工作记忆的保持与操控_腹侧和背侧额叶皮层的特异性功能磁共振成像活动_英文_

心理学报2009, Vol. 41, No.11, 1054−1062Acta Psychologica Sinica DOI:10.3724/SP.J.1041.2009.01054Maintenance and Manipulation in Working Memory: Differential Ventral and Dorsal Frontal Cortex fMRI ActivitySara Pudas1,4, Jonas Persson1,4, L-G Nilsson1,4 & Lars Nyberg2,3,4(1 Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden)(2 Departments of Integrative Medical Biology (Physiology) and Radiation Sciences (Diagnostic Radiology), Umeå University, 90187, Umeå,Sweden)(3Umeå Center for Functional Brain Imaging (UFBI); 4Stockholm Brain Institute)Abstract: A verbal working memory protocol was designed and evaluated on a group of healthy younger adults in preparation for a large-scale functional magnetic resonance (fMRI) study on aging and memory. Letters were presented in two critical conditions: (i) maintenance, in which letters were to be memorized and kept in mind over a four second interval, and (ii) manipulation, in which letters were shifted forward in alphabetical order, and the new order was kept in mind. Analyses of fMRI data showed that the protocol elicited reliable activation in the frontal cortex, with manipulation producing more extensive activation patterns, both in whole-brain analyses and in predefined regions of interest (ROIs). There was also a distinction between dorsal and ventral lateral prefrontal regions, such that manipulation elicited more dorsolateral prefrontal activation. The protocol also elicited activation in various subcortical areas, previously associated with working-memory tasks. It was concluded that this working memory protocol is appropriate for investigating age-related changes in frontal-cortex functioning.Key wor d s: Frontal cortex; fMRI; working memory; maintenance; manipulationWorking memory (WM) is usually defined as a cognitive system for both temporary storage and manipulation of information (e.g. Baddeley, 1986). Structures within the frontal cortices are activated in many functional neuroimaging studies of various forms of WM tasks, (see e.g. Wager & Smith, 2003), typically in concert with parietal cortex and various sub-cortical regions (e.g. Cabeza, Dolcos, Graham & Nyberg, 2002). Further, different WM tasks seem to elicit different activation patterns within the prefrontal cortex. One distinction is between the kinds of material processed in the tasks. Verbal materials, such as words and letters, usually produce left-lateralizedReceived date: 2009-09-11Correspondence to: Sara Pudas, Department of Psychology, Umeå University, 901 87 Umeå, Sweden.E-mail: sara.pudas@psychology.su.se activation (e.g. Reuter-Lorenz et al., 2000). Spatial materials, on the other hand, tend to activate the right frontal cortex to a larger degree (e.g. McCarthy et al., 1996). Another notable distinction is that between ventral and dorsal lateral frontal regions, and this distinction is related to type of processing. Several studies have shown that maintenance (i.e. simple storage) of information in WM predominantly engages ventral frontal cortical areas, whereas more dorsal frontal regions are recruited if the task require additional processing (i.e. manipulation) of the information (e.g. D’Esposito et al., 1999, for a review, see Wager & Smith, 2003).WM has been extensively studied in relation to aging, prompted by that fact that a reduction in WM capacity is one of the most characteristic signs of cognitive aging (Prull, Gabrieli & Bunge, 2000). Imaging studies of the aging brain have11期Maintenance and Manipulation in Working Memory 1055revealed that prefrontal areas are the predominant site of age-related differences in WM-related brain activity. More specifically, age differences are mainly expressed in the dorsolateral portion of prefrontal cortex with minimal differences in ventrolateral prefrontal cortex (e.g., Rypma & D’Esposito, 2000). This effect seems to be particularly salient during the retrieval phase of working memory tasks, rather than during encoding and maintenance phases.In preparation for a large-scale study on memory and aging, we designed and evaluated a maintenance and manipulation WM task. The objective was to find a task that met the needs of a short scanning time, ease of administration to participants across the adult age span, as well as reliably evoking prefrontal activation. We modeled the task after Chee and Choo (2004). Specifically, our protocol comprised of sets of to-be-remembered letters presented in two critical conditions: maintenance, in which four letters were to be memorized and kept in mind over a four second interval, and manipulation, in which two letters were shifted forward in the alphabet and the results of the shift was kept in mind. In addition, there was a control condition in which four identical letters were presented. The protocol useda blocked design, adapted for functional magnetic resonance imaging (fMRI).The main purpose of the study was to assess whether the maintenance and manipulation task would be associated with a reliable dorsal/ventral PFC distinction in healthy young volunteers. That is, we asked whether manipulation would elicit more dorsolateral activation than maintenance, in accordance with previous findings. Further, we were also