Téo Kronovsek

Eric Hermand

Alain Berthoz

Alexander Castilla

Matthieu Gallou-Guyot

Jean-Christophe Daviet

Anaick Perrochon
email: anaick.perrochon@unilim.fr

PhD Anaïck Perrochon

Age-related decline in visuo-spatial working memory is reflected by dorsolateral prefrontal activation and cognitive capabilities

Keywords: Functional near-infrared spectroscopy, prefrontal cortex, ageing, visuo-spatial working memory, spatial navigation, cognition VSWM, visuo-spatial working memory, CBT, Corsi Block Tapping-test, e-CBT, electronic Corsi Block Tapping-test, VWCT, Virtual Walking Corsi Task, dlPFC, dorsolateral prefrontal cortex, fNIRS, functional Near-Infrared Spectroscopy, ΔO 2 Hb, oxyhaemoglobin, ΔHHb, deoxyhaemoglobin, EF, executive functions, OA, Older adults, YA, Young adults, CRUNCH, Compensation-related Utilization of Neural Circuits Hypothesis, WM, Working Memory

Introduction

Visuo-spatial working memory (VSWM) performances undergo a decline throughout ageing and are affected by the space in which the task is performed (reaching or navigational).

Cerebral oxygenation and cognitive capabilities could explain this decline. We assessed the effects of age on cerebral oxygenation of the dorsolateral prefrontal cortex (dlPFC) in VSWM tasks in reaching and navigational space. We also assessed cognitive correlates of VSWM performance in each space.

Method

Thirty-one (31) young adults (YA) and 24 healthy older adults (OA) performed a battery of neuropsychological tests and the electronic Corsi Block-tapping Test in reaching space (e-CBT) and in navigational space on the "Virtual Carpet" (VWCT). Participants were asked to memorize and recall a sequential pathway, progressively increasing from 2 to 9 blocks. Their span score reflected VSWM performance. The dlPFC oxygenation (oxyhaemoglobin: ΔO 2 Hb and deoxyhaemoglobin: ΔHHb) was measured by using functional NIRS (fNIRS) during the encoding of the sequential pathway in both tasks.

Results

YA had higher span scores than OA in both spaces. We identified a significantly stronger decrease of ΔHHb in YA compared to OA during encoding in VWCT. OA also exhibited significantly lower cerebral oxygenation in VWCT compared to e-CBT. A decrease of ΔHHb was also associated with a better performance in VWCT. Finally, we identified an association of mental rotation and executive functions with VSWM performance in both tasks.

Conclusion

3

VSWM performance and cerebral oxygenation during encoding are impacted by ageing.

Space in which the task was performed was associated with different cognitive functions and revealed differences in cerebral oxygenation.

Introduction

Ageing is associated with spatial memory decline, including visuo-spatial working memory (VSWM) [START_REF] Iachini | Visuospatial memory in healthy elderly, AD and MCI: a review[END_REF]. VSWM seems to be one of the major cognitive processes involved in spatial navigation and route learning [START_REF] Meneghetti | Environment learning using descriptions or navigation: The involvement of working memory in young and older adults[END_REF][START_REF] Lithfous | Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies[END_REF]. VSWM could be involved in maintaining spatial information during navigation, recall of previously visited locations and cognitive mapping of the environment [START_REF] Lithfous | Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies[END_REF].

The Corsi Block Tapping-Test (CBT) [START_REF] Corsi | Human memory and the medial temporal region of the brain[END_REF] is one of the most widely used clinical tests to assess VSWM in reaching space and has also been developed on a larger scale for performance in navigational space: the Walking Corsi Test [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF]. This test has been further improved by computer control of both a table electronic Corsi Block Test and a computer-controlled set of light and tactile tiles: the "Magic Carpet". These have been used

for navigational deficit studies in several pathologies in adult patients [START_REF] Perrochon | Cognitive impairment assessment through visuospatial memory can be performed with a modified walking Corsi test using the 'magic carpet[END_REF], and children (age 6 to adulthood) (Belmonti, Berthoz, Cioni, Fiori & Guzetta, 2015). Studies in ageing have also shown that young adults (YA) outperformed older adults (OA) in VSWM performances in different spaces (reaching vs. navigational) [START_REF] Piccardi | Dissociated deficits of visuo-spatial memory in near space and navigational space: evidence from brain-damaged patients and healthy older participants[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Perrochon | Cognitive impairment assessment through visuospatial memory can be performed with a modified walking Corsi test using the 'magic carpet[END_REF][START_REF] Perrochon | The influence of age in women in visuo-spatial memory in reaching and navigation tasks with and without landmarks[END_REF].

