Neural Correlates of Strategic Memory Retrieval: Differentiating Between Spatial-Associative and Temporal-Associative Strategies

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1 Human Bain Mapping 29: (2008) Neual Coelates of Stategic Memoy Retieval: Diffeentiating Between Spatial-Associative and Tempoal-Associative Stategies Mischa de Rove, 1 * Kal Magnus Petesson, 1 Siebeen P. van de Wef, 2 Alexande R. Cools, 3 Hans J. Bege, 2 and Guillén Fenández 1,4 1 F.C. Dondes Cente fo Cognitive Neuoimaging, Radboud Univesity Nijmegen, 6500 HB Nijmegen, The Nethelands 2 Depatment of Medical Psychology, Univesity Medical Cente Nijmegen, 6500 HB Nijmegen, The Nethelands 3 Depatment of Psychoneuophamacology, Univesity Medical Cente Nijmegen, 6500 HB Nijmegen, The Nethelands 4 Depatment of Neuology, Univesity Medical Cente Nijmegen, 6500 HB Nijmegen, The Nethelands Abstact: Remembeing complex, multidimensional infomation typically equies stategic memoy etieval, duing which infomation is stuctued, fo instance by spatial- o tempoal associations. Although bain egions involved in stategic memoy etieval in geneal have been identified, diffeences in etieval opeations elated to distinct etieval stategies ae not well-undestood. Thus, ou aim was to identify bain egions whose activity is diffeentially involved in spatial-associative and tempoal-associative etieval. Fist, we showed that ou behavioal paadigm pobing memoy fo a set of object-location associations pomoted the use of a spatial-associative stuctue following an encoding condition that povided multiple associations to neighboing objects (spatial-associative condition) and the use of a tempoal-associative stuctue following anothe study condition that povided pedominantly tempoal associations between sequentially pesented items (tempoal-associative condition). Next, we used an adapted vesion of this paadigm fo functional MRI, whee we contasted bain activity elated to the ecall of object-location associations that wee eithe encoded in the spatial- o the tempoal-associative condition. In addition to bain egions geneally involved in ecall, we found that activity in highe-ode visual egions, including the fusifom gyus, the lingual gyus, and the cuneus, was elatively enhanced when subjects used a spatial-associative stuctue fo etieval. In contast, activity in the globus pallidus and the thalamus was elatively enhanced when subjects used a tempoal-associative stuctue fo etieval. In conclusion, we povide evidence fo diffeential involvement of these bain egions elated to diffeent types of stategic memoy etieval and the neual stuctues descibed play a ole in eithe spatial-associative o tempoal-associative memoy etieval. Hum Bain Mapp 29: , VC 2007 Wiley-Liss, Inc. Key wods: basal ganglia; humans; thalamus; declaative memoy; fmri *Coespondence to: Mischa de Rove, Depatment of Expeimental Psychology, Behavioual and Clinical Neuoscience Institute, Univesity of Cambidge, Downing Site, Cambidge, CB2 3EB, United Kingdom. md415@cam.ac.uk Received fo publication 1 Apil 2007; Accepted 12 June 2007 DOI: /hbm Published online 19 Octobe 2007 in Wiley InteScience (www. intescience.wiley.com). INTRODUCTION Episodic memoies of pevious expeience ae based on spatially and tempoally defined sequences of events. The focus of this study is on episodic memoy etieval of these sequences of events, athe than single item memoy. In geneal, neual opeations in distinct bain egions includ- VC 2007 Wiley-Liss, Inc.

2 Stategic Memoy Retieval ing the medial tempoal lobe, the pefontal and tempoalpaietal cotices suppot episodic memoy etieval enabling people to tavel backwads in subjective time to emembe specific sequences of events fom thei pesonal past (Baddeley, 2001; Tulving, 2002; Wheele, 2000). When the episodic memoies to be etieved epesent complex, associative infomation, stategic pocessing (e.g., focusing on specific aspects of the memoy epesentations o types of stoed infomation) is beneficial in addition to the necessay opeations suppoting the etieval of simple item infomation. Although still not well-undestood, stategic pocessing, o woking with memoy, is essential fo the oganization (e.g., clusteing o chunking along vaious dimensions), selection, integation, and monitoing of the output fom memoy stoes (Moscovitch, 1994). Within the concept of stategic pocessing, thee ae seveal diffeent poblem-solving stategies possible (Kichhoff and Buckne, 2006) as fo instance the use of the spatial and/o tempoal context of the encoded infomation (Henson et al., 1999). Seveal bain egions involved in the etieval of spatial and/o tempoal context have been identified, as fo instance pefontal and paietal netwoks involved in pefoming tempoal memoy tasks (Cabeza et al., 1997; Dobbins et al., 2003; Simons et al., 2005). Futhe, dosal midlateal ight pefontal cotex was shown to be involved in context monitoing (Henson et al., 1999). Upon etieval of the tempoal ode in which wods wee pesented, dosal pefontal, cuneus/pecuneus and ight posteio paietal egions wee also shown activated in a PET study (Cabeza et al., 1997). Howeve, when sequences of events, like objectlocation associations, ae to be etieved, the spatial o tempoal stuctue of the sequence itself is not necessaily etieved, but may implicitly facilitate etieval of objectlocation associations. A pefontal-paietal netwok was found to be involved in implicit foms of stategic memoy, as fo instance in ecoding infomation within woking memoy (Bo and Owen, 2007; Petesson et al., 2006). It is cuently unclea whethe this netwok is involved in diffeent foms of implicit stategic