Center for Cognitive Medicine, Department of Psychiatry, University of Illinois, Chicago, IL, USA
Correspondence to: Lucia S. Simó, Northwestern University, The Feinberg School of Medicine, Department of Physiology, Ward 5315, 303 East Chicago Avenue, Chicago, IL 60611, USA. Email: l-simo{at}northwestern.edu.
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Abstract |
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Key Words: frontal eye fields functional MRI human parietal eye fields predictive saccades procedural learning
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Introduction |
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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.
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Material and Methods |
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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 (VGSPREDVGSPREDvisual 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 x 20 cm; acquisition matrix = 64 x 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.
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Results |
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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.
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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).
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Predictive Saccade TaskFixation (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 TaskVisually 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).
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Visually Guided Saccade TaskPredictive 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 1719) (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.
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Discussion |
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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 1719) 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 (VIVII) 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.
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Acknowledgments |
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Balan PF, Ferrera VP (2003) Effects of gaze shifts on maintenance of spatial working memory in macaque frontal eye field. J Neurosci 23:54465454.
Becker W (1989) The neurobiology of saccadic eye movements. Metrics Rev Oculomot Res 3:1367.
Beiser DG, Houk JC (1998) Model of corticalbasal ganglionic processing: encoding the serial order of sensory events. J Neurophysiol 79:31683188.
Berman RA, Colby CL, Genovese CR, Voyvodic JT, Luna B, Thulborn KR, Sweeney JA (1999) Cortical networks subserving pursuit and saccadic eye movements in humans: an fMRI study. Hum Brain Mapp ng 8:209225.[CrossRef]
Boussaud D (2001) Attention versus intention in the primate premotor cortex. Neuroimage 14:S40S45.[CrossRef][ISI][Medline]
Broinstein AM, Kennard C (1985) Predictive ocular motor control in Parkinson disease. Brain 108:925940.[Abstract]
Cavada C (2001) The visual parietal areas in the macaque monkey:current structural knowledge and ignorance. Neuroimage 14:S21S26.[CrossRef][ISI][Medline]
Chafee MV, Goldman-Rakic PS (1998) Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task. J Neurophysiol 79:29192940.
Chafee MV, Goldman-Rakic PS (2000) Inactivation of parietal and prefrontal cortex reveals interdependence of neural activity during memory-guided saccades. J Neurophysiol 83:15501566.
Connolly JD, Goodale MA, Desouza JFX, Menon RS, Vilis T (2000) A comparison of frontoparietal activation during anti-saccades and anti-pointing. J Neurophysiol 84:16451655.
Connolly JD, Goodale MA, Menon RS, Munoz DP (2002) Human fMRI evidence for the neural correlates of preparatory sets. Nat Neurosci 5:13451352.[CrossRef][ISI][Medline]
Corbetta M, Shulman GL (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev 3:201215.[ISI]
Coull JT, Walsh V, Frith CD, Nobre AC (2003) Distinct neural substrates for visual search amongst spatial versus temporal distractors. Cognitive Brain Res 17:368379.[CrossRef][ISI][Medline]
Cox RW (1996) AFNI: software for analysis and visualization of functional magnetic neuroimages. Comput Bimed Res 29:162173.[CrossRef]
Crawford T, Goodrich S, Henderson L, Kennard C (1989) Predictive responses in Parkinson's disease: manual keypresses and saccadic eye movement to regular stimulus events. J Neurol Neurosurg Psychol 52:10331042.[Abstract]
Culham JC, Brandt SA, Cavanagh P, Kanwisher NG, Dale AM, Tootell RBH (1998) Cortical fMRI activation produced by attentive tracking of moving targets. J Neurophysiol 80:26572670.
Culham JC, Kanwisher NG (2001) Neuroimaging of cognitive functions in human parietal cortex. Curr Opin Neurobiol 11:157163.[CrossRef][ISI][Medline]
Delinte A, Gomez CM, Decostre MF, Crommelinck M, Roucoux A (2002) Amplitude transition function of human express saccades. Neurosci Res 42:2134.[CrossRef][ISI][Medline]
D'Esposito M, Ballard D, Zarahn E, Aguirre K (2000) The role of prefrontal cortex in sensory memory and motor preparation: an event-related fMRI study. Neuroimage 11:400408.[CrossRef][ISI][Medline]
Doyon J, Gaudreau D, Laforce R, Castonguay M, Bedard PJ, Bedard F, Bouchard JP (1997) Role of the striatum, cerebellum, and frontal lobes in the learning of a visuomotor sequence. Brain Cogn 34:218245.[CrossRef][ISI][Medline]
Dum RP, Strick P (2002) Motor areas in the frontal lobe of the primate. Physiol Behav 77:677682.[CrossRef][ISI][Medline]
Eddy WF, Fitzgerald M, Noll DC (1996) Improved image registration by using Fourier interpolation. Magn Res Med 36:923931.[ISI][Medline]
Fisher (1950) Statistical methods for research workers, 11th edn. London: Oliver & Boyd.
