Age-related alterations in default mode network: impact on working memory performance

The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.     

Aging and the neural correlates of source memory: over-recruitment and functional reorganization

Behavioral evidence suggests that memory for context (i.e., source memory) is more vulnerable to age-related decline than item memory. It is not clear, however, whether this pattern reflects a specific age-related deficit in context memory or a more general effect of task difficulty. In the present study, we used event-related functional magnetic resonance imaging (fMRI) with healthy younger and older adults to dissociate the effects of age, task (item vs. source memory), and task difficulty (1 vs. 2 study presentations) on patterns of blood oxygen level-dependent (BOLD) signal changes during memory retrieval. Behavioral performance was similar in both age groups, but was sensitive to task and difficulty (item > source; easy > difficult). Data-driven multivariate analyses revealed age differences consistent with age-related overrecruitment of frontoparietal regions during difficult task conditions, and age-related functional reorganization in bilateral frontal and right-lateralized posterior regions that were sensitive to difficulty in younger adults, but to task (i.e., context demand) in older adults. These findings support the hypothesis of a specific context memory deficit in older adults.     

Aging-related changes of neural mechanisms underlying visual-spatial working memory

Capacities of the prefrontal cortex (PFC) such as working memory (WM) are known to decline with increasing age. However, it is unclear which neurofunctional mechanisms may underlie this aging-related cognitive decline. The finding that PFC activity tends to be less lateralized in older subjects has led to the assumption of a hemispheric asymmetry reduction in the PFC associated with aging (HAROLD). Using functional magnetic resonance imaging (fMRI), we here investigated aging-related neurofunctional alterations during the performance of a visual-spatial WM task with differential levels of difficulty. Older volunteers activated dorsolateral PFC regions bilaterally while young subjects recruited these areas only in the left hemisphere. These data corroborate the hemispheric asymmetry reduction in the PFC associated with aging (HAROLD) account. However, we also observed functional reorganizations in parieto-occipital areas, and with increasing WM demands, an aging-related reversed hemispheric asymmetry of prefrontal activations. Importantly, neither PFC nor parieto-occipital reorganizations prevented older participants from showing worse WM performance than young volunteers. We conclude that frontal-parietal functional reorganizations may reflect compensational mechanisms related to aging, but do not obviate diminished visual-spatial WM performance in older people.     

Effects of aging on transient and sustained successful memory encoding activity

Event-related fMRI studies have investigated age-related changes in encoding by identifying greater activity for items that are later remembered than for those that are forgotten (difference in memory, or Dm). The present study used hybrid blocked/event-related analyses to distinguish between transient Dm versus sustained Dm. Dm was identified as parametric increases in encoding activity as a function of a combined subsequent memory/confidence scale. Dm was measured in each trial (transient activity) and in blocks of eight trials (sustained activity). Transient Dm analyses showed age-related reductions in the left hippocampus but increases in left prefrontal cortex (PFC). Sustained Dm analyses showed age-related reductions in right PFC, but no region showing increased activity in older adults. These findings suggests that during semantic classification older adults show less spontaneous hippocampal-mediated encoding processes, but greater PFC-mediated semantic processes. Additionally, the decline in sustained Dm in PFC may involve age-related deficits in sustained attention that impact encoding processes. The results underscore the importance of investigating aging effects on both transient and sustained neural activity.     

