GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer's disease.

In this review, we focus on the potential role of the γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments in humans, with a particular focus on Alzheimer's disease (AD). Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD. Neuroimaging research in humans has documented hyperactivity in the hippocampus and losses of resting state functional connectivity in the Default Mode Network, a network that itself prominently includes the hippocampus-presaging episodic memory decline in individuals at-risk for AD. Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans. In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss. Here, we will review the current state of literature supporting this hypothesis. First, we will focus on the molecular and cellular basis of the GABAergic system and its role in memory and cognition. Next, we report the evidence of GABA dysregulations in AD and normal aging, both in animal models and human studies. Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association.

Reference ability neural networks and behavioral performance across the adult life span.

To better understand the impact of aging, along with other demographic and brain health variables, on the neural networks that support different aspects of cognitive performance, we applied a brute-force search technique based on Principal Components Analysis to derive 4 corresponding spatial covariance patterns (termed Reference Ability Neural Networks -RANNs) from a large sample of participants across the age range. 255 clinically healthy, community-dwelling adults, aged 20-77, underwent fMRI while performing 12 tasks, 3 tasks for each of the following cognitive reference abilities: Episodic Memory, Reasoning, Perceptual Speed, and Vocabulary. The derived RANNs (1) showed selective activation to their specific cognitive domain and (2) correlated with behavioral performance. Quasi out-of-sample replication with Monte-Carlo 5-fold cross validation was built into our approach, and all patterns indicated their corresponding reference ability and predicted performance in held-out data to a degree significantly greater than chance level. RANN-pattern expression for Episodic Memory, Reasoning and Vocabulary were associated selectively with age, while the pattern for Perceptual Speed showed no such age-related influences. For each participant we also looked at residual activity unaccounted for by the RANN-pattern derived for the cognitive reference ability. Higher residual activity was associated with poorer brain-structural health and older age, but -apart from Vocabulary-not with cognitive performance, indicating that older participants with worse brain-structural health might recruit alternative neural resources to maintain performance levels.

Dynamic Patterns of Brain Structure-Behavior Correlation Across the Lifespan.

Although the brain/behavior correlation is one of the premises of cognitive neuroscience, there is still no consensus about the relationship between brain measures and cognitive function, and only little is known about the effect of age on this relationship. We investigated the age-associated variations on the spatial patterns of cortical thickness correlates of four cognitive domains. We showed that the spatial distribution of the cortical thickness correlates of each cognitive domain is distinctive and depicts varying age-association differences across the adult lifespan. Specifically, the present study provides evidence that distinct cognitive domains are associated with unique structural patterns in three adulthood periods: Early, middle, and late adulthood. These findings suggest a dynamic interaction between multiple neural substrates supporting each cognitive domain across the adult lifespan.

Daytime somnolence as an early sign of cognitive decline in a community-based study of older people.

OBJECTIVE: This study aimed to examine the association between self-reported sleep problems and cognitive decline in community-dwelling older people. We hypothesized that daytime somnolence predicts subsequent cognitive decline. METHODS: This is a longitudinal study in a 3.2-year follow-up, with 18-month intervals. The setting is the Washington Heights-Inwood Community Aging Project. There were 1098 participants, who were over 65 years old and recruited from the community. Sleep problems were estimated using five sleep categories derived from the RAND Medical Outcome Study Sleep Scale: sleep disturbance, snoring, awaken short of breath/with a headache, sleep adequacy, and daytime somnolence. Four distinct cognitive composite scores were calculated: memory, language, speed of processing, and executive functioning. We used generalized estimating equations analyses with cognitive scores as the outcome, and time, sleep categories and their interactions as the main predictors. Models were initially unadjusted and then adjusted for age, gender, education, ethnicity, depression, and apolipoprotein E-ε4 genotype. RESULTS: Increased daytime somnolence (including feeling drowsy/sleepy, having trouble staying awake, and taking naps during the day) was linked to slower speed of processing both cross-sectionally (B = -0.143, p = 0.047) and longitudinally (B = -0.003, p = 0.027). After excluding the demented participants at baseline, the results remained significant (B = -0.003, p = 0.021). CONCLUSIONS: Our findings suggest that daytime somnolence may be an early sign of cognitive decline in the older population.

