Dissociating prefrontal contributions during a recency memory task

Transcription

1 Neuropsychologia 44 (2006) Dissociating prefrontal contributions during a recency memory task M.N. Rajah a,, A.R. McIntosh b a Helen Wills Neuroscience Institute, University of California, 132 Barker Hall MC #3190, Berkeley, CA , USA b Rotman Research Institute of Baycrest Centre, University of Toronto, Ont., Canada M6A 2E1 Received 30 July 2004; received in revised form 3 June 2005; accepted 9 June 2005 Available online 26 July 2005 Abstract Neuroimaging studies of normal young adults have consistently found right prefrontal cortex (RPFC) activity during the performance of recency memory tasks. However, it is unclear whether the involvement of RPFC during these tasks reflects retrieval processes or executive processes such as: strategic ordering or monitoring. In the current study, we distinguish between those PFC regions that are more related to retrieval processes, versus strategic ordering processes. An event-related fmri study was conducted in which eight young subjects were scanned while performing verbal episodic retrieval tasks (recognition and recency memory tasks), and verbal non-memory strategic organizing control tasks (reverse alphabetizing of words). The fmri results show that young subjects engaged right dorsolateral PFC during recency and reverse alphabetizing control tasks. Left ventral PFC was engaged across all tasks; however, a subset of voxels within this region was more active during retrieval tasks. Left dorsolateral and right ventral PFC activity was more related to the performance of reverse alphabetizing tasks, respectively. We conclude that right dorsolateral PFC activity during recency memory reflects more general strategic organizational or monitoring processes, and is not EM-specific Elsevier Ltd. All rights reserved. Keywords: Episodic memory; fmri; Context memory; Recognition memory 1. Introduction Episodic memory (EM) was originally defined as a form of memory specialized in encoding, storing and retrieving temporally dated perceptual information pertaining to events from ones personal past (Tulving, 1972, 1984). Each event can be broken down into the salient focal element or elements of attention (content/item memory) and the temporal spatial setting in which an episode occurred (context memory) (Tulving, 1972, 1984). Behavioral studies have shown that healthy young adults perform with greater accuracy on content memory tests, such as item recognition tests, compared to context memory tests, such as source and temporal order/recency memory tests (Brown & Craik, 2000; Cabeza, Anderson, Houle, Mangels, & Nyberg, 2000; Dobbins, Foley, Schacter, & Wagner, 2002; Dobbins, Rice, Wagner, & Schacter, 2003). There are a growing number Corresponding author. Tel.: ; fax: address: mnrajah@berkeley.edu (M.N. Rajah). of neuroimaging studies that indicate that these behavioral differences may be related to the engagement of different prefrontal cortex (PFC) regions when subjects retrieve content versus context information. For example, neuroimaging studies comparing source and item memory in healthy young adults have identified increased activation in left anterior, ventrolateral and dorsolateral PFC during source retrieval compared to item retrieval (Kahn, Davachi, & Wagner, 2004; Nolde, Johnson, & D Esposito, 1998; Ranganath, Johnson, & D Esposito, 2000). In contrast, neuroimaging studies that have compared recency memory to item memory have found greater activation in right anterior and dorsolateral PFC during recency task performance, compared to recognition memory (Cabeza et al., 2000; Dobbins et al., 2003). Recognition memory task performance is related to activity in right lateral and bilateral ventrolateral PFC regions (Henson, Rugg, Shallice, Josephs, & Dolan, 1999a; Ranganath, Cohen, Dam, & D Esposito, 2004a). Taken together, these findings indicate that, behaviorally, context retrieval is more difficult than content retrieval, and on a /$ see front matter 2005 Elsevier Ltd. All rights reserved. doi: /j.neuropsychologia

2 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) neural level, context retrieval engages distinct PFC regions from those involved during content retrieval; though there is overlap in the regions engaged as well. However, assuming there are regional differences in process-specificity within the PFC, it is still uncertain whether the cognitive processes mediated by these various PFC regions during content versus context retrieval are related to these regions roles in different retrieval processes, such as reactivation, retrieval success or being in retrieval mode, or to their roles in different executive processes, such as monitoring or strategic organization (Cabeza, Locantore, & Anderson, 2003; Dobbins, Simons, & Schacter, 2004; Henson, Rugg, Shallice, & Dolan, 2000; Henson, Shallice, & Dolan, 1999b; Johnson, Hashtroudi, & Lindsay, 1993; Milner, Petrides, & Smith, 1985; Milner, McAndrews, & Leonard, 1990; Mitchell, Johnson, Raye, & Greene, 2004; Moscovitch & Winocur, 2002; Stuss & Alexander, 2000; Stuss & Benson, 1987). Several cognitive models have been put forth to account for the aforementioned behavioral differences observed during context versus content memory task performance (Dobbins, Khoe, Yonelinas, & Kroll, 2000; Jacoby & Dallas, 1981; Yonelinas, Dobbins, Szymanski, Dhaliwal, & King, 1996; Yonelinas, 2001). However, recent behavioral and neuroimaging studies have favored the dual-process perspective when interpreting behavioral and brain activation differences in context versus content EM retrieval (McKenzie & Tiberghien, 2004; Ranganath & Rainer, 2003; Ranganath et al., 2004b; Yonelinas, 2001; Yonelinas et al., 1996). According to the dual-process model, content memory tasks, such as item recognition, are performed by predominantly using familiarity-based retrieval (though recollection-based retrieval processes may also be engaged); whereas, context memory tasks, such as source memory tasks, place greater demands on recollection-based retrieval since they require subjects to retrieve more detailed information (Dobbins et al., 2002, 2003; Yonelinas, 2001; Yonelinas et al., 1996). It has also been posited that familiarity-based retrieval engages heuristic decision processes that are involved when trying to retrieve undifferentiated information from memory and recollection-based retrieval engages systematic decision processes, thus relying more on executive processes such as monitoring and strategic organization (Cabeza et al., 2003; Dobbins et al., 2002, 2004; Mitchell et al., 2004; Ranganath et al., 2004b). Thus, according to this model the difference between content and context memory tasks can be