Brain and Behavior: A Task-Dependent Eye Movement Study

Brain and Behavior: A Task-DependentEye Movement Study

M.R. Burke and G.R. Barnes

Faculty of Life Sciences, University of Manchester, Manchester

M60 1QD, UK

Recent electrophysiological and behavioral studies have foundsimilarities in the neurology of pursuit and saccadic eye movements.In a previous study on eye movements using closely matchedparadigms for pursuit and saccades, we revealed that both exhibitbimodal distributions of latency to predictable (PRD) and randomized(RND) stimuli; however, the latency to each type of stimulus wasdifferent, and there was more segregation of latencies in saccadesthan pursuit (Burke MR, Barnes GR. 2006. Quantitative differences insmooth pursuit and saccadic eye movements in humans. Exp BrainRes. 175(4):596--608). To investigate the brain areas involved inthese tasks, and to search for correlates of behavior, we usedfunctional magnetic resonance imaging during equivalent PRD andRND target presentations. In the contrast pursuit > saccades, whichreflects velocity-dependent versus position-dependent activities,respectively, we found higher activation in the dorsolateral pre-frontal cortex (DLPFC) for pursuit and in the frontopolar region forsaccades. In the contrast RND > PRD, which principally reflectsactivation related to visually driven versus memory-driven re-sponses, respectively, we found a higher sustained level ofactivation in the frontal eye fields during visually guided eyemovements. The reverse contrast revealed higher activity for thememory-guided responses in the supplementary eye fields and thesuperior parietal lobe. In addition, we found learning-relatedactivation during the PRD condition in visual area V5, the DLPFC,and the cerebellum.

Keywords: fMRI, human, prediction, saccades, smooth pursuit, vision

Introduction

The 2 principal types of eye movement used for obtaining

detailed information about the visual world are pursuit and

saccades. The primary function of pursuit is to maintain an

object of interest near to the fovea during motion of the object,

which is achieved with a combination of smooth and saccadic

movements. Conversely, goal-directed saccades rapidly redirect

the fovea onto stationary objects of interest. In a previous paper,

we have addressed the behavioral similarities between pursuit

and saccadic eye movements to randomized (RND) and pre-

dictable (PRD) target motion that principally reflect the visually

driven versus memory-driven responses of pursuit and saccades,

respectively. The idea that working memory is used in pre-

dictive saccadic control to hold positional information is

a familiar one (Droulez and Berthoz 1991). Less familiar,

perhaps, is the evidence that a similar form of working memory

is used to hold velocity information for predictive pursuit (Collins

and Barnes 2005; Burke and Barnes 2007). The segregation of

memory-based and feedback-driven components for pursuit is

more demanding than for saccades because continued pursuit

employs a combination of eye velocity memory and visual

feedback for maintenance (Becker and Fuchs 1985; Morris and

Lisberger 1987; Bennett and Barnes 2005). In addition to the

differences observed in the maintenance of these eye move-

ments, a previous experiment comparing the latency of

responses to PRD or RND targets revealed a greater distinction

between the PRD and RND stimuli for saccades than for pursuit

(Burke and Barnes 2006). In support of this finding, Liston and

Krauzlis (2005) found that pursuit and saccades share the same

decision signal but differ in the response thresholds to random

target presentations. In contrast, other behavioral studies have

found that pursuit and saccades share similar mean preparation

times to PRD and RND stimuli (Joiner and Shelhamer 2006).

Electrophysiological recording and functional imaging have

provided detailed information about the pathways involved in

the generation of pursuit and saccades (for a review, see Pierrot-

Deseilligny et al. 2004). For both pursuit and saccades, visual

information about the target is conveyed to primary occipital

regions in thebrain (V1,V2, andV3)before information is relayed

to other areas including the medial temporal areas (MT), medial

superior temporal area (MST), parietal eye fields, frontal eye

fields (FEF), supplementary eye fields (SEF), dorsolateral pre-

frontal cortex (DLPFC), superior colliculus, brainstem, and

cerebellum (CBM) (Petit et al. 1997; Berman et al. 1999; Gaymard

and Pierrot-Deseilligny 1999; Petit and Haxby 1999; O’Driscoll

et al. 2000; Yan et al. 2001; Missal and Keller 2002; Rosano et al.

2002; Keller and Missal 2003; Krauzlis 2004). Several of these

areas have been implicated in the maintenance of short-term

memory, including the DLPFC (pursuit: Schmid et al. 2001;

saccades: Pierrot-Deseilligny et al. 2005), FEF (pursuit: MacAvoy

et al. 1991; saccades: Gaymard et al. 1999; Pierrot-Deseilligny

et al. 2005) and MT (in monkeys) (Bisley et al. 2004). This

extensive overlap in activation during the initiation and mainte-

nance of these eye movements is not fully understood and has

thus prompted the following study.

This study employs both pursuit that uses principally velocity

information, and saccades/gaze-shifting that principally uses

positional information, to study eye movements (Rashbass

1961). We have incorporated a blocked design using either

pursuit or saccadic eye movement responses made to PRD or

RND target motion in a 2 factorial block design (PRD pursuit,

RND pursuit, PRD SAC, and RND saccades). The control has

provided a baseline measurement of visual activation and fixation

and thus allows us to establish activation in relation to the eye

movement alone in the test paradigms. We used both a boxcar

basis function and a linear time-dependent basis function in order

to evaluate the sustained activation and time-dependent changes

in activation, respectively, over a block of presentations.

