A neural mechanism of cognitive reserve: The case of bilingualism.

Cognitive Reserve (CR) refers to the preservation of cognitive function in the face of age- or disease-related neuroanatomical decline. While bilingualism has been shown to contribute to CR, the extent to which, and what particular aspect of, second language experience contributes to CR are debated, and the underlying neural mechanism(s) unknown. Intrinsic functional connectivity reflects experience-dependent neuroplasticity that occurs across timescales ranging from minutes to decades, and may be a neural mechanism underlying CR. To test this hypothesis, we used voxel-based morphometry and resting-state functional connectivity analyses of MRI data to compare structural and functional brain integrity between monolingual and bilingual older adults, matched on cognitive performance, and across levels of second language proficiency measured as a continuous variable. Bilingualism, and degree of second language proficiency specifically, were associated with lower gray matter integrity in a hub of the default mode network - a region that is particularly vulnerable to decline in aging and dementia - but preserved intrinsic functional network organization. Bilingualism moderated the association between neuroanatomical differences and cognitive decline, such that lower gray matter integrity was associated with lower executive function in monolinguals, but not bilinguals. Intrinsic functional network integrity predicted executive function when controlling for group differences in gray matter integrity and language status. Our findings confirm that lifelong bilingualism is a CR factor, as bilingual older adults performed just as well as their monolingual peers on tasks of executive function, despite showing signs of more advanced neuroanatomical aging, and that this is a consequence of preserved intrinsic functional network organization.

Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing.

Cognitive ageing research examines the cognitive abilities that are preserved and/or those that decline with advanced age. There is great individual variability in cognitive ageing trajectories. Some older adults show little decline in cognitive ability compared with young adults and are thus termed 'optimally ageing'. By contrast, others exhibit substantial cognitive decline and may develop dementia. Human neuroimaging research has led to a number of important advances in our understanding of the neural mechanisms underlying these two outcomes. However, interpreting the age-related changes and differences in brain structure, activation and functional connectivity that this research reveals is an ongoing challenge. Ambiguous terminology is a major source of difficulty in this venture. Three terms in particular - compensation, maintenance and reserve - have been used in a number of different ways, and researchers continue to disagree about the kinds of evidence or patterns of results that are required to interpret findings related to these concepts. As such inconsistencies can impede progress in both theoretical and empirical research, here, we aim to clarify and propose consensual definitions of these terms.

Author Correction: Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing.

In the originally published version of article, there were two errors in the references. The reference "Nilsson, J. & Lövdén, M. Naming is not explaining: future directions for the "cognitive reserve" and "brain maintenance" theories. Alzheimer's Res. Ther. 10, 34 (2018)" was missing. This reference has been added as REF. 14 in the HTML and PDF versions of the article and cited at the end of the sentence "However, over the years, these terms have been used inconsistently, creating confusion and slowing progress." on page 701 and at the end of the sentence "If reserve is defined merely as the factor that individuals with greater reserve have and then this factor is used to explain why some individuals have greater reserve, the argument is clearly circular." on page 704. The reference list has been renumbered accordingly. In addition, in the original reference list, REF. 91 was incorrect. The reference should have read "Cabeza, R. Hemispheric asymmetry reduction in older adults. The HAROLD model. Psychol. Aging 17, 85-100 (2002)". This reference, which is REF. 92 in the corrected reference list, has been corrected in the HTML and PDF versions of the article.

Publisher Correction: Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing.

In Figure 3b of the originally published article, the colours of the bars were incorrectly reversed. The bars shown in green should have been shown in blue to represent the findings from older adults, whereas the bars shown in blue should have been shown in green to represent the findings from young adults. This has been corrected in the HTML and PDF versions of the article. Images of the original figure are shown in the correction notice.

Exploration of salient risk factors involved in mild cognitive impairment.

