1 INSERM EPI 007, Hôpital de la Salpêtrière, Paris, , 2 CEA, Service Hospitalier Frédéric Joliot, rsay and , 3 Department of Neuroradiology, Hôpital de la Salpêtrière, Paris; and France
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Abstract |
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Introduction |
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Materials and Methods |
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Eight right-handed healthy volunteers (four men, four women, range 2025 years) with no history of neurological or psychiatric disease were included in the study. They were paid for their participation and all gave informed consent. The experiment was approved by the Ethics Committee for Biomedical Research of the Salpêtrière Hospital.
Cognitive Tasks
Two different WM tasks, visuospatial matching (MAT) and visuospatial reproduction (REP), were designed (Fig. 1a). Both tasks were based on the same sequence of events: the presentation of a visuospatial pattern, a delay period and a response. In both tasks, the presentation and delay periods were similar, differing only by the expected responses. The presentation consisted of ten open white squares (presented at fixed locations) appearing on a screen for 500 ms. Five of these squares (i.e. the stimulus) sequentially turned black for 1400 ms each. During the delay period, subjects were asked to fixate a central cross on a blank screen for 6000 ms. In the MAT task, after the delay, a new sequence of five black squares was presented and subjects had only to indicate whether this sequence was identical or different from the one presented before the delay. Subjects responded by pressing the right (for identical) or left (for different) mouse button. In the REP task, after the delay, the ten open white squares reappeared on the screen. Using the mouse, subjects were required to sequentially point and click on each of the five squares of the stimulus in the correct order. In both tasks, responses depended upon the stimulus presented before the delay. However, only in the REP task could subjects mentally prepare a sequential motor response according to the format of the stimulus held on line.
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All subjects were trained in each task, first outside and then inside the scanner before image acquisition. In addition, two other visuospatial WM tasks were performed by all subjects. These tasks are not described here since they are outside the scope of the present study.
MRI Scanning
Visual stimuli were projected using an active matrix video projector (EGA mode, 70 Hz refresh rate, Eiki, Osaka, Japan) connected to a computer located in the control room and presented on a screen that the subjects viewed through mirror glasses. A mouse connected to the computer was placed near the subject's right hand and a mouse-pad was fixed on the subject's chest. The subject's head was firmly positioned in a foam-rubber holder which minimized movement.
Functional images were acquired on a 3 T whole-body scanner (Brucker, Germany), using T2* weighed gradient echo, echo-planar imaging sequence, sensitive to blood oxygen level-dependent contrast (repetition time 2000 ms, echo time 40 ms, flip angle of 90°, matrix 64 x 64, field of view 220 x 220 mm2). The images consisted of 18 contiguous axial slices (interleaved acquistion), with 6 mm thickness and 3.4 x 3.4 mm in plane resolution. The lower parts of the temporal and occipital lobes and the cerebellum were not imaged.
During fMRI acquisition subject were required to perform five separate runs of 13 trials. During each run (Fig. 2), 208 volumes of 18 slices were continuously acquired over a total duration of 416 s. A 30 s rest period was interleaved between two consecutive runs. Each run began with a REP CONT trial. This first trial was used to familiarize the subjects to the noisy environment of the scanner and to the handling of the mouse. Thus, the first 16 volumes corresponding to this trial were always discarded. Following this discarded trial and for each run, two trials of each task were presented in a pseudo-random order separated by a 6000 ms inter-trial interval (including two trials of the two tasks not presented in this study). A total of 10 trials per tasks were analyzed. High-resolution T1-weighted anatomical images were acquired in the same session (gradient-echo inversion-recovery sequence, repetition time 1600 ms, echo time 5 ms, matrix 256 x 256 x 128, field of view 220 x 220 mm2, slice thickness 1 mm).
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Data were analyzed on a individual basis and across subject (group analysis) using across subject variance (random effect analysis) (Friston et al., 1999). All analyses were done with SPM'96 software (Wellcome Department of Cognitive Neurology; www.fil.ion.ucl.ac.uk/spm) modi- fied for fMRI (Friston et al., 1995b
). For each subject, anatomical images were transformed stereotactically with nine linear rigid transformations to the Talairach coordinate system (Talairach and Tournoux, 1988
). The functional scans, corrected for subject motion (Friston et al., 1995a
), were then normalized using the same transformations and smoothed with a 5 mm full-width half-maximum Gaussian filter.