memoy, o whethe the implicit use of spatial context involves diffeent bain aeas than the implicit use of tempoal context in stategic episodic memoy. In this study, we focus on episodic memoy fo sequences of object-location associations, wheeby the location of each object has to be emembeed and the spatial o tempoal stuctue of the sequence may only be implicitly used as a etieval stategy. When stategic memoy etieval is pedominantly diven by a stategy using spatialassociative epesentations, bain egions known to be involved in highe ode visual pocessing and mental imagey like the cuneus and pecuneus seem to be involved (Fletche et al., 1995, 1996; Kosslyn et al., 1995; Wheele et al., 2000). In contast, the thalamus as well as the basal ganglia, in paticula thei output stuctue, the globus pallidus, ae involved in foms of memoy in which tempoal infomation is cucial, fo example in implicit leaning of moto as well as nonmoto sequences (Fokstam and Petesson, 2005; Fokstam et al., 2006; Leheicy et al., 2005; Packad and Knowlton, 2002; Smith and McDowall, 2006; Vakil et al., 2000). In line with this, patients with basal ganglia degeneation like Pakinson s disease show deficits in implicit sequence leaning (Smith and McDowall, 2006) and stategic spatial location memoy (Pillon et al., 1998). Futhemoe, the basal ganglia ae known to be involved in behavioal sequencing and stategy selection (Cools, 1980) and the basal ganglia as well as the ceebellum ae thought to be involved in intenal time keeping function (Haington and Haaland, 1999; Ivy and Spence, 2004; Lalonde and Hannequin, 1999; Meck, 2005). Thus, it appeas that the thalamus and the basal ganglia can suppot episodic memoy etieval of object-location associations when this is facilitated by a stategy oganizing the infomation along a tempoal-associative stuctue. The pimay objective of the pesent study was to identify bain egions whose activity is diffeentially involved in implicit use of spatial-associatively and tempoal-associatively diven stategies. To this end, we designed two expeiments (Fig. 1) in which sets of object-location associations wee encoded unde two diffeent conditions: (1) Spatial-associative condition: Encoding of object-location associations, poviding multiple spatial associations between the item location to be leaned and its neighboing objects; (2) Tempoal-associative condition: Encoding of object-location associations by poviding tempoal ode associations and educing the availability of spatial associations. Impotantly, the etieval conditions in the pesent study diffeed only in the way the infomation was encoded. Theefoe, we expected to find only those bain aeas activated that ae specifically involved in stategies focusing on spatial-associative o tempoal-associative epesentations duing object-location etieval. In contast, we did not expect to find any diffeential activation in those bain egions that ae involved in episodic etieval of tempoal stuctues themselves (as outlined above; Konishi et al., 2002, 2006). Fist we investigated ou expeimental paadigm in a behavioal expeiment to show that these encoding conditions elicited the use of eithe a spatial-associative o tempoal-associative stategy duing ecall with unconstained esponse ode. Next, we measued bain activity duing the ecall test, using functional magnetic esonance imaging (fmri), contasting activity elated to etieval of associations memoized eithe in the spatial o the tempoal encoding condition. In contast to the behavioal expeiment, the esponse ode duing the ecall test was pedefined in the fmri expeiment. Thus, diffeences in bain activity elated to diffeent etieval stategies wee not confounded by any ovet esponse diffeences. We expected both ecall conditions to engage ovelapping etieval netwoks, including tempoal, paietal, and pefontal bain egions. These netwoks ae geneally consideed to be involved in diffeent aspects of object-location etieval, including the hippocampus (Smith and Milne, 1069

3 de Rove et al. 1989), the paahippocampal gyus (Düzel et al., 2003; Epstein et al., 2003; Hayes et al., 2004; Somme et al., 2005), paietal cotex (Konishi et al., 2000), and pats of the pefontal cotex (Cabeza et al., 2003; Dobbins and Han, 2006; Dobbins et al., 2002). Because the etieval aspects mediated by these netwoks might be ecuited to the same o simila extent in both etieval conditions in this study, we did not expect these bain egions to be diffeentially activated. In contast, we hypothesized that the two ecall conditions would diffeentially activate bain egions involved in the use of the specific associative epesentations used fo stategic memoy etieval. The paietal lobe is impotant fo spatial memoy, but not necessaily fo mental imagination of a coheent pictue. Theefoe, we pedicted an inceased activity in the cuneus and/o pecuneus duing the ecall of spatial-associatively encoded object-location associations and in the basal ganglia and/ o the thalamus duing the ecall of tempoal-associatively encoded object-location associations. MATERIALS AND METHODS Expeiment 1 The Use of Diffeent Retieval Stategies Duing Recall Paticipants Six young healthy voluntees paticipated in the fist expeiment (3 female; mean age 5 27 yeas, SD 5 3.6, ange 21 31). The mean numbe of yeas of fomal educa- Figue 1. Expeimental design, showing the timeline fo a single phase. Thee-by-thee gids with simple line dawings wee shown. (a) Fo a spatial-associative encoding block, the subjects saw all the nine pictues at once (pesented simultaneously) and had to make a living nonliving decision on each of the pictues in a fixed