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Head Movement Evoked By Electrical Stimulation in the Supplementary Eye Field of the Rhesus Monkey

Department of Otolaryngology, University of Texas Medical Branch, Galveston, Texas; and Department of Otolaryngology University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 16 May 2005; accepted in final form 1 September 2005

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
Although the supplementary eye field (SEF) has been implicated in the control of head movements associated with gaze shifts, there is no direct evidence that SEF plays a role in the generation of head movements independent of gaze. If the SEF does, varying the duration of stimulation should selectively alter the head-movement kinematics during the postgaze-shift period. The duration of the stimulation was manipulated while head-unrestrained monkeys maintained stable head forward postures. The initial positions of the eyes in the orbits were systematically varied. Although combined movements of the eyes and head were produced in the majority of the trials, head movements were sometimes evoked in the absence of gaze shifts. These head-alone movements were most frequent when the initial eye position was contralateral to the stimulated side. When the stimulation produced eye and head movements, gaze onset was sometimes preceded by a relatively low-velocity phase of the head movement. Evoked head movements were primarily horizontal, unlike the gaze shifts, which typically had vertical components that varied according to the initial positions of the eyes in the orbits. The postgaze-shift head movements tended to be of low velocity and in many cases persisted until stimulation offset. In general, prolonging the stimulation resulted in improved centering of the eyes in the orbits. These findings suggest that, in addition to its previously described role in the generation of coordinated eye-head gaze shifts, the SEF is also involved in the control of head movements in the absence of a change of gaze.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
The supplementary eye field (SEF) occupies a small region in the dorsomedial frontal cortex. The SEF extends from the caudal end of the arcuate sulcus to the rostral end of the superior arm of the arcuate sulcus and is 2–5 mm from the midline (Huerta and Kaas 1990; Matelli et al. 1991; Schall 1991; Schlag and Schlag-Rey 1987; Wise et al. 1997). Early observations have suggested that this region is associated with the initiation of both eye and head movements (Ferrier and Yeo 1884; Penfield and Welch 1951; Smith 1949). Due to the lack of techniques for adequate assessment, these anecdotal observations have received little attention until recently. It is of interest that Levinsohn (1909; described in Smith 1949) noted that stimulating the dorsomedial frontal cortex, i.e., the SEF, evoked head movements that preceded eye movements. He also reported that the electric current needed to evoke such movements was relatively higher for the dorsomedial frontal cortex compared with that of the lateral oculomotor cortex, i.e., the frontal eye field (FEF). These unique characteristics were reported by these investigators as the major differences between the two regions, later identified as the SEF and the FEF.

Schlag and Schlag-Rey (1987) redefined the SEF based on the stimulation-evoked eye movements in head-fixed preparations. Since then, the role of the SEF in saccadic eye movement has been extensively studied (Amador et al. 2000; Bon and Lucchetti 1997; Chen and Wise 1995, 1996; Fujii et al. 1995; Missal and Heinen 2004; Russo and Bruce 1993, 2000; Schall 1991; Schiller and Chou 2000; Schlag and Schlag-Rey 1987; Stuphorn et al. 2000; Tehovnik and Lee 1993). All of these studies were conducted in head-restrained conditions. There were four anecdotal examples provided by Schlag and Schlag-Rey (1987), suggesting that SEF stimulation evoked not only eye movements but also head movements.

Several findings emerge in the studies involving SEF stimulation. Like the other oculomotor regions in the cortex, the evoked saccades in the SEF were directed toward the side contralateral to the stimulated hemisphere. In the large-amplitude sites, the stimulation-evoked saccades often converged toward a region located on the contralateral side (Russo and Bruce 1993; Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993). When the horizontal initial eye positions (IEPh) were deviated toward the ends of the converging saccades, the probability of stimulation-evoked saccades decreased and the threshold current (i.e., the stimulation current that evoked eye movements 50% of the time) increased up to 100 µA or higher. In some cases, eye movements were not elicited even at the highest current levels tested (Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993; Tehovnik and Sommer 1997). When saccades did occur, their onset latencies increased. It was also reported that, when the eyes were deviated in the unresponsive initial eye positions (IEPs) at target onset, stimulating the SEF prevented the saccadic execution (Tehovnik and Lee 1993). This unresponsive oculomotor space often covered a large contralateral field or occasionally up to the entire contralateral hemisphere. Whether head movements could be evoked within this relatively unresponsive oculomotor region remains unknown.

Recent developments in movement control techniques have made it possible to adequately assess the stimulation-evoked movements in head-unrestrained monkeys (Corneil et al. 2002a,b; Freedman and Sparks 1997; Phillips et al. 1995; Sparks et al. 2001). A recent microstimulation study investigated the SEF in head-unrestrained monkeys (Martinez–Trujillo et al. 2003). This study observed that SEF stimulation evoked coordinated movements of the eyes and head. This study also noted no sign of site-specific clustering for particular movements, e.g., segregation of eye- and head-movement sites. Instead the SEF stimulation evoked both eye and head movements that were kinematically similar to the visually guided eye-head movements.

If the SEF plays a role in controlling movements of the eyes and head, the following issues can be raised. First, are the stimulation-evoked head movements in the SEF necessarily accompanied by gaze shifts? It has been shown that subthreshold stimulation in the superior colliculus, which is interconnected with the SEF, can evoke slow head movements in the absence of gaze (monkey: Corneil et al. 2002a,b; cat: Galiana and Guitton 1992; Pelisson et al. 2001). It is not known whether, under similar or different circumstances, the SEF stimulation evokes similar types of head movements. Second, do the stimulation-evoked head movements in the SEF follow the rules established under the visually guided conditions, i.e., is the relative contribution of the eyes and head to the gaze shift affected by the initial positions of the eyes in the orbits (Delreux et al. 1991; Freedman and Sparks 1997; Fuller 1992; Gandhi and Sparks 2001; Goossens and Van Opstal 1997; Guitton et al. 1990; Sparks et al. 2001; Tomlinson and Bahra 1986; Volle and Guitton 1993)? Third, does SEF stimulation affect a process that is unique to head-movement control following gaze shifts, i.e., centering the eyes in the orbits (Sparks et al. 2001)? Previous research has shown that a short-duration of microstimulation truncates movements prematurely (for review, see Graziano et al. 2002). When the stimulation duration is extended to permit movement completion, complex movement sequences rather than muscle twitches or movement segments could be observed. Previous SEF stimulation studies in head-unrestrained conditions had used relatively short stimulation trains (160–200 ms) (Martinez-Trujillo et al. 2003; Schlag and Schlag-Rey 1987); the stimulation was terminated before the head movement was completed. Whether extending the stimulation in the SEF affects the postgaze-shift head movements, which in turn facilitate centering the eyes in the orbits, is not known.

The present study was designed to address our questions by employing stimulation of the SEF in head-unrestrained monkeys. Stimulation duration and the initial eye positions were varied systematically. The present data showed that stimulation in the SEF evoked head movements in the absence of gaze on some trials, particularly when the eyes were deviated in the contralateral direction at stimulation onset. Increases in stimulation duration resulted in increases in the duration of the head movements during the postgaze-shift periods. This portion of the head movements contributed significantly to centering the eyes in the orbits. The present results suggest the SEF plays a role in head-movement control independent of gaze.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
Subject and experimental procedures

Two juvenile rhesus monkeys (Macaca mulatta, 5–7 kg) served as subjects. In each monkey, a scleral coil was implanted over one eye to monitor eye movements (Fuchs and Robinson 1966; Judge et al. 1980). A different search coil, serving to monitor head movements, was cemented above the parietal bone near the midline. A stainless steel head-post was implanted over the occipital bone to restrict the animal's head movements during part of the experiments. A separate stainless steel post was implanted on the anterior ridge of the frontal bone; this post served to secure a lightweight microlaser (Edmund Scientific, No. M52263) fixture and juice-delivering tubing. A rectangular recording chamber (36 x 28 x 6 mm) was implanted and cemented over the left side of the frontal bone (17 mm A-P and 12 mm M-L). During recording, a cylindrical adaptor (18 mm diam) was used to fix the microdrive and the micropositioner to the recording chamber at the known coordinates to facilitate access to the SEF.