The main goals of the study are to 1) identify brain areas

specific for motion processing (pursuit) and position processing

Cerebral Cortex January 2008;18:126--135

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saccades, 2) establish differences in the predominantly mem-

ory-driven (PRD) and visually driven (RND) pathways in the

brain, and 3) segregate the functional magnetic resonance

imaging (fMRI) responses into sustained- and learning-related

activations. We hypothesize that pursuit and saccades will reveal

many brain regions in common during their eye movement

responses, but differences will exist in the use of these areas

during either the velocity-dependent or position-dependent

tasks. In addition, we expect to observe activation in the DLPFC

and SEF in response to the PRD paradigm based on previous

studies (Pierrot-Deseilligny et al. 2005; Simo et al. 2005, Heinen

and Liu 1997).

Methods

Subject PopulationTwelve right-handed healthy adults (7 females) between the ages of 20

and 39 years (mean age 26.4 years) took part in the experiment. Full

informed written consent was obtained in compliance with the Code of

Ethics of the World Medical Association (Declaration of Helsinki, 1964).

The subjects had no known neurological, psychological, or oculomotor

abnormalities, and no abnormalities were found on their structural

magnetic resonance imaging scans. Subjects were free to wear contact

lenses to correct for any visual impairment during the experiment.

Experimental DesignAll scanning took place in the Welcome Trust Clinical Research Facility

(Manchester, UK) using a 1.5-T Philips Intera scanner with a SENSE head

coil. Subjects were supine in the scanner and viewed target motion on

a large gray screen positioned ~1 m from the end of the scanner via

a reflective mirror system positioned on the head coil. Eye movements

were monitored throughout using an infrared limbus-tracking device

(MR-eyetracker, CRS Ltd., Cambridge, UK) attached to the head coil by

a custom-built holding device (CRS Ltd.). Foam pillows were used to

minimize head motion during the scanning session. The visual stimulus

was presented using custom-made software that back projected

a moving target onto the screen in front of the subject. The visual

fixation stimulus comprised a circular annulus positioned in the center

of the screen (FIX), and the tracking target was a white (unfilled) square

(T1) with similar dimensions to the fixation target (subtending 1.2� onthe eye). All subjects also performed the experiment under laboratory

conditions using a similar limbus tracker (IRIS, Skalar Medical BV, CRS

Ltd.) prior to being scanned, to obtain behavioral performance data.

ParadigmsThe paradigms were designed to equalize the timing aspects of the 2

types of stimuli, pursuit and saccades. Note that in order to reduce the

number of corrective saccadic intrusions during pursuit eye move-

ments, we incorporated a variation of the Rashbass paradigm (1961).

This paradigm uses a step followed by smooth motion in the opposite

direction and has been found to significantly reduce the number of

corrective saccades (see Burke and Barnes 2006). We also used a gap for

both pursuit and saccade trials to optimize the latency of the responses

by releasing fixation prior to target appearance (saccade Reuter-Lorenz

et al. 1991; pursuit: Krauzlis and Miles 1996). A return step-ramp

movement back to the center of the screen was also included for pursuit,

which served to remove any return saccade made by the subject at the

end of the motion and place the eyes back to center of the screen ready

for the next stimulus. Similarly, a step back to center was used in the

saccadic task. As the target stimulus was presented for a maximum of

800 ms for the outward and also the return movement, the differences

in movement time between saccades and pursuit were minimized.

Double Cue-Gap-Step-Ramp (pursuit)

In this paradigm, subjects were initially given a visual fixation cue (FIX)

(200--400 ms) positioned in the center of the screen. This cue was then

extinguished during a GAP (200--600 ms) before a target appeared (T11)

either to the left or to the right of the prior cue (3� or 6�: equivalent to200 ms of target motion). The target proceeded to move through the

center of the screen with velocities of 15� or 30� per second for 500--

800 ms before being extinguished. This target (T12) then reappeared,

displaced by a more eccentric step (step magnitude as defined above),

and moved toward the center of the screen for 500--800 ms before being

extinguished at the center. Subjects were required to fixate FIX and

smoothly track T11 and T12 (see Fig. 1) (see Burke and Barnes 2006).

Double Cue-Gap-Step (SAC)

This paradigm was designed to mimic the above condition, but with

steps rather than smoothly moving ramps. Subjects again were given

a visual fixation cue (FIX) for 200--400 ms in the center of the screen,

followed by a GAP (200--600 ms). A target then appeared (T11) either to

the left or to the right of the prior cue at amplitudes of 5� or 15� and was

visible for 500--800 ms. This same target (T12) then reappeared in the

center of the screen. Subjects were required to fixate FIX and make a

saccade to T11 and T12 (see Fig. 1) (Burke and Barnes 2006).

PRD Condition (PRD)

For the PRD conditions, the subjects were presented with the same

stimulus ‘‘presentation,’’ either pursuit or SAC, 8 times in a row denoting

a ‘‘block.’’ The stimuli presented had the same direction and speed/

amplitude in all 8 presentations. The gap time remained the same for

each stimulus presentation; however, the interstimulus interval (ISI:

time between each stimulus presentation) was randomized from 500--

1500 ms (see Fig. 2A).

Random Condition (RND)

For the random condition, the subjects were again presented with the

stimulus presentation, pursuit or SAC, 8 times in a row. However, each of

the 8 stimulus presentations differed in direction and/or speed/

amplitude. The timing of the gap and ISI were also randomized within

each presentation in the range 200--600 ms and between presentations

by 500--1500 ms, respectively (see Fig. 2B).