pseudo andom ode as indicated by the moving ed fame. (b) Half of the cycles stated with a tempoal-associative encoding block in which paticipants looked at the nine pictues one-by-one, while the othes wee hidden and a living nonliving decision had to be made on each pictue in a andom but pedefined ode. (c) In both cases, the encoding phase was followed by a 1-back woking memoy task, which seved as distaction. In this task, subjects had to indicate whethe o not the pictue in the blue fame was the same as the pevious pictue in the blue fame, iespective of the location of the pictue. (d) The 1-back woking memoy task was always followed by a ecall phase in which each of the nine pictues shown in the peceding encoding phase wee shown again and subjects had to indicate thei oiginal location in the gid. In the behavioal expeiment (Expeiment 1), subjects wee allowed to ode thei ecall esponses feely. They wee pesented with the studied objects each pinted on a small pape cad, which had to be put on the gid on the positions studied in the peceding encoding phase. (e) In the fmri expeiment (Expeiment 2), the objects studied in the peceding encoding block wee shown below the gid, all nine of them sequentially but in andom ode and subjects had to indicate thei locations as A1, B2, etc., by appopiate button pesses. The ecall phase was always followed by a est phase, a simple fixation coss (not shown hee) afte which the next cycle stated with the same sequence of tasks, andomly stating with eithe a spatial-associative o a tempoal-associative encoding condition. 1070

4 Stategic Memoy Retieval tion was 18 (SD 5 1.0). All subjects wee ight-handed as indexed by an Edinbugh handedness index (90; Oldfield, 1971). Vision was nomal o coected-to-nomal in evey paticipant. All subjects gave witten infomed consent accoding to the Helsinki Declaation and the local medical ethics committee. Stimulus mateial and expeimental pocedue We selected 117 black-on-white line dawings of common living and nonliving objects (Snodgass and Vandewat, 1980). Fo each subject, we andomly chose nine dawings (five living and fou nonliving) fo the distaction task, 54 dawings (27 living and 27 nonliving) fo the spatial-associative encoding condition and 54 dawings (27 living and 27 nonliving) fo the tempoal-associative encoding condition. In line with the subsequent fmri expeiment, this behavioal expeiment was stuctued in 12 cycles each including fou phases: encoding, distaction, visual fixation, and ecall test (Fig. 1). Each cycle stated with eithe a spatial-associative o a tempoal-associative encoding condition, in which object-location associations wee memoized, and ended with an object-location cuedecall memoy test. Duing encoding, subjects wee equied to memoize nine objects and thei paticula location in a gid displayed on a compute sceen. The subjects wee instucted to make a living-nonliving decision on each object and to espond vebally to ensue active paticipation and good ecall pefomance. In the spatial-associative encoding condition, a ed fame moved though the gid in a fixed pseudo andom ode highlighting each item fo 3 s, one item at a time, on which the living-nonliving decision was made (Fig. 1a). The complete gid-display with all nine objects was visible duing the entie encoding phase poviding a ich spatial-associative encoding context, in which each item location could easily be associated with neighboing objects and the entie gid. The tempoal-associative encoding condition was identical to the spatial study condition except that each object was only tansiently visible fo 3 s, highlighted by the ed fame and while all othe items wee hidden by non-infomative masks (Fig. 1b). Thus, this condition did not povide the entie gid with all objects as an associatively ich spatial stuctue and its stuctue was theefoe dominated by the sequence of the pesented objects. To ovewite potentially maintained woking memoy of the pevious encoding phase, we intoduced a one-back object memoy distaction task (Fig. 1c; Baddeley, 1995). Subjects wee shown a gid with nine novel objects. In this distaction condition, the sequential, andom movement of a blue fame ove each gid-box was accompanied by a andom eaangement of objects within the gid evey 3 s. Fo each highlighted (blue fame) object, subjects had to indicate whethe this object was identical with the one shown peviously in the blue fame independently of the location within the gid ove nine successive tials. To paallelize this expeiment as much as possible with the subsequent fmri expeiment, we included a visual fixation phase that was equally timed to the othe phases (such that evey phase lasted 27 s). Duing this condition, a white, cental fixation coss on a black backgound was displayed. No esponse was equied in this condition. Subjects wee instucted to attentively fixate the coss. Duing the ecall task, which was identical fo the spatial-associative and the tempoal-associative encoding cycles, subjects wee pesented with a gid in caton papeboad, without dawings, as well as the studied objects each pinted on a small pape cad and povided at once in andom spatial positions (Fig. 1d). Subjects wee instucted to put the cads on the gid on the positions studied duing the encoding phase in any ode. Befoe the actual expeiment, subjects pacticed the task with two cycles (one spatial-associative and one tempoalassociative study condition) with additional line dawings, which wee not othewise used duing the expeiment. Paticipants wee comfotably seated at a desk with a compute monito fo stimulus pesentation and the gid in font of