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Human Brain Mapping 35:3687–3700 (2014)

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The Relationship Between Task-Related and Subsequent Memory Effects Marianne de Chastelaine* and Michael D. Rugg Center for Vital Longevity and School of Behavioral and Brain Sciences, University of Texas at Dallas, Texas r

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Abstract: The primary aim of this fMRI study was to assess the proposal that negative subsequent memory effects—greater activity for later forgotten relative to later remembered study items—are localized to regions demonstrating task-negative effects, and hence to potential components of the default mode network. Additionally, we assessed whether positive subsequent memory effects overlapped with regions demonstrating task-positive effects. Eighteen participants were scanned while they made easy or difficult relational judgments on visually presented word pairs. Easy and hard task blocks were interleaved with fixation-only rest periods. In the later unscanned test phase, associative recognition judgments were required on intact word pairs (studied pairs), rearranged pairs (pairs formed from words presented on different study trials) and new pairs. Subsequent memory effects were identified by contrasting the activity elicited by study pairs that went on to be correctly endorsed as intact versus incorrectly endorsed as rearranged. Task effects were identified by contrasting all study items and rest blocks. Both task-negative and task-positive effects were evident in widespread cortical regions and negative and positive subsequent memory effects were generally confined to tasknegative and task-positive regions respectively. However, subsequent memory effects could be identified in only a fraction of task-sensitive voxels and, unlike task effects, were insensitive to the difficulty manipulation. The findings for the negative subsequent memory effects are consistent with recent proposals that the default mode network is functionally heterogeneous, and suggest that these effects are not accurately characterized as reflections of the modulation of the network as a whole. Hum Brain Mapp 35:3687–3700, 2014. VC 2014 Wiley Periodicals, Inc. Key words: fMRI; memory encoding; episodic memory; associative recognition; default mode network r

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INTRODUCTION Additional Supporting Information may be found in the online version of this article. Contract grant sponsor: National Institute of Mental Health (NIH); Contract grant number: 1R01MH074528. *Correspondence to: Marianne de Chastelaine, University of Texas at Dallas, Center for Vital Longevity, 1600 Viceroy Drive, Suite 800, Dallas, TX 75235. E-mail: [email protected] Received for publication 13 June 2013; Revised 31 October 2013; Accepted 31 October 2013. DOI 10.1002/hbm.22430 Published online 14 February 2014 in Wiley Online Library (wileyonlinelibrary.com). C 2014 Wiley Periodicals, Inc. V

Numerous functional magnetic resonance imaging (fMRI) studies of episodic memory encoding have employed the subsequent memory procedure, in which fMRI BOLD activity elicited by study items is segregated according to performance on a later memory test [for reviews see Kim, 2011; Paller and Wagner, 2002]. Most typically, the neural correlates of successful encoding are identified by searching for where there is greater BOLD activity for study items that go on to receive accurate rather than inaccurate judgments on the later memory test. The results of these contrasts are known as “subsequent

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memory effects” or, to distinguish them from “negative” subsequent memory effects (see below), as “positive” subsequent memory effects. In the case of visually-presented items subjected to semantically-oriented study processing, positive subsequent memory effects are consistently identified in the left inferior frontal gyrus (LIFG) and the medial temporal lobe (MTL). These regions also demonstrate subsequent memory effects when item pairs are studied and associative rather than item memory is later tested [Kim, 2011]. Subsequent memory studies have invariably searched for regions where successfully encoded items elicit enhanced BOLD activity relative to unsuccessfully encoded items. Only a subset of these studies, however, also reported the outcome of the reverse contrast, identifying regions where successful encoding is associated with a relative decrement in study activity—referred to hereafter as ‘negative’ subsequent memory effects. Two early studies of these effects investigated the encoding of single words [Otten and Rugg, 2001; Wagner and Davachi, 2001; see Wagner et al, 1998, for the first description of negative subsequent memory effects]. In Otten and Rugg [2001] negative effects were identified in inferior parietal, medial parietal, posterior cingulate, and dorsolateral prefrontal cortices. The authors suggested that the enhanced activity for items that were less effectively encoded into memory reflected the allocation of resources away from processes that benefited encoding to processing unconnected with encoding, such as response selection. Negative subsequent memory effects were identified in a similar set of brain regions by Wagner and Davachi [2001]. Similarly to Otten and Rugg [2001], these authors suggested that the effects might reflect the diversion of resources away from processes that support effective encoding to the processing of task-irrelevant stimulus features or “irrelevant thoughts.” Wagner and Davachi [2001] also suggested that negative effects might reflect encoding of memory representations that are inaccessible on the later memory test. Daselaar et al. [2004] noted that the brain regions identified by negative subsequent memory contrasts tend to overlap those belonging to the “default mode network.” This term refers to a set of brain regions that demonstrate “task-negative” effects (i.e., greater activity during rest1 than during task engagement) and high resting state inter-regional functional connectivity [see Buckner et al., 2008, for a review]. It has been argued that the regions belonging to this network support internally-directed processes that must be disengaged to allow optimal allocation of cognitive resources to an external stimulus event [McKiernan et al., 2003; Raichle et al., 2001]. Accordingly, Daselaar et al. [2004] suggested that nega1 “Rest” is used here to describe the situation where participants are undergoing scanning while not performing an externally imposed task. The term is not meant to imply that participants are cognitively inactive, merely that their cognitive activity is unconstrained.

