Lifespan differences in hippocampal subregion connectivity patterns during movie watching.

Age-related episodic memory decline is attributed to functional alternations in the hippocampus. Less clear is how aging affects the functional connections of the hippocampus to the rest of the brain during episodic memory processing. We examined fMRI data from the CamCAN dataset, in which a large cohort of participants watched a movie (N = 643; 18-88 years), a proxy for naturalistic episodic memory encoding. We examined connectivity profiles across the lifespan both within the hippocampus (anterior, posterior), and between the hippocampal subregions and cortical networks. Aging was associated with reductions in contralateral (left, right) but not ipsilateral (anterior, posterior) hippocampal subregion connectivity. Aging was primarily associated with increased coupling between the anterior hippocampus and regions affiliated with Control, Dorsal Attention and Default Mode networks, yet decreased coupling between the posterior hippocampus and a selection of these regions. Differences in age-related hippocampal-cortical, but not within-hippocampus circuitry selectively predicted worse memory performance. Our findings comprehensively characterize hippocampal functional topography in relation to cognition in older age, suggesting that shifts in cortico-hippocampal connectivity may be sensitive markers of age-related episodic memory decline.

A network correspondence toolbox for quantitative evaluation of novel neuroimaging results.

Decades of neuroscience research has shown that macroscale brain dynamics can be reliably decomposed into a subset of large-scale functional networks, but the specific spatial topographies of these networks and the names used to describe them can vary across studies. Such discordance has hampered interpretation and convergence of research findings across the field. To address this problem, we have developed the Network Correspondence Toolbox (NCT) to permit researchers to examine and report spatial correspondence between their novel neuroimaging results and sixteen widely used functional brain atlases, consistent with recommended reporting standards developed by the Organization for Human Brain Mapping. The atlases included in the toolbox show some topographical convergence for specific networks, such as those labeled as default or visual. Network naming varies across atlases, particularly for networks spanning frontoparietal association cortices. For this reason, quantitative comparison with multiple atlases is recommended to benchmark novel neuroimaging findings. We provide several exemplar demonstrations using the Human Connectome Project task fMRI results and UK Biobank independent component analysis maps to illustrate how researchers can use the NCT to report their own findings through quantitative evaluation against multiple published atlases. The NCT provides a convenient means for computing Dice coefficients with spin test permutations to determine the magnitude and statistical significance of correspondence among user-defined maps and existing atlas labels. The NCT also includes functionality to incorporate additional atlases in the future. The adoption of the NCT will make it easier for network neuroscience researchers to report their findings in a standardized manner, thus aiding reproducibility and facilitating comparisons between studies to produce interdisciplinary insights.

Precision Mapping of the Default Network Reveals Common and Distinct (Inter)activity for Autobiographical Memory and Theory of Mind.

The default network is widely implicated as a common neural substrate for self-generated thought, such as remembering one's past (autobiographical memory) and imagining the thoughts and feelings of others (theory of mind). Findings that the default network comprises subnetworks of regions - some commonly and some distinctly involved across processes - suggest that one's own experiences inform their understanding of others. With the advent of precision fMRI methods, however, it is unclear if this shared substrate is observed instead due to traditional group analysis methods. We investigated this possibility using a novel combination of methodological strategies. Twenty-three participants underwent multi-echo resting-state and task fMRI. We used their resting-state scans to conduct cortical parcellation sensitive to individual variation but preserving our ability to conduct group analysis. Using multivariate analyses, we assessed the functional activation and connectivity profiles of default network regions while participants engaged in autobiographical memory, theory of mind, or a sensorimotor control condition. Across the default network, we observed stronger activity associated with both autobiographical memory and theory of mind compared to the control condition. Nonetheless, we also observed that some regions showed preferential activity to either experimental condition, in line with past work. The connectivity results similarly indicated shared and distinct functional profiles. Our results support that autobiographical memory and theory of mind - two theoretically important and widely-studied domains of social cognition - evoke common and distinct aspects of the default network even when ensuring high fidelity to individual-specific characteristics.

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Locus coeruleus integrity is related to an exploitation-based decision-making bias in older adulthood.

Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.

Structural white matter properties and cognitive resilience to tau pathology.

INTRODUCTION: We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-ß/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. HIGHLIGHTS: Aß and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties.

Degeneration in Nucleus basalis of Meynert signals earliest stage of Alzheimer's disease progression.

Nucleus Basalis of Meynert (NbM), a crucial source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), has shown sensitivity to neurofibrillary degeneration in the early stages of Alzheimer's Disease. Using deformation-based morphometry (DBM) on up-sampled MRI scans from 1447 Alzheimer's Disease Neuroimaging Initiative participants, we aimed to quantify NbM degeneration along the disease trajectory. Results from cross-sectional analysis revealed significant differences of NbM volume between cognitively normal and early mild cognitive impairment cohorts, confirming recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. Longitudinal linear mixed-effect models were then used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results indicated the earliest deviations in NbM volumes from the cognitively healthy trajectory, challenging the prevailing idea that Alzheimer's originates in the EC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

Neurobehavioral Mechanisms Influencing the Association Between Generativity, the Desire to Promote Well-Being of Younger Generations, and Purpose in Life in Older Adults at Risk for Alzheimer's Disease.

