special issue evidence for quantitative domain ... - Science Direct

SPECIAL ISSUE EVIDENCE FOR QUANTITATIVE DOMAIN DOMINANCE FOR VERBAL AND SPATIAL WORKING MEMORY IN FRONTAL AND PARIETAL CORTEX Henrik Walter1, Volker Bretschneider1, Georg Grön1, Bartosz Zurowski1, Arthur P. Wunderlich2, Reinhard Tomczak2 and Manfred Spitzer1 (1Department of Psychiatry and 2Department of Radiology, University of Ulm, Germany)

ABSTRACT Neuroimaging studies in humans have shown that different working memory (WM) tasks recruit a common bilateral fronto-parietal cortical network. Animal studies as well as neuroimaging studies in humans have suggested that this network, in particular the prefrontal cortex, is preferentially recruited when material from different domains (e.g. spatial information or verbal/object information) has to be memorized. Early imaging studies have suggested qualitative dissociations in the prefrontal cortex for spatial and object/verbal WM, either in a left-right or a ventral-dorsal dimension. However, results from different studies are inconsistent. Moreover, recent fMRI studies have failed to find evidence for domain dependent dissociations of WM-related activity in prefrontal cortex. Here we present evidence from two independent fMRI studies using physically identical stimuli in a verbal and spatial WM task showing that domain dominance for WM does indeed exist, although only in the form of quantitative differences in activation and not in the form of a dissociation with different prefrontal regions showing mutually exclusive activation in different domains. Our results support a mixed dimension model of domain dominance for WM within the prefrontal cortex, with left ventral prefrontal cortex (PFC) supporting preferentially verbal WM and right dorsal PFC supporting preferentially spatial WM. The concept of domain dominance is discussed in the light of recent theories of prefrontal cortex function. Key words: working memory, prefrontal cortex, parietal cortex, domain dominance, fMRI

INTRODUCTION Working memory (WM) is the ability to temporarily hold a limited amount of information in an active state for a brief period of time and to use or manipulate this information (Baddeley, 1986). Neurophysiological studies of primates have found cells in prefrontal cortex (PFC) firing during delay periods in tasks requiring the short term internal maintenance of information (Fuster, 1996; Goldman-Rakic, 1987; Miller, 2000). Neuroimaging studies in humans have consistently reported several cortical regions to be involved in the storage and manipulation of information during WM tasks, i.e. left inferior frontal cortex (LIFC), dorsolateral prefrontal cortex (DLPFC), premotor cortex (PMC), superior frontal cortex, supplementary motor area (SMA) and the parietal cortex along the intraparietal sulcus, for reviews see Cabeza and Nyberg (2000), D’Esposito et al. (1998), D’Esposito et al. (2000), Smith and Jonides (1998), and Smith and Jonides (1999). Cortex, (2003) 39, 897-911

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Henrik Walter and Others

In his original formulation of the WM concept, Baddeley has proposed that WM is subserved by three distinct functional subunits: the “central executive” and two slave systems subserving maintenance of different kinds of information (Baddeley, 1986; Baddeley and Della Sala, 1996). The phonological/articulatory subsystem was proposed to subserve maintenance of verbal information and the visuospatial sketchpad to deal with visuospatial WM information. Neuroimaging studies have aimed to find and differentiate the neural substrates of these postulated systems in humans. In particular, the prefrontal cortex has been subject of many studies using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) (D’Esposito et al., 1998). It has been proposed that the PFC may be functionally organized either with respect to the stimulus material processed, e.g. material from spatial or nonspatial (object, verbal) domains or with respect to the processes involved, e.g. maintenance versus manipulation of information. Recently, Postle and D’Esposito (2000) have reviewed the relevant neuroimaging literature and isolated four variants of the ‘domain view’ and two variants of the ‘process view’. Both types of views have their origin in single-cell studies in primates; for reviews compare Goldman-Rakic (1998) for the domain approach and Petrides (1998) for the process approach. The ‘process views’ are based on the idea that the prefrontal cortex is organized according to the processes of WM with dorsal PFC supporting manipulation and ventral PFC supporting maintenance processes. The ‘domain views’ differ with regard to whether domain dominance for WM in PFC is to be found in a left-right or a ventral-dorsal dimension. There is neuroimaging evidence for the view that object/verbal WM is subserved mainly by the left PFC hemisphere (Gabrieli et al., 1998; Owen et al., 1996; Smith and Jonides, 1999; Smith et al., 1998). Some studies have found a left-right dissociation for verbalspatial WM only for the ventrolateral PFC (D’Esposito et al., 1998; Smith et al., 1995). Other studies have described left-right dissociation of object-spatial WM for mid-dorsolateral PFC (Baker et al., 1996; Belger et al., 1998; McCarthy et al., 1996). Finally, dorsolateral and ventrolateral regions of PFC have been found to differentially support WM for spatial (dorsal) and object stimuli (ventral), respectively (Courtney et al., 1996; Smith and Jonides, 1999; Smith et al., 1995). However, all studies cited so far have used physically different stimuli for spatial and object/verbal WM tasks. This is problematic because these studies cannot reliably distinguish between perceptual stimulus effects and effects related to domain related WM processes per se. Only if using physically identical stimuli, differences in activation can be convincingly attributed to WM processes. One PET study used physically identical stimuli (Smith et al., 1996). However, in this study, no direct statistical comparison was performed between verbal and spatial WM tasks. Only recently, fMRI studies using physically identical stimuli in non-spatial (object or verbal) and spatial domains testing for significance of condition differences in a within subject design have been published (Nystrom et al., 2000; Postle and D’Esposito, 1999; Postle et al., 2000). Only one of these studies included an experiment comparing verbal and spatial WM directly (Nystrom et al., 2000) whereas the other studies compared object and spatial WM (Postle and D’Esposito, 1999; Postle et al., 2000). In