operationalized by the degree to which they engage familiarity-based versus recollection-based retrieval processes, respectively. Based on this perspective, right lateral PFC activations observed during item recognition have been interpreted as reflecting a familiarity-based retrieval processes and the left PFC activations observed during source recognition have been interpreted as reflecting recollectionbased retrieval processes (Dobbins et al., 2002; Mitchell et al., 2004; Ranganath et al., 2000; Ranganath et al., 2004b). More recently, neuroimaging studies have examined whether these familiarity-based and recollection-based retrieval processes could be fractionated further into more specific cognitive processes, mediated by distinct PFC regions. For example, Dobbins et al (Dobbins et al., 2002) had subjects perform semantic encoding, item memory and source memory tasks while undergoing fmri scans. It was hypothesized that by comparing activations across these three tasks they would be able to dissociate those left PFC regions that were related to lexical maintenance (common to all three tasks), retrieval cue specification (common to semantic encoding and source memory) and recollection monitoring (source memory only). They found left anterior ventrolateral activation to be related to cue specification, left dorsolateral and frontopolar activation to be related to recollection monitoring, and left posterior ventrolateral activation to be related to lexical maintenance. Comparisons of PFC activation patterns across a variety of neuroimaging and ERP studies examining recognition memory suggests that the right lateralized PFC activations may be related to familiarity-based monitoring processes that are engaged when it is difficult to discern whether a stimulus is old or new due to a lack of detailed recollection (Rugg, Fletcher, Frith, Fracowiak, & Dolan, 1996; Rugg, Fletcher, Chua, & Dolan 1999; Rugg, Henson, & Robb, 2003). Monitoring refers to the ability to verify whether information retrieved from EM is appropriate for the task at hand (Henson et al., 2000; Henson et al., 1999b; Rugg et al., 1999). Therefore, the increased right PFC activations observed during recency memory tasks versus source and recognition memory tasks have also been interpreted as reflecting increases in familiarity-based, heuristic, monitoring processes. For example, in an event-related fmri study comparing PFC activations during the performance of source versus recency memory, Dobbins et al. (2003) found greater left anterior PFC activity during correct source judgments and greater right anterior and dorsolateral PFC activity during recency judgments. Increased right PFC activity during recency memory was interpreted as reflecting greater heuristic-based monitoring demands. According to this interpretation both recognition and recency tasks are assumed to involve the reactivation of undifferentiated information (familiarity-based retrieval) and heuristic-based decision and monitoring processes. Thus, the increased right PFC activity observed during recency tasks versus source and item recognition, is believed to reflect greater engagement of these processes when one makes recency judgments. It is assumed from this operational definition that judgments of recency do not require the retrieval of temporal information nor do they require the recruitment of unique recency-related processes. However, Dobbins et al. (2003) do note that an alternate explanation for this increased right lateralized PFC activation during recency memory tasks is, that these regional activations reflect temporal recollection processes that are different from the recollective processes engaged during source retrieval. Therefore, the increased right PFC activity during recency memory may reflect, increases in heuristic-based decision

3 352 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) processes and monitoring or greater temporal recollection, respectively. Yet another alternate explanation of this increased right PFC activation during recency tasks is, that this right PFC activity reflects the implementation of strategic processing. Strategic processing has been defined as, the ability to apply a rule, to organize information, according to task demands (Moscovitch & Winocur, 2002). For example, Moscovitch & Winocur, (2002) Working-with-memory theory of PFC function in EM hypothesizes that the PFC mediates memory performance on strategic, explicit memory tasks. The PFC is believed to be vital in controlling retrieval search and organizing retrieved information (Moscovitch & Winocur, 2002). Interestingly, Milner (1982); Milner et al., (1985); Milner et al., (1990); Milner and Petrides (1984); have shown that damage to right PFC results in deficits in temporal ordering and sequencing of information, which has been interpreted as reflecting deficits in strategic organization (Mangels, 1997). Therefore, it is possible that the increased right PFC activity, observed during recency task performance, may be related to the implementation of general strategic organizational processes such as ordering and sequencing (McAndrews & Milner, 1991; Milner et al., 1985, 1990; Moscovitch & Winocur, 2002). Thus, there are several possible interpretations for the increased right PFC activity during recency memory tasks that are dependent on how one operationalizes these tasks. In the current fmri study we aim to examine whether the right PFC involvement during recency memory tasks is related to retrieval processes, such as familiarity-based retrieval, reactivation or being in retrieval mode, or to more general, executive, strategic organization processes. To do so, first, the following operational definition for recency tasks was assumed: recency tasks are performed by first requiring the retrieval of episodic information, followed by the strategic organization/ordering of stimuli, based on either the systematic recollection of temporal information or relative feelings of familiarity, to make the desired motor response. According to this definition, monitoring processes would still be more engaged during recency tasks, since these tasks require the use of multiple processes and sometimes also require multiple responses (McAndrews & Milner, 1991; Milner et al., 1985, 1990). Several points should be noted based on this operational definition. First, we do not take a stance on whether recency judgments involve greater temporal recollection versus greater familiarity-based retrieval, compared to item recognition. Instead, the focus of the current operational definition is on whether recency judgments require greater strategic organization processes, compared to item recognition tasks. It is also important to note, that strategic