Many authors have shown that VSWM performances in reaching and navigation spaces are different, leading to the existence of two distinct VSWM systems [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Piccardi | Spatial location and pathway memory compared in the reaching vs. walking domains[END_REF][START_REF] Nori | The virtual reality walking corsi test[END_REF]. Space seems to impact OA VSWM performances, since performances in reaching space appeared to be superior to those in navigational space [START_REF] Perrochon | Cognitive impairment assessment through visuospatial memory can be performed with a modified walking Corsi test using the 'magic carpet[END_REF][START_REF] Piccardi | Dissociated deficits of visuo-spatial memory in near space and navigational space: evidence from brain-damaged patients and healthy older participants[END_REF]. These differences could be based on the fact that CBT in navigational space may require more and richer cognitive processes than in reaching space (storage of spatial information), and thus may be more suited for the measure of a spatial memory closer to ecological conditions [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Piccardi | Spatial location and pathway memory compared in the reaching vs. walking domains[END_REF][START_REF] Nori | The virtual reality walking corsi test[END_REF]. Indeed, spatial cognition is associated with various perceptual and cognitive processes, such as executive functions (EF) [START_REF] Berthoz | Multisensory integration in spatial orientation[END_REF][START_REF] Wolbers | What determines our navigational abilities?[END_REF][START_REF] Lithfous | Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies[END_REF][START_REF] Taillade | Executive and memory correlates of age-related differences in wayfinding performances using a virtual reality application[END_REF][START_REF] Korthauer | Cognitive correlates of spatial navigation: associations between executive functioning and the virtual Morris Water Task[END_REF]. EF may allow individuals to maintain their goal, plan and select the appropriate strategies, manage their performance and flexibly adapt their mental state to environmental properties by maintaining relevant information and inhibiting irrelevant ones [START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF]. Anatomically, EF are known to strongly rely on the frontal lobe and especially the dorsolateral prefrontal cortex (dlPFC) [START_REF] Baddeley | Recent developments in working memory[END_REF][START_REF] Curtis | Persistent activity in the prefrontal cortex during working memory[END_REF]. Also, the involvement of VSWM and EF can be reflected in increased cerebral blood flow in the dlPFC during several spatial cognition tasks [START_REF] Lithfous | Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies[END_REF][START_REF] Maguire | Knowing where and getting there: a human navigation network[END_REF].

More precisely for VSWM, a fMRI study has highlighted dlPFC activation in a young population during the encoding of sequences in reaching space [START_REF] Toepper | Hippocampal involvement in working memory encoding of changing locations: an fMRI study[END_REF]. In another fMRI study comparing brain activation of a young population in reaching and in navigational space, authors found that the dlPFC was specifically associated with navigational space [START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF]. Although this theory still requires investigation, Nemmi et al. have hypothesized that the two VSWM systems depending on spaces [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Piccardi | Spatial location and pathway memory compared in the reaching vs. walking domains[END_REF][START_REF] Nori | The virtual reality walking corsi test[END_REF] may be supported by distinct neural basis [START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF].

Global cognition and EF are declining with age due to impairment in the functional and structural integrity of the brain (Craik & Salthouse, 2011;[START_REF] Raz | Aging of the brain and its impact on cognitive performance: Integration of structural and functional findings[END_REF][START_REF] Park | The basic mechanisms accounting for age-related decline in cognitive function[END_REF][START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF]. Specifically, the dlPFC exhibits major shrinkage with age, which could explain the age-related EF decline in normal aging [START_REF] Raz | Aging of the brain and its impact on cognitive performance: Integration of structural and functional findings[END_REF][START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF]. OA compensate for these age-related brain changes by using new strategies and by recruiting new neural structures, as suggested by the Compensation-related Utilization of Neural Circuits Hypothesis (CRUNCH model), a model of neurocognitive ageing [START_REF] Reuter-Lorenz | Neurocognitive aging and the compensation hypothesis[END_REF][START_REF] Reuter-Lorenz | Brain aging: reorganizing discoveries about the aging mind[END_REF]). It appears that OA show different patterns of brain activation than YA. The first pattern is an age-related overactivation occurring at easy and intermediate levels (low cognitive load). As OA reach their maximal load capacity sooner than YA, they recruit more neural circuits involved in the task, a compensatory mechanisms that allows age-equivalent performances. These are interpreted as strategic or neural adjustments to compensate processing inefficiency, local or elsewhere. Another pattern seems to be frequently observed at high levels of difficulty (high cognitive load): we detect an under-activation of the required brain areas in OA compared to YA, which leads to poorer cognitive performances.

Compensatory mechanisms for the functional deficiency in the processing mediated by the areas are no longer effective at these levels of cognitive load, as a result of reaching a resource ceiling. This under-activation might reflect poor strategy uses and the subsequent recruitment of brain structures which are inadequate for the task [START_REF] Logan | Underrecruitment and nonselective recruitment: dissociable neural mechanisms associated with aging[END_REF][START_REF] Reuter-Lorenz | Brain aging: reorganizing discoveries about the aging mind[END_REF], and therefore may explain low performances in OA. Rather than simply occurring at a high cognitive load, Schneider-Garces, Gordon, [START_REF] Schneider-Garces | Span, CRUNCH, and beyond: working memory capacity and the aging brain[END_REF] found evidence that this under-activation may be linked to individual variations in working memory (WM) span; the reaching of a resource ceiling could be associated with a subjective WM span. Yet, the few studies assessing the brain activation in reaching and navigational space have only focused on a young population [START_REF] Toepper | Hippocampal involvement in working memory encoding of changing locations: an fMRI study[END_REF][START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF], and little is known about agerelated compensation and the brain mechanisms supporting VSWM in both spaces. This lack of literature is probably due to the technical limitations of neuroimaging systems in real conditions. Recent advances in mobile brain imaging, such as functional Near-Infrared Spectroscopy (fNIRS), allow new opportunities in spatial cognition and navigation studies [START_REF] Park | Navigation in real-world environments: new opportunities afforded by advances in mobile brain imaging[END_REF]. fNIRS allows to measure local variations of haemoglobin concentration changes related to neuronal activity by the phenomenon of neurovascular coupling [START_REF] Perrey | Non-invasive NIR spectroscopy of human brain function during exercise[END_REF]. The cortical activity in stimulated area increases the oxygen demand. Oxygen is carried by the haemoglobin. Thus, the local vasculature responds by flooding the cortical area and surrounding tissue with oxygenated form of haemoglobin (ΔO 2 Hb) usually accompanied with a concomitant drop in its deoxygenated form (ΔHHb).