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contrast to older findings in the neuroimaging literature, these studies found no evidence for a dissociation of ventral-dorsal or left-right dissociation of spatial and non-spatial working memory. However, all experiments in these studies included only a few subjects (from four to ten). This is critical, when the null hypothesis is supported (i.e. no domain differences). As fMRI studies on WM often describe a common fronto-parietal network showing load effects in WM tasks in different domains, we hypothesized that the influence of the type of information to be processed in WM will manifest itself in this network only in the magnitude of activation, but not in differences in location of activation. In other words, rather than local dissociation (a qualitative phenomenon), domain dominance of WM (a quantitative phenomenon) was predicted. We performed two independent experiments to test this hypothesis. Both experiments used variants of the n-back task and involved physically identical stimuli for the different domain conditions. GENERAL METHODS Subjects. All subjects were screened to exclude a history of major head trauma, significant medical, neurological or psychiatric illness, and substance abuse or dependence. All subjects gave written informed consent. The experimental protocol was approved by the local institutional review board. WM tasks. Visual presentation of stimuli as well as recording of accuracy and reaction times (RTs) were controlled by PsyScope software (Cohen et al., 1993) in Experiment 1 and by ERTS (Berisoft, Frankfurt, Germany) in Experiment 2. Before scanning, subjects were instructed and trained offline with parallel versions of the tasks until they were familiar with all procedures and reached a predefined accuracy criterion of at least 80% accuracy. FMRI data acquistion. Within the scanner, stimuli were presented by means of LCD video goggles (Resonance Technologies, Northridge, California). Head movement was minimized by using padded earphones fixating the head within the gradient insert coil. Data were acquired with a 1.5 Tesla Magnetom VISION (Siemens, Erlangen, Germany) whole-body MRI system equipped with a head volume coil. T2* weighted functional MR images were obtained using echo-planar imaging in an axial orientation. Analysis of behavioural data. Accuracy is given in percent of correct responses. Median reaction times (RT) are given for targets. Between condition differences were analyzed using MANOVAs for repeated measures using a 2 × 3 factorial MANOVA in Experiment 1 and a 2 × 2 factorial MANOVA in Experiment 2. FMRI data. Preprocessing and statistical analysis were carried out with Statistical Parametric Mapping (SPM99, http://www.fil.ion.ucl.ac.uk) executed in MATLAB 5.3 (MathWorks, Natick, Massachusetts). All individual functional images were corrected for motion artifacts by realignment to the first volume of each session. All images were spatially normalized to the EPI standard template of 3 × 3 × 3 mm voxels and then spatially smoothed with an 12-mm full width at half maximum (FWHM) isotropic Gaussian kernel. Regions were determined by the coordinates of the maximum peak activity of a cluster as

