Abstract

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 subserved by a distributed cortico-subcortical memory system including prefronto-striatal circuitry.

Introduction

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 stimulus 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 procedural memory, allowing investigation of the differences between predictive and sensory-guided behavior to be systematically 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 appearance 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. Consequently, we could expect a different network of brain structures 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 during performance of a predictive saccade task, and we contrasted it with that of a visually guided saccade task.

Material and Methods

Subjects

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.

Experimental Paradigms

A standard block design was used (VGS–PRED–VGS–PRED–visual fixation, 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 number to 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.

Image Acquisition

Brain imaging studies were performed using a 3.0 T whole-body scanner (Signa, General Electric Medical Systems, Milwaukee, WI) and a commercial 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 × 20 cm; acquisition matrix = 64 × 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.

Data Analysis

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 transformed 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 first undertaken to compare each of these two tasks to the visual fixation condition. This was done to provide information about brain activity associated with performing these two tasks before evaluating the differences between them.

Results

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 the cerebellum.

Table 1

Brain regions activated during the VGS and PRED tasks, each compared separately to the central fixation baseline

 VGS–fixation
 
   PRED–fixation
 
   

 
t
 
x
 
y
 
z
 
t
 
x
 
y
 
z
 
Frontal lobe         
    R FEFm 9.51 28 −13 54 7.81 27 −13 57 
    L FEFm 10.42 −28 −8 47 8.14 −29 −3 49 
    R FEFl 10.17 51 38 9.71 50 −2 46 
    L FEFl 9.67 −46 −10 39 9.47 −40 −12 44 
    R SEF 10.39 −7 59 10.13 −7 60 
    L SEF 9.83 −2 −7 58 8.37 −5 −3 57 
    R pre-SMA 7.46 63 7.26 60 
    L pre-SMA 6.72 −3 60 6.55 −6 58 
    R ACG – – – – 6.21 43 
    L ACG – – – – 7.71 −4 −1 47 
    R SFG 6.88 49 30 8.00 16 58 41 
    L SFG 7.10 −5 44 33 7.05 −6 47 46 
    R MFG – – – – 7.36 44 27 46 
    L MFG – – – – 7.76 −39 33 43 
    R IFG 6.94 48 36 19 7.26 49 36 20 
    L IFG 8.64 −45 22 13 7.71 −46 26 27 
    R LOG 8.46 36 50 9.15 40 49 
    L LOG 5.90 −40 51 6.99 −40 51 
Parietal lobe         
    R PCG 7.31 14 −27 34 6.72 12 −27 34 
    L PCG 6.32 −12 −23 32 6.67 −9 −23 34 
    R SPL 9.71 19 −73 51 8.00 19 −73 52 
    L SPL 9.47 −24 −63 49 7.20 −20 −66 47 
    R IPS 8.72 24 −59 39 7.41 23 −57 41 
    L IPS 8.37 −20 −60 44 6.94 −20 −60 43 
    R SMG – – – – 7.76 48 −45 44 
    L SMG – – – – 7.90 −51 −48 46 
    R AG – – – – 8.18 31 −66 46 
    L AG – – – – 7.95 −46 −54 48 
Temporal lobe         
    R STL 9.11 59 −43 14 9.63 59 −42 14 
    L STL 7.90 −47 −42 16 7.36 −46 −44 14 
    R HIP – – – – 7.81 21 −20 −13 
    L HIP – – – – 7.20 −27 −20 −12 
    R Tm-Oc 10.20 49 −61 – – – – 
    L Tm-Oc 8.41 −50 −63 – – – – 
Occipital lobe         
    R SOG 8.37 20 −90 – – – – 
    L SOG 7.36 −18 −91 – – – – 
    R MOG 8.37 43 −74 – – – – 
    L MOG 8.67 −44 −74 – – – – 
    R CUN 7.36 18 −90 14 6.99 17 −92 14 
    L CUN 8.04 −15 −93 11 7.66 −15 −93 11 
    R FusG 6.88 19 −92 −15 6.88 19 −91 −15 
    L FusG 6.99 −21 −82 −11 6.67 −20 −72 −16 
    R LingG 7.41 12 −81 −12 7.71 −79 −16 
    L LingG 7.31 −15 −83 −13 6.62 −11 −83 −17 
Basal ganglia and thalamus         
    R CAUD – – – – – – – – 
    L CAUD – – – – 5.90 −11 −2 
    R PUT – – – – 5.35 22 −9 
    L PUT – – – – 5.86 −26 −3 
    R GP – – – – 6.21 29 −19 −3 
    L GP – – – – – – – – 
    R MDTH – – – – 5.35 −15 
    L MDTH – – – – 6.88 −3 −16 
Cerebellum         
    CerVmIII – – – – 6.62 −1 −50 −15 
    CerVmVI 5.86 −6 −63 −23 5.55 −0 −64 −26 
    R CerHVI-l 7.95 30 −60 −24 8.23 30 −60 −25 
    L CerHVI-l 7.66 −32 −67 −25 7.46 −32 −65 −25 
    R CerHVI-m 8.97 13 −77 −24 6.88 −67 −25 
    L CerHVI-m 8.32 −12 −65 −26 9.51 −12 −65 −26 
    R CerCrusI 7.46 26 −78 −27 7.05 31 −76 −28 
    L CerCrusI
 
