Age-related brain activation during forward and backward verbal memory tasks

neurology, psychiatry and brain research 20 (2014) 76–86

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/npbr

Age-related brain activation during forward and backward verbal memory tasks Hanani Abdul Manan a,*, Elizabeth A. Franz b, Ahmad Nazlim Yusoff a, Siti Zamratol-Mai Sarah Mukari c a Diagnostic Imaging and Radiotherapy Program, School of Diagnostic Science and Applied Health, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia b Department of Psychology and fMRIotago, University of Otago, William James Building, 275 Leith Walk, Dunedin 9016, New Zealand c Audiology Program, School of Rehabilitation Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia

article info

abstract

Article history:

The present study used fMRI to investigate the neural basis of memory for verbal information

Received 18 June 2013

using a forward repeat (FRT) and backward repeat task (BRT) administered in participants

Received in revised form

ranging between 20 and 65 years who were divided into four non-overlapping age groups.

18 June 2014

Results of behavioral performance on the FRT revealed no significant difference across age

Accepted 8 August 2014

groups. In contrast, behavioral performance on the BRT decreased with increasing age. fMRI

Available online 12 September 2014

results demonstrate that both FRT and BRT activated frontal areas, temporal areas and the cerebellum. However, parietal areas were only activated in BRT, suggesting increased task demands during the task. Furthermore, almost all activated areas demonstrated a larger number of activated voxels and greater percent signal change during BRT compared to FRT.

Keywords:

Interestingly, there was an apparent laterality shift with aging in that those areas that normally

Backward repeat task

show a leftward asymmetry in young participants change to more rightward asymmetry in the

Forward repeat task

older participants. In the FRT, areas involved in the laterality shift were the superior temporal

Laterality shift

gyrus, Heschl's gyrus and cerebellum, whereas in BRT the laterality shift involved the middle

Aging

frontal gyrus, superior parietal lobe and Heschl's gyrus. In all, the behavioral results were

fMRI

consistent with the fMRI results, with a decline in performance on the BRT with age, in contrast to rather unchanging performance on the FRT, possibly reflecting effective neurocompensatory processes in the latter. These results suggest that different neural mechanisms may be involved in FRT and BRT, issues which are elaborated with respect to memory processes during aging. © 2014 Elsevier GmbH. All rights reserved.

1.

Introduction

The aging brain is characterized by cell loss and widespread decreases in neural and metabolic efficiency which lead to deficits in cognitive performance.1–3 However, the mechanisms

by which these changes influence memory processes such as those involved in span recall task, for example, the commonly used forward repeat task (FRT) and backward repeat task (BRT), are not well understood. Both of those tasks require encoding auditory information (often verbal), and then repeating it back in forward (FRT) or backward (BRT) order. Furthermore, previous

* Corresponding author at: Diagnostic Imaging and Radiotherapy Program, School of Diagnostic Science and Applied Health, Faculty of Health Sciences, Universiti Kebangsaan Malaysia. Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Tel.: +60 3 26878084; fax: +60 3 26878108. E-mail addresses: [email protected], [email protected] (H.A. Manan). http://dx.doi.org/10.1016/j.npbr.2014.08.001 0941-9500/© 2014 Elsevier GmbH. All rights reserved.

neurology, psychiatry and brain research 20 (2014) 76–86

literature reports mixed evidence on both tasks. Some researchers have suggested that BRT employs the same memory mechanisms as FRT; i.e., both are involved in temporary storage of information, the mechanism that allows us to retain and retrieve information over time.4–7 Other neuropsychological studies have suggested that BRT might also involve processes of manipulation of information, rearranging the words presented in the backward manner4–6,8,9 which might be linked to executive processing and visual mental imagery (VMI).10–13 Previous literature concerning age-related decline on FRT and BRT processing also presents conflicting evidence. On the one hand, the neuropsychological and aging research of Hester et al.14 conducted on participants ranging in age between 16 and 89 years (using the Wechsler Adult Intelligence Scale, Third Edition: WAIS III and Wechsler Memory Scale, Third Edition: WMS III) reported that their findings reveal no evidence of a differential rate of decline between FRT and BRT tasks, given that both tasks equally demonstrated decline in older adults. Furthermore, Gregoire and Van der Linden,15 using a French adaptation of the WAIS-Revised (WAIS R) across 10 age groups of participants ranging in age between 16 and 79 years, confirms that there are age-related declines in both FRT and BRT. Indeed, significant age differences were observed in both tasks and these differences began to appear around the age of 65. However, the BRT did not yield larger age differences than the FRT. In addition, Myerson et al.16 examined 11 groups of participants ranging in age between 20 and 89 years using WAIS III and also reported no difference between FRT and BRT tasks for either verbal or visual spatial material. In contrast to findings reported above, Verhaeghen et al.17 compared younger (16–30 years) and older adults (60–80 years), reporting quite large age-related differences in memory, with BRT performance more affected than FRT performance in the older adults. This research is supported by further neuroimaging results using fMRI. Sun et al.11 compared younger adults with mean age 23 years and older adults with mean age 64 years and found that more regions, especially in the frontal cortex, exhibited greater activation in the BRT than in the FRT in the older adults. For example, right BA 44/45 showed more activation during the BRT in older adults than in young adults suggesting that BRT is more affected by aging than FRT at the neural level. Their analysis supported a clinical perspective in which, with advancing age, FRT processing tends to remain stable while BRT processing tends to decline. Given the mixed evidence of age-related changes and decline on both FRT and BRT tasks, a re-examination of the neural mechanisms for both tasks seems necessary if we are to eventually understand age-related cognitive declines at the neural level. In the present study, FRT and BRT protocols adapted from Light and Anderson18 were used. FRT required participants to recall the presented stimuli in the same order as presented; in contrast BRT required a backward recall of the presented stimuli (i.e., recalling in the reverse order). FRT task is considered ``a low demand memory task'' as this task only requires storage, rehearsal and retrieval processing. In contrast, BRT task is considered ``a high demand memory task'' as this task requires memory storage, rehearsal, retrieval and additional manipulation of information processing.5,6 The