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determined by the peak Z-value. Stereotaxic coordinates as given by SPM 99 (MNI-coordinates) were converted into Talairach coordinates using the function mni2tal (http://ww.mrc.cbu.cam.ac.uk/imaging/index.html). All areas were anatomically identified using the atlas of Talairach and Tournoux (Talairach and Tournoux, 1988) and Duvernoy (Duvernoy, 1999). Brodman areas (BA) were labeled according to the atlas of Talairach and Tournoux. METHODS (EXPERIMENT 1) Subjects. Thirteen right-handed (Oldfield, 1971) healthy subjects (8 female, 5 male, mean age 27.1 ± 4.7 years). WM tasks. We used a 2 × 3 factorial design in a modified n-back task (Cohen et al., 1994), with load (0-back, 2-back) x relevant stimulus feature (letter, location, color) as factors. Physically identical stimuli (colored letters shown at different screen locations) were used in all conditions, differing only in the order of appearance. We used 14 different consonants, 9 colors and 13 locations. Locations were pseudorandomly arranged so that they were not easily verbalizable (e.g. not clockwise). Stimulus duration was 500 ms, interstimulus interval (ISI) was 3000 ms. Each of the three sessions (letter, color, location) lasted approximately 9 minutes with 5 alternating epochs of 0-back and 2-back. Each epoch (50 sec) started with the instruction (5 sec) followed by 15 stimuli. Subjects were instructed to press a button whenever a target was presented. All conditions contained targets and non-targets of the same frequency. In the three 0-back conditions targets were “H” (letter condition), “the color magenta” (color condition) or “letter in the centre of the screen” (location condition). In the three 2-back conditions, subjects were instructed to press a button when the respective feature of the present stimulus was identical to that of the stimulus preceding the last stimulus of the sequence (‘2 back’) i.e. “same letter” or “same color” or “same location”, according to the current instruction. fMRI data acquisition. TR was 5000 ms, TE = 66 ms. Image size was 128 × 128 pixels (1.8 × 1.8 mm), slice thickness was 5 mm with a gap of 1 mm. FMRI protocol was a blocked design with three separate sessions in fixed order (letter, color, location). Each session contained five off-on-epochs of 50 sec. Each epoch comprised 10 volumes. The first six volumes of each session were discarded in order to allow for equilibration of T1-effects. Thus, in each session 106 functional volumes were acquired. FMRI data analysis. Load and interaction effects (load by domain = WM domain effects) were calculated using a fixed effects model. For each session, the variance of each voxel was estimated according to the general linear model, using a box car model convoluted with the hemodynamic response function as predictor (Friston et al., 1995). Images were adjusted for global effects, low-frequency drifts were removed via a high pass filter using low-frequency cosine functions with a cutoff of 100 sec. Only effects surviving a threshold of p < 0.05 at the voxel-level, corrected for multiple comparisons, are reported. A contiguity threshold of 5 voxels was used. Load effects were asessed by calculating the contrast [2-back minus 0-back] separately for all three


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conditions resulting in a t-statistic for each voxel. Interaction analyses of load × domain were calculated to test for WM related domain effects, e.g. (verbal 2-back minus verbal 0-back) minus (location 2-back minus location 0-back). To ascertain that a WM domain effect represents only WM related activity of the respective condition, the interaction contrasts were inclusively masked (p for mask: p < 0.05) with the load effect of the respective condition, e.g. with the contrast verbal 2-back minus verbal 0-back. This means that only those WM domain effects remain which also show a load effect. RESULTS (EXPERIMENT 1) Behavioral data. Reaction times (Figure 1): A MANOVA for repeated measures revealed a significant main effect of the factors “load“ [F (1, 12) = 23.77, p < 0.001] and “domain” [F (2, 11) = 133.65; p < 0.001] and no significant interaction of these factors p > 0.05). Post-hoc Newman-Keuls tests revealed that the color condition differed from the letter and location condition for both load levels (0-back, 2-back) (p < 0.05). Accuracy (Figure 1): a MANOVA for repeated measures demonstrated no significant main effects for the factors “load“ [F (1, 12) = 3.83, p > 0.05] and “domain” [F (2, 11) = 1.17; p > 0.05]. However, there was a significant interaction of “load” by “domain” [F (2, 11) = 4.13; p < 0.05]. Post-hoc Newman-Keuls tests (p < 0.05) revealed that there was a load effect in the color condition only with lower accuracy in the 2-back condition. FMRI-Data. In all three conditions (letter, location, color) there was a highly significant effect of load bilaterally in inferior frontal cortex, DLPFC, dorsal prefrontal cortex, premotor cortex, SMA, cingulate cortex, parietal cortex, supramarginal gyrus and thalamus (Figure 2, Table I). Domain effects related to WM are shown in Figure 3 with details listed in Table II. Considering all

Fig. 1 – Behavioral results of Experiment 1: The figures show the behavioral results (n = 13) for median reaction times (left) and accuracy (right) for all three conditions. Error bars show standard deviations.