Control/Baseline (CON)

In this condition, the visual fixation cue appeared and disappeared using

the same timing as the PRD pursuit and SAC conditions mentioned

above in order to mimic visual stimulation without any eye movements.

This was used as the baseline to specifically isolate the eye movement

component from the activity associated with the visual stimulus.

Five blocks (2 3 PRD, 2 3 RND, and 1 3 CON block) comprised a

‘‘template.’’ A template either contained the pursuit or SAC stimulus

presentations using the sequence 1) PRD, RND, PRD, RND, and CON or

2) RND, PRD, RND, PRD, and CON. The experiments formed a design of

alternating pursuit and SAC templates with a calibration (CAL) per-

formed at the beginning of each of these sets (see Fig. 2). The CAL

involved the subject continuously tracking a sinusoidally moving target

Figure 1. A diagrammatic representation of the timeline used in the stimuluspresentations for the PUR paradigm (left) and SAC paradigm (right). Timing for theRND and PRD trials is shown in black and gray, respectively.

Cerebral Cortex January 2008, V 18 N 1 127

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(amplitude ± 15�) in the horizontal plane of motion. Each of the 12

subjects performed the eye-movement paradigms in a single-recording

session lasting ~45 min each. The subjects performed 6 pursuit and

6 SAC templates per session containing 5 blocks in each. This resulted in

a total of 12 blocks for each condition; PRD pursuit, RND pursuit, PRD

SAC, RND SAC, and CON for each subject.

fMRI Data Acquisition and AnalysisAll recordings were obtained on a 1.5-T Philips Gyroscan Intera scanner

using a SENSE head coil. All scans used appropriate angles (flip angle =90�) to include whole-brain coverage (field of view = 256 mm, ac-

quisitionmatrix = 64 3 64, repetition time = 3000ms, echo time = 40ms,

voxel size = 3.5 mm3, slice thickness = 3.5 mm, gap thickness = 1.5 mm,

number of axial slices = 38 slices/dynamic). Prior to each functional

run, 2 dummy scans were performed to allow for stabilization of the

longitudinal magnetization. In total, subjects performed 11 volumes per

block and 55 volumes per template that resulted in 660 volumes during

a single session. fMRI data were obtained in radiological convention in

DICOM format and transformed into ANALYZE format using Statistical

Parametric Mapping software (SPM2) (Wellcome Department of Imag-

ing Neuroscience: http://www.fil.ion.ucl.ac.uk/spm/). Data were then

preprocessed in SPM2 in the following way; slice timing was corrected,

followed by spatial realignment of head motion (Friston et al. 1995), and

normalization into Montreal Neurological Institute (MNI) coordinates

(Mazziotta et al. 1995). Smoothing was performed using a 9-mm

full-width half maximumGaussian filter. The data were high-pass filtered

(cutoff at 128 s), and global drifts were removed using proportional

scaling. Prior to each session a T1-weighted axial anatomical image was

acquired from each subject.

In order to observe both mean-level sustained activation and learning-

related activation (i.e., linear increases or decreases in activation over

time), we performed both a boxcar analysis and a first-order parametric

time-dependent analysis, respectively. For this, 2 design matrices were

generated using A) all 11 volumes in each block for the ‘‘time-dependent

parametric design’’ and B) the last 9 volumes in a block for the ‘‘boxcar

design.’’ The latter design was devised in order to remove the initial

transient responses observed in behavioral studies to the PRD stimulus

(Barnes and Asselman 1991).

We used a general linear model with a boxcar basis function to

generate contrasts for each participant (Worsley and Friston 1995). The

contrasts for each subject were then placed into a secondary random

effects analysis (one sample t-test) in order to obtain a mean activation

for all subjects to each resultant contrast. Design A was used to convolve

a linear basis function with the hemodynamic response function in

order to observe any task 3 time-dependent interactions, that is, linear

increases or decreases of brain activity over time (Buchel et al. 1996).

Again, the results from each subject were placed into a random effects

analysis (one sample t-test) in order to obtain a group-level response. All

reported activation is shown at a level of t > ±3.5 and with small volume

corrections (region of interest [ROI] = 10 mm) on the maximum

activated cluster in the brain regions mentioned (Figs 4 and 5) using

a family wise error (P < 0.05) to correct for multiple comparisons. This

is with the exception of the DLPFC in Figure 5D and MT in Figure 4

(upper graph) that did not reach this significance (ROI = 8 mm, P <

0.09). All data are plotted using the MNI convention. All figures display

group activations on a T1--weighted anatomical template with the

anatomical identification of areas being processed in the anatomy

toolbox provided by SPM2 or the WFU_pickatlas (Maldjian et al. 2003).

Eye-Movement AnalysisEye movements were sampled at 200 Hz in both the scanning and

laboratory environment. We applied a low-pass filter (80 Hz) to all eye-

movement data including target data in order to reduce noise, before

being stored for further off-line analysis. pursuit eye-movement data were

preprocessed in order to remove the saccadic component in velocity

profiles based on previously defined and established acceleration (750�/s2) and velocity (40�/s) criteria; a linear interpolation was then used to

join the gap in the data (for details of this analysis, see Bennett and

Barnes 2003). The saccades captured using this technique were stored

for later analysis. Data were filtered at 30 Hz using a zero-phase digital

filter. The eye-movement data obtained in the scanner were useful for

ensuring qualitative similarity between the scanning and laboratory

environments. However, we found the signal during scanning could be

lost due to its fixture to the head coil and therefore the data from the

scanner could not be used to generate quantitative results of magnitude

or latency. Preprocessed data from the laboratory were then analyzed

in MatLab (The Mathworks, Inc, Natick, MA). Latency from target onset

was found using a method similar to Lekwuwa and Barnes (1996b), by

calculating 10% of the peak eye velocity and forming a linear regression

from this point back to the abscissa. The point at which the eye velocity

and abscissa crossed was defined as eye-movement onset. Target onset

was subtracted from eye-movement onset in order to obtain latency.