them. We used a video camea to ecod the esponses made by the subjects fo futhe analysis. Fist, the ecall pefomance was analyzed pe subject, by dividing the numbe of coect answes by the total numbe of answes, to check that all subjects pefomed above chance level. Next, to investigate the etieval stategies used duing ecall, we analyzed the coect answes only. Specifically, we analyzed the elationship between the spatial stuctue of the gid and the ecall ode chosen by the subjects, to detemine whethe subjects used the spatial stuctue of the gid duing etieval in eithe of the two conditions. The numbe of successive coect answes in contiguous positions in the gid (Fig. 1: fo instance B1 followed by B2 o B1 followed by A1 is a contiguous answe, but B1 followed by C3 is a noncontiguous answe) was counted pe subject and cycle. Fo example, in the case of one cycle containing only two successive coect answes being B1 and A1, the actual numbe of contiguous coect answes would be 1. To coect this numbe of contiguous coect answes fo diffeences in pefomance, it was expessed as a pecentage of the numbe of contiguous coect answes that would be expected by chance. The chance level of contiguous coect answes was calculated as the numbe of contiguous coect answes divided by the total numbe of coect answes available in the gid and then set at 100%. In the example outlined above of a cycle containing only two successive coect answes the fist one being B1, the chance that the next coect answe is in a contiguous position is 0.375; following B1 thee ae thee available contiguous answes: A1, B2, and C1, divided by eight available coect answes (all nine positions except B1). The chance level of contiguous coect answes would then be set at 100%; so, in this example, contiguous coect answes ae expected by chance. Since the actual numbe of contiguous coect answes in this example cycle is 1, the pecentage of contiguous coect answes is 1/ % 5 267% of chance level (

5 de Rove et al. 100%) fo this paticula example cycle. The pecentage of contiguous answes was calculated as a measue of the use of the spatial-associative stuctue of the gid duing etieval independent of the actual pefomance level in eithe of the two conditions. To investigate whethe subjects used the encoding ode duing etieval in eithe of the two conditions, we also analyzed the elationship between the given encoding ode and the ecall ode chosen by the subjects. Ou measue of inteest in this analysis was the Peason s coelation between the encoding ode and the etieval ode. Expeiment 2 Bain Activity Duing Recall Paticipants Twenty young healthy voluntees paticipated in the second expeiment (not included in Expeiment 1; 10 female; mean age 5 25 yeas, SD 5 4, ange 19 33). The mean numbe of yeas of fomal education was 19 (SD 5 3). All emaining subject chaacteistics wee identical to the ones descibed fo Expeiment 1. Stimulus mateial and expeimental pocedue Expeiment 2 was identical to expeiment 1 except fo: (1) To obtain sufficient powe; the second expeiment consisted of 20 instead of 12 cycles, each including fou phases: encoding, distaction, visual fixation, and ecall test (Fig. 1). Evey phase lasted 29.7 s (nine items, 3.3 s each). We selected 189 black-on-white line dawings [nine dawings (five living and fou nonliving) fo the distaction task, 90 dawings (45 living and 45 nonliving) fo the spatial-associative encoding condition and 90 dawings (45 living and 45 nonliving) fo the tempoal-associative encoding condition]; (2) Responses duing encoding, distaction, and ecall wee made by appopiate button pesses; (3) Duing the ecall task, subjects wee pesented with the gid without dawings. The paticipants could ead the coodinates of each gid box, A1, A2,..., C3 in the coesponding box. The encoded objects wee shown one at a time below the gid in andom ode (Fig. 1e; 3.3 s pe item). Subjects wee instucted to indicate the position in the gid in which the object was pesented duing the study phase by an appopiate combination of left and ight hand key pesses. The assignment of the items to the diffeent conditions and gid positions as well as the condition with which the expeiment stated was andomized acoss subjects. Befoe going into the scanne, subjects pacticed the task in fou cycles (two spatial-associative and two tempoalassociative study conditions) with additional line dawings, which wee not othewise used duing the expeiment. We used the Pesentation softwae ( to pesent the stimuli and ecoded the esponses made by the subjects. Stimuli wee back-pojected via an LCD-pojecto onto a tanslucent sceen that subjects viewed though a mio mounted on the head coil. Subjects esponded with two optical key-devices, one in each hand. The subject s head was immobilized with a vacuum cushion to educe head motion duing fmri data acquisition. The behavioal esponses subjects made while in the scanne wee analyzed fo accuacy and eaction time. The use of diffeent etieval stategies duing ecall was analyzed in Expeiment 1 and thus not futhe analyzed in Expeiment 2. This appoach was chosen, because it allowed us to pedefine the esponse ode duing ecall in the scanne, so that diffeences in bain activity elated to the diffeent etieval stategies would not be confounded by any ovet diffeences in esponses. MRI Data Acquisition Whole head T2*-weighted EPI-BOLD fmri data wee acquied with a Siemens Sonata 1.5T MR scanne using an inteleaved slice acquisition sequence (EPI; volume TR s, TE 5 40 ms, 908 flip-angle, 37 axial slices, slicematix size , slice thickness mm, no slice gap, FOV mm, isotopic voxel-size mm 3 ). High-esolution