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Fig. 2 – Images of statistic parametric mapping for the load effect of the n-back task (2-back minus 0-back) from Experiment 1 for the letter, location and color condition (p < 0.05, corrected for multiple comparisons). Areas of activation are shown within orthogonally orientated “glass brains” (i.e., maximum intensity projections) from the right, behind and above.

contrasts, the most important results were that left inferior frontal cortex (BA 44) showed verbal WM domain dominance. Spatial WM domain dominance was found in parietal cortex (BA 7, BA 40), dorsal (superior) PFC (BA6, BA 8) and right ventrolateral PFC (BA 47).

DISCUSSION Significantly longer reaction times were observed during the color task compared to the letter and spatial tasks. Debriefing the subjects revealed that all transcoded the color stimuli internally into color words. This additional transformation process of the color percept into a verbal-semantic code can substantially account for the observed longer RTs. On the other hand, there was no difference in RT between the spatial and the letter WM conditions. Subjects reported not using verbal strategies for the memorization of location information. Thus, we conclude that our task was successful in inducing spatial and verbal encoding strategies depending on instructions.

Region

Precentral sulcus Inferior temporal gyrus Occipital Thalamus

Inferior parietal cortex

Superior parietal cortex

Middle frontal gyrus

Middle frontal gyrus

Inferior frontal gyrus

Anterior cingulate/Pre-SMA Inferior frontal gyrus/anterior operculum

Superior frontal sulcus

18 9 9 39 21 51 51 – 63 – 66 – 48 – 48 3

– 24 – 24

9 –6

9 0 21 21

y

– 33 45 – 48 39 – 45 36 – 39 30 – 24 39 – 33 – 42

36 – 30 3 36

x

Letter z

–9 –6

0 30 30 27 27 9 12 54 51 39 39 45

57 57 45 –3

Z

6.11 6.49

Inf Inf

Inf Inf Inf Inf Inf Inf Inf Inf Inf

Inf Inf Inf Inf

–6

– 33 45 – 48 39 – 45 36 – 45 24 – 18 36 – 30 – 42

30 – 27 3 36

x

– 24

18 9 12 39 27 54 48 – 66 – 66 – 48 – 51 3

3 0 21 21

y

Color z

6

–3 33 27 27 27 0 6 57 57 42 42 45

51 57 45 –3

Z

7.20

Inf Inf


Inf Inf Inf Inf

– 33 – 42 54 12 9 –9

– 30 – 45 45 39 – 45 36 – 42 24 – 15

33 – 27 3 36

x

– 45 3 – 57 – 93 – 24 – 24

18 12 9 39 30 57 51 – 63 – 66

6 0 18 21

y

39 45 –9 –9 9 9

0 33 30 27 30 0 12 57 57

54 57 48 –6

z

Location Z

Inf Inf Inf 6.88 6.23 5.92


Inf Inf Inf Inf

The table shows the results of main effects of load (2-back > 0-back) for each of the three conditions (p < 0.05, corrected) Hem = Hemisphere, L = left; R = right; M = medial; x, y and z are the Talairach-coordinates, Z is the Z-value of the peak activation within a region.

L R L R L R L R L R L L R R R L

R L M R

Hem

Main effects of load

TABLE I

Main effects of load (Experiment 1)

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Fig. 3 – Domain specific working memory activity in Experiment 1: Results of the interaction contrasts (load × domain) calculated between each of the conditions (p < 0.05, corrected) masked inclusively with the load effect for the respective condition (mask p < 0.05) projected onto the canonical single-subject T1-image of SPM 99. The upper row shows the results for the contrasts letter/color minus location load effects, the lower row shows the results for the location minus the letter/color load effects.

