Functional Neuroanatomy of Anticipatory
Behavior: Dissociation between Sensory-
driven and Memory-driven Systems
Lucia S. Simo ´ , Christine M. Krisky and John A. Sweeney
Center for Cognitive Medicine, Department of Psychiatry,
University of Illinois, Chicago, IL, USA
The ability to anticipate predictable stimuli allows faster responses.
The predictive saccade (PRED) task has been shown to quickly
induce such anticipatory behavior in humans. In a PRED task
subjects track a visual target jumping back and forth between fixed
positions at a fixed time interval. During this task, saccade
latencies drop from ~ 200 ms to <80 ms as subjects anticipate
target appearance. This change in saccade latency indicates that
subjects’ behavior shifts from being sensory driven to being memory
driven. We conducted functional magnetic resonance imaging
studies with 10 healthy adults performing the PRED task using a
standard block design. We compared the PRED task with a visually
guided saccade (VGS) task using unpredictable targets matched for
number, direction and amplitude of required saccades. Our results
show greater activation during the PRED task in the prefrontal, pre-
supplementary motor and anterior cingulate cortices, hippocampus,
mediodorsal thalamus, striatum and cerebellum. The VGS task
elicited greater activation in the cortical eye fields and occipital
cortex. These results demonstrate the important dissociation
between sensory and predictive neural control of similar saccadic
eye movements. Anticipatory behavior induced by the PRED task
required less sensory-related processing activity and was sub-
served by a distributed cortico-subcortical memory system in-
cluding prefronto-striatal circuitry.
Keywords: frontal eye fields, functional MRI, human, parietal eye fields,
predictive saccades, procedural learning
Anticipatory behavior is based on predictions that depend on
memories of past events and performance. It typically involves
earlier preplanned responses that can have a considerable
adaptive advantage. Experience with at least two types of tasks
can induce faster responses. One type, common in operant
conditioning paradigms, results from learning that a cue stim-
ulus indicates that a certain specific response will be required,
allowing advanced response preparation which leads to faster
initiation of responses (D’Esposito et al., 2000). The other type
of task belongs to the category of procedural learning (Hikosaka
et al., 1998). During procedural learning a subject learns to
perform a task, often a sequence of responses, by performing
that specific set of behaviors repeatedly. Learning is typically
expressed in shorter response latencies and fewer errors (but
see Shanks and Channon, 2002).
The neural substrate of procedural learning has been studied
in humans using visuomotor sequences and other predictive
tasks. Fronto-striatal, fronto-cerebellar and fronto-parietal loops
have been implicated in procedural learning (Pascual-Leone
et al., 1993, 1996; Doyon et al., 1997; Shadmehr and Holcomb,
1997; Hikosaka et al., 1998; Ghilardi et al., 2000). However,
their interaction during simple tasks where learning is very
rapid is not well documented. For some tasks motor learning
may extend over a period of weeks, months or even years, but
for some simple tasks learning can take place during a period of
minutes or even seconds (Karni, 1996). The predictive saccade
task studied here is one task that very rapidly induces pro-
cedural memory, allowing investigation of the differences
between predictive and sensory-guided behavior to be system-
atically investigated within the time course of a single functional
magnetic resonance imaging (fMRI) paradigm.
In the predictive saccade (PRED) task a visual target typically
alternates between fixed positions at a fixed time interval, i.e.
square-wave stimulus (Broinstein and Kennard, 1985; Ross and
Ross, 1987; Smit and Van Gisbergen, 1989; Tian et al., 1991;
Karoumi et al., 1998; Krebs et al., 2000). Therefore, task
requirements are fully predictable in time and space. After
a few trials, subjects begin to anticipate the appearance of the
target and more rapidly issue a saccade towards the expected
target location. Thus, reaction times drop and saccades become
anticipatory. Behavioral experiments have shown that the
saccade latency distribution in the PRED task is mainly
comprised of anticipatory saccades (latencies of <80 ms) in
comparison with saccades to unpredictable targets that are
usually initiated between 150 and 225 ms after target appear-
ance in a visually guided saccade (VGS) task (Becker, 1989; Smit
and Van Gisbergen, 1989; Fischer et al., 1993; Delinte et al.,
2002). Thus, while saccades in the VGS task are sensory driven
by the visual stimulus, anticipatory saccades in the PRED task
are considered to be internally generated. Anticipatory saccades
could be generated by the memory trace of the sensory (visual)
and/or motor signals generated during earlier trials. Conse-
quently, we could expect a different network of brain struc-
tures to be active during performance of the PRED task as
contrasted with a VGS task, including brain areas specialized for
memory-related processes and those supporting internally
planned and generated behavior. Interestingly, fMRI studies
during two saccade tasks that are also internally driven — the
delayed saccade and antisaccade tasks — have shown greater
activity in the prefrontal cortex as well as in the fronto-parietal
system when contrasted with a VGS task (Sweeney et al., 1996;
Connolly et al., 2000; Matsuda et al., 2004). Note that saccades
during both the delayed saccade and antisaccade tasks have
much longer latencies than during the VGS task, and therefore
anticipatory saccades are not produced when these tasks are
performed. The PRED task therefore differs in a fundamental
way from the delayed and antisaccade tasks for it is mainly
comprised of anticipatory saccades.