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tive subsequent memory effects largely reflect not enhanced activity (relative to an idealized baseline) for ‘forgotten’ study items but, rather, diminished activity for “remembered” items. Daselaar et al. [2004] obtained evidence consistent with this proposal by comparing the BOLD responses elicited by subsequently remembered and forgotten items relative to the implicit baseline derived from the General Linear Model employed to estimate item-related BOLD responses. They reported negative subsequent memory effects in many of the same regions originally identified by Otten and Rugg [2001] and Wagner and Davachi [2001]. The BOLD responses elicited by both remembered and forgotten items were below baseline in these regions. Daselaar et al. [2004] therefore suggested that negative subsequent memory effects largely index the extent to which a stimulus event elicits reallocation of resources away from processes supported by the default mode network to processes supporting successful encoding. Negative subsequent memory effects may however reflect more than just differential modulation of tasknegative responses. In addition to regions demonstrating below-baseline responses for subsequently remembered items, Daselaar et al. [2004] reported above-baseline activity for subsequently forgotten items in the left insula [insula activity at encoding has been associated with relatively poor memory performance in other studies also; Cabeza et al. 1997; Mattson et al., in press; Reynolds et al., 2004; Wagner and Davachi, 2001]. This finding highlights the fact that the direction (with respect to baseline) of generic task effects does not dictate the direction of the differences in activity elicited by different classes of items, in this case, later remembered versus later forgotten study items [see Gusnard and Raichle, 2001, for discussion of this point]. Additionally, a review by Uncapher and Wagner [2009] highlighted the consistency with which negative subsequent memory effects have been reported in the vicinity of the temporo-parietal junction (TPJ). This region has been hypothesized to form part of the “ventral attention network” that supports stimulus-driven attentional reorienting [see Corbetta et al., 2008, for a review]. Uncapher and Wagner [2009] proposed that negative subsequent memory effects in this region may reflect attentional capture by stimulus features that are not conducive to the formation of a durable memory representation. This proposal was explicitly tested by Uncapher et al. [2011], who reported that stimulus-driven attention effects and negative subsequent memory effects demonstrated overlap in the TPJ bilaterally. In short, there are grounds for supposing that negative subsequent memory effects may reflect processes additional to those associated with the default mode network. The primary aim of the present study was to investigate the relationship between task-negative and negative subsequent memory effects. In contrast to Daselaar et al. [2004], who characterized BOLD responses elicited by subsequently remembered and forgotten items with respect to the implicit baseline of a rapid event-related design, the present study employed a design in which task effects

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could be evaluated with respect to no-task (“rest”) periods, a baseline comparable to that typically employed in studies that identified default mode activity by contrasting blocks of task engagement with rest blocks [e.g., Gusnard et al., 2001; McKiernan et al., 2003; Persson et al., 2007]. The study and test tasks—relational encoding of word pairs followed by an associative recognition test—were chosen in light of findings that associative encoding elicits robust and widespread negative subsequent memory effects [e.g. Daselaar et al., 2004; de Chastelaine et al., 2011; Park and Rugg, 2008]. By employing a design that alternated between task and rest blocks, we were able to operationalize the default mode network as those regions where activity was lower during the task than during rest. Thus, we could directly assess the extent of the overlap between this network and negative subsequent memory effects. A second aim of the present study was to assess the extent to which positive subsequent memory effects overlapped with regions where activity was greater during task engagement than during rest [so-called “taskpositive” regions; Fox et al., 2005]. It has been proposed that positive subsequent memory effects reflect the modulation of activity in cortical regions engaged in service of the on-line demands of the study task [Rugg et al., 2008]. Therefore, to the extent that the contrast between activity elicited by study items and activity during rest accurately identifies such regions, positive subsequent memory effects should overlap with task-positive effects, and should not be evident in regions demonstrating either task-negative effects or no sensitivity to task engagement. A final question addressed by the present experiment concerns the relationship between the magnitude of taskrelated and subsequent memory effects. As was noted earlier, it has been proposed that task-negative responses reflect a reallocation of cognitive resources from processes engaged during ‘rest’ to those supporting the processing of task-relevant input. In support of this proposal, McKiernan et al. [2003]; [see also Gilbert et al., 2012; Persson et al., 2007] reported that task-negative effects covaried with task difficulty, and hence with the demand for attentional or cognitive resources. In light of these findings, we manipulated the difficulty of the study task with the expectation that the more difficult condition would be associated with larger task-negative effects than the easier condition. At issue was whether negative subsequent memory effects would also co-vary with difficulty. Such a finding would suggest that the amount of additional disengagement of default mode processes required to support successful encoding depends upon the processing demands of the study task. By contrast, an additive relationship between task-negative and negative subsequent memory effects would suggest that the amount of the additional resources required for successful encoding is independent of overall task demands.

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METHODS Participants Eighteen young adults (seven males), aged between 18 and 24 years, contributed data to the experiment. Data collected from four additional participants were excluded because of inadequate behavioral performance. All participants were healthy, right-handed, fluent English speakers with no self-reported history of neurological or psychiatric disease, and were remunerated for their time. The study was approved by the Institutional Review Board of the University of California, Irvine. Informed consent was obtained from each participant before proceeding with the experiment.