Association between prefrontal activity and volume change in prefrontal and medial temporal lobes in aging and dementia: A review

Functional neuroimaging studies have consistently reported age-related changes in prefrontal cortex (PFC) activity during a variety of cognitive tasks, including episodic memory. These changes are often interpreted within the context of one of the following three neural models of age-related changes in brain function: dedifferentiation, neural inefficiency, and neural plasticity and compensation models. Distinguishing between these competing models has proven difficult when interpreting results using functional imaging data alone. In this paper we suggest that a more accurate interpretation of age-related changes in PFC activity requires consideration of age-related differences in gray matter volume (GMv) in PFC and the medial temporal lobes (MTL). We review fMRI studies of cognitive aging that have directly examined the relationship between PFC activity and both local (PFC) and distal (MTL) GMv in older versus younger adults. We also considered how structure–function relationships may be further modified in pathological aging (i.e. mild cognitive impairment (MCI) and Alzheimer's disease (AD)).We found that when task performance was matched between age-groups there was a negative association between regional PFC volume and activity in older adults. However, when older adults performed worse than young adults we observed a positive association between volume and activity in right lateral PFC. Additionally during memory tasks, several studies revealed that PFC activity is positively related to GM volume in MTL in healthy older adults, but negatively related in MCI and AD patients. We conclude that PFC activity is related to age-related changes in local and distal GM volume reductions and that consideration of these structural measures aids the interpretation of fMRI results. Furthermore, the study of structure–function relationships may provide important insights into the biological mechanisms underlying healthy versus pathological aging.     

Executive functions and neurocognitive aging: dissociable patterns of brain activity

Studies of neurocognitive aging report altered patterns of brain activity in older versus younger adults performing executive function tasks. We review the extant literature, using activation likelihood estimation meta-analytic methods, to compare age-related differences in the pattern of brain activity across studies examining 2 categories of tasks associated with executive control processing: working memory and inhibition. In a direct contrast of young and older adult activations, older adults engaged bilateral regions of dorsolateral prefrontal cortex as well as supplementary motor cortex and left inferior parietal lobule during working memory. In contrast, age-related changes during inhibitory control were observed in right inferior frontal gyrus and presupplementary motor area. Additionally, when we examined task-related differences within each age group we observed the predicted pattern of differentiated neural response in the younger subjects: lateral prefrontal cortex activity associated with working memory versus right anterior insula/frontal opercular activity associated with inhibition. This separation was largely maintained in older subjects. These data provide the first quantitative meta-analytic evidence that age-related patterns of functional brain change during executive functioning depend on the specific control process being challenged.     

Relationship of negative mood with prefrontal cortex activity during working memory tasks: an optical topography study

Mood has a substantial impact on cognitive functions. Although studies have shown that the interaction between mood and cognition is mediated by the prefrontal cortex (PFC), little is known about how naturalistic mood in everyday life is associated with PFC activity during cognitive tasks. We investigated whether inter-individual variation in perceived mood under current life situations (recent week) is related to PFC activity during working memory (WM) tasks in healthy adults. Levels of positive and negative moods were quantified with the Profile of Mood States (POMS) questionnaire. PFC activities during verbal and spatial WM tasks were measured by optical topography (OT), a non-invasive low-constraint neuroimaging tool, to minimize experimental intervention in participants' moods. Group-average analysis showed significant activations in the bilateral dorsolateral PFC in both WM tasks. Correlation analysis revealed that the participants reporting higher levels of negative moods showed lower levels of PFC activity during the verbal WM task but not during the spatial WM task. This relationship was significant even after controlling for possible confounding factors such as age, gender, and task performance. Our results suggest that verbal WM is linked with naturalistic negative mood and that the PFC is involved in the mood-cognition interaction in daily circumstances.     

Ageing-related changes of neural activity associated with spatial contextual memory

Neuropsychological studies provide evidence for an ageing-related decline of memory for contextual information related to remembered items. Using event-related fMRI we investigated the neural correlates of ageing-related changes during encoding and retrieval of spatial contextual memory. Eighteen young and 17 older subjects were included in the analysis (mean age 24 and 60 years, respectively). Although young and older subjects recognised the same amount of items during retrieval, spatial context memory for remembered items was superior in younger subjects. In both groups, left parahippocampal activity during encoding predicted contextual memory performance during retrieval. During encoding, an interaction between age and success of spatial context encoding was found in the left fusiform gyrus. During retrieval, the left hippocampal formation showed higher activity for successful than for unsuccessful spatial context retrieval as well as an interaction between age and spatial context judgement. Both findings are likely to underlie the contextual memory deficit observed in older subjects.     