To study human brain systems supporting anticipatory
behavior, we used fMRI to measure human cerebral activity
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during performance of a predictive saccade task, and we
contrasted it with that of a visually guided saccade task.
Material and Methods
Ten healthy right-handed adults (seven females and three males)
participated in this study. Experimental procedures complied with the
Code of Ethics of the World Medical Association (1964 Declaration of
Helsinki) and the standards of the University of Illinois Internal Review
Board. All subjects provided written informed consent.
A standard block design was used (VGS--PRED--VGS--PRED--visual fixa-
tion, repeated four times), with each epoch lasting 30 s; the entire task
was therefore completed in 10 min. In both saccade tasks targets
consisted of a small white round dot (0.5? of visual angle) that moved
only along the horizontal plane. The duration of target presentation was
always 750 ms, and subjects were simply instructed to track the target.
In the VGS task, targets were presented at one of seven possible target
locations with the distance between them being 3? of visual angle.
The target stepped unpredictably 3? to the left or right with equal
probability. In the PRED task, target position alternated in 3? steps but
between only two spatial locations. Thus, VGS and PRED tasks were
balanced in terms of the number of saccades required to perform the
task (40 per block of trials), and in their amplitude (3?) and direction
(equal numberto the left and right on average). The PRED and VGS tasks
were contiguous, without any type of explicit cue denoting transition
from one task to the other. Transition between predictable and
unpredictable blocks was made from the last target position of the
prior condition. The visual fixation (FIX) task required subjects to fixate
a cross in the middle of the screen, which, in addition to providing
a baseline control condition, also provided an opportunity to rest.
Brain imaging studies were performed using a 3.0 T whole-body scanner
(Signa, General Electric Medical Systems, Milwaukee, WI) and a com-
mercial head radiofrequency coil. Subjects’ heads were positioned
comfortably within the head coil, and head motion was minimized
with firm cushions. Functional images were acquired using gradient-
echo echo-planar imaging that is sensitive to regional alterations in
blood flow via blood oxygenation level dependent (BOLD) contrast
effects. Twenty five axial (horizontal) slices were acquired, covering
virtually the whole brain. The following parameters were used for
functional scans: TE= 25 ms; flip angle = 90?; field of view = 20 3 20 cm;
acquisition matrix = 64 3 64; TR= 2.5 s; 5 mm slice thickness with 1 mm
gap; 240 images per slice. High-resolution T1-weighted structural
images were acquired in the axial plane from all subjects (three-
dimensional spoiled gradient recalled, 1.5-mm-thick contiguous slices)
for coregistration with the functional data. Visual stimuli were back-
projected by an LCD video projector onto a screen which the subject
viewed through an angled mirror. Performance of the task was
monitored with a video camera throughout testing to verify that these
healthy cooperative subjects were complying with task demands.
Image data were analyzed using FIASCO software (Functional Imaging
Analysis Software-Computational Olio; Eddy et al., 1996). Head motion
was corrected in three dimensions using a two level optimization
algorithm to estimate rotation and translation values. A smoothing
function was applied to remove slow signal drift. The fMRI time series
were shifted by 6 s to compensate for delay in the BOLD response.
Functional activation maps for each subject were based on t-tests
performed on the data obtained during performance of the different
task conditions. Functional and anatomical data were spatially trans-
formed into Talairach space (Talairach and Tournoux, 1988) using
Analysis of Functional NeuroImages software (AFNI; Cox, 1996). A small
Gaussian spatial filter with SD = 0.25 mm was applied to the functional
image sets before averaging them across subjects. The group activation
maps were created by averaging activation maps across subjects using
Fisher’s method of combining independent data tests (Fisher, 1950).
This method, in the present context, involved computing and averaging
a log transform of P values associated with results of within-subject
voxelwise t-tests comparing two task conditions of interest (Lazar et al.,
2002). We translated the resulting P values to a t-distribution for
presentation purposes, and set the a priori voxel-wise significance level
at a t-value of 5.0 to identify activated voxels. In addition to the primary
analysis of interest comparing the VGS and PRED tasks, analyses were
firstundertaken to compareeach ofthesetwotasks to thevisual fixation
condition. This was done to provide information about brain activity
associated with performing these two tasks before evaluating the
differences between them.