Experimental Items Items comprised 320 semantically-unrelated word pairs and 80 semantically- or associatively-related word pairs. The words were selected from the word association norms compiled by Nelson et al. [2004]. Each word denoted a common object and ranged in length from 3 to 11 letters. From the pool of stimulus word pairs, 240 unrelated pairs were randomly chosen for each participant, along with the 80 related pairs, to make up the study lists. The 320 pairs were divided into 20 lists of 16 pairs each. The majority of the pairs in each list were unrelated, the number of related pairs varying between two and six, to give a mean of 4 over each subset of 10 “easy” and 10 “hard” lists (see below). For each participant, pairs within each list were pseudo-randomly presented with the constraint that no more than three of the same type (related, intactunrelated, and rearranged-unrelated—see below) were presented consecutively. The 20 study lists were divided into two randomly interleaved subsets of 10 (with the constraint that no more than three lists from one particular subset were presented consecutively). In the “easy” subset, related pairs comprised items sharing an unambiguous relationship (e.g., onion–garlic), whereas in the “hard” subset, the relationship was less transparent and depended upon the appropriate interpretation of a semantically ambiguous word (e.g., division–arm). As task difficulty has previously been shown to co-vary strongly with tasknegative effects [e.g., McKiernan et al., 2003], the difficulty manipulation was employed to investigate whether there is a relationship between the magnitudes of negative subsequent memory effects and task-negative effects. The test list comprised 320 critical word pairs along with two initial buffer pairs. One hundred and sixty of the test pairs had been presented at study (intact pairs), 80 of the test pairs were studied items that had been re-paired from study (rearranged pairs; both items comprising these pairs were taken either from hard or easy study blocks, with half of the pairs derived from each type of block) and the remaining 80 pairs were unstudied (new). All test pairs were semantically-unrelated. Items within the test

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list were pseudo-randomly ordered for each participant such that the same pair-type did not occur more than three times in succession. Practice study and test lists were formed from items additional to those used to create the experimental lists.

Procedure Participants were given instructions and a practice session on the study task before scanning. They were not aware that their memory for the study items would later be tested. Before functional scanning, a 9-min structural scan was acquired. During functional scanning, study pairs were presented in four consecutive blocks (each containing five study lists) that were separated by brief rest periods (approximately 1 min.). The study task was to discriminate between related and unrelated word pairs, signaling the discrimination with a button press using the left or right index finger. The mapping of fingers to response (related vs. unrelated) was counterbalanced across participants. Instructions emphasized the need for both speed and accuracy. Experimental stimuli were viewed via a mirror located above the head coil. Figure 1 gives a schematic overview of the study procedure. Word pairs were presented in task blocks of 20 word pairs. Each task block was preceded by a 30 s rest block, during which time participants were required to fixate a centrallypresented white cross. A final 30 s rest block occurred after the last word pair list. The order and timing of events for each trial during functional scanning was as follows: A red fixation cross (500 ms), a “REST” cue (1500 ms), a white fixation cross (30 s), a red fixation cross (500 ms), a study cue indicating whether the upcoming study list would be “HARD” or “EASY” (1,500 ms), a red fixation cross (500 ms), a word pair (2,000 ms), and a white fixation cross (1,000 ms). The words in each pair were presented one above the other. Word pairs subtended an approximate vertical visual angle of 1.72 and a maximum horizontal visual angle of 4.70 at a 1 m viewing distance. Word pairs and cues (REST, HARD, and EASY) were centrally presented in white uppercase Helvetica 30 point font against a black background. Approximately 30 min after the scanning session, participants undertook an associative recognition memory test. Test pairs were presented on a computer screen in the same format as at study. Each trial consisted of a red fixation cross for 500 ms, followed by the test pair which stayed on the screen until a response was made. One of three key presses was required to indicate whether each pair was judged to be intact, rearranged or new. Participants were required to respond “intact” when they recognized both words and had a specific memory of the two words being presented together previously. A “rearranged” response was required when both words were recognized from the study phase but there was no specific memory of the words being paired together previ-

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Figure 1. Schematic overview of the study phase procedure. ously. A “new” response was required if one or both of the words were not recognized as having been studied. Although the test was self-paced, participants were instructed to respond as quickly as possible without sacrificing accuracy. Word pairs were replaced by a white fixation cross for 1,000 ms once a response was made. Experimental control, including stimulus presentation, was implemented in the “Cogent” software package (http://www.vislab.ucl.ac.uk/cogent.php).

MRI Acquisition Functional and anatomical images were acquired on a Philips Achieva 3T MR scanner equipped with an eightchannel parallel imaging head coil. Functional scans were acquired with a T2*-weighted echo-planar image (EPI) sequence using a sensitivity encoding (SENSE) reduction factor of 1.5 (TR 2 s, TE 30 ms, flip angle 70 , FOV 240 3 240, matrix size 80 3 78). Each EPI volume consisted of 30 slices (3 mm thickness, 1 mm interslice gap) acquired in ascending order, oriented parallel to the AC–PC line and positioned for full coverage of the cerebrum and most of the cerebellum. Functional data were acquired during each study block (234 volumes for the first three blocks and 250 volumes for the last block) and concatenated across the four blocks prior to model estimation. An additional five volumes at the start of each block were discarded to allow tissue magnetization to achieve a steady state. A T1-weighted anatomical image was acquired using a three-dimensional magnetization-prepared rapid gradient echo (MP-RAGE) pulse sequence (FOV 5 240 3 150, matrix size 320 3 320, voxel size 0.75 mm3, 200 slices, sagittal acquisition).