Latency to the last 5 targets in each block was used to generate themean

responses for both PRD and RND responses. This resulted in 1440

latency values for each subject (720 pursuit and 720 SAC responses). We

calculated the percentage correct of appropriate responses by using

a latency of 80 ms as a border between PRD and RND responses, that is,<80 ms correct for PRD trials and a latency >80 ms was correct for RND

trials. We used 80 ms as it has been established that approximately 80--

100 ms is the approximate time needed for the brain to process visual

information and prepare an appropriate response (Carl and Gellman

1987; Gellman et al. 1990), and for gap paradigms, this reaction time is

reduced (Reuter-Lorenz et al. 1991; Knox 1996). For details of analysis

and behavioral results, please refer to Burke and Barnes (2006).

Results

Eye-Movement Results

Inspection of the scanning data revealed that subjects were

performing in a qualitatively similar manner in both the lab-

oratory and scanning environments. By the second or third

Figure 2. The schematic diagram of experimental protocol for 2 of the 12 templates is shown above. The black block refers to the CAL taken every 2 templates. This was followedby a PUR template (TEM 1) consisting of RND (dark gray), PRD (light gray), and CON (white) blocks. The trigger signal from the scanner is shown by the black arrows and was givenevery 33 s (11 full brain volumes). The area between templates represents a short break for subjects to relax before the next SAC template (TEM 2) began. A diagrammatic exampleof a PRD PUR and RND SAC block is shown in the lower plots A and B.

128 Neural Control of Eye Movements d Burke and Barnes

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http://www.fil.ion.ucl.ac.uk/spm/

presentation of the PRD stimulus, subjects were making

anticipatory eye movements where the eyes were starting to

move prior to the target onset (resulting in a negative latency)

in both the pursuit and SAC tasks. Conversely, in the RND tasks,

eye movements were initiated after target onset.

Mean Latency

Presented below are mean latencies for all subjects from the

laboratory-based environment (Fig. 3). All subjects revealed

a significant difference between RND and PRD conditions in

both pursuit and SAC trials although the pursuit trial latencies

were less distinctly segregated. We observed no significant

difference in the latency between differing target velocity

(pursuit) or displacement (SAC) levels. The overall mean latency

for RND pursuit was 156 ms (±27 ms) and for PRD pursuit

was 0 ms (±57 ms), that is, at target onset. Mean latency for RND

SAC trials was 212 ms (±86 ms) and for PRD SAC was –213 ms

(±39 ms), that is, 213 ms prior to target onset. The standard

deviation for PRD trials was significantly higher than RND trials

(P > 0.01) in both pursuit and SAC. Note that the range of

latencies in the RND condition did not show any evidence of

a second population of ‘‘express saccades’’ (Fischer and Ram-

sperger 1986; Burke and Barnes 2006).

fMRI Results

Eye-Movement Activation (pursuit Alone and SAC Alone)

Analysis of the subject data revealed many areas in common

during the production of pursuit and saccadic eye movements

and displayed both overlapping and segregated activation

within these areas. In relation to the pursuit eye-movement

conditions, we found significant activation in the right FEF

(BA6), right inferior temporal gyrus, BA21, the right prefrontal

cortex (PFC, BA9/46), visual area 5 (V5), the left CBM, and

brainstem (see Fig. 4, upper graph). Negatively activated regions

for pursuit revealed higher bilateral activation in the early visual

areas V1 and V2 and bilaterally in the supramarginal gyrus (SMG,

BA40).

For saccades only, we found significant activation bilaterally

in the SEF (BA6), the right middle temporal gyrus (MTG, BA37/

39) the right frontopolar regions (FP, BA10), the left PFC (BA9),

and the left CBM (see Fig. 4). We found negative activation for

saccades bilaterally in the inferior frontal gyrus (IFG, BA45/44),

in the right PFC (BA9), and at a lower level of significance in

early visual areas V1 and V2 (not shown in Fig. 4). It should be

noted that much of this activation was bilateral at lower levels of

significance.

Pursuit versus Saccades (Combined PRD and RND)

Boxcar Block Design. We found that pursuit had higher

activation than SAC in the contrast pursuit > saccades in the

right PFC (BA9), with additional activation also observed in the

right MTG (BA21) (see Fig. 5A). Saccade trials revealed higher

activation in the right SEF (BA6) and bilaterally in the IFG

(BA45/44), the left FP (BA10), and the left visual area BA18.

Time-Dependent Block Design. We observed time-dependent

linear increases in activation in the contrasts pursuit > SAC in

bilateral SMG, BA40, V5, and the dorsal posterior cingulate,

BA31 (see Fig. 5B). The linear increases for the SAC stimulus

were found bilaterally in the superior temporal gyrus (STG,

BA22/42/41), bilaterally in visual area 2 (V2, BA18), bilaterally in

the superior parietal lobe (SPL, BA7), and the right IFG (BA44/

45) (see Fig. 5B).