interested in examining whether the additional demands in the manipulation condition would produce differences in brain regions outside the frontal cortex. Of particular interest were parietal and basal ganglia regions, which were expected to be differentially involved in the manipulation condition of the current WM task.MethodsParticipantsSixteen undergraduate students (21-40 years;10 females) were recruited from Umeå University and financially compensated for their participation. All volunteers were right-handed on self report, had normal or corrected to normal vision and were in good general health. The study was approved by the ethics committee at the University hospital of Northern Sweden (Norrlands Universitetssjukhus). Two participants (out of 16) were excluded from the fMRI analyses due to movement artifacts on the images.Working memory taskThe current working memory task has been used in previous work on verbal working memory (e.g. Chee & Choo, 2004), and comprises three conditions (Fig 1). For the MAINTENACE condition, four different lowercase letters were presented for 2 s followed by a delay period of 4 s during which a fixation cross was displayed. A probe letter (in uppercase) was then presented for 1.5 s and this was followed by fixation for a further 0.5 s. Subjects signaled a match or a non-match by pressing one of two response buttons on the MR compatible response system within the duration that the probe letter was present. Half of the probes were matches, and the other half were non-matches.The MANIPULATE condition was designed to engage manipulation of items retained in verbal working memory. Two different letters were presented and subjects were instructed to mentally alphabetically shift each letter forward and to keep in mind the results. For example, if ‘b’ and ‘j’ were presented, subjects had to remember ‘C’ and ‘K’ which were to be matched with the probe. Matches comprised half of the trials. Stimulus presentation sequence, timing and control condition were identical to that used in MAINTENANCE.The CONTROL condition was designed to match for perceptual and motor responses. Four1056 心 理 学 报 41卷identical uppercase letters appeared for 0.5 s. The presentation phase was followed by a 0.5 s delay period prior to the appearance of a lower case probe that matched the target in half the trials.Figure 1. Schematic description of the three conditions in the working memory task, including timing. All three examples display items that are hits.Each participant performed 18 blocks of the working memory task, six from each condition, in a single scanning session. Each block started with a four second instruction, followed by four items presented for eight seconds each . The participants received instructions before entering the scanner, including a practice task. The total scanning time for this protocol was approximately 11 minutes.Equipment and softwareThe fMRI study was carried out on a Philips 3.0 T high-speed echo-planar imaging device using a quadrature headcoil. The following parameters were used: repetition time: 1512 ms (31 slices acquired), echo time: 30 ms, flip angle: 70 degrees, field of view: 22 × 22 cm, 64 × 64 matrix and 4.65 mm slice thickness. To avoid signals arising from progressive saturation, ten dummy scans were performed prior to image acquisition. Structural high-resolution T1 and T2-weighted images were also acquired. For the T1-weighted images a 3D turbo field-echo sequence was used with the following parameters: repetition time: 10.5 ms,echo time: 5 ms, flip angle: 8 degrees, and field of view: 24 × 24 cm. 170 sagittal slices with a slice thickness of 1 mm were acquired in 336 × 332 matrices and reconstructed to 800 × 800 matrices. Also, T2-weighted images a turbo spin-echo images collected in the transaxial plane with the following parameters: repetition time: 3000 ms, echo time: 80 ms, flip angle: 90 degrees and field of view: 24 × 24 cm, slice thickness: 5 mm (1 mm gap) were acquired in 400 × 319 matrices and reconstructed to 512 × 512 matrices. All images were sent to a PC and converted to Analyze format.The stimuli were presented on a computer screen visible to the subjects through a tilted mirror that was attached to the head coil. Lumitouch fMRI optical response keypads (photon Control Inc., Canada) were used to collect responses. Presentation, responses and reaction times for all involved phases were handled by a PC running E-prime 1.2 (Psychology Software Tools, Inc. USA). fMRI data analysesFunctional images were analyzed with11期 Maintenance and Manipulation in Working Memory 1057Statistical Parametric Mapping Software (SPM2; Wellcome Department of Imaging Science, Functional Imaging Laboratory; http://www.fil.ion. /fil.html) implemented in Matlab 7.3 (Mathworks Inc, MA, US). After correcting for differences in slice timing within each image volume, all images were realigned to the first image volume acquired, then normalized to standard anatomic space defined by the MNI atlas (SPM2), and finally spatially smoothed using a 6.0-mm full-width at half-maximum Gaussian filter kernel.Statistical analyses were performed on a voxel-by-voxel basis. Each of the experimental and baseline conditions was modelled as