stuctual MR images wee acquied with a T1-weighted MP-RAGE sequence (volume TR s, TE ms, 158 flip-angle, 176 sagittal slices, slice-matix size , slice thickness 5 1 mm, no slice gap, voxel-size mm 3 ). MR Image Pepocessing and Statistical Analysis Image pepocessing and statistical analysis was executed with the SPM2 softwae ( The functional EPI-BOLD images wee ealigned and the subject-mean functional MR images wee coegisteed with the coesponding stuctual MR images using mutual infomation optimization. These wee subsequently spatially nomalized (i.e., the nomalization tansfomations wee geneated fom the stuctual MR images and applied to the functional MR images) and tansfomed into a common appoximate Talaiach space (Talaiach and Tounoux, 1988) defined by the SPM2 MNI T1 template, and finally spatially filteed by convolving the functional images with an isotopic 3D spatial Gaussian filte kenel (8 mm FWHM; Hayasaka and Nichols, 2003; Petesson et al., 1999). The fmri data was popotionally scaled to account fo global effects and analyzed statistically using the geneal linea model and statistical paametic mapping (Fiston et al., 1995). The linea model included convolved explanatoy vaiables (box-ca egessos) modeling the expeimental conditions in a blocked fmri design. The explanatoy vaiables wee tempoally convolved with the canonical hemodynamic esponse function povided by SPM2. In addition, the linea model included as effects of no-inteest: session/subject-effects, ealignment paametes, and a tempoal high-pass filte to account fo vaious low-fequency effects. In the statistical analysis, elevant contasts coesponding to null-hypotheses wee used to 1072

6 Stategic Memoy Retieval geneate contast images fo each subject, which wee subsequently subjected to a second-level andom effects analysis. The supatheshold cluste-size was used as test statistic. In the andom effects analyses, the supatheshold clustes wee defined by the theshold t (except fo the baseline compaisons, in which the theshold was set at t to geneate clustes that wee not too lage to ende thei intepetation difficult). Only clustes significant at P < 0.05 coected fo multiple nonindependent compaisons based on the family-wise eo ate (Wosley et al., 1996) ae epoted. Subsequently, the significant clustes wee esolved into local maxima and only local maxima significant at P < 0.05 coected fo multiple nonindependent compaisons based on the false discovey ate (Genovese et al., 2002) ae epoted and no masking pocedue was applied. The tems of activation and deactivation ae used as synonyms fo a elative incease and decease in BOLD signal, espectively. RESULTS Expeiment 1 The Use of Diffeent Retieval Stategies Duing Recall The cued object-location ecall pefomance was significantly above chance level (5 11% 5 1/9 items 3 100%) fo both the spatial-associatively and tempoal-associatively encoded pictues (spatial: mean coect 5 74%, SD 5 27, t , P ; tempoal: mean coect 5 71%, SD 5 26, t , P ) and at a simila level fo both conditions (t , n.s.). To investigate whethe subjects used the spatial-associative stuctue of the gid duing etieval in eithe of the two conditions, independent of pefomance, we analyzed the positions in the gid of the coect answes only. The numbe of spatial contiguous coect answes, in the ecall ode chosen by the subjects, was compaed to the numbe of spatial contiguous coect answes to be expected by chance (chance level was set at 100% fo evey sequence of coect answes). Only coect answes wee included in this analysis. On aveage, fo spatial-associatively encoded items, in the sequence povided by the subjects duing fee ecall, the pecentage of coect answes that wee in spatially contiguous positions in the gid, was significantly above the defined chance level (mean: 132% SD 5 26%; one-sample t-test, test value 5 100, P ). Thus, of all coect answes thee ae significantly moe answes in contiguous positions than would be expected by chance. On the othe hand, fo tempoal-associatively encoded items, the pecentage of spatial contiguous coect answes was not significantly diffeent fom chance level (mean: 78.4% SD 5 46%, one-sample t- test, test value 5 100, P 5 0.3). To investigate whethe subjects used the encoding ode duing etieval in eithe of the conditions, we analyzed the ode of the coect answes. Thee was a significant negative coelation between the given encoding ode and the ecall ode chosen by the subjects fo the tempoal-associatively encoded object-location associations ( ; P < 0.05), but not fo the spatial-associatively encoded associations ( , n.s.). This negative coelation epesents a memoy etieval stategy athe than a simple ecency effect, since it was absent in etieval of the spatial-associatively encoded associations, whee a ecency effect would be expected to play a simila ole. Thus, these findings suggest that duing the ecall test without a constained etieval ode subjects tend to utilize two diffeent etieval stuctues, depending on the way the infomation was encoded. Fo spatial-associatively encoded items, etieval is pedominately diven by a stategy using a spatial-associative stuctue, wheeas subjects used the inveted encoding ode as a stuctue fo object-location associations leaned in the tempoal-associative encoding condition. Expeiment 2 Bain Activity Duing Recall Behavioal data The cued ecall pefomance was obust and significantly above the chance level of 11% in both conditions (spatial: mean coect 5 73%, SD 5 16, t , P < 0.001; tempoal: mean coect 5 67%, SD 5 16, t , P < 0.001) and slightly bette fo spatial- than fo tempoal-associatively studied