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additional processing in BRT may suggest the need for increased demands on central executive functions.4–6,9 Executive function is not a memory store and is assumed to be an attentional control system responsible for strategy selection and for control and coordination of various processes.5,6 It is also a guide for the attention system and is believed to play an important role in controlling attention during VMI processes.4,9,19 The focus of this paper is on the effects of age in processing of FRT and BRT with the specific aim to assess possible changes in neural activity on the two tasks. Based on previous literature, we hypothesized that FRT and BRT processing involve different neural mechanisms, with BRT engaging processes of memory storage and manipulation of information, and FRT engaging only the memory storage processing and not the processes underlying manipulation of the remembered information. We also hypothesized that BRT performance would decline to a larger degree than FRT performance due to the former requiring additional demands on executive functioning. So as to avoid possible confounds that might arise when mixing males and females in the same study, we limited our study to just males. For example, a previous study reported that males had more prominent agerelated gray matter decreases and white matter and corpus callosal area increases compared to females.20

2.

Materials and methods

2.1.

Participants

Fifty-four Malay male right handed21 adult participants, ranging in age from 20 to 65 comprised the four age groups of participants (see Table 1). All participants were native Malay speakers. The groups of participants were matched in years of education. Furthermore, each participant's health status was examined through an interview prior to the experiment and the included participants had normal hearing and were free of tinnitus or neurological disease to best of their knowledge. The older adults (age 50 and above) were given the mini mental status examination (MMSE),22 with all of them scoring in the normal range between 28 and 30. After full explanation of the nature and risks of the study, written informed consent was obtained from all participants in accordance with the protocol approved by the Institutional Ethics Committee (IEC) of the Universiti Kebangsaan Malaysia (Reference no: UKM 1.5.3.5/ 244/NN-075-2009).

2.2.

Audiometry

Prior to the fMRI scan, a standard questionnaire and online audiometric measures were obtained from all participants (Rochester Hearing and Speech Center and http://myhearingtest.net/). Participants had hearing thresholds in a normal limit in the frequency range relevant for speech stimuli.23

2.3.

Data acquisition

This study was conducted in the Department of Radiology, UKM Medical Centre, using a 1.5-tesla magnetic resonance

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neurology, psychiatry and brain research 20 (2014) 76–86

Table 1 – Demographic and performance data obtained from 54 participants. Age groups

(Group 1) 20–29

(Group 2) 30–39

(Group 3) 40–49

(Group 4) 50–65

15 23–29 27  2.18 14.8  0.79 16.49  2.28 17.37  4.68

15 30–37 33  2.18 15.4  1.5 17.73  2.26 9.1  4.2

10 41–47 45  2.28 13.9 3.16 14.44  4.5 5.45  4.2

14 50–65 59  2.65 13  2.46 14.64  3.57 5.714  4.6

N Age (range) Age (mean  SD) Years of education (mean  SD) FRT, performance accuracy (mean  SD) BRT, performance accuracy (mean  SD)

Abbreviations: FRT, forward repeat task; BRT, backward repeat task.

= 192 mm  192 mm, flip angle (a) = 908, matrix size = 128  128 and slice thickness = 5 mm with 1.25 mm gap. A sparse temporal sampling was used to avoid the interference of scanner sound onto the stimulus.24 Data acquisition in the present study was similar to that in our previous published studies.25,26

imaging (MRI) system (Siemens Avanto) equipped with functional imaging options and echo planar imaging capabilities. A radiofrequency (RF) head coil was used for signal transmission and reception. Prior to collection of functional imaging scans, structural T1-weighted images were acquired using multi planar reconstruction (MPR) spin-echo pulse sequences with the following parameters: TR = 1240 ms, FOV = 250 mm  250 mm, flip angle = 908, matrix size = 128  128 and slice thickness = 1 mm. Functional images were then acquired using a gradient echo-echo planar imaging (GRE-EPI) pulse sequence. Each whole brain acquisition consisted of 21 axial slices covering all brain regions including the cerebellum. The following parameters were used for the functional scans: Repetition time (TR) = 2000 ms, echo time (TE) = 50 ms, field of view (FOV)

2.4.

Task materials

Stimuli for the backward repeat task (BRT) and forward repeat task (FRT) consisted of a series of natural speech words produced by a Malay male adult and were digitally recorded (Sony Digital Voice Editor), stored and edited using Adobe Audition 2.0 software. An intensity level of 55 dB was used for stimulus presentation.

(a) 0.5s

0.6s Verb

Verb

Noun

Verb

Noun

5s

(b)

T2

T1

Stimulus 0s

6s

111s 16s

Participants wait for the stimulus.

