Age-related Changes In Brain Function Research Articles

Higher handgrip strength is linked to higher salience ventral attention functional network segregation in older adults

Converging evidence suggests that handgrip strength is linked to cognition in older adults, and this may be subserved by shared age-related changes in brain function and structure. However, the interplay among handgrip strength, brain functional connectivity, and cognitive function remains poorly elucidated. Hence, our study sought to examine these relationships in 148 community-dwelling older adults. Specifically, we examined functional segregation, a measure of functional brain organization sensitive to ageing and cognitive decline, and its associations with handgrip strength and cognitive function. We showed that higher handgrip strength was related to better processing speed, attention, and global cognition. Further, higher handgrip strength was associated with higher segregation of the salience/ventral attention network, driven particularly by higher salience/ventral attention intra-network functional connectivity of the right anterior insula to the left posterior insula/frontal operculum and right midcingulate/medial parietal cortex. Importantly, these handgrip strength-related inter-individual differences in salience/ventral attention network functional connectivity were linked to cognitive function, as revealed by functional decoding and brain-cognition association analyses. Our findings thus highlight the importance of the salience/ventral attention network in handgrip strength and cognition, and suggest that inter-individual differences in salience/ventral attention network segregation and intra-network connectivity could underpin the handgrip strength-cognition relationship in older adults.

Frontoparietal function and underlying structure reflect capacity for motor skill acquisition during healthy aging

While capacity for motor skill acquisition changes with healthy aging, there has been little consideration of how age-related changes in brain function or baseline brain structure support motor skill acquisition. We examined: (1) age-dependent changes in functional reorganization related to frontoparietal regions during motor skill acquisition, and (2) whether capacity for motor skill acquisition relates to baseline white matter microstructure in frontoparietal tracts. Healthy older and younger adults engaged in 4 weeks of skilled motor practice. Resting-state functional connectivity (rsFC) assessed functional reorganization before and after practice. Diffusion tensor imaging indexed microstructure of a frontoparietal tract at baseline, generated by rsFC seeds. Motor skill acquisition was associated with decreases in rsFC in healthy older adults and increases in rsFC in healthy younger adults. Frontoparietal tract microstructure was lower in healthy older versus younger adults, yet it was negatively associated with rate of skill acquisition regardless of group. Findings indicate that age-dependent alterations in frontoparietal function and baseline structure of a frontoparietal tract reflect capacity for motor skill acquisition.

Component-specific reduction in perineuronal nets in senescence-accelerated mouse strains.

With increased life expectancy, age-related diseases are a significant health concern in Western societies. Animal models (e.g., rodents) have been used to understand age-related changes in brain function-particularly through the senescence-accelerated mouse (SAM) strain. Previous reports have shown that the senescence-accelerated mouse propensity (SAMP)8 and SAMP10 strains have learning disabilities. In this study, we analyzed the prefrontal cortex, which is involved in cognitive function. We aimed to clarify the changes in parvalbumin-positive interneurons (PV-positive neurons), which are related to cognitive function, and perineuronal nets (PNNs), which are special extracellular matrix molecules formed around them. We performed histological analysis of PV-positive neurons and PNNs in the prefrontal cortex to elucidate the mechanism of behavioral abnormalities in SAMP8 and SAMP10 strains. Expression of Cat-315-positive PNN was not confirmed in the prefrontal cortex of SAMP10 mice. However, the density of AB1031-positive PNN, tenascin-R-positive PNN, and brevican-positive PNN decreased in the prefrontal cortex of SAMP8 and SAMP10 mice compared to that of the senescence-accelerated mouse resistance (SAMR1) mice. In addition, the density of PV-positive neurons was lower in SAMP8 mice than in SAMR1 mice. These mice, which exhibited behavioral and neuropathological phenotypes with age, showed different PV-positive neurons and PNNs in the prefrontal cortex compared with the SAMR1 mice. We believe that the results of this study will be useful for elucidating the mechanisms of age-related decline in cognitive and learning functions using SAM.