object-location associations (t , P < 0.001). To futhe investigate this small but significant diffeence in behavioal pefomance, we did a coelation between behavioal pefomance (accuacy scoe) and fmri data eveywhee in the bain (not esticted to the identified peak voxels o ROI data). We found that the pefomance scoes did not explain any vaiance in the fmri data, not even at high a-levels (P > 0.5). Theefoe, the pefomance scoes wee not analyzed futhe. The eaction times fo coect esponses duing ecall did not diffe significantly between spatial-associatively compaed with tempoal-associatively encoded infomation (spatial: mean RT s, SD ; tempoal: mean RT s, SD ; t , n.s.). Howeve, these data may be difficult to intepet, since two button pesses wee equied pe answe, wheeby a ight hand button pess indicated A, B, o C, and a left hand button pess indicated 1, 2, o 3. The eaction times mentioned ae the times until the fist button pess (A, B, o C). Since the complete answe has not been given at that time point, putative diffeences in eaction time between the conditions may have been diluted. The use of two diffeent etieval stategies fo spatial-associatively and tempoal-associatively encoded infomation was aleady shown in Expeiment 1. Relying on this esult, we had the unique oppotunity to focus on the quality of ou fmri data in Expeiment 2. Theefoe, the esponse ode duing the ecall test in the scanne was pedefined so that diffeences in bain activity elated to diffeent etieval stategies and would not be confounded by any ovet diffeences in esponses. Thus, 1073

7 de Rove et al. the use of etieval stategies was not futhe analyzed in the fmri expeiment. Imaging data Compaed to the visual-fixation baseline condition, ecall of both spatial-associatively and tempoal-associatively studied object-location associations activated simila bain egions, including visual and associative pocessing egions in the occipital [Bodmann s aea (BA) 17/18/19], paietal (BA 7, 23/31, and 39/40), and tempoal lobes (BA 37), as well as medial tempoal (BA 36) and pefontal (BA 6/8/9/44/45/46) egions (Fig. 2; all clustes P < 0.05, coected). Additional significant bilateal clustes wee obseved in the anteio cingulate (BA 6/32), the fontal opeculum/anteio insula (BA 13/15/47), and the anteio middle fontal egion (BA 10/11) in the tempoal-associative etieval condition only. With espect to subcotical stuctues, we obseved significant activations in the thalamus and the basal ganglia in both the spatial-associative condition [ight thalamus, (x, y, z) 5 (14, 214, 18), P ; (16, 26, 12), P ; left thalamus, (216, 210, 16), P ; (212, 216, 8), P ; ight caudate/putamen: (20, 6, 8), P ; left caudate/putamen: (220, 6, 8), P ; left putamen/globus pallidus: (218, 0, 10), P ; (222, 26, 6), P ] and the tempoalassociative condition [ight thalamus, (14, 216, 16), P < 0.001; left thalamus, (212, 214, 10), P < 0.001; ight caudate/putamen: (18, 6, 6), P < 0.001; left caudate/putamen: (218, 4, 6), P < 0.001; left putamen/globus pallidus: (214, 22, 12), P ; all local maxima P-values epoted wee coected fo multiple nonindependent compaisons]. A diect compaison of bain activity associated with ecall of spatial-associatively and tempoal-associatively encoded object-location associations evealed that the globus pallidus and the thalamus wee significantly moe active duing ecall of tempoal-associatively compaed to spatial-associatively studied object-location conjunctions [bilateal cluste P , coected; including local maxima in left thalamus: (210, 214, 0), Z ; ight thalamus: (8, 28, 4), Z ; left thalamus/globus pallidus: (214, 26, 0), Z ; ight thalamus/globus pallidus: (12, 22, 4), Z ; ight thalamus: (28, 222, 4), Z ; left globus pallidus: (218, 24, 0), Z ; left globus pallidus: (218, 28, 4), Z ; Fig. 3 and Table I]. Convesely, the cuneus extending into the lingual and fusifom gyi (BA 17/18/19) wee significantly moe active duing ecall of spatial-associatively compaed to tempoal-associatively encoded object-location conjunctions [bilateal cluste P < 0.001, coected; including local maxima in ight cuneus: (6, 284, 26), Z ; left cuneus: (24, 290, 10), Z ; ight lingual gyus: (10, 272, 0), Z ; left lingual gyus: (28, 272, 12), Z ; ight posteio fusifom gyus: (26, 262, 22), Z ; Fig. 3 and Table I]. DISCUSSION In addition to opeations suppoting etieval of item infomation, ecall of complex sequences of infomation, as commonly equied fo episodic etieval, typically entails stategic pocessing, and this has been conceptualized in tems of woking with memoy (Gabieli et al., 1996; Moscovitch, 1994). Ou fmri esults show diffeential ecuitment of distinct bain egions duing etieval, depending only on the way in which the infomation was encoded. Togethe with the esults fom the behavioal expeiment, these data suggest that two diffeent types of epesentations ae used in stategic etieval pocessing. In othe wods, the use of a tempoal-associative stuctue vesus a spatial-associative stuctue diffeentially ecuits distinct bain egions. Moe specifically, activity in the globus pallidus and the thalamus is associated with memoy etieval when subjects implicitly use the tempoal-associative stuctue of the encoding sequence. On the othe hand, inceased activity in posteio midline stuctues like the lingual/fusifom gyus and the cuneus is associated with memoy etieval when subjects implicitly use a spatialassociative stuctue. These esults povide initial evidence fo a functional diffeentiation between two impotant pocesses in stategic memoy etieval and also suggest that the ole of the basal ganglia in pocessing sequences extends to the