MRI Data Analysis Functional images were preprocessed and analyzed with Statistical Parametric Mapping (SPM8, Wellcome Department of Cognitive Neurology, London, UK: http:// www.fil.ion.ucl.ac.uk/spm). Volumes were motion and slice-time corrected, realigned and then spatially normalized to a standard EPI template (based on the Montreal Neurological Institute or “MNI” reference brain; Cocosco

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TABLE I. Study performance (6SD) for the hard and easy conditions Hard blocks

Accuracy RTs

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RESULTS Behavioral Performance

Easy blocks

Study phase

Related

Unrelated

Related

Unrelated

0.72 (.03) 1,423 (78)

0.95 (.03) 1,603 (102)

0.97 (0.01) 1,161 (76)

0.98 (0.01) 1,403 (80)

The table shows the proportion of correct responses for related and unrelated pairs along with their associated RTs.

et al., 1997]. Normalized volumes were resampled to 3 mm isotropic voxels and smoothed with an isotropic 8 mm full-width half-maximum Gaussian kernel. The time series in each voxel were high-pass filtered to 1/128 Hz to remove low-frequency noise and scaled within-session to a grand mean of 100 across voxels and scans. A single General Linear Model (GLM) was used to estimate both item-related neural activity and activity related to the rest blocks. To estimate item-related effects, neural activity for each participant was modeled by a delta function (impulse event) at stimulus onset, while the rest blocks (30 s duration) were modeled with a boxcar function. These functions were convolved with a canonical hemodynamic response function (HRF) and its temporal and dispersion derivatives [Friston et al. 1998]. This yielded regressors in the GLM that modeled the BOLD response during the rest blocks, and to the two pair types of interest (separately for hard and easy lists). The two pair-types comprised studied pairs correctly endorsed as intact (associative hits) and those incorrectly identified as rearranged (associative misses) on the subsequent memory test. Studied pairs incorrectly identified as new, as well as task and rest cues, were also modeled. In addition, six regressors were used to model movement-related variance and session-specific constant terms were used to model differences in mean image intensity between sessions. The resulting parameter estimates from both models were taken forward to a second stage of analysis in which participants were treated as a random effect. Unless otherwise specified, only task and subsequent memory effects from the canonical HRF surviving a height threshold of P < 0.001 (one-sided) and comprising clusters of 21 or more contiguous voxels were considered reliable. The cluster extent threshold was determined by a Monte Carlo simulation implemented in AlphaSim (http://afni. nimh.nih.gov/afni/AFNI[lowem]Help/AlphaSim.html) to give a corrected cluster-wise significance level of P < 0.05. As is described below, these principal contrasts were interrogated with a combination of inclusive and exclusive masks to address each of the questions outlined in the Introduction. The cluster extent threshold of 21 voxels was maintained for all analyses involving a mask.

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Performance on the study task is summarized in Table I. The data were analyzed with 2 (task difficulty: hard, easy)3 2 (pair type: related, unrelated) ANOVAs. For the accuracy data, ANOVA revealed main effects of task difficulty (F(1,17) 5 70.28, P < 0.001) and pair type (F(1,17) 5 43.59, P < 0.001) along with a difficulty by pair type interaction (F(1,17) 5 66.37, P < 0.001). Follow-up tests showed that accuracy for unrelated pairs did not differ according to difficulty, whereas accuracy for related pairs was significantly higher in the easy task (t(17) 5 9.87, P < 0.001). ANOVA of the reaction time (RT) data revealed a main effect of task difficulty (F(1,17) 5 28.72, P < 0.001), indicating faster responses in the easy task. The ANOVA also revealed a main effect of pair type (F(1,17) 5 21.17, P < 0.001), reflecting faster responses to related than to unrelated pairs. In a further analysis, study RTs for word pairs represented as intact pairs at test were segregated according to whether the pairs were correctly endorsed as intact or incorrectly endorsed as rearranged (paralleling the fMRI subsequent memory analyses described below). ANOVA [factors of task difficulty (hard, easy) and subsequent memory (intact, rearranged)] revealed a main effect of task difficulty (F(1,17) 5 11.41, P < 0.005) indicating faster responses in the easy task. There was no effect of subsequent memory, and no evidence of an interaction between task difficulty and subsequent memory.

Test phase Performance on the associative recognition task is summarized in Table II. Associative recognition accuracy was TABLE II. Mean associative recognition performance (6SD) for the hard and easy conditions

“Intact” responses Intact pairs Rearranged pairs New pairs “Rearranged” responses Intact pairs Rearranged pairs New pairs “New” responses Intact pairs Rearranged pairs New pairs

Hard

Easy

0.44 (0.16) 0.10 (0.08)

0.40 (0.14) 0.09 (0.08) 0.01 (0.02)

0.40 (0.13) 0.62 (0.11)

0.40 (0.12) 0.62 (0.14) 0.21 (0.13)

0.17 (0.10) 0.28 (0.13)

0.21 (0.10) 0.28 (0.13) 0.78 (0.14)

The table shows the proportion of intact, rearranged and new pairs given “intact,” “rearranged,” and “new” responses.

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indexed as the difference between the proportion of intact test pairs correctly endorsed as intact and the proportion of rearranged pairs incorrectly judged intact. Accuracy did not differ as a function of study task difficulty: means (SDS) of 0.33 (0.14) and 0.31 (0.09) for the hard and easy conditions respectively. In both cases, accuracy was significantly different from the chance value of zero (P < 0.001).

fMRI Data BOLD activity elicited by all study pairs was contrasted with the activity during rest blocks so as to identify taskpositive (all > rest) and task-negative (rest > all) effects. For the subsequent memory analyses, BOLD responses to study pairs that were re-presented at test were segregated according to whether the pairs were later correctly endorsed as intact (hits) or incorrectly identified as rearranged (misses) on the associative recognition test. The responses to these two classes of study item were contrasted to identify both positive (hits > misses) and negative (misses > hits) subsequent memory effects. To identify regions where positive and negative subsequent memory effects overlapped with the analogous task effects we inclusively masked the respective pairs of contrasts (see below). Similarly, to identify regions where positive and negative subsequent memory effects did not overlap with the analogous task effects we exclusively masked the respective pairs of contrasts with the subsequent memory effects (and vice versa). As was noted in the Introduction, we were also interested in identifying any influence of task difficulty on task effects and subsequent memory effects. To identify where task-positive and task-negative effects were modulated by difficulty, we inclusively masked each effect by the corresponding difficulty effect (hard > easy for task-positive effects, easy > hard for task-negative effects). Regions where subsequent memory effects were modulated by difficulty were identified by inclusively masking each of the effects by the appropriate directional subsequent memory 3 difficulty interaction contrast.