Mild cognitive impairment (MCI) is a prevalent and complex condition among older adults that often progresses into Alzheimer's disease (AD). Although MCI affects individuals differently, there are specific indicators of risk commonly associated with the development of MCI. The present study explored the prevalence of seven established MCI risk categories within a large sample of older adults with and without MCI. We explored trends across the different diagnostic groups and extracted the most salient risk factors related to MCI using partial least squares. Neuropsychological risk categories showed the largest differences across groups, with the cognitively unimpaired groups outperforming the MCI groups on all measures. Apolipoprotein E4 (ApoE4) carriers were significantly more common among the more severe MCI group, whereas ApoE4 non-carriers were more common in the healthy controls. Participants with subjective and objective cognitive impairment were trending towards AD-like cerebral spinal fluid (CSF) biomarker levels. Increased age, being male and having fewer years of education were identified as important risk factors of MCI. Higher CSF tau levels were correlated with ApoE4 carrier status, age and a decrease in the ability to carry out daily activities across all diagnostic groups. Amyloid beta1-42 CSF concentration was positively correlated with cognitive and memory performance and non-ApoE4 carrier status regardless of diagnostic status. Unlike previous research, poor cardiovascular health or being female had no relation to MCI. Altogether, the results highlighted risk factors that were specific to persons with MCI, findings that will inform future research in healthy aging, MCI and AD.

Contributions of Brain Function and Structure to Three Different Domains of Cognitive Control in Normal Aging.

Cognitive control involves the flexible allocation of mental resources during goal-directed behavior and comprises three correlated but distinct domains-inhibition, shifting, and working memory. The work of Don Stuss and others has demonstrated that frontal and parietal cortices are crucial to cognitive control, particularly in normal aging, which is characterized by reduced control mechanisms. However, the structure-function relationships specific to each domain and subsequent impact on performance are not well understood. In the current study, we examined both age and individual differences in functional activity associated with core domains of cognitive control in relation to fronto-parietal structure and task performance. Participants (n = 140, aged 20-86 years) completed three fMRI tasks: go/no-go (inhibition), task switching (shifting), and n-back (working memory), in addition to structural and diffusion imaging. All three tasks engaged a common set of fronto-parietal regions; however, the contributions of age, brain structure, and task performance to functional activity were unique to each domain. Aging was associated with differences in functional activity for all tasks, largely in regions outside common fronto-parietal control regions. Shifting and inhibition showed greater contributions of structure to overall decreases in brain activity, suggesting that more intact fronto-parietal structure may serve as a scaffold for efficient functional response. Working memory showed no contribution of structure to functional activity but had strong effects of age and task performance. Together, these results provide a comprehensive and novel examination of the joint contributions of aging, performance, and brain structure to functional activity across multiple domains of cognitive control.

Reminders activate the prefrontal-medial temporal cortex and attenuate forgetting of event memory.

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory-enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non-reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all-or-none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro-lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre-retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non-reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC-hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.

Influence of sample size and analytic approach on stability and interpretation of brain-behavior correlations in task-related fMRI data.

Limited statistical power due to small sample sizes is a problem in fMRI research. Most of the work to date has examined the impact of sample size on task-related activation, with less attention paid to the influence of sample size on brain-behavior correlations, especially in actual experimental fMRI data. We addressed this issue using two large data sets (a working memory task, N = 171, and a relational processing task, N = 865) and both univariate and multivariate approaches to voxel-wise correlations. We created subsamples of different sizes and calculated correlations between task-related activity at each voxel and task performance. Across both data sets the magnitude of the brain-behavior correlations decreased and similarity across spatial maps increased with larger sample sizes. The multivariate technique identified more extensive correlated areas and more similarity across spatial maps, suggesting that a multivariate approach would provide a consistent advantage over univariate approaches in the stability of brain-behavior correlations. In addition, the multivariate analyses showed that a sample size of roughly 80 or more participants would be needed for stable estimates of correlation magnitude in these data sets. Importantly, a number of additional factors would likely influence the choice of sample size for assessing such correlations in any given experiment, including the cognitive task of interest and the amount of data collected per participant. Our results provide novel experimental evidence in two independent data sets that the sample size commonly used in fMRI studies of 20-30 participants is very unlikely to be sufficient for obtaining reproducible brain-behavior correlations, regardless of analytic approach.

