Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter?

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Research report

Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter?

Q1

Lucie Angela,b,n, Christine Bastina, Sarah Genona, Eric Salmona, Se´verine Fayb, Evelyne Balteaua, Pierre Maqueta, Andre´ Luxena, Michel Isingrinib, Fabienne Collettea,c a

Cyclotron Research Centre, University of Liège, Liège, Belgium University François-Rabelais of Tours, UMR CNRS 7295 CeRCA, Tours, France c Department of Psychology: Cognition and Behavior, University of Liège, Liège, Belgium b

art i cle i nfo

ab st rac t

Article history:

The current experiment aimed to explore age differences in brain activity associated with

Accepted 2 October 2015

successful memory retrieval in older adults with different levels of executive functioning, at different levels of task demand. Memory performance and fMRI activity during a

Keywords:

recognition task were compared between a young group and two older groups character-

FMRI

ized by a low (old-low group) vs. high (old-high group) level of executive functioning.

Aging

Participants first encoded pictures, presented once (Hard condition) or twice (Easy

Retrieval success

condition), and then completed a recognition memory task. Old-low adults had poorer

Task difficulty

memory performance than the two other groups, which did not differ, in both levels of task

Executive functioning

demands. In the Easy condition, even though older adults demonstrated reduced activity compared to young adults in several regions, they also showed additional activations in the right superior frontal gyrus and right parietal lobule (positively correlated to memory accuracy) for the old-high group and in the right precuneus (negatively correlated to memory accuracy), right anterior cingulate gyrus and right supramarginal gyrus for the old-low group. In the Hard condition, some regions were also more activated in the young group than in the older groups. Vice versa, old-high participants demonstrated more activity than either the young or the old-low group in the right frontal gyrus, associated with more accurate memory performance, and in the left frontal gyrus. In sum, the present study clearly showed that age differences in the neural correlates of retrieval success were modulated by task difficulty, as suggested by the CRUNCH model, but also by interindividual variability, in particular regarding executive functioning. & 2015 Elsevier B.V. All rights reserved.

Q2

n

Corresponding author at: University François-Rabelais of Tours, UMR CNRS 7295 CeRCA, Tours, France. E-mail address: [email protected] (L. Angel).

http://dx.doi.org/10.1016/j.brainres.2015.10.009 0006-8993/& 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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1.

Introduction

It is well established that episodic memory, i.e. memory for personal events associated with their spatio-temporal context, declines markedly during aging (for reviews, see Craik and Jennings, 1992; Light, 1991; McDaniel et al., 2008; Zacks et al., 2000). Neuroimaging studies have shed light on the neural underpinnings of these age-related changes in episodic memory abilities, especially during retrieval success (see Dennis and Cabeza, 2008; Grady, 2008; Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Lustig, 2005 for reviews; see Spreng et al. (2010) for a meta-analysis). Two contradictory findings in these age-related differences are especially noteworthy. Initially, studies mostly reported reduced brain activity in older compared to young adults, in various memory tasks and in different brain regions such as the left prefrontal cortex or medial temporal regions (e.g., Cabeza et al., 1997; Grady et al., 1994; see Spreng et al. (2010) for a meta-analysis). However, intriguingly, older adults sometimes show additional recruitments in some brain areas not or less activated by the young during memory tasks, mainly in frontal regions but also in other regions such as the parietal cortex (Angel et al., 2013; Huang et al., 2012), that may reflect either inefficient processes or compensatory mechanisms. Consequently, identifying the boundary conditions where these age-related differences in brain activity (under vs. over-recruitment) associated with memory retrieval happen and what they mean is currently a challenge for our understanding of the mechanisms underlying cognitive aging. The concept of task difficulty may help accommodate these discrepant findings. The CRUNCH model (Compensation-Related Utilization of Neural Circuits Hypothesis; Reuter-Lorenz and Cappell, 2008) predicts that at low levels of task demands, older adults would show overactivations relative to young adults, associated with relatively preserved performance, suggesting that these additional activations are functional and support episodic memory operations. When task demands are higher, older adults, once their cognitive limits have been reached, because of their reduced resources, would show underactivations compared to young adults, resulting in impaired performance. Evidence supporting the CRUNCH model has been provided by several studies using working memory tasks in which task load has been modulated (Cappell et al., 2010; Mattay et al., 2006; Schneider-Garces et al., 2009). In addition, several studies in the context of episodic memory seem to support the hypotheses derived from the CRUNCH model. For instance, Morcom et al. (2007) manipulated the number of presentations (one vs. two) of target items during encoding. Even though some brain regions were commonly activated during retrieval in both age groups (anterior and lateral prefrontal cortex), other brain areas in the prefrontal cortex and the parietal cortex were found to be more activated in the older group. Interestingly, these age-related over-recruitments associated with retrieval success were less marked in the hardest condition (one presentation during study), where performance was poorer in older adults than in the Easy condition (two presentations) where performance was unimpaired, which appears broadly consistent with the CRUNCH hypothesis. Another study conducted by Stern et al. (2012)

manipulated task demands parametrically by varying the response deadline in a recognition memory task (time between the appearance of the probe and the signal for response; response-signal method; Reed, 1973). fMRI activations varied between young and older groups, depending on task demands. Older adults were more likely to show a greater level of brain activity compared to young adults when task demands were low (short delay between the probe and response), while the reverse pattern of age differences was observed when the retrieval task was harder, in agreement with the predictions of the CRUNCH model. Thus, if this model applies to the episodic memory domain, age-related overactivations should mostly be observed in easiest conditions where older adults are able to compensate their memory deficits. Another possible approach to account for the divergent findings across neuroimaging studies of memory aging comes from evidence showing a high degree of heterogeneity in cognitive performance among older adults as well as in brain aging (Christensen et al., 1999; Nyberg et al., 2012; Wilson et al., 2002). For instance, the cognitive reserve hypothesis (Stern, 2002) posits that some individual characteristics (e.g., educational level) influence the impact of the aging process on cognitive functioning. The few neuroimaging studies that have directly addressed this variability among older adults have revealed conflicting patterns of results, with greater activity for older adults with either a high (during retrieval: Cabeza et al., 2002; Duarte et al., 2008, and also during encoding: Rosen et al., 2002) or a low level of memory performance (during retrieval: Duverne et al., 2009, during encoding: Miller et al., 2008; Persson et al., 2006). One important limitation of all these studies is that older participants were split into high or low performers according to their level of memory accuracy, which does not provide any explanation about the sources of these individual variations. In the present experiment, we specifically looked at the influence of individual differences in executive functioning, defined as high level cognitive processes which supervise and control other cognitive sub-processes. These executive functions are assumed to contribute strongly to memory performance variability in older adults. Indeed, the executive decline hypothesis of cognitive aging (Dempster, 1992; Parkin and Walter, 1992; West, 1996) posits that the pattern of cognitive changes associated with normal aging may be a consequence of an age-related decline in the efficiency of the frontal lobes, known to play a major role in executive functioning. In particular, individual differences in executive functioning appear to be an important mediator of changes in episodic memory in old age, especially in tasks that are highly dependent upon strategic processes (Baudouin et al., 2009; Bouazzoui et al., 2013; Bryan and Luszcz, 2000; Bryan et al., 1999; Crawford et al., 2000; Ferrer-Caja et al., 2002; Lee et al., 2012; Perrotin et al., 2008; Troyer et al., 1994). Another line of evidence supporting the executive decline hypothesis comes from studies comparing two groups of older participants categorized as having high or low frontal-executive functioning (Angel et al., 2010; Butler et al., 2004; Glisky et al., 1995). They consistently reported that older adults with a high executive level outperformed those with a low executive level in memory accuracy in a