OBJECTIVES: Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. METHODS: Fifty-eight older adults (mean age = 70.8, SD = 5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. RESULTS: Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC rsFC moderated the association between generative desire and purpose in life. DISCUSSION: These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.

Structure-Function Interactions in the Hippocampus and Prefrontal Cortex Are Associated with Episodic Memory in Healthy Aging.

Aging comes with declines in episodic memory. Memory decline is accompanied by structural and functional alterations within key brain regions, including the hippocampus and lateral prefrontal cortex, as well as their affiliated default and frontoparietal control networks. Most studies have examined how structural or functional differences relate to memory independently. Here we implemented a multimodal, multivariate approach to investigate how interactions between individual differences in structural integrity and functional connectivity relate to episodic memory performance in healthy aging. In a sample of younger (N = 111; mean age, 22.11 years) and older (N = 78; mean age, 67.29 years) adults, we analyzed structural MRI and multiecho resting-state fMRI data. Participants completed measures of list recall (free recall of words from a list), associative memory (cued recall of paired words), and source memory (cued recall of the trial type, or the sensory modality in which a word was presented). The findings revealed that greater structural integrity of the posterior hippocampus and middle frontal gyrus were linked with a pattern of increased within-network connectivity, which together were related to better associative and source memory in older adulthood. Critically, older adults displayed better memory performance in the context of decreased hippocampal volumes when structural differences were accompanied by functional reorganization. This functional reorganization was characterized by a pruning of connections between the hippocampus and the limbic and frontoparietal control networks. Our work provides insight into the neural mechanisms that underlie age-related compensation, revealing that the functional architecture associated with better memory performance in healthy aging is tied to the structural integrity of the hippocampus and prefrontal cortex.

Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.

Analyzing the Factor Structure of the Toronto Empathy Questionnaire: Dimensionality, Reliability, Validity, Measurement Invariance and One-Year Stability of the German Version.

In the face of heterogeneity in the measurement of empathy, the Toronto Empathy Questionnaire (TEQ; Spreng et al., Journal of Personality Assessment, 91(1), 62-71 (2009)) was developed as a brief unidimensional tool by statistically forming a consensus from existing measures of the construct. The present study aimed to (1) validate a German version of the TEQ, and (2) contribute empirical evidence to the ongoing debate regarding a singular versus multidimensional factor structure of the TEQ. One cross-sectional and two longitudinal studies were performed, with a total of 1,075 participants. Our initial exploratory factor analyses suggested either a one- or a two-factor structure (with the two-factors clustering straight and reverse-scored items); the two-factor model outperformed the one-factor model using confirmatory factor analyses. However, after negated items were replaced by positively reworded alternatives, both models fit the data equally well. A comparison of the correlation patterns with numerous external measures indicated that a second factor of the TEQ is a methodological artifact of item wording. Finally, a unidimensional TEQ scale showed sufficient internal consistency, two-week test-retest reliability, one-year stability, as well as convergent and discriminant validity with measures of empathy, emotion recognition, emotion regulation, altruism, social desirability, and the Big Five personality traits.

Differences in the content and coherence of autobiographical memories between younger and older adults: Insights from text analysis.

Several studies have shown that older adults generate autobiographical memories with fewer specific details than younger adults, a pattern typically attributed to age-relate declines in episodic memory. A relatively unexplored question is how aging affects the content used to represent and recall these memories. We recently proposed that older adults may predominately represent and recall autobiographical memories at the gist level. Emerging from this proposal is the hypothesis that older adults represent memories with a wider array of content topics and recall memories with a distinct narrative style when compared to younger adults. We tested this hypothesis by applying natural language processing approaches to a data set of autobiographical memories described by healthy younger and older adults. We used topic modeling to estimate the distribution (i.e., diversity) of content topics used to represent a memory, and sentence embedding to derive an internal similarity score to estimate the shifts in content when narrating a memory. First, we found that older adults referenced a wider array of content topics (higher content diversity) than younger adults when recalling their autobiographical memories. Second, we found older adults were included more content shifts when narrating their memories than younger adults, suggesting a reduced reliance on choronology to form a coherent memory. Third, we found that the content diversity measures were positively related to specific detail generation for older adults, potentially reflecting age-related compensation for episodic memory difficulties. We discuss how our results shed light on how younger and older adults differ in the way they remember and describe the past. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Taking stock of the past: A psychometric evaluation of the Autobiographical Interview.

