Trajectories and contributing factors of neural compensation in healthy and pathological aging.

Neural degeneration is a hallmark of healthy aging and can be associated with specific cognitive impairments. However, neural degeneration per se is not matched by unremitting declines in cognitive abilities. Instead, middle-aged and older adults typically maintain surprisingly high levels of cognitive functioning, suggesting that the human brain can adapt to structural degeneration by neural compensation. Here, we summarize prevailing theories and recent empirical studies on neural compensation with a focus on often neglected contributing factors, such as lifestyle, metabolism and neural plasticity. We suggest that these factors moderate the relationship between structural integrity and neural compensation, maintaining psychological well-being and behavioral functioning. Finally, we discuss that a breakdown in neural compensation may pose a tipping point that distinguishes the trajectories of healthy vs pathological aging, but conjoint support from psychology and cognitive neuroscience for this alluring view is still scarce. Therefore, future experiments that target the concomitant processes of neural compensation and associated behavior will foster a comprehensive understanding of both healthy and pathological aging.

Differential effects of expectancy on memory formation in young and older adults.

Novelty can promote subsequent long-term memory via the mesolimbic system, including the medial temporal lobe and midbrain structures. Importantly, these and other brain regions typically degenerate during healthy aging, which suggests a reduced impact of novelty on learning. However, evidence in favor of such a hypothesis is scarce. Thus, we used functional MRI in combination with an established paradigm in healthy young (19-32 years, n = 30) and older (51-81 years, n = 32) humans. During encoding, colored cues predicted the subsequent presentation of either a novel or previously familiarized image (75% cue validity), and approximately 24 h later, recognition memory for novel images was tested. Behaviorally, expected novel images, as compared to unexpected novel images, were better recognized in young and, to a lesser degree, older subjects. At the neural level, familiar cues activated memory related areas, especially the medial temporal lobe, whereas novelty cues activated the angular gyrus and inferior parietal lobe, which may reflect enhanced attentional processing. During outcome processing, expected novel images activated the medial temporal lobe, angular gyrus and inferior parietal lobe. Importantly, a similar activation pattern was observed for subsequently recognized novel items, which helps to explain the behavioral effect of novelty on long-term memory. Finally, age-effects were pronounced for successfully recognized novel images with relatively stronger activations in attention-related brain regions in older adults; younger adults, on the other hand, showed stronger hippocampal activation. Together, expectancy promotes memory formation for novel items via neural activity in medial temporal lobe structures and this effect appears to be reduced with age.

Set Size of Information in Long-Term Memory Similarly Modulates Retrieval Dynamics in Young and Older Adults.

Our ability to rapidly distinguish new from already stored (old) information is important for behavior and decision making, but the underlying processes remain unclear. Here, we tested the hypothesis that contextual cues lead to a preselection of information and, therefore, faster recognition. Specifically, on the basis of previous modeling work, we hypothesized that recognition time depends on the amount of relevant content stored in long-term memory, i.e., set size, and we explored possible age-related changes of this relationship in older humans. In our paradigm, subjects learned by heart four different word lists (24, 48, 72, and 96 words) written in different colors (green, red, orange, and blue). On the day of testing, a color cue (e.g., green) indicated with a probability of 50% that a subsequent word might be from the corresponding list or from a list of new words. The old/new status of the word had to be distinguished via button press. As a main finding, we can show in a sample of n = 49 subjects, including 26 younger and 23 older humans, that response times increased linearly and logarithmically as a function of set size in both age groups. Conversely, corrected hit rates decreased as a function of set size with no statistically significant differences between both age groups. As such, our findings provide empirical evidence that contextual information can lead to a preselection of relevant information stored in long-term memory to promote efficient recognition, possibly by cyclical top-down and bottom-up processing.

Novelty processing associated with neural beta oscillations improves recognition memory in young and older adults.

Novelty anticipation activates the mesolimbic system and promotes subsequent long-term memory in younger adults. Importantly, mesolimbic structures typically degenerate with age, which might reduce positive effects of novelty anticipation. Here, we used electroencephalography in combination with an established paradigm in healthy young (19-33 years old, n = 28) and older (53-84, n = 27) humans. Colored cues predicted the subsequent presentation of either a novel or previously familiarized image (75% cue validity). On the subsequent day, recognition memory for the novel images was tested. Behaviorally, novelty anticipation improved recollection-based but not familiarity-based recognition memory in both groups, and this effect was more pronounced in older subjects. Furthermore, novelty and familiarity cues increased theta (4-8 Hz) and decreased alpha/beta power (9-20 Hz); at outcome, expected novel and familiar images both increased beta power (13-25 Hz). Finally, a subsequent memory effect for expected novel images was associated with increases in beta power independent of age. Together, novelty anticipation drives hippocampus-dependent long-term recognition memory across the life span, and this effect appears to be related to neural beta oscillations.