Schizophrenia and emotional rubbernecking.

Orienting toward emotionally salient information can be adaptive, as when danger needs to be avoided. Consistent with this idea, research has shown that emotionally valenced information draws attention more so than does neutral information in healthy individuals. However, at times this tendency is not adaptive, and it may distract the individual from goals. People with schizophrenia (PSZ), though they frequently show deficits in attentional control, have also been shown to exhibit diminished recognition of and attention to emotional information. In the present study, we investigated how the presentation of emotionally salient information affected performance on a working memory task for PSZ and healthy controls (HC). We found that although hit rates were equal to those of HCs for PSZ, the PSZ made fewer false alarms-resulting in overall better performance-than did the HCs. Deficits in emotional processing in PSZ appear to provide an advantage to them in situations in which salient emotional information competes with active cognitive goals.

Assessing neurocognitive function in psychiatric disorders: a roadmap for enhancing consensus.

It has been challenging to identify core neurocognitive deficits that are consistent across multiple studies in patients with Obsessive Compulsive Disorder (OCD). In turn, this leads to difficulty in translating findings from human studies into animal models to dissect pathophysiology. In this article, we use primary data from a working memory task in OCD patients to illustrate this issue. Working memory deficiencies have been proposed as an explanatory model for the evolution of checking compulsions in a subset of OCD patients. However, findings have been mixed due to variability in task design, examination of spatial vs. verbal working memory, and heterogeneity in patient populations. Two major questions therefore remain: first, do OCD patients have disturbances in working memory? Second, if there are working memory deficits in OCD, do they cause checking compulsions? In order to investigate these questions, we tested 19 unmedicated OCD patients and 23 matched healthy controls using a verbal working memory task that has increased difficulty/task-load compared to classic digit-span tasks. OCD patients did not significantly differ in their performance on this task compared to healthy controls, regardless of the outcome measure used (i.e. reaction time or accuracy). Exploratory analyses suggest that a subset of patients with predominant doubt/checking symptoms may have decreased memory confidence despite normal performance on trials with the highest working memory load. These results suggest that other etiologic factors for checking compulsions should be considered. In addition, they serve as a touchstone for discussion, and therefore help us to generate a roadmap for increasing consensus in the assessment of neurocognitive function in psychiatric disorders.

The relationship between cortical thickness and white matter hyperintensities in mid to late life.

White matter hyperintensities (WMH) are associated with cortical thinning. Although they are primarily detected in older participants, these lesions can appear in younger and midlife individuals. Here, we tested whether WMH are associated with cortical thinning in relatively younger (26-50 years) and relatively older (58-84) participants who were free of dementia, and how these associations are moderated by WMH localization. WMH were automatically quantified and categorized according to the localization of three classes of white matter tracts: association, commissural and projection fibers. Mediation analyses were used to infer whether differences in cortical thickness between younger and older participants were explained by WMH. Our results revealed that total WMH explained between 20.6 % and 65.5 % of the effect of age on cortical thickness in AD-signature regions including the lateral temporal lobes and supramarginal gyrus, among others. This mediation was slightly stronger for projection WMH, although it was still significant for association and commissural WMH. These results suggest that there is an interplay between vascular and AD causes of cognitive impairment that starts at younger ages.

Metacognition of agency: proximal action and distal outcome.