Predictive versus Random (Combined pursuit and SAC)

Boxcar Block Design. The contrast between PRD > RND trials

for both pursuit and saccadic eye movements (see Fig. 5C)

revealed high activation levels bilaterally in SEF (BA6), in the left

angular gyrus (BA39), the left SPL (BA7), and the left IFG (BA44/

Figure 3. The mean for each subject to each target is shown by the light gray lines in the RND condition and dark gray lines for the PRD conditions for PUR (left graph) and SAC(right graph). The mean latency for all subjects to the RND condition (light gray squares) and to the PRD condition (dark gray squares). Error bars denote one standard deviation fromthe mean. The table below shows the overall mean latency for each condition and the percentage of latencies that are\80 ms in PRD trials and[80 ms in RND trials (% correct)for all subjects.


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45). Higher activations in the RND conditions were observed

bilaterally in the early visual areas (BA17 and BA18), the right

IFG (BA44/45), the left FEF (BA6), the left inferior parietal lobe

(IPL, BA40), and bilaterally in the PFC (BA46).

Time-Dependent Block Design. We observed a linear increase

in activation during the PRD trials in left visual area V5 (BA19/

37), bilaterally in the PFC (BA9), and the right CBM (see Fig. 5D).

Discussion

The specific objective of this experiment was to compare brain

activity in 2 very different oculomotor tasks, one related to

shifting gaze from one position to another and the other related

to continuous pursuit of amoving object. Moreover, we aimed to

compare 2 different forms of these tasks, predictive and

nonpredictive, that resulted in anticipatory or reactive behavior,

respectively, as evidenced by the major differences in timing of

response initiation (Fig. 3). The tasks were carefully designed to

ensure that the stimulus paradigms were equivalent in both

their temporal and spatial characteristics, thus avoiding some of

the problems associated with previous fMRI studies on smooth

pursuit and saccades. The experiment was also specifically

designed to remove brain activation related to the visual

stimulus itself by incorporation of the baseline condition, thus

isolating the observed activation to the eye-movement plan,

retrieval, and execution only. We have identified isolated areas

that are specific to the comparison between PRD and RND

conditions; we hypothesize that these areas reflect differences

in activation between the predominantly visually generated

(RND) and the predominantly memory-generated (PRD) com-

ponents of the eye-movement response, respectively. We

acknowledge that during PRD pursuit eye movements, the

picture is more complex than for saccades, in that pursuit is

maintained via a combination of memory-driven feed-forward

and visual information.We assume that ourRNDpursuit responses

are predominately visually driven because the predictive network

is unlikely to become fully enabledwithin the period of each ramp

(maximum duration 800ms) (Morris and Lisberger 1987). On this

basis, we expect that the contrast of PRD with RND conditions

will reveal greater activity in areas related to predictive

processing, particularly the use of short-term memory.

Another key aspect of our findings in this respect is the

implementation of a linear time-dependent parametric model

over a block of trials, which has allowed the changes over time,

associated with learning in the PRD paradigm, to be assessed.

We have identified other areas specific to the comparison of

ocular pursuit and saccadic gaze shifts, which we suggest are

related to motion processing versus the processing of positional

information, respectively. An important factor in this compar-

ison has been the implementation of a novel design matrix

(partial block analysis). The rationale for this is based on

previous behavioral findings (Barnes and Asselman 1991; Burke

and Barnes 2006), showing that learning in the PRD paradigm

takes place over the first 2--3 presentations of the stimulus, after

which a steady state is attained. The partial block analysis allows

the transient part of the response (which is basically equivalent

to the RND response) to be ignored, so that the observed blood

oxygen level--dependent (BOLD) activation over the remainder

of the block more clearly identifies the difference between the

steady state PRD and RND conditions. This approach has not

previously been used in comparative pursuit and saccadic fMRI

studies and has provided us with the ability to contrast these

eye-movement types more appropriately.

It should be noted that our objective in this study has not

been to discriminate between the forms of eye movement,

smooth and saccadic, but between pursuit and gaze shifting.

Ocular pursuit in natural situations involves a combination of

smooth and occasional saccadic components; our pursuit task

was designed to minimize the saccadic component and obtain

reasonable equivalence in the PRD and RND paradigms. As

expected, the findings for the pursuit and gaze-shifting tasks

presented here not only show clear similarities with many

previous studies (Berman et al. 1999; Gaymard and Pierrot-

Deseilligny 1999; O’Driscoll et al. 2000; Tanabe et al. 2002;

Pierrot-Deseilligny et al. 2005) but also show distinct activation

related to the specific paradigms and contrasts we have used.

We have thus provided a novel approach to looking at pre-

dictive eye movements inside the fMRI scanner. In order to

interpret our findings, we will consider them in the context of

the specific areas of interest previously associated with oculo-

motor control, notably those identified by Krauzlis (2005). For

this purpose, we will refer to Figure 6, where we have

attempted to relate the organization in general terms to

functional models of pursuit and saccadic control. The basis of

such models is that they contain 2 parts, a direct visual feedback

Figure 4. Results from all subjects for the contrasts PUR only (upper graph) and SAConly (lower graph) when the baseline activation has been removed for the partialvolume analysis. Red to yellow colors display positive activation to that contrast andblue to cyan colors show negative activation. A lighter color reflects a higher t value.View of the brain is shown by the white letters: L 5 left side, R 5 right side, ANT5anterior, and POS 5 posterior. BS 5 brainstem, ITG 5 inferior temporal gyrus, andV1/V2/V5 5 visual areas 1, 2, and 5.