Visually Guided Saccade Task--Fixation (VGS-FIX)
Performance of the spatially random visually guided saccade
task (Table 1) compared with the fixation task activated
a cortical network of frontal, parietal and occipital areas that
has already been described in human neuroimaging studies
(Sweeney et al., 1996; Luna et al., 1998; Perry and Zeki, 2000).
Briefly, we found activation bilaterally in two regions that have
been identified in humans as the frontal eye field (FEF) and the
supplementary eye field (SEF), as well as in the posterior
cingulate cortex (PCg), superior parietal lobule and occipital
lobe. In addition, we found task-related activation bilaterally in
the prefrontal cortex (superior and inferior frontal gyri and
lateral orbital gyrus), the middle and superior temporal gyri, and
Because of recent discussions regarding the location of
human FEF and SEF with respect to nonhuman primates
(Tehovnik et al., 2000), we present the following anatomical
description of the field of activation found in BA 6 in the frontal
lobes relative to sulcal anatomy. In nonhuman primates, the FEF
corresponds to the border of BA 6 and BA 8. However, in
humans, recent fMRI and anatomical studies have localized the
FEF in what is accepted to be a more posterior region in BA 6
(Petit et al., 1993,1997; Paus, 1996; Luna et al., 1998; Berman
et al., 1999; Perry and Zeki, 2000;Tehovnik et al., 2000; Rosano
et al., 2003) and sometimes extend it into the central sulcus BA
4 (Gagnon et al., 2002). Interestingly, an oculomotor represen-
tation area has been found in very close proximity to motor
cortex (BA 4) in the ventral premotor cortex of nonhuman
primates (Fujii et al., 1998), which may account for activation
near the central sulcus during saccades.
The main activation in the frontal lobe was located bilaterally
in the precentral sulcus and gyrus (BA 6) extending in some
areas into the central sulcus (Fig. 1A,B). Two large and intense
foci of activation were observed in this region, one medial and
located cluster (FEFm) extended into slightly more dorsal areas
of the premotor cortex than the lateral cluster (FEFl) that
extended into more anterior and ventral areas. These clusters
had significant overlap in the group maps and in some individual
maps (Fig. 1A,B). The medial focus of FEF activation was close to
another large cluster of intense activation in a mesial area of the
frontal cortex lying within the interhemispheric fissure that
corresponds to the SEF (Luna et al., 1998) (Fig. 1A,B). Activity in
the SEF encroached upon the pre-supplementary motor area
(pre-SMA) (with the AC line serving as a border, Picard and
Strick, 2001). Significant activation in the lateral orbital gyrus
and superior and inferior frontal gyri was observed bilaterally. In
the parietal lobe, two fields of activation were found in the
superior parietal lobule; one was located in the precuneus and
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Brain regions activated during the VGS and PRED tasks, each compared separately to the central fixation baseline
Basal ganglia and thalamus
x, y, z Talairach coordinates represent the location of the voxel showing peak activation (highest t-test value) in each of the specified anatomical regions. Abbreviations from top: R, right hemisphere; L,
left hemisphere; FEFm, frontal eye field medial region; FEFl, frontal eye field lateral region; SEF, supplementary eye field; pre-SMA, pre-supplementary motor area; ACG, anterior cingulate gyrus; PCG,
posterior cingulate gyrus; SFG, superior frontal gyrus; MFG, middle frontal gyrus; IFG, inferior frontal gyrus; LOG, lateral orbital gyrus; SPL, superior parietal lobule; IPS, intraparietal sulcus; SMG,
supramarginal gyrus; AG, angular gyrus; STL, superior temporal lobule; HIP, hippocampus; Tm-Oc, temporo-occipital junction; SOG, superior occipital gyrus; MOG, middle occipital gyrus; CUN, cuneus;
FusG, fusiform gyrus; LingG, lingual gyrus; CAUD, caudate nucleus; PUT, putamen; GP, globus pallidus; MDTH, medio-dorsal region of the thalamus; CerVmIII, cerbellar vermis lobule III; CerHVI-l,
cerebellar hemisphere lobule VI lateral region; CerHVI-m, cerbellar hemisphere lobule VI medial region; CerCrusI, cerebellar hemisphere Crus I.
fMRI Anticipatory Behavior
Simo ´ et al.
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the other occupied a larger, more posterior and lateral region in
the intraparietal sulcus (Fig. 1A).
Outside the cerebral cortex the main focus of activation was
found in the cerebellum. Activation in the cerebellum was
identified in the posterior cerebellar vermis (lobule VI) and
hemispheres (lobule VI and Crus I).