The monkeys were seated in a primate chair for daily training and experiments. The monkeys' heads were placed in a position near the center of the magnetic field. On head-restrained conditions, the head-post was clamped to a fixture that was secured to a rigid bar attached to the frame of the primate chair. On head-unrestrained conditions, the head post and the clamping bar were removed. A primate chair designed for conducting the head-unrestrained monkey experiment was used. The typical, horizontal neck plate that prevented the animals from moving their heads vertically was removed. Instead, the monkeys' collar (Primate Products) was secured between two pieces of paralleled Plexiglas plates, one against the animals' chests and the other against the animals' backs. When the monkeys' heads were free to move, the fore-aft displacements of their upper torsos and shoulders were limited to <2 cm between the two plates. Given these constraints, the head rotations were likely accounted for by neck rotations in the cervical segments of the spine. Contribution of the rest of the body to head rotations was minimal. The range of the head rotations was approximately ±50° along the horizontal meridian and ±30° along the vertical meridian. All surgical and experimental procedures conformed to the guidelines for the Care and Use of Animals of National Institutes of Health and the Institutional Animal Care and Use Committee.

Data acquisition

A 42-in cubic coil and a phase-angle detection system (CNC Engineering) were used to measure the horizontal and vertical position signals of the gaze (eye re space) and head sampled at 500 Hz. This system, in the horizontal dimension, was linear within 2% error over the entire range. Signals of the gaze coil were calibrated in the head-fixed condition by rewarding the monkeys for aligning their line of sight with the visual targets. In head-unrestrained conditions, the signal of the eye coil would reflect the line of sight with respect to the space (i.e., gaze) not with respect to the head. Signals of the head coil were calibrated in a head-fixed condition in which the overhead microlaser was turned on and the microlaser beam (with the head) was aligned with the visual targets of known angles. The position of the eyes (re head) was computed off-line by mathematically converting the horizontal and vertical coil signals to unit vectors, and the vectors were rotated with respect to the head in Fick coordinate. All of the displacement measurement was carried out following vector rotations by assuming zero torsion (Haslwanter 1995; Straumann et al. 1991).

A hydraulic microdrive (Kopf Instruments) was used to advance the epoxylite-insulated tungsten electrodes (Frederic Haer) through the dura surface, which was prepunctured by a sharpened needle (details see Chen et al. 2001). Neural signals were band-pass (500 Hz to 5 kHz) filtered using a differential amplifier (Bak Electronics). Microstimulation was carried out using a stimulator (S88, Grass Instruments) and an optical isolation unit (PSIU6, Grass Instruments). The stimulation pulses were discriminated using a BAK window discriminator. The stimulation trains consisted of 0.2-ms, monopolar, cathodal pulses. Stimulation duration ranged from 300 to 600 ms. Because there was no previous report regarding the current threshold of the stimulation-evoked head movements in the SEF, we typically explored with a two to three times suprathreshold current identified for evoking gaze shifts. Typical current intensity and stimulation frequency were 100 µA (range: 80–150 µA) and 200 Hz (range: 100–200 Hz), respectively. We found that the current of 100 µA was, in general, effective in evoking eye-head combined gaze shifts. It was difficult to monitor the actual current delivered through the high-impedance electrodes; all of the current intensity reported in the present report was taken from the face value of the stimulator.

Data were acquired using a Pentium microcomputer running an in-house data acquisition software originally developed by P. Glimcher and D. Sparks. This data-acquisition program allowed a laboratory computer to control the location and duration of visual targets and to monitor horizontal and vertical positions of gaze and head. In addition, the software allowed for controlling the delivery of the stimulation trains and the juice reward.

Behavioral paradigms and microstimulation

Visual targets were presented on a tangent screen with a rectangular array of tri-state (red, green, yellow) light-emitting diodes (LEDs), which consisted of 41 rows of 49 lights equally spaced (by 2 in) in either horizontal or vertical dimension. Throughout the experiments, the LED board was placed at a distance of 72 cm (28.5 in) from the monkeys. The spacing between the adjacent horizontal or vertical LEDs near the center of the board was 2° with respect to the monkeys.

The monkeys were trained in a visually guided gaze shift task that permitted independent control of the gaze and head. Figure 1A illustrates the onset and offset sequence of the targets in the task. The task began with the monkeys sitting straight ahead, aligning a head-mounted microlaser beam with a visual (red) target via visual feedback. Later, a second (green) target was illuminated, and the monkeys deviated their eyes to the target while maintaining a stable head posture. The green target was usually displayed in 27° steps (i.e., 15 LED in spacing) horizontally or vertically with respect to the horizontal or vertical meridian of the initial red target. Some 600–800 ms after the onset of the green target, all targets and the microlaser were extinguished for 400–500 ms. The same red and green targets and the microlaser were re-illuminated (500–700 ms) and then re-extinguished. Some 400–600 ms later, a third (yellow) target was illuminated at a randomly chosen location, and the monkeys made a gaze shift to acquire the target. A drop of juice reward was delivered in contingency on the successful execution of the gaze shift. To achieve eye-head postural constraints, gaze and head "windows," typically ranging 5 and 10° in radius, respectively, were set up in a close-loop real-time control. Reward was contingent on the monkeys keeping their gaze and head positions within these windows. If either gaze or head stepped outside of the windows during the designated period of postural constraints, the trial was aborted.

View larger version (26K): [in this window] [in a new window]   FIG. 1. Schematic flow charts illustrating onsets and offsets for the targets (indicated as red, green, and yellow) and the microlaser (indicated as laser) in the control trials (A) and stimulation trials (B). The open rightward arrows indicate the epochs when the targets were illuminated, whereas the filled rightward arrows indicate the epochs when the targets were extinguished. The vertical filled arrow in A corresponds to the onset of electrical stimulation in B, whereas the open arrow corresponds to the onset for a visual (yellow) target. Note in B, stimulation was delivered 200 ms after the extinction of all visual targets and microlaser; these visual sources remained extinguished throughout the period of electrical stimulation (300–600 ms) and the subsequent period of 500–800 ms.

Electrical microstimulation trials (Fig. 1B), interleaved with control trials, were carried out in 50% of the trials for each block. The stimulation trials were similar to the control trials except that the electrical stimulation was always delivered 200 ms after the first extinction of both the red and green targets. From that point on, the red and green visual targets and the microlaser remained extinguished. Approximately 800–1,400 ms later, a visual (yellow) target was illuminated, just like that in the control trials, and the monkeys were rewarded for making a gaze shift to the target. A major difference between the stimulation and the control trials was that the former imposed postural constraints up to the point before stimulation was delivered, whereas the latter imposed postural constraints throughout the task.

The control trials were designed to mimic the stimulation trials. Both trial types imposed that the monkeys maintained stable eye and head postures in darkness after the extinction of the red and green targets and the microlaser. Two critical features in these designs are worth of pointing out. The red and green targets were re-illuminated 500–700 ms after the beginning of the gap period (in the control trials), and the stimulation was always applied 200 ms after the beginning of the gap period (in the stimulation trials). Therefore at the time of stimulation, there was no way for the monkeys to know whether the trial was a stimulation trial or a control trial. The monkey could only anticipate the re-appearance of the red and green targets at locations corresponding to their current eye and head positions. In other words, re-illuminating the visual targets in the control trials ensured that the animals were motivated to maintain their current eye and head positions rather than anticipating and executing volitional or anticipatory movements.

In some stimulation sites, we carried out the "nontask mode" stimulation, in which the stimulation train was delivered during the inter-trial interval (duration: 500–1,500 ms; see RESULTS). Like the "task mode" stimulation, there was no visual target and no postural constraints prior to, during, or after the delivery of the stimulation. However, a visual (yellow) target was illuminated after a similar time course as the task-mode stimulation, and the monkeys were rewarded for making a gaze shift to the target. There were two important aspects of this trial type. First, the stimulation was delivered without warning, i.e., there were no visual or auditory stimuli that cued the animals as to when the trial started. Even if the animals wanted to, they could not time the upcoming stimulation. Second, there was no postural restriction for the positions of the eyes or head. The animals were presumably as relaxed as they could be in any natural upright postures. It was unlikely for the animals to generate volitional movements on a consistent basis within tens of milliseconds after the stimulation.