Functional Connectivity within and beyond the Face Network Is Related to Reduced Discrimination of Degraded Faces in Young and Older Adults.

Degrading face stimuli reduces face discrimination in both young and older adults, but the brain correlates of this decline in performance are not fully understood. We used functional magnetic resonance imaging to examine the effects of degraded face stimuli on face and nonface brain networks and tested whether these changes would predict the linear declines seen in performance. We found decreased activity in the face network (FN) and a decrease in the similarity of functional connectivity (FC) in the FN across conditions as degradation increased but no effect of age. FC in whole-brain networks also changed with increasing degradation, including increasing FC between the visual network and cognitive control networks. Older adults showed reduced modulation of this whole-brain FC pattern. The strongest predictors of within-participant decline in accuracy were changes in whole-brain network FC and FC similarity of the FN. There was no influence of age on these brain-behavior relations. These results suggest that a systems-level approach beyond the FN is required to understand the brain correlates of performance decline when faces are obscured with noise. In addition, the association between brain and behavior changes was maintained into older age, despite the dampened FC response to face degradation seen in older adults.

Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC.

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.

Holding On to the Past: Older Adults Show Lingering Neural Activation of No-Longer-Relevant Items in Working Memory.

Goal-relevant information can be maintained in working memory over a brief delay interval to guide an upcoming decision. There is also evidence suggesting the existence of a complementary process: namely, the ability to suppress information that is no longer relevant to ongoing task goals. Moreover, this ability to suppress or inhibit irrelevant information appears to decline with age. In this study, we compared younger and older adults undergoing fMRI on a working memory task designed to address whether the modulation of neural representations of relevant and no-longer-relevant items during a delay interval is related to age and overall task performance. Following from the theoretical predictions of the inhibitory deficit hypothesis of aging, we hypothesized that older adults would show higher activation of no-longer-relevant items during a retention delay compared to young adults and that higher activation of these no-longer-relevant items would predict worse recognition memory accuracy for relevant items. Our results support this prediction and more generally demonstrate the importance of goal-driven modulation of neural activity in successful working memory maintenance. Furthermore, we showed that the largest age differences in the regulation of category-specific pattern activity during working memory maintenance were seen throughout the medial temporal lobe and prominently in the hippocampus, further establishing the importance of "long-term memory" retrieval mechanisms in the context of high-load working memory tasks that place large demands on attentional selection mechanisms.

Creative, internally-directed cognition is associated with reduced BOLD variability.

In a range of externally-directed tasks, intra-individual variability of fMRI BOLD signal has been shown to be a stronger predictor of cognitive performance than mean BOLD signal. BOLD variability's strong association with cognitive performance is hypothesised to be due to it capturing the dynamic range of neural systems. Although increased BOLD variability is also speculated to play a role in internally-directed thought, particularly when creative and flexible cognition is required, there is a relative lack of research exploring whether BOLD variability is related to internally-directed cognition. Thus, we investigated the relationship between BOLD variability and a key component of creativity - divergent thinking - in various tasks that required participants to think flexibly. We also determined whether any associations between BOLD variability and creativity overlapped with, or differed, from associations between mean BOLD signal and creativity. First, we performed task Partial Least Squares (PLS) analyses that compared BOLD signal (either mean or variability) during two future imagination conditions that differed in the amount of cognitive flexibility required: a Congruent condition in which autobiographical details (people, places, objects) comprising an imagined event belonged to the same social sphere (e.g., university) and an Incongruent condition in which details belonged to different social spheres and required greater cognitive flexibility to integrate. Results indicated that the Incongruent condition was associated with a widespread reduction in both BOLD variability and mean signal (relative to the Congruent condition), but in largely non-overlapping regions. Next, we used behavioral PLS to determine whether individual differences in performance on future simulation tasks as well as the Alternate Uses Task relates to BOLD variability and mean BOLD signal. Better performance on these tasks was predominantly associated with increases in mean BOLD signal and decreases in BOLD variability, in a range of disparate brain regions. Together, the results suggest that, unlike tasks requiring externally-directed cognition, superior performance on tasks requiring creative internal mentation is associated with less (not more) variability.