TABLE II

Domain specific working memory activity (Experiment 1) Contrast Letter > Location Color > Location Location > Letter

Location > Color

Letter > Color Color > Letter

Hem

Region

L L L L

Precentral gyrus Inferior frontal gyrus Inferior frontal gyrus Precuneus

R

Precuneus

R R R R L

Inferior parietal cortex Middle frontal gyrus Middle frontal gyrus Inferior frontal gyrus Precuneus

L R

Superior parietal cortex Precuneus

R L R R R R L

Inferior parietal cortex Superior frontal gyrus Inferior frontal gyrus Middle frontal gyrus Superior frontal gyrus Inferior parietal cortex Inferior frontal gyrus

BA

x

y

z

Z

6 44 44 7 7 7 7 40 6/8 6 47 7 7 40 7 7 40 8 47 6 8 40 44

– 45 – 56 – 50 –9 –9 18 27 42 24 39 30 –9 – 15 – 33 27 18 50 – 30 33 39 24 50 – 39

–4 12 16 – 55 – 71 – 58 – 68 – 41 8 5 23 – 55 – 64 – 44 – 52 – 70 – 32 17 23 8 34 – 53 7

39 10 21 58 45 58 45 55 49 44 – 14 64 53 60 63 51 51 52 – 14 49 48 41 25

5.37 5.22 6.57 Inf 7.38 Inf 6.18 5.90 5.65 5.25 5.73 7.66 6.54 6.94 Inf 6.59 5.61 4.80 5.22 4.97 4.93 5.06 4.83

The table shows the results of the interaction contrasts (load × domain) calculated between each of the conditions (p < 0.05, corrected) masked inclusively with the load effect for the respective condition (mask p < 0.05). Hem = Hemisphere, L = left; R = right; BA = Brodman’s area; x, y and z are the Talairach-coordinates, Z is the Z-value of the peak activation within a region.


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As expected, fMRI results showed a bilateral fronto-parietal network for the effect of load. Regarding WM domain effects in PFC, we found evidence for verbal WM domain dominance in left inferior frontal cortex (for both “verbal”, i.e. letter and color task) and left premotor cortex (for the letter task only). Both, the LIFC and the left lateral premotor cortex are thought to subserve verbal rehearsal in human WM (Henson et al., 2000; Smith and Jonides, 1999). Furthermore, we found right dorsal (superior) PFC (BA 6, BA 8) and right ventrolateral PFC (BA 47) to show spatial WM domain dominance. In an fMRI study comparing WM for faces and spatial WM for scrambeld faces, the dorsal superior frontal cortex has been implicated to be specifically involved in spatial WM (Courtney et al., 1998) and this region has been postulated to subserve spatial rehearsal (Gabrieli et al., 1998; Owen et al., 1996; Smith and Jonides, 1999; Smith et al., 1996). Additionally, we found superior parietal and intraparietal cortex bilaterally to exhibit domain dominance for spatial WM. The superior parietal and intraparietal cortex are involved in the processing of spatial information including attention, spatial imagery, and mental rotation (Cabeza and Nyberg, 2000). The fact that a considerable number of fMRI studies have not reported the parietal cortex to be dominant for spatial WM can in part be explained by the fact that many fMRI studies have taken an ROI-approach and only analyzed subdivisions of the PFC and not other cortical regions for domain differences. Turning back to the PFC activation our results are consistent with one PET study also comparing verbal and spatial WM with physically identical stimuli (Smith et al., 1996). In this study, the authors found a clear-cut hemispheric double dissociation, with the right dorsal PFC (BA 46) subserving spatial and the left ventral PFC (BA 44) as well as left premotor cortex (BA 6) subserving verbal WM. However, there was no direct statistical comparison between the two WM tasks. More recent fMRI experiments however, do contradict our results. In an fMRI experiment comparing letter and location, D’Esposito et al. (1998) found no evidence either for a left/right or a ventral/dorsal dichotomy. This study however, used physical different stimuli for testing different domains. Furthermore, two fMRI studies compared object and spatial WM with physical identical stimuli and could not demonstrate evidence for a left-right or ventraldorsal dissociation in WM for object and spatial information (Postle and D’Esposito, 1999; Postle et al., 2000). Finally, in the only fMRI experiment, apart from ours, that directly compared verbal (not object) and spatial WM with physically identical stimuli (Nystrom et al., 2000) the authors also found no leftright or dorsal-ventral dichotomy. The question that arises is why the other fMRI studies using physically identical stimuli in WM tasks have not found evidence for domain dominance. Let us turn first to the studies of Postle et al. (Postle and D’Esposito, 1999; Postle et al., 2000). These studies differed in several respects from the present study. (i) They used WM tasks which involved ‘maintenance only’ conditions, whereas in our study a manipulation component was critically involved. (ii) They compared object (not verbal) WM with spatial WM. (iii) In these studies an ROI approach was used whereas we used a voxel-based