The cues contributing to people's metacognitions of agency were investigated in two experiments in which people played a computer game that involved trying to "touch", via a mouse moving a cursor, downward scrolling X's (Experiment 1), or trying to "explode" the downward scrolling X's (Experiment 2). Both experiments varied (a) proximal action-related information by either introducing or not introducing Turbulence into the mouse controls and (b) distal outcome-related information such that touched X's "exploded" either 100 or 75 % of the time. Both variables affected people's judgments of agency (JOAs), but the effect was different. First, the decrement in feelings of agency was greater with the proximal variable than with distal variable. Second, while the proximal variable always had a large direct effect on JOAs, even taking judgments of performance (JOPs) into account, JOPs completely accounted for the effect of the distal variable in Experiment 1, where the instructions were just to touch the X's. And even in Experiment 2, in which the instructions were to explode the X's, the direct effect of the distal variable on JOAs was small. These data indicate that these two cues exhibit different psychological profiles. The proximal action-related information is a diagnostic cue to agency indicating the match between one's own intentions and actions. Internal monitoring of intentions is necessary and so the self is implicated. However, distal outcome can be largely monitored using information external to the agent, and so-while it is used by people to make agency judgments-it is a non-diagnostic cue.

Curiosity: The effects of feedback and confidence on the desire to know.

In 10 experiments, we investigated the relations among curiosity and people's confidence in their answers to general information questions after receiving different kinds of feedback: yes/no feedback, true or false informational feedback under uncertainty, or no feedback. The results showed that when people had given a correct answer, yes/no feedback resulted in a near complete loss of curiosity. Upon learning they had made an error via yes/no feedback, curiosity increased, especially for high-confidence errors. When people were given true feedback under uncertainty (they were given the correct answer but were not told that it was correct), curiosity increased for high-confidence errors but was unchanged for correct responses. In contrast, when people were given false feedback under uncertainty, curiosity increased for high-confidence correct responses but was unchanged for errors. These results, taken as a whole, are consistent with the region of proximal learning model which proposes that while curiosity is minimal when people are completely certain that they know the answer, it is maximal when people believe that they almost know. Manipulations that drew participants toward this region of "almost knowing" resulted in increased curiosity. A serendipitous result was the finding (replicated four times in this study) that when no feedback was given, people were more curious about high-confidence errors than they were about equally high-confidence correct answers. It was as if they had some knowledge, tapped selectively by their feelings of curiosity, that there was something special (and possibly amiss) about high-confidence errors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Does stereotype threat influence age-related differences on directed forgetting tasks?

Objectives: The Directed Forgetting paradigm has proven to be a powerful tool to explore motivated forgetting in the lab. Past work has shown that older adults are less able to intentionally suppress information from memory relative to younger adults, which is often attributed to deficits in inhibitory abilities. Instructions in traditional Directed Forgetting tasks contain terms that may elicit stereotype threat in older adults, which may negatively impact memory. Here, we tested whether the instructions in a Directed Forgetting task affected older adults' ability to appropriately control the contents of memory. Methods: In two experiments that differed in the number of words presented (30 vs. 48 items), younger and older adults were randomized into one of four crossed Conditions of a Directed Forgetting task. At encoding, participants were either instructed to remember/ forget items, or to think about/not think about items. At test, they were either asked whether the memory probe was old or new, or whether they had seen it before (yes/no). Each experiment contained data from 100 younger (18- 40 years) and 98 older (60+ years) adults, with ~25 participants per Condition. All participants were recruited from Prolific and tested online. Results: In neither Experiment 1 nor Experiment 2 did we find evidence of a stereotype threat effect, or age-related effects of directed forgetting. We did find that performance for to-be-forgotten items was worse in conditions with encoding instructions that contained words that might trigger stereotype threat relative to conditions that did not contain such words: when explicitly told to forget items, both older and younger adults forgot more items than did participants who were cued to not think about the words and put them out of mind. However, we found no such difference across the two different remember instructions: regardless of whether participants were told to remember or to think about items, recognition memory for to be retained items was high. The pattern of results across the two experiments was similar, except, not surprisingly, participants performed worse in Experiment 2 than Experiment 1. Interestingly, we found that higher accuracy for to be remembered items was associated with a more positive outlook of one's own memory relative to others. Discussion: These results suggest that directed forgetting may not always be impaired in older adults.

Value-directed memory selectivity relies on goal-directed knowledge of value structure prior to encoding in young and older adults.