Is the dissociability of working memory systems for name identity, visual-object identity, and spatial location maintained in old age?

The dissociability of working memory for name identity (verbal information), visual objects, and spatial location was explored in 3 experiments. Consistent with previous results, the 3 working memory systems were dissociable in younger adults. Both younger and older adults showed involvement of name identity in an object identity task, and older adults showed this involvement in a spatial memory task. Results were interpreted as showing that the systems are generally separable but that involvement of 1 with another is possible and more likely in older adults. A 4th, correlational study showed that there is generalized decline in working memory systems in old age, with the age differences in memory mediated to a moderate extent by age-related differences in speed of processing. It was speculated that the specific, possibly strategic changes are independent of and take place against a backdrop of generalized loss of nervous system integrity.     

Neural processing of emotional pictures and words: a comparison of young and older adults

Recent findings have revealed age-related changes in neural recruitment during the processing of emotional information. The present study examined whether these age-related changes would be more pronounced for words, thought to be processed in a controlled manner versus relatively automatically processed pictures. Compared to young adults, older adults showed less amygdala activation, and more medial prefrontal cortex (PFC) activation, for negative than positive pictures. The opposite pattern was observed for words. Older adults showed a positivity effect in memory for words, but not for pictures, suggesting that their positivity effect may stem from age-related changes in medial PFC engagement during encoding.     

Age-Related Task Sensitivity of Frontal EEG Entropy During Encoding Predicts Retrieval

Age-related declines in memory may be due in part to changes in the complexity of neural activity in the aging brain. Electrophysiological entropy provides an accessible measure of the complexity of ongoing neural activity. In the current study, we calculated the permutation entropy of the electroencephalogram (EEG) during encoding of relevant (to be learned) and irrelevant (to be ignored) stimuli by younger adults, older adults, and older cognitively declined adults. EEG entropy was differentially sensitive to task requirements across groups, with younger and older controls exhibiting greater control of encoding-related activity than older declined participants. Task sensitivity of frontal EEG during encoding predicted later retrieval, in line with previous evidence that cognitive decline is associated with reduced ability to self-initiate encoding-related processes.     

tDCS selectively improves working memory in older adults with more education

Cognitive performance, including performance on working memory (WM) tasks declines with age. Changes in brain activations are one presumed contributor to WM decline in the healthy aging population. In particular, neuroimaging studies show that when older adults perform WM tasks there tends to be greater bilateral frontal activity than in younger adults. We hypothesized that stimulating the prefrontal cortex in healthy older adults would improve WM performance. To test this hypothesis we employed transcranial direct current stimulation (tDCS), a neurostimulation technique in which small amounts of electrical current are applied to the scalp with the intent of modulating the activity in underlying neurons. Across three testing sessions we applied sham stimulation or anodal tDCS to the left (F3) or right (F4) prefrontal cortex to healthy older adults as they performed trials of verbal and visual 2-back WM tasks. Surprisingly, tDCS was uniformly beneficial across site and WM task, but only in older adults with more education. In the less educated group, tDCS provided no benefit to verbal or visual WM performance. We interpret these findings as evidence for differential frontal recruitment as a function of strategy when older adults perform WM tasks.     

Age-related effects on the neural correlates of autobiographical memory retrieval

Older adults recall less episodically rich autobiographical memories (AM), however, the neural basis of this effect is not clear. Using functional MRI, we examined the effects of age during search and elaboration phases of AM retrieval. Our results suggest that the age-related attenuation in the episodic richness of AMs is associated with difficulty in the strategic retrieval processes underlying recovery of information during elaboration. First, age effects on AM activity were more pronounced during elaboration than search, with older adults showing less sustained recruitment of the hippocampus and ventrolateral prefrontal cortex (VLPFC) for less episodically rich AMs. Second, there was an age-related reduction in the modulation of top-down coupling of the VLPFC on the hippocampus for episodically rich AMs. In sum, the present study shows that changes in the sustained response and coupling of the hippocampus and prefrontal cortex (PFC) underlie age-related reductions in episodic richness of the personal past.     