T3

Baseline

T4

Baseline

Stimulus 32s

48s

. . . T40

T5

. . . Baseline

Stimulus 64s

80s

. . . . 960s

Participants need to clear mind and keep still Response Time

Fig. 1 – (a) Illustration of stimulus train consisting of a sequence of five unrelated familiar words (verbs and nouns were randomly selected) to produce FRT/BRT conditions. (b) The same stimulus was used for both FRT and BRT tasks. The sequence of the conditions was fixed: FRT/BRT-baseline-FRT/BRT-baseline (although counterbalanced for the order of FRT and BRT). There were 40 trials for each task (trial 1 is indicate as T1 in the Figure and so on) and total duration of each trial is 16 s. During stimulus trials, stimuli were presented at the 6th second, and lasted approximately 5 s, and participants were given 5 s to repeat forward or backward all the words presented.

neurology, psychiatry and brain research 20 (2014) 76–86

2.5.

Experimental design

For both FRT and BRT the same stimuli were used. However, FRT and BRT tasks were tested in different scanning sessions. For FRT, participants were required to repeat in forward order, the five unrelated familiar words (verbs and nouns) presented. For BRT participants were required to repeat backward all five words. Fig. 1(a) shows an example of the FRT and BRT trial which consists of five consecutive 0.6 s duration stimuli separated by 0.5 s of silence, making up a total stimulus time of 5 s per stimulus train. During a trial, the stimuli were presented at the 6th second and lasted approximately 5 s, as in Fig. 1(b). For both FRT and BRT, participants were given 5 s to repeat (forward: FRT, or backward: BRT) the five words presented. Fig. 1(b) shows examples of trial sequences. There were 80 trials in total, 16 s for each trial, comprised of 20 trials with each type of stimulus (FRT or BRT) along with 20 trials with no stimulus (baseline) in each of those sessions. Before a participant entered the MRI scanner, instructions about the task were explained in detail and it was emphasized that participants were to focus with an otherwise clear mind throughout the procedure and to keep still. During scanning, participants lay comfortably in a supine position in the MRI scanner. An adjusted head holder restricted head movement. Auditory stimuli were presented through earphones. During scanning, for BRT, participants were also instructed to use visual mental imagery (VMI) strategies (imagine the words presented and rearrange in the reverse order), as this technique greatly improves BRT processing.10,12 Each participant's scores (for both FRT and BRT) were recorded manually by an experimenter in the console room (i.e. number of correct forward/backward repetition trials).

2.6.

Data analysis

Each participant's behavioral performance in both FRT and BRT conditions was scored as the mean of the series of words correctly repeated. Repeated measure analyses of variance (ANOVAs) (SPSS 20.0 statistical software package) were then used for all participants' data using age group as a betweensubjects factor, to evaluate age related differences on performance accuracy. The data were further analyzed using post hoc Tukey tests to evaluate which groups show age-related differences. Linear regression was used to evaluate performance accuracy verses age for FRT and BRT separately. To compare between tasks (FRT and BRT) paired t-tests on different age groups were conducted on performance accuracy. For fMRI data processing, our sparse-imaging data were analyzed in a manner similar to procedures in our previous studies25,26 using MATLAB 7.4 – R2008a (Mathworks Inc., MA, USA) and Statistical Parametric Mapping (SPM8) (Functional Imaging Laboratory, Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College of London, UK; http://www.fil.ion.ucl.ac.uk/spm). The first two images of every EPI-recording session were discarded to account for the approach to steady state of the MR signal. Prior to image analysis, each participant's raw data were motion-corrected and normalized.27 The amount of absolute

79

motion did not exceed 3 mm for any participant. Four participants' data were discarded from data analysis due to excessive motion. Data were further analyzed using a 12parameter non-linear normalization into the MNI-reference state as implemented in SPM8, and with smoothing (FWHM = 6 mm). The fMRI data were analyzed according to the general linear model as implemented in SPM8. With regard to the different conditions, two regressors were included in the design: BRT/FRT and baseline (Q). The regressors were convolved using the hemodynamic response function as provided in SPM8. Statistical analysis was performed using a mixed effects model: fixed effects analysis (FFX) was used for single participant analysis and random effects analysis (RFX) for group analysis. For group analysis, contrast images were computed for each participant, and then one-sample t-tests were performed. For FFX analysis, statistical significance was set at p < 0.05, emerging from whole-brain analyses. For RFX analysis, statistical significance was set at p < 0.05 cluster level.28 Finally, the region of interest (ROI) approach was used, focusing on the cortical brain region with a minimum cluster size of 15 voxels and p < 0.05 at cluster size defined using automatic anatomic templates derived from the toolbox WFU pickatlas.29 The rationale of using the cut-off with minimum 15 voxels and p < 0.05 at cluster level is to discard the unwanted voxels which arise due to high levels of activation for small cluster sizes that are not interpretable. The ROIs in this study included the superior temporal gyrus (BA 22), middle temporal gyrus, precentral gyrus, post central gyrus, inferior parietal lobe, superior parietal lobe, cerebellum, and Heschl's gyrus, as these areas have been suggested to be involved in memory processing and attention in previous imaging studies.2,3,30 These ROIs were all defined for each participant anatomically. In each participant, the activated voxels in each ROI were collected and used in further analysis. In each group, the activated volumes in the anatomically defined ROIs for the two experimental tasks (FRT and BRT) were compared using paired t-tests to ascertain which ROIs exhibited a significant effect. Then, a two-way ANOVA was used to examine the effects of aging on the number of activated voxels (NOV) and whether the effect was different for FRT and BRT. Bonferroni correction was applied for multiple comparisons where appropriate. The laterality index (LI) was calculated using the formula LI = (VL VR)/(VL + VR), in which VL is the number of the activated voxels in the left hemisphere and VR is the number of activated voxels in the right hemisphere. The LI ranges from 1 to 1 from which the values between 1 and 0 indicate right hemisphere dominance and from >0 to 1 indicate left hemisphere dominance.31

3.