People are generally able to selectively attend and remember high-value over low-value information. Here, we investigated whether young and older adults would display typical value-based memory selectivity effects for to-be-learned item-value associations when goal-directed information about the meaning of associated values was presented before and after encoding. In two experiments, both young and older adults were presented with one (Experiment 1) or multiple (Experiment 2) lists of words that were arbitrarily paired with different numerical values (e.g., "door-8") or font colors (e.g., "door" presented in red), which indicated each word's value. In Experiment 1, participants were told that the numerical value indicated the relative importance of each item either before they studied the list (preencoding), after they studied it (postencoding), or not at all (no value control instructions). Older adults were significantly more selective in the preencoding condition relative to the other conditions, whereas younger adults were not selective in any condition on this single-list (numerical) value task of Experiment 1. In Experiment 2, young and older adults were tested on four additional lists of both pre- and postencoding trials each after studying and recalling four lists of words without any value instructions. Results from Experiment 2 revealed that both young and older adults selectively prioritized high-value words on the preencoding trials, but not on postencoding trials, on this color-based categorical (low-medium-high) value task. The present study highlights a critical role of goal-directed knowledge of value-based instructions prior to encoding to facilitate typically observed value-directed memory selectivity for important information. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Older adults compensate for switch, but not mixing costs, relative to younger adults on an intrinsically cued task switching experiment.

Introduction: Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called "switch costs"), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called "mixing costs"). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects. Methods: Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials). Results: We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas. Discussion: These results suggest an age-based dissociation between executive components that contribute to task switching.

Principal component analysis suggests multiple dimensions of memory inhibition that are differentially affected by age.

Background: Cognitive inhibition is among the executive functions that decline early in the course of normal aging. Failures to be able to inhibit irrelevant information from memory may represent an essential factor of age-associated memory impairment. While a variety of elaborate behavioral tasks have been developed that presumably all index memory inhibition, the extent to which these different tasks measure the same underlying cognitive construct that declines with age has not been well explored. Methods: In the current study, 100 and 75 cognitively healthy younger (n = 71; age = 30.7 ± 5.4 years, 56.7% female) and older (n = 104, age = 69.3 ± 5.9 years, 66.2% female) adults with equivalent educational attainment performed three computer-based memory inhibition tasks: the Retrieval Induced Forgetting task, the Suppress task, and the Directed Forgetting task. We conducted a principal component analysis using scores derived from different components of these tasks to explore whether and how the tasks relate to one another. We further investigated how age, sex and education, along with, in a subsample of the participants, a neuropsychological measure of episodic memory, impacted both the task scores individually, and the principal components derived from the exploratory analysis. Results: We identified 3 distinct sources of variability which represent potentially independent cognitive processes: memory retrieval facilitation, and two memory inhibition processes that distinguished themselves by the degree of volitional initiation of memory suppression. Only the memory retrieval component correlated with a neuropsychologically-derived episodic memory score, and both memory inhibition principal components were age dependent. Conclusion: Our findings provide support for a distinction in memory suppression processes between those 'instructed' to be performed and those which happen without explicit instruction. This distinction adds nuance to the dichotomous classification of controlled vs. automatic inhibitory mechanisms, which have been shown in previous work to vary as a function of the degree of frontal involvement. Our findings further demonstrate that while both of these measures of inhibition were affected by age, the episodic memory component was not, suggesting that inhibitory impairments may precede memory deficits in healthy aging.

Effects of white matter hyperintensities distribution and clustering on late-life cognitive impairment.

White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.

Age, Sex, and Inhibitory Control: Identifying a Specific Impairment in Memorial, But Not Perceptual, Inhibition in Older Women.