Fischer B, Weber H, Biscaldi M, Aiple F, Otto P, Stuhr V (1993) Separate populations of visually guided saccades in humans: reaction times and amplitudes. Exp Brain Res 92:528541.[ISI][Medline]
Fox MT, Barense MD, Baxter MG (2003) Perceptual set-shifting is impaired in rats with neurotoxic lesions of posterior parietal cortex. J Neurosci 23:676681.
Fujii N, Mushiake H Tanji J (1998) An oculomotor representation area within the ventral premotor cortex. Proc Natl Acad Sci 95:1203412037.
Fuster JM (2000) Prefrontal neurons in networks of executive memory. Brain Res Bull 52:331336.
Fuster JM (2001) The prefrontal cortex an update: time is the essence. Neuron 30:319333.[CrossRef][ISI][Medline]
Gabernet L, Meskenaite V, Hepp-Reymond M-C (1999) Parcellation of the lateral premotor cortex of the macaque monkey based on staining with the neurofilament antibody SMI-32. Exp Brain Res 128:188193.[CrossRef][ISI][Medline]
Gagnon D, O'Driscoll GA, Petrides M, Pike GB (2002) The effect of spatial and temporal information on saccades and neural activity in oculomotor structures. Brain 125:123139.
Ghilardi M, Ghez C, Dhawan V, Moeller J, Mentis M, Nakamura T, Antonini A, Eidelberg D (2000) Patterns of regional brain activation associated with different forms of motor learning. Brain Res 871:12745.[CrossRef][ISI][Medline]
Gomez-Beldarrain M, Garcia-Monco JC Rubio B, Pascual-Leone A (1998) Effect of focal cerebellar lesions on procedural learning in the serial reaction time task. Exp Brain Res 120:2530.[CrossRef][ISI][Medline]
Gottlieb J (2002) Parietal mechanisms of target representation. Curr Opin Neurobiol 12:134140.[CrossRef][ISI][Medline]
Grosbras M-H, Leonards U, Lobel E, Poline J-B, LeBihan D, Berthoz A (2001) Human cortical networks for new and familiar sequences of saccades. Cereb Cortex 11:936945.
Hayakawa Y, Nakajima T, Takagi M, Fukuhama N, Abe H (2002) Human cerebellar activation in relation to saccadic eye movements: a functional magnetic resonance imaging study. Ophthalmologica 216:399405.[CrossRef][ISI][Medline]
Hikosaka O, Miyashita K, Miyachi S, Sakai K, Lux (1998) Differential roles of the frontal cortex, basal ganglia, and cerebellum in visuomotor sequence learning. Neurobiol Learn Mem 70:137149.[CrossRef][ISI][Medline]
Hikosaka O, Nakamura K, Sakai K, Nakahara H (2002) Central mechanisms of motor skill learning. Curr Opin Neurobiol 12:217222.[CrossRef][ISI][Medline]
Horwitz B, Deiber M-P, Ibañez V, Sadato N, Hallet M (2000) Correlations between reaction time and cerebral blood flow during motor preparation. Neuroimage 12:434441.[CrossRef][ISI][Medline]
Houk JC (2001) Neurophysiology of frontalsubcortical loops. In: Frontalsubcortical circuits in psychiatry and neurology (Lichter DG and Cummings JL, eds), pp. 92-113. New York: Guilford Publications.
Jog MS, Kubota Y, Connolly CI, Hillegaart V, Graybiel AM (1999) Building neural representations of habits. Science 286:17451749.
Karni A (1996) The acquisition of perceptual and motor skills:a memory system in the adult human cortex. Cogn Brain Res 5:3948.[CrossRef][ISI][Medline]
Karoumi B, Ventre-Dominey J, Vighetto A, Dalery J, D'Amato T (1998) Saccadic eye movements in schizophrenic patients. Psychiatry Res 77:919.[CrossRef][ISI][Medline]
Kelly RM, Strick PL (2003a) Macro-architecture of basal ganglia loops with the cerebral cortex:use of rabies virus to reveal multisynaptic circuits. Prog Brain Res 143:447459.