Due to the fact that it was impossible to know whether a given electrode penetration was made parallel, orthogonal, or oblique with respect to the cortical surface, we considered the stimulation depth separated by 500 µm as different sites. Concerning the fact that SEF was located on top of the dorsomedial frontal cortex and was relatively shallow, in general, a successful electrode penetration yielded one stimulation site with usable data. Occasionally, two sites with distinctive characteristics were obtained in the same penetration. The evoked movements in different sites were analyzed separately. In addition, care was taken to avoid stimulating the white matter beneath the cortex. The electrodes were always advanced sufficiently deep, and the border between gray and white matter was identified based on the diminishing unit discharge in the background. Once the electrode was confirmed to have reached the white matter, the electrodes were then slowly withdrawn. The stimulation was carried out 100 µm away from the border of the white and gray matter. Data obtained in the white matter, if any, were excluded from the analyses.

Data analyses

Data analyses were performed using an in-house program on a Windows platform. Movement onsets and offsets were determined based on a set of velocity criteria (gaze: 80°/s for the horizontal onset and 60°/s for the vertical offset; head: 6°/s for both horizontal and vertical onset and offset). Movements were displayed 100 ms prior to and 800 ms after the stimulation onset, and measurements were taken strictly based on velocity criteria. Any movement detected prior to stimulation onset was removed from further analysis. Due to the inherent noise in the low-velocity head-movement data, the head-movement velocity was filtered separately from the gaze data. A digital Taylor-series filter and a sliding probabilistic threshold-window were implemented. The latter, probabilistic threshold-filter computation was designed to circumvent the situation in which the head velocity fluctuated around the velocity threshold (Chen and Walton 2004). For the head-movement onset velocity cutoff, a 36/50 ratio (i.e., 72 vs. 100 ms) was used. For head-movement offset velocity cutoff, a 11/16 ratio (i.e., 22 vs. 32 ms) was used. In our experience, there were only a few cases, if any, where the onset of the head movements was ambiguous. These head movements often had an inconsistent velocity profile near or below the detection threshold, such that no human intervention would make much difference. These trials were abandoned.

Staircase gaze shifts were occasionally encountered in the SEF stimulation data. These gaze trials could be accompanied by multiple head movements that were not within the scope of the present study. These trials were excluded from the analyses. Statistical analyses were performed using Statistica (Statsoft). Throughout this paper, the averages of the data are presented as means ± SD unless otherwise indicated.

At the end of experiments, the monkeys were killed with an overdose of pentobarbital, and the brains were removed for histological examination. Stainless-steel pins were inserted through the known coordinates and left in the brain during perfusion for the facilitation of coordinate reconstruction.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
A total of 78 stimulation sites were studied in the left SEF of two head-unrestrained monkeys (72 in M1 and 6 in M2). The SEF was identified based on the existence of low current threshold for evoking gaze shifts and staircase saccades (Russo and Bruce 1993; Schall 1991; Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993). Large-amplitude sites (10° when the eyes deviated in the direction ipsilateral to the stimulated side) were selected for conducting the stimulation experiment as large-amplitude gaze shifts would recruit significant head movements (Guitton et al. 1990; Sparks et al. 2001; Tomlinson and Bahra 1986). Data shown in the present study included the conditions in which the monkeys' initial head positions were maintained in head forward positions (see METHODS). That is, the initial head position was controlled within a limited and consistent range. The initial eye position (re head, IEP) was systematically varied. Due to the fact that the observations in the SEF stimulation of both monkeys were comparable, the data from both monkeys were pooled in all analyses.

Figure 2 illustrates the horizontal position (A) and velocity traces (B) of the stimulation-evoked [gaze, eye (re head), and head] movements in a given SEF site. Because the head velocities were typically lower than those of the gaze and eye movements, the peaks of gaze- and eye-velocity traces were truncated to facilitate the display of head-velocity profiles (Fig. 2, B–D). As shown in the velocity traces in Fig. 2B, the gaze-, eye-, and head-velocity traces initially overlapped one another. About 70 ms after the onset of stimulation, the head velocity increased to 20°/s. At the same time, the eye velocity increased in synchrony with the head by approximately the same magnitude but opposite in direction (i.e., VOR gain equals one). Some 100 ms later, the gaze shift was initiated; head velocity increased to 40–50°/s. Head velocity peaked after the offset of gaze shift and eventually declined to 0. As in the examples shown in Fig. 2, the entire movement was accomplished within 300–400 ms. The gaze shifts, which occurred with the head movements, were as brief as 50–100 ms. Furthermore, the onset latency of the head movements could vary relative to either the onset of stimulation or the onset of gaze shifts. Head onset preceded gaze onset by 60–100 ms as was the case in Fig. 2, B and D. By contrast, head onset lagged gaze onset by 35 ms in Fig. 2C.

View larger version (23K): [in this window] [in a new window]   FIG. 2. Examples of horizontal position (A) and velocity (B–D) traces of the stimulation-evoked movements in a (left) supplementary eye field (SEF) site. A: horizontal position traces for gaze (G), eye (E), and head (H) when horizontal initial eye position (IEPh) was centered in the orbits (IEPo). The horizontal bar indicates the duration of electrical stimulation, 300 ms in this case. Upward deflection indicates rightward movement, whereas downward deflection indicates leftward movements. B: horizontal velocity traces of head, gaze, and eye for the same data displayed in A. The arrowhead and the arrow indicate the onset and the offset of the evoked head movements. C and D: horizontal velocity traces for eye, gaze, and head when IEPh was in the direction ipsilateral (IEPi) or contralateral (IEPc) to the stimulated side, respectively. Stimulation: 120 µA, 200 Hz, and 300 ms. E: horizontal velocity traces for eye, gaze, and head of a control trial (IEPo) in the same block. The filled and open arrows correspond to those plotted in Fig. 1A. Open box, the period in which the red and green targets and the microlaser were re-illuminated, as shown in Fig. 1. All traces are plotted in the same horizontal scale.

We often observed eye and head, head alone, and eye alone trials in the same site. There was no indication of any site-specific clustering for the movements evoked by electrical stimulation. However, depending on the context of movement execution (e.g., stimulation duration and eye positions in the orbits), the characteristics of the stimulation-evoked movements would vary. These points will be elaborated in later sections.

Kinematics of the stimulation-evoked head movements

The trials in which the initial head position was centered with respect to the body (see METHODS) and the head displacements were 2° (n = 1,163) were selected for the kinematics analysis. Figure 3A plots the relationship between the horizontal and vertical components of these head movements, in which two features can be noted. First, the overwhelming majority (99.1%, 1,153/1,163; M1 = 1,074/1,084; M2 = 79/79) of these head movements were directed away from (i.e., contralateral with respect to) the stimulated side. The rest of the head movements had very small displacements (–2.6 ± 1.2°) in the ipsilateral direction.

View larger version (43K): [in this window] [in a new window]   FIG. 3. Amplitude and velocity of the stimulation-evoked movements in the SEF. A and B: horizontal and vertical components of the head displacement (A) and peak velocity of the horizontal head (Hh) movements plotted as a function of horizontal head displacement (B). Only the trials in which the total head displacement exceeded 2° were included. C and D: horizontal and vertical components of the eye displacement (C) and peak velocity of the horizontal eye (Eh; re head) movements plotted as a function of horizontal eye displacement (D). Positive values in A and C reflect movement in the rightward (i.e., contralateral from the side of stimulation) or upward direction. The central line of box plots indicates the median; each side of the box indicates either 25 or 75% of the total. The whisker at both ends indicates 1 or 99% of the total. Data from the stimulation sites (n = 78) of both monkeys were included in the plots.