For individual analysis, data from each run were processed using the general linear model with separate delayed box-car functions modeling hemodynamic responses of each period of tasks. Overall signal differences between runs were also modeled. A temporal cut-off of 120 s was applied to filter subject-specific low-frequency drift, mostly related to subject biological rhythms and magnetic field drift. An SPM {F} map was obtained, reflecting significant activated voxels according to the model used (P < 0.05). To test hypotheses about regionally specific condition effects, the estimates were compared using linear contrasts. The resulting set of voxel values for each contrast constituted an SPM {t} map which was transformed to the unit normal distribution to give an SPM {Z} map. The resulting set of Z values was then thresholded at P < 0.001 and P < 0.01. Separate analyses were performed during the presentation, the delay (or interstimulus interval) and the response phases. The MAT and the REP tasks were contrasted with their respective control tasks (MAT/MAT CONT, REP/REP CONT; Fig. 1a,b). Contrasting MAT to its control during the delay should highlight the activated regions related to the short-term storage of temporalspatial information. During the delay, the contrast between REP and its control (REP/REP CONT) and between the REP and the MAT tasks (REP/MAT) should reveal, in addition to the activation related to the short-term storage, activation specific to the binding between the stimulus held on line and the forthcoming sequence of actions.
For group analysis, parametric maps were constructed using the same contrast as for the subject per subject analysis. Contrasts during the presentation and response phases were also performed in this analysis, in order to determine whether the activation found during the delay was specific to the cognitive processes studied. Results were obtained using a threshold of P < 0.001 corrected for multiple comparisons across the volume. Activated clusters were considered significant if their spatial extent was >18 voxels (or 172 mm3), corresponding to a risk of error (type I error) of P < 0.05.
For each subject, the signal-to-time curve was calculated for voxels presenting the highest Z values in those regions activated in the group study (parietal, motor, premotor, prefrontal cortices and striatum). These curves were obtain by dividing all data point values with the overall mean value of the subject' voxel signal. The signals of individual data points were next averaged across trials of the same type. The curves obtained were then averaged across subjects, allowing us to obtain a mean time- course of the fMRI signal for each task.
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Results |
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SPM Analysis during the Delay
When the MAT task was compared with its control condition, significant activation was found in the right premotor cortex [Brodmann's area (BA) 6] and the intraparietal sulcus (IPS; BA 7/40, 19) bilaterally (Fig. 3a, Table 1
). No significant prefrontal activation was observed on the basis of the chosen threshold (P < 0.001). When the REP task was compared with its control, the same cortical regions were activated and additional activa- tion was detected in the right DLPFC (BA 9/46; Fig. 3b
, Table 1
). The REP/MAT contrast showed activation in the right DLPFC (BA 9/46), the left motor (BA 4) and premotor (BA 6) cortices, the left supplementary motor area (SMA; BA 6) and bilaterally in the anterior putamen (Fig. 3c
, Table 1
).
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In both the presentation and response phases, no activation reached the level of significance in the left or right DLPFC for the MAT/MAT CONT, REP/REP CONT or REP/MAT contrasts (Fig. 4af).
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Individual Analysis
Analysis of individual data is presented in Table 2. Individual analysis allowed us to study inter-subject variability of areas activated in the group study. For the MAT versus MAT CONT comparison (P < 0.001), the left parietal area was activated in all subjects, the right parietal cortex in six subjects and the right premotor in four subjects. At P < 0.01, seven subjects activated the right parietal cortex and six the right premotor cortex.
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For the REP versus MAT comparison, all regions found in the group study were activated in all subjects (P < 0.001), including the right DLPFC, the left SMA, the left sensorimotor cortex and the anterior striatum bilaterally.
fMRI Time-courses
Time-courses of activation were studied in the DLPFC, premotor cortex, parietal cortex, sensorimotor cortex and anterior stri- atum in both hemispheres. They were identical in both sides for the premotor and parietal cortices and the anterior striatum. As already mentioned, activation was only found in the left sensorimotor cortex and the right DLPFC. Figure 5 illustrates the time-course curves of theses regions.