organization is defined as a general ordering computation that would be observed in any task requiring rule-based organization and the controlled sequencing of information. In this study, subjects will perform verbal recognition, verbal recency and reverse alphabetizing tasks while undergoing fmri scans. Assuming the preceding operational definitions, we predict that PFC regions that are more active during both EM tasks, versus reverse alphabetizing tasks, may be related to retrieval processing. However, based on the current experimental design, it is not possible to distinguish between specific retrieval processes such as: familiaritybased retrieval, temporal retrieval, retrieval success or being in retrieval mode. In contrast, we also predict that PFC regions that are more active during recency and reverse alphabetizing tasks, versus recognition tasks, may be related to general strategic ordering processing. In addition, a difficulty manipulation is incorporated into the current experimental design, in an attempt to dissociate those PFC activations that are more related to increases in task effort, versus, EM retrieval or strategic organization. 2. Methods 2.1. Subjects Seventeen healthy young right-handed adults (four males and 13 females) between the ages of 21 and 35 (mean age = 26.94) participated in the behavioral portion of this study. Eight of these young adults were part of the fmri portion of this study and their data were collected while in the scanner (fmri subjects). The remaining behavioral subjects were run outside of the scanner (behavioral subjects). There were no differences in behavioral performance based on whether the data were collected inside the scanner versus outside (p > 0.05); thus, the behavioral data from both pools of subjects were combined in the behavioral analysis section of this study. All subjects were screened for any history of major medical, neurological and psychiatric disorders. Those subjects who agreed to participate provided informed consent and the experiment was conducted with approval from the Ethics Review Board of Baycrest Geriatric Centre, University of Toronto Behavioral methods Subjects were told when they were recruited for the study that they would be participating in a visual verbal memory experiment. Subjects performed the following 20 tasks in a single experimental session: eight encoding tasks, four recognition tasks, four recency tasks and four reverse alphabetizing tasks. All tasks were visually presented, and subjects were required to make a key-press response for the retrieval and reverse alphabetizing tasks, respectively. The entire behavioral procedure took approximately 1.5 h. During the encoding tasks subjects were presented with a list of 16 concrete words. Subjects were told to intentionally commit both the items and the temporal order, in which they were presented, to memory. The word lists used in the current study have been used in previous word list learning studies by Stuss and colleagues (Stuss et al., 1994; Stuss, Craik, Sayer,

4 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) Franchi, and Alexander, 1996). The encoding lists that preceded each of the memory tasks were counterbalanced such that all encoding lists had an equal chance of preceding either recognition or a recency memory task across subjects. Subjects did not know during encoding which type of memory task would follow. Approximately 1 min after each of the encoding tasks the subjects performed one of the retrieval tasks. In the recognition tasks eight pairs of words were presented. Each pair consisted of one old, previously seen, word and one new word. Subjects were instructed to only respond to the old word, that they remembered seeing from the previous encoding list. The recency memory tasks also involved the presentation of eight word pairs. However, in this task each word pair consisted of two old words, from the preceding encoding list. Subjects were instructed to only respond to the most recently seen word: the word that was later in the encoding lists. The two words for each recency trial varied in the number of interleaved words that separated them at encoding, thus the temporal distance, between recency word pairs, varied randomly. Prior cognitive research indicates that, if, there are six or more stimuli between the encoding, and subsequent retrieval, of a particular stimulus, or if, there is a 1 min interval between encoding and retrieval, then, the information is being retrieved from secondary/long-term memory (Gershberg & Shimamura, 1994; Simon, Leach, Winocur, & Moscovitch, 1994; Tulving & Colotla, 1970). Thus, when taking into account this information, and the 1 min interval between encoding and retrieval, it is assumed that the majority of the retrieval task stimuli were being retrieved from long-term (secondary) memory. In fact, based on this framework, only three words from the retrieval lists employed were retrieved from primary memory. Thus, the behavioral responses to these stimuli may have been based on recency effects. Subjects also performed reverse alphabetizing tasks (strategic control tasks) in which they were presented with three words on the monitor, and asked to order them in reverse alphabetical order from Z to A. Eight sets of three words (word trios) were presented consecutively and each trial required three responses. The word trios were on the computer monitor while subjects reverse alphabetized them; therefore, there was minimal episodic memory retrieval, or working memory maintenance processing during this task. This task served as a control for general strategic organization which was operationalized as: a general ordering computation that would be observed in any task requiring rule-based organization and controlled sequencing of information, and could be considered a type of working memory manipulation process. Unbeknown st to the subjects there was a difficulty manipulation incorporated into the experiment. The easy/difficult manipulation employed for the retrieval tasks involved using semantically related and unrelated words during encoding. Recency memory for semantically related words, compared to semantically unrelated words, has been found to be more difficult (Mangels, 1997). Yet, semantically related word lists are better recognized, compared to semantically unrelated word lists (Smith, Theodor, & Franklin, 1983). Behavioral pilot studies, confirmed that this semantic manipulation did affect retrieval success, thus showing that this was a valid difficulty manipulation. There were four encoding lists that contained semantically related words and four that contained semantically unrelated words. Each of the semantic encoding lists, and non-semantic encoding