Results

3.1.

Behavioral data

Behavioral data (performance accuracy) were first analyzed for FRT and BRT for the four age groups: group 1 (20–29 years), group 2 (30–39 years), group 3 (40–49 years) and group 4 (50–65 years). ANOVA and paired t-tests with a between-subjects

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neurology, psychiatry and brain research 20 (2014) 76–86

factor of age group and within-subjects factor of task (FRT and BRT) were conducted. Bonferroni was applied where appropriate due to multiple comparisons (using p < 0.01); behavioral results are shown in Table 1 for each group. For the FRT, results showed no significant differences across age groups on any test, nor was there a significant correlation between age and behavioral scores. In marked contrast, for the BRT, there was significant main effect of age group on behavioral scores F (3, 50) = 6.302, p = 0.001. Tukey comparisons further revealed differences between group 1 (the youngest group) and group 2 ( p = 0.005), groups 1 and 3 ( p = 0.003) and groups 2 and 3 ( p = 0.004). The comparison between groups 3 and 4 (the oldest group) did not reach significance on its own. A further analysis using linear regression was conducted to evaluate the age-related effects on behavioral scores, revealing a significant effect (R2 = 0.151, F (1, 52) = 9.279, p = 0.004). Thus, results clearly demonstrate decreases in performance accuracy with increasing age for the BRT. Paired t-tests demonstrated that all four age groups scored significantly better on the FRT task compared to the BRT task ( p < 0.003 on all comparisons).

3.2.

fMRI data

3.2.1.

Effects of aging on FRT

The FRT task activated the superior temporal gyrus (STG), middle temporal gyrus (MTG), precentral gyrus (PCG), postcentral gyrus (Post-CG), cerebellum, and Heschl's gyrus (HG). The activated volume, t-value and percentage of signal change (PSC) in each brain region for FRT for each age group are given in Table 2 (for the left hemisphere) and Table 3 (for the right hemisphere). The brain activation pattern and plots of the four age groups are as in Fig. 2. Results on the laterality index (LI) calculation reveal evidence consistent with a hemispheric laterality shift with aging. The LI for all activated areas for all four groups of participants is tabulated in Table 4. Brain areas involved in this laterality shift were the STG, cerebellum, and HG. These areas demonstrated normal leftward asymmetries in young participants. However, the same brain areas appeared to shift to a more rightward asymmetry in the older participants. Results also reveal that these laterality shifts vary from one brain region to another. For example, the STG and HG show a rather late shift which begins only in group 4 participants (i.e., it was not yet present in the younger groups). In contrast, the cerebellum shows an earlier shift in laterality, apparent already in group 2 participants.

3.2.2.

Effects of aging on BRT

All four groups of participants activated the same brain areas including bilateral STG (covering BA 22), MTG, PCG, inferior frontal gyrus (IFG), middle frontal gyrus (MFG), inferior parietal lobe (IPL), superior parietal lobe (SPL), cerebellum, Post-CG and HG. However, group 4 participants did not significantly activate left MFG, left SPL, right IFG, and right IPL during the task. The activated volume, t-values, and PSC of the activated areas are given in Table 2 (left hemisphere) and Table 3 (right hemisphere) and are plotted in Fig. 2. Results on the LI indicate a hemispheric laterality shift with age on areas of the MFG, SPL and HG and are tabulated in

Table 4. These brain areas revealed the normal leftward asymmetries in young participants. The laterality asymmetry then appears to shift to a more rightward asymmetry in the older groups of participants. Results also reveal that these laterality shifts vary from one region to another, with both the MFG and SPL showing early shifts (apparent already in group 2). Conversely, HG shows a later laterality shift, apparent in group 3 and older.

3.2.3.

Brain volume: effects of aging on FRT versus BRT

Compared to FRT, results reveal additional activation in bilateral IPL and SPL during BRT (as in Tables 2 and 3). Brain activity of all the activated voxels was higher during BRT (plotted in Fig. 2a–h) compared to FRT. However, four brain regions did not show differences after Bonferroni corrections. The areas were left Post-CG in group 2 participants (t = 0.325, p = 0.03), right STG in group 2 (t = 0.126, p = 0.025), right IFG in group 2 (t = 1.029, p = 0.011), and right PCG in group 2 (t = 0.536, p = 0.032). These effects support the hypothesis that there is a relative increase in brain activity related to greater memory load during BRT compared to FRT. The present study also reveals that frontal areas, notably bilateral IFG (plot 2g) and MFG (plot 2h), were activated to a greater spatial extent and with a higher percentage of signal change (PSC) in BRT compared to FRT. To determine whether there is an interaction between age groups (all four groups of participants) and both tasks (FRT and BRT) on the number of activated voxels of STG, MTG, PCG, MFG, cerebellum, Post-CG and HG a two-way ANOVA was used. Three areas show significant main effects: bilateral STG, bilateral MFG and right cerebellum. For the STG, results reveal a significant main effect of age group on the number of activated voxels (NOV): left STG F (3, 50) = 39.140, p = 0.025; right STG F (3, 50) = 31.130, p = 0.027. Result also reveal a significant main effect of task on the NOV: F (1, 50) = 2.150, p = 0.037. Results for MFG further reveal a significant main effect of age group on the NOV: left MFG F (3, 50) = 26.117, p = 0.050; right MFG F (3, 50) = 32.001, p = 0.042. There was also a significant main effect of task on the NOV: F (1, 50) = 3.546, p = 0.026. Results for right cerebellum also reveal a significant main effect of age group on the NOV: right HG F (3, 50) = 19.020, p = 0.019. Finally, there was a significant main effect of task on the NOV: F (1, 50) = 5.977, p = 0.010. Other activated brain areas (including bilateral MTG, bilateral PCG, bilateral HG and left cerebellum) revealed non-significant main effects age group and tasks on NOV. Results of the PSC were similar to those of activated volumes (as in Tables 2 and 3). PSC of all activated areas were relatively higher in BRT in all four groups of participants as comparison to FRT, (threshold p < 0.05).