Figure 3B plots the main sequence characteristics, i.e., peak velocity versus displacement, of these head movements. The slope of the linear regression of the data were 3.86 (Pearson Correlation r = 0.90; P < 0.01), which closely resembled the main sequence of the visually guided head movements. When the data were separated for IEPh conditions, the slope in the IEPo condition (slope = 3.5, r = 0.89) was slightly lower than that in IEPi (slope = 4.2, r = 0.95) or IEPc (slope = 4.7, r = 0.89) conditions (ANCOVA for homogeneity of slope model, F = 7.8, P < 0.01).

The horizontal peak head velocity (Fig. 3B) was dwarfed when compared with the horizontal peak eye (re head) velocity (Fig. 3D). In general, the horizontal peak head velocity was highly limited, e.g. 1/6 of the magnitude of the horizontal peak eye velocity for a 20° horizontal eye displacement. These data were consistent with those of visually guided head movements (Corneil et al. 2002a,b; Freedman and Sparks 1997; Guitton et al. 1990; Martinez-Trujillo et al. 2003; Phillips et al. 1995).

Effects of stimulation duration

To gain insights into the detailed characteristics and timing of the stimulation-evoked movements, Fig. 4 plots individual traces of the horizontal head and gaze velocities for a given SEF site. The top panels illustrate the example head-velocity traces evoked by 300-ms stimulation, and the bottom panels illustrate the traces evoked by 600-ms stimulation. The plots are grouped by IEPh conditions. Five traces (2 of high peak velocities, 2 of low peak velocities, and 1 of medium peak velocity) were selected to represent the typical head- and gaze-velocity profiles for a given stimulation condition. Several features can be noted in the plots. First, similar to those observed in the visually guided eye-head combined movements, the stimulation-evoked head velocity typically rose to peak near or following the end of gaze shifts (i.e., when the gaze velocity declined to near baseline). The peak velocities of the head movements varied from 20 to 120°/s. However, for a given IEPh condition, there was no consistent trend that could predict the peak head velocity on a particular trial.

View larger version (51K): [in this window] [in a new window]   FIG. 4. Effects of stimulation duration (top: 300 ms; bottom: 600 ms) on the velocities and durations of stimulation-evoked head movements, separated for IEPi (range: –28:–15°, left), IEPo (range: –6:6°; middle), and IEPc (range: 15:28°, right) conditions in one SEF site. The horizontal velocity traces for head and gaze are plotted in black and gray, respectively. Upward deflection indicates rightward movement, which is contralateral to the stimulated (left) SEF. Shaded regions indicate the epoch in which the electrical stimulation was delivered. Arrowheads show the head onsets, and arrows indicate the head offsets. The trials in which staircase gaze shifts occurred and those in which the gaze shift latency was longer than 300 ms were excluded from the analysis. Stimulation: 120 µA, 200 Hz, and 300 (and 600) ms.

Third, head onset varied significantly with respect to stimulation onset. Also, head onset varied significantly with respect to gaze onset. The variability of head onset persisted from trial to trial in all IEPh conditions. A close examination of this figure suggests that the stimulation often produced a low-velocity phase of head movement that remained below threshold for up to several tens of milliseconds. Unfortunately, this early phase of the movement was sometimes of such a low velocity that it was impossible to reliably detect. Nonetheless, it is clear that the stimulation did not consistently produce a robust head movement beginning at a particular latency.

Fourth, significant head movements were sometimes evoked in the absence of gaze shifts. These head-alone movements were fairly common in the IEPc condition (93%, 1,000/1,074). Head-alone movements were also sometimes observed in the IEPo condition (114/212). In sharp contrast, the majority (97%, 289/297) of the trials obtained in the IEPi condition contained eye-and-head movements. In general, the peak head velocities of the head-alone trials were comparable to those of the eye-and-head trials. The biased occurrence of the head-alone trials in the IEPc condition was consistent with the notion that the majority of SEF sites contained unresponsive IEP regions in the direction contralateral to the stimulated sides (Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993). Also, the existence of the head-alone trials suggests that gaze shifts were not a prerequisite for the stimulation-evoked head movements.

Onset and offset latencies of head movements

To quantify the effects of stimulation duration on the onset and offset latencies of head movements, the data obtained in two SEF sites were selected for plots in Fig. 5. It can be noted that the distributions of the head onset latencies for 300-ms [117 ± 44 ms (n = 50) and 120 ± 52 ms (n = 48) for sites A and B, respectively] and 600-ms [107 ± 39 ms (n = 30) and 134 ± 54 ms (n = 41) for sites A and B, respectively] trials overlapped each other. No significant differences were found between the two trial types (F = 1.5, P = 0.22 for Fig. 5A1; F = 1.1 P = 0.29 for Fig. 5B1).

View larger version (35K): [in this window] [in a new window]   FIG. 5. Examples of the effect of stimulation duration on the onset (A1 and B1) and offset (A2 and B2) latencies of the stimulation-evoked head movements in 2 SEF sites. . 300-ms trials (n = 56 in site A and n = 53 in site B); . 600-ms stimulation trials (n = 31 in site A and n = 37 in site B); , the overlap bins between the 2 trial types. Data in B were obtained in the same site as in Fig. 4. Stimulation: site A: 100 µA and 200 Hz; site B: 120 µA and 200 Hz.

Figure 6 quantifies the latencies of head onset as a function of IEPh across all of the stimulated sites in the SEF. When head movements with onset latencies within 50–300 ms were selected for this analysis, there was a significant correlation between the head onset latencies and the IEPh [slope = –1.13 (M1 = –1.11; M2 = –1.14); r = 0.32, F = 178, P < 0.01; Fig. 6]. When the IEPh was deviated in the direction opposite of the movements (i.e., IEPi; negative IEPh values), the latency of head onset was increased as compared with the other conditions. Post hoc analyses revealed that the head onset latency in the IEPi condition (mean latency: 155 ± 63 ms, n = 297) was significantly longer than those in IEPo (mean latency: 123 ± 68 ms, n = 326) and IEPc (mean latency: 111 ± 46 ms, n = 493) conditions (ANOVA, Scheffe test, P < 0.01 for both). There was no significant difference in the latencies of head onset between IEPo and IEPc conditions (Scheffe test, P = 0.31).

View larger version (19K): [in this window] [in a new window]   FIG. 6. Correlation between the onset latency of horizontal head movement and IEPh. Data points represent means ± SD of all stimulation trials. Bin width: 10°. Positive IEPh values indicate that the eyes were contralateral with respect to the stimulated side, whereas negative values indicate that the eyes were ipsilateral with respect to the stimulated side.

View larger version (21K): [in this window] [in a new window]   FIG. 7. Effects of stimulation duration (A: 300 ms, B: 500 ms, and C: 600 ms) on the offset latencies of the stimulation-evoked head movements. Only the head movements 200 ms in duration were included in the plots. , the time point when the stimulation train was terminated.

As the stimulation-evoked gaze shifts often drive the eyes to the eccentric positions in which the visual and oculomotor performances were limited, one may wonder whether the eye positions in the orbits are correlated with the displacements of the postgaze-shift head movements. Figure 8 illustrates the examples of the effect of eye positions at gaze offset on the displacement of the postgaze-shift head movement. The displacement of the postgaze-shift head movement, measured as the head displacement between gaze offset and head offset during which the gaze was stabilized (Fig. 8A), will be referred to as "head contribution to eye counter-roll (HcEc) during the postgaze-shift period" in the remainder of the text. Several observations are described in the following text.

View larger version (26K): [in this window] [in a new window]   FIG. 8. Examples of horizontal gaze (G) and horizontal head (H) position traces of the eye-and-head trials in which SEF stimulation evoked both gaze shifts and head movements, illustrating the metrics of horizontal head contribution to eye counter-roll (HcEch; A). B and C: positive correlation between horizontal head contribution to eye counter-roll and EPh at gaze offset in 2 SEF sites. Extended stimulation prolonged the horizontal head contribution to eye counter-roll ( and —, 600-ms stimulation; and - - -, 300-ms stimulation). Site C is the same as that illustrated in Fig. 4. EPh: horizontal eye position; EPv: vertical eye position.