lists, were counterbalanced, so that each list could be followed by either recognition or a recency task, respectively. Thus, there were two recognition tasks performed using semantically related encoding lists (recognition easy tasks; RgE), two recognition tasks performed using semantically un-related lists (recognition difficult tasks; RgD), two recency tasks performed using semantically related lists (recency difficult tasks; RD) and two recency tasks performed using semantically un-related lists (recency easy tasks; RE). The easy/difficult manipulation for the strategic control tasks involved manipulating the orthographic similarity of the words to be reverse alphabetized. In the two difficult versions of this task (reverse alphabetizing difficult tasks; AD) each of the word trio trials consisted of words that were similar looking (the first letters of the words were the same) for example, BRUNCH BROOK BRIDGE. In the two easy versions of this task (reverse alphabetizing easy tasks; AE) each of the word trio trials were very dissimilar, orthographically; for example, DRESS CARROT HEART. Prior to the experiment, subjects were run through examples of each task, to ensure that they understood the instructions, and were comfortable with the motor responses required for each task Stimulus presentation and apparatus E-prime 1.0 (Beta 4 version) by Psychology Software Tools Inc. (Pittsburgh, PA, USA) was used to program, run and collect reaction time (RT) and accuracy (ACC) data for all experimental tasks. The encoding tasks consisted of pseudorandomized presentations of 16 real events (in which a verbal stimulus was presented) and 16 null events (in which a fixation cross was presented). Each of these stimulus events was 4 s with a 2 s ITI. During the ITI a fixation-cross appeared on the screen. Thus, the null events and ITI were in discriminable, visually. However, they each served a different purpose during fmri data analysis (mentioned below). The encoding task was 3 min and 24 s in length. During each of the retrieval tasks eight word pairs and eight null events were presented. Each event was 4 s long with an ITI of 2 s. Subjects had to make the motor response during the 4 s that the stimulus was presented. The retrieval tasks were 1 min and 47 s long, each. Eight word trios and eight null events were presented during each reverse alphabetizing task, respectively. Each stimulus event was 8 s in length with an ITI of 2 s. Subjects had to make their motor responses to the word trios within the 8 s that they were presented. The reverse alphabetizing

5 354 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) tasks were 2 min and 52 s long, each. The reverse alphabetizing task required a longer presentation rate than other tasks due to the number of motor responses required in that task. The apparatus used to visualize the stimuli and make responses differed between behavioral and fmri subjects. Also, fmri subjects were lying down in the fmri scanner while performing these tasks. For fmri subjects the visual stimuli were presented to them through fiber optic binocular goggles (Silent Vision 4000 Avotec, Jensen Beach, FL, USA). FMRI subjects made their motor response using both hands and a four-button fiber optic, response system (Lightwave Medical Industries Ltd. Burnaby, BC, Canada). For behavioral subjects the stimuli were presented on a computer monitor positioned perpendicular to their line of sight, and they made responses using a standard computer keyboard Behavioral analysis SPSS for Windows (version 11.01) was used to conduct the behavioral analyses. Within group, repeated measures, 3 2 analysis of variance (ANOVA) was conducted on the subjects RT and ACC measures, respectively, to test for the main effects of task and difficulty, and the task-by-difficulty interaction effect. Nine, planned, two-tailed paired t-tests, were also conducted using Excel for Windows 2000 to clarify the ANOVA results fmri methods After the behavioral protocol was explained to the fmri subjects, and they viewed examples of the tasks they would perform, they were asked to lie down in a 1.5T Signa MRI scanner (CV/i hardware, LX8.3 software; General Electric Medical Systems, Waukesha, WI) equipped with a standard head coil, and attached goggles. Prior to each task, subjects were given verbal instructions by the experimenter using a microphone that was audible to the subject in the MRI scanner room. Prior to starting the fmri acquisition, a structural MR image was acquired (3D T1-weighted gradient echo pulse sequence, TR = 12.4 ms, RE = 5.4 ms, flip angle 35, FOV, acquisition matrix, 124 axial slices with slice thickness of 1.4 mm). As subjects performed the experimental tasks described above, functional brain images reflecting regional changes in BOLD response were acquired using a single shot T2 * -weighted gradient echo pulse sequence, with spiral readout, and off-line griding and reconstruction (TR = 2000 ms, RE = 40 ms, FOV = 20, flip angle = 80, effective acquisition matrix). Twenty-four axial slices of 5.0 mm thickness were acquired per functional scan Stimulus presentation and experimental design A stochastic, rapid presentation, mixed, event-related fmri design was employed. Real and null events were rapidly presented, in pseudo-random order, within each experimental block (Dale & Buckner, 1997; Friston, Zarahn, Josephs, Henson, & Dale, 1999). Each block consisted of one of the following real (as opposed to null) event types, interspersed with null events: encoding, recognition, recency or reverse alphabetizing tasks, respectively. This design is referred to as a mixed design since it has both real and null events randomly presented within a block so that event-related information for real events could be discerned. Each block corresponded to one of the 20 behavioral tasks described above. Therefore, there were 20 blocks in total. The use of null events within each block reduced the acquisition time for the fmri images. As mentioned above, each of the 20 blocks contained an equivalent number of real and null events. Within each block/task, real and null events were of equal length, and they were presented in a pseudo random order. Therefore, the null events served as baselines for the real events. Null events were also used to incorporate a temporal jitter by varying the time between the presentations of real events. The rapid presentation rate (ITI=2s)allowed for a shorter experimental duration. Rapid presentation of stimuli causes an overlap in the HR of the two closely presented stimuli, which could obscure event-specific BOLD responses. However, previous eventrelated fmri studies have shown that the overlap of the HR that occurs with two rapidly presented events