Age-related changes in word retrieval: role of bilateral frontal and subcortical networks

Healthy older adults frequently report word-finding difficulties, yet the underlying cause of these problems is not well understood. This study examined whether age-related changes in word retrieval are related to changes in areas of the frontal lobes thought to subserve word retrieval or changes in areas of the inferior temporal lobes thought to be involved in semantic knowledge. Twenty younger and 20 older healthy adults named aloud photographs during event-related fMRI. Results showed that in the face of equivalent naming accuracy, older adults activated a larger frontal network than younger adults during word retrieval, but there were no activity differences between groups in the fusiform gyrus, suggesting that the substrates for word retrieval but not for semantic knowledge change with aging. Additionally, correlations between BOLD response and naming accuracy and response latency were found in several frontal and subcortical regions in older adults. Findings are discussed in the context of possible compensatory mechanisms invoked to maintain performance in healthy aging, and suggest that increased involvement of the right hemisphere is not universally beneficial to performance.     

Age-related frontoparietal changes during the control of bottom-up and top-down attention: an ERP study

We investigated age-related changes in frontal and parietal scalp event-related potential (ERP) activity during bottom-up and top-down attention. Younger and older participants were presented with arrays constructed to induce either automatic “pop-out” (bottom-up) or effortful “search” (top-down) behavior. Reaction times (RTs) increased and accuracy decreased with age, with a greater age-related decline in accuracy for the search than for the pop-out condition. The latency of the P300 elicited by the visual search array was shorter in both conditions in the younger than in the older adults. Pop-out target detection was associated with greater activity at parietal than at prefrontal locations in younger participants and with a more equipotential prefrontal-parietal distribution in older adults. Search target detection was associated with greater activity at prefrontal than at parietal locations in older relative to younger participants. Thus, aging was associated with a more prefrontal P300 scalp distribution during the control of bottom-up and top-down attention. Early latency extrastriate potentials were enhanced and N2-posterior-contralateral (N2pc) was reduced in the older group, supporting the idea that the frontal enhancements may be due to a compensation for disinhibition and distraction in the older adults. Taken together these findings provide evidence that younger and older adults recruit different frontal-parietal networks during top-down and bottom-up attention, with older adults increasing their recruitment of a more frontally distributed network in both of these types of attention. This work is in accord with previous neuroimaging findings suggesting that older adults recruit more frontal activity in the service of a variety of tasks than younger adults.     

Distinct mechanisms for the impact of distraction and interruption on working memory in aging

Interference is known to negatively impact the ability to maintain information in working memory (WM), an effect that is exacerbated with aging. Here, we explore how distinct sources of interference, i.e., distraction (stimuli to-be-ignored) and interruption (stimuli requiring attention), differentially influence WM in younger and older adults. EEG was recorded while participants engaged in three versions of a delayed-recognition task: no interference, a distracting stimulus, and an interrupting stimulus presented during WM maintenance. Behaviorally, both types of interference negatively impacted WM accuracy in older adults significantly more than younger adults (with a larger deficit for interruptions). N170 latency measures revealed that the degree of processing both distractors and interruptors predicted WM accuracy in both populations. However, while WM impairments could be explained by excessive attention to distractors by older adults (a suppression deficit), impairment induced by interruption were not clearly mediated by age-related increases in attention to interruptors. These results suggest that distinct underlying mechanisms mediate the impact of different types of external interference on WM in normal aging.     