Semantic Congruence Drives Long-Term Memory and Similarly Affects Neural Retrieval Dynamics in Young and Older Adults.

Learning novel information can be promoted if it is congruent with already stored knowledge. This so-called semantic congruence effect has been broadly studied in healthy young adults with a focus on neural encoding mechanisms. However, the impacts on retrieval, and possible impairments during healthy aging, which is typically associated with changes in declarative long-term memory, remain unclear. To investigate these issues, we used a previously established paradigm in healthy young and older humans with a focus on the neural activity at a final retrieval stage as measured with electroencephalography (EEG). In both age groups, semantic congruence at encoding enhanced subsequent long-term recognition memory of words. Compatible with this observation, semantic congruence led to differences in event-related potentials (ERPs) at retrieval, and this effect was not modulated by age. Specifically, congruence modulated old/new ERPs at a fronto-central (Fz) and left parietal (P3) electrode in a late (400-600 ms) time window, which has previously been associated with recognition memory processes. Importantly, ERPs to old items also correlated with the positive effect of semantic congruence on long-term memory independent of age. Together, our findings suggest that semantic congruence drives subsequent recognition memory across the lifespan through changes in neural retrieval processes.

Age-related iron accumulation and demyelination in the basal ganglia are closely related to verbal memory and executive functioning.

Age-related cognitive decline has been linked to alterations of the dopaminergic system and its subcortical trajectories. Recent work suggests a critical role of iron accumulation within the basal ganglia (BG) in verbal memory performance, and increased iron levels have been related to demyelination. However, the specificity of age-related iron increases with respect to cognitive functions remains unclear. Therefore, we investigated the interplay of age, cognitive performance, and structural integrity of the BG. In total, 79 healthy older participants underwent a broad cognitive assessment (fluid and crystallized intelligence, verbal and numeric memory, processing speed, executive functions) and structural MRI. As expected, performance in most cognitive tests had a negative relationship with age. Moreover, BG grey matter volume and magnetization transfer (MT, indicative of myelin) decreased, and R2* (indicative of iron) increased with age. Importantly, R2* and demyelination negatively correlated with verbal memory and executive functions. Within the SN/VTA, age correlated negatively with MT, but there was no clear evidence in favor of a relationship between behavior and R2* or MT. Our results suggest that age-related increases in iron and demyelination within the BG, which are part of a fronto-striatal network, not only impact on verbal memory but also executive functions.

Neural oscillations and event-related potentials reveal how semantic congruence drives long-term memory in both young and older humans.

Long-term memory can improve when incoming information is congruent with known semantic information. This so-called congruence effect has widely been shown in younger adults, but age-related changes and neural mechanisms remain unclear. Here, congruence improved recognition memory in younger and older adults (i.e. congruence effect), with only weak evidence for age-related decline in one behavioral study. In an EEG study, however, no significant behavioral differences in the congruence effect could be observed between age-groups. In line with this observation, electroencephalography data show that, in both groups, congruence led to widespread differences in Event-Related Potentials (ERPs), starting at around 400 ms after stimulus onset, and theta, alpha and beta oscillations (4-20 Hz). Importantly, these congruence-related ERPs were associated to increases in memory performance for congruent items, in both age groups. Finally, the described ERPs and neural oscillations in the theta-alpha range (5-13 Hz) were less pronounced in the elderly despite a preserved congruence effect. Together, semantic congruence increases long-term memory across the lifespan, and, at the neural level, this could be linked to neural oscillations in the theta, alpha and beta range, as well as ERPs that were previously associated with semantic processing.

The gains of a 4-week cognitive training are not modulated by novelty.