The fNIRS allows to measure cerebral oxygenation in situ with a significant temporal resolution [START_REF] Perrey | Non-invasive NIR spectroscopy of human brain function during exercise[END_REF]. Besides, this tool seems robust in measuring functional activity during cognitive tasks, as the result of prefrontal cortex activation is similar to magnetic resonance imaging [START_REF] Cui | A quantitative comparison of NIRS and fMRI across multiple cognitive tasks[END_REF]. This device is currently used to examine the neural control of gait in real walking conditions [START_REF] Perrey | Possibilities for examining the neural control of gait in humans with fNIRS[END_REF]. Also, fNIRS may be used to study the effect of age-related brain activity in VSWM tasks, and more globally in spatial navigation.

The main objective of this pilot-study was to assess the effect of age on cerebral oxygenation in VSWM tasks according to space (reaching or navigational). A secondary objective of this study was to determine if EF and cerebral oxygenation were involved in VSWM, either in reaching or navigational space. We hypothesized that: i) YA would show a better VSWM performance and therefore higher cerebral oxygenation than OA resulting in a stronger increase of ΔO 2 Hb concentration and a stronger decrease in ΔHHb concentration, and ii) performances in cognitive tests would be explicative variables of VSWM performances, especially for navigational space.

Material and methods

Population

Fifty-five participants were recruited in this cross-sectional study, including 31 YA and 24 healthy OA. The inclusion criteria were: i) age between 18 and 35 years old for YA and over 65 for OA, ii) fluency in the French language. Exclusion criteria were: i) motor, sleep and perception (visual and auditive) disorders, ii) the presence of depressive symptoms (mini Geriatric Depression Scale (GDS) score >1), cognitive impairment (Mini Mental State Examination (MMSE) score <24), an amnesic complaint, the history or presence of neurological and/or psychiatric diseases, and the use of medications altering memory or cognitive functions. Written informed consent was obtained from each participant, and this study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983).

Experimental design

The experimental protocol was divided into two phases: i) VSWM performance assessment in reaching space (i.e., e-CBT: electronic Corsi Block Tapping-test) and in navigational space (i.e., VWCT: Virtual Walking Corsi Task), ii) the administration of a battery of neuropsychological tests. The test administration order was randomized by a computed random number generator algorithm.

VSWM performance assessment

The e-CBT and VWCT conditions were based on [START_REF] Perrochon | The influence of age in women in visuo-spatial memory in reaching and navigation tasks with and without landmarks[END_REF] (Figure 1: A andB). A main difference with the original study is that in the present study the participant performed the e-CBT while standing up. In both tests, the participant had to memorize (encoding phase) a sequence of blocks successively lighting up in red. After a computergenerated audible signal marking the end of the sequence, the participant had to reproduce (restitution phase) the sequence in the same order. The number of items gradually increased from 2 to 9. The participant had 2 trials per sequence length. If he succeeded in reproducing one of the two sequences, the sequence length increased by one item [START_REF] Berch | The Corsi block-tapping task: Methodological and theoretical considerations[END_REF]. If the participant failed in both trials, the test ended and his span score was the number of items in the last sequence successfully reproduced.

In reaching space (i.e., the e-CBT), the participant stood in front of the computer screen in order to maintain the same head angle as during the encoding phase of VWCT and thus to ensure the reliability of the fNIRS measurement (Figure 1: A). The computer was mounted at 700 mm on a table adjusted (min = 90 cm; max = 120 cm) according to the participant's height. The e-CBT sequences were displayed on a 15-inch computer screen. In this situation, the participant had to point out the blocks one after the other by touching the computer screen in order to reproduce the sequence. Although the screen was close to vertical and the floor (VWCT) was horizontal, we ensured, by the angle of the computer screen, that the participant maintained the same visual direction as much as possible (Figure 1: A andB).

For navigational space (i.e., VWCT), we used the "Virtual Carpet"™ developed by A.

Berthoz and M. Zaoui, previously described in [START_REF] Perrochon | The influence of age in women in visuo-spatial memory in reaching and navigation tasks with and without landmarks[END_REF]. The participant stood on a starting point 1500 mm away from the test projection space during the encoding phase (Figure 1: B). During the restitution phase, the participant had to walk on the numbered blocks in the same order as the presentation, beginning from the starting point and returning to it when finished. The projection space (W316ST Optoma® projector, Taiwan) was 3000 mm x 2400 mm (scale 1:10 in regards to the e-CBT) and reproduced the same layout as the e-CBT (Figure 1: C).