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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cued recall paradigm (Angel et al., 2010), a false memory paradigm (Butler et al., 2004) or a source memory paradigm (Glisky et al., 1995). Using event-related potentials (ERPs), we have recently demonstrated that age-related differences in the magnitude and latency of the so-called “ERP old/new effect”, associated with retrieval success processes, were modulated according to older adults' level of executive functioning (Angel et al., 2010). More precisely, in the oldhigh group, ERP effects on frontal areas were relatively intact while the effect on parietal electrodes appeared later and was of smaller magnitude than for young adults. In addition, these high-level older adults exhibited a parietal effect that was more symmetrically distributed than in either the lowlevel older adults or the young adults, assumed to reflect compensatory mechanisms helping them perform the memory task efficiently. In the group of older adults with the lowest executive functioning level, a significant old/new effect also appeared at parietal electrode sites, but only on the left side, and later, shorter and of reduced magnitude compared to the young adults or to the old-high participants. On frontal areas, we also described a late negative component specific to these old-low adults, which was interpreted as an unsuccessful additional attempt to cope with retrieval difficulty. In summary, both interindividual variability, in particular regarding executive functioning, and task demand may contribute to the age-related differences in memory accuracy and in brain activity associated with episodic retrieval. However, to date, no study has examined simultaneously the impact of these two factors. The main aim of this experiment was thus to examine how individual variability in executive functioning and task demands may modulate age differences in the ability to recruit neural resources when performing an episodic memory task. In other words, we aimed at testing the CRUNCH model within the context of episodic memory and exploring whether executive functioning modulated these age-related differences. We compared memory performance and fMRI activity during an episodic recognition memory task in young adults and in a large sample of older adults divided into high and low sub-groups according to their level of executive functioning (old-high and old-low). Participants were administered the episodic memory task at two levels of difficulty1, with one (Hard condition) or two (Easy condition) presentations of items during the study phase (Morcom et al., 2007; Spaniol and Grady, 2012). They then completed the recognition memory task, with a Remember/Know paradigm (Tulving, 1985). Despite the use of this paradigm, the number of trials was insufficient to identify recollectionbased activity vs. familiarity-based activity in some older adults, especially in old-low participants, and in the Hard condition. In addition, the aim of the present work was not to 1 It is worth noting that the “task difficulty” that was manipulated here differs from the concept of « environmental support » as defined by Craik (1986) (see Lindenberger and Mayr, 2014 for a recent review). Indeed, environmental support is provided by procedures allowing to reduce the amount of self-initiated operations and resource demands, for instance, instructions inducing a deeper encoding. This is not the case here since the information was merely presented twice, without any additional instructions on how to process it.

3

dissociate functional networks related to the two retrieval strategies but to explore the neural correlates of successful memory retrieval.2 Thus, Remember and Know responses were collapsed to assess global memory performance and to examine retrieval success effects (“old/new effects”) in each group and at each level of difficulty. At the behavioral level, based on previous studies (Angel et al., 2010; Morcom et al., 2007; Spaniol and Grady, 2012) and on the CRUNCH model (Reuter-Lorenz and Cappell, 2008), we hypothesized that old-high adults would have intact memory performance, at least in the Easy condition. By contrast, oldlow participants were expected to have impaired memory performance compared to the two other groups, under both difficulty conditions, but especially under the Hard condition. As suggested by Spreng et al. (2010) meta-analysis , we also expected to observe common old/new effects across groups in a network of regions including lateral and medial prefrontal regions, medial temporal lobes and the occipital cortex, as well as some group differences in this neural activity associated with retrieval success. As reported in several previous studies, older adults, especially those with a low executive functioning level, should show less activity than young adults in several regions such as the occipital cortex, prefrontal areas or regions in the medial temporal lobe (e.g. Angel et al., 2013; Cabeza et al., 1997; Grady et al., 1995). The CRUNCH model predicts that these agerelated underactivations would be expressed more under the Hard condition, where older adults would have reached their resource limits. In addition, we expected to observe some regions, mainly in the right prefrontal cortex but also possibly in other regions, such as in the parietal cortex, in which activations would be greater in older than young adults or would be specific to older adults to help mitigate age-related deficits. If the predictions of the CRUNCH model are confirmed, these additional recruitments would be attenuated or would even disappear in the Hard compared to the Easy condition. Moreover, given the involvement of executive functioning in memory, it was assumed that older adults with the highest level would be more likely than those with a Q3 low level to recruit these additional neural resources compared to young adults, especially when task demands were high (Table 1).

2.

Results

2.1.

Behavioral results

2.1.1.

Recognition memory accuracy

Behavioral performance for each group under each difficulty condition is summarized in Table 2. A group (3)  difficulty (2) analysis of variance (ANOVA) on the discrimination index revealed a main effect of group (F(2,57)¼9.69; po.001), young and old-high adults demonstrating a similar level of accuracy and both performing better than old-low participants, and a main effect of difficulty (F(1,57)¼ 328.02; po.001) with better 2 A full description of activity associated with recollection and familiarity processes in young adults and in a subset of older adults is provided in a previous study (Angel et al., 2013).

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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performance in the Easy than the Hard condition. The interaction between group and difficulty was not significant (F(2,57)¼1.05). Reaction times for Hit responses (collapsed across Remember and Know judgments) were also submitted to an ANOVA with the factors of group (3) and difficulty (2). This analysis revealed a significant main effect of difficulty (F(1,57) ¼ 97.73; po.001), reflecting slower responses under the Hard than the Easy condition. However, neither the main effect of group (F(2,57)¼1.09) nor the group by difficulty interaction (F (2,57)¼ 0.28) were significant.

2.1.2.

Remember/Know judgments

The proportions of Remember and Know judgments given to studied items (Hits) in the Hard and Easy condition, as well as Table 1 – Participants' characteristics in each group (means and standard deviations).

Age Education (number of years) Mill Hill vocabulary test Beck depression scale Executive functioning Stroop test N-back test Plus–minus test Executive index

Young (n ¼ 20)

Old-high (n ¼20)

Old-low (n ¼20)

25.40 (2.98) 16.30 (2.45)

66.80 (4.85) 14.60 (2.14)

67.1 (4.84) 15.3 (4.09)

27.12 (2.92)

29.25 (2.77)

28.95 (4.08)

5.7 (5.10)

5.45 (4.03)

7.95 (4.03)

0.34 (0.07) 24.65 (2.03) 24.70 (15.52) 0.54 (0.55)

0.43 (0.09) 23.85 (2.13) 21.87 (12.51) 0.45 (0.42)

0.52 (0.09) 20.75 (2.49) 41.20 (20.79) -0.76 (0.61)

to New items (False alarms) are reported in Table 2. A group (3)  difficulty (2) ANOVA on the proportion of Remember responses (Hits judged as recollected – False recollections) showed a significant main effect of group (F(2, 57)¼12.39; po.001), which indicated that both old-high and old-low participants gave less Remember judgments to studied items than young participants (planned comparisons: pso.001). The main effect of difficulty was also significant (F(1, 57)¼ 95.97; po.001), due to more Remember responses in the Easy than the Hard condition. The group by difficulty interaction was not significant (F(2, 57)¼ 1.54, p¼ .22). A group (3)  difficulty (2) ANOVA on the proportion of Know responses (Hits judged as familiar – New items judged as familiar) yielded a significant effect of group (F(2, 57)¼ 3.59; po.05), with more Know responses in old-high participants than young participants (po.05), but no difference between old-low participants and young adults (p¼ .63). The main effect of difficulty was not significant (F(1, 57)¼ 2.04; p ¼.15), but the group by difficulty interaction reached significance (F (2, 57)¼3.48; po.05). The post-hoc exploration of the interaction confirmed that old-high participants gave more Know responses than young participants in both the Hard and Easy condition (pso.05), whereas old-low participants produced as many Know judgments as young participants in both conditions (ps4.12). Moreover, old-high participants produced more Know responses compared to old-low participants only in the Hard condition (po.05).

2.2.

fMRI results

We first explored the regions where the three groups demonstrated significant old/new effects, for each level of difficulty.

Note: standard deviations in parentheses.