OBJECTIVES: Declines in the ability to inhibit information, and the consequences to memory of unsuccessful inhibition, have been frequently reported to increase with age. However, few studies have investigated whether sex moderates such effects. Here, we examined whether inhibitory ability may vary as a function of age and sex, and the interaction between these two factors. METHOD: 202 older (mean age = 69.40 years) and younger (mean age =30.59 years) participants who had equivalent educational attainment and self-reported health completed 2 tasks that varied only in the time point at which inhibition should occur: either prior to, or after, encoding. RESULTS: While we did not find evidence for age or sex differences in inhibitory processes when information needed to be inhibited prior to encoding, when encoded information being actively held in working memory needed to be suppressed, we found that older women were particularly impaired relative to both younger women and men of either age group. DISCUSSION: These results provide further support for the presence of memorial inhibitory deficits in older age, but add nuance by implicating biological sex as an important mediator in this relationship, with it more difficult for older women to inhibit what was once relevant in memory.

Cortical thickness in the right inferior frontal gyrus mediates age-related performance differences on an item-method directed forgetting task.

Evidence suggests that older adults have difficulty relative to younger adults in forgetting irrelevant information. Here we sought to understand the physical basis of this deficit by investigating the relationship between cortical thickness and intentional forgetting, using an item-method directed forgetting task. We tested younger (n = 44) and older (n = 54) adults' memories for words that they were instructed to either remember or to forget, and then extracted cortical thickness values from brain regions previously shown, using functional neuroimaging, to be associated with memory suppression, including the right inferior frontal gyrus, the right postcentral gyrus and the left superior/middle frontal gyrus. Results from a parallel mediation model indicated that variations in cortical thickness in the right inferior frontal gyrus, but not the right postcentral gyrus or left superior/middle frontal gyrus, partially explained age-related differences in directed forgetting: older adults with thinner cortices in this area showed worse forgetting ability. This is the first study to explore how neuromorphological differences affect the ability to intentionally suppress items in memory. The results suggest that age-related differences in directed forgetting may be partly driven by cortical thickness in a brain structure known to be functionally involved in directed forgetting, and inhibitory control more broadly, supporting a contribution of deficient inhibition to this phenomenon.

Reduced Hippocampal GABA+ Is Associated With Poorer Episodic Memory in Healthy Older Women: A Pilot Study.

Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer's disease (AD)-female sex and Apolipoprotein ε4 (ApoE ε4) genotype-on this relationship. Methods: Twenty healthy, community-dwelling individuals aged 50-71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education. Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001). Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.

Epistemic Curiosity and the Region of Proximal Learning.

We propose a framework for understanding epistemic curiosity as a metacognitive feeling state that is related to the individual's Region of Proximal Learning (RPL), an adaptive mental space where we feel we are on the verge of knowing or understanding. First, we review several historical views, contrasting the RPL perspective with alternative views of curiosity. Second, we detail the processes, conditions, and outcomes within the RPL framework which are proposed to be related to curiosity. Finally, we review several lines of evidence relevant to the relation between RPL and curiosity. These include (1) differences in the conditions under which experts and novices mind wander, (2) experiments investigating people's choices of whether to study materials for which they have high versus low feelings of knowing, (3) results related to people's engagement with corrections to errors made with high confidence, and (4) curiosity, attention, and learning data related to the tip-of-the-tongue state.

Corrigendum: Occupational Patterns of Structural Brain Health: Independent Contributions Beyond Education, Gender, Intelligence, and Age.

[This corrects the article DOI: 10.3389/fnhum.2019.00449.].

Towards an ontology of cognitive processes and their neural substrates: A structural equation modeling approach.

A key challenge in the field of cognitive neuroscience is to identify discriminable cognitive functions, and then map these functions to brain activity. In the current study, we set out to explore the relationships between performance arising from different cognitive tasks thought to tap different domains of cognition, and then to test whether these distinct latent cognitive abilities also are subserved by corresponding "latent" brain substrates. To this end, we tested a large sample of adults under the age of 40 on twelve cognitive tasks as they underwent fMRI scanning. Exploratory factor analysis revealed 4-factor model, dissociating tasks into processes corresponding to episodic memory retrieval, reasoning, speed of processing and vocabulary. An analysis of the topographic covariance patterns of the BOLD-response acquired during each task similarity also converged on four neural networks that corresponded to the 4 latent factors. These results suggest that distinct ontologies of cognition are subserved by corresponding distinct neural networks.