- -----------------------------------------------Insert Figure 1 about here --------------------------------Participants were wearing an fNIRS device (Portalite®, Artinis Medical, Netherlands) during VSWM tasks. The device consists of two bilateral optodes positioned on the right (Fp2) and left (Fp1) dorsolateral areas of the prefrontal lobe (EEG 10-20 system). Both optodes were connected to an independent portable battery maintained by armbands (Figure 1). During the baseline measurements and encoding of the sequences, the participant was asked to limit head movements in order to avoid motion artefacts. In support of this, we ensured that the participant could have a global vision of the entire test layout from the starting point without having to move his head.

Cognitive functions assessment

The participants performed a neuropsychological test battery to measure executive functioning. We used the ZOO map test part A [START_REF] Wilson | The development of an ecologically valid test for assessing patients with a dysexecutive syndrome[END_REF] which assesses planning abilities. The participant is asked to navigate through a zoo map while sticking to instructions on places to visit and their order, the variable was the score. We used the Trail Making Test (TMT) [START_REF] Reitan | The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation[END_REF] which assesses mental flexibility (part B) and attention (part A) as well as visuo-spatial exploration. The participant must connect in ascending order circles containing numbers from 1 to 25 in part A, whereas he alternate between numbers of letters in part B. For TMT we measured time and the number of errors. We also used REY's figure [START_REF] Rey | L'examen psychologique dans les cas d'encéphalopathie traumatique[END_REF] for planning function, attention and working memory. Participant was asked to copy a figure, without knowing he would be asked to reproduce it after a quick distraction. The score was based on the number of correct reproduced items of the figure for both copy and retrieval conditions. To measure inhibition, we used the Stroop test [START_REF] Stroop | Studies of interference in serial verbal reactions[END_REF] consisting in three conditions: naming the colours of squares, reading words of colours in black ink, and naming the ink colour while inhibiting the non-congruent word reading (interference condition). We measured time for the three conditions. In addition to these executive functioning tests, we used the redrawn Mental Rotation Test (MRT) to assess mental rotation capabilities [START_REF] Peters | A redrawn Vandenberg and Kuse mental rotations test-different versions and factors that affect performance[END_REF]. In MRT the participant is asked to determine which two of a four sample stimuli are rotated versions of a target stimulus; we measured the score on 24 items. The order of neuropsychological tests was randomized to avoid biases related to cognitive fatigue.

Outcomes

The main outcome was bilateral dlPFC activation measured by fNIRS and calculated by the change in oxygenated and deoxygenated haemoglobin relative concentration (respectively ΔO 2 Hb and ΔHHb) (Acquisition Software -Oxysoft® version 3.0.97.1). The Differential Pathlength Factor was calculated from the age of YA and set by default to 5 for OA [START_REF] Duncan | Measurement of cranial optical path length as a function of age using phase resolved near infrared spectroscopy[END_REF]. A baseline was performed before e-CBT and VWCT: the participant had to stare at a red cross located in the centre of the test's layout (i.e., the screen in e-CBT and the carpet in VWCT) for a 20-second period. The baseline was done while standing in front of the screen in e-CBT and on the starting point in VWCT, in order to maintain the same angle of the head in both conditions (Figure 1: A andB). We assessed dlPFC oxygenation only during the encoding of the sequences, as head motion during the restitution phase was producing significant artifacts. Since there were two sequences of encoding for the span score in each test, we computed the mean oxygenation in both sequences. We used Matlab-based scripts when needed for detection and correction of motion artifacts, and a 0.1 Hz low-pass filter was used to remove physiological and instrumental noise [START_REF] Fishburn | Temporal Derivative Distribution Repair (TDDR): A motion correction method for fNIRS[END_REF]. We obtained the relative concentration changes in oxyhaemoglobin (ΔO 2 Hb) and deoxyhaemoglobin (ΔHHb) (µmol.L -1 ) in the selected interval of the test (i.e., the last 10 seconds), which was normalized by subtracting the mean values of the last 10 seconds of baseline from them. According to CRUNCH, we measured those parameters during the encoding of the 4 th span and failure span in order to have two points of comparison for patterns of activation (over-recruitment vs. under-recruitment). The 4 th span was chosen to assess dlPFC oxygenation at a low/intermediate cognitive load, due to the fNIRS temporal resolution; dlPFC oxygenation measurements in loads lower than the 4 th span were not available. Indeed, a systematic methodology-focused study have enlightened a certain delay (≈ 6s) between stimulus presentation and cortical hemodynamic response [START_REF] Herold | Applications of functional near-infrared spectroscopy (fNIRS) neuroimaging in exercise-cognition science: a systematic, methodology-focused review[END_REF]. In addition, we need the last 10s during the encoding phase for signal analysis. For this reason, we cannot analyse span 3 or lower (14s duration). The failure span was chosen in order to assess prefrontal oxygenation during the subjective resource ceiling, in accordance with the Schneider-Garces et al. ( 2010

Statistical analysis

The normality of our variables data was verified with a Shapiro-Wilk test. Student tests were used in order to compare the socio-demographic variables and neuropsychological scores between both groups. We performed a 2*2 mixed ANOVA with the two populations (OA vs. YA) and the two spaces (VWCT vs. e-CBT) to study their effect on the VSWM span score.