Predictive Saccade Task--Fixation (PRED-FIX)
During execution of the PRED task (Table 1) we observed
activation in the premotor cortex, including the FEF and the
SEF, the prefrontal cortex (superior and inferior frontal gyri, and
lateral orbital gyrus), the anterior and posterior cingulate
cortices, the superior parietal lobule, the superior and middle
temporal gyri, the occipital lobe, and the cerebellum.
Most activity in the FEF corresponded to the FEFl, which
extended into slightly more anterior and ventral areas of
precentral gyrus as previously described in the VGS-FIX
contrast. Additional activation was found bilaterally in the
parietal lobe (BA 40) (Fig. 1C), mostly located in the supra-
marginal and angular gyri lateralized toward the left hemi-
sphere, but also in the parietal operculum, the pre-SMA, the
middle frontal gyrus corresponding to dorsolateral prefrontal
cortex (BA 46/8), the insula and the anterior medial temporal
lobe in the hippocampus/parahippocampal area (Reber et al.,
Subcortically, several foci of activation were identified bi-
laterally in the striatum, thalamus and cerebellum. In striatum,
most of the activity was found in the ventral putamen with
a posterior location. Although bilateral, somewhat greater
activation was observed in the left putamen. This focus of
activity appeared to extend to the adjacent globus pallidus. In
addition, activation was observed bilaterally in the caudate
nucleus with somewhat greater activation in the left side.
Activation in the thalamus was located mostly in the medial
regions, with an especially large and intense focus in a region
corresponding to the mediodorsal thalamus. Cerebellar activa-
tion was found in the vermis (lobules III and VI) and hemi-
spheres (lobule VI and Crus I). It is interesting to note that the
pattern of activity seemed to be greater in the left side in several
brain regions: the middle frontal gyrus, inferior parietal lobule,
lenticular nuclei and cerebellar hemispheres.
Predictive Saccade Task--Visually Guided
Saccade Task (PRED-VGS)
There was significantly greater activation in the PRED than VGS
task in the middle, superior and inferior frontal gyri bilaterally
(Table 2, Figs 2B--D and 3A). Significantly greater activation in
the PRED task was also observed in the pre-SMA bilaterally
(Fig. 2A), in the anterior (BA 24) (Fig. 2D) and posterior
cingulate (BA 23) cortices bilaterally, and in the inferior parietal
lobule (BA 40), mostly located in the angular and supramarginal
gyri of the left hemisphere (Figs 2B and 3C,D). Greater
activation during the PRED task was observed in the hippocam-
pus bilaterally (Figs 2F and 3B).
Subcortically, significantly greater activity was observed bi-
laterally in the dorsal striatum in the head and body of the
caudate in the PRED task than in the VGS task, and a larger
field of activity was found in the posterior and ventral putamen
(Fig. 2E). The substantia nigra pars reticulata (SNr) is one of
the output stations of the basal ganglia. A focus of increased
activation in the PRED task relative to the VGS task was
identified in a region corresponding to the SNr in the left
hemisphere. In the thalamus, significantly greater activity
during the PRED task was well circumscribed to a medial
region, in an area corresponding to the mediodorsal nuclei
(Fig. 3B). Both the VGS-Fix and PRED-Fix contrasts revealed
substantial cerebellar activation. However, the activity during
performance of the PRED task was significantly greater bi-
laterally in the cerebellar vermis lobule VI and hemispheres
(lobule VI and Crus I) (Fig. 2G,H).
Visually Guided Saccade Task--Predictive
Saccade Task (VGS-PRED)
In other areas, greater activation was seen in the VGS than in
the PRED task (Table 3). Activation during the VGS task was
significantly greater than during the PRED task bilaterally in the
medial (dorsal and posterior) region of the FEF (Figs 2A and 3B).
This medial FEF region corresponds to the fundus of the
precentral sulcus and its medial branches characterized by
Rosano et al. (2002). Activity related to VGS was also greater in
the superior parietal gyrus (BA 7), occipital lobe (BA 17--19)
(Fig. 2E) and a region of posterior cingulate cortex (BA 31).
Greater activity was also observed during the VGS task in the
cerebellar hemispheres (Crus I), in a region more dorsally
located than the focus of activity observed during the PRED
Figure 1. Distribution of task-related activity in frontal (FEF, SEF) and parietal lobes
(SPL and IPL). Images follow radiological convention (left is right and right is left). The
greenline in axialsectionsA and C goes throughtheregion of theFEF andindicatesthe
anterior--posterior level of the coronal sections B and D, and vice versa. Sections A and
B correspond to the VGS-FIX contrast. Sections C and D correspond to the PRED-FIX
contrast.Note that in sections C and D, activity in the region of the FEF is much smaller
than in sections A and B.