Task Effects The outcomes of the contrasts identifying task-positive and task-negative effects are illustrated in Figure 2 and documented in Table III. Task-positive effects were identified in left inferior and bilateral superior frontal and occipital cortices, as well as in the striatum and thalamus. Effects in the left inferior occipital gyrus extended to the anterior hippocampus/entorhinal cortex via the inferior and middle temporal gyri. Task-negative effects were identified in many of the regions previously identified as belonging to the default mode network, including medial, superior, and lateral frontal cortex, lateral temporal and occipital cortices, medial and lateral parietal cortex (including the angular gyrus) and the posterior cingulate.

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Figure 2. Regions demonstrating task-positive and task-negative effects shown on lateral (top) and medial (bottom) surfaces of a standardized brain (PALS-B12) atlas using Caret 5. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Regions where task-positive effects were enhanced for hard relative to easy study blocks were identified by inclusively masking these effects with the hard > easy contrast, thresholded at P < 0.01, one-sided (as estimated by Fisher’s procedure [Lazar et al., 2002], the conjoint significance level of the resulting SPM was P < .0001). As is evident in Figure 3A and detailed in Table IV, this procedure identified two clusters in the LIFG where task-positive effects were greater in the hard condition. The parameter estimates corresponding to the peak voxels of the two clusters were extracted (see Fig. 3B illustrating these data) and subjected to a three-way ANOVA, with levels of cluster location, difficulty (hard vs. easy), and subsequent memory (hits vs. misses). Whereas the difficulty effect is of course a foregone conclusion, given how these voxels were selected, the effects of location and subsequent memory, along with any interaction effects, are free to vary. This analysis revealed a main effect of difficulty (F(1,17) 5 18.98, P < 0.001) and a main effect of subsequent memory (F(1,17) 5 19.99, P < 0.001), but no interactions involving the factors of cluster location, difficulty or subsequent memory (maximum F(1,17) 5 0.54). Inclusive masking was also employed to identify where task-negative effects were enhanced by difficulty. As is illustrated in Figure 3A and documented in Table IV, tasknegative effects were enhanced in bilateral posterior cingulate and superior parietal cortex. ANOVAs were conducted

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TABLE III. Peak voxels of positive and negative task effects Coordinates

Positive

Negative

x

y

z

Peak Z

No. above-threshold voxels

245 26 224 212 230 21 260 239 24 3

23 14 2 216 294 2100 2 288 38 21

19 49 4 4 214 25 229 31 49 10

4.48 4.40 3.93 3.93 5.94 6.41 5.40 6.09 6.49 5.18

420 105 80 22 1,142 808 1,057 886 13,517 141

Region Left inferior frontal gyrus Left superior frontal gyrus Left putamen Left thalamus Left occipital cortex Right occipital cortex Left middle temporal gyrus Left occipital cortex Right middle/superior frontal gyrus Right caudate nucleus

on the peak parameter estimates from the left and right posterior cingulate (factors of hemisphere, difficulty, and subsequent memory) and, separately, from the superior parietal peak (see Fig. 3B for a plot of these data). For both sets of analyses, there were of course main effects of difficulty [posterior cingulate peaks: (F(1,17) 5 14.98, P < 0.005); superior parietal peak: (F(1,17) 5 5.64, P < 0.05)]. There were also effects of subsequent memory [posterior cingulate peaks: (F(1,17) 5 29.73, P < 0.001); superior parietal peak: (F(1,17) 5 7.70, P < 0.05)] but no interactions involving difficulty and subsequent memory (maximum F(1,17) 5 1.02).

Subsequent Memory Effects

Figure 3. (A) Regions demonstrating task-positive and task-negative effects that were enhanced by difficulty shown on lateral (left) and medial (right) surfaces of a standardized brain (PALS-B12) atlas using Caret 5; (B) Mean parameter estimates (and standard errors) for subsequent hits and misses from the hard and easy conditions, plus rest activity, across peak voxels from left inferior frontal gyrus and bilateral precuneus regions where task-effects were enhanced by difficulty. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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As is illustrated in Figure 4, positive subsequent memory effects were identified in the left inferior frontal and left fusiform gyri, and negative subsequent memory effects were evident in right dorsolateral and right superior frontal cortex, the posterior cingulate, and medial and lateral parietal cortex (including the supramarginal and angular gyri). Peak voxels demonstrating negative and positive subsequent memory effects in each region are listed in Table V. To assess the effects of task difficulty on subsequent memory effects, we inclusively masked the positive and negative subsequent memory effects (thresholded at P < .001) with directional interactions identifying regions where subsequent memory effects were sensitive to difficulty. Even at masking thresholds of P < .05 (one sided), these analyses failed to identify any clusters where task difficulty modulated the size of either positive or negative subsequent memory effects.