Kelly RM, Strick PL (2003b) Cerebellar loops with motor cortex and prefrontal cortex of nonhuman primate. J Neurosci 23:84328444.
Kim JJ, Baxter MG (2001) Multiple brain-memory systems: the whole does not equal the sum of its parts. Trends Neurosci 24:324330.[CrossRef][ISI][Medline]
Kim Y-H, Gitelman DR, Nobre AC, Parrish TB, LaBar KS, Mesulam MM (1999) The large-scale neural network for spatial attention displays multifunctional overlap but differential asymmetry. Neuroimage 9:269277.[CrossRef][ISI][Medline]
Kimberg DY, Aguirre GK, D'Esposito M (2000) Modulation of task-related neural activity in task-switching: an fMRI study. Cogn Brain Res 10:189196.[CrossRef][ISI][Medline]
Konishi S, Donaldson DI, Buckner RL (2001) Transient activation during block transition. Neuroimage 13:364374.[CrossRef][ISI][Medline]
Krebs M-O, Gut-Fayand A, Amado I, Daban C, Bourdel M-C, Poirier M-F, Berthoz A (2001) Impairment of predictive saccades in schizophrenia. Neuro Report 12:465469.[CrossRef][ISI][Medline]
Lazar N A, Luna B, Sweeney JA, Eddy WF (2002) Combining brains: a survey of methods for statistical pooling of Information. Neuroimage 16:538550.[CrossRef][ISI][Medline]
Levy R, Goldman-Rakic PS (2000) Segregation of working memory functions within the dorsolateral prefrontal cortex. Exp Brain Res 133:2332.[CrossRef][ISI][Medline]
Levy R, Friedman HR, Davachi L, Goldman-Rakic PS (1997) Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks. J Neurosci 17:38703882.
Luna B, Thulborn KR, Strojwas MH, McCurtain BJ, Berman RA, Genovese CR, Sweeney JA (1998) Dorsal cortical regions subserving visually guided saccades in humans: an fMRI study. Cereb Cortex 8:4047.[Abstract]
Luppino G, Murata A, Govoni P, Matelli M (1999) Largely segregated parietofrontal connections linking rostral intraparietal cortex (areas AIP and VIP) and the ventral premotor cortex (areas F5 and F4). Exp Brain Res 128:181187.[CrossRef][ISI][Medline]
Matelli M, Luppino G (2001) Parietofrontal circuits for action and space perception in the macaque monkey. Neuroimage 14:S27-S32.[CrossRef][ISI][Medline]
Matsuda T, Matsuura M, Ohkubo T, Ohkubo H, Mtsuchima E, Inoue K, Taira M, Kojima T (2004) Functional MRI mapping of brain activation during visually guided saccades and antisaccades: cortical and subcortical networks. Psychiatry Res Neuroimag 131:147155.[CrossRef][ISI]
Merriam EP, Colby CL, Thulborn KR, Luna B, Olson CR, Sweeney JA (2001) Stimulusresponse incompatibility activates cortex proximate to three eye fields. Neuroimage 13:794800.[ISI][Medline]
Mesulam M-M (1998) From sensation to cognition. Brain 121:10131052.[Abstract]
Nadel L, Samsonovich A, Ryan L, Moscovitch M (2000) Multiple trace theory of human memory: computational, neuroimaging, and neuropsychological results. Hippocampus 10:352368.[CrossRef][ISI][Medline]
Pascual-Leone A, Grafman J, Clark K, Stewart M, Massaquoi S, Lou JS, Hallett M (1993) Procedural learning in Parkinson's disease and cerebellar degeneration. Ann Neurol 34:594602.[CrossRef][ISI][Medline]
Pascual-Leone A, Wassermann EM, Grafman J, Hallett M (1996) The role of the dorsolateral prefrontal cortex in implicit procedural learning. Exp Brain Res 107:479485.[ISI][Medline]
Paus T (1996) Location and function of human frontal eye field:a selective review. Neuropsychologia 34:475483.[CrossRef][ISI][Medline]
Perry RJ, Zeki S (2000) The neurology of saccades and covert shifts in spatial attention: and event-related fMRI study. Brain 123:22732288.
Pessoa L, Kastner, Ungerleider LG (2003) Neuroimaging studies of attention: from modulation of sensory processing to top-down control. J Neurosci 23:39903998.