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Predictive behavior relies on memories and leads to more
accurate and faster responses. Our fMRI study contrasting tasks
in which subjects made saccades to rhythmic predictable and
unpredictable visual stimuli show a fundamentally different
pattern of brain activation in the two task conditions, demon-
strating a marked dissociation between sensory and predictive
control of similar saccadic eye movements. Sensory-guided
behavior was heavily dependent on a fronto-superior parieto-
occipital system, while anticipatory behavior involved less
activity in sensory-related processing areas with more activity
in a distributed memory system that included the prefrontal and
the inferior parietal cortices, the striatum, dorsomedial thala-
mus, the cerebellum and the hippocampus.
Anticipatory Behavior: Earlier Motor Activity
Our results suggest that during anticipatory behavior there is
a shift from neural systems supporting sensory-guided behavior
to a different neural system supporting internally generated,
anticipatory or ‘memory-guided’ behavior. Previous work (using
delayed response tasks with explicit preparatory cues) has
focused on preparatory signals as the basis for faster movement
reaction times (Horwitz et al., 2000; Thoenissen et al., 2002).
Our results indicate that a parallel reduction in the early stages
of sensory processing and sensorimotor transformations seems
to parallel this shift to memory-guided behavior during pro-
cedural learning. Our observations of less activation in the PRED
than the VGS tasks in the occipital lobe (BA 17--19) and in the
region of the precuneus in the superior parietal lobule (BA 7),
which plays a role in shifting spatial attention (Vandenberghe
et al., 2001; Coull et al., 2003), and in the medial FEF are
consistent with this interpretation.
Our fMRI results also suggest that different regions of the
premotor cortex in the FEF area might be differentially involved
in sensory-guided versus memory-guided behavior, with the
medial region of the FEF being more involved in sensorimotor
transformations than the lateral region. This points to a possible
differential connectivity within subregions of the human FEF.
Several studies have reported different patterns of activation in
superior and inferior precentral sulcus in saccade tasks with
differing cognitive load (Petit et al., 1997; Culham et al., 1998;
Merriam et al., 2001). Futhermore, a distinction between
(dorso)medial and lateral FEF has been made in a recent fMRI
study in which performance of new versus familiar sequences of
saccades was compared (Grosbras et al., 2001). In that study
activity in the FEFl was similar in both tasks; however, more
activation was found in the dorso-medial region of FEF during
performance of saccades to unpredictable targets, which
requires more spatial attention for sensory-related processing.
Thus, similarly to Grosbras et al. (2001), we found more
activation in the medial FEF during performance of the VGS
task that is more demanding in terms of spatial attention than
the PRED task, while the lateral FEF was similarly active in both
Different connectivity has been demonstrated for the dorsal
and ventral premotor cortex in the arm region (Luppino et al.,
1999; Dum and Strick, 2002; Rizzolatti et al., 2002) and the
relevance for visuomotor control of this circuitry between the
dorsal premotor cortex, superior parietal lobule and extrastriate
visual cortex has been emphasized (Wise et al., 1997). In-
terestingly, activation in the area of FEF during sustained
smooth pursuit tracking of predictable targets is similarly
reduced relative to visually guided saccades in a way that
parallels findings reported here for predictive saccades (Berman
et al., 1999). Their Figure 2 is very similar to our Figure 1.
Sustained smooth pursuit eye movements have an important
predictive component that allows tracking a visual target
without lagging behind, which may contribute to the widely
reported lower level activation in the FEF during pursuit versus
saccadic eye movements tasks.
In a previous fMRI study on predictive saccades (Gagnon
et al., 2002), including tasks that were either directionally
predictable or temporally predictable as well as a task that was
both temporally and spatially predictable, a larger volume of FEF
activation was found in the predictable tasks when compared
with a saccade control task with unpredictable timing and
direction of target movements. Those findings are in contradic-
tion with the present study, in which activity in the FEF was
greater in our unpredictable task (the VGS task) with respect to
our predictable task. Additional differences between our results
and those of Gagnon et al. (2002) include that we found greater
activity in our predictable task (with respect to our unpredict-
able task) in the prefrontal cortex, pre-supplementary motor
area, inferior parietal lobule, medial thalamus, cerebellum and
hippocampus. Methodological differences may underlie this
discrepancy. In our study, the timing of the target movement
was predictable in both the PRED and VGS tasks, and they
differed only in the predictability of the direction of target
movement. The latter is known to be a far more powerful factor
in supporting anticipatory behavior (Saslow, 1967a,b; Delinte
et al., 2002). A key difference may be that their paradigm
included three targets (three fixed spatial locations), thus
requiring subjects to learn a multistep response sequence in
their spatially predictable task. In our PRED task, targets
Brain regions activated during the PRED task more than during the VGS task
CerHV, cerebellar hemisphere lobule V. For other abbreviations, see Table 1.