Prebiotic supplementation modulates selective effects of stress on behavior and brain metabolome in aged mice

Aging has a significant impact on physiology with implications for central nervous system function coincident with increased vulnerability to stress exposures. A number of stress-sensitive molecular mechanisms are hypothesized to underpin age-related changes in brain function. Recent cumulative evidence also suggests that aging impacts gut microbiota composition. However, the impact of such effects on the ability of mammals to respond to stress in aging is still relatively unexplored. Therefore, in this study we assessed the ability of a microbiota-targeted intervention (the prebiotic FOS-Inulin) to alleviate age-related responses to stress. Exposure of aged C57BL/6 mice to social defeat led to an altered social interaction phenotype in the social interaction test, which was reversed by FOS-Inulin supplementation. Interestingly, this occured independent of affecting social defeat-induced elevations in the stress hormone corticosterone. Additionally, the behavioral modifications following FOS-Inulin supplementation were also not coincident with improvement of pro-inflammatory markers. Metabolomics analysis was performed and intriguingly, age associated metabolites were shown to be reduced in the prefrontal cortex of stressed aged mice and this deficit was recovered by FOS-Inulin supplementation. Taken together these results suggest that prebiotic dietary intervention rescued the behavioral response to stress in aged mice, not through amelioration of the inflammatory response, but by restoring the levels of key metabolites in the prefrontal cortex of aged animals. Therefore, dietary interventions could be a compelling avenue to improve the molecular and behavioral manifestations of chronic stress exposures in aging via targeting the microbiota-gut brain axis.

Chronic Musculoskeletal Pain Moderates the Association between Sleep Quality and Dorsostriatal-Sensorimotor Resting State Functional Connectivity in Community-Dwelling Older Adults

Aging is associated with poor sleep quality, and greater chronic pain prevalence with age-related changes in brain function as potential underlying mechanisms. The following cross-sectional study aimed to determine whether self-reported chronic musculoskeletal pain in community-dwelling older adults moderates the association between sleep quality and resting state functional brain connectivity (rsFC). Community-dwelling older individuals (mean age=73.29 years) part of the NEPAL study who completed the Pittsburg Sleep Quality Index (PSQI) and an rsFC scan were included (n=48) in the present investigation. To that end, we tested the effect of chronic pain-by-PSQI interaction on rsFC among atlas-based brain regions-of-interest, controlling for age and sex. A significant network connecting the bilateral putamen and left caudate with bilateral precentral gyrus, postcentral gyrus and juxtapositional lobule cortex, survived global multiple comparisons (FDR; q<0.05) and threshold-free network-based-statistics. Greater PSQI scores were significantly associated with greater dorsostriatal-sensorimotor rsFC in the no-pain group, suggesting that a state of somatomotor hyperarousal may be associated with poorer sleep quality in this group. However, in the pain group greater PSQI scores were associated with less dorsostriatal-sensorimotor rsFC, possibly due to a shift of striatal functions toward regulation sensorimotor aspects of the pain experience, and/or aberrant cortico-striatal loops in the presence of chronic pain. This preliminary investigation advances knowledge about the neurobiology underlying the associations between chronic pain and sleep in community-dwelling older adults that may contribute to the development of effectitractve therapies to decrease disability in geriatric populations. This work was supported by the National Institutes of Aging (NIAK01AG048259, R01AG059809, R01AG067757, and T32AG049673). A portion of this work was performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory's Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility, which is supported by National Science Foundation Cooperative Agreement No. DMR-1644779 and DMR-1157490, and the State of Florida and the University of Florida Claude D. Pepper Older Americans Independence Center.

Chronic Musculoskeletal Pain Moderates the Association between Sleep Quality and Dorsostriatal-Sensorimotor Resting State Functional Connectivity in Community-Dwelling Older Adults.