4.

Discussion

The objective of this study was to examine age-related cognitive changes on a forward repeat task (FRT) and backward repeat task (BRT) in four groups of participants of different ages. Results reveal that both FRT and BRT activated a network of brain areas in the frontal and temporal lobes, and in the cerebellum. However, results revealed that FRT did not

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neurology, psychiatry and brain research 20 (2014) 76–86

Table 2 – Anatomical area, brain hemisphere, t-value, coordinates of maximum intensity (x, y, z), number of activated voxels, and percentage of signal change obtained from group analysis ( pFWEcorr < 0.001), showing comparisons of the four age groups on left hemisphere effects in BRT and FRT tasks. Left

ROIs

FRT

BRT Coordinate (x, y, z)

Activated volume (mm3)

PSC (%)

t

Coordinate (x, y, z)

Activated volume (mm3)

PSC (%)

t

60, 12, 12 54, 28, 4 50, 4, 46 40, 22, 16

276 122 96 20 – – – 59 300 49

1.157 0.637 0.835 0.826 – – – 0.694 0.806 0.874

6.61 5.59 5.09 5.89 – – – 5.34 7.67 5.58

1204 299 737 85 12 – – 469 530 185

1.173 1.972 0.765 0.28 0.53 – – 0.219 0.502 1.221

13.13 9.9 8.71 2.83 2.01 – – 8.18 9.56 6.08

571 145 203 – 17 – – 51 66 42

0.932 0.819 0.417 – 0.395 – – 0.756 0.262 0.277

12.72 8.49 8.79 – 2.8 – – 10.23 8.19 6.55

253 106 105 – – – – – 99 11

0.797 0.956 0.587 – – – – – 0.252 0.302

6.04 5.91 7.83 – – – – – 6.96 4.61

Group 1 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

52, 36, 14 62, 26, 6 46, 6, 46 48, 32,26 40, 54, 14 30, 56, 40 32, 60, 44 28, 60, 30 46, 12, 34 36, 28, 8

1403 847 747 77 307 473 151 405 929 120

1.271 0.67 0.873 0.213 0.637 0.469 0.848 0.483 0.827 0.906

8.58 8.49 6.83 6.57 6.17 6.12 4.72 6.57 6.84 7.34

Group 2 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

60, 10, 2 62, 12, 0 50, 8, 30 42, 28, 22 34, 2, 56 38, 38, 38 36, 48, 56 26, 58, 30 50, 10, 30 64, 8, 8

1384 648 1220 1407 165 256 12 1389 789 134

1.29 1.17 0.972 0.833 0.637 0.327 0.324 0.31 0.696 0.908

9.29 9.15 12.75 6.17 4.85 4.7 4.28 11.45 13.82 5.42

Group 3 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

56, 66, 36, 36, 34, 38, 30, 4, 62, 60,

1274 555 606 479 137 176 27 482 549 104

0.982 1.352 0.65 0.36 0.642 0.294 0.253 1.503 0.295 0.296

24.17 13.59 11.32 7.52 5.79 5.73 5.58 7.4 9.47 6.4

1104 466 426 154 – 13 – 790 553 93

1.216 0.916 0.712 0.387 – 0.334 – 0.699 0.334 0.422

9.28 4.69 6.73 4.59 – 3.54 – 6 7.93 6.94

Group 4 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

0, 8 24, 4 0, 58 22, 8 2, 56 48, 46 60, 46 86, 20 2, 14 14, 8

58, 12, 0 60, 14, 0 52, 4, 36 30, 28, 4 – 32,

50, 38

– 8, 82, 26 44, 10, 36 56, 12, 8

– – – 4, 74, 24 62, 10, 14 32, 30, 10

56, 6, 0 62, 14, 0 54, 6, 34 44, 22, 28 44, 14, 14 – – 24, 56, 36,

62, 28 6, 16 30, 14

58, 20, 2 58, 20, 0 42, 2, 38 – 24, 0, 50 – – 40, 58, 48,

68, 28 2, 20 16, 6

58, 58, 42,

32, 10 32, 8 8, 44

44, 42,

10, 40 4, 6

– – – – –

(–) Not significant. Abbreviations: BRT, backward repeat task; FRT, forward repeat task; PSC, percentage of signal change; STG, superior temporal gyrus; MTG, middle temporal gyrus; PCG, precentral gyrus; IFG, inferior frontal gyrus; MFG, middle frontal gyrus; IPL, inferior parietal lobes; SPL, superior parietal lobes; Post-CG, postcentral gyrus; HG, Heschl's gyrus.

significantly activate parietal areas, whereas BRT did. Results also revealed that neural activity in frontal areas exhibited greater activation in BRT compared to FRT. Furthermore, fMRI results and behavioral performance (behavioral scores) revealed interesting differences associated with FRT and BRT tasks. Responses in key regions of interest will be discussed in more detail and possible neural mechanisms

underlying these two types of memory tasks will also be considered.