7.46
 
−29
 
−70
 
−35
 
9.39
 
−36
 
−67
 
−33
 
 VGS–fixation
 
   PRED–fixation
 
   

 
t
 
x
 
y
 
z
 
t
 
x
 
y
 
z
 
Frontal lobe         
    R FEFm 9.51 28 −13 54 7.81 27 −13 57 
    L FEFm 10.42 −28 −8 47 8.14 −29 −3 49 
    R FEFl 10.17 51 38 9.71 50 −2 46 
    L FEFl 9.67 −46 −10 39 9.47 −40 −12 44 
    R SEF 10.39 −7 59 10.13 −7 60 
    L SEF 9.83 −2 −7 58 8.37 −5 −3 57 
    R pre-SMA 7.46 63 7.26 60 
    L pre-SMA 6.72 −3 60 6.55 −6 58 
    R ACG – – – – 6.21 43 
    L ACG – – – – 7.71 −4 −1 47 
    R SFG 6.88 49 30 8.00 16 58 41 
    L SFG 7.10 −5 44 33 7.05 −6 47 46 
    R MFG – – – – 7.36 44 27 46 
    L MFG – – – – 7.76 −39 33 43 
    R IFG 6.94 48 36 19 7.26 49 36 20 
    L IFG 8.64 −45 22 13 7.71 −46 26 27 
    R LOG 8.46 36 50 9.15 40 49 
    L LOG 5.90 −40 51 6.99 −40 51 
Parietal lobe         
    R PCG 7.31 14 −27 34 6.72 12 −27 34 
    L PCG 6.32 −12 −23 32 6.67 −9 −23 34 
    R SPL 9.71 19 −73 51 8.00 19 −73 52 
    L SPL 9.47 −24 −63 49 7.20 −20 −66 47 
    R IPS 8.72 24 −59 39 7.41 23 −57 41 
    L IPS 8.37 −20 −60 44 6.94 −20 −60 43 
    R SMG – – – – 7.76 48 −45 44 
    L SMG – – – – 7.90 −51 −48 46 
    R AG – – – – 8.18 31 −66 46 
    L AG – – – – 7.95 −46 −54 48 
Temporal lobe         
    R STL 9.11 59 −43 14 9.63 59 −42 14 
    L STL 7.90 −47 −42 16 7.36 −46 −44 14 
    R HIP – – – – 7.81 21 −20 −13 
    L HIP – – – – 7.20 −27 −20 −12 
    R Tm-Oc 10.20 49 −61 – – – – 
    L Tm-Oc 8.41 −50 −63 – – – – 
Occipital lobe         
    R SOG 8.37 20 −90 – – – – 
    L SOG 7.36 −18 −91 – – – – 
    R MOG 8.37 43 −74 – – – – 
    L MOG 8.67 −44 −74 – – – – 
    R CUN 7.36 18 −90 14 6.99 17 −92 14 
    L CUN 8.04 −15 −93 11 7.66 −15 −93 11 
    R FusG 6.88 19 −92 −15 6.88 19 −91 −15 
    L FusG 6.99 −21 −82 −11 6.67 −20 −72 −16 
    R LingG 7.41 12 −81 −12 7.71 −79 −16 
    L LingG 7.31 −15 −83 −13 6.62 −11 −83 −17 
Basal ganglia and thalamus         
    R CAUD – – – – – – – – 
    L CAUD – – – – 5.90 −11 −2 
    R PUT – – – – 5.35 22 −9 
    L PUT – – – – 5.86 −26 −3 
    R GP – – – – 6.21 29 −19 −3 
    L GP – – – – – – – – 
    R MDTH – – – – 5.35 −15 
    L MDTH – – – – 6.88 −3 −16 
Cerebellum         
    CerVmIII – – – – 6.62 −1 −50 −15 
    CerVmVI 5.86 −6 −63 −23 5.55 −0 −64 −26 
    R CerHVI-l 7.95 30 −60 −24 8.23 30 −60 −25 
    L CerHVI-l 7.66 −32 −67 −25 7.46 −32 −65 −25 
    R CerHVI-m 8.97 13 −77 −24 6.88 −67 −25 
    L CerHVI-m 8.32 −12 −65 −26 9.51 −12 −65 −26 
    R CerCrusI 7.46 26 −78 −27 7.05 31 −76 −28 
    L CerCrusI
 