is generally linearly additive (Dale & Buckner, 1997). Therefore, the HR to a particular event can still be deconvolved, even with rapidly presented events. The jittered presentation, used in the present experiment, also helps the deconvolution of event-specific BOLD responses across time, for closely timed events, thereby maximizing the detection of event-related BOLD response for rapidly occurring events (Friston et al., 1999) Image processing The anatomical and functional images were reconstructed from raw k-space, to image space, and the analysis of functional neuroimages (AFNI) software, Version 2.31i, was used to reformat, pre-process and statistically analyze the fmri images (Cox, 1996a,b; Ward, 2001). For each subject, the functional images acquired across blocks were first spatially realigned to one image, to correct for head motion using a 3D Fourier transform interpolation (Cox, 1996a,b). The functional images for the onset of each event, plus the 5 time lags (i.e., 5 TRs) following each real event (for a total of 6 lags: lag 0 to lag 5), were extracted and compared to an equivalent time span for the null events, using the AFNI program 3dDeconvolve (Cox, 1996a, 1996b; Ward, 2001). The extraction was performed separately for each block/task, and for each subject. A multiple linear regression analysis was then conducted on the extracted events, to identify the best linear fit for the BOLD response of each voxel, at each of the time lags. The best fit for a lag was used to estimate the impulse response function across time for each voxel, for a given task (Ward, 2001). Each extracted image represented the difference images between a real versus a corresponding null event. The

6 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) extracted difference images for all subjects were then individually normalized to Tailarach coordinate space using a linear transform as implemented in AFNI (Talairach & Tournoux, 1988). The average, normalized, images were smoothed using a 6 mm full-width-half-maximum (FWHM) Gaussian filter to control for individual anatomic variability and facilitate the subsequent within group statistical image analyses Image analysis A within group random effects repeated measures ANOVA, with specified a priori contrasts, was conducted to examine regional changes in BOLD response across tasks. The repeated-measures factor was task (t) and it had six levels corresponding to the following tasks, respectively: reverse alphabetizing difficult condition (AD), reverse alphabetizing easy (AE), recency difficult (RD), recency easy (RE), recognition difficult (RgD) and recognition easy (RgE). The images included in the ANOVA were the smoothed and Tailarach-normalized, extracted image at the time lag of 3 (6 s after event), for each subject, in each of the six conditions. Only voxel clusters with F-value equal to or greater than 2.53, p < 0.05 uncorrected, and cluster size greater than 20 mm 3, were identified as displaying a significant difference in BOLD response across tasks. Preplanned contrasts were conducted to examine task differences in activation for those voxels that showed a significant task main effect. Table 1 presents the contrasts used to examine task differences and the experimental question that each contrast addresses. For each contrast, a t-statistic was calculated for each voxel to determine whether there was a contrast-related change in BOLD response within that voxel. Regional changes were considered significant if the voxel clusters had a t-value > 3.0, which corresponds to an alpha of 0.005, and had a minimum cluster size of 20 mm 3. This significance level was chosen because the focus of this study was only prefrontal cortex rather than the entire brain image. The time course of activity for each peak voxel, from each PFC activation observed from the AFNI contrast results was plotted. These graphs depict the standardized raw activity (percent signal change) from event-onset (time 0) to the seventh TR (14 s) after event-onset. These time courses were not modeled to fit the hemodynamic (gamma) function since the AFNI analysis was based on impulse response function data. However, only those significant PFC regions in which the peak voxel exhibited a time course plot that resembled a plausible hemodynamic response function (HRF) were considered valid, contrast-related activations. 3. Results 3.1. Behavioral results The reaction time (RT) data are presented in Fig. 1a. The results of the 3 2 repeated measures ANOVA indicated that there were significant task (F (2, 32) = , p < 0.001) and difficulty (F(1, 16) = , p < 0.001) main effects. There was also a significant task-by-difficulty interaction (F(2, 32) = 70.20, p < 0.001). The planned paired t-tests indicated that the significant task main effect was due to the subjects RT during recognition tasks being significantly faster than recency and reverse alphabetizing tasks, and the subjects RT during recency tasks being significantly faster than in the reverse alphabetizing tasks, collapsed across difficulty level (Rg versus R, p < 0.001; Rg versus A, p < and R Table 1 AFNI contrasts tested in the within group ANOVAs Contrast coded Rationale Contrast 1 [ 2, 2, 1, 1, 1, 1] To identify regions that are on average differentially engaged during Effect EM tasks vs. A tasks (R + Rg vs. A) episodic retrieval tasks (R and Rg) vs. non-episodic tasks (A) Contrast 2 [1, 1, 2, 2, 1, 1] To identify regions that are preferentially related to strategic Effect Strategic ordering tasks vs. non-strategic tasks (A + R vs. Rg) processing of information, regardless of memory involvement, (A + R) compared to non-strategic memory tasks (Rg). To identify those regions involved in R that are not related to episodic retrieval, but related to the strategic component of the task. Contrast 3 [1, 1, 1, 1, 1, 1] To identify regions related to effortfulness or difficulty of tasks Effect Difficult tasks vs. easy tasks (D vs. E) regardless of task type Contrast 4 [1, 1, 0, 0, 1, 1] To identify regions that are more active when there are greater Effect Alphabetizing vs. recency (A vs. R) number of stimuli and responses (A) and examine whether prefrontal activations during strategic tasks (A and R) are related to these confounds Contrast 5 [0, 0, 1, 1, 1, 1] To identify regions preferentially involved during episodic retrieval Effect Recency vs. Recognition memory tasks (R vs. Rg) when task involves strategic processing of episodic information (R) vs. simple episodic retrieval (Rg) Note: Task ordering of the functional images used for the within group ANOVA, was as follows: AD, AE, RgD, RgE, RD, RE. Each task-related functional image represented the average activations between the two runs of the task.