Meta-analytic and functional connectivity evidence from functional magnetic resonance imaging for an anterior to posterior gradient of function along the hippocampal axis.

There is considerable evidence from non-human animal studies that the anterior and posterior regions of the hippocampus have different anatomical connections and support different behavioural functions. Although there are some recent human studies using functional magnetic resonance imaging (fMRI) that have addressed this idea directly in the memory and spatial processing domains and provided support for it, there has been no broader meta-analysis of the fMRI literature to determine if there is consistent evidence for functional dissociations in anterior and posterior hippocampus across all of the different cognitive domains in which the hippocampus participates. The purpose of this review is to address this gap in our knowledge using three approaches. One approach involved PubMed searches to identify relevant fMRI papers reporting hippocampal activation during episodic encoding and retrieval, semantic retrieval, working memory, spatial navigation, simulation/scene construction, transitive inference, and social cognition tasks. The second was to use a large meta-analytic database (neurosynth) to find text terms and coactivation maps associated with the anterior and posterior hippocampal regions identified in the literature search. The third approach was to contrast the resting-state functional connectivity of the anterior and posterior hippocampal regions using a publicly available database that includes a large sample of adults. These three approaches provided converging evidence that not only are cognitive processes differently distributed along the hippocampal axis, but there also are distinct areas coactivated and functionally connected with the anterior and posterior segments. This anterior/posterior distinction involving multiple cognitive domains is consistent with the animal literature and provides strong support from fMRI for the idea of functional dissociations across the long axis of the hippocampus.

Neural Correlates of Enhanced Memory for Meaningful Associations with Age.

Evidence suggests that age differences in associative memory are attenuated for associations that are consistent with prior knowledge. Such knowledge structures have traditionally been associated with the default network (DN), which also shows reduced modulation with age. In the present study, we investigated whether DN activity and connectivity patterns could account for this age-related effect. Younger and older adults underwent functional magnetic resonance imaging as they learned realistic and unrealistic prices of common grocery items. Both groups showed greater activity in the DN during the encoding of realistic, relative to unrealistic, prices. Moreover, DN activity at encoding and retrieval and its connectivity with an attention control network at encoding were associated with enhanced memory for realistic prices. Finally, older adults showed overactivation of control regions during retrieval of realistic prices relative to younger adults. Our findings suggest that DN activity and connectivity patterns (traditionally viewed as indicators of cognitive failure with age), and additional recruitment of control regions, might underlie older adults' enhanced memory for meaningful associations.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

Contextual and Developmental Differences in the Neural Architecture of Cognitive Control.