a fixed response (box-car) waveform convolved with the canonical hemodynamic response function. Single-subject statistical contrasts were set up using the general linear model, and group data were analyzed in a random-effects model. Statistical parametric maps (SPMs) were generated using t statistics to identify regions activated according to the model. All reported activations passed a threshold of 0.01 using FDR correction for multiple comparisons and had a cluster size larger than 10 voxels. The Marsbar toolbox (/) was used to create region-of-interests (ROIs), and extract each ROIs mean BOLD parameter estimate value for each condition on an individual level. ROIs were functionally defined on the voxels that showed peak activations in a comparison of the MANIPULATE condition versus the MAINTENANCE condition in the current dataset, and that corresponded to regions that are typically activated by manipulation in working memory in the literature (e.g. Wendelken, Bunge & Carter, 2008; Champod & Petrides, 2007; Rypma & D'Esposito, 2000; D'Esposito et al., 1999). Each region was created by including activated voxels (p <0.01, FDR corrected) within a 10-mm sphere around the peak voxel, and had a cluster size larger than 10 voxels.Figure 2. Activations in the maintenance and manipulate conditions, compared to baselineResultsBehavioral dataThe mean accuracy across the 14 participants in the current study were 85%, 78% and 95% for the maintenance, manipulate, and control conditions, respectively. In the critical comparison between the maintenance and manipulationconditions, the difference in accuracy was significant (t =2.24, p <0.05). Accuracy was also significantly higher in the control condition than in both maintenance (t =−4.02,p <0.01) andmanipulation (t =−5.51, p <0.01). For the response time measures medians were used for each subject to minimize the effect of extreme values. Group1058 心 理 学 报 41卷level mean response time was 1006.5 ms (SD = 120.3) in the maintenance condition, 931.3 ms (SD =99.4) in manipulation and 841.5 ms (SD = 145.8) in the control condition. Response times were significantly shorter in the manipulation condition compared to maintenance (t =3.82, p < 0.01). The response times in the control condition were significantly shorter than in both maintenance (t =7.65, p <0.01) and manipulation (t =4.23, p <0.01) conditions.Figure 3. Areas more active in the manipulate condition compared to maintenancefMRI whole-brain analysesAs can be seen in Figure 2, when compared tothe baseline condition, both the maintenance and manipulation working-memory conditions activated frontal and parietal areas, but the activation wasmore extensive in the manipulation condition. Bothconditions also produced a tendency to a left-lateralization of activation patterns in frontaland parietal areas, coupled with activation in theright cerebellum.Direct comparison of the manipulation andmaintenance conditions confirmed that manipulation was associated with a more extensivepattern of brain activity, as can be seen in Figure 3.In the frontal cortex, the [manipulation- maintenance] contrast revealed greater bilateralactivations in both dorsolateral (BA 9) and ventrolateral (BA 44/45/47) frontal areas as well as anterior prefrontal cortex (BA 10). However, asshown in Figure 3, the prefrontal activation difference was most pronounced in dorsolateral areas. There was also increased activation in parietal areas (BA 39/40), including bilateral precuneus (BA 7). Other areas that also showed increased activation in this contrast were thalamus, cerebellum and globus pallidus. Table 1 summarizes the activation clusters for the contrast between manipulation and maintenance, including exact coordinates in stereotaxic space. As can be seen, the strongest activation was in dorsolateralfrontal cortex (BA 9). fMRI region-of-interest analyses In order to further investigate the activationsfound in the whole-brain analysis described above, 11 regions of interest (ROIs) were created. They were defined based on the clusters generated in thewhole-brain analysis and based on previous literature (e.g. Wendelken, Bunge & Carter, 2008; Champod & Petrides, 2007; Rypma & D'Esposito, 2000; D'Esposito et al., 1999). The main objective of the ROI analyses was to check the robustness ofregional activations at the individual level. Figures 4 & 5 show ROIs that were analyzed, individual activation profiles, and group-based statistics.Critically, at the individual level, the manipulation condition was consistently associated withrelatively higher activity in each examined ROI.DiscussionThe present results show that this maintenance and manipulate working memory fMRI protocol can be used to elicit robust prefrontal activation. Further, the results also show that manipulation is associated with more extensive functional brain activity than maintenance, which is in line with previous research (Wager & Smith, 2003). Importantly, the direct comparison (Figure 3) revealed that the difference between manipulation and maintenance was most salient in dorsal frontal cortex (BA 9).11期Maintenance and Manipulation in Working Memory 1059 Table 1.Clusters that were more activated during manipulation compared to