declaative memoy system. If subjects ae allowed to ode thei ecall esponses feely (as in Expeiment 1), they tend to ode thei esponses along the type of stuctue that was pedominantly povided duing the peceding encoding condition. Thus, the paticipants odeed thei esponses along the spatial-associative stuctue povided duing the spatialassociative encoding condition, and along the tempoalassociative stuctue povided duing the tempoal-associative encoding condition. This esult suggests that ou expeimental design manipulates the utilization of stuctued memoy epesentation fo complex infomation povided by the nine object-location associations duing stategic memoy etieval. Although the two ecall conditions wee identical in Expeiment 2, fmri evealed a diffeential involvement of distinct neual substates: one fo the etieval of spatial-associatively encoded and anothe fo tempoal-associatively encoded object-location associations. While the ovelapping bain egions ae well-known to be involved in associative memoy etieval (Buckne et al., 1998a,b; Konishi et al., 2000) but not in tempoal ode etieval itself o in ecency judgment (Cabeza et al., 1997; Dobbins et al., 2003), the pesent esults suppot the idea that the implicit use of diffeent stategies duing etieval involve distinct neual substates. Ou esults cannot be explained by diffeences in ovet behavio, because the ode of ecall esponses was andomly pedefined in the fmri expeiment and thus, in contast to an unconstained etieval ode, in ou design, evey subject etieved the same object-location association on exactly the same (elative) point in time. The two conditions of 1074

8 Stategic Memoy Retieval Figue 2. Bain egions activated in the compaison of the ecall of spatialassociatively encoded object-location associations (left hand columns) o the ecall of tempoal-associatively encoded objectlocation associations (ight hand columns) vesus the visual fixation condition. Activations ae shown on an individual bain endeed in 3D. Only significant clustes ae shown. main inteest diffeed only in the way in which the infomation was encoded. Theefoe, the identical design of the two ecall conditions pevents ou findings fom being confounded by extenal factos, including diffeential visual o moto demands. A possible limitation of this appoach is that an objective measue confiming the diffeential use of the two diffeent stategies in the scanne is lacking. In this espect, we ely on the behavioal expeiment showing that ou two diffeent encoding conditions lead to the use of two diffeent etieval stategies. This is a stong agument fo assuming that, upon pesentation of the same types of encoding conditions, diffeent etieval stategies would be used in the scanne as well. Thus, the esult that activity in posteio midline stuctues like the lingual/fusifom gyus and the cuneus is inceased duing etieval of spatial-associatively encoded object-location associations may be explained by the use of a spatial-associatively diven stategy. It is conceivable that this spatial-associatively diven stategy depended on imagining the spatial-associative stuctue, in othe wods, imagining the gid containing the nine objects as encounteed duing the entie encoding phase as a coheent image (Fletche et al., 1995, 1996; Kosslyn et al., 1995; Wheele et al., 2000). The highe ode visual pocessing Figue 3. Bain egions activated in the diect compaison of the ecall of spatial-associatively encoded object-location associations vesus the ecall of tempoal-associatively encoded object-location associations (a) and the convese compaison (b). Activations ae shown supeimposed onto selected slices of an individual high-esolution T1-weighted volume (left and middle figues) and as intensity pojections (ight-hand figues). Only significant clustes ae shown. 1075

9 de Rove et al. TABLE I. Bain egions diffeentially activated duing ecall of tempoal-associatively and spatial-associatively encoded object-location associations Bain egion BA Z-scoe Local maxima Spatial vesus tempoal, Cuneus cluste, P < Right cuneus (6, 284, 26) Left cuneus (24, 290, 10) Left cuneus 17/ (26, 286, 16) Left cuneus 17/ (28, 280, 20) Right lingual gyus (10, 272, 0) Right lingual gyus (10, 274, 4) Right lingual gyus (14, 270, 26) Right lingual gyus 18/ (4, 272, 8) Left lingual gyus 17/ (28, 272, 12) Right posteio fusifom gyus (26, 262, 22) Right posteio fusifom gyus (24, 266, 22) Right posteio fusifom gyus (20, 262, 2) Tempoal vesus spatial, Basal ganglia cluste, P Left thalamus 3.53 (210, 214, 0) Left thalamus 3.52 (210, 220, 22) Left thalamus 3.49 (28, 210, 0) Left thalamus 3.36 (26, 214, 4) Right thalamus 3.25 (8, 28, 4) Right thalamus 3.14 (10, 28, 8) Right thalamus 3.02 (6, 210, 8) Left thalamus/globus pallidus 3.33 (214, 26, 0) Right thalamus/globus pallidus 3.42 (12, 22, 4) Left globus pallidus/putamen 3.48 (218, 24, 0) Left globus pallidus 3.00 (218, 28, 4) Right thalamus/posteio putamen 3.19 (28, 222, 4) Right posteio lateal putamen 3.24 (34, 220, 4) BA 5 Bodmann s aea. aeas, which we found to be ecuited in elation to the use of spatial-associative epesentations, ae located in the paietal and infeio tempoal lobes. The paietal lobe contibutes impotantly to aspects of episodic memoy etieval (Shannon and Buckne, 2004; Wagne et al., 2005). Reactivation of highe ode visual pocessing aeas that wee activated duing peception of items was shown to mediate thei etieval (Wheele et al., 2000). The mechanism mediating this eactivation duing etieval emains as yet unclea. Anatomical data in monkeys showed the pesence of neuonal pojections between the medial tempoal lobe and