7 356 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) Fig. 1. Behavioral results. (a) Mean reaction time (RT), in milliseconds, for participants across all behavioral tasks. (b) Mean accuracy data (percent correct) for participants across all behavioral tasks. RgE: recognition easy, RgD: recognition difficult, RE: recency easy, RD: recency difficult, AE: reverse-alphabetizing easy, AD: reverse-alphabetizing difficult. versus A, p < 0.001). The significant difficulty main effect and task-by-difficulty interaction was due to the subjects RT during difficult task versions being significantly slower for the reverse alphabetizing tasks (AD versus AE, p < 0.01) and for the recency tasks (RD versus RE, p < 0.01). There were no significant difficulty effect between RgE and RgD tasks (p > 0.05). Fig. 1b contains a bar graph of the mean accuracy (percent correct) across all six behavioral task conditions. The within group repeated measures 3 2 ANOVA indicated there were significant task (F(2, 32) = 30.57, p < 0.001) and difficulty (F(1, 16) = 8.12, p = 0.012) main effects. There was also a significant task-by-difficulty interaction (F(2, 32) = 8.53, p = 0.001). The significant task main effect was due the subjects accuracy performance during Rg tasks being significantly better than R and A tasks, respectively (p < 0.001). However, the subjects accuracy performance during R and A tasks were not significant different (p > 0.20). The significant difficulty main effect and task-by-difficulty interaction was due to the subjects performing significantly worse during RD tasks versus RE tasks. There were no significant difficulty effects for Rg tasks (RgE versus RgD, p > 0.05) and for A tasks (AE versus AD, p > 0.05) fmri results AFNI results The ANOVA result indicated there was a significant main effect of task (F(5, 35) = 2.53, p < 0.05 uncorrected for multiple comparisons) in a large number of voxels across tasks. These activation differences included voxel clusters in bilateral superior frontal gyrus, bilateral inferior frontal gyrus and bilateral middle frontal gyrus. Table 2 lists the significant (p < 0.005, uncorrected) PFC activations for each of the pre-specified a priori contrasts. Only those regions for which the time course of activity for

8 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) Table 2 Within group PFC activations for the a priori contrasts Stereotaxic coordinates Contrast effect T-statistic for voxel Spatial extent of regional activity (# of voxels) X Y Z Gyral location BA HEM Contrast 1: EM vs. A tasks EM > A tasks Inferior frontal gyrus 47 L A > EM tasks Middle frontal gyrus 46 L Inferior frontal gyrus 44/45 R Middle frontal gyrus 9 R Contrast 2: strategic vs. non-strategic tasks Strategic > non-strategic tasks Middle frontal gyrus 9 R Non-strategic > strategic tasks Middle frontal gyrus 10 L Contrast 3: difficult vs. easy tasks n.s. voxels Contrast 4: alphabetizing vs. recency tasks A > R tasks Inferior frontal gyrus 44 R Inferior frontal gyrus 47 L Middle frontal gyrus 6 R R > A tasks Inferior frontal gyrus 47 L Contrast 5: recency vs. recognition tasks Recency > recognition tasks Inferior frontal gyrus 45 L Recognition > recency tasks Inferior frontal gyrus 45 L Note: The T-values represent the value for local maxima which had a p < The spatial extent refers to the total number of voxels included in the voxel cluster. The stereotaxic coordinates are measured in mm and the gyral locations and Brodmann areas (BA) were determined by reference to Talairach and Tournoux (1988). HEM refers to the cerebral hemisphere (L for left: R for right: M for medial) in which the activation occurred. the peak voxel resembled a plausible HRF, and for which activity was consistent with the contrast effect, are reported. Activation sites that were either near areas suffering from susceptibility artifact or on the antero-lateral edge of the brain were excluded due to noisy HRFs. Thus, only the robust experimental effects are reported in this manuscript. The results for contrast 1 (EM tasks versus reverse alphabetizing (A) tasks) shows that on average, A tasks recruited bilateral middle frontal (MFG, Brodmann area [BA] 46 and BA 9) and right inferior frontal gyrus (IFG; BA 44 or 45) compared to EM tasks. In contrast, the averaged EM tasks only showed greater activity in left IFG (BA 47) compared to the averaged A tasks. Contrast 2 identified those brain regions that were on average more active during tasks requiring greater strategic organizing (A + R; strategic tasks) compared to tasks requiring less strategic organizing (Rg; non-strategic tasks). This contrast was conducted to examine which, if any, right PFC areas traditionally recruited during R tasks (Cabeza et al., 2000; Dobbins et al., 2003) were common to general strategic ordering process, which would be common to R and A tasks, based on the operational definitions adopted in the current study. Mean activity across strategic tasks was greater in right MFG (BA 9), compared to Rg tasks. Mean activity during non-strategic Rg tasks was greater in left anterior MFG (BA 10), compared to the mean activity across strategic tasks. The third contrast identified those brain regions with a differential average activity between all easy (E) tasks versus all difficult (D) tasks, regardless of task type. Surprisingly, there were no significant voxels at the threshold specified within PFC that differentiated D and E tasks, and also exhibited a stable HRF. The fourth contrast compared mean activity during recency memory (R) tasks versus mean activity during A tasks. The average activity across A tasks was greater in bilateral IFG (BA 47 and 44) and right precentral gyrus (BA 6), compared to the average activity across R tasks. However, there was greater activity in a different region within left IFG (BA 47) during R versus A tasks. Interestingly, the right MFG (BA 9) region that was more active during strategic versus non-strategic tasks (see contrast 2 results), was not differentially active during A or R tasks, since this region did not show up in contrast 4. Fig. 2a presents the right MFG (BA 9) activity from contrast 2, and the results for this same region from contrast 4. Since, the focus of this paper was to understand right PFC contributions to recency memory, the time courses for the peak right MFG (BA 9) voxels identified from contrasts 1 and 2 were plotted and are presented in Fig. 2b, for the three tasks, averaged across difficulty (since the AFNI results show that this region was not sensitive to the difficulty manipulation). The time course plot for contrast 1 BA 9 voxel indicates that this, more anterior, BA 9 region showed an interpretable time course pattern for R and A tasks, but not Rg tasks. However, the time course for the contrast 2 BA 9 voxel indicates that this more posterior region was engaged across all three tasks; but, was more active during the recency (R) and the strategic control (A) tasks. Together