Table 2 – Behavioral performance of each group in the memory task. Young

Global memory performance Response rates Hits False alarms Discrimination index (Pr) Reaction times (ms) Hits False alarms Remember/Know judgments Hits-Remember Hits-Know False alarms-Remember False alarms-Know Discrimination index-Remember (PrR) Discrimination index-Know (Pr-K)

Old-high

Old-low

Easy

Hard

Easy

Hard

Easy

Hard

.93 (.06) .07 (.04) .86 (.07)

.79 (.08) .06 (.04) .73 (.08)

.93 (.04) .13 (.08) .80 (.08)

.79 (.09) .13 (.08) .66 (.09)

.88 (.07) .17 (.14) .71 (.19)

.72 (.06) .17 (.14) .55 (.16)

1500.42 (167.79) 1604.55 (197.63) 1645.31 (268.42) 1731.92 (269.68) 1539.25 (386.87) 1633.19 (398.77) 1731.76 (408.76) 1876.36 (331.41) 1858.72 (646.80) .54 .39 .01 .06 .53

(.17) (.16) (.01) (.04) (.18)

.33 (.16)

.39 (.14) .41 (.14)

.38 (.14)

.37 .56 .03 .09 .34

(.17) (.16) (.03) (.06) (.17)

.35 (.14)

.47 (.17)

.24 (.11) .54 (.12)

.21 (.10)

.35 .53 .05 .12 .30

(.16) (.15) (.05) (.10) (.18)

.25 (.09) .46 (.11)

.20 (.10)

.45 (.13)

.41 (.17)

.34 (.13)

Note: standard deviations in parentheses. Discrimination index (Pr) ¼p(Hits)
p(False alarms). Discrimination index-Remember (Pr-R) ¼ p(Hits-Remember)
p(False alarms-Remember). Discrimination index-Know (Pr-K) ¼p(Hits-Know)
p(False alarms-Know).

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Table 3 – Regions showing old/new effects common to all groups in the Easy condition at a cluster value po.001 uncorrected. Region Hits4CR Inferior frontal gyrus

Left/right

Location (MNI coordinates, x, y, z)

T score

Cluster size

Left Right

5.35 3.72 3.30 6.12 5.67 4.30 10.98 10.72 13.46 5.32 5.10 3.94 10.38 9.36 10.37 4.46 3.68 3.48 3.35 8.35 5.49 7.12 7.30 7.16 4.08 4.94 6.75 6.39 7.67 6.52 6.31 6.08

3 2 2 1 4 2 7278

Superior frontal gyrus

Left Right

Middle frontal gyrusn

Left

Anterior cingulate gyrus Middle frontal gyrus

Left Right

Inferior parietal lobulen

Left

Supramarginal gyrus Inferior parietal lobule

Left Right

Superior parietal lobule Precuneusn Posterior cingulate gyrus Cingulate gyrus Middle temporal gyrus

Right Left Left Left Left

Thalamusn

Left

Caudate

Right

Lentiform nucleus CR4Hits Parahippocampal gyrus Insula

Right


26, 20,
14§ 56, 24, 2 58, 20, 6
22, 54, 28§ 14, 24, 60§ 20, 20, 62
46, 20, 34
46, 42,
6
4, 24, 42 38, 10, 54§ 38, 12, 40§ 42, 30, 28
54,
54, 40
36,
54, 38
54,
58, 32 48,
50, 42 44,
46, 36 34,
52, 36 36,
60, 50
2,
70, 36
10,
46, 32
2,
26, 28
56,
38,
6
60,
48, 0
56,
24,
12
52,
4,
24
10,
14, 4
8,
6, 6
12, 8, 4 12, 10, 2 14, 4, 8 14,
2,
2

Right Left

22,
8,
16§
54,
32, 20

n §

5.31 4.62

346 19 2685

180

3 2103

560

40 554

444

5 13

Significant results at a statistical threshold of po.001 FWE-corrected at the cluster level. Significant results at a statistical threshold of po.05 FWE-corrected at the voxel level.

Next, we examined the between-group differences in these old/new effects, according to the level of difficulty.

2.2.1. Old/new effects common to the groups 2.2.1.1. Easy condition. Analyses revealed an extensive network of regions where activity was greater for Hits than Correct rejections in all groups (see Table 3 and Fig. 1a). This network included areas in the superior, middle and inferior frontal gyri bilaterally, the left anterior and posterior cingu-

2.2.1.2. Hard condition. Under this condition, we also found different regions showing more activity for Hits than Correct rejections across groups (see Table 4 and Fig. 1b). These old/ new effects were observed in the left superior frontal gyrus, the left anterior cingulate gyrus, the right middle frontal gyrus, the right inferior frontal gyrus, the inferior parietal lobule bilaterally, the precuneus bilaterally, the right superior parietal lobule, the left middle temporal gyrus and the left thalamus.4 The reverse contrast, with greater activity for Correct rejections than Hits identified two regions, the left post-central gyrus and the left precentral gyrus.

late gyrus, the inferior parietal lobule bilaterally, the supramarginal gyrus bilaterally, the left precuneus, the right superior parietal lobule, the left middle temporal gyrus and the left thalamus. We also observed two regions, the right anterior parahippocampal gyrus and the left insula, where Correct rejections demonstrated greater activity than Hits.

3

3 Activity in the left middle frontal gyrus, the left inferior parietal lobule and in the left precuneus survives correction for multiple comparisons at the cluster level.

2.2.2. Group differences in the old/new effects 2.2.2.1. Easy condition 2.2.2.1.1.Young vs. Old-high. The comparison of old/new effects under the Easy condition between the young and the old-high groups (see Table 5 and Fig. 2) revealed that several 4 Activity in the left inferior frontal gyrus, right middle frontal gyrus, left inferior parietal lobule and left middle temporal gyrus survives correction for multiple comparisons at the cluster level.

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Fig. 1 – Regions showing old/new effects (Hits 4 CR) common to the three groups (depicted at a statistical threshold of po.05 FWE-corrected at the voxel level) in the Easy condition (a) and the Hard condition (b). The regions are displayed on the 3D rendered MNI reference brain. Table 4 – Regions showing old/new effects common to all groups in the Hard condition at a cluster value of po0.001 uncorrected. Region

Left/right

Location (MNI coordinates, x, y, z)

T score

Cluster size

Hits4CR Inferior frontal gyrus1 Anterior cingulate gyrus

Left Left Right

Posterior cingulate Superior frontal gyrus

Left Left Right Right

Left

11.41 13.12 12.58 3.59 3.39 3.28 5.15 5.62 5.35 7.03 4.78 3.82 3.60 5.17 10.69 9.92 9.78 4.41 4.33 9.13 8.99 6.25 8.90 3.84 3.60 8.28

8804

Inferior frontal gyrus


54, 16, 18§
4, 24, 42§
4, 26, 34§ 56, 18, 0 58, 20, 6 60, 20, 10
6,
46, 6§
22, 50, 24§ 14, 12, 62§ 40, 8, 54§ 44, 36, 30§ 44, 18, 36§ 22, 20, 60 36, 50, 22§
54,
54, 38§
42,
58, 50§
36,
52, 40§ 48,
50, 44 30,
62, 44
2,
70, 44§
2,
26, 26§ 12,
66, 32§
56,
38,
6§
58,
56, 10§
56,
26,
10§
8,
14, 4

Left Left


50,
6, 8
54,
30, 20

3.99 4.95

1 6

Middle frontal gyrus1

Inferior parietal lobule1

Left

Superior parietal lobule Precuneus1

Right Right Left

Middle temporal gyrus1

Right Left

Thalamus1 CR4Hits Precentral gyrus Postcentral gyrus § 1

4 2 1 27 90 24 794

24 47 2442

68 56 1680

478

324

Significant results at a statistical threshold of po.05 FWE-corrected at the voxel level. Significant results at a statistical threshold of po.05 FWE-corrected at the cluster level.

regions demonstrated greater activity for Hits than Correct

with simple effects in each group also revealed that two other

rejections only in the young, including the left middle frontal

regions, the left anterior cingulate gyrus and the left superior

gyrus, the left inferior frontal gyrus, the left posterior para-

temporal gyrus, showed significant old/new effects in both

hippocampal gyrus, the left thalamus and the left insula

groups but which were larger in the young group. In addition,

(Fig. 2a). Inclusive masking of group differences contrasts

the old-high group demonstrated old/new effects in two

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847

Table 5 – Regions showing group-related differences in old/new effects in the Easy condition at a cluster p value po.001 uncorrected. Region