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Simo ´ et al.
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alternated between only two fixed spatial locations. Further-
more, trials in our VGS task did not all start from center fixation
as in the Gagnon et al. spatially unpredictable task. Therefore, in
the Gagnon et al. (2002) study half of the saccades in the
unpredictable task were predictable in time and space (return
saccades to center fixation target). In contrast, in our VGS
paradigm, all saccades were made to directionally unpredictable
targets. These two key differences, the greater level of un-
predictability in our VGS task and a much simpler and quickly
learned PRED task, could account for differences in the
functional anatomy mapped by our different behavioral para-
Altogether, based on the present results we conclude that
a network comprising occipital lobe, superior parietal lobule
and medial regions of the FEF is most importantly involved in
externally-directed attentional states and sensorimotor trans-
formations required for visually guided saccades, and that
activity in this network decreases when saccades become
anticipatory and thus less sensory-driven. In contrast, during
anticipatory behavior the pattern of activity increases in other
brain regions involved in maintaining a spatial and/or motor
memory of the task. These data highlight the significant
distinction between the sensory-driven system supporting
sensory-guided responses during the VGS task and the mem-
ory-driven system supporting the anticipatory responses during
the PRED task. Note that our memory-guided task, the PRED
task, differs fundamentally from another frequently used mem-
ory task in saccade experiments, the delayed saccade task, also
called memory saccade task, in which activity in the frontal and
parietal eye fields is higher when contrasted with the VGS task
Figure 2. Distribution of task-related activity in the fronto-parieto-occipital system, hippocampus, basal ganglia and cerebellum. Axial sections through brain levels Z 55 (A), 47 (B),
41 (C), 34 (D), 3 (E), ?15 (F), ?26 (G) and ?31 (H). The green line in section A indicates the AC line location. Areas colored in blue indicates significantly greater activity during the
PRED task with respect to the VGS task. Areas colored in red correspond to areas where there was significantly greater activity during the VGS task with respect to the PRED task.
ACG, anterior cingulated cortex; IPL, inferior parietal lobule; LG, lingual gyrus. Other abbreviations are as in Table 1.
Figure 3. Distribution of task related activity in frontal and parietal lobes, thalamus and hippocampus. Coronal sections through brain levels Y 42 (A), ?16 (B), ?35 (C) and
?51(D). Section A shows in blue significantly greater activity in prefrontal cortex during the PRED task. Section B shows in red greater activity in the medial region of FEF in the VGS
task and in blue greater activity in mediodorsal thalamus and hippocampus during the PRED task. Section C shows in blue the greater activity in the IPL in the left supramarginal
gyrus during the PRED task. Section D shows in blue greater activity in IPL in the left angular gyrus during the PRED task.
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(Sweeney et al., 1996). The delayed saccade task is also
a memory-guided task that requires short-term memory, but it
is a working memory task involving trial-wise storage of target
locations, which contrasts with the PRED task which relies on
procedural learning during repeated performance of the same
behavior. Interestingly, fMRI studies contrasting antisaccade
and VGS tasks have also shown increased activity in the frontal
and parietal eye fields in the antisaccade task (Sweeney et al.,
1996; Connolly et al., 2000; Matsuda et al., 2004). In the
antisaccade task subjects are required to make saccades not
towards the visual stimulus but to its mirror-symmetrical
position in the opposite visual field. This task is demanding in
terms of re-mapping the stimulus location in the opposite visual
field and inhibiting the tendency to look towards the stimulus,
which is reflected in response errors and correct responses
with longer latencies than the VGS task. In this respect, our
PRED task is less complex than the delayed saccade and
antisaccade tasks, making the production of anticipatory
saccades possible and almost automatic. We think that the
decrease in the activity of the FEF and superior parietal lobule is
an expression of the automaticity of this task due in part to the
decrease in sensorimotor transformations.
Anticipatory Behavior: Distributed Memory
In our memory-guided PRED task, we found significantly
increased activation with respect to the sensory-guided task
in the inferior parietal lobule (BA 40), prefrontal cortex (BA 46
and 8), pre-SMA, anterior cingulate cortex, hippocampus,
striatum, mediodorsal thalamus and cerebellum. Thus, our
results indicate that our memory-guided task is mostly sup-
ported by a network of brain regions other than the sensory and
cortical eye fields that support visually guided saccades. This is
similar to results in nonhuman primates indicating that spatial
working memory is maintained primarily outside the FEF (Balan
and Ferrera, 2003). Other studies have suggested that the FEF is
involved not only in the execution of the movement but also in
certain types of preparatory states (Connnolly et al., 2002).