Because both development and context impact functional brain architecture, the neural connectivity signature of a cognitive or affective predisposition may similarly vary across different ages and circumstances. To test this hypothesis, we investigated the effects of age and cognitive versus social-affective context on the stable and time-varying neural architecture of inhibition, the putative core cognitive control component, in a subsample (N = 359, 22-36 years, 174 men) of the Human Connectome Project. Among younger individuals, a neural signature of superior inhibition emerged in both stable and dynamic connectivity analyses. Dynamically, a context-free signature emerged as stronger segregation of internal cognition (default mode) and environmentally driven control (salience, cingulo-opercular) systems. A dynamic social-affective context-specific signature was observed most clearly in the visual system. Stable connectivity analyses revealed both context-free (greater default mode segregation) and context-specific (greater frontoparietal segregation for higher cognitive load; greater attentional and environmentally driven control system segregation for greater reward value) signatures of inhibition. Superior inhibition in more mature adulthood was typified by reduced segregation in the default network with increasing reward value and increased ventral attention but reduced cingulo-opercular and subcortical system segregation with increasing cognitive load. Failure to evidence this neural profile after the age of 30 predicted poorer life functioning. Our results suggest that distinguishable neural mechanisms underlie individual differences in cognitive control during different young adult stages and across tasks, thereby underscoring the importance of better understanding the interplay among dispositional, developmental, and contextual factors in shaping adaptive versus maladaptive patterns of thought and behavior.SIGNIFICANCE STATEMENT The brain's functional architecture changes across different contexts and life stages. To test whether the neural signature of a trait similarly varies, we investigated cognitive versus social-affective context effects on the stable and time-varying neural architecture of inhibition during a period of neurobehavioral fine-tuning (age 22-36 years). Younger individuals with superior inhibition showed distinguishable context-free and context-specific neural profiles, evidenced in both static and dynamic connectivity analyses. More mature individuals with superior inhibition evidenced only context-specific profiles, revealed in the static connectivity patterns linked to increased reward or cognitive load. Delayed expression of this profile predicted poorer life functioning. Our results underscore the importance of understanding the interplay among dispositional, developmental, and contextual factors in shaping behavior.

Brain signal variability is modulated as a function of internal and external demand in younger and older adults.

Variability in the Blood Oxygen-Level Dependent (BOLD) signal from fMRI is often associated with better cognitive performance and younger age. It has been proposed that neural variability enables flexible responding to uncertainty in a changing environment. However, signal variability reflecting environmental uncertainty may reduce to the extent that a task depends on internally-directed attention and is supported by neural "solutions" that are schematic and relatively stable within each individual. Accordingly, we examined the hypothesis that BOLD variability will be low at rest, higher during internally-directed tasks, and higher still during externally-directed tasks, and that this effect will be reduced with aging. Modulation of BOLD variability across conditions was consistent with these hypotheses, and was associated with faster and more stable behavioral performance in both young and older adults. These data support the idea that brain signal variability may modulate in response to environmental uncertainty, which is presumed to be greater in the external environment than in the internal milieu. Reduced flexibility of signal variability with age may indicate less ability to switch between internal and external brain states.

Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans.

The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.

Prior knowledge modulates the neural substrates of encoding and retrieving naturalistic events at short and long delays.

Congruence with prior knowledge and incongruence/novelty have long been identified as two prominent factors that, despite their opposing characteristics, can both enhance episodic memory. Using narrative film clip stimuli, this study investigated these effects in naturalistic event memories - examining behaviour and neural activation to help explain this paradox. Furthermore, we examined encoding, immediate retrieval, and one-week delayed retrieval to determine how these effects evolve over time. Behaviourally, both congruence with prior knowledge and incongruence/novelty enhanced memory for events, though incongruent events were recalled with more errors over time. During encoding, greater congruence with prior knowledge was correlated with medial prefrontal cortex (mPFC) and parietal activation, suggesting that these areas may play a key role in linking current episodic processing with prior knowledge. Encoding of increasingly incongruent events, on the other hand, was correlated with increasing activation in, and functional connectivity between, the medial temporal lobe (MTL) and posterior sensory cortices. During immediate and delayed retrieval the mPFC and MTL each demonstrated functional connectivity that varied based on the congruence of events with prior knowledge; with connectivity between the MTL and occipital regions found for incongruent events, while congruent events were associated with functional connectivity between the mPFC and the inferior parietal lobules and middle frontal gyri. These results demonstrate patterns of neural activity and connectivity that shift based on the nature of the event being experienced or remembered, and that evolve over time. Furthermore, they suggest potential mechanisms by which both congruence with prior knowledge and incongruence/novelty may enhance memory, through mPFC and MTL functional connectivity, respectively.