Overlap Between Task Effects and Subsequent Memory Effects To determine the degree of overlap between subsequent memory effects and task-effects we inclusively masked

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TABLE IV. Peak voxels of positive and negative task effects that were sensitive to task difficulty Coordinates

Positive Negative

x

y

z

Peak Z

No. above-threshold voxels

245 236 23 12

29 5 273 240

16 31 58 11

4.77 4.23 3.88 3.57

131 70 408 23

each of the subsequent memory effects (positive and negative, thresholded at P < 0.001) with the respective taskpositive and task-negative effects (liberally thresholded at P < 0.05 so as to minimize the likelihood of a type II error). No overlap was found between positive subsequent memory effects and task-negative effects or between negative subsequent memory effects and task-positive effects. However, as is shown in Figure 5, these analyses identified areas of overlap between positive subsequent memory and task-positive effects in the left inferior frontal gyrus (peak: 257, 29, 16; Z 5 4.57, 291 voxels) and left fusiform gyrus (peak: 245, 258, 214; Z 5 3.57, 35 voxels), and extensive areas of overlap between negative subsequent memory effects and task-negative effects in right superior frontal cortex (peaks: 27, 23, 58; Z 5 4.53, 246 voxels and 18, 56, 22; Z 5 4.03, 33 voxels), right dorsolateral PFC (peak: 21, 56, 31; Z 5 3.99, 27 voxels), posterior cingulate/medial parietal cortex (peak: 12, 261, 28; Z 5 4.45, 1,031 voxels), and lateral parietal cortex (right—peak: 57, 249, 40; Z 5 4.05, 195 voxels and left—peak: 245, 255, 46; Z 5 3.79, 34 voxels).

Region Left inferior frontal gyrus Left inferior frontal gyrus Posterior cingulate / precuneus Tectum

Subsequent Memory Effects Outside Regions Showing Task-Effects To determine the extent to which subsequent memory effects fell outside of regions demonstrating a task effect we exclusively masked each of the subsequent memory effects (positive and negative-thresholded at P < 0.001) with the corresponding task-positive and task-negative effects (with one-sided thresholds of P < 0.05; note that the more liberally an exclusive mask is thresholded, the more conservative is the analysis). There were no positive subsequent memory effects that fell outside regions demonstrating task-positive effects. By contrast, as is illustrated in Figure 6A, three regions—middle posterior cingulate (peak: 0, 228, 28; Z 5 3.58, 30 voxels), right superior PFC (peak: 42, 14, 55; Z 5 4.26, 38 voxels) and right dorsolateral PFC (peak: 45, 32, 43; Z 5 4.04, 44 voxels)—demonstrated negative subsequent memory effects in the absence of a reliable task effect. The parameter estimates associated with these effects are illustrated in Figure 6B. In keeping with the impression given by the figure, in each case the mean estimates for items later correctly judged intact differed reliably from rest (all Ps < 0.01), whereas the estimates for items incorrectly endorsed as rearranged did not significantly differ from rest.

Task Effects Outside Regions Showing Subsequent Memory Effects

Figure 4. Regions demonstrating positive (red) and negative (blue) subsequent memory (SM) effects shown on lateral (top) and medial (bottom) surfaces of a standardized brain (PALS-B12) atlas using Caret 5. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Whereas the foregoing analyses conservatively identify subsequent memory effects that fall within and outside task-sensitive regions, they leave open the question of whether a similarly conservative approach would demonstrate the existence of task-sensitive regions that extend beyond those demonstrating subsequent memory effects. To address this question, we exclusively masked each of the task effects (thresholded at P < 0.001) with the corresponding positive and negative subsequent memory effects (one-sided thresholds of P < 0.05). The outcomes of these analyses are illustrated in Figure 7 and listed in Table VI. Five regions—bilateral occipital cortex, left superior frontal gyrus, left insula and the left putamen—demonstrated task-positive effects in the absence of a reliable positive subsequent memory effect. As is evident from Figure 7, despite the liberal threshold of the subsequent

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TABLE V. Peak voxels of positive and negative subsequent memory effects Coordinates

Positive Negative

x

y

z

Peak Z

No. above-threshold voxels

Region

257 245 227 245 18 21 27 57 12

29 258 50 255 56 56 23 249 261

16 214 37 46 22 31 58 40 28

4.57 3.57 4.00 3.79 4.03 3.99 4.53 4.05 4.45

299 35 27 39 33 28 330 197 1,062

Left inferior frontal gyrus Left fusiform gyrus Left superior frontal gyrus Left lateral parietal cortex Right superior frontal gyrus Right dorsolateral PFC Right superior frontal gyrus Right lateral parietal cortex Right posterior cingulate

memory mask, task-negative effects were widespread in lateral and medial cortex bilaterally. A reviewer queried whether the different spatial extents of the subsequent memory and task effects might reflect differences in the power of the contrasts employed to derive the two classes of effect (for example, the task contrasts included all study items, whereas the subsequent memory effects were derived from only two classes of item). To address this question, we repeated the foregoing analyses using only later remembered study items (contrasted with rest) to identify task-positive and task-

Figure 5. Regions where positive (red) and negative (blue) subsequent memory (SM) effects overlap their respective task effects shown on lateral (top) and medial (bottom) surfaces of a standardized brain (PALS-B12) atlas using Caret 5. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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negative effects. The outcomes of these analyses were very similar to those reported above, supporting the proposal that task and subsequent memory effects are not coextensive (see Supporting Information).

Figure 6. (A) Regions where negative subsequent memory effects fell outside of regions demonstrating task-negative effects shown on coronal and sagittal sections of the across-participants mean T1weighted structural image; (B) mean parameter estimates (and standard errors) for subsequent hits and misses across difficulty, plus rest activity, from the peak voxels from regions where negative subsequent memory effects fell outside task-negative regions. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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by correlating (across participants) associative recognition performance with the mean across-region negative subsequent memory effect (using the peak parameter estimates from each region). The correlation (see Fig. 8 for scatterplot) was 0.476 (P < 0.05, two-tailed; 0.582, P < 0.025, with the obvious outlier removed), consistent with previous reports that memory performance is positively associated with the magnitude of negative subsequent memory effects. The corresponding correlation for the positive subsequent memory effects was not significant. When correlations were computed separately for each of the seven regions demonstrating a negative subsequent memory effect (listed in Table V), they were found to be individually significant in the right posterior cingulate (r 5 0.468, P < 0.05) and left supramarginal gyrus (r 5 0.646, P < 0.005). Task-negative effects derived from the same locations failed to demonstrate reliable correlations with subsequent memory performance (rs 5 20.116 to 20.281), as did the effect when collapsed across regions (r 5 20.209).