7.46
 
−29
 
−70
 
−35
 
9.39
 
−36
 
−67
 
−33
 

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.

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 representation 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 one lateral, delineated by the black lines in Figure 1. The medially 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 the other occupied a larger, more posterior and lateral region in the intraparietal sulcus (Fig. 1A).

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 green line in axial sections A and C goes through the region of the FEF and indicates the 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.

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 green line in axial sections A and C goes through the region of the FEF and indicates the 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.

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 supramarginal and angular gyri lateralized toward the left hemisphere, 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., 2002).

Subcortically, several foci of activation were identified bilaterally 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 activation was found in the vermis (lobules III and VI) and hemispheres (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 2BD 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 hippocampus bilaterally (Figs 2F and 3B).

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 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.

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.

Table 2

Brain regions activated during the PRED task more than during the VGS task


 
t
 
x
 
y
 
z
 
SFG 7.21 21 57 
R MFG 7.15 48 17 41 
L MFG 7.51 −36 25 40 
R IFG 7.61 45 42 11 
L IFG 7.85 −38 42 
R pre-SMA 7.15 56 
L pre-SMA 5.40 −2 54 
R ACg 7.36 17 33 
L ACg 6.56 −2 20 33 
L SMG 7.71 −60 −34 27 
L AG 7.26 −41 −68 45 
R INS 5.98 40 12 
L INS 5.86 −33 12 
R HIPP 6.56 28 −16 −15 
L HIPP 6.10 −24 −16 −15 
R CAUD 6.04 13 10 
L CAUD 5.98 −10 −1 13 
R PUT 6.84 28 −9 
L PUT 6.10 −28 −1 
L PUT 7.31 −28 −8 −6 
L GP 7.61 −26 −7 −1 
R MDTH 7.31 −16 
L MDTH 6.89 −4 −17 12 
R CerHVI 5.80 17 −61 −26 
R CerHVI 6.39 −69 −24 
L CerHVI 7.00 −25 −62 −26 
L CerHV 5.98 −25 −46 −20 
LCerCrusI 5.80 −36 −49 −34 
LCerCrusI
 