maintenanceAnatomical localization BA X y z z-valueFrontalLeft middle frontal gyrus 9 −5220 34 5.06*10−3050 12 4.40*Left inferior frontal gyrus 47 −2824 -8 4.13*44/45−4216 20 4.72*45/46−3236 12 3.80Right middle frontal gyrus 6 30 6 60 4.6295628324.16*10325444.06*Left Anterior cingulate 32 12 30 32 3.86ParietalRight parietal lobe 40 44 −4240 4.75*Right precuneus 7 10 −6850 3.92Left angular gyrus 39 −32−6834 4.47Left precuneus 7 −12−6836 4.35*OtherThalamus−4 −14 4 4.81*Cerebellum38−68−50 4.778−8026 3.99Globus pallidus −10−2 −2 4.15*Caudate nucleus −140 8 3.20*Note: BA, Brodmann’s Area; x, y, z coordinates in MNI (Montreal Neurological Institute)stereotaxic space; *Regions that were selected for ROI-analysesAreas outside of the frontal cortex which were more activated in manipulation than maintenance included the parietal cortex, the cerebellum, the thalamus, as well as the globus pallidus and caudate nucleus of the basal ganglia. Parietal activation is found in many studies of WM (e.g. Cabeza et al., 2002; Chee & Choo, 2004; see Cabeza & Nyberg, 2000), and it has recently been suggested that the parietal cortex, in conjunction with dorsolateral prefrontal cortex, supports organization of information (i.e. manipulation) and the maintenance of that information in an organized state (Wendelken, Bunge & Carter, 2008). This hypothesis is consistent with the current results. The thalamus likely mediates attentional demands (e.g. Portas, Rees, Howseman, Turner & Frith, 1998), while the role of the cerebellum could be linked to higher executive demands (Cabeza & Nyberg, 2000).Basal ganglia structures are important for WM, as shown by neuroimaging studies (e.g. Dahlin et al., 2008; Lewis, Dove, Robbins, Barker & Owen, 2004) and computational studies (see O’Reilly, 2006). The exact nature of their contribution remains to be clarified, but a recent study suggests that the basal ganglia, in concert with the prefrontal cortex, acts as a form of gate-keeper to allow only relevant information to enter WM (McNab & Klingberg, 2008). This could be reconciled with our current results when considering that the manipulation condition in our protocol involved remembering not the presented letters, but the next letters in the alphabet. In this case the presented letters could be hypothesized to constitute irrelevant information, not to be allowed to enter WM. Moreover, the manipulation condition should have had a strong updating component, which has been linked to the caudate1060 心 理 学 报 41卷region in working-memory studies (Dahlin et al., 2008; also see O’Reilly, 2006).A possible confound is that the manipulation condition proved to be more difficult than the maintenance condition, given the significant difference in accuracy for these two conditions. This difference could have accounted for some of the observed differences in brain activity . However , the shorter response times in the manipulation condition would argue against this possibility. Also, given the relative simplicity of the task and the high accuracy in both conditions difference in level of difficulty likely had a relatively minoreffect.Figure 4. Results from the ROI analyses, line charts show individual activation and bar charts ROI activation on a group level (error bars represent the standard error of the mean); maintenance condition on left-hand side of charts, manipulation on right-hand side11期 Maintenance and Manipulation in Working Memory 1061Figure 5. Results from the ROI analyses, line charts show individual activation and bar charts ROI activation on a group level (error bars represent the standard error of the mean); maintenance condition on left-hand side of charts, manipulation on right-hand sideIn conclusion, the working memory protocol described here produces reliable activation in the frontal cortex, as well as a differentiation betweenactivation patterns for maintenance and manipulation conditions. The protocol is thus appropriate for use in future WM studies, and willbe employed in our upcoming study on memory and aging, which is aimed at investigating the neural underpinnings of age-related decline in WMprocesses.References Baddeley, A. D. (1986). Working memory . Oxford University Press:New York.Cabeza, R., Dolcos, F., Graham, R., & Nyberg, L. (2002). Similaritiesand Differences in the Neural Correlates of Episodic Memory Retrieval and Working Memory. NeuroImage, 16, 317−330.Cabeza, R. & Nyberg, L. 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Neuroimaging studies of working memory: A meta-analysis. Cognitive, Affective, & Behavioral Neuroscience, 3(4), 255−274.Wendelken, C., Bunge, S. A., & Carter, C. S. (2008). Maintaining structured information: An investigation into functions of parietal and lateral prefrontal cortices. Neuropsychologia, 46, 665−678.工作记忆的保持与操控：腹侧和背侧额叶皮层的特异性功能磁共振成像活动 Sara Pudas1,4, Jonas Persson1,4, L-G Nilsson1,4 and Lars Nyberg2,3,4(1 Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden)(2 Departments of Integrative Medical Biology (Physiology) and Radiation Sciences (Diagnostic Radiology), Umeå University, 90187, Umeå,Sweden)(3Umeå Center for Functional Brain Imaging (UFBI); 4Stockholm Brain Institute)摘 要为了进行大样本的老化与记忆的功能磁共振成像(fMRI)研究, 研究者设计了言语工作记忆的方案, 并且对一组健康青年人进行了施测。