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In the premotor cortex (Fig. 5b), the MAT and REP tasks' related activation increased continuously during the presenta- tion period, reaching a maximum 2 s after the onset of the delay period. The signal then decreased slowly during both tasks, more in the MAT than the REP task, and returned to baseline at the end of the ISI. For both control tasks, signal-to-time curves were similar, showing a first increase with a maximum at the end of the presentation period and a slight decrease during the delay period, followed by a second increase during the response period reaching a maximum at the end of this period. During the last 10 s, REP CONT signal amplitude was higher than in the MAT CONT task.
In the parietal cortex (Fig. 5c), time-courses of activation were similar to those observed in the premotor cortex.
In the left sensorimotor cortex (Fig. 5d), the signal increased in all tasks during the delay and response periods, reaching a maximum at the end of the later. The amplitude of signal in- crease was similar in the tasks and in their respective controls but higher in the REP than the MAT ones.
In the anterior striatum (Fig. 5e), the signal increased during the delay and the response periods in the REP task. In all three other tasks it increased only during the response period, reach- ing a maximum at the end of this period.
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Discussion |
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The differential patterns of activation between the REP and MAT conditions during the delay period, i.e. at a time when the subjects had experienced the same events, are probably related to what the subjects were required to do after the delay, namely to recognize the sequence (MAT task) or to program a sequential response (REP task). In the MAT task, which required the sub- ject to maintain on line during the delay, the temporalspatial information that could only be used after the presentation of a second sequence, a sustained activation was found mainly in the parietal and premotor areas when compared with the control condition. The parietal areas activated in this task, namely the intraparietal sulci, correspond to regions classically involved in visuospatial processing (Andersen et al., 1985), including visuospatial WM (Friedman and Goldman-Rakic, 1994
; Chafee and Goldman-Rakic, 1998
). It is noteworthy that the IPS was also activated during the presentation phase. This may suggest that the IPS is involved in attention by selecting the information to be encoded for further processing (Andersen, 1995
) and/or in maintaining information in WM as one may consider that memory phase starts after the presentation of the first square of the temporo-spatial sequence. The IPS may also contribute to more basic perceptual aspects because an increase of activation was also observed, although at a more modest level, in the two control tasks. Regarding the premotor areas, when activation maps obtained in this condition were superimposed on anatom- ical images, we found that the right premotor activation observed during the delay phase was located partly in a cortical region where the precentral and the superior frontal sulci intersect, an area that may include the right frontal eye field (FEF) in humans (Paus, 1996
). The FEF is indeed activated in WM tasks requiring saccadic or sequential eye movements (Sweeney et al., 1996
) and also when subjects have to sequentially shift attention to different targets (Dias and Bruce, 1994
; Corbetta, 1998
). A similar activation was also found in the premotor areas during the presentation phase (see Figs 4a,b
and 5b
), indicating that these areas may also participate in the encoding phase of the temporo-visual stimulus which relies in part on saccadic eye movements (Schall and Hanes, 1993
). The persistence of sig- nificant activation in the premotor area during the delay may indicate a spatial rehearsal (Smith et al., 1995
), as subjects have to mentally shift their attention from one target to another within the visual sequence maintained in mind. In this case, the premotor activation would be related to the storage of mental representation in terms of visuomotor engrams. In line with these data are the studies of Courtney et al. (Courtney et al., 1997
, 1998
), who reported activation in the same parietal and premotor areas during the delay phase of a WM task in which subjects had to decide whether a probe matched any of three sequentially presented spatial targets. Regarding the role attri- buted to the DLPFC in WM, it should be noted that no activation above threshold was found in this region in the MAT task. As no specific forthcoming action could be prepared during the delay, it seems likely that the parietalpremotor network is sufficient for the short-term storage of this information. However, we cannot rule out that, even though the DLPFC is not activated above threshold, it may intervene to some extent in the mainten- ance of the information in STM. Indeed, the time-course curves showed that there was a slight increase of the signal during the delay period. Taken together, these data suggest the parietal premotor network represents a first level of visuospatial WM processing when little demand on executive processing, such as selection and preparation of response, is required. Therefore, it is predicted that additional areas, including the DLPFC, will be triggered above threshold when these executive requirements increase.