4.1.

Neural basis of FRT and BRT

In the present study, with neuroimaging measurements we found that the brain regions involved in FRT are different to

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neurology, psychiatry and brain research 20 (2014) 76–86

Table 3 – Anatomical area, brain hemisphere, t-value, coordinates of maximum intensity (x, y, z), number of activated voxels, and percentage of signal change are obtained from group analysis ( pFWEcorr < 0.001), comparing four groups of participants on right hemisphere effects in BRT and FRT tasks. Right

ROIs

FRT

BRT Coordinate (x, y, z)

Activated volume (mm3)

PSC (%)

t

Coordinate (x, y, z)

Activated volume (mm3)

PSC (%)

t

Group 1 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

54, 30, 12 58, 20, 8 46, 8, 30 52, 14, 2 38, 44, 22 40, 40, 40 36, 64, 56 24, 62, 30 50, 6, 28 46, 18, 4

1436 459 413 84 211 10 27 428 537 139

0.826 1.124 0.814 0.234 0.469 0.517 0.62 0.821 0.613 0.528

6.39 5.31 8.84 6.52 4.95 3.94 3.56 6.02 8.88 5.42

46, 24, 4 48, 22, 8 50, 8, 36 42, 22, 24 – – – 26, 64, 30 56, 10, 22 –

170 25 23 18 – – – 35 145 –

0.682 1.124 0.282 0.76 – – – 0.415 0.35 –

7.23 4.92 4.64 5.89 – – – 6.4 5.25 –

Group 2 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

66, 14, 4 64, 16, 8 56, 2, 26 30, 24, 6 36, 56, 12 – – 22, 66, 28 54, 2, 24 60, 8, 6

1426 108 698 378 214 – – 1653 283 94

1.124 0.329 0.814 0.529 0.469 – – 0.821 0.268 0.295

10.34 5.84 9.12 7.65 5.56 – – 13.71 9.04 4.76

64, 10, 6 69, 20, 4 50, 4, 40 48, 18, 12 40, 16, 4 – – 34, 60, 30 56, 4, 30 40, 20, 6

1192 23 393 173 44 – – 646 227 124

1.018 0.227 0.743 0.452 0.635 – – 0.802 0.213 0.183

12.45 6.15 9.24 6.38 5.53 – – 9.69 8.19 6.92

Group 3 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

66, 66, 62, 38, 36, 48, 14, 16, 60, 62,

18, 4 18, 8 2, 22 30, 2 44, 18 38, 56 72, 54 62, 24 0, 20 4, 6

1265 309 242 157 160 180 42 451 301 109

1.939 0.979 0.737 0.348 0.501 0.284 0.578 0.702 0.665 0.939

11.23 8.87 10.93 7.03 6.29 5.85 5.64 7.22 18.77 7.01

54, 16, 8 52, 16, 10 46, 0, 34 48, 12, 34 28, 4, 56 – – 36, 58, 32 56, 2, 22 60, 4, 6

430 108 148 14 20 – – 108 73 10

1.279 0.781 0.441 0.314 0.512 – – 0.541 0.645 0.516

14.3 11.42 6.66 12.74 7.42 – – 8.86 6.31 5.57

Group 4 STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

62, 18, 0 60, 24, 4 46, 10, 36 – 32, 56, 18 – 14, 72, 54 32, 74, 28 46, 10, 34 60, 8, 6

1267 255 217 – 23 – 30 1179 168 153

1.118 0.308 0.836 – 0.25 – 0.334 1.695 0.584 0.52

11.84 3.58 6.03 – 4.95 – 4.4 8.89 4.13 7.2

64, – 44, – – – – 38, – 64,

435 – 51 – – – – 19 – 31

1.08 – 0.333 – – – – 1.848 – 0.378

8.11 – 5.68 – – – – 4.59 – 6.69

18, 0 6, 42

78, 4, 6

24

(–) Not significant. Abbreviations: BRT, backward repeat task; FRT, forward repeat task; PSC, percentage of signal change; STG, superior temporal gyrus; MTG, middle temporal gyrus; PCG, precentral gyrus; IFG, inferior frontal gyrus; MFG, middle frontal gyrus; IPL, inferior parietal lobes; SPL, superior parietal lobes; Post-CG, postcentral gyrus; HG, Heschl's gyrus.

some extent from those involved in BRT. These point to possible differences in cognitive operations underlying the tasks. FRT is believed to reflect ``a low demand memory task'' which primarily involves information storage. In contrast, BRT is thought to reflect ``a high demand memory task'', which involves primarily information storage, manipulation of information and additional executive functions.32