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pathway associated with reactive control, supplemented by

a secondary (indirect) efference copy pathway, that is associated

with predictive control (Barnes and Asselman 1991; Droulez

and Berthoz 1991). The latter includes short-term memory

processes for either positional or velocity information that are

likely to be located in PFC and/or the parietal cortex and

activated via SEF (Fig. 6). Our assumption is that predictive

activity induced in our behavioral paradigms specifically re-

quires the use of short-term memory because responses are

based on prior experience; there are no other motion or di-

rection cues.

Occipital Lobe

In our model, processing starts appropriately with visual input

to the occipital areas (left side of Fig. 6). We found higher

activation bilaterally in the primary visual areas (V1 and V2) in

association with the reactive (RND) condition in the contrast

PRD < RND. This finding has not been reported previously for

PRD versus RND trials, which may be due to the differences in

our design when compared with previous studies. This in-

creased activation in early visual areas is possibly due to the

need for increased attention to the visual stimulus during RND

trials (Buchel et al. 1998). Floyer-Lea and Matthews (2004)

recently found that activity in early motor areas (M1), during

the tracking of a visual stimulus with the hand, is also decreased

with learning. Another plausible explanation could relate to the

extent of activation, as the RND trials would generate a larger

surface area of retinal activation when compared with the PRD

trials over a block.

Figure 5. Results from all subjects for the contrasts PUR[SAC (A and B) and PRD[RND (C and D) during the partial block boxcar analysis (A and C) and the time-dependentparametric analysis (B and D). Activation is shown using a threshold of t[±3.5. Red to yellow colors display positive activation to that contrast and blue to cyan colors shownegative activation. View of the brain is shown by the white letters: L 5 left, R 5 right, ANT 5 anterior, and POS 5 posterior. AG 5 angular gyrus, FEF (BA6), FP (BA10), IFG(BA44/45/47), MTG (BA20/21/22), PCC5 posterior cingulate, PFC (BA9/46), SEF (BA6), SMG (BA40), SPL5 (BA7), V1/V25 visual areas 1 and 2 (BA17/18), and V55 visual area5 (BA19/37).

Figure 6. This diagram shows a summary of some of the basic findings in thispaper. The pathways used principally by the visually driven (RND) responses areshown by the lower section or direct pathway and memory-driven (PRD) pathwayby the upper section or indirect pathway. Dark gray boxes denote areas principal invelocity-dependent processing (PUR), light gray boxes for position-dependentprocessing (SAC), and white boxes for areas principally active in both (PUR andSAC).


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Parietal Lobe and Extrastriate Cortex

The next stage of processing our model highlights are 3 closely

related parietal areas (V5, SMG, and SPL) that are known to be

involved in spatiotemporal integration (see Fig. 6).

Visual Area 5

V5 is classically associated with the processing of visual motion

information (Newsome et al. 1985). In this study, V5 was only

minimally activated in the left hemisphere by the contrast of

pursuit with baseline (Fig. 4), but this is probably because our

baseline specifically invoked visual fixation, which is known to

excite multiple visual association areas including V5 (Richter

et al. 2004), and the primary visual cortex. By contrast, left V5

was highly activated in the time-dependent contrast for both

pursuit > SAC and PRD > RND, implying a particularly prom-

inent role in the PRD pursuit condition. This study and others

show that V5 clearly contributes to PRD eye movements in both

pursuit and saccades. However, it is still unclear how this area

contributes to generating predictive eye movements and if it is

part of the feed-forward network also involved in maintained

pursuit when vision of the target is provided.

Supramarginal Gyrus

The contrast pursuit > SAC also revealed a significant bilateral

time-dependent increase in activation in SMG (BA40) within

each block of presentations for the pursuit task. In contrast,

time-dependent increases in activity were found in the SPL for

the SAC condition in the contrast pursuit < SAC. SMG has

previously been associated with both saccades and smooth

pursuit, with lesions in this area causing an increase in latency

for visually guided saccades and affecting latency, initial

velocity, and acceleration in pursuit (Thurston et al. 1988;

Heide et al. 1996). Lencer et al. (2004) found the SMG to be

more active during the blanking of a smooth pursuit target

when compared with continuous target presentations, reveal-

ing a functional role for the maintenance of velocity information

when no visual feedback is available. This implies that the SMG

may be associated with velocity memory, perhaps as part of the

indirect efference copy feedback system shown in Figure 6, and

our findings are consistent with this conclusion.

Superior Parietal Lobe

In the time-dependent contrast of pursuit with SAC (Fig. 5B), it

is evident that there is more activity associated with SMG during

pursuit but more activity in SPL during gaze shifting. That SPL is

more associated with gaze shifting is supported by the evidence

of Duhamel et al. (1992), who showed that SPL plays a role in

updating the representation of visual space during a remem-

bered saccadic eye movement and anticipating the retinal

consequence of an intended eye movement (Duhamel et al.

1992). The findings in the current study add to previous findings

by providing evidence of a graduation of activity from SPL,

providing more positional control, via IPL, to SMG that

integrates time and position/velocity information. In support

of this, others have found that the IPL (lying between SPL and

SMG) plays a critical role in the integration of spatial and

temporal information (Assmus et al. 2003).

Frontal Lobe

Central to our model are regions in the frontal lobe, which

include DLPFC, SEF, and FEF (see Fig. 6).