We also conducted 2*2 mixed ANOVAs with the two age groups (YA vs. OA) and the two spaces (VWCT vs. e-CBT) in order to study their effect on cerebral oxygenation parameters during the encoding of the 4 th span and failure span. Univariable linear regressions were performed to examine relationships between cerebral oxygenation parameters and cognitive function capabilities (independent variables) and span scores in e-CBT and VWCT (dependent variable). Separate multivariable linear regressions by stepwise method were run to examine whether cognitive function variables and cerebral oxygenation parameters would explain VSWM performance in different spaces. For all analyses, the statistical significance level was set at alpha <0.05. The statistical analysis was performed using IBM SPSS® Statistics version 22 (IBM Corp, Armonk, USA).

Results

55 participants were included in this study: 31 YA (22.8 ± 2.8 years; 19 female) and 24 OA (70.4 ± 3.7 years; 17 female). Socio-demographic and cognitive capabilities are presented in Table 1. We observed a decreased cognitive performance in OA (vs. YA) in many neuropsychological tests, such as the MRT, ZOO, REY, TMT and STROOP (p<0.05).

We also observed through the age*space ANOVA on span scores an overall effect of age, with YA showing higher span scores than OA (respectively 7.0 ± 0.2 vs. 5.1 ± 0.2; F(1,53) = 39.657; p<0.001). We also found an overall effect of space, as participants showed better span scores in reaching space compared to navigational space (respectively 6.5 ± 0.2 vs. 5.5 ± 0.2; F(1,53) = 55.496; p<0.001) (Figure 2). We found no significant age*space interaction effect on VSWM span scores (p>0.05).

- ---------------------------------------Insert Figure 2 and Table 1 about here ------------------------- -------------------------------------------------Insert figure 3 about here----------------------------------ANOVA on dlPFC oxygenation during the 4 th span encoding revealed no main effects of age and space and no interaction effects for the ΔO 2 Hb value (p>0.05; Figure 3: A), but an age*space interaction effect for ΔHHb (F(1,53) = 4.35; p<0.05; Figure 3: B). Post hoc analysis revealed a significantly lower ΔHHb value for YA compared to OA only in navigational space (respectively -0.7 ± 1.2 vs. -0.1 ± 1.2 µmol.L -1 , p<0.05). We also observed a significantly higher ΔHHb concentration in navigational space compared to reaching space among OA (respectively -0.1 ± 1.2 vs. -0.7 ± 1.2 µmol.L -1 , p<0.05, Figure 3: B). p<0.001), TMT B (r = -0.40; p<0.01) and ΔTMTs (r=-0.28; p<0.05) were associated with the span score in reaching space (Table 2). Similarly, MRT (r = 0.68; p<0.001), ZOO (r = 0.34; p<0.05), REY R (r = 0.59; p<0.001), STROOP I (r = -0.54; p<0.001), TMT A (r = -0.49; p<0.001) and TMT B (r = -0.33; p<0.05) were associated with the span score in navigational space.

Effects of ageing on cerebral oxygenation in VSWM tasks

Stepwise regression model

By performing stepwise regression, including age, level of education, sex, MRT, ZOO, REY R, STROOP I and TMT B and dlPFC oxygenation parameters, we found associations between the span score and age, MRT (p<0.01) and ZOO (p<0.05) performance in reaching space (Table 3). Furthermore, we observed additional associations between the span score and dlPFC oxygenation during failure span encoding (ΔHHb: p<0.05), MRT (p<0.001) and REY (p<0.05) scores in navigational space (Table 3). The total variance accounted for these models was strong, while these variables explain 67% of VSWM performance in reaching space and 63% of VSWM performance in navigational space (Table 3).

- -------------------------------------------Insert Table 3 about here - --------------------------------4

. Discussion

This is the first study assessing the age-related effect on cerebral oxygenation and the association of cognitive capabilities with VSWM according to space. We observed a significant difference of cerebral oxygenation depending on age, with higher dlPFC activation (i.e., decreased ΔHHb) for YA compared to OA when the participant was encoding the subsequent task in navigational space. dlPFC activation seems to be associated with VSWM performance, specifically in the navigational task. Finally, different EF (i.e., mental rotation, planning capabilities, attention) are associated with VSWM performance according to space.

Effect of ageing on cerebral oxygenation in VSWM

First, we observed an effect of ageing on VSWM performance, as YA outperformed OA.

These results match findings of other studies, which demonstrated age-related deficits in VSWM performances in similar paradigms [START_REF] Piccardi | Dissociated deficits of visuo-spatial memory in near space and navigational space: evidence from brain-damaged patients and healthy older participants[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Perrochon | Cognitive impairment assessment through visuospatial memory can be performed with a modified walking Corsi test using the 'magic carpet[END_REF][START_REF] Perrochon | The influence of age in women in visuo-spatial memory in reaching and navigation tasks with and without landmarks[END_REF].