During BRT we found parietal regions were activated: bilateral SPL and IPL. It is likely that such differences in neural activity between the tasks were due to the additional mechanisms required in BRT processing, notably that of holding items in a memory store while rearranging them into their reverse order in preparation for responding. Thus, based on the nature of the BRT, we propose that activation in the

neurology, psychiatry and brain research 20 (2014) 76–86

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Fig. 2 – Plot shows primary effects of brain activation during FRT and BRT tasks for the four groups of participants: (a) STG, (b) MTG, (c) PCG, (d) cerebellum, (e) Post-CG, (f) HG, (g) IFG and (h) MFG.

parietal lobe (bilateral IPL and SPL) reflects the use of visual mental imagery (VMI) processing. Indeed, VMI has been shown to greatly improve memory processing,33 and our findings are consistent with previous studies demonstrating the involvement of the parietal lobe in VMI (seeing with the mind's eye).10–12 The present study also reveals that frontal areas, notably bilateral IFG and MFG, were activated to a greater spatial extent and with a higher percentage of signal change (PSC) in BRT compared to FRT. These results are consistent with the view

that backward recall taps into executive processes. Specifically, the BRT requires holding information for short periods of time and performing a further mental manipulation, reflecting the need for additional executive processing.5–7,34 Moreover, the involvement of IFG and MFG in BRT is consistent with the previous studies; information is temporarily stored and at the same time other activities of the phonological loop are coordinated.35,35,36 The present results are also supported by previous claims that frontal areas are involved in cognitive tasks requiring executive functioning.2,3,30 Specifically, activation of

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neurology, psychiatry and brain research 20 (2014) 76–86

Table 4 – Laterality index (LI) value for each activated voxel obtained from the group analysis comparing four groups of participants during BRT and FRT tasks. Group 1

STG (BA 22) MTG PCG IFG MFG IPL SPL Cerebellum Post-CG HG

Group 2

Group 3

Group 4

BRT

FRT

BRT

FRT

BRT

FRT

BRT

FRT

0.01 0.29 0.29 0.04 0.18 0.95 0.69 0.03 0.26 0.07

0.23 0.65 0.61 0.05 0 – – 0.25 0.34 1

0.01 0.71 0.27 0.58 0.13 1 1 0.09 0.47 0.17

0.01 0.85 0.31 0.34 0.57 – – 0.16 0.41 0.19

0.01 0.28 0.43 0.51 0.08 0.01 0.22 0.33 0.31 0.02

0.14 0.14 0.15 1 0.08 – – 0.36 0.05 0.61

0.07 0.29 0.32 1 1 1 1 0.19 0.53 0.24

0.26 1 0.34 – – – – 1 1 0.48

(–) Not significant. Abbreviations: BRT, backward repeat task; FRT, forward repeat task; STG, superior temporal gyrus; MTG, middle temporal gyrus; PCG, precentral gyrus; IFG, inferior frontal gyrus; MFG, middle frontal gyrus; IPL, inferior parietal lobes; SPL, superior parietal lobes; PostCG, postcentral gyrus; HG, Heschl's gyrus.

frontal areas (IFG and MFG) found in the present study is consistent with support based on Dara et al.37 and Dong et al.38 suggesting that frontal areas play an important role in backward recall. Thus, our findings implicate executive function involvement in BRT not necessarily required in FRT.

4.2. Comparison between FRT and BRT across the four age groups The results of the present study indicate that both FRT and BRT tasks are affected by the process of aging. This is clearly shown in the areas that play a major role in both such as STG, cerebellum and MTG. Additionally, the results indicate that the changes (in terms of NOV, p-values, and PSC) in the brain are more pronounced in BRT compared to FRT processing across age groups. The present results are supported by other claims indicating that performance differences across age groups increase with greater task complexity.39,40 As suggested earlier, aging effects are more detrimental in tasks requiring engagement of processes used in storage and manipulation of information as in BRT, in comparison with tasks involving storage only, as in FRT.41 The present study also found that right IFG and left MFG were not significantly activated in group 4 (the oldest participants) participants during BRT. Furthermore, the neural activity and PSC in bilateral MFG decreased with age. We suggest that the decrease of activity across the four age groups might be related directly to differences in brain processes underlying executive functions, although specific processes remain to be determined; early structural or volumetric deterioration within the frontal areas has been suggested to be responsible for executive function decline.42–44 It is difficult at this time to interpret precisely the brain changes underlying a decrease or omission of significant brain activity to a particular area as reflecting some sort of decline or degeneration, versus something more related to changes in efficiency which also might be possible (although notably there were also some performance declines on the BRT in older participants that also must be accounted for). Indeed, executive components are the most sensitive (in terms of functional and connectivity factors) and are most affected by aging. According to the frontal-executive hypothesis, early

age-related changes implicating frontal areas are associated with deficits in executive processes.45 As mentioned earlier, the BRT depends on executive functions such as information manipulation. Moreover, age-related changes are more apparent in tasks demanding high levels of attention and control processes. In addition, numerous studies report reliable age differences on BRT, suggesting the possibility of age-related declines in executive processing operations.43,45 But as stated above, more research is necessary to disentangle these interesting issues. During FRT, we found bilateral IFG and MFG were not significantly activated in groups 1 and 4 participants, suggesting that FRT might not depend on executive function in the same manner as BRT, and other literature seems to support this possibility.39,41 Given that both BRT and FRT require encoding and storage processes, but BRT requires additional manipulation, it seems reasonable to suggest that the difference across the two tasks best reflects executive processes involved in information manipulation. The inference is that some aging effects appear to preserve storage operations despite selectively affecting neural operations associated with executive processing and possibly also, VMI processes.