Left/right

Location (MNI coordinates, x, y, z)

T score

Cluster size

Left Left Left Left Left Left Left


32, 58, 10
36, 24,
6
4, 24, 42
48, 16,
10
22,
34,
4
16,
34, 2
36, 20, 14

3.38 3.31 4.02 3.48 4.16 3.52 3.48

1 3 29 18 67

Left

4.07 3.80 3.66 3.56 4.56 3.60 3.48 3.40 4.96 4.48 3.96 3.28 3.26 3.41

30 45 36 8 775 36 60 9

Right


52, 16, 18
36, 26,
6
6, 38, 52
26, 48, 24 2, 12, 64
8, 48, 42
48, 16, 36
38, 0, 50
2, 28, 28 14, 26, 22
48, 16,
10
10, 12, 8
10, 16, 6 8, 16, 2

Old-high 4 Young Superior frontal gyrusb Inferior parietal lobuleb Old-low 4 Young

Right Right

22, 12, 56 38,
66, 40

3.73 3.62

10 5

Anterior cingulate gyrusc Precuneusc Supramarginal gyrusc

Right Right Right

10,
46, 40 14,
70, 44 50,
60, 32

3.67 3.43 3.30

9 4 2

Left Right Left Right Left /


54, 26, 14 16, 12, 56
6, 38, 42 18, 48, 20
38, 2,
48 /

3.42 3.55 3.32 4.73 3.27 /

7 10 1 18 2 /

Young 4 Old-high Middle frontal gyrusa Inferior frontal gyrusa Anterior cingulate gyrus Superior temporal gyrus Parahippocampal gyrusa Thalamusa Insulaa Young 4 Old-low Inferior frontal gyrusa Superior frontal gyrusa

Left

Medial frontal gyrus Middle frontal gyrusa

Right Left Left

Anterior cingulate gyrusa Superior temporal gyrusa Caudate

Old-high 4 Old-low Inferior frontal gyrus Superior frontal gyrusb Medial frontal gyrusb Middle frontal gyrusb Old-low 4 Old-high

Left Right Left Left

3

51 60 1 2 8

a

Significant old/new effect (Hits4CR) in the Young group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Young group). b Significant old/new effect (Hits4CR) in the Old-high group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Old-high group). c Significant old/new effect (Hits4CR) in the Old-low group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Old-low group).

regions in the right superior frontal gyrus and the right inferior parietal lobule, while they were not significant for the young group (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the young group and then with the simple effect of the old-high group; Fig. 2b). In order to elucidate the meaning of these activations specific to the old-high group, we extracted mean parameter estimates for activity elicited by Hits and Correct rejections at these voxels of interest and computed correlations between these old/new effects in old-high participants and accuracy of their memory responses (Hits minus False alarms) in this Easy condition. We found in the Old-high group a marginally significant positive correlation between memory accuracy performance and the old/new effect in the right parietal

lobule (r¼ .44; p ¼.05) but not in in the right superior frontal gyrus (r¼.32). 2.2.2.1.2.Young vs. Old-low. By inclusively masking the ttest contrast with the simple effects of each group, we identified a great number of regions significantly more activated in the young than the old-low group. These areas were located in the superior frontal gyrus bilaterally, the left inferior frontal gyrus, the left anterior cingulate bilaterally, the left middle frontal gyrus and the left superior temporal gyrus. Other regions were found to be activated only for the young group, such as the left medial frontal gyrus, and the bilateral caudate nuclei (see Table 5 and Fig. 3a). By contrast, three regions demonstrated an old/new effect specifically in the old-low group, namely the right precuneus, the right

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Fig. 2 – Regions showing differences in old/new effects in the Easy condition between young and old-high adults, inclusively masked with the simple effects in each group (po.001 uncorrected). (a) Regions showing greater activity for the young group; (b) regions showing greater activity for the older group.

anterior cingulate gyrus and the right supramarginal gyrus (Fig. 3b). Correlational analyses revealed that memory accuracy in older adults was significantly negatively correlated with activity in the right precuneus (r¼
.50; po.05) but not with activity in the right supramarginal gyrus (r¼
.23) or in the right anterior cingulate gyrus (r¼
.08). 2.2.2.1.3.Old-high vs. Old-low. The comparison between the effects of the two older groups, inclusively masked with the simple effects of each group revealed that several frontal regions, such as the right superior frontal gyrus, the left middle frontal gyrus and the medial frontal gyrus bilaterally were activated only in the old-high group (see Table 5 and Fig. 4). In addition, activation in the left inferior frontal gyrus was significant in both groups but was greater in the old-high than the old-low group. Conversely, no region was more activated in the old-low than the old-high group. Interestingly, correlation between memory accuracy in old-high adults and neural activity was significant in the left middle frontal gyrus (r¼ .54; po.05) and marginally significant in regions of the right superior frontal gyrus (r¼ .43; p¼ .06) and the left medial frontal gyrus (r¼ .37; p¼ .10).

2.2.2.2. Hard condition 2.2.2.2.1.Young vs. Old-high. In this condition, the old-high group showed reduced activity compared to the young group in

the left inferior frontal gyrus, and in the bilateral anterior cingulate gyri (as demonstrated by the inclusive masking of the t-test contrast with the simple effects of each group; see Table 6 and Fig. 5a). By contrast, old-high participants overactivated right frontal regions, more precisely in the right superior frontal gyrus, the right middle frontal gyrus and the right inferior frontal gyrus compared to young participants (Fig. 5b). The correlation between memory accuracy performance and neural activity was significantly for the right inferior frontal gyrus (r¼.45; po.05) and marginally significant for the right middle frontal gyrus (r¼ .39; p¼ .09). 2.2.2.2.2.Young vs. Old-low. Inclusive masking of the t-test contrast with the simple effects of each group revealed that several regions, located in the left middle frontal gyrus, the inferior frontal gyrus bilaterally and the left superior temporal gyrus, demonstrated greater activations in the young group than the older group (see Table 6 and Fig. 6). In addition, areas in the right medial frontal gyrus, the lentiform nucleus and the right anterior cingulate gyrus were activated for young but not old-low participants. The reverse contrast did not reveal any region where activations were greater in the old-low group than the young group. 2.2.2.2.3.Old-high vs. Old-low. Several regions demonstrated a reliable old/new effect only in the old-high group, namely the right medial frontal gyrus, the left middle frontal

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Fig. 3 – Regions showing differences in old/new effects in the Easy condition between the young group and the old-low group, inclusively masked with the simple effects in each group (po.001 uncorrected). (a) Regions showing greater activity for the young group; (b) regions showing greater activity for the older group.

gyrus and the right anterior cingulate gyrus (as demonstrated by the inclusive masking of the t-test contrast with the simple effects of each group; see Table 6). For two other regions, in the left medial frontal and the left middle frontal gyrus, old-high participants exhibited greater effects than old-low participants.

2.2.2.3. Additional analyses. Additional analyses comparing recollection-related activity (Hits_Remember vs. Hits-Know) between the young and old-high groups only revealed greater activity for young than old-high adults in the left angular gyrus (at a statistical threshold of po.001 uncorrected).

3.

Discussion

This study investigated whether and how individual differences in executive functioning may influence age-related differences in long-term memory retrieval and its neural correlates, at different levels of task demand. The behavioral data indicated that older adults with high executive abilities showed intact memory performance compared to the young adults, whatever the level of task difficulty. By contrast, older adults with low executive abilities performed less well than the other two groups. At the neural level, comparison of

retrieval success effects across groups revealed both commonalities and differences. These behavioral and neural between-group differences are fully described and discussed below.

3.1.