Neurophysiological correlates of age-related changes in working memory capacity

Cognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age=29) and twelve older subjects (>55 years of age; mean age=59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE=24 ms, TR=56 ms, FA=60 degrees , voxel dimensions=3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (1-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p=0.4), but performed worse than the younger subjects at 2-Back (p<0.01) and 3-Back (p=0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p<0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in 1-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs.     

Age-related spatiotemporal reorganization during response inhibition

As a key high-level cognitive function in human beings, response inhibition is crucial for adaptive behavior. Previous neuroimaging studies have shown that older individuals exhibit greater neural activation than younger individuals during response inhibition tasks. This finding has been interpreted within a neural compensation framework, in which additional neural resources are recruited in response to age-related cognitive decline. Although this interpretation has received empirical support, the precise event-related temporal course of this age-related compensatory neural response remains unexplored. In the present study, we conducted source analysis on inhibition-related ERP components (i.e., N2 and P3) that were recorded while healthy younger and older adults participated in a visual Go/NoGo task. We found that older adults showed increased source current densities of the N2 and P3 components than younger adults, which support previous hemodynamic findings. Further, such age-related differences in neural activation were successfully separated between the N2 and P3 periods by source localization analysis. Interestingly, the increased activations in older adults were primarily localized to the right precentral and postcentral gyri during the N2 period, which shifted to the right dorsolateral prefrontal cortex and the right inferior frontal gyrus during the P3 period. Taken together, our results clearly illustrate the spatiotemporal dynamics of age-related functional brain reorganization, and further specify the exact temporal course at the millisecond scale by which age-related compensatory neural responses occur during response inhibition.     

Age-related ERP differences at retrieval persist despite age-invariant performance and left-frontal negativity during encoding

Although it has been reported repeatedly that retrieval-related processes decline with aging, the influence of well-documented age-related encoding deficiencies on the observed changes at retrieval have not been ruled out as a contributing factor. Here, we disentangle this confound by using a serendipitous finding reported by Nessler et al. [D. Nessler, R. Johnson Jr., M. Bersick, D. Friedman, On why the elderly have normal semantic retrieval but deficient episodic encoding: a study of left inferior frontal ERP activity, Neuroimage 30 (2006) 299–312]. In that study, age-related differences in the magnitude of left inferior frontal brain activity at encoding and subsequent recognition memory performance were eliminated when a deeper level of semantic encoding in the older adults was compared with a shallow level in the young. Based on this earlier result, the present paper is concerned with the question of whether the matched recognition performance resulting from age-equivalent ERP encoding activity was also accompanied by age-invariant retrieval-related brain activity. The results in the young were consistent with dual-process models of recognition memory due to the presence of ERP activity linked previously to familiarity (frontal EM effect) and recollection (parietal EM effect). By contrast the older adults only showed evidence of familiarity-based processes. Thus, despite age-equivalent brain activity at encoding and subsequent recognition performance, older relative to young adults appeared to base their old–new decisions on a qualitatively different pattern of retrieval processes (i.e., more on familiarity and less on recollection). Consequently, these data suggest that the age-related changes in retrieval observed here are independent of, and likely occur in addition to, any age-related changes in encoding processes.     

Neural correlates of source memory retrieval in young, middle-aged and elderly adults

Event-related potentials (ERPs) were recorded in young (21-27 years old), middle-aged (50-57 years old) and older adults (70-77 years old) to determine whether the decline in source memory that occurs with advancing age coincides with contemporaneous neurophysiological changes. Source memory for the spatial location (quadrant on the screen) of images presented during encoding was examined. The images were shown in the center of the screen during the retrieval task. Retrieval success for source information was characterized by different scalp topographies at frontal electrode sites in young adults relative to middle-aged and older adults. The right frontal effect during unsuccessful retrieval attempts showed amplitude and latency differences across age groups and was related to the ability to discriminate between old and new images only in young adults. These results suggest that the neural correlates of the retrieval success and attempt were affected by age and these effects were present by middle-age.