Figure 9 quantifies this effect across all SEF sites tested. The analysis was carried out on the eye-and-head trials among those analyzed in Fig. 7. For the sake of comparison, the trials in which gaze shifts were most consistently observed across three different stimulation durations (i.e., IEPi and IEPo conditions) were pooled together for analysis. Overall, the horizontal head contribution to eye counter-roll was strongly correlated with the horizontal eye position at gaze offset (Fig. 9A; r = 0.59, P < 0.01, n = 560). Note that in Fig. 9A, when EPh was 0° (i.e., ipsilateral to the stimulated side), the head contribution to eye counter-roll was negligible (0.5 ± 0.8°, n = 27). In other words, when the eyes were already near the center of the orbits, stimulation failed to drive the head to continue moving. But as the horizontal eye positions were deviated further contralaterally, the head contribution to eye counter-roll was increased systematically as a function of the horizontal eye positions at gaze offset.

View larger version (19K): [in this window] [in a new window]   FIG. 9. Positive correlation between horizontal head contribution to eye counter-roll (HcEch) and horizontal eye positions (EPh) after gaze offset (A) and lack of correlation between vertical head contribution to eye counter-roll (HcEcv) and vertical eye positions (EPv) following gaze offset (B). Data were obtained from the eye-and-head trials, separated for different stimulation durations (, 300 ms; +, 500 ms; , 600 ms) for all sites. Positive values in A indicate the (right) positions contralateral to the stimulated (left) side; positive values in B indicate the (up or down) positions in the direction of movements. Only trials with head displacements of 2° were included. Data points represent means ± SE. Bin width: 5°.

As pointed out earlier (Fig. 3), the stimulation-evoked head movements in the SEF were primarily horizontal. The vertical head contribution to eye counter-roll in these trials was negligible (average: 0.2 ± 0.7°) regardless of stimulation durations (r = 0.01, P > 0.80; Fig. 9B).

Head-alone trials

In these trials, the correlation between horizontal head contribution to eye counter-roll and eye position at head onset was relatively weak but remained significant. Figure 10A illustrates the example of a positive correlation between the horizontal head displacement and the horizontal eye positions (r = 0.60, P < 0.01, n = 53 for site B; r = 0.58, P = 0.001, n = 28 for site C) in two SEF sites. The stimulation duration had a significant interactive effect in these trials (F = 17.5, P < 0.01 in Fig. 10B; F = 8.9, P < 0.01 in Fig. 10C), indicating that extended stimulation indeed improved the horizontal head contribution to centering the eyes in the orbits.

View larger version (24K): [in this window] [in a new window]   FIG. 10. Examples of horizontal head and gaze position traces of the head-alone trials illustrating the metrics for the horizontal head displacement (A). B and C: positive correlation between horizontal head displacement and EPh at gaze offset in 2 SEF sites. Extended stimulation prolonged the head displacements ( and —, 600-ms stimulation; and - - -300-ms stimulation). Site C is the same as that illustrated in Fig. 4.

View larger version (21K): [in this window] [in a new window]   FIG. 11. Positive correlations between horizontal head displacement and eye positions at head onset (A) and weak correlation between vertical head displacement (Hv) and eye positions (EPv) at head onset (B). Data were obtained from head-alone trials, separated for different stimulation durations (300, 500, and 600 ms). Positive values in A indicate the (right) positions contralateral to the stimulated (left) side; positive values in B indicate the (up or down) positions in the direction of movements. Data points represent means ± SE. Bin width: 5°. Only the trials with head displacements of 2° were included.

Several unique differences could be noted in the comparison between the eye-and-head trials (Fig. 9A) and the head-alone trials (Fig. 11A). First, the former contained a negligible horizontal head contribution to eye counter-roll when EPh was 0°. The latter contained a small but consistent horizontal head displacement (4.1 ± 2.2°, n = 76) even when EPh was centered in the orbit (range: 0:5°) or biased ipsilaterally (range: –5:0°; indicated by a downward arrow in Fig. 11A). The difference between the two trial types was highly significant (t-test, P < 0.01). This unique feature was reminiscent of the stimulation-evoked head-alone movements in the superior colliculus and had not been reported in the SEF in the past (Corneil et al. 2002a,b; Pelisson et al. 2001). Second, the head-alone trials (Fig. 11A) did exhibit a general tendency for the horizontal head displacement to increase as a function of the horizontal eye positions. However, detailed inspection indicated that this effect was not significant between when the eyes were deviated 20–25° in the orbits and when the eyes were deviated 25–30° in the orbits (F = 0.02, P > 0.86 for 600-ms trials; F = 0.03, P > 0.87 for 500-ms trials; F = 3.6, P > 0.06 for 300-ms trials; Fig. 11A). It appears that the differences occurred depending on whether or not gaze shifts took place.

Head contribution to gaze shift

Figure 12 illustrates the effect of IEPh on the relationship between head contribution to gaze shift and gaze amplitude. The horizontal head contribution to gaze shift (HcGh; defined as the horizontal head displacement between gaze onset and gaze offset; Fig. 12A) was positively correlated with horizontal gaze (Gh) amplitudes (Fig. 12B). This relationship shifted when the IEPh was systematically varied. The vertical head contribution to gaze shift (HcGv, defined as the vertical head displacement between gaze onset and gaze offset) was negligible (0.32 ± 0.77°; slope = 0.00–0.01; Fig. 12C). These results were reminiscent of those observed in the visually guided gaze shifts (Guitton et al. 1990; Phillips et al. 1995; Sparks et al. 2001; Tomlinson and Bahra 1986).

View larger version (27K): [in this window] [in a new window]   FIG. 12. Examples of head and gaze position traces of the eye-and-head trials illustrating the metrics of horizontal head contribution to gaze shifts (HcGh; A, top traces) and vertical head contribution to gaze shift (HcGv; A, bottom traces). B: systematic varying IEPh shifted the horizontal head contribution to gaze shift as a function of horizontal gaze amplitude. C: vertical head contribution to gaze shifts was negligible despite the variability of vertical gaze amplitude and IEPh. Data were separated for IEPi (), IEPo (*), and IEPc (). Bin width: 5°.

View larger version (22K): [in this window] [in a new window]   FIG. 13. Effect of IEPh on the distributions of the latency difference between head onset and gaze onset (top and middle) and horizontal head contribution to gaze shifts (bottom). Data were obtained from the eye-and-head trials, separated for IEPi, IEPo, and IEPc. Box plots follow the same format as Fig. 2.

We further contrasted the timing difference between the head and gaze onsets of the stimulation trials with that of the visually guided gaze shift trials. The latter trials took place following the illumination of the yellow target in the task (see Fig. 1 and METHODS). This timing difference in the visually guided gaze shifts ranged from –204 to 196 ms with an average of –5.1 ± 43.4 ms (n = 1370; –5.2 ± 39.6 ms for M1, n = 638; –4.9 ± 46.6 ms for M2, n = 732). Similar to the finding illustrated in Fig. 13, when the horizontal head contributions to gaze shifts of 1° were considered, the values leaned toward the negative end, i.e., the difference between head onset and gaze onset became –20.8 ± 29.2 ms (–19.1 ± 24.9 ms for M1; –22.2 ± 32.4 ms for M2). In essence, consistent with previous studies, the significant head contributions to gaze shifts in these visually guided trials came primarily from those in which head onset led gaze onset (Galiana and Guitton 1992; Gandhi and Sparks 2001; Goossens and Van Opstal 1997; Guitton et al. 1990).