9 358 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) Fig. 2. AFNI results. (a) Presents the AFNI results for contrast 2, on the left hand side, and contrast 4, on the right hand side, at p < uncorrected. A single coronal slice at Y = +12 mm, for each contrast, is presented in Talairach and Tournoux (1988) space. The left side of the image corresponds to the right side of the brain. For contrast 2 the regions colorized in yellow were more related to A and R tasks vs. Rg Tasks based on the multiple regression results, and included right middle frontal gyrus (MFG; BA 9) which is circled in red. Regions colored in blue were more related to the Rg tasks. For contrast 4, the regions colorized in yellow were more related to A tasks vs. R tasks and regions colorized in blue exhibited the opposite effect. It is clear from these AFNI results that the right MFG region that was commonly engaged during both A and R tasks in contrast 2, was not differentially engaged between these two tasks since it does not appear in contrast 4, which directly compared A and R tasks. Thus, this region is similarly engaged in both A and R tasks. (b) Time course plots for right DLPFC (BA 9). These graphs show the percent signal change of the peak voxel, from the right BA 9 activations from contrast 1 and 2, for 14 s following an event-onset. These graphs show that the hemodynamic response within this region was similar for both R and A tasks and that activity in this region was greater during these tasks vs. the Rg tasks. This supports the idea that the process mediate by this region is similarly engaged during both A and R tasks. these data suggest anterior BA 9 is involved in mediating a cognitive process that is engaged during A and R tasks to a greater degree than Rg tasks. Contrast 5 identified brain regions that were differentially active during the performance of recency memory (R) versus recognition memory (Rg) tasks. Both EM tasks engaged different subregions within left IFG (BA 45). The peak activation within this region was more anterior during R versus Rg tasks Reconstructed time course analysis The time course analysis of the voxels from the left MFG and right IFG regions identified in the AFNI contrasts indicated that both of these two regions were related to the performance of A tasks. Moreover, the time courses of these regions were both noisy, and did not resemble a HRF, during Rg and R tasks, respectively. Fig. 3 presents the time course plots for the three left IFG, BA 47, activations that were identified in contrasts 1 and 4,

10 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) Fig. 3. Time course plots for left ventral PFC (BA 47) activations. These graphs show the percent signal change of the peak voxel within the left ventral PFC (BA 47) activations from contrasts 1 and 4, for 14 s following an event-onset. (i) Depicts the time course of activity for the BA 47 region that was more active during EM tasks compared to the A tasks in contrast 1. (ii) Depicts the time course of activity for the BA 47 region that was more active during the A vs. R tasks in contrast 4 (referred to as left 47a). (iii) Depicts the time course of activity for the BA 47 region that was more active during R vs. A tasks in contrast 4 (referred to as left 47b). These graphs show that the hemodynamic response within this region was similar for all three tasks, but (i) and (iii) suggest that there is more activity in this region during the EM tasks. respectively. These graphs verify the contrast effects. Moreover, they show that left BA 47 was recruited across all tasks (see Fig. 3ii left BA 47a), suggesting that the process mediated by this region was engaged across all tasks. However, the graphs for contrasts 1 and 4 (Fig. 3i and iii left 47b) indicates that subsets of voxels within this region may be more related to the performance of EM tasks. 4. Discussion In the current study we focused on PFC contributions to verbal recency memory. The goal of this study was to determine whether the right PFC activity, traditionally observed during recency memory tasks, was related to strategic organizational processes or to retrieval processes (Cabeza et al., 2000; Dobbins et al., 2002, 2003). To address this point, subjects were scanned while performing verbal recency memory, recognition memory and strategic organizational control tasks. We rationalized that if, the right PFC activity traditionally observed during recency memory tasks was related to strategic organizational processes, then, there would be greater right PFC activity during both recency memory and strategic organizational control tasks versus recognition memory tasks. In contrast, if the right PFC activity traditionally observed during recency memory tasks was related to retrieval processes, such as reactivation or being in retrieval mode, then, greater activity in right PFC would be observed during both recency and recognition memory tasks, versus the strategic organizational control task. Since the design of this experiment was not aimed at dissociating amongst retrieval processes, we do not attempt to differentiate amongst them in our interpretations. The behavioral results from the current study corroborate previous findings. Subjects exhibited longer reaction times (RTs) during recency tasks compared to recognition tasks. However, subjects RTs were longest during strategic control (A) tasks. This is not surprising since these tasks required three button presses during the response period, whereas the memory tasks required only one button press. The observation that subjects were slowest on AD tasks suggests, that the perceptual similarity of the stimuli used in these tasks impaired alphabetizing. This may be due to the increased requirement of response inhibition during these tasks, due to the high level of stimulus similarity, which may have required subjects to suppress the desire to reverse alphabetize based on the first letter in the word, and instead process more of the word, to perform the task accurately. This idea is corroborated by Zeef, Sonke, Kok, Buiten, and Kenemans (1996), who found that in a flanker task, the increased feature similarity of letter stimuli, which were also in close spatial proximity to one another (as was the case during AD tasks in the current experiment), caused increased levels of stimulus interference and response inhibition, resulting in poorer task performance. The accuracy results from the current study also support previous findings (Tendolkar & Rugg, 1998): subjects were less accurate on recency tasks than on recognition tasks. Subjects were also more accurate on recognition tasks versus