In navigational space, we found that YA showed a stronger dlPFC activation (i.e., decrease of ΔHHb) compared to OA during the encoding phase in navigation space (4 th span and failure span in VWCT). The decrease of ΔHHb is a typical intravascular oxygenation response to brain activity [START_REF] Villringer | Near infrared spectroscopy (NIRS): a new tool to study hemodynamic changes during activation of brain function in human adults[END_REF][START_REF] Scholkmann | A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology[END_REF][START_REF] Buxton | Dynamic models of BOLD contrast[END_REF]. Thus, in our framework, OA showed an under-activation of dlPFC compared to YA. Whereas it seems coherent for the failure span, this under activation pattern is already appearing at 4 th span. It may be related to behavioural data, since OA reached on average their VWCT span score at 4.6 ± 0.8 and the mode span score of the OA distribution was 4 (14 participants out of 24). As the reaching of a resource ceiling has been found to be individually WM load dependant [START_REF] Schneider-Garces | Span, CRUNCH, and beyond: working memory capacity and the aging brain[END_REF][START_REF] Cappell | Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load[END_REF], we can suppose that most of the OA have reached this resource ceiling around 4 th span, and are no longer able to compensate, leading to under activation pattern. These results corroborate partly with the CRUNCH model [START_REF] Reuter-Lorenz | Neurocognitive aging and the compensation hypothesis[END_REF], since we observed an under-activation of OA compared to YA at high levels of cognitive load.

At higher levels of cognitive load, OA processing capacity limits are reached, and processing areas show less activity than those of YA, as compensatory mechanisms of the functional deficiency may no longer be effective. The decrease in ΔHHb during encoding was associated to VSWM behavioural performance in VWCT. These data add evidence to the observed age-related effects (weaker ΔHHb decrease) and allow us to assume that OA dlPFC under-activation during the encoding of the sequences may be directly involved in their poorer performance.

The lower spans (2 and 3) were not usable given their short duration and the delay between stimulus presentation and hemodynamic response. However, low levels of cognitive load remain to be investigated for proof of age-related overactivation by adapting the task to fNIRS data processing.

Overall, ΔHHb was more affected by age-related effects and associated with VSWM performance in navigational space, whereas ΔO 2 Hb was not. ΔHHb is more affected by oxygen consumption than ΔO 2 Hb, and therefore is a better indicator of activation than ΔO 2 Hb [START_REF] Scholkmann | A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology[END_REF]. However, ΔO 2 Hb is often described as a more reliable indicator for functional brain activity because of its higher amplitude, and is less sensitive to noise [START_REF] Strangman | A quantitative comparison of simultaneous BOLD fMRI and NIRS recordings during functional brain activation[END_REF][START_REF] Wolf | Correlation of functional and resting state connectivity of cerebral oxy-, deoxy-, and total hemoglobin concentration changes measured by near-infrared spectrophotometry[END_REF]. Still, ΔHHb is a reliable indicator of functional activation, and we followed the [START_REF] Fishburn | Temporal Derivative Distribution Repair (TDDR): A motion correction method for fNIRS[END_REF] correction method to remove noise effects from the signal. There may possibly be non-neuronal driven changes in haemodynamic, such as physiological confounders in the signal which might influence our results. This is an issue for all haemodynamic-based functional brain imaging techniques. Nevertheless, most of the recommended guidelines, from the design of the protocol to fNIRS instrumentation and analysis approaches to avoid false positives/negatives, were followed [START_REF] Tachtsidis | False positives and false negatives in functional near-infrared spectroscopy: issues, challenges, and the way forward[END_REF].

The age-related under-activation during encoding could be linked to poorer cognitive strategies use by OA to encode the stimuli in memory and to plan restitution, hence leading to the recruitment of inaccurate cerebral areas [START_REF] Reuter-Lorenz | Brain aging: reorganizing discoveries about the aging mind[END_REF][START_REF] Logan | Underrecruitment and nonselective recruitment: dissociable neural mechanisms associated with aging[END_REF]. OA often fail to use controlled and costly processing strategies to support their performance. EF are required in acquiring new skills, selecting appropriate strategies, planning the execution of the task, monitoring behavioural responses and finding alternative strategies if the selected one is not efficient [START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF]. We observed deficits in most of the assessed EF and their association to performance in VWCT. Considering these observations, we could hypothesize that under-activation during encoding in navigational space could result from the use of inefficient cognitive strategies mediated by the age-related decline in EF. Further studies are needed to investigate this hypothesis as we did not demonstrate it clearly. Except its role in executive functioning and VSWM, the dlPFC may also be implied in processing the movement along a learned route in a navigational environment, as it would be involved in the processing of self-generated locomotor movements and of strategy related to motor imagery [START_REF] Berthoz | Parietal and hippocampal contribution to topokinetic and topographic memory[END_REF][START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF].

This study thus highlights the major role of prefrontal circuits in age-related performance in VSWM. . Age differences in cerebral activation were only observed in navigational space. Since dlPFC has been specifically linked with navigational space and not reaching space [START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF], we can assume that it may explain why dlPFC oxygenation differences between our populations is only discriminated in VWCT. However, we found an overall effect of space on ΔO 2 Hb, with higher concentration values in reaching space compared to navigational space during failure span encoding. Thus, dlPFC oxygenation seems to be stronger in reaching space. It may be load-dependent, since reaching space allows better performances for both our populations than navigational space, which is known to be more complex and requires more resources [START_REF] Röser | Modality dependence and intermodal transfer in the Corsi Spatial Sequence Task: Screen vs[END_REF]. Nevertheless, we did not find ΔO 2 Hb to be linked with VSWM performance. Another result contrasts with the observations of [START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF], as we found that ΔHHb was different in OA, with a stronger decrease in reaching space compared to navigational space. However, the observations of [START_REF] Nemmi | Segregation of neural circuits involved in spatial learning in reaching and navigational space[END_REF] were only done in a study of a young adult population (mean age 24.7 ± 4.5), and we cannot state that tests in both spaces lie on a distinct neural basis exactly in the same way as in the OA population. Thus, dlPFC may play a role in better performances of OA in reaching space compared to navigational space; however, we did not find ΔHHb to be linked with performance in reaching space and it remains to be investigated.