Eye-alone trials

As pointed out earlier, SEF stimulation sometimes evoked gaze shifts in the absence of head movements. The head movements in these eye-alone trials (n = 543) were simply nonexistent or below the velocity criteria (see METHODS). The majority (81%; n = 438; M1 = 419/522; M2 = 19/21) of the eye-alone trials were obtained in the IEPi condition, whereas the minority (19%; n = 104; M1 = 102/522; M2 = 2/21) was obtained in the IEPo condition. In the IEPi condition (average IEPh: –23.0 ± 2.7°), the average horizontal gaze displacement was 22.5 ± 7.4°, and the average EPh at horizontal gaze offset was –0.2 ± 6.6°. In the IEPo condition (average IEPh: –0.2 ± 1.5°), the average horizontal gaze displacement was 7.7 ± 5.0°, and the average horizontal eye position (EPh) at gaze offset was 7.2 ± 4.6°. Only one eye-alone trial was found in the IEPc condition; this trial had a horizontal gaze displacement of 3.4°. In essence, the movement metrics exhibited in the eye-alone trials had two main features: the horizontal gaze displacements remained comfortably within the oculomotor range and the eye deviations at the end of the gaze shifts remained close to the center of the orbits. In such a case, head movements were not recruited as shown in visually guided gaze shifts (Freedman and Sparks 1997; Guitton et al. 1990; Sparks et al. 2001).

Nontask mode stimulation

One may wonder whether the visual stimuli or the postural control in the task had biased the outcome of SEF stimulation. Specifically, one may wonder whether the observed early head movements had been voluntary movements initiated by the animals. To rule out these possibilities, we conducted the nontask mode stimulation in 18 SEF sites (16 in M1 and 2 in M2) during the intertrial interval in the dark (see METHODS).

Figure 14A illustrates the stimulation-evoked movement traces under this trial type in a SEF site. Based on the comparison between the traces of Fig. 14A and those of Fig. 4, one can note that these trials were alike in many aspects. Head onset could lag or lead gaze onset (Fig. 14A, 300-ms stimulation). The head-alone trial could be evoked occasionally (Fig. 14A, middle traces in 600-ms stimulation). Also, the early head trials were prevalent. These trial types were present in both monkeys.

View larger version (33K): [in this window] [in a new window]   FIG. 14. Examples traces of horizontal head velocities and horizontal gaze shifts of the stimulation-evoked movements during the nontask mode stimulation (A). The range of the IEPh and the IHPh at stimulation onset are shown on the right of the traces. Stimulation parameters: 120 µA and 200 Hz. B: positive correlation between horizontal head contribution to eye counter-roll and EPh at gaze offset of all nontask mode stimulation trials (300-ms stimulation: , n = 128; 600-ms stimulation trial: , n = 46; means ± SE). Data points represent the average values in 5° bins [horizontal initial head position (IHPh) range: –10:10°]. Also included in B are visually guided gaze shift trials obtained from the control trials (, n = 1,233; mean ± SD). , the range of all data obtained from the visually guided gaze shifts trials.

We further compared the stimulation-evoked head movements to the visually guided head movements. Figure 14B illustrates the average () and the range () of head contribution to eye counter-roll for the visually guided gaze shift trials (n = 1,370; n = 638 for M1 and n = 732 for M2). Two major points can be noted. First, the data points of both 300- and 600-ms stimulation trials fell within the range of the visually guided gaze shift trials. Second, consistent with the fact that 300-ms stimulation prematurely truncated the head movements, the 300-ms stimulation trials exhibited smaller head contribution to eye counter-roll as compared with the average of the visually guided gaze shift trials. On the other hand, 600-ms stimulation exceeded the completion of typical head movements, and thus these trials exhibited higher than average head contribution to eye counter-roll.

SEF map

Figure 15 summarizes the distributions of eye-alone, head-alone, and eye-and-head trials in the SEF of one monkey in which the SEF was thoroughly mapped. Only movements of 2° were included in this analysis. It can be noted that the eye-alone trials were relatively evenly distributed (Fig. 15B). The center of gravity for these sites was 7 mm rostral from the caudal end of the arcuate sulcus and 4 mm from the midline. This SEF map appears consistent with previous studies that suggest that the saccadic sites are located rostrally whereas the smooth pursuit sites are located caudally (Chen and Wise 1995; Fujii et al. 2002; Fukushima et al. 2004; Schall et al. 1993).

View larger version (25K): [in this window] [in a new window]   FIG. 15. Stimulation sites (A) and the distribution of eye-alone (E-alone; B), head-alone (H-alone; C), and eye-and-head (E-and-H; C) trials in the SEF of a monkey. The vertical dashed line in A indicates the (chamber) coordinate which is approximately in line with the caudal end of the arcuate sulcus. Ar: arcuate sulcus; Ce: central sulcus; Pr: principal sulcus. The size of the symbols in B and C is plotted in proportion to the number of trials indicated in the bottom-left corner in each panel.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
The present study has provided several lines of evidence supporting the hypothesis that the SEF is directly involved in the control of head movements independent of gaze. First, when the eyes were deviated in the contralateral direction (or near the unresponsive IEP region) at stimulation onset, head movements were often evoked in the absence of gaze shifts. Second, when the stimulation duration was increased, the postgaze-shift portion of the head movements was prolonged, and the head contribution to centering the eyes in the orbits was greater. Finally, stimulation sometimes evoked low-velocity head movements that preceded the onset of gaze shifts. When this happened, the head contribution to gaze shifts often increased. Some alternative interpretations of these findings are discussed in the following text.

Head contribution to eye centering and SEF

Two hypotheses have been postulated to account for the fact that the head often continues to move following large-amplitude gaze shifts. The head displacement command hypothesis states that the entire head movement is preprogrammed, and the head amplitude is determined by the desired displacement (Bizzi et al. 1971; Laurutis and Robinson 1986; Morasso et al. 1973). Data supporting this hypothesis come from studies showing that the total head displacement is positively correlated with target and gaze amplitudes (Freedman and Sparks 1997; Laurutis and Robinson 1986; Phillips et al. 1995; Volle and Guitton 1993). If the SEF indeed codes for head displacement, one would expect the stimulation to evoke consistent head displacements at least in some SEF sites. However, as shown in our results, even though the stimulation duration was extended 600 ms, these head displacements remained highly variable for any given site (e.g., Fig. 4). That is, there is no site-specific maximum head amplitude encoded in the SEF. This result is in sharp contrast to the stimulation-evoked gaze shifts. Given that the stimulation is extended beyond the end of gaze, the site-specific maximum gaze amplitude would be evoked independent of the duration of the extended stimulation (Freedman et al. 1996; Stanford et al. 1996). Nonetheless, our finding does not preclude the possibility that other cortical areas may contain a pure head displacement command.

The results of Figs. 9 and 14 suggest that head-movement control is programmed not based on the desired head displacement per se. The eye positions in the orbits provide the justification for the head to continue to move or to stop from moving. Ultimately, the eyes were rolled to the most flexible oculomotor range, i.e., near the center of the orbits (Goossens and van Opstal 1997; Guitton et al. 1990; Sparks 1999; Sparks et al. 2001; Tomlinson and Bahra 1986). These rationales suggest an alternative eye centering hypothesis with the following predictions (Sparks et al. 2001). First, if the eyes were already centered (or within the flexible oculomotor range), the head should move very little. Second, there must be a lawful relationship existing between the amount of eye deviation in the orbit and the amount of postgaze-shift head displacement. Our findings (e.g., Fig. 9A) are consistent with these two predictions. On the other hand, in the eye-alone trials, the endpoints of the eyes at gaze completion often fell within the range near the center of the orbits. Thus little head contribution to eye counter-roll was recruited. The finding that extended stimulation improved head contribution to centering the eyes in the orbits (e.g., Figs. 9A and 14B) further supports the prediction of this hypothesis.

This physiological eye-centering is not a precise and automated mechanism. If the eyes were to be perfectly centered in the orbits, the data points in Fig. 9A should fall on the regression line with the slope of one. This was not the case. In the case of the visually guided gaze shifts (Fig. 14B), the head contribution to eye centering was not precise either. The average postgaze-shift head movements in general fell short of bringing the eyes to precisely the center of the orbits. On the other hand, depending on the duration of the stimulation, the magnitude of the head contribution to eye counter-roll was above or below that of the averaged visually guided trials (e.g., 300- vs. 600-ms stimulation trials in Fig. 14B). The results confirm that extended stimulation indeed altered the metrics of head contribution to eye centering.