Dorsolateral Prefrontal Cortex

In line with original expectations, we found major differences in

activity in PFC when comparing PRD and RND conditions. Most

notably, we found a bilateral time-dependent increase in DLPFC

within each block (Fig. 5D). The time-dependent changes

mirror the changes in the predictive component of eye

movement that principally occur over the first 2--3 presenta-

tions of each block (Barnes and Asselman 1991). One previous

study on PRD pursuit eye movements (Schmid et al. 2001)

demonstrated a time-dependent decrease in activation in

DLPFC during the PRD conditions, but the area involved lay

approximately midway between, and anterior to, the 2 areas

identified above; it was actually closer to the area of PFC that we

identified as having more sustained activity in the RND response

(Fig. 5C). The rationalization for decreasing activity associated

with learning is that it represents transition to a more auto-

mated response with less decision making and use of working

memory than required in early stages of learning. This greater

activity in random conditions has been found in other studies

showing the DLPFC’s involvement in response selection but not

maintenance (Rowe et al. 2000; Koch et al. 2006). However,

a major difference in our study is that learning occurs much

more rapidly than in other experiments (e.g., Koch et al. 2006),

the time-dependent changes occurring within blocks lasting

33 s and containing only 8 repetitions. The increase in DLPFC

activity in the PRD condition is expected in the first stages of

the learning process, when the positional or velocity informa-

tion is rapidly being laid down in working memory. Given that

almost exactly the same area of DLPFC was activated in our

study and the more prolonged learning study of Koch et al.

(2006), it is possible that the initial increase in working memory

load is followed by a subsequent decrease as the shift occurs

from controlled to automatic processing. This is also in line with

a recent connectivity study in PFC (Baeg et al. 2007).

We also found higher sustained activations in the right DLPFC

(BA9) for pursuit when contrasted with saccades, in approxi-

mately the same area as that exhibiting the time-dependent

predictive activity. The DLPFC has been associated with pursuit

eye movements in other previous studies (Schmid et al. 2001;

Lencer et al. 2004; Pierrot-Deseilligny et al. 2005; Nagel et al.

2006), although Heide et al. (1996) reported that lesions in this

area do not cause deficits in pursuit eye movements. However,

in a comparison of patients with similar left- and right-sided PFC

lesions, Lekwuwa and Barnes (1996a) did find that right-sided

lesions caused a greater deficit in sinusoidal pursuit at frequen-

cies where prediction is required ( >0.4 Hz), suggesting that the

right side is more important for pursuit that requires the use of

short-term memory. Our observation that right-sided DLPFC

activation is greater for the velocity-dependent pursuit task than

for the position-dependent saccade task may therefore indicate

that this area is specifically associated with velocity storage and/

or processing. This is supported by the finding (Fig. 4) that the

same area is active in the pursuit task alone but is deactivated for

the saccade task alone. Interestingly, the reverse appears to be

true for the left DLPFC (Fig. 4), suggesting that it may be more

specialized for short-term storage of positional information.

DLPFC has long been associated with working memory

(Fuster 1973; Passingham 1985; Goldman-Rakic 1990), as well

as being involved in executive functions such as decision mak-

ing and selection (Milner 1963, Rowe et al. 2000). In addition,

recent papers by Hagler and Sereno (2006) have shown that the


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DLPFC is probably multifunctional, suggesting roles in target

selection, working memory, and attention to salient objects. We

have concentrated here on the area of DLPFC normally asso-

ciated with working memory, but it is evident that other areas of

PFC are also involved, probably reflecting other executive

functions associated with our tasks.

Supplementary Eye Fields

The demonstration of higher sustained activation in the SEF in

the predictive condition was one of the principal predicted

outcomes of this experiment. SEF involvement in pursuit has

previously been demonstrated in monkeys (Heinen and Liu

1997; Missal and Heinen 2004) and is thought to be involved in

timing and initiation of internally generated responses. During

the sequential performance of saccadic eye movements in

monkeys, SEF plays an important role in memorizing the

saccade location and order (Isoda and Tanji 2003). In humans,

Gaymard et al. (1990) found a deficit in memory-guided

saccades in subjects with lesions in SEF. Our results are in

agreement with these previous studies and demonstrate a clear

involvement of the SEF in the PRD control of both saccades and

pursuit eye movements, establishing its role in memory-guided

eye movements in humans. Note that our analysis implies that

this role is sustained throughout a block of presentations

because SEF does not feature in the time-dependent analysis

discussed below. This is to be expected because internal

response initiation is required for each individual presentation

within a block. The higher activation observed in SEF during

saccades when contrasted against the pursuit condition may be

associated with the differences in actual motor response.

saccadic activity requires a stronger burst of activity than the

more sustained activity of pursuit. In addition, the behavioral

results associated with this experiment (Fig. 2) indicate that

timing of response initiation for saccades is much more tightly

clustered than for pursuit. Both of these factors are likely to

result in a higher level of BOLD activity for saccades than

pursuit. Clearly SEF is important in the generation of both

pursuit and saccades (Fig. 6), but interestingly, we show it is

more prominent in the position-dependent saccadic tasks when

a direct contrast can be performed against pursuit.

Frontal Eye Fields

It has been found previously by Keating (1991) that FEF plays an

important role in both PRD and RND pursuit. Interestingly, in

this study FEFwas found to bemore active during the RND target

motion for both pursuit and saccades. This greater activation of

the FEF for RND targetmotion and SEF for PRD targetmotion has

been found previously in saccades. Gaymard et al. (1990) found

a severe deficit in memory-guided sequences of saccades in

patients with lesions in SEF. In addition Simo et al. (2005) found

higher activity for sensory-driven (RND) saccades. It is therefore

believed that FEF is more involved in the preparation and

triggering of purposive saccades (Gaymard et al. 1999). Isoda

and Tanji (2003) performed a comparative study looking at the

neuronal responses in both SEF and FEF in monkeys to

peripheral saccadic targets in a memorized order. They found

SEF was more involved in planning, decoding, and updating

sequences of eye movements and FEF more involved in de-

termining the direction of the upcoming saccade. These findings

support our results in demonstrating that FEF has a more

prominent role in visually guided responses, whereas SEF is

more involved in memory-guided responses for both saccades

and pursuit.