the paietal lobe enabling inteactions between the two (Insausti et al., 1987; Kobayashi and Amaal, 2003; Suzuki and Amaal, 1994). Possibly, pats of the paietal lobe act as an inteface between the pefontal cotex (executive functions) and the medial tempoal lobe (declaative memoy functions; Kobayashi and Amaal, 2003; Shannon and Buckne, 2004; Valenstein et al., 1987), facilitating mental imagey and thus mediating etieval using a spatial-associative stategy. In suppot of this hypothesis, pats of the paietal lobe wee found activated in tandem with the pefontal cotex duing etieval of imagined pictues (Lundstom et al., 2003, 2005). The esult that activity in the globus pallidus and the thalamus inceased duing etieval of tempoal-associatively encoded object-location associations may be explained by the use of a tempoal-associatively diven stategy. It is likely that the tempoal-associatively diven stategy depended on sequencing of the objects, o odeing them chonologically as encounteed duing the encoding phase. The globus pallidus is pat of the output system of the basal ganglia and pojects via the thalamus to the pefontal cotex (Alexande et al., 1986; Lawence et al., 1998) and thus is pat of the cotico-stiatal cicuit (Middleton and Stick, 2000, 2001), which is consideed to be cucial fo inteval timing and coincidence detection (Hinton and Meck, 2004; Matell and Meck, 2004; Meck and Benson, 2002). Both the globus pallidus and the thalamus, in which we obseved activation specifically elated to the etieval of tempoal-associatively encoded infomation, have also been obseved to be activated in multiple foms of sequencing, including memoy-guided movement sequencing (Menon et al., 2000), moto sequencing (Chan et al., 2006), and semantic event sequencing (Tinaz et al., 2006). Ou esults thus povide initial evidence that these subcotical stuctues ae also involved in oganizing declaative memoies into a tempoal-associative stuctue. Moeove, ou findings suggest yet anothe ole of the basal ganglia in the declaative memoy system (Gabieli, 1998; Poldack et al., 2001; Voemans et al., 2004). It has been poposed that, by inhibiting cotical aeas not needed fo the task in question, the globus pallidus subseves a focusing ole and thus might povide a selection mechanism in its inteaction with the pefontal cotex (Mink and Thach, 1991). This focusing function of the globus pallidus was ecently consideed to be cucial to accomplish a pictue sequencing task (Tinaz et al., 2006). Subthalamic inputs can excite pallidal neuons via the indiect pathway, wheeas stiatal inputs inhibit pallidal neuons via the diect pathway (Paent and Hazati, 1993). Depending on the elative activity of the diect and the indiect pathway, this can lead to activity in the globus pallidus that is impotant fo selection of pefontal aeas equied in a paticula cognitive task (Levy and Dubois, 2005). A task-elated incease in globus pallidus activity, as obseved hee duing ecall of tempoal-associatively encoded object-location associations, might thus eflect a focusing on o selection of specific pefontal aeas. Theefoe, the deficits in stategic memoy etieval seen in patients with basal ganglia dysfunction ae likely to be the esult of abnomal input to the pefontal cotex caused by malfunctioning basal ganglia cicuity athe than of intinsic pefontal dysfunction pe se (Bege et al., 2004; Owen et al., 1998). Nevetheless, stategic memoy is likely to ecuit pats of the pefontal cotex. It is clea that stategic pocessing, which is hee conceptualized in tems of woking with o easoning about encoded infomation etieved fom memoy stoes, engages pefontal functions (Bo et al., 2003, 2004; Fletche and Henson, 2001; Henson et al., 1999; 1076

10 Stategic Memoy Retieval Simons and Spies, 2003). It was peviously shown that the use of the spatiotempoal context duing etieval was associated with activation of a dosal midlateal egion of the ight pefontal cotex (Henson et al., 1999). In the pesent study, both ecall conditions activated seveal pefontal egions when compaed with the visual-fixation baseline condition. These included both dosolateal and ventolateal pefontal egions (Fig. 2). Howeve, we did not obseve any significant diffeence in pefontal activity between the two ecall conditions. The lack of diffeential activation of the pefontal cotex in the pesent study might be due to an inteaction of both sets of bain egions (o a thid set) with the pefontal cotex to a simila degee. If this is the case, the absence of a diffeential pefontal esponse can be explained by the simila extent to which both stategies involve pefontal activity. It has been shown that the basal ganglia and the medial tempoal lobe memoy system can inteact unde cetain conditions in declaative memoy (Poldack et al., 2001; Voemans et al., 2004) and it is well established that pats of the thalamus fom an integal pat of the declaative memoy system (Aggleton and Bown, 1999). It theefoe appeas that the globus pallidus and the thalamus ae well suited to egulate one fom of stategic memoy etieval. In inteaction with the pefontal cotex, the globus pallidus and thalamus may select and oganize infomation etieved fom the medial tempoal lobe memoy system, thus extending the ole of the basal ganglia in pocessing sequences to the declaative memoy system. In conclusion, ou study povides new evidence fo diffeential involvement of distinct neual coelates in diffeent types of stategic memoy etieval and shows that the ole of the basal ganglia in pocessing sequences extends to the declaative memoy system. 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