Figure 7. Regions demonstrating task-positive (red) and task-negative (blue) effects in the absence of reliable positive and negative subsequent memory (SM) effects respectively shown on lateral (top) and medial (bottom) surfaces of a standardized brain (PALS-B12) atlas using Caret 5. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Relationship Between Subsequent Memory Effects and Memory Performance Finally, motivated by prior reports that the magnitude of negative subsequent memory effects covaries with memory performance [at least in older participants; Duverne et al., 2009; Miller et al., 2008; Mormino et al., 2011; Mattson et al., in press], we investigated the relationship between negative effects and memory performance

DISCUSSION We investigated the relationship between positive and negative task and subsequent memory effects using a design in which an associative encoding task was interspersed with rest periods, allowing item-related activity to be referred to a baseline analogous to that employed in prior studies of the default mode network [e.g., Gusnard et al., 2001; McKiernan et al., 2003; Persson et al., 2007]. Whereas both classes of task effect (task-negative effects especially) were evident in multiple cortical regions, subsequent memory effects were identified in only a subset of task-sensitive voxels. There were no cases where a negative subsequent memory effect and a positive task effect co-existed, or where a positive subsequent memory effect overlapped with a task-negative effect. The difficulty of the study task modulated the size of a subset of the task effects, but subsequent memory effects were unaffected by

TABLE VI. Peak voxels of task effects outside regions showing subsequent memory effects Coordinates

Positive

Negative

x

y

z

Peak Z

No. above-threshold voxels

Region

224 26 224 230 21 260 239 39 30 45

229 14 2 294 2100 2 288 41 20 285

25 49 4 214 25 229 31 7 229 22

4.36 4.40 3.93 5.94 6.41 5.40 6.09 3.64 4.73 6.20

54 105 80 905 790 1041 727 34 97 7967

Left insula Left superior frontal gyrus Left putamen Left occipital cortex Right occipital cortex Left middle temporal gyrus Left occipital cortex Right inferior frontal gyrus Right temporal pole Right occipital cortex

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task difficulty. Finally, negative subsequent memory effects, but not task-negative effects, correlated across participants with memory performance. We discuss the implications of these findings below.

Behavioral Findings Participants identified unrelated study pairs some 200 ms more quickly in the easy than in the hard condition, indicating that the difficulty manipulation strongly influenced the processing of the items that were carried forward to the subsequent memory test. RTs did not differ, however, according to subsequent memory. Thus, fMRI subsequent memory effects were not confounded by gross differences in the efficacy of the processing of study pairs that went on to be remembered or forgotten. Although the difficulty of the study task influenced RT, it did not affect later associative recognition performance. Therefore the additional processing accorded study pairs in the difficult condition did not enhance associative encoding of these items. The absence of a difficulty effect on memory performance may be relevant to the finding that subsequent memory effects were also unaffected by difficulty, as we discuss below.

fMRI Findings Task-negative effects were evident in all regions typically considered part of the default mode network, as well as in other regions, such as occipital cortex and the caudate, that are not usually included as part of the network2. Unlike in two prior studies [McKiernan et al., 2003; Persson et al., 2007], increased task difficulty was associated with greater task-negative effects in only one component of the network, namely, medial parietal cortex. The limited impact of difficulty may have been a consequence of an insufficiently strong manipulation, although it has previously been reported that difficulty does not modulate all components of the default network equally [Gilbert et al., 2012]. Robust negative subsequent memory effects were evident in several cortical regions, demonstrating a pattern similar to that reported previously for associative encoding tasks [e.g., Daselaar et al., 2004; de Chastelaine et al., 2011; Park and Rugg, 2008]. The effects were located almost exclusively in regions demonstrating task-negative effects and, even in regions where task effects were not detectable, negative subsequent memory effects took the form of greater activity reductions (relative to rest) for later remembered than later forgotten study pairs. Thus the 2 Connectivity analyses of the fMRI data during each rest block (using seeds in either medial parietal or medial PFC) were also employed to define the default mode network. These analyses identified very similar networks that encompassed the regions demonstrating task-negative effects.

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Figure 8. Scatterplot showing the relationship (across participants) between the mean across-region negative subsequent memory (SM) effect and associative memory performance. findings are consistent with the proposal [Daselaar et al., 2004] that negative subsequent memory effects—at least in the associative encoding tasks employed here and in the study of Daselaar et al. [2004]—largely reflect modulation of task-negative activity [see Mattson et al. in press for evidence that negative subsequent memory effects can also be identified in task-positive cortical regions]. That said, even when they were identified using a very liberal statistical threshold, negative subsequent memory effects were evident in only a small fraction of the voxels that demonstrated task-negative effects (cf. Figs. 2 and 5; see also Supporting Information). Negative effects were not detectable in the present study, for example, in medial prefrontal cortex, a “hub” of the default mode network that demonstrated prominent task negative effects (see Fig. 2). It is unclear why relatively greater disengagement of only some components of the default network should be associated with successful memory encoding. One possibility is that encoding benefits from the suspension of only some of the default processes that are engaged when task demands are minimal. By this account—which is consistent with other evidence pointing to functional dissociations among the different components of the default network [e.g., Andrews-Hanna et al., 2010; Gilbert et al., 2012; Leech et al., 2011; Lin et al., 2011]—the regions that demonstrate negative subsequent memory effects support processes that either compete or interfere with processes supporting successful encoding in the context of a given study task. The more that these competing or interfering processes are disengaged, the more effectively can encoding proceed. Disengagement of other default processes, by contrast, while necessary perhaps for the demands of the study task to be met, does not impact encoding. From this perspective it would not be surprising if negative subsequent memory effects were to demonstrate task- or material-specificity; to the extent that the processes that support successful encoding differ according to such