Inferior Frontal Gyrus

We also found higher sustained activation in the IFG (ventral

PFC) for saccades, as well as a time-dependent decrease

combined with an overall reduction in sustained level in the

predictive condition (Fig. 5C). This area has also been identified

in recent studies revealing activation for both memory and

visually driven responses, with a particular emphasis on spatial

working memory (D’Esposito et al. 2000; Ozyurt et al. 2006).

Our findings support these previous studies but, in particular,

suggest that the IFG is more involved in position-dependent

tasks (SAC) than motion-dependent tasks (pursuit).

Frontopolar Regions

The frontopolar area (BA10) revealed sustained activation for

saccades when contrasted with pursuit. This area has previously

been associated with saccadic eye movements and is thought to

play a role in subgoal monitoring during both working memory

and episodic memory tasks (Braver and Bongiolatti 2002). Our

results suggest that this area may be more involved in ma-

nipulating or monitoring position-dependent responses than

motion-dependent responses and is more concerned with the

spatial locations of targets.

The results presented in this study show time-dependent

increases in activity in DLPFC for PRD eye movements in both

pursuit and saccades. In addition, we find specialized pathways

in the frontal lobe via DLPFC and/or IFG and FP that subserve

either pursuit and/or saccades, respectively. Finally, we have

found that a direct comparison between the PRD and RND

conditions reveal a stronger role of SEF in memory-guided

behavior and FEF in visually guided responses.

Cerebellum

The CBM represents the final output stage in our model (see

Fig. 6). Interestingly, a linear increase in activation was observed

in the right cerebellar hemisphere, possibly providing some evi-

dence that the mechanism or region of reactive responses dif-

fers from that of PRD at this motor preparation stage. It may also

suggest that the differences in timing between the PRD and

RND conditions (Fig. 3) are associated with different areas of

activation in the CBM. Previous studies have found the CBM to

be essential in the timing and learning of motor skills and thus

this linear increase could reflect the associated learning during

the PRD condition (for reviews, see Ivry 1997; Robinson and

Fuchs 2001; Bloedel 2004). This study provides new evidence

that the signal in some areas linearly increase over time, possibly

reflecting the buildup of the stored information; however,

further event-related studies are needed to substantiate this

claim.

Temporal Lobe

The temporal lobe does not feature in our model as its role in

eye movements is not clearly understood, possibly due to a lack

of investigation or inclusion. However, the role of the right MTG

(BA21) in this study appears to be associated with the process-

ing of velocity information (for pursuit) when compared with

the saccadic eye-movement condition. Interestingly, we found

increasing BOLD activity over a block of presentations in a more

superior region of the temporal lobe (STG, BA22) during

saccades and sustained BOLD signals in MTG for pursuit

(see Fig. 5A,B, respectively). This suggests a dissociation of

activity for saccades and pursuit in the temporal lobe for either


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learning-related positional information (STG) or maintained

velocity (MTG) information, respectively. This is the first fMRI

study to show specific temporal lobe activity to pursuit and

saccadic stimuli. A lack of information from primate neurophys-

iology studies has also resulted in a lack of understanding in the

role of these areas in eye movements. More studies need to be

done in order to establish the roles of STG and MTG in PRD and

RND pursuit and saccades.

Conclusions

This is the first study to use directly comparable paradigms,

matched for temporal and spatial characteristics, to contrast the

PRD and random responses of both pursuit and saccades and

their associated velocity- and position-dependent attributes,

respectively. The results presented here support recent findings

that pursuit and saccades indeed share common brain regions

for control; however this study provides novel evidence in-

dicating that these regions are utilized to varying degrees

depending on the task demands. For example, we found

differing regions of activation in the frontal cortex, with

position-dependent responses in the ventral PFC and left DLPFC

and motion dependence in the right DLPFC. We also found

a linear increase during pursuit in the SMG and linear increases

for saccades in the superior temporal cortex, again revealing

dissociation between areas related to spatiotemporal integra-

tion and spatial location information, respectively.

The results presented also show brain activity specific for

either the visually driven (RND) or memory-driven (PRD)

stimuli. Based on our original hypothesis, the SEF are important

for the control and release of timing information for both

pursuit and saccades in the PRD task, but in addition to this, we

found the FEF were more important in the RND task for visually

guided responses. The SPL was shown to be important for the

maintenance of visual information over a block of PRD trials;

whereas left V5, bilateral DLPFC, and the right CBM all revealed

time-dependent linear increases in activation during PRD

responses. The observed linear increase in activation reveals

a more specific mechanism for these areas in motor learning.

Notes

This work was supported by the Medical Research Council and

Manchester Wellcome Trust Clinical Research Facility. We would like

to thank all participants who willingly gave their time to this project

and also Shane Mckie, Rebecca Elliott, and Steve Williams for their help

and support in the design and analysis. We would also like to thank the

reviewers for their help and advice on improving this manuscript.

Conflict of Interest: None declared.

Address correspondence to Dr M.R. Burke, Faculty of Life Sciences,

Moffat Building, The University of Manchester, PO Box 88, Sackville

Street, Manchester M60 1QD, UK. Email: [email protected].

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Brain and Behavior: A Task-Dependent Eye Movement Study