Group-invariant retrieval success effects

Our data revealed a network of regions associated with retrieval success that were similarly engaged by young adults and the two groups of older adults under both difficulty conditions. All the groups showed greater activity for Hits than Correct rejections in bilateral frontal regions (Easy and Hard conditions: bilateral superior frontal gyri, left inferior frontal gyrus, left cingulate gyrus, right middle frontal gyrus; Easy condition only: left middle frontal gyrus), bilateral parietal areas (Easy and Hard conditions: bilateral inferior parietal lobule, left precuneus, right inferior parietal lobule; Easy condition only: left supramarginal gyrus; Hard condition only: right superior parietal lobule and right precuneus), left middle temporal gyrus and left thalamus. In addition, in the Easy condition, two other areas, in the right anterior parahippocampal gyrus and the left insula, demonstrated more activity for Correct rejections than Hits in the three groups. In the Hard condition, Correct rejections showed increased

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Fig. 4 – Regions showing greater old/new effects in the Easy condition in the old-high group than the old-low group, inclusively masked with the simple effects in each group (po.001 uncorrected).

activity compared to Hits in the left post-central gyrus and the left precentral gyrus. Thus, the brain networks associated

3.2. Intact memory performance in the old-high group under both difficulty conditions

with retrieval success across groups were broadly similar in both difficulty conditions. These brain regions largely show consistency with results from previous neuroimaging studies recently reported in two meta-analyses of episodic memory retrieval in young adults (Kim, 2010; Spaniol et al., 2009). This pattern of activity thus adds support to findings showing that retrieval success effects are mainly associated with components of both the default-mode network and the cognitivecontrol network (Kim, 2010). Activity in these regions differed little across groups, which is consistent with a meta-analysis of age differences in brain activity showing that several brain regions are often similarly engaged by both young and older adults during episodic memory retrieval (Spreng et al., 2010).

At the behavioral level, older adults with high executive functioning showed similar global memory performance to young adults, under both difficulty conditions. Nevertheless, the quality of their memory differed, as these older participants recollected the encoding context of the pictures less often than young participants did, but did judge old items as familiar more often. So, old-high participants' memories were of impoverished quality and an increased reliance on familiarity processes may have allowed maintaining adequate memory performance. Given that these groups had similar educational and cultural level but also equivalent general cognitive level, this finding may be related to the specific impact of a high executive functioning level. This is

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327

Q4

Table 6 – Regions showing group-related differences in old/new effects in the Hard condition at a cluster p value po.001 uncorrected. Region Young4Old-high Anterior cingulate gyrusa Inferior frontal gyrus Young4Old-low Inferior frontal gyrus

Middle frontal gyrus Medial frontal gyrusa Anterior cingulate gyrusa Superior temporal gyrus Lentiform nucleusa Old-high4Young Inferior frontal gyrusb Superior frontal gyrusb Middle frontal gyrusb Old-low4Young

Left/right

Location (MNI coordinates, x, y, z)

T score

Cluster size

Right Left Left

16, 26, 22
4, 28, 28
40, 16,
14

3.74 3.72 3.43

17 21 7

Left


28, 24,
2
50, 8, 34 38, 22,
2
48, 16, 36 10, 38, 30
4, 28, 28 12, 24, 22
48, 16,
10
22,
14, 0

4.49 3.49 3.43 3.48 3.33 5.89 4.89 4.44 3.47

165 34 13 34 1 673

48, 22, 38, 30, /

3.69 3.66 3.48 3.46 /

4 20 21 18

Right Left Right Left Right Left Left Right Right Right /

24, 12, 26, 36,

8 52 38 42

165 3

/ Old-high4Old-low Medial frontal gyrusb

Middle frontal gyrus Anterior cingulate gyrusb

Left Right

Lentiform nucleusb

Left


8, 30, 44 12, 38, 30 18, 48, 18
40, 4, 50 16, 24, 38 2, 18, 38
22, 4, 14

Old-Low4Old-High

/

/

Left Right

3.25 4.16 3.32 3.45 3.36 3.34 3.74

1 4 2 6 4 2 4

/

/

Significant old/new effect (Hits4CR) in the Old-low group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Old-low group). a Significant old/new effect (Hits4CR) in the Young group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Young group). b Significant old/new effect (Hits4CR) in the Old-high group only (as demonstrated by the inclusive masking of the t-test contrast with the simple effect of the Old-high group).

consistent with previous studies showing that high executive abilities allow older adults to maintain a memory level close to that of young adults (Angel et al., 2010; Butler et al., 2004; Glisky et al., 1995), in agreement with the executive hypothesis (Dempster, 1992; Parkin and Walter, 1992; West, 1996). As reviewed earlier, some regions demonstrated similar activity in the young and old-high groups during the recognition memory task. However, in line with behavioral evidence of age-related changes in the nature of the memories of oldhigh adults, a substantial number of regions showed agerelated differences in retrieval success activity. In the Easy condition, old-high participants showed reduced activity compared to the young group in different regions of the left hemisphere (left posterior parahippocampal gyrus, left thalamus, left middle and inferior frontal gyri, left cingulate gyrus, left temporal gyrus, left insula). The finding of an agerelated decrease in neural recruitment during episodic retrieval is in agreement with the results of several previous

studies (Angel et al., 2013; Cabeza et al., 1997; Grady et al., 1994; Spreng et al., 2010) and can be assumed to reflect the reduced efficiency of memory functioning with aging. However, these older adults with high executive abilities also demonstrated additional activations in the right superior frontal gyrus and the right inferior parietal lobule. This is consistent with the results of several previous studies showing greater recruitment with increasing age, most often in frontal areas (e.g. Daselaar et al., 2006) but also in parietal areas (Angel et al., 2013; Huang et al., 2012). It is worth noting that these overactivations in the old-high group were observed only in the right hemisphere whereas, as reported above, activations in several regions of the left hemisphere were found to be reduced. This finding is consistent with a study (Angel et al., 2009) in which the ERP parietal old/new effect was more symmetrically distributed in a group of older adults with high executive abilities than either a group of older adults with low executive abilities or young adults.

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Fig. 5 – Regions showing differences in old/new effects in the Hard condition between the young group and the old-high group, inclusively masked with the simple effects in each group (po.001 uncorrected). (a) Regions showing greater activity for the young group; (b) regions showing greater activity for the older group.

Based on the HAROLD model (Cabeza, 2002), it might be suggested that older adults tend to recruit areas in the contralateral hemisphere that are not engaged by young adults, possibly to compensate age-related decline of memory efficiency. Correlational analyses further revealed that activity in the right inferior parietal lobule in the old-high group was associated with higher memory accuracy, suggesting that they reflect successful compensation for age-related decline (for a discussion of the usefulness of brain-behavior correlations to define compensatory activity, see Dennis and Cabeza, 2012). One question that arises then is the nature of these mechanisms assumed to help old-high adults to compensate for their deficits and reach the level of memory accuracy of young adults. As indicated by the aged-related decrease in Remember responses and increase in Know responses, , it is possible that differences in retrieval strategies contributed to group differences in retrieval success activity. A few possible explanations can be proposed for the additional activity in the right superior frontal gyrus and the right inferior parietal lobule. First, as frontal and parietal regions are known to be part of a large executive control system (Collette et al., 2006), these additional activations may reflect the fact that older adults with high executive abilities rely more on some executive processes (e.g., monitoring processes or self-related processes) than younger people to

compensate for age-related decline and support episodic retrieval. Hypothetically, compensatory processes may serve recollection and/or familiarity by engaging strategies and processes that would foster the remaining recollection abilities or boost the reliability of familiarity judgments (for instance, by promoting cue specification, the search for details, verification strategies…). The idea of the increasing involvement of executive functions during memory retrieval with aging is supported by two recent works by Bouazzaoui et al. (2013, 2014) demonstrating that episodic memory performance in different tasks is strongly correlated with executive functions in older but not in young adults. Secondly, the additional activation in the right inferior parietal lobule may be in keeping with the AtoM model (Attention To Memory; Ciaramelli et al., 2010) which postulates functional subdivisions within the parietal cortex according to their role in attention and memory processes. The superior parietal lobe is assumed to mediate top–down attention to memory, while inferior parietal regions are believed to be associated with bottom–up processes. One can then hypothesize that in the Easy condition, where items were presented twice at encoding, older adults' attention may have been automatically directed towards salient retrieved contents, reflected in greater activity in the inferior parietal lobule. The additional presentation during encoding may have facilitated a mental

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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Fig. 6 – Regions showing greater old/new effects in the Hard condition in the young group than the old-low group, inclusively masked with the simple effects in each group (po.001 uncorrected).

re-experiencing of the studied item, through an ecphoric mechanism. This idea is supported by the fact that such age-related overactivations in the right inferior parietal lobule were not observed in the Hard condition where items were presented only once. Although the fMRI data, throughout the brain regions activated, provide some information about the strategy that may have been used, a paradigm in which participants are asked to explicitly verbalize their memory strategies would provide more direct information about the operations engaged by young and older adults according to their executive functioning and the level of task difficulty.