In the REP task, in addition to the processes involved in the MAT task, there is the mental representation of the forthcoming action, i.e. the selection and preparation of a sequence of moves, based on the information stored in WM. Several findings from our study argue in favor of the idea that the link between the information held on line and a specific program of actions is the upgraded function leading to DLPFC recruitment in this paradigm: (i) the main finding supporting this hypothesis is that the DLPFC was activated during the delay in the REP/REP CONT and, above all, in the REP/MAT comparisons; (ii) this DLPFC activation is mainly due to the mental representation of the forthcoming action. Indeed, because of the short length of the delay period (6000 ms) we cannot totally dissociate activation related to the cue, the memory and the preparation of response. However, if the activation observed in the REP task was only related to cue, the increase in the signal should have started from the beginning of the presentation phase and peaked in the delay period, according to hemodynamic response delay. Analyses of time-course curves demonstrated that this was not the case. Furthermore, no such delayed peak of activation was seen in the DLPFC in the two control tasks, which are identical to WM tasks in terms of sensory cues. If the activation observed in the REP task was related only to memory, one should have noticed a similar hemodynamic response in the MAT task. If activation observed during the delay period of the REP task was due to the overlap of signals from the cue and memory, one should expect a time-course curve and/or increase of signal quantitatively similar to the one observed during the delay period of the MAT task. The significant activation found in the left motor cortex in the REP/MAT comparison during the delay period, at a time when no response has started, also suggests that, during the delay period of the REP task, activation can be partly related to the forthcoming action. However, the peak of activation ob- served in the response phase during the REP task was probably not due only to the response preparation because the activation related to the response occurred more lately in the REP CONT than in the REP tasks; and (iii) to conclude, our findings indicate that the DLPFC contributes to the mnemonic processing, and above all, to the preparatory set. However, the relationship between the preparatory set and the information maintained on line is of a complex nature. Indeed, this relationship may require more attentional resources than in the MAT task as the forthcoming response necessitates the holding on line of accurate features of the information. An alternative explanation might be that the DLPFC is activated in the REP task in relation to a prominent inhibition process in order to temporally repress the forthcoming action until the go signal, as it has already been shown in memory-guided saccade tasks, both in humans and monkeys with DLPFC lesions (Funahashi et al., 1993a, b
). This seems unlikely, however, given the well-known function of the DLPFC in response programming (Shallice, 1982
). Interestingly, it is likely that this activation, which was restricted to the right DLPFC, was related to the nature of the sensory information processed (i.e. spatial domain), as it has already been reported in humans (Smith et al., 1995
; McCarthy et al.,1996).
In fact, our data strongly agree with the results of a recent neuropsychological study in patients with focal lesions of the prefrontal cortex in which similar visuo-spatial WM tasks were used (Ferreira-Texeira et al., 1998). In this study, when com- pared with normal subjects or patients with post-rolandic lesions, patients with prefrontal lesions were only impaired in the REP task, whereas they had no deficit when (i) encoding and maintaining visuo-spatial information, as shown by their normal performance in the MAT task with or without a delay; or (ii) executing a sequential response immediately after its presenta- tion, as in the REP task without a delay.
In conclusion, we have identified the neural correlates involved during the delay period of two WM tasks requiring different levels of processing. The results of this study, congru- ent with a previous neuropsychological study in patients with frontal lobe lesions, validates the hypothesis that a parietal premotor network is sufficient to store visual temporo-spatial sequences in STM; and, in situations when the planning and preparing of a predictable sequence of actions is required, then the DLPFC and additional regions (SMA, sensorimotor cortex, anterior putamen) might be recruited. This is in agreement, at least in humans, with the expected role of the prefrontal cortex, involved in the planning of actions rather than in the short-term storage of information. In this view, the prefrontal cortex would be solicited mainly when a specific or new program of actions is required for an adaptive behavior.
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Notes |
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Address correspondence to Richard Levy, INSERM EPI 007 Pavillon Claude Bernard, Hôpital de la Salpêtrière, 47 boulevard de lHôpital, F-75013 Paris, France. Email: richard.levy{at}psl.ap-hop-paris.fr.
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