4.3.

Behavioral data in relation to fMRI findings

Our behavioral results during FRT were approximately the same across our four age groups, suggesting that performance accuracy is not considerably impaired with aging on that task. Indeed, FRT processing is thought to reflect a limited capacity store which keeps information active for a brief period of time (3–30 s),,35,36 and is thought to remain relatively stable until about age 70.46 Our behavioral results are also supported by the claim of Dobbs and Rule41 that the form of memory underlying FRT processing is more stable than that underlying BRT. In contrast, our neuroimaging results reveal age-related brain changes with respect to hemispheric laterality. As already described, changes in the spatial distribution of brain activation patterns indicated a leftward asymmetry in young groups and a change to more rightward shift in the asymmetry in the older groups (in STG, HG, and cerebellum). Interestingly, these apparent shifts occurred even though performance does not appear to have been affected. One might infer that the

neurology, psychiatry and brain research 20 (2014) 76–86

over-recruitment of contralateral (right-sided) regions of the brain in the older groups is evidence of effective neurocompensatory functions. In other words, the additional activity of contralateral areas might be brought on-line in the older groups to mediate task-relevant cognitive operations and enable optimal performance.2,47 The additional neural activity of right-sided brain areas (right hemisphere of STG, HG, and cerebellum) might also be in association with increased task difficulty with aging. Thus, in response to neural decline with aging, the brain retains a certain amount of residual functional plasticity and may remodel or reorganize activation patterns and neural networks to mitigate the effects of the decreasing integrity of the aging brain.3,48,49 We further suggest that in FRT the older brain processes the task differently, even when performance is comparable to that of younger adults. In contrast to that of the FRT, performance accuracy during the BRT shows that older groups perform less well than the younger groups. Thus, task performance was significantly affected by aging. Neuroimaging results further reveal that frontal area activity drastically decreases in older participants compared to younger participants on the BRT. Moreover, bilateral MFG was not significantly activated in older participants. It is well established that higher-order cognitive functions (likely including those underlying BRT) have been associated with prominent activation in the prefrontal cortex.30 Thus, the poorer performance of the older participants might result from under-activation of frontal areas such as the IFG and MFG. This interpretation is strengthened by evidence indicating that damage to frontal areas commonly produces impairments in executive control.2,30 Moreover, our behavioral results are consistent with findings showing executive function deficits with increasing age.3,49,50 Additionally, age-related underactivation often involves the prefrontal cortex, a general pattern that converges with conclusions from lesion models of aging.51,52 Compared to the FRT, the BRT shows steady performance declines across the age groups which are accompanied by a progressive decrease in activation of frontal areas (bilateral MFG and IFG) and changes in brain laterality in three areas: MFG, SPL and HG. These results again suggest that aging differentially affects FRT and BRT tasks and that FRT task performance is relatively stable at least until age 65 (the maximum age in our study), consistent with the notion that the BRT is more sensitive to age-related cognitive decline53 and that age-related changes are more apparent in tasks placing demands on executive functions.41 That aging seems to spare performance on FRT tasks while leading to marked declines on BRT task that explicitly require executive processes, argues for a fundamental difference between brain-related processing of these two types of memory. In summary, performance differences across the four age groups are minimal on FRT, which is a simple span task that requires only rote rehearsal. In comparison, differences across age groups were pronounced in the BRT, a task which likely requires far higher demands on visual imagery and executive functions.

5.

Conclusions

In the present study, we examined and compared brain activity associated with performance of a FRT and BRT in healthy

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participants classified into four age groups (ranging from 20 to 65 years; see Table 1). Both FRT and BRT tasks are affected by the process of aging. However, the functional brain changes are more pronounced during BRT compared to FRT. Compared to FRT, the BRT produced greater activation of frontal areas (IFG and MFG), supporting the possible contribution of executive functions. Furthermore, there was additional activation in parietal areas (SPL and IPL) during BRT compared to FRT; these regions are suggested to be involved in VMI. These results strongly suggest that FRT and BRT tax different neural processes. In addition there was a shift in laterality asymmetry from leftward in the younger participants to more rightward in the older participants, in areas including the STG, HG and cerebellum for the FRT, and including MFG, SPL and HG for the BRT. These effects varied from one region to another. In both tasks, the STG and HG showed evidence consistent with a shift occurring rather late in age. In contrast, in the cerebellum, MFG and SPL evidence is consistent with a relatively early shift in terms of age. We propose that these laterality shifts are due to alterations in brain function with aging, and therefore reflect neurocompensatory processes which also reveal differential sensitivity depending on brain area. Overall, behavioral data support the findings of the fMRI results, with a decline in performance on the BRT with age (reflecting processes of both visual imagery and executive function), and rather unchanging performance on the FRT, possibly reflecting effective neurocompensatory processes.

Acknowledgements We thank Azrul Yahya from Diagnostic Imaging and Radiotherapy Program, School of Diagnostic Science and Applied Health, for his support, ideas, and insight. We also thank Sa'don Samian from Department of Radiology, Universiti Kebangsaan Malaysia Medical Centre, for the assistance in fMRI scans and finally we also thank Mohammad Hairol Isa from Jabatan Kesihatan Masyarakat Universiti Kebangsaan Medical Center, for his help on managing older participants. This work is supported by the Research University Grant UKM GUP-SK-07-020-205.

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