Cognitive correlates of space

We had assumed that raw scores on cognitive tests would be more associated to VSWM performance in navigational space because of the more active and complex nature of this task compared to the VSWM task in reaching space [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF][START_REF] Piccardi | The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population[END_REF][START_REF] Piccardi | Spatial location and pathway memory compared in the reaching vs. walking domains[END_REF][START_REF] Nori | The virtual reality walking corsi test[END_REF]. Our results would not allow us to confirm this hypothesis, as we observed that both spaces imply distinct cognitive processes (see R 2 values in Table 3) as well as common processes. Nonetheless, these results highlight the major association of mental rotation with VSWM performances (Gallou-Guyot et al., 2020). Mental rotation may support the updating and mental manipulation of spatial information as the participant is orientating and moving through the environment [START_REF] Piccardi | Walking in the Corsi test: which type of memory do you need?[END_REF][START_REF] Röser | Modality dependence and intermodal transfer in the Corsi Spatial Sequence Task: Screen vs[END_REF]. On one hand, the ZOO test [START_REF] Wilson | The development of an ecologically valid test for assessing patients with a dysexecutive syndrome[END_REF] evidenced that planning ability was one of the EF associated with VSWM performance in reaching space. On the other hand, the analyses of the Rey figure [START_REF] Rey | L'examen psychologique dans les cas d'encéphalopathie traumatique[END_REF] confirmed the strong association between executive functioning, in the maintenance of spatial information, the selection of appropriate strategies, the control of performance and mental flexibility and VSWM performance in navigational space .

Our results allowed us to demonstrate a clear link between executive functioning and VSWM performances in different space. As we observed age-related deficits in all of these cognitive tests (Table 1) and a relation between dlPFC oxygenation and VSWM performance, we could suppose that the decline of EF could partly explain the poorer VSWM performance in ageing through their potential role in strategy production in navigational space . In such case it would support the executive hypothesis of cognitive ageing, that age-related memory differences and global decline in cognition may be mediated by the prefrontal area deterioration that supports WM and EF [START_REF] West | An application of prefrontal cortex function theory to cognitive aging[END_REF][START_REF] Raz | Aging of the brain and its impact on cognitive performance: Integration of structural and functional findings[END_REF]. However, we have no proof that EF effectively mediate the age-related variance in VSWM performance. The nature of the relation between age and VSWM performances and how executive functioning mediate this relation thus need to be developed to provide empirical evidences for the executive hypothesis of cognitive ageing.

To summarise, VSWM performances in navigational space were associated with prefrontal ΔHHb concentration during the encoding of sequences, and appear to be associated with ageing, mental rotation abilities and Rey's figure performances, whereas reaching space VSWM performances were associated with mental rotation abilities and ZOO test performances.

Limitations

Several limitations should be considered in future studies. First, fNIRS acquisition could only be done during the encoding phase of the sequences, due to the great number of head rotations and movements during the restitution phase in navigational space that induced large motion artefacts in the signal. Nevertheless, it has been demonstrated by means of EEG power analysis that encoding of visuo-spatial information is more cognitively challenging than retrieval because it requires more cerebral efforts [START_REF] Jaiswal | Encoding of visual-spatial information in working memory requires more cerebral efforts than retrieval: Evidence from an EEG and virtual reality study[END_REF].

Moreover, as being said fNIRS analysis could not be done for low spans and thus they still need to be studied to demonstrate if patterns of cerebral activation really fit with CRUNCH model. Second, despite its important temporal resolution, fNIRS cannot be used to investigate deep brain structures involved in spatial memory, such as the hippocampus [START_REF] Maguire | Knowing where and getting there: a human navigation network[END_REF][START_REF] Lithfous | Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies[END_REF][START_REF] Latini-Corazzini | Route and survey processing of topographical memory during navigation[END_REF] . We were also limited to two optodes in this study thus, we could not assess the lateralization effect. Since our device was not a multi-channel fNIRS, we were not able to investigate the involvement of the parietal cortex, which is a key structure in spatial working memory [START_REF] Constantinidis | A neural circuit basis for spatial working memory[END_REF].

Furthermore, because of the switch of engaged brain areas due to ageing from posterior to more anterior structures (PASA model) [START_REF] Davis | Que PASA? The posterior-anterior shift in aging[END_REF], it would be relevant in future studies to investigate the effects of age on parietal cortex activation. Third, cognitive tests allowed us to identify several implied cognitive functions such as mental rotation and EF in VSWM tasks, but this work remains to be conducted with more varied cognitive tests, as we limited them to avoid cognitive fatigue.