Due to the concern about possible tissue damage by high current, we did not attempt stimulation with durations exceeding 600 ms with the same current intensity and frequency. We did not know whether continuing stimulation would ultimately counter roll the eyes to the orbital limit of the opposite end. However, the examples provided in Figs. 4 (e.g., the 1st trace of 600-ms stimulation trials in the IEPi condition) and 14A (the 1st trace of 600-ms stimulation trials) offered some hints. These results suggest that the head movements of higher velocities tended to decrease their velocities to baselines before the stimulation was terminated. In these cases, the eyes approached the center of the orbits sooner, and the head movements stopped accordingly. It appears that extended stimulation was unlikely to drive the eyes to the orbital limit of the opposite end. Future experiments are needed to confirm this assertion.

Head contribution to eye counter-roll is also significant in the head-alone trials (Fig. 11A). When the eyes were deviated in the movement directions, the head movements could be robust and thus served to counter-roll the eyes away from eccentric positions (Fig. 11A). However, in the other cases, the head movements actually drove the eyes away (ipsilaterally) from the center of the orbits (Fig. 11A, downward arrow). The latter head movements were in general small, and the eyes remained within 5° from the center of the orbits. This type of head movement was reminiscent of those evoked in the superior collicular stimulation (Corneil et al. 2002a; Galiana and Guitton 1992; Pelisson et al. 2001).

Note that the stimulation-evoked head movements were primarily horizontal, whereas the stimulation-evoked gaze shifts tended to have significant vertical components (Fig. 3). That is, both the head contribution to eye counter-roll and the head contribution to gaze shift were limited to the horizontal movements (Figs. 9, 11, and 12). The unique head-movement direction in the SEF stands out in comparison with a different cortical field near the SEF, in which electrical stimulation evoked head movement in all directions to achieve centering the eyes in the orbits (Sparks et al. 2001). Also, the head-movement representation in the cortex, especially the SEF, appears different from that of the superior colliculus. The latter tends to contain significant vertical head amplitudes depending on the direction of the stimulation-evoked gaze shifts (Freedman et al. 1996; Martinez-Trujillo et al. 2003).

Early head and head-alone movements

One may wonder whether the early head (and head-alone) trials were the animals' anticipatory movements. Similar argument can be made regarding whether these trials were greatly affected by the eye-head postural constraints. These possibilities are unlikely for several reasons. First, Levinsohn (1909; described in Smith 1949), who performed clinical assessments using electric stimulation, had reported similar observations. In these early investigations, the animals were lightly anesthetized, and there were no sophisticated task or postural demands. Second, the directions of these stimulation-evoked head movements were not random but primarily horizontal and contralateral with respect to the stimulated side. Note that the reward was not contingent on the animals holding a particular position or moving in a particular direction following the stimulation. Third, the early head trials were observed in the nontask mode as well as the task-mode stimulation trials. There were no task or postural constraints in the former trial type, yet the results of both trial types were comparable (Fig. 14). Fourth, the stimulation was conducted in darkness. There was no visual or auditory cue that promoted or repressed conditional movements. None of the stimulation-evoked gaze shifts exhibited the hallmark signature of the visually guided gaze shifts, i.e., corrective saccades. Finally, the stimulation-evoked movements were dramatically different across different cortical regions, even in the same animals under the same task demands. For instance, in our FEF stimulation data, we rarely, if at all, observed trials in which the head movements were initiated prior to gaze shifts (L. L. Chen and D. L. Sparks, unpublished observations; van der Steen et al. 1986). Also worth mentioning is the fact that these results were obtained on different recording days. The same monkeys could not have been conditioned to suppress one type of movement 1 day and conditioned to suppress another type of movement the next day. Based on these reasons, it is clear that variables other than animal training and task demands need to be taken into account.

The question is then how could SEF stimulation evoke eye-and-head movements in some trials and head-alone movements in other trials? A two-pathway hypothesis has been proposed to account for similar findings in collicular stimulation studies (monkey: Corneil et al. 2002b; cat: Galiana and Guitton 1992; Pelisson et al. 2001). These authors argue that two pathways—one head and one eye—may be initiated depending on the threshold of activation. When the stimulation activates the head-alone (presumably low-threshold) pathway but fails to activate the eye [presumably high-threshold, omni-pause-neuron (OPN) gated] pathway, early head or head-alone trials will be observed. The saccadic pulse generators are gated by the OPNs in the nucleus raphe interpositus, which is connected with the SEF (for review, see Moschovakis et al. 1996). The OPN gating works like an ON-OFF switch. As soon as the gaze shift is over (or prior to the gaze initiation), the OPN gating resumes and the gaze position is prevented from changing (Fuchs et al. 1985; Hepp et al. 1989; Keller 1981; Moschovakis et al. 1996). Hence via the activation of the VOR, the head displacement observed is approximately equivalent to (but in opposite sign of) the eye counter-roll in the orbit (Cullen 2004; Green and Angelaki 2004; Guitton et al. 1990). These regulations exist in the visually guided and the stimulation-evoked gaze shifts (Corneil et al. 2002a,b; Freedman and Sparks 1997; Freedman et al. 1996; Fujii et al. 1995; Guitton et al. 1990; Martinez-Trujillo et al. 2003, 2004; Morasso et al. 1973; Phillips et al. 1995; this study).

Tehovnik and colleagues (Tehovnik and Lee 1993; Tehovnik and Sommer 1997) have proposed an oculomotor-suppression hypothesis that too may account for our observations of early head and head-alone movements. The authors argue that the SEF stimulation within the unresponsive IEP region (referred to as the "termination zone") either overrides the visual (external) input or inactivates the gaze/eye signal. Their hypothesis predicts the following: no gaze shifts will occur when the IEPh is deviated in the unresponsive IEP region at stimulation onset and the probability of the visually triggered saccades is a function of the IEPh from the unresponsive IEP region. Two observations in this study are in line with the two predictions. First, when the IEPh was deviated in the contralateral direction (i.e., most likely within the unresponsive IEP region; e.g., Figs. 4 and 6A), SEF stimulation often evoked the head-alone trials. There were very few trials that were accompanied by gaze shifts. Second, when the gaze shifts did occur in this case, the head movements often occurred earlier than the gaze shifts. That is, these head movements drove the eyes away (ipsilaterally) from the unresponsive IEPh (contralateral) region (e.g., the IEPc or IEPo conditions in Fig. 13C), thus increasing the probability for the gaze shifts to be evoked by SEF stimulation.

At this point, whether the SEF contains local inhibitory circuitry that is sensitive to IEPh or whether the SEF contains separate head and eye pathways that are sensitive to threshold of activation remains unclear. Nonetheless, the finding that the unresponsive IEPh regions remained largely unchanged in head-unrestrained conditions is consistent with the notion that the movements evoked in the SEF are organized in either head-centered or body-centered frames of reference (Martinez-Trujillo et al. 2004; Schlag and Schlag-Rey 1987; Tehovnik et al. 1998). Distinguishing these coordinate frames of reference remains open for further studies.

There are established methodologies that can reliably produce the early head movements. It has been shown that in normal gaze shifts, the difference between head and gaze onset results primarily from target predictability and/or motor set. These situations include experimental tasks in which visual targets are off eccentric, flashed briefly, or there is a conflict between targets that are sequentially presented (Bizzi et al. 1972; Corneil and Eleley 2005; Fuller 1992; Guitton et al. 1990; Moschner and Zangemeister 1993; Roucoux et al. 1981; Zangemeister and Stark 1982). Whether SEF stimulation evokes different head movements in response to these unique situations remains to be investigated.

The early head movements are usually slow and often accompanied by a gradually increased activity of agonist neck muscles (Bizzi et al. 1971; Corneil et al. 2002a,b). In contrast, the head movements recruited around the time of gaze shifts typically have burst-like neck muscle activation patterns. It has been shown that the SEF neurons and those in the neighboring interconnected cortices are strongly modulated by changes in the motor significance of the instructions; these neurons are often responsive to self-initiated, as opposed to externally guided, movements (Amador et al. 2000; Chen and Wise 1995, 1996; Fujii et al. 1995; Isoda and Tanji 2002; Kurata and Wise 1988; Olson and Gettner 1995; Stuphorn et al. 2000). It is possible that the independent head-movement control in the SEF provides one of the mechanisms supporting these physiological functions.