11 360 M.N. Rajah, A.R. McIntosh / Neuropsychologia 44 (2006) reverse alphabetizing tasks. However, there was no significant difference between the accuracy scores of recency versus reverse alphabetizing tasks. The AFNI contrast results from the current study shows, there were several PFC regions that were differentially active across EM and reverse alphabetizing (strategic control) tasks, respectively (see Table 2). Moreover, the current results suggest that the right dorslolateral PFC (DLPFC; BA 9) activity, traditionally observed during recency tasks, may be related to general strategic organizational processes, since, right BA 9 was more active during recency and strategic control tasks compared to recognition tasks (see Fig. 2). There was also a region in left ventral PFC (VLPFC; BA 47) that was more active during EM tasks compared to strategic control tasks. Left DLPFC (BA 46) and right VLPFC (BA 45) were more active during the strategic control tasks versus the EM tasks. Since the focus of this study was examine PFC contributions to recency memory, in the following sections we discuss the possible cognitive processes mediated by the right DLPFC and left VLPFC Left ventral PFC involvement in EM retrieval Left ventral PFC was more active during EM tasks, versus reverse-alphabetizing tasks. Direct comparisons of the recognition versus recency memory tasks identified distinct regions within left ventral PFC that were differentially related to the performance of these two EM tasks. The time course plots, for the left BA 47 activations observed in these contrasts, show that activity in this region exhibited a similar pattern across all three tasks (see Fig. 3). However, the time courses also show that for two of the three BA 47 activations (Fig. 3i and iii), there was greater activity this region during EM versus reverse alphabetizing tasks. This latter observation confirms the AFNI contrast results. Previous fmri studies of EM have suggested that this region plays a EM-specific role. For example, left ventral PFC activity in BA 47 has been reported during both context and item retrieval (Dobbins et al., 2003; Kahn et al., 2004). In an fmri study of the remember/know paradigm, Henson et al. (1999a,b) found left BA 47 activity during both remember and know responses, versus responses for new items. Dobbins et al. (2003) found increased left ventral PFC activation during source versus recency memory, but activity in this region did not differ between successful versus unsuccessful source recollection. In a more recent study comparing source and item memory, Kahn et al. (2004) found left ventral PFC activity during both the retrieval of item only, and the retrieval of item plus source information. By examining activity during hits, misses, and false alarms, Kahn et al. (2004) concluded that this region did not differentiate across these three response types, and, that left ventral PFC activation during EM retrieval may not be related to retrieval success, but may instead, be related to retrieval attempt (Dobbins et al., 2003; Kahn et al., 2004). Unfortunately, in the current experiment, we did not have enough trials of hits, misses and false alarms, to conduct this analysis. However, the observation that the time course of activity for this region was similar across all tasks, including a non-em task (reverse alphabetizing task), suggests that activity in this region may be related to a more general, non-em specific, cognitive process. One possibility is that the retrieval attempt related activations in left anterior ventral PFC (BA 47) reflects the level of controlled semantic and/or phonological processing occurring at retrieval, which may not differ between hits, misses and false alarms (Gold & Buckner, 2002). This interpretation is consistent with results from several lines of neuroimaging research that have associated left ventral PFC activity with: depth of semantic processing at encoding and retrieval (Grady, Bernstein, Beig, & Siegenthaler, 2002; Lepage, Habib, Cormier, Houle, & McIntosh, 2000; Otten, Henson, & Rugg, 2001), lexical decisions (Binder et al., 2003) and maintenance of verbal information in WM tasks (D Esposito, Postle, Ballard, & Lease, 1999; Wager & Smith, 2003; Walter et al., 2003). Therefore, in the current experiment, it is likely that activity in this region was related to the level of semantic and/or phonological processing engaged, since, all tasks included concrete words, and thus, required some level of semantic processing. The increased left ventral PFC reported during EM tasks (see Table 2, AFNI contrast 1) might be due to EM retrieval tasks involving deeper levels of semantic access compared to reverse alphabetizing tasks (Gold & Buckner, 2002; Lepage et al., 2000) PFC regions involved in general strategic organization The AFNI results indicated that right DLPFC (BA 9) activity was most strongly related to the performance of reverse alphabetizing tasks versus EM tasks (contrast 1; see Table 2). In addition, this region was also found to be more active during recency and reverse-alphabetizing tasks, compared to recognition tasks (contrast 2). The time course plots for the two right DLPFC peaks from contrasts 1 and 2 show, that this region exhibited a similar hemodynamic response function, and more activity, during recency and reverse alphabetizing tasks, versus recognition tasks (see Fig. 2b). Taken together, these results indicate that right DLPFC activity was related to performing a cognitive process that was common, and more active, during both reverse-alphabetizing and recency tasks, relative to recognition tasks. One possibility is that the right DLPFC activity reflects strategic organizational processing during these tasks. More specifically, this activation may reflect a specific type of strategic organization: the strategic ordering of information. This interpretation is supported by previous neuropsychological and neuroimaging findings about EM, as well as by the working memory literature, which shows that the DLPFC is important for the manipulation of stimuli (McAndrews & Milner, 1991; Milner et al., 1990; Milner et al., 1985; Moscovitch & Winocur, 2002; Stuss & Benson, 1987; Stuss et al., 1996). In fact, the current result is consistent with the idea that right DLPFC activation during