In the Hard condition, old-high participants also showed reduced activity compared to the young group in several areas in the left inferior frontal gyrus and the bilateral anterior cingulate gyri. Thus, fewer regions were found to be underactivated by older adults in the Hard condition than in the Easy condition.Analyses of the Hard condition also revealed that old-high adults demonstrated activity in a subset of areas that were not recruited by young adults. These regions were all located in the right frontal lobe, including, as in the Easy condition, the right superior frontal gyrus, and additionally the right middle frontal gyrus and the right inferior frontal gyrus. Some of these additional activations in the group of old-high participants were positively correlated with

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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their memory performance. This suggests that frontal overactivations reflect functional successful compensation helping older adults with high executive functioning to mitigate the effects of aging and maintain a high level of memory performance, even in this Hard condition. Interestingly, additional activations in the right superior frontal region, associated with good performance, were observed in both difficulty conditions but frontal overactivations were more widespread in the Hard than in the Easy condition. These results can be interpreted as supporting the CRUNCH model (Reuter-Lorenz and Cappell, 2008). According to this model, age differences in the degree of activation depend on task difficulty. Age-related overactivations are more likely to be observed at low than high levels of difficulty because of older adults’ limited resources. Our results show that the pattern of age differences between young and high-functioning older adults in retrieval success activity may be moderated according to task difficulty. Our old-high participants, thanks to their largely preserved executive resources, may have been able to deploy more effort than young adults, even in the Hard condition, as reflected in greater over-recruitments, which allowed them to maintain the same level of performance as the young participants, even in this effortful condition. However, in this condition, old-high adults did not show the additional recruitment of the right inferior parietal lobule that was observed in the Easy condition, possibly because they had reached their resource limits, as suggested by the CRUNCH model. This finding supports the idea that the increased activation of this region in the old-high group for the Easy condition may reflect the involvement of bottom–up processes. In the Hard condition, bottom–up processes would be less involved because items were presented only once during encoding. One might expect age-related overactivations to disappear in old-high participants in extremely difficult conditions. Thus, it would be interesting to investigate age-related differences in neural activity associated with memory across a range of task difficulties including even hardest conditions that those used in the present experiment, to challenge old-high participants’ resource limits.5

3.3.

Impaired memory performance in the old-low group

Consistently with our predictions, old-low adults performed less well than the two other groups under both difficulty. As old-high participants, old-low participants demonstrated impoverished memories, as shown by reduced Remember responses. Contrary to old-high participants, they did not increase their reliance on familiarity, which was at the same level as in young adults. Thus, the level of executive functioning modulates the effects of aging on memory abilities, as older adults with low executive abilities are more impaired than those with high executive functioning. Old-high adults may have been more able to implement efficient encoding and retrieval strategies. This is consistent with the cumulating evidence suggesting that the degree of executive decline during aging plays a prominent role in age-related deficits in episodic memory, especially under effortful conditions (Angel 5 It is worth noting that given the exploratory nature of this study, we chose a quite liberal statistical threshold so results significant only at an uncorrected threshold should be considered with cautious.

et al., 2010; Baudouin et al., 2009; Bouazzoui et al. 2013; Bryan and Luszcz, 2000; Bryan et al., 1999; Butler et al., 2004; Crawford et al., 2000; Ferrer-Caja et al., 2001; Glisky et al., 1995; Lee et al., 2012; Perrotin et al., 2008; Troyer et al., 1994) and thus adds support to the executive decline hypothesis. The aim of this study was thus to elucidate how these behavioral differences between young and older adults with different levels of executive functioning may be paralleled at the neural level. In the Easy condition, old-low participants showed reduced activity in different regions, mostly in frontal areas (bilateral anterior cingulate gyri, bilateral superior frontal gyri, left inferior frontal gyrus, left medial frontal gyrus, left middle frontal gyrus) but also in bilateral caudate and the left superior temporal gyrus compared to the young group. These age-related reductions of activity were more widespread than those observed for the old-high group in this Easy condition. This is in agreement with a recent ERP study showing that age-related differences in the old/new effect were greater in a group of older adults with low executive functioning than among those with high executive functioning (Angel et al., 2010). However, these old-low adults also exhibited additional activations in right parietal areas, more precisely in the right precuneus, the right cingulate gyrus and the right supramarginal gyrus. Nevertheless, despite this additional activity, their memory performance was still strongly impaired compared to the two other groups and the additional activity in the right precuneus was negatively correlated with memory accuracy. One possibility is that the recruitment of this region by old-low adults reflects an attempt to compensate for age-related deficits, but is insufficient to overcome their difficulties (for a full discussion of “attempted compensation”, see Cabeza and Dennis, 2012). This would be consistent with findings of Angel et al. (2009) that older adults with low executive abilities showed a late frontal negative ERP component during a cued recall task, which was interpreted as an unsuccessful additional attempt to cope with retrieval difficulties. However, old-low participants did not show the additional activations in frontal areas that were described in the old-high group. Several frontal lobe regions, including the right superior frontal gyrus, the left middle frontal gyrus, the left inferior frontal gyrus and the bilateral medial frontal gyri, were found to be less activated by the old-low than the old-high adults. The finding of reduced recruitment of frontal regions in this group compared to the other two groups is consistent with the fact that these older adults are strongly impaired in executive functioning which may partly explain their memory deficits. This adds further support to the hypothesis that additional frontal activations reflect a mechanism helping older adults with a high executive level to reach the same memory accuracy level as young people. Alternatively, additional recruitment observed in old-low adults may rather reflect declining neural efficiency, resulting in disruption of episodic memory performance. For instance, some authors have proposed that patterns of overactivation in older adults reflect dedifferentiation, ie. a reduced ability to engage focal activations of relevant areas when performing a task (e.g. Park et al., 2004, 2012; see Reuter-Lorenz, 2002 for a review). This interpretation is interesting since it suggests that age-related overactivations may reflect either successful compensation or

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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inefficient processes. The main difference between older adults of high vs. low executive functioning may be the ability to recruit neural regions whose activity is useful and may help boost memory performance. In the Hard condition, old-low participants also showed reduced activity in different bilateral frontal regions compared to the young and old-high groups, largely overlapping the network of regions underactivated in the Easy condition. In addition, they no longer showed additional activations compared to the young group in right parietal areas, in either the precuneus or in the supramarginal gyrus. The lack of increased activity in this Hard condition might be seen as consistent with the predictions of the CRUNCH model. As described earlier, in the Easy condition, the old-low participants showed greater activation in two right parietal areas (the right precuneus and the right supramarginal gyrus), supporting their memory performance but not enough to reach the level of the other groups. In the Hard condition, they may not have had enough available resources to engage compensatory processes, because of their limited executive abilities. In sum, the present study provides new insights into age differences in successful memory retrieval and its neural correlates and highlights the impact of both task difficulty and executive abilities. At a behavioral level, young adults and older individuals with more efficient executive functioning performed better in the episodic memory task. Neuroimaging results revealed that age differences in neural correlates of retrieval success were modulated by task difficulty, in line with the predictions of the CRUNCH model. In order to test this model more fully, it would be useful to look at taskrelated activation across a range of task difficulties including at least three degrees of difficulty. It would also be interesting to find a paradigm allowing to investigate the impact of task difficulty in aging on the neural correlates of recollection and familiarity processes separately, which was not possible in this experiment. Importantly, this study showed for the first time that these age-related differences according to the level of task demand, predicted by the CRUNCH model, were also influenced by individual differences in executive functioning. Older adults with a high executive functioning level demonstrated additional activity compared to the other two groups in right frontal and parietal regions, in the Easy condition and to a greater extent the Hard condition, which may have helped them compensate their difficulties and maintain a high level of memory performance, even in the hardest condition. Old-low participants showed additional recruitments in right parietal regions only in the Easy condition, reflecting possibly inefficient processes or an unsuccessful attempt of compensation. When task difficulty was greater, they no longer demonstrated these additional activations, suggesting that their limits of capacity were maybe reached. In addition to retrieval success, future work should also examine how executive level and task demands modulate encoding-related cerebral activations during aging, as one cannot exclude that the better memory performance of oldhigh participants was at least partly due to more efficient encoding operations. In terms of clinical perspective, one could evaluate the extent to which individual differences in how older adults cope with memory changes may predict