It is of interest that the head-alone movements were more often evoked rostrally compared with caudally in the SEF map (Fig. 15). This rostral representation of head movement in the SEF appears consistent with the somatotopic organization of the supplementary motor cortices adjacent to the SEF, in which the forelimb and hindlimb representations are located rostrally and caudally, respectively (for review, see Tanji 1994). Nevertheless, this apparent correlation cannot resolve the issue of whether the SEF is intermixed with the supplementary motor cortices or whether the SEF contains a unique head representation in its map.

The SEF is extensively connected with many other cortical and subcortical areas that are implicated in skeletomotor functions (Huerta and Kaas 1990; Shook et al. 1990). Somatosensory mapping studies have indicated that the SEF contains neurons responsive to neck manipulations (Luppino et al. 1991; Rizzolatti et al. 1990; Schlag and Schlag-Rey 1987). This pattern of anatomical connections in the SEF is drastically different from that in the FEF, as the latter is heavily connected with visual and oculomotor regions (Huerta and Kaas 1990; Schall et al. 1993; Schiller and Chou 2000; Shook et al. 1991). It is feasible that like the neighboring complex of supplementary motor cortices, the SEF contains mechanisms that permit extensive cross-talks between different motor apparatuses, thus higher-order movement controls can be achieved (Bon and Lucchetti 1997; Hoshi and Tanji 2004; Isoda and Tanji 2002, 2004; Kurata and Wise 1988; Missal and Heinen 2004; Olson and Gettner 1995; Tehovnik and Lee 1993).

Comparison with the superior colliculus

There are similarities in the stimulation-evoked head movements between the SEF and the superior colliculus. First, the stimulation-evoked head movements in both the SEF and the superior colliculus are primarily contralateral (Corneil et al. 2002a,b; Freedman et al. 1996; Guitton et al. 1990; Martinez-Trujillo et al. 2003; this study). Second, both the SEF and the superior colliculus have large-amplitude sites in which unresponsive IEP regions exist (Freedman et al. 1996; Guitton et al. 1990; Russo and Bruce 1993; Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993). Third, the early head and head-alone trials could sometimes be evoked by electrical stimulation in both the SEF and the superior colliculus (Corneil et al. 2002a,b; Galiana and Guitton 1992; Pelisson et al. 2001). These similarities should not be surprising considering that the SEF is heavily connected with the intermediate and deep layers of the superior colliculus, the function of which is associated with the initiations of gaze shifts and head movements (Huerta and Kaas 1990; Moschovakis et al. 1996; Shook et al. 1991; Schall et al. 1993).

It is worthy noting that there exist extensive network interactions between the eye and head plants via the VOR (Bizzi et al. 1971; Guitton et al. 1990; Morasso et al. 1973; Moschovakis et al. 1996). As a result, the executed movements of the eye and head are coordinated via vestibular regulation such that the movements observed are not necessarily equivalent to the commands that are issued (for review, see Sparks 1999). Because both outputs of the SEF and the superior colliculus are subject to regulation by the same brain stem mechanisms, one should be cautioned in making direct data comparison between the head-restrained and -unrestrained experiments.

There are at least three major differences in the stimulation-evoked head movements between the SEF and the superior colliculus. First, the head movements evoked in the SEF have little vertical components, whereas those evoked in the superior colliculus have significant vertical components (Corneil et al. 2002a,b; Freedman et al. 1996; Guitton et al. 1990; Martinez-Trujillo et al. 2003; this study). Second, Corneil et al. (2002b) found that high current stimulation in the superior colliculus tended to evoke eye-and-head movements, whereas subthreshold current (as low as 10 µA) stimulation tended to evoke early head or head-alone movements. Interestingly, we had never found such a differential effect in the SEF. We found that the higher currents (typically suprathreshold currents, e.g., 100–150 µA) simply improved the detectability of these slow, pregaze head movements that otherwise remained undetected (e.g., Fig. 4). Third, it has been shown that the optimal stimulation frequency for the collicular stimulation to evoke the site-specific maximum saccades is 500 Hz, if not higher (head-unrestrained monkeys: Freedman et al. 1996; head-restrained monkeys: Stanford et al. 1996). Given that all other variables remain unchanged, the probability for the collicular stimulation to evoke saccades is a monotonic saturating function of the stimulation frequency. By contrast, the optimal frequency for the SEF to evoke saccades is within a relatively low and narrow range (100–200 Hz); increasing the stimulation frequency >200 Hz often decreased the probability for the SEF stimulation to evoke saccades (Tehovnik and Lee 1993; Tehovnik and Sommer 1997).

In light of the preceding notion, we carried out testing in the stimulation-evoked head movements in the SEF (e.g., Fig. 16). As shown in RESULTS, under some circumstances (i.e., IEPc and IEPo conditions), SEF stimulation often evoked head-alone movements in the absence of gaze. We tested under these unique circumstances the effect of stimulation frequency in 10 SEF sites (n = 9 in M1 and n = 1 in M2). In each tested site, the stimulation current and duration remained constant. In eight of these sites in which both 100- and 200-Hz stimulations were evaluated, 100-Hz stimulation evoked the largest head displacements in half of the sites and 200-Hz stimulation, the other half. An example of the testing is illustrated in Fig. 16. In six sites, 200-Hz frequencies [400 Hz (n = 4), 800 Hz (n = 1), and 1,000 Hz (n = 1)] were evaluated. In all six sites, frequencies >200-Hz decreased the head displacements by 18–79% as compared with that evoked by 200-Hz stimulation. Thus the optimal stimulation frequency for evoking head movements (this study) and for evoking saccades (Tehovnik and Lee 1993; Tehovnik and Sommer 1997) appeared within similar ranges.

View larger version (25K): [in this window] [in a new window]   FIG. 16. Effects of stimulation frequency on the stimulation-evoked horizontal head displacements (A, top) and velocities (A, bottom) in a SEF site. Each trace represents the average position or velocity of the stimulation-evoked head movements and gaze shift in IEPc condition. Data were obtained from the head-alone trials, separated for different stimulation frequencies. B: systematic effect of stimulation frequency on the horizontal amplitude of the stimulation-evoked head movements. Data were separated for IEPh conditions (IEPc: filled squares, IEPo: open squares). Control trials (open triangles) were obtained from the interleaved, nonstimulation trials of the same block. Each data point represents the average (means ± SE) of 3–6 trials for the stimulation trials or the average of 10 trials in the control trials. Note that the horizontal head displacements were measured in every trial regardless of whether a head movement was detected. In the stimulation trials, the head movements were measured from stimulation onset to head offset (when the head movements were detected) or from stimulation onset to 500 ms after the stimulation onset (when the head movement was not detected). In the control trials, the head movements were measured as the head displacement during the 500-ms epoch starting at the time point comparable to the stimulation onset in the stimulation trials (see METHODS).

Remarks

It is pertinent to measure the stimulation-evoked pre- and postgaze-shift head movements in the SEF under adequate control. Without consistent postural stability, such as the task control performed in this study, these low-velocity head movements could easily be misidentified or ignored. One should be aware of the fact that these head movements may be intermixed with the eye-head combined gaze shifts. The existence of the head movements independent of gaze places constraints on interpreting the stimulation data in the SEF.

	GRANTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
This work was supported by National Institutes of Health Grants EY-13444, EY-015060, and DC-06429.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
The authors thank H. Samuel for designing the primate chair and microlaser fixture, K. Pearson and J. Li for programming support, D. Sparks for generous support throughout all phases of the project, and C. Langford for editorial assistance. The authors thank X. Hu and B. Corneil for stimulating discussions and comments.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: L. L. Chen, Dept. of Otolaryngology, University of Texas Medical Branch, Galveston, TX 77555 (E-mail: lochen{at}utmb.edu)

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