Petit L, Orssaud C, Tzourio N, Salamon G, Mazoyer B, Berthoz A (1993) PET study of voluntary saccadic eye movements in humans: basal gangliathalamocortical system and cingulate cortex involvement. J Neurophysiol 69:10091017.
Petit L, Clark VP, Ingeholm J, Haxby JV (1997) Dissociation of saccade-related and pursuit-related activation in human frontal eye fields as revealed by fMRI. J Neurophysiol 77:33863390.
Picard N, Strick PL (2001) Imaging the premotor areas. Curr Opin Neurobiol 11:663672.[CrossRef][ISI][Medline]
Reber PJ, Wong EC, Buxton RA (2002) Encoding activity in the medial temporal lobe examined with anatomically constrained fMRI analysis. Hippocampus 12:363376.[CrossRef][ISI][Medline]
Rizzolatti G, Fogassi L, Gallese V (2002) Motor and cognitive functions of the ventral premotor cortex. Curr Opin Neurobiol 12:149154.[CrossRef][ISI][Medline]
Rosano C, Krisky CM, Welling JS, Eddy WF, Luna B, Thulborn KR, Sweeney JA (2002) Pursuit and saccadic eye movement subregions in human frontal eye field: a high-resolution fMRI investigation. Cereb Cortex 12:107115.
Rosano C, Sweeney JA, Melchitzky DS, Lewis DA (2003) The human precentral sulcus: chemoarchitecture of a region corresponding to the frontal eye fields. Brain Res 972:1630.[CrossRef][ISI][Medline]
Ross SM, Ross LE (1987) Children's and adults' predictive saccades to square-wave targets. Vision Res 27:21772180.[CrossRef][ISI][Medline]
Saslow MG (1967a) Effects of components of displacement-step stimuli upon latency of saccadic eye movements. J Opt Soc Am 57:10241029.[ISI][Medline]
Saslow MG (1967b) Latency for saccadic eye movement. J Opt Soc Am 57:10301033.[ISI][Medline]
Shadmehr R, Holcomb H-H (1997) Neural correlates of motor memory consolidation. Science 277:821825.
Shanks DR, Channon S (2002) Effects of a secondary task on implicit sequence learning: learning or performance? Psychol Res 66:99109.[CrossRef][ISI][Medline]
Smit AC, Van Gisbergen JA (1989) A short-latency transition in saccade dynamics during square-wave tracking and its significance for the differentiation of visually-guided and predictive saccades. Exp Bran Res 76:6474.
Sweeney JA, Mintun MA, Kwee S, Wiseman MB, Brown DL, Rosenberg DR, Carl JR (1996) Positron emission tomography study of voluntary saccadic eye movements and spatial working memory. J Neurophysiol 75:454468.
Tanibuchi I, Goldman-Rakic PS (2003) Dissociation of spatial-, and sound-coding neurons in mediodorsal nucleus of the primate thalamus. J Neurophysiol 89:10671077.
Talairach J, Tournaux P (1988) Co-planar stereotaxic atlas of the human brain. New York: Thieme.
Tehovnik EJ, Sommer MA, Chou IH, Slocum WM, Schiller PH (2000) Eye fields in the frontal lobes of primates. Brain Res Rev 32:413448.[CrossRef][ISI][Medline]
Tian JR, Zee DS, Lasker AG, Folstein SE (1991) Saccades in Huntington's disease: predictive tracking and interaction between relesase of fixation and initiation of saccades. Neurology 41:875881.[Abstract]
Thoenissen D, Zilles K, Toni I (2002) Differential involvement of parietal and precentral regions in movement preparation and motor intention. J Neurosci 22:90249034.
Vandenberghe R, Gitelman DR, Parrish TB, Mesulam MM (2001) Functional specificity of superior parietal mediation of spatial shifting. Neuroimage 14:661673.[CrossRef][ISI][Medline]
Wise SP, Boussaud D, Johnson PB, Caminitti R (1997) Premotor cortex and parietal cortex: corticocortical connectivity and combinatorial computations. Annu Rev Neurosci 20:2542.[CrossRef][ISI][Medline]
Wyder MT, Massoglia DP, Stanford TR (2003) Quantitative assessment of the timing and tuning of visual-related, saccade-related, and delay period activity in primate central thalamus. J Neurophysiol 90:20292052.
Zilles K, Palomero-Gallagher N (2001) Cyto-, Myeo-, and receptor architectonics of uman parietal cortex. NeuroImage 14:S8S20.[CrossRef][ISI][Medline]