Aging is associated with poor sleep quality and greater chronic pain prevalence, with age-related changes in brain function as potential underlying mechanisms. Objective. The following cross-sectional study aimed to determine whether self-reported chronic musculoskeletal pain in community-dwelling older adults moderates the association between sleep quality and resting state functional brain connectivity (rsFC). Methods. Community-dwelling older individuals (mean age = 73.29 years) part of the NEPAL study who completed the Pittsburg Sleep Quality Index (PSQI) and a rsFC scan were included (n = 48) in the present investigation. To that end, we tested the effect of chronic pain-by-PSQI interaction on rsFC among atlas-based brain regions-of-interest, controlling for age and sex. Results and Discussion. A significant network connecting the bilateral putamen and left caudate with bilateral precentral gyrus, postcentral gyrus, and juxtapositional lobule cortex, survived global multiple comparisons (FDR; q < 0.05) and threshold-free network-based-statistics. Greater PSQI scores were significantly associated with greater dorsostriatal-sensorimotor rsFC in the no-pain group, suggesting that a state of somatomotor hyperarousal may be associated with poorer sleep quality in this group. However, in the pain group, greater PSQI scores were associated with less dorsostriatal-sensorimotor rsFC, possibly due to a shift of striatal functions toward regulation sensorimotor aspects of the pain experience, and/or aberrant cortico-striatal loops in the presence of chronic pain. This preliminary investigation advances knowledge about the neurobiology underlying the associations between chronic pain and sleep in community-dwelling older adults that may contribute to the development of effective therapies to decrease disability in geriatric populations.

Alterations in Brain Network Organization in Adults With Obesity as Compared With Healthy-Weight Individuals and Seniors.

Life expectancy and obesity rates have drastically increased in recent years. An unhealthy weight is related to long-lasting medical disorders that might compromise the normal course of aging. The aim of the current study of brain connectivity patterns was to examine whether adults with obesity would show signs of premature aging, such as lower segregation, in large-scale networks. Participants with obesity (n = 30, mean age = 32.8 ± 5.68 years) were compared with healthy-weight controls (n = 33, mean age = 30.9 ± 6.24 years) and senior participants who were stroke-free and without dementia (n = 30, mean age = 67.1 ± 6.65 years) using resting-state magnetic resonance imaging and graph theory metrics (i.e., small-world index, clustering coefficient, characteristic path length, and degree). Contrary to our hypothesis, participants with obesity exhibited a higher clustering coefficient compared with senior participants (t = 5.06, p < .001, d = 1.23, 95% CIbca = 0.64 to 1.88). Participants with obesity also showed lower global degree relative to seniors (t = -2.98, p = .014, d = -0.77, 95% CIbca = -1.26 to -0.26) and healthy-weight controls (t = -2.92, p = .019, d = -0.72, 95% CIbca = -1.19 to -0.25). Regional degree alterations in this group were present in several functional networks. Participants with obesity displayed greater network clustering than did seniors and also had lower degree compared with seniors and individuals with normal weight, which is not consistent with the notion that obesity is associated with premature aging of the brain. Although the cross-sectional nature of the study precludes causal inference, the overly clustered network patterns in obese participants could be relevant to age-related changes in brain function because regular networks might be less resilient and metabolically inefficient.

A238 ABSENCE OF AGE-RELATED MEMORY DECLINE IN GERM-FREE MICE

Abstract Background Age-associated deterioration of cognitive function and memory capacity occur in a variety of mammals, from humans to rodents. For example, significant memory deficits have been reported in conventionally raised (SPF) old mice compared to conventionally raised young mice submitted to a spatial memory task (Prevot et al., Mol Neuropsychiatry 2019). Microbiota to brain signaling is now well established in mice, but the extent to which this influences age-related memory decline is unknown. Aims Our project aims to determine whether the intestinal microbiota contributes to age-related changes in brain function. We address the hypothesis that age-related cognitive decline is attenuated in the absence of the intestinal microbiota. Methods We studied locomotor behavior and spatial memory performance in young germ-free (GF) mice (2–3 months of age, n=24) and senescent GF mice (13–27 months old, n=22) maintained in axenic conditions, and compared them to conventionally raised (SPF) mice. We used the Y-maze test based on a spontaneous alternations task to assess cognition, with alternation rate as a proxy of spatial working memory performance. The locomotor activity was measured using the open-field test. Results GF old mice traveled less distance (458.9 cm) than GF young mice (875.7 cm, p &amp;lt; 0.001) but these differences in locomotor activity did not influence spatial memory performance. Indeed, both GF old and GF young mice had an identical alternation rate of 73.3% (p &amp;gt; 0.05). This contrasted with the memory impairment found in old SPF mice that displayed lower alternation rate of 58.3%, compared to that found in young SPF mice (76.2%, p = 0.13). Conclusions We conclude that the absence of age-related memory decline in germ-free mice is consistent with a role for the microbiota in the cognitive decline associated with aging, likely through action on the immune system, well documented in SPF mice (Thevaranjan et al., Cell Host &amp; Microbe 2017). We propose that novel microbiota-targeted therapeutic strategies may delay or prevent the cognitive decline of aging. Funding Agencies CIHRBalsam Family Foundation

The Effect of Transcranial Direct Current Stimulation (tDCS) on functional performance of healthy older subjects

Background and Purpose: Age-related changes in brain function happen with aging. Noninvasive brain stimulation is one of the strategies for preventing this functional loss. The purpose of this study was to investigate the effect of 5 consecutive days transcranial Direct Current Stimulation (tDCS) on lower and upper extremities’ functional performance.