However, unlike delayed response tasks (Sweeney et al, 1996),
activity in sensorimotor systems during our memory-guided
PRED task was reduced. Thus, there is a fundamental difference
between the neural systems supporting memory-guided behav-
ior in delayed response tasks, where locations need to be
maintained in working memory to direct subsequent actions,
and those supporting our memory-guided task where a specific
pattern of responding to predictable sensory stimuli is learned.
Our results showing activation in the medial temporal areas in
our PRED task is consistent with the participation of the
hippocampus in simple visuomotor tasks with a spatial memory
component. Traditionally, a distinction between declarative and
procedural learning has been made. While declarative memory
has been linked to medial temporal areas, procedural learning
typically has been related to basal ganglia and cerebellum. Our
results extend the role of the hippocampus/parahippocampal
region to include at least some types of procedural learning in
The prefrontal cortex is fundamental to working memory and
the temporal organization of behavior (Levy and Goldman-
Rakic, 2000; Fuster, 2001). At least two important loops through
the prefrontal cortex have been described for the maintenance
of spatial working memory. One loop involves the prefrontal
cortex and the posterior parietal cortex (Chafee and Goldman-
Rakic, 1998, 2000). The posterior parietal cortex has a prom-
inent role in spatial orientation and attention (Mesulam, 1998;
Kim et al., 1999; Pessoa et al., 2003). The other loop is between
the mediodorsal thalamus and the prefrontal cortex (Alexander
and Fuster, 1973; Beiser and Houk, 1998). Very recently, in
nonhuman primates, spatially tuned cells have been reported in
mediodorsal thalamus in the region that projects to the
dorsolateral prefrontal cortex (Tanibuchi and Goldman-Rakic,
2003). Furthermore, an oculomotor region involving several
nuclei in the primate central thalamus has been identified
(Wyder et al., 2003). This oculomotor thalamus displays
multiple projections to cortical and subcortical visuomotor
areas such as the FEF, prefrontal cortex, SEF, posterior parietal
cortex, caudate and SNr. Our results indicate that both loops
could be involved in anticipatory responses, but the differential
contributions of each remain to be delineated.
Recently, the distributed nature of brain memory systems has
been emphasized (Mesulam, 1998; Nadel et al., 2000; Fuster,
2000, 2001; Kim and Baxter, 2001). Goldman-Rakic and collab-
orators have proposed a working memory network that
includes the dorsolateral prefrontal cortex, inferior parietal
lobule and medial temporal areas, including the hippocampus,
mediodorsal and anterior thalamus, and caudate nucleus (Levy
et al., 1997). Our results support the existence of such
a memory network and extend its role to the generation of
anticipatory responses in the context of procedural learning. In
addition, our results suggest that this loop in the left (versus
right) hemisphere could be more important for anticipatory
saccadic eye movements, consistent with some previous
reports (Thoenissen et al., 2002).
Anticipatory Behavior: Switching from a Sensory-driven
System to a Memory-driven System — the Basal Ganglia
and the Cerebellum
Both the basal ganglia and the cerebellum have been implicated
in procedural learning (Gomez-Beldarrain et al., 1998; Hikosaka
et al., 1998, 2002). The basal ganglia and the cerebellum project
onto numerous regions of the cerebral cortex, and thus they are
in a position to influence several cortical areas during a given
behavioral context (Kelly and Strick, 2003a,b). Futhermore,
Brain regions activated more during the VGS task than during the PRED task
Precu-PO, precuneus parieto-occipital region. For other abbrevations, see Table 1.
fMRI Anticipatory Behavior
Simo ´ et al.
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a theory of brain function based on cortico-basal ganglia and
cortico-cerebellar loops has also been postulated for multiple
aspects of motor control and cognition (Houk, 2001).
Anticipatory responses during performance of predictive
saccade tasks are clearly impaired in basal ganglia disorders
such as Parkinson’s disease and Huntington’s chorea (Broinstein
and Kennard, 1985; Crawford et al., 1989; Tian et al., 1991). Our
results, showing greater activation in striatum in our memory-
guidedPRED task inrelation to our sensory-guided task, support
the role of the basal ganglia in anticipatory responses.
Fronto-striatal circuits have been implicated in set-shifting, as
well as skill and habit learning (Jog et al., 1999). Cortical areas in
the medial prefrontal cortex, insular cortex and anterior
cingulate cortex receive input from mediodorsal thalamus and
hippocampus and project into the ventral caudate. These
striato-cortical loops, with thalamic and hippocampal involve-
ment, have been postulated to mediate responses according to
their behavioral context and could be implicated in switching
from a sensory-guided behavior to an internally generated or
memory-guided behavior (Kimberg et al., 2000; Konishi et al.,
2001; Fox et al., 2003).