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analysis. (iv) Perhaps most importantly, the number of subjects studied differed markedly. In the Postle et al. (1999) study only 6 subjects were studied in the relevant Experiment 1. In the Postle et al. (2000) study 8 subjects were studied in the relevant Experiment 2. Furthermore, only three subjects showed a suprathreshold PFC activation at all at an ROI-wise t threshold in both conditions. In Experiment 3 of the Postle et al. (2000) study, only 4 subjects were studied. A small number of subjects is especially critical if a non-finding is claimed. If domain dominance is only a subtle quantitative phenomenon it may be necesseary to study a larger number of subjects to obtain a significant effect. The FMRI study most similar to ours is the study by Nystrom et al. (2000). In this study n-back tasks and a voxel-based analysis was used. In two out of three experiments of this study physically identical stimuli were used. In Experiment 2 seven subjects were studied in a letter and a location 0-back and 3-back task with letters at different locations as stimuli. In Experiment 3 ten subjects were studied in an object and location 0-back and 2-back task using shapes at different locations. Actually, Experiment 3 was a dual task as subjects were additionally instructed to read words during the delay in all conditions. The authors conclude from these experiments that they have found evidence against a stimulus based organization of the prefrontal cortex. However, a closer look at their results reveals that in fact they do support at least partly our view of a quantitative WM domain dominance. For example, in Experiment 2, they found a greater sensitivity to spatial location in bilateral superior frontal sulcus and in right-lateralized parietal regions. Furthermore, in Experiment 3 they found a more shape-sensitive region in the left inferior frontal gyrus and a more location-sensitive region in the right superior frontal sulcus (the same region as in their Experiment 2). Moreover, in Experiment 3, they found location-sensitve regions in the parietal cortex, mostly in the right hemisphere. The interpretation of the authors in terms of evidence against domain dominance must be seen in the context of the hypothesis of a clear-cut qualitative left-right or ventral-dorsal dissociation revisited by the authors. Evidence for spatial WM domain dominance that is in accordance with our findings was also demonstrated by a recently published PET-study by our group in which we compared a phonological and a spatial WM task using physically identical stimuli (senseless syllables at different locations) (Zurowski et al., 2002). We found a more location-sensitive region in right superior frontal cortex and superior parietal cortex bilaterally, i.e. a region exhibiting spatial WM domain dominance. Our experiment presented here had several limitations. First, we did not balance the order of conditions so we cannot exclude order effects. Secondly, our analysis used a fixed-effects model thus limiting our evidence to the group studied. Therefore, a replication of our results within the framework of random effects modeling would be desirable. In Experiment 2 we present such a replication. Experiment 2 was developed for the application of our task on patients with schizophrenia. Thus, we made it easier by including only one verbal task (letter only, the color condition was skipped) and by increasing the length of stimulus presentation (from 500 ms to 1000 ms).


