko 2006; Scudder et al. 1988; Strassman et al. 1986a,b). Although a metric-based analysis preformed by Scudder et al. (1988) did report that the number of spikes generally increased for larger vertical movements this is the first study to describe the dynamic relationship between SBN discharge and eye velocity during vertical and/or oblique saccades. We found that for SBNs that were not completely silent during vertical saccades, the firing rates during vertical saccades were dynamically related to vertical eye velocity (see Supplemental Table S1). Furthermore, the discharge characteristics during horizontal and vertical saccades could be used to accurately predict the firing rate of all SBNs during oblique saccades that had varying vertical and horizontal components.
SBNs contribute to increasing vergence velocities during disconjugate saccades
We have previously shown that the saccadic burst generator in the PPRF, which was commonly thought to encode horizontal conjugate saccades (Busettini and Mays 2005b), in fact provides temporally appropriate vergence information to facilitate vergence during horizontal disconjugate saccades (Van Horn et al. 2008). In particular, the information was encoded in terms of an individual eye, where the majority of the neurons encoded the movement of the ipsilateral eye. In the present study, we tested the prediction that if the monocular commands issued by the SBNs are important for facilitating vergence during horizontal saccades they should also contribute to facilitating vergence associated with a vertical saccade when the conjugate component of the movement is negligible. As predicted, we found that SBNs are also well suited for facilitating vergence during a vertical saccadic eye movement. In particular, SBNs contribute to generating increased vergence velocities by dynamically encoding the movement of an individual eye rather than the conjugate component of the movement.
To directly compare our present results with those previously described (Van Horn et al. 2008), we recorded a subset of SBNs during both horizontal- and vertical-facilitated vergence. On a neuron-by-neuron basis, we found that SBNs have similar ocular preferences during both conditions. For example, a neuron that was found to dynamically encode the movement of the ipsilateral eye during horizontal disconjugate saccades was also found to encode the movement of the ipsilateral eye during vertical-facilitated vergence. Taken together with previous findings (Van Horn et al. 2008), this implies that the command provided by a given SBN is appropriate for facilitating shifts of vergence during disconjugate saccades by encoding integrated conjugate and vergence commands.
Interestingly, a number of neurons in this study were found to encode the movement of the "wrong" eye (e.g., the contralateral eye) or a combination of both eyes (e.g., binocular cells). This finding is consistent with the results of previous studies that have evaluated the responses of neurons in other premotor and motor nuclei. For instance, individual neurons in both the nucleus prepositus and abducens nucleus can preferentially encode the movement of either the contralateral or ipsilateral eye (McConville et al. 1994; Sylvestre and Cullen 2002; Sylvestre et al. 2003; Van Horn et al. 2008; Zhou and King 1998). Although at first glance this observation might appear surprising, it can be easily reconciled with the existing circuitry. First, the abducens nucleus consists of both internuclear and motoneurons and neurons. Thus a premotor neuron (such as an EBN) that preferentially encodes information about the contralateral eye may in fact project to the appropriate eye through internuclear neurons. Second, although neurons are generally assumed to have equal synaptic weights, unequal weighting of the projections most certainly exists. For example, premotor neurons that encode the movement of the ipsilateral eye may provide stronger synaptic inputs to the motoneurons. Finally, inappropriate signals that are sent to abducens nuclei could be both cancelled out by additional premotor inputs such that the final drive to the lateral rectus muscle is correct and/or offset by a cocontraction of the antagonist muscle (i.e., medial rectus; see DISCUSSION of Sylvestre and Cullen 2002).
Premotor circuits for the control of changes in vergence angle
Although SBNs have been shown to carry vergence-related (e.g., monocular) information during disconjugate saccades, two important questions remain when considering the neural control of gaze in three-dimensional space: 1) What is the source of the vergence-related information to the horizontal SBNs? and 2) What additional vergence commands are required to drive nonsaccadic vergence movements (i.e., when the saccadic burst generator is silent)?
First, although it is well recognized that information about an individual eye is available throughout most of the visual and visual-motor cortex the source of monocular information to the SBNs remains unknown (Gnadt and Beyer 1998; Hubel and Wiesel 1962, 1970). Two possible candidates are the mesencephalic reticular formation (MRF) and superior colliculus (SC) (Ferraina et al. 2000; Genovesio and Ferraina 2004; Gnadt and Beyer 1998; Gnadt and Mays 1995; Mimeault et al. 2004). Both of these structures receive inputs from disparity-sensitive cortical and subcortical regions and stimulation of both the MRF (goldfish: Luque et al. 2006; monkey: Waitzman et al. 2008) and SC (monkey: Chaturvedi and Van Gisbergen 1999, 2000; Suzuki et al. 2004; cat: Suzuki et al. 2004) have clear effects on vergence. Moreover, neurons in the SC (cat: Jiang et al. 1996; monkey: Walton and Mays 2003) and the MRF (Gamlin et al. 1994; Judge and Cumming 1986; Mays et al. 1986; Waitzman et al. 2008) are modulated during vergence eye movements. Notably, a recent report has shown that saccade-related burst neurons in the central MRF dynamically encode the movement of an individual eye during disjunctive saccades (Waitzman et al. 2008). These findings further support the proposal that inputs from the MRF and SC to the saccadic premotor neurons function in parallel with the cortico-pontine-cerbellar-midbrain loop, which has traditionally been viewed as the main pathway for the control of vergence (reviewed in Gamlin 1999). Although the traditional view describes the vergence and saccadic pathways as two distinct neural systems, our results, taken together with those of other recent studies, support the proposal that changes in vergence angle are controlled by means of a more distributed network.
Second, although we have clearly demonstrated that SBNs carry important vergence-related information to control saccades in three-dimensional space, SBNs are silent during slow vergence movements. For example, we have previously shown that the saccadic burst generator does not fire any action potentials during symmetric vergence as well as during periods of slow vergence that precede or follow disconjugate saccades (Van Horn et al. 2008). Thus this suggests that, whereas the SBNs function to rapidly drive the eyes to a new position, an additional vergence command is required to ensure accurate binocular realignment of gaze (King and Zhou 2000). Notably, neurons encoding slow vergence, which have been described near the abducens nucleus (Gnadt et al. 1988) and oculomotor nucleus (Judge and Cumming 1986; Mays 1984; Zhang et al. 1991, 1992), are likely candidates to drive such eye movements. Further work will be required to understand how neural circuits in the brain stem and cerebellum interact with descending control pathways to ensure the accurate control of gaze in three dimensions.
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ACKNOWLEDGMENTS |
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1 The online version of this article contains supplemental data. 
Address for reprint requests and other correspondence: K. E. Cullen, McIntyre Medical Research Building, Room 1220, 3655 Prom. Sir William Osler, Montreal, PQ, Canada H3G 1Y6 (E-mail: kathleen.cullen{at}mcgill.ca)
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