6.67
 
−46
 
−69
 
−31
 

 
t
 
x
 
y
 
z
 
SFG 7.21 21 57 
R MFG 7.15 48 17 41 
L MFG 7.51 −36 25 40 
R IFG 7.61 45 42 11 
L IFG 7.85 −38 42 
R pre-SMA 7.15 56 
L pre-SMA 5.40 −2 54 
R ACg 7.36 17 33 
L ACg 6.56 −2 20 33 
L SMG 7.71 −60 −34 27 
L AG 7.26 −41 −68 45 
R INS 5.98 40 12 
L INS 5.86 −33 12 
R HIPP 6.56 28 −16 −15 
L HIPP 6.10 −24 −16 −15 
R CAUD 6.04 13 10 
L CAUD 5.98 −10 −1 13 
R PUT 6.84 28 −9 
L PUT 6.10 −28 −1 
L PUT 7.31 −28 −8 −6 
L GP 7.61 −26 −7 −1 
R MDTH 7.31 −16 
L MDTH 6.89 −4 −17 12 
R CerHVI 5.80 17 −61 −26 
R CerHVI 6.39 −69 −24 
L CerHVI 7.00 −25 −62 −26 
L CerHV 5.98 −25 −46 −20 
LCerCrusI 5.80 −36 −49 −34 
LCerCrusI
 
6.67
 
−46
 
−69
 
−31
 

CerHV, cerebellar hemisphere lobule V. For other abbreviations, see Table 1.

Subcortically, significantly greater activity was observed bilaterally 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 bilaterally 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 task.

Table 3

Brain regions activated more during the VGS task than during the PRED task


 
t
 
x
 
y
 
z
 
RFEFm 8.45 25 −9 45 
LFEFm 9.70 −30 −17 62 
LFEFm 8.89 −22 −11 52 
RSMA 7.00 −3 58 
LSMA 6.22 −8 49 
RSPL 8.59 15 −72 47 
RSPL 8.59 12 −80 48 
LSPL 7.76 −18 −69 50 
LSPL 7.85 −13 −73 51 
LIPS 7.51 −25 −62 47 
RPrecu-PO 6.50 −57 16 
RTm-Oc 6.10 49 −60 
RSOG 6.62 27 −79 
LSOG 6.33 −31 −83 
RCUN 5.67 −83 
LCUN 6.78 −7 −81 
RlingG 6.62 13 −74 
LlingG 6.39 −3 −77 −2 
RCerHVI 6.39 28 −69 −23 
RCerHVI 6.89 42 −47 −31 
LCerCrusI
 
5.67
 
−43
 
−48
 
−38
 

 
t
 
x
 
y
 
z
 
RFEFm 8.45 25 −9 45 
LFEFm 9.70 −30 −17 62 
LFEFm 8.89 −22 −11 52 
RSMA 7.00 −3 58 
LSMA 6.22 −8 49 
RSPL 8.59 15 −72 47 
RSPL 8.59 12 −80 48 
LSPL 7.76 −18 −69 50 
LSPL 7.85 −13 −73 51 
LIPS 7.51 −25 −62 47 
RPrecu-PO 6.50 −57 16 
RTm-Oc 6.10 49 −60 
RSOG 6.62 27 −79 
LSOG 6.33 −31 −83 
RCUN 5.67 −83 
LCUN 6.78 −7 −81 
RlingG 6.62 13 −74 
LlingG 6.39 −3 −77 −2 
RCerHVI 6.39 28 −69 −23 
RCerHVI 6.89 42 −47 −31 
LCerCrusI
 
5.67
 
−43
 
−48
 
−38
 

Precu-PO, precuneus parieto-occipital region. For other abbrevations, see Table 1.

Discussion

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, demonstrating 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 thalamus, 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 procedural 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 tasks.

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). Interestingly, 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 contradiction 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 unpredictable 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 alternated between only two fixed spatial locations. Furthermore, 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 unpredictability 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 paradigms.

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 transformations 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 memory-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 memory 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 (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 supported 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 behavior 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 which responses to spatially predictable information are learned.

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 prominent 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 collaborators 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, 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-guided PRED task in relation 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 involvement, 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 neuroimaging studies have shown increased activity in the lateral cerebellar hemispheres during voluntary visually guided saccades (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 maintaining anticipatory behavior.

Orienting and Attentive Behavior: The Fronto-parietal System

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 between 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 and pre-supplementary motor cortices, spatial memory-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.

In addition, our results suggest the distinction of two different subregions in the human FEF area: a medial, slightly more dorsally located region and a lateral region. These two regions of FEF are probably connected to different cortical areas in the parietal 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 previous draft of this manuscript. This work was supported by the NIH (MH62134 and NS35949).

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