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METHODS (EXPERIMENT 2) Subjects. Fifteen right-handed (Oldfield, 1971) healthy subjects (7 female, 8 male, mean age 29.8 ± 7.3 years). WM tasks. Stimuli were the same as in Experiment 1, except that letters were not colored. We used a 2 × 2 design with the factors load (0-back/2-back) and domain (verbal/spatial). The experiment was performed in two different sessions, i.e. one session for letter WM and one for location WM. Stimulus presentation time was 1000 ms, ISI was 3000. Each session contained 6 alternating epochs of 0-back and 2-back. Each epoch lasted 32 seconds including 10 stimuli. Instructions for letter and loacation 0-back and 2-back tasks were the same as in experiment 1. fMRI data acquisition. TR was 3980 ms, TE = 66 ms. Image size was 64 × 64 pixels (3.6 × 3.6 mm), slice thickness was 3mm with a gap of 0.6 mm. Thus, voxel size was isotropic. FMRI protocol was a block design with two sessions: letter and location. The order of sessions was balanced across subjects. Each session contained six off-on-epochs of 32 sec/epoch. Each epoch comprised 8 volumes. The first six volumes of each session were discarded in order to allow for equilibration of T1-effects. Thus, in each session 102 functional volumes were acquired. FMRI data analysis. Load and interactions effects (domain by load = WM domain effects) were calculated using a random effects model on the second level. For this purpose, single subject analyses of domain effects were performed. For each session, the variance of each voxel was estimated according to the general linear model, using a box car model convoluted with the hemodynamic response function as predictor. Images were adjusted for global effects, low-frequency drifts were removed via a high pass filter using low-frequency cosine functions with a cutoff of 127 sec. The resulting contrast images were then used in a second level analysis in one sample t-tests. For random effects group analysis significance thresholds of p = 0.001 at the voxel and p = 0.05 at the cluster level (both uncorrected) were defined. RESULTS (EXPERIMENT 2) Behavioral data. Reaction times (Figure 4): a MANOVA for repeated measures revealed significant main effects of the factors “load“ [F (1, 14) = 10.87, p = 0.005] and “domain” [F (1, 14) = 9.54; p = 0.008]. These factors showed an interaction effect [F (1, 14) = 4.65, p = 0.049] with increasing differences in RT (letter slower than location) at higher loads. Accuracy (Figure 4): a MANOVA for repeated measures demonstrated significant main effects for the factors “load“ [F (1, 14) = 6.91, p = 0.02] and “domain” [F (1, 14) = 6.89; p = 0.02). No significant interaction effect was found (p > 0.05). FMRI-data. In both conditions there was a significant effect of load comprising the same regions as in experiment 1 (data not shown, detailed table available on request). WM domain effects (interaction of load by domain) are shown in Figure 5. In the comparison of letter WM minus location WM, left

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Fig. 4 – Behavioral results of Experiment 2: The figures show the behavioral results (n = 15) for median reaction times (left) and accuracy (right) for the two conditions. Error bars show standard deviations.

inferior frontal cortex (x = – 45 y = 15 z = 16, BA 44, z-value = 3.83) and occipital cortex bilaterally (x = – 30 y = – 85 z = – 6, BA 18, z-value = 4.59; x = 36 y = – 88 z = – 3, BA 18, z-value = 3.87) showed verbal domain dominance. Spatial WM domain dominance was found in right parietal cortex (x = 12 y = – 63 z = 41, BA 40, z-value = 4.26) and (x = 24 y = – 74 z = 31, BA 39, z-value = 3.67) and right middle frontal gyrus (x = 30 y = 28 z = 35; BA 9, z-value = 3.56).

Fig. 5 – Domain specific working memory activity of Experiment 2: Results of the interaction contrasts (load × domain) calculated between each of the conditions in a random effects model (p < 0.001, uncorrected) projected onto the canonical single-subject T1-image of SPM 99. The upper row shows the results for the contrasts letter load effect minus location load effect, the lower row shows the results for the location load effect minus the letter load effect.


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DISCUSSION In Experiment 2 we were basically able to replicate our results concerning domain dominance using a reduced paradigm and a random effects model allowing us to generalize our findings. Verbal domain dominance again was found in left inferior frontal cortex (BA 44) very close to the location found in Experiment 1. Additionally, we found regions in bilateral occipital cortex showing an interaction of load by domain. This may be due to the fact that in order to read letters more detailed visual analysis is necessary. We found two regions that exhibited spatial WM domain doimance, namely the right parietal cortex and the right dorsal prefrontal cortex. The right PFC was located more anterioly and inferiorly than the locus we found in Experiment 1 but still belonged to the dorsal part of the PFC. Because we used a random effects model our result can be generalized to be valid for other samples of healthy young subjects (Friston et al., 1999) GENERAL DISCUSSION

AND

CONCLUSION

In two independent fMRI studies using physically identical stimuli to test for WM-related domain differences we found evidence for domain dominance in terms of different activation levels. Both experiments show that WM domain dominance is a quantitative and not a qualitative phenomenon because the regions found to exhibit domain dominance were not exclusively activated in the respective domain but only to a larger extent. In accordance with this view, it has been argued recently that hemispheric specialization is not absolute but only relative because most prefrontal cells are able to tune their properties adaptively in response to task affordances (Duncan, 2001). Taken together the results of the two experiments presented here support a mixed dimension model of domain dominance in the prefrontal cortex. Whereas left ventral prefrontal areas exhibit verbal WM domain dominance, right dorsal prefrontal cortex exhibits spatial WM domain dominance. The fact that recent fMRI studies of verbal/object versus spatial WM did not find such evidence may be due to the fact that quantitive differences only show up when larger groups are studied. It is important in this regard that we were able to replicate our results in a second independent study although design and fMRI parameters differed. The block design of our study as well as the nature of the task used (n-back) do limit the interpretation of our results with respect to specific subprocesses involved in domain dominance. With tasks that allow one to distinguish components, e.g. delayed-match-to-sample-tasks, event-related fMRI (D’Esposito et al., 2000) is able to provide information on which stage of WM putative domain related differences occur. Moreover, new designs might help to disentangle subprocesses of verbal-phonological WM by a still closer matching of cognitive components between compared conditions WM (Zurowski et al., 2002). Despite all these efforts to improve design and techniques there is another argument trying to explain why the results of all attempts to explore domain related regional specialization of PFC in WM are so inconsistent. The argument