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1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 4. Experimental procedure 1818 1819 4.1. Participants 1820 1821 Twenty young adults (8 men, 12 women) aged 19–29 and forty 1822 older adults (15 men, 25 women) aged 60–78 participated in 1823 this experiment. Most of the young participants were stu1824 dents at the University of Liège and older adults were 1825 recruited from senior clubs in Liège. All were right-handed, 1826 as assessed by the Edinburgh laterality test (Oldfield, 1971). 1827 None reported any history of psychiatric or neurological 1828 disorder or were taking medication likely to affect the central 1829 nervous system. All had normal or corrected-to-normal 1830 vision and none reported having a hearing problem. All the 1831 older adults scored above the cut-off of 124 (range: 133–144) 1832 1833 on the Mattis dementia rating scale (Mattis, 1976), reducing 1834 the risk of including anyone suffering from a neurodegenerative disorder. Participants' executive functioning level was Q5 1835 1836 assessed through different tests: the Stroop test (Stroop, 1837 1935), the N-back test (Kirchner, 1958) and the Plus–Minus 1838 test (Jersild, 1927; see Section 4.2 for a complete description of 1839 each test and of the measures used). A composite index was 1840 calculated as the average of z-scores on these tests (com1841 puted on the basis of the global mean of the scores of both 1842 groups). According to the procedure developed by Glisky et al. 1843 (1995), older adults were then divided into two subgroups 1844 (old-high vs. old-low) according to their median score on this 1845 composite index (see also Angel et al., 2010). The old-low 1846 group demonstrated significantly lower score in this execu1847 tive index compared to the old-high group and the young 1848 group who did not differ from each other (F(2,57)¼ 42,26, 1849 po.001). The same pattern was observed for each executive 1850 test individually (Stroop test: F(2,57)¼ 22.32, po.001; N-back 1851 test: F(2,57)¼ 17.10, po.001; Plus–Minus test: F(2,57)¼7.88, 1852 po.001). Participants' characteristics for the young group 1853 and the two groups of older adults are shown in Table 1. 1854 The three groups did not differ in years of education (F(2,57)¼ 1855 1.60), or cultural level as assessed by the Mill Hill vocabulary 1856 test (Deltour, 1993) (F(2,57)¼ 2,35), and had similar scores on 1857 the Beck Depression Inventory (F(2,57)¼1.94; BDI; Beck et al., 1858 1961). Age (t(38)¼
0.19) and the score to the Mattis demen1859 tia rating scale (t(38) ¼1.25) did not significantly differ 1860 between the two groups of older adults. The experimental 1861 procedures were approved by the Ethics committee of the 1862 University of Liege and were performed in accordance with 1863 the ethical standards laid down in the Declaration of Helsinki 1864 of 1964. All participants gave their signed informed consent 1865 prior to the experiment and were paid twenty euros for their 1866 1867 participation. future cognitive decline or the development of neurodegenerative symptoms. Taken together, these findings suggest that great caution must be used when interpreting differences in the degree of activation between young and older groups and highlight that it is important to consider the heterogeneity among older adults as well as the level of difficulty of the task.

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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4.2.

Material and procedure

4.2.1.

Executive tests

Based on Miyake et al. (2000) and on previous work (Angel et al., 2010; Glisky et al., 1995), executive functioning was assessed using three tests assumed to tap each of the three specific executive functions: inhibition (Stroop test), updating (N-back test) and shifting (Plus–Minus test).

4.2.1.1. Stroop test. (Stroop, 1935). Two subtests of the standard Stroop test were used in the present experiment, the color subtest in which participants had to name the color of crosses (XXX), and the color-word interference subtest in which they had to name the color of the printed color name and not read the word. In each subtest, participants were required to name colors aloud as quickly as possible for 45 s. In each condition, the number of correct responses was recorded. Using the cross condition as the baseline, an interference score was calculated for each participant as follows: [(color-naming baseline condition score – color-naming word-color score)/color-naming baseline condition score]. We chose this more conservative measure of interference, as recommended by Li and Bosman (1996), rather than absolute difference scores, in order to take into account the lower baseline score of the older adults. Low scores indicated better inhibition abilities. 4.2.1.2. N-back test. (Gevins and Cutillo, 1993). In this test, classically used to assess updating abilities, a list of 30 letters was presented orally by the experimenter. For each letter, participants had to decide whether it was identical to the one presented two steps back in the sequence. They gave their answers orally and the number of correct responses was used as the dependent measure. 4.2.1.3. Plus–Minus test. (Jersild, 1927). This test involves three subtests each comprising 32 stimuli. In the first subtest, participants had to add three to each number, in the second (B), they had to subtract three from each number and in the third (C), they had to alternate between adding and subtracting three. For each list, they had to write down their answers and the time to complete each list was recorded. The measure used was the shifting cost, computed with the following formula: Time subtest C–((Time subtest AþTime subtest B)/2).

4.2.2.

Recognition memory task

The critical stimuli consisted of three hundred black-andwhite line drawings of common objects selected from the Cycowicz et al. (1997) database and standardized for Frenchspeaking subjects (Alario and Ferrand, 1999). These pictures were randomly divided into three lists of one hundred pictures, according to three possible versions. The lists were matched for name agreement, image agreement, complexity, familiarity, variability and age of acquisition (for a detailed description of each characteristic, see Alario and Ferrand, 1999). Each subject was allocated one version of the stimulus lists. In each version, the three lists were used for: 1) study items presented once (Hard condition), 2) study items presented twice (Easy condition), and 3) new items presented

only during the test phase. Fifteen additional items were selected to form practice lists for the study and test phases. We also included 30 scrambled pictures to serve as null events. Study lists were created by pseudo-arranging critical items and null events, with the constraint that two presentations of the same stimulus should be separated by at least ten stimuli. Two additional pictures were used at the beginning of the study phase to reduce the risk of primacy effects. Test lists consisted of items from the study lists, mixed with new items and null events, so that no more than three items of the same condition (studied, new or null events) should occur consecutively. Two filler items were added at the beginning of the block. The experiment included a study phase and a test phase, both performed in the MRI scanner. Before entering the scanner, participants carried out a practice session for the study phase. They were then positioned in the scanner and the study phase began. The study phase consisted of 332 trials corresponding to the 100 items presented once (Hard condition), 100 items presented twice (Easy condition), 30 null events, and the two filler items. All stimuli appeared on a black screen that participants could see in an overhead mirror. For each trial, a fixation cross was displayed for 500 ms in white and for 500 ms in red. The item then appeared for 3000 ms, with a jitter from 0 to 750 ms. Participants were not informed of the subsequent memory task. However, to encourage incidental encoding of the item and to reduce between-group variability in encoding strategies, a semantic task was introduced in which participants had to decide whether the depicted object would fit into a shoebox. They answered using a response box held in their right hand (yes/no response). There was a short break (30 s) after every 110 items. After the study phase, participants left the scanner for a break (5 min) and performed a practice session for the test phase. Then, in the scanner, participants completed the test phase which included 332 trials, with the 100 items studied in the Easy condition, the 100 items studied in the Hard condition, 100 unstudied items, 30 null events and two filler items. Each test trial began with a white fixation cross for 500 ms that then became red for 500 ms. The item was displayed until the subject responded, with a maximum of 4000 ms. Depending on response speed, a black screen sometimes appeared after the item to ensure intertrial intervals of 3000 ms minimum, with a jitter from 0 to 750 ms. For each item, participants were instructed to choose between three possible answers: remember (studied item associated with the recollection of some contextual details), Know (studied item recognized as old but without any contextual information), New (unstudied item). The answer was given by pressing one of the buttons of the response box. There was a short break (30 s) after every 110 items. As explained earlier, we chose to collapse Remember and Know responses for fMRI analyses because of the small number of items in some conditions and since the aim of the present experiment was to explore the neural correlates of successful memory retrieval, without dissociating the neural correlates of recollection and familiarity processes. Global accuracy in the memory task was examined through the discrimination index (Pr), computed as the difference between the proportion of Hits (collapsed across Remember and Know