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variables as study task and material [Gottlieb et al., 2010; Uncapher and Rugg, 2009], encoding should benefit by disengagement of different default processes depending on the nature of the study event. A recent report [Gottlieb et al., 2012] that negative subsequent memory effects demonstrated a regional dissociation that depended on which of two different contextual features (location or voice identity) were successfully encoded is consistent with this proposal. Positive subsequent memory effects also overlapped with only a fraction of the voxels demonstrating a taskpositive effect. The effects were largely restricted to left inferior frontal and left fusiform gyri, regions consistently reported to manifest such effects in prior studies of associative encoding [e.g., Chua et al., 2007; Park and Rugg, 2011; Sperling et al., 2003]. It has been proposed that positive subsequent memory effects reflect modulation of processes engaged by the online demands of the study task [Rugg et al., 2008]. To the extent that task-positive effects reflect neural activity that supports such processing, the present finding that positive subsequent memory effects were confined to task-positive regions is consistent with this proposal. As in the case of negative subsequent memory effects, however, the question remains as to why positive subsequent memory effects were manifest in only some of the voxels demonstrating task-positive effects. One possibility is that the memory effects reflect enhanced processing of only those features of the study event that are incorporated into its encoded memory representation. According to this proposal [Uncapher and Rugg, 2009], the identity of these features is determined by how attention is allocated across the study event, and positive subsequent memory effects reflect enhancement of activity in cortical regions that support the processing of attended features. Task difficulty modulated the magnitude of both tasknegative and task-positive effects, as has been reported previously [Bank o et al., 2011; Dumontheil et al., 2010; Gilbert et al., 2012; McKiernan et al., 2003; Persson et al., 2007; Xu et al., 2007]. As is evident in Figure 3A, the difficulty effects were comparable in size to the subsequent memory effects manifest in the same regions. Difficulty did not, however, influence the efficacy of memory encoding, at least as this was reflected in subsequent associative recognition performance. Thus, enhanced task effects are not necessarily indicative of more effective encoding: if this were the case, subsequent memory performance would have been higher in the more difficult condition. Evidently, task effects can be modulated by variables other than those that influence memory encoding. One such variable might be the duration for which neural activity is engaged (or disengaged, in the case of task-negative effects) during a study trial. By this argument—which is potentially applicable to other fMRI studies of difficulty where increasing difficulty was associated with a lengthening of RT [e.g., Dumontheil et al., 2010; Gilbert et al., 2012;

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McKiernan et al., 2003; Persson et al., 2007]—the present difficulty effects reflected differences in the duration over which activity was modulated by the study task, rather than differences in the amplitude of the modulation (distinguishing between these two different mechanisms of fMRI BOLD signal change is challenging; for discussion see Grinband et al. [2008] and Henson and Rugg [2003]). In light of the behavioral evidence suggesting that the additional processing time required by study items in the difficult condition had no mnemonic consequence (see above), it is unsurprising that its neural correlate was also unrelated to subsequent memory performance. This proposal is compatible with the finding that both negative and positive subsequent memory effects were insensitive to difficulty. This was the case even for the effects in regions where task-related activity was reliably modulated by the difficulty manipulation (see Fig. 3A). Extending the account advanced above, we conjecture that difficulty effects largely reflected the duration over which processing resources were allocated to the study task, whereas subsequent memory effects reflect the amount of allocated resources. We further conjecture that only this latter variable influences the likelihood of encoding success. In a replication of prior findings in older individuals [Duverne et al., 2009; Miller et al., 2008; Mormino et al., 2011], the magnitude of negative subsequent memory effects correlated across participants with memory performance, demonstrating a particularly strong relationship in the left supramarginal gyrus. This region is adjacent to, and possibly overlapping with, the left temporo-parietal region that was reported by Uncapher et al. [2011] to demonstrate both a negative subsequent memory effect and “bottom-up” attentional enhancement (see Introduction). In light of these prior findings, it is tempting to speculate that the present result is a reflection of individual differences in the ability to resist distraction during a study episode, and to maintain attention on mnemonically-relevant features of the study event [cf. Uncapher et al., 2011]. Whatever the merits of this account, together with the aforementioned results from aging studies, the present finding that the magnitude of negative subsequent memory effects is predictive of later memory performance highlights the potential significance of these effects for an understanding of the determinants of successful episodic encoding. The absence of an analogous relationship between task-negative effects and memory performance adds to the evidence that these effects are functionally dissociable from subsequent memory effects. In conclusion, the findings described here indicate that positive and negative subsequent associative memory effects overlap with task-positive and task-negative cortical regions respectively, but in only a subset of these regions. The factors determining which task-sensitive regions will also demonstrate subsequent memory effects remain to be identified. The present results clearly indicate however

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that negative subsequent effects are not accurately characterized as reflections of the modulation of a functionally homogeneous default mode network. Additionally, the findings with respect to task difficulty indicate that positive and negative subsequent memory effects reflect processes that are independent of those modulated by at least one other variable that influences the magnitude of the fMRI response to study items.

ACKNOWLEDGMENTS The authors thank the staff of the University of California, Irvine Research Imaging Center for their assistance in the collection of the data reported here.

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