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is that traditional designs of WM experiments are flawed insofar as WM representations of stimulus information in PFC might be organized along less obvious dimensions than verbal code, shape, or location (Nystrom et al., 2000). Rather, representations in PFC may be defined by a complex, abstract, multimodal space that does not correspond in any obvious manner with simpler representational dimensions coded in posterior cortical regions. Recent singlecell recording studies in nonhuman primates as well as neural network models of prefrontal functions have led to the hypothesis that the primary function of prefrontal cortex is to provide bias signals to other brain structures. The net effect of these signals is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, external states and outputs needed to perform a given task. In other words, the function of the prefrontal cortex is to exert cognitive control in a context-dependent way (Miller and Cohen, 2001; see also Duncan, 2001). If this indeed is the case than it would explain why neuroimaging experiments on prefrontal function in WM do not yield consistent results and depend on the particular task affordances tested. In summary, the findings of our studies are consistent with a mixed dimension model of quantitiative WM domain dominance but not mutually exclusive dissociation. Verbal WM domain dominance was found in left inferior PFC and spatial WM domain dominance was found in right dorsal PFC as well as parietal cortex. Future experiments using new designs will help to decide if these results can be better explained by a more general theory of prefrontal function which does not operate with the traditional concepts of verbal, object and spatial representations. Acknowledgments. Part of this work was done as an MD dissertation project by V.B. We thank Susanne Erk for critical discussions. REFERENCES BADDELEY A. Working memory. Oxford: Oxford University Press, 1986. BADDELEY A and DELLA SALA S. Working memory and executive control. Philosophical Transactions of the Royal Society London. Series B: Biological Sciences, 351: 1397-1403; discussion 1403-4, 1996. BAKER SC, FRITH CD, FRACKOWIAK RS and DOLAN RJ. Active representation of shape and spatial location in man. Cerebral Cortex, 6: 612-619, 1996. BELGER A, PUCE A, KRYSTAL JH, GORE JC, GOLDMAN-RAKIC P and MCCARTHY G. Dissociation of mnemonic and perceptual processes during spatial and nonspatial working memory using fMRI. Human Brain Mapping, 6: 14-32, 1998. CABEZA R and NYBERG L. Imaging cognition II: An empirical review of 275 PET and fMRI studies. Journal of Cognitive Neuroscience, 12: 1-47, 2000. COHEN JD, FORMAN SD, BRAVER TS, CASEY BJ, SERVAN-SCHREIBER D and NOLL DC. Activation of prefrontal cortex in a nonspatial working memory task with functional MRI. Human Brain Mapping, 1: 293-304, 1994. COHEN JD, MACWHINNEY B, FLATT M and PROVOST J. PsyScope: An interactive graphic system for designing and controlling experiments in the psychology laboratory using Macintosh computers. Behavioral Research Methods Instruments Comput, 25: 257-271, 1993. COURTNEY SM, PETIT L, MAISOG JM, UNGERLEIDER LG and HAXBY JV. An area specialized for spatial working memory in human frontal cortex. Science, 279: 1347-1351, 1998. COURTNEY SM, UNGERLEIDER LG, KEIL K and HAXBY JV. Object and spatial visual working memory activate separate neural systems in human cortex. Cerebral Cortex, 6: 39-49, 1996. D’ESPOSITO M, AGUIRRE GK, ZARAHN E, BALLARD D, SHIN RK and LEASE J. Functional MRI studies of spatial and nonspatial working memory. Cognitive Brain Research, 7: 1-13, 1998. D’ESPOSITO M, POSTLE BR and RYPMA B. Prefrontal cortical contributions to working memory: Evidence from event-related fMRI studies. Experimental Brain Research, 133: 3-11, 2000.


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