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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judgments) and the proportion of False alarms (collapsed across Remember and Know judgments) when excluding items that had not received a response, for each level of difficulty. Behavioral analyses also examined the proportion of Remember and Know responses given to studied items of each condition and to new items (excluding items that received no response).

4.3.

fMRI acquisition

Functional MRI time series were acquired on a 3T head-only scanner (Magnetom Allegra, Siemens Medical Solutions, Erlangen, Germany) operated with the standard transmit-receive quadrature head coil. Multislice T2*-weighted functional images were acquired with a gradient echo-planar imaging sequence using axial slice orientation and covering the whole brain (34 slices, FoV¼ 192  192 mm2, voxel size 3  3x3 mm3, 25% interslice gap, matrix size 64  64  34, TR¼ 2040 ms, TE¼ 30 ms, FA¼901). The three initial volumes were discarded to avoid T1 saturation effects. Gradient-recalled sequences were applied directly after the study and test phases to acquire two complex images with different echo times (TE¼ 4.92 and 7.38 ms respectively) and to generate field maps for distortion correction of the echo-planar images (EPI). The other acquisition parameters of these sequences were TR¼367 ms, FoV¼ 230  230 mm2, 64  64 matrix, 34 transverse slices (3 mm thickness, 25% inter-slice gap), flip angle¼ 901, bandwidth¼ 260 Hz/pixel. For anatomical reference, a highresolution T1-weighted image was acquired for each subject (T1-weighted 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence, TR¼1960 ms, TE¼4.43 ms, inversion time (TI)¼ 1100 ms, FoV¼ 230  173 mm2, matrix size¼256  192  176, voxel size¼ 0.9  0.9  0.9 mm3).

4.4.

Data analysis

Only data from the retrieval session were analyzed and are included here. fMRI data were preprocessed and analyzed using SPM8 (Wellcome Department of Imaging Neuroscience, http//www.fil.ion.ucl.ac.uk/spm) implemented in MATLAB (Mathworks Inc., Sherborn, MA). For each subject, EPI time Q6 series were corrected for motion and distortion using Realign and Unwarp (Andersson et al., 2001) together with the FieldMap toolbox (Hutton et al., 2002) in SPM. Next, functional scans were realigned using rigid body transformations, iteratively optimized to minimize the residual sum of squares between the first and each subsequent image separately, and a mean realigned image was created. The structural T1-image was coregistered to this mean functional image using a rigid body transformation optimized to maximize the normalized mutual information between the two images. The mapping from subject to MNI space was estimated from the structural image with the “unified segmentation” approach (Ashburner and Friston, 2005). The warping parameters were then separately applied to the functional and structural images to produce normalized images of resolution 2  2  2 mm3 and 1  1  1 mm3 respectively. Finally, the warped functional images were spatially smoothed with a Gaussian kernel of 8 mm full-width at half maximum (FWHM). Neural activity was modeled at each voxel with a general linear model, using event types as regressors. These events

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2048 were sorted by item status (Old, New, Null event), encoding 2049 condition (Easy vs. Hard) and participants' response in the 2050 test phase (Remember, Know, New). Consequently, the 2051 design matrix included 10 events modeled separately: 1) 2052 Hits-Remember in the Easy condition, 2) Hits-Remember in 2053 the Hard condition, 3) Hits-Know in the Easy condition, 4) 2054 Hits-Know in the Hard condition, 5) Correct rejections, 6) 2055 Misses in the Easy condition, 7) Misses in the Hard condition, 2056 8) False alarms-Remember, 9) False alarms-Know, 10) Null 2057 events. The onset vector of each event type was convolved 2058 with a canonical hemodynamic response function. The 2059 design matrix also included the realignment parameters to 2060 account for any residual movement-related effect. A high2061 pass filter was implemented using a cut-off period of 128 s in 2062 order to remove low-frequency drifts from the time series. 2063 Serial autocorrelations were estimated with a restricted 2064 maximum likelihood algorithm with an autoregressive model 2065 of order one (plus white noise). 2066 To explore the neural correlates of successful memory 2067 retrieval processes at each level of difficulty, a series of linear 2068 contrasts was performed at the individual subject's level. 2069 Brain areas associated with retrieval success (“old/new 2070 effects”) were identified by comparing changes in brain 2071 activity for Hits, collapsed across Remember and Know 2072 judgments (“common effect”), and Correct rejections. Each 2073 side of the main effect of item type (Hits 4 CR and CR 4 Hits) 2074 was analyzed. This contrast was performed for the Easy and 2075 the Hard conditions separately. 2076 Individual contrast images were submitted to a second2077 level analysis corresponding to a random effects model in 2078 which subjects are considered as random variables. These 2079 individual contrast images were used to analyze: 1) neural 2080 activity common to both age groups for each level of diffi- Q7 2081 culty, and 2) between-group differences, according to task 2082 demand level. For a complete description of data, we report in 2083 the following analyses all significant results at a statistical 2084 threshold of po.001 uncorrected for multiple comparisons 2085 (e.g. Angel et al., 2013; Duarte et al., 2008). Significant results 2086 at a statistical threshold of po.05 FWE-corrected at the voxel 2087 level are also precised in tables when necessary . First, the 2088 retrieval success effects common to the three groups were 2089 identified by computing each side of the main effect of 2090 retrieval success (Hits 4 CR and CR 4 Hits) observed in the 2091 young, at a cluster p value po.001 uncorrected for multiple 2092 comparisons, and inclusively masking the resulting statisti2093 cal maps with the correspondent effects observed in the older 2094 groups, for each level of difficulty (Easy vs. Hard). Secondly, 2095 we focused on group differences in the neural correlates of 2096 retrieval success, according to task demand level. We per2097 formed t-test comparisons to compare the three groups two2098 by-two (Young vs. Old-high, Young vs. Old-Low, Old-High vs. 2099 Old-Low) for the retrieval success contrasts, at each level of 2100 difficulty, at a cluster p value po.001 uncorrected for multiple 2101 comparisons. These contrasts were inclusively masked with 2102 the simple effects of each group (Hits 4 CR and CR 4 Hits), at 2103 a cluster p value po.001 uncorrected for multiple compar2104 isons. This inclusive masking allowed us to evaluate the 2105 significance of the activations in each group and thus, to 2106 2107 determine whether these group differences reflected 1)

Please cite this article as: Angel, L., et al., Neural correlates of successful memory retrieval in aging: Do executive functioning and task difficulty matter? Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.10.009

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significant activations in both groups but greater in one group than the other or 2) activations significant in one group only.

Disclosure statement There are no actual or potential conflicts of interest.

Q8

Uncited references Anderssonn et al. (2001), Colette et al. (2006), Manenti et al. (2011), Nagel et al. (2011), Reuter-Lorenz et al. (2000) and Rossi et al. (2004).

Acknowledgments Q9 This work was supported by the National Fund for Scientific

Research (FRS-FNRS) in Belgium, the University of Liège, and a Belgian InterUniversity Attraction Pole (P7/11). SG is a research fellow, and FC a research director at the FRS-FNRS.

references

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