The cerebellum plays an important role in the motor
adjustment of saccadic eye movements. Traditionally, only the
cerebellar vermis (VI--VII) and the underlying fastigial nucleus
were implicated in saccades. In recent years, several neuro-
imaging studies have shown increased activity in the lateral
cerebellar hemispheres during voluntary visually guided sac-
cades (Perry and Zeki, 2000; Hayakawa et al., 2002), and our
results confirm the participation of cerebellar hemispheres in
human saccades. In addition, our results show a different
pattern of activation in the cerebellum during sensory-guided
and memory-guided tasks. Overall, cerebellar activity tended to
be greater during our predictive task, specifically in left
cerebellar hemisphere lobule VI and Crus I. Therefore, it is
possible that loops through the basal ganglia and cerebellum are
both fundamental to switching the control of behavior from
sensory-driven to memory-driven brain systems, and for main-
taining anticipatory behavior.
Orienting and Attentive Behavior: The Fronto-parietal
Research in human orienting behavior and attention using fMRI
has led to the development of the model that two partially
segregated brain networks support goal-directed and sensory-
guided behavior (Corbetta and Shulman, 2002). Goal-directed
behavior implicates a top-down processing network more
dependent on cognition. This system includes, according to
Corbetta and Shulman (2002), the dorsal posterior parietal
cortex and the dorsal frontal cortex. The sensory-guided
behavior that follows the detection of novel relevant sensory
stimuli implicates the temporo-parietal and ventral frontal
cortex and is lateralized towards the right hemisphere. Our
results further segregate this orienting network into a sensory-
guided system that includes the FEFm and superior parietal
gyrus, and a memory-guided system that, in concert with
striatal, cerebellar, and hippocampal networks, allows the
development of anticipatory goal directed behavior. This last
system included the FEFl and the supramarginal and angular gyri
of the inferior parietal lobule.
Thus, based on our results and previous studies, it seems
likely that there are multiple orienting systems or one large
orienting network with differential active nodes, depending on
the type of task and the context in which the task evolves.
Therefore, different areas of the parietal lobe might be activated
in relation to different areas of frontal, temporal and occipital
lobes and in general to different cortical and subcortical brain
regions, depending on the particular task demands. The frontal
and parietal lobes have been the focus of many studies in
relation to spatial orientation and attention (Mesulam, 1998;
Kim et al., 1999; Perry and Zeki, 2000; Gottlieb, 2002; Pessoa
et al., 2003), and its parcellation into different regions is still
evolving (Gabernet et al., 1999; Luppino et al., 1999; Boussaud,
2001; Cavada, 2001; Culham and Kanwisher, 2001; Matelli and
Luppino, 2001; Zilles et al., 2001; Rizzolatti et al., 2002).
Summary and Conclusions
The present study demonstrates the robust dissociation be-
tween the brain systems that control sensory-guided and
anticipatory memory-guided behavior for similar saccadic eye
movements. The sensory-guided system supports saccades to
unpredictable but behaviorally relevant stimuli, and it comprises
visual sensory areas of occipital lobe together with the superior
parietal gyrus (region of precuneus) and a dorsomedial FEF
region of the premotor cortex. The memory-guided system
supporting predictive or anticipatory behavior is supported by
executive prefrontal centers such as the dorsolateral prefrontal
related circuits such as the fronto-parietal, fronto-thalamic
loop and hippocampus-inferior parietal network, as well as
cortico-striatal and cortico-cerebellar loops that are involved in
procedural learning. Thus, during the rapid shift from sensory-
driven to predictive behavior that occurs during the PRED task,
major shifts in brain activity controlling the same motor output
are observed. Activity in exogenous visual orienting systems is
reduced while activity in regions supporting endogenous
actions, memory and motor learning increases.
Inaddition, ourresultssuggest thedistinction of twodifferent
located region and a lateral region. These two regions of FEF are
probably connected todifferentcortical areasintheparietal and
occipital lobes and to different subcortical channels through
basal ganglia and cerebellum, thus forming brain networks
related to different sensorimotor task requirements.
The authors would like to acknowledge Werner Graf, James Houk, Lee
Miller, Paul Reber and anonymous reviewers for comments on a pre-
vious draft of this manuscript. This work was supported by the NIH
(MH62134 and NS35949).
Correspondence to: Lucia S. Simo ´ , Northwestern University, The
Feinberg School of Medicine, Department of Physiology, Ward 5--315,
303 East Chicago Avenue, Chicago, IL 60611, USA. Email: l-simo@
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