Perspectives

This research takes part in the investigation of brain mechanisms that tend to decline in ageing and may be essential factors in age-related deficits in VSWM . VWCT could be used in the early detection of spatial memory impairment, such as in the dementias [START_REF] Iachini | Visuospatial memory in healthy elderly, AD and MCI: a review[END_REF].

This study could be reproduced in those with neurological pathologies such as stroke, in which brain damage leads to different haemodynamic responses [START_REF] Hermand | Prefrontal cortex activation during dual task with increasing cognitive load in subacute stroke patients: A pilot study[END_REF].

Finally, fNIRS could be used in complex navigation tests [START_REF] Perrochon | Cognitive impairment assessment through visuospatial memory can be performed with a modified walking Corsi test using the 'magic carpet[END_REF] to reflect the involvement of EF in these tasks.

Conclusion

This study demonstrated that healthy OA seem to have less activation of their dlPFC compared to YA in VSWM tasks. This dlPFC activation seems to be associated with VSWM performance, particularly in navigational space . Finally, we identified the major association of some cognitive functions, such as mental rotation and EF with VSWM performance in reaching and navigational spaces. Table 1. Demographic, psychologic, and cognitive characteristics of the study participants.

Table 2. Correlations between raw scores in cognitive tests and VSWM tasks and oxygenation parameters in 4 th span and failure span.

Table 3. Regression analysis for the variables identified as correlated to VSWM tasks.

  ) findings. The secondary outcomes were span scores in VSWM and cognitive performance. In e-CBT, the sequence validation was approved by the experimenter, while it was computerized in VWCT. During VWCT, the participant had to wear two motion trackers (HTC® Vive Tracker, HTC, Taiwan) coupled with the base stations (HTC® Vive Lighthouse). The entire device was connected to the RigidBodyViewer Software (Collège de France, Paris, France) (Figure 1: B). For neuropsychological tests, we focused on the raw scores in MRT, ZOO, REY, Stroop and TMT.

Figure and Tables Figure 1 .

 Tables1 Figure and Tables

Figure 2 .

 2 Figure 2. Span scores means and standard deviations (represented by error bars) in VWCT and e-CBT for older adults (OA) and young adults (YA). Main effects of age ( *** : p<0.001) and space ( +++ *** : p<0.001) were represented.

Figure 3 .

 3 Figure 3. dlPFC oxygenation means and standard deviations (represented by error bars) for older adults (OA) and young adults (YA) in reaching and navigational space for 4 th span and failure span. A) ΔO 2 Hb during the encoding of 4 th span. B) ΔHHb during the encoding of 4 thspan. We represented differences between YA and OA in VWCT ( * : p<0.05) and space effect for the OA group ( x * : p<0.05). C) ΔO 2 Hb during the encoding of failure span. Main effects of age ( ++ ** : p<0.01) and space ( ## ** : p<0.01) are represented. D) ΔHHb during the encoding of failure span. We represented significant differences between YA and OA in VWCT ( * : p<0.05) and space effect for OA group ( x * : p<0.05).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

For the failure span encoding, we observed an overall effect of age, with YA showing higher ΔO 2 Hb concentration than OA (respectively 6.3 ± 0.5 vs. 3.8 ± 0.6 µmol.L -1 , F(1,53) = 11.07; p<0.01). We also found an overall effect of space, with participants showing higher ΔO 2 Hb values in reaching space compared to navigational space (respectively 6.2 ± 0.6 vs. 3.8 ± 0.5 µmol.L -1 , F(1,53) = 7.36; p<0.01; Figure 3: C). However, we did not find any significant age*space interaction effect (p>0.05). Finally, we found a significant age*space interaction effect on the ΔHHb concentration (F(1,53) = 6.90; p<0.05). Post hoc analysis revealed a significant difference between groups only in navigational space, with a lower ΔHHb concentration for YA compared to OA (respectively -1.7 ± 2 vs. -0.3 ± 1.4 µmol.L -1 , p<0.05).

Post hoc also revealed that only OA showed significant differences of ΔHHb between both spaces, with a lower value in reaching space compared to navigational space (respectively - --------------------------------------------------Insert table 2 about here- --------------------------------For the e-CBT, the span score showed a positive correlation only with the dlPFC ΔO 2 Hb during failure span encoding (r = 0.32, p<0.05, Table 2). For the VWCT, the span score was associated with more oxygenation parameters such as ΔHHb concentration during the 4 th span encoding and failure span encoding (r = -0.34; p<0.05, r = -0.50; p<0.001 respectively) and with the dlPFC ΔO 2 Hb during the failure span encoding (r = 0.31; p<0.05).

Association between dlPFC activation and VSWM performance

Cognitive functions involved in VSWM according to space

Most of the neuropsychological tests, such as MRT (r = 0.64; p<0.001), ZOO (r = 0.45; p<0.001), REY R (r = 0.60; p<0.001), STROOP I (r = -0.63; p<0.001), TMT A (r = -0.54;

Author contributions

TK: Conceptualization and methodology, data acquisition and analysis, manuscript drafting; EH: Methodology, formal analysis, and manuscript review; AB: Conceptualization, software and manuscript review; AC and MGG : Methodology and manuscript review; JCD: Resources, conceptualization, manuscript review; AP: Conceptualization and methodology, data analysis, supervision, resources, manuscript drafting.

Declarations of interest

None