Cognitive training should not only improve performance of the trained task, but also untrained abilities. Exposure to novelty can improve subsequent memory performance, suggesting that novelty exposure might be a critical factor to promote the effects of cognitive training. Therefore, we combined a 4-week working memory training with novelty exposure. Neuropsychological tests and MRI data were acquired before and after training to analyze behavior and changes in gray matter volume, myelination, and iron levels. In total, 83 healthy older humans participated in one of three groups: Two groups completed a 4-week computerized cognitive training of a two-back working memory task, either in combination with novel or with familiarized nature movies. A third group did not receive any training. As expected, both training groups showed improvements in task specific working memory performance and reaction times. However, there were no transfer or novelty effects on fluid intelligence, verbal memory, digit-span, and executive functions. At the neural level, no significant micro- or macrostructural changes emerged in either group. Our findings suggest that working memory training in healthy older adults is associated with task-specific improvements, but these gains do not transfer to other cognitive domains, and it does not lead to structural brain changes.

Working memory performance in the elderly relates to theta-alpha oscillations and is predicted by parahippocampal and striatal integrity.

The ability to maintain information for a short period of time (i.e. working memory, WM) tends to decrease across the life span with large inter-individual variability; the underlying neuronal bases, however, remain unclear. To address this issue, we used a multimodal imaging approach (voxel-based morphometry, diffusion-tensor imaging, electroencephalography) to test the contribution of brain structures and neural oscillations in an elderly population. Thirty-one healthy elderly participants performed a change-detection task with different load conditions. As expected, accuracy decreased with increasing WM load, reflected by power modulations in the theta-alpha band (5-12 Hz). Importantly, these power changes were directly related to the tract strength between parahippocampus and parietal cortex. Furthermore, between-subject variance in gray matter volume of the parahippocampus and dorsal striatum predicted WM accuracy. Together, our findings provide new evidence that WM performance critically depends on parahippocampal and striatal integrity, while theta-alpha oscillations may provide a mechanism to bind the nodes within the WM network.

Reward Dependent Invigoration Relates to Theta Oscillations and Is Predicted by Dopaminergic Midbrain Integrity in Healthy Elderly.

Motivation can have invigorating effects on behavior via dopaminergic neuromodulation. While this relationship has mainly been established in theoretical models and studies in younger subjects, the impact of structural declines of the dopaminergic system during healthy aging remains unclear. To investigate this issue, we used electroencephalography (EEG) in healthy young and elderly humans in a reward-learning paradigm. Specifically, scene images were initially encoded by combining them with cues predicting monetary reward (high vs. low reward). Subsequently, recognition memory for the scenes was tested. As a main finding, we can show that response times (RTs) during encoding were faster for high reward predicting images in the young but not elderly participants. This pattern was resembled in power changes in the theta-band (4-7 Hz). Importantly, analyses of structural MRI data revealed that individual reward-related differences in the elderlies' response time could be predicted by the structural integrity of the dopaminergic substantia nigra (SN; as measured by magnetization transfer (MT)). These findings suggest a close relationship between reward-based invigoration, theta oscillations and age-dependent changes of the dopaminergic system.

Iron Level and Myelin Content in the Ventral Striatum Predict Memory Performance in the Aging Brain.

Age-related memory impairments have been associated with structural changes in the dopaminergic system, but the underlying mechanisms remain unclear. Recent work indicates that iron accumulation might be of particular relevance. As iron accumulates, a degeneration of myelin sheaths has been observed in the elderly, but the relationship between both and their impact on memory performance in healthy elderly humans remain important open questions. To address this issue, we combined an established behavioral paradigm to test memory performance [verbal learning memory test (VLMT)] with state of the art quantitative magnetic resonance imaging techniques allowing us to quantify the degree of myelination and iron accumulation via markers of tissue microstructure in a group of young (18-32 years) and healthy elderly humans (55-79 years). As expected, we observed a decrease in gray matter volume and myelin, and an increase of iron in the elderly relative to the young subjects within widespread brain regions, including the basal ganglia. Furthermore, higher levels of iron within the ventral striatum were accompanied by a negative correlation between myelin and iron specific for the elderly participants. Importantly, both markers of iron and myelin (and their ratio) predicted the performance of the elderly in the VLMT. This suggests that ventral striatum iron accumulation is linked to demyelination and impairments in declarative memory. Together, our data provide novel insights into underlying microstructural mechanisms of memory decline in the elderly. SIGNIFICANCE STATEMENT: Memory decline in healthy elderly is a common phenomenon, but the underlying neural mechanisms remain unclear. We used a novel approach that allowed us to combine behavior and whole-brain measures of iron, myelin, and gray matter in the participant's individual subspace to analyze structure-structure and structure-behavior interactions. We were able to show, that age-related high levels of iron are accompanied by a negative correlation of iron and myelin in the ventral striatum, which predicted individual memory performance. As such, our findings provide unprecedented insights into the basic mechanisms of memory decline in the elderly.