Autobiographical memory (AM) involves a rich phenomenological re-experiencing of a spatio-temporal event from the past, which is challenging to objectively quantify. The Autobiographical Interview (AI; Levine et al. Psychology and Aging, 17(4), 677-689, 2002) is a manualized performance-based assessment designed to quantify episodic (internal) and semantic (external) features of recalled and verbally conveyed prior experiences. The AI has been widely adopted, yet has not undergone a comprehensive psychometric validation. We investigated the reliability, validity, association to individual differences measures, and factor structure in healthy younger and older adults (N = 352). Evidence for the AI's reliability was strong: the subjective scoring protocol showed high inter-rater reliability and previously identified age effects were replicated. Internal consistency across timepoints was robust, suggesting stability in recollection. Central to our validation, internal AI scores were positively correlated with standard, performance-based measures of episodic memory, demonstrating convergent validity. The two-factor structure for the AI was not well supported by confirmatory factor analysis. Adjusting internal and external detail scores for the number of words spoken (detail density) improved trait estimation of AM performance. Overall, the AI demonstrated sound psychometric properties for inquiry into the qualities of autobiographical remembering.

A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex.

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

Exploration versus exploitation decisions in the human brain: A systematic review of functional neuroimaging and neuropsychological studies.

Thoughts and actions are often driven by a decision to either explore new avenues with unknown outcomes, or to exploit known options with predictable outcomes. Yet, the neural mechanisms underlying this exploration-exploitation trade-off in humans remain poorly understood. This is attributable to variability in the operationalization of exploration and exploitation as psychological constructs, as well as the heterogeneity of experimental protocols and paradigms used to study these choice behaviours. To address this gap, here we present a comprehensive review of the literature to investigate the neural basis of explore-exploit decision-making in humans. We first conducted a systematic review of functional magnetic resonance imaging (fMRI) studies of exploration-versus exploitation-based decision-making in healthy adult humans during foraging, reinforcement learning, and information search. Eleven fMRI studies met inclusion criterion for this review. Adopting a network neuroscience framework, synthesis of the findings across these studies revealed that exploration-based choice was associated with the engagement of attentional, control, and salience networks. In contrast, exploitation-based choice was associated with engagement of default network brain regions. We interpret these results in the context of a network architecture that supports the flexible switching between externally and internally directed cognitive processes, necessary for adaptive, goal-directed behaviour. To further investigate potential neural mechanisms underlying the exploration-exploitation trade-off we next surveyed studies involving neurodevelopmental, neuropsychological, and neuropsychiatric disorders, as well as lifespan development, and neurodegenerative diseases. We observed striking differences in patterns of explore-exploit decision-making across these populations, again suggesting that these two decision-making modes are supported by independent neural circuits. Taken together, our review highlights the need for precision-mapping of the neural circuitry and behavioural correlates associated with exploration and exploitation in humans. Characterizing exploration versus exploitation decision-making biases may offer a novel, trans-diagnostic approach to assessment, surveillance, and intervention for cognitive decline and dysfunction in normal development and clinical populations.

The biological role of local and global fMRI BOLD signal variability in human brain organization.

Variability drives the organization and behavior of complex systems, including the human brain. Understanding the variability of brain signals is thus necessary to broaden our window into brain function and behavior. Few empirical investigations of macroscale brain signal variability have yet been undertaken, given the difficulty in separating biological sources of variance from artefactual noise. Here, we characterize the temporal variability of the most predominant macroscale brain signal, the fMRI BOLD signal, and systematically investigate its statistical, topographical and neurobiological properties. We contrast fMRI acquisition protocols, and integrate across histology, microstructure, transcriptomics, neurotransmitter receptor and metabolic data, fMRI static connectivity, and empirical and simulated magnetoencephalography data. We show that BOLD signal variability represents a spatially heterogeneous, central property of multi-scale multi-modal brain organization, distinct from noise. Our work establishes the biological relevance of BOLD signal variability and provides a lens on brain stochasticity across spatial and temporal scales.

Controversies and progress on standardization of large-scale brain network nomenclature.

Progress in scientific disciplines is accompanied by standardization of terminology. Network neuroscience, at the level of macroscale organization of the brain, is beginning to confront the challenges associated with developing a taxonomy of its fundamental explanatory constructs. The Workgroup for HArmonized Taxonomy of NETworks (WHATNET) was formed in 2020 as an Organization for Human Brain Mapping (OHBM)-endorsed best practices committee to provide recommendations on points of consensus, identify open questions, and highlight areas of ongoing debate in the service of moving the field toward standardized reporting of network neuroscience results. The committee conducted a survey to catalog current practices in large-scale brain network nomenclature. A few well-known network names (e.g., default mode network) dominated responses to the survey, and a number of illuminating points of disagreement emerged. We summarize survey results and