The effects of human leukocyte antigen DRB1*13 and apolipoprotein E on age-related variability of synchronous neural interactions in healthy women.

BackgroundAge-related brain changes are well-documented and influenced by genetics. Extensive research links apolipoprotein E (apoE) to brain function, with the E4 allele serving as a risk factor for brain disease, including Alzheimer's disease, and the E2 allele conferring protection. Recent evidence also supports protective effects of another gene, human leukocyte antigen (HLA) DRB1*13, on brain disease and age-related brain atrophy in cognitively healthy adults. Here we investigated the effects of apoE and HLA DRB1*13 on brain function by examining changes in neural network properties with age in healthy adults.MethodsOne hundred seventy-eight cognitively healthy women (28–99 y old) underwent a magnetoencephalography scan and provided a blood sample for genetic analysis. Age-related changes in neural network variability in genetic subgroups of DRB1*13 × apoE genotype combinations were assessed using linear regression of network variability against age.FindingsFor individuals lacking a DRB1*13 allele and/or carrying an apoE4 allele, network variability increased significantly with age. In contrast, no such increase was observed in the presence of DRB1*13 and/or apoE2.InterpretationThese findings extend previous research documenting the protective effect of DRB1*13 on brain structure to include protection against age-related changes in brain function, and demonstrate similar protective effects on neural network variability for either DRB1*13 or apoE2. These protective effects could be due to reduction or elimination of factors known to disrupt brain function, including neuroinflammation and amyloid beta protein.FundingU.S. Department of Veterans Affairs, and University of Minnesota.

Individual Differences in Dynamic Functional Brain Connectivity across the Human Lifespan.

Individual differences in brain functional networks may be related to complex personal identifiers, including health, age, and ability. Dynamic network theory has been used to identify properties of dynamic brain function from fMRI data, but the majority of analyses and findings remain at the level of the group. Here, we apply hypergraph analysis, a method from dynamic network theory, to quantify individual differences in brain functional dynamics. Using a summary metric derived from the hypergraph formalism—hypergraph cardinality—we investigate individual variations in two separate, complementary data sets. The first data set (“multi-task”) consists of 77 individuals engaging in four consecutive cognitive tasks. We observe that hypergraph cardinality exhibits variation across individuals while remaining consistent within individuals between tasks; moreover, the analysis of one of the memory tasks revealed a marginally significant correspondence between hypergraph cardinality and age. This finding motivated a similar analysis of the second data set (“age-memory”), in which 95 individuals, aged 18–75, performed a memory task with a similar structure to the multi-task memory task. With the increased age range in the age-memory data set, the correlation between hypergraph cardinality and age correspondence becomes significant. We discuss these results in the context of the well-known finding linking age with network structure, and suggest that hypergraph analysis should serve as a useful tool in furthering our understanding of the dynamic network structure of the brain.

Evaluation of a clinically practical, ERP-based neurometric battery: Application to age-related changes in brain function.

Event-related potentials (ERPs) show promise as markers of neurocognitive dysfunction, but conventional recording procedures render measurement of many ERP-based neurometrics clinically impractical. The purpose of this work was (a) to develop a brief neurometric battery capable of eliciting a broad profile of ERPs in a single, clinically practical recording session, and (b) to evaluate the sensitivity of this neurometric profile to age-related changes in brain function. Nested auditory stimuli were interleaved with visual stimuli to create a 20-min battery designed to elicit at least eight ERP components representing multiple sensory, perceptual, and cognitive processes (Frequency & Gap MMN, P50, P3, vMMN, C1, N2pc, and ERN). Data were recorded from 21 younger and 21 high-functioning older adults. Significant multivariate differences were observed between ERP profiles of younger and older adults. Metrics derived from ERP profiles could be used to classify individuals into age groups with a jackknifed classification accuracy of 78.6%. Results support the utility of this design for neurometric profiling in clinical settings. This study demonstrates a method for measuring a broad profile of ERP-based neurometrics in a single, brief recording session. These markers may be used individually or in combination to characterize/classify patterns of sensory and/or perceptual brain function in clinical populations.

Investigating Age-related changes in fine motor control across different effectors and the impact of white matter integrity

Changes in fine motor control that eventually compromise dexterity accompany advanced age; however there is evidence that age-related decline in motor control may not be uniform across effectors. Particularly, the role of central mechanisms in effector-specific decline has not been examined but is relevant for placing age-related motor declines into the growing literature of age-related changes in brain function. We examined sub-maximal force control across three different effectors (fingers, lips, and tongue) in 18 young and 14 older adults. In parallel with the force variability measures we examined changes in white matter structural integrity in effector-specific pathways in the brain with diffusion tensor imaging (DTI). Motor pathways for each effector were identified by using an fMRI localizer task followed by tractography to identify the fiber tracts propagating to the midbrain. Increases in force control variability were found with age in all three effectors but the effectors showed different degrees of age-related variability. Motor control changes were accompanied by a decline in white matter structural integrity with age shown by measures of fractional anisotropy and radial diffusivity. The DTI metrics appear to mediate some of the age-related declines in motor control. Our findings indicate that the structural integrity of descending motor systems may play a significant role in age-related increases in motor performance variability, but that differential age-related declines in oral and manual effectors are not likely due to structural integrity of descending motor pathways in the brain.

The Dependency of Parietal Activation on Visuospacial Operation Performance in the Elderly – An Event-Related fMRI Study

Event Abstract Back to Event The Dependency of Parietal Activation on Visuospacial Operation Performance in the Elderly – An Event-Related fMRI Study Toshiharu Nakai1*, Mitsunobu Kunimi1, Sachiko Kiyama1, Ayuko Tanaka1 and Yoshiaki Shiraishi2 1 National Center for Geriatrics and Gerontology, NeuroImaging & Informatics, Japan 2 Kobe University, Electrical and Electronic Engineering, Japan It has been proposed that physical exercises can assist cognitive recovery in the elderly [1], however, their effectiveness has been controversial [2]. The backgrounds of this discrepancy may be heterogeneity of the populations studied and various exercise protocols employed. In order to clarify the conditions to predict validity of physical exercises, it is desirable to establish a method to classify the subjects based on their cognitive and physiological status. For this evaluation, the neuronal basis of the tasks used in the exercises should be clarified. We investigated the availability of a virtual performance task designed from exercises for the elderly as a model to test age-related changes in brain function. Twenty-four elderly (over 60, 12 females) and 24 non-elderly (20 - 54, 12 females) healthy volunteers participated in an event-related fMRI experiment simulating the visuo-motor transformation of bean transfer test (BTT), one of the physical test batteries for elderly [3]. Functional data were obtained by using a 3T-MR scanner (TR = 3000 ms, TE = 30 ms, 39 axial slices, 3 mm thick, 0.75 mm gap, matrix = 64 x 64, FOV = 192 mm, BW = 1420 Hz/Px, 128 volumes), and the reaction time in each trial were recorded at 6 points by synchronizing to the TTL signal from the MR scanner. The functional images were processed using SPM8. It was indicated that the activations representing the whole trial of virtual BTT (VBTT) were contributed by different steps in each age group. In young subjects, major activations were detected at CP0 (bean appearance), CP1 (start clipping) and CP4 (finish transferring), while they were detected at CP0 and CP2 (finish clipping) in the elderly subjects. Activations in the left BA 3, 5, 6, 40, 43 and the right BA7 were significantly augmented in the elderly group at CP2 (FEW, p< 0.05). Within the elderly subjects, further activations in the left BA5 and right BA7 were augmented in the higher bean clipping performance group (12 subjects, FDR, p< 0.001) at CP2. However, no augmentation of brain activations was detected in the higher bean transfer performance group in contrast to the lower performance group at CP2, 3 (start transfer) or 4. The activations were not significantly different between the two age groups when the contrasts obtained from the whole trial were compared. By using partitioning analysis employing accurate response times for each step of VBTT, differential activations characteristic to the two age groups could be extracted. In conclusion, it was suggested that the relationship between performance of visuo-spatial operation and parietal activation may be a potential indicator of functional compensation capability in the elderly depending on further neuronal recruitment. Acknowledgements This research was supported by Grant-in-Aid for Scientific Research (KAKENHI) # 21300196 and 24300186 supported by MEXT.

Vessel‐encoded arterial spin labeling (VE‐ASL) reveals elevated flow territory asymmetry in older adults with substandard verbal memory performance

To evaluate how flow territory asymmetry and/or the distribution of blood through collateral pathways may adversely affect the brain's ability to respond to age-related changes in brain function. These patterns have been investigated in cerebrovascular disease; however, here we evaluated how flow-territory asymmetry related to memory generally in older adults. A multi-faceted MRI protocol, including vessel-encoded arterial spin labeling capable of flow territory mapping, was applied to assess how flow territory asymmetry; memory performance (CERAD-Immediate Recall); cortical cerebral blood flow (CBF), white matter lesion (WML) count, and cortical gray matter volume were related in older healthy control volunteers (HC; n = 15; age = 64.5 ± 7 years) and age-matched mild cognitive impairment volunteers (MCI; n = 7; age = 62.7 ± 3.7 years). An inverse relationship was found between memory performance and flow territory asymmetry in HC volunteers (P = 0.04), which reversed in MCI volunteers (P = 0.04). No relationship was found between memory performance and cortical tissue volume in either group (P > 0.05). Group-level differences for HC volunteers performing above versus below average on CERAD-I were observed for flow territory asymmetry (P < 0.02) and cortical volume (P < 0.05) only. Findings suggest that flow territory asymmetry may correlate more sensitively with memory performance than CBF, atrophy and WML count in older adults.

Partitioning age-related changes in brain activation using a virtual performance task to simulate complex movements

Event Abstract Back to Event Partitioning age-related changes in brain activation using a virtual performance task to simulate complex movements Toshiharu Nakai1*, Ayuko Tanaka1, Mitsunobu Kunimi1, Sachiko Kiyama1 and Yoshiaki Shiraishi2 1 National Center for Geriatrics and Gerontology, Neuroimaging & Informatics, Japan 2 Nagoya Institute of Technology Graduate School of Engineering, Computer Science and Engineering, Japan Aging has become a serious social issue, especially in Asian countries. In order to maintain the activities of elderly people, social programs to promote physical and mental exercises are conducted. Although some investigations have reported that those activities potentially contribute to the prevention of cognitive decline [1], the neurological background has not been systematically verified. We investigated the availability of a virtual performance task designed from such exercises as a model to test age-related changes in brain function [2]. An event-related fMRI task representing the motor behavior in the bean transfer test (BTT), which is used as one component of the test battery to evaluate the physical ability of elderly in Japan, was designed. The task consisted of two operations using a 2 by 2 turnkey system. With the left-hand key, a small, round object (bean) is pinched with two lines representing chopsticks. Then, the object with chopsticks is moved to a round target (pot) with the right-hand key to put the bean in. The behavioral data were marked with 6 checkpoints (Fig.1). The onset of each trial was determined using the sum of two jittering factors, the execution time for each trial by the subject and periodically altering the interval time before the onset of each trial. fMRI data were obtained using the EPI sequence on a 3T MR scanner, and the data sets were analyzed using SPM8. fMRI data were obtained from 11 elderly (over 60, 6 females) and 7 non-elderly (under 54) volunteers. In the activation representing the total trial, the network for the upper visuo-spatial transformation tract and higher motor control was observed in the elderly (two-sample t-test, p<0.05). Differential peaks between the two age groups were detected as augmented activation in the left BA5 ([-23 -38 59]) and bilateral BA6 ([-60 -2 47], [60 2 38]) in the elderly group (Fig.2, CPall). In the partitioned maps, it was indicated that this difference was mostly contributed to by the first task switching point (CP2) and pinching the object (CP1). Activation of these areas was not significant in the CP3 and CP4 map in the elderly. On the other hand, activation was augmented in the dorsal visuo-motor pathway in the young subjects during these steps. It was suggested that these results represent: 1) a higher demand for visuo-spatial transformation by adjusting the asymmetric (two independent) rotation of the sticks, and 2) a lower frequency of object transference to the goal than pinching it in elderly subjects. By recording self-paced object manipulation in the interactive task, complex brain activation during a combined motor processing could be more precisely attributed to cognitive elements. This feature was useful to further partitioning age-related changes in brain activation. Figure 1 Figure 2 Acknowledgements This research was supported by a Grant-in-Aid for Scientific Research (KAKENHI) # 21300196 and 24300186 supported by MEXT.

Default distrust? An fMRI investigation of the neural development of trust and cooperation

The tendency to trust and to cooperate increases from adolescence to adulthood. This social development has been associated with improved mentalizing and age-related changes in brain function. Thus far, there is limited imaging data investigating these associations. We used two trust games with a trustworthy and an unfair partner to explore the brain mechanisms underlying trust and cooperation in subjects ranging from adolescence to mid-adulthood. Increasing age was associated with higher trust at the onset of social interactions, increased levels of trust during interactions with a trustworthy partner and a stronger decline in trust during interactions with an unfair partner. Our findings demonstrate a behavioural shift towards higher trust and an age-related increase in the sensitivity to others' negative social signals. Increased brain activation in mentalizing regions, i.e. temporo-parietal junction, posterior cingulate and precuneus, supported the behavioural change. Additionally, age was associated with reduced activation in the reward-related orbitofrontal cortex and caudate nucleus during interactions with a trustworthy partner, possibly reflecting stronger expectations of trustworthiness. During unfair interactions, age-related increases in anterior cingulate activation, an area implicated in conflict monitoring, may mirror the necessity to inhibit pro-social tendencies in the face of the partner's actual levels of cooperation.

Age-related changes in the somatosensory processing of tactile stimulation—An fMRI study

Age-related changes in brain function are complex. Although ageing is associated with a reduction in cerebral blood flow and neuronal activity, task-related processing is often correlated with an enlargement of the corresponding and additionally recruited brain areas. This supplemental employment is considered an attempt to compensate for deficits in the ageing brain. Although there are contradictory reports regarding the role of the primary somatosensory cortex (SI), currently, there is little knowledge about age-related functional changes in other brain areas in the somatosensory network (secondary somatosensory cortex (SII), and insular, anterior (ACC) and posterior cingulate cortices (PCC)).We investigated 16 elderly (age range, 62–71 years) and 18 young subjects (age range, 21–28 years) by determining the current perception threshold (CPT) and applying functional magnetic resonance imaging (fMRI) using a 3.0Tesla scanner under tactile stimulation of the right hand.CPT was positively correlated with age. fMRI analysis revealed significantly increased activation in the contralateral SI and ipsilateral motor cortex in elderly subjects. Furthermore, we demonstrated age-related reductions in the activity in the SII, ACC, PCC, and dorsal parts of the corpus callosum.Our study revealed dramatic age-related differences in the processing of a simple tactile stimulus in the somatosensory network. Specifically, we detected enhanced activation in the contralateral SI and ipsilateral motor cortex assumingly caused by deficient inhibition and decreased activation in later stages of somatosensory processing (SII, cingulate cortex) in elderly subjects. These results indicate that, in addition to over-activation to compensate for impaired brain functions, there are complex mechanisms of modified inhibition and excitability involved in somatosensory processing in the ageing brain.

Secrets of aging: What does a normally aging brain look like?

Over the past half century, remarkable progress has been made in understanding the biological basis of memory and how it changes over the lifespan. An important conceptual advance during this period was the realization that normative cognitive trajectories can exist independently of dementing illness. In fact, mammals as different as rats and monkeys, who do not spontaneously develop Alzheimer’s disease, show memory impairments at advanced ages in similar domains as those observed in older humans. Thus, animal models have been particularly helpful in revealing brain mechanisms responsible for the cognitive changes that occur in aging. During these past decades, a number of empirical and technical advances enabled the discoveries that began to link age-related changes in brain function to behavior. The pace of innovation continues to accelerate today, resulting in an expanded window through which the secrets of the aging brain are being deciphered.

Differential effects of the APOE genotype on brain function across the lifespan

Increasing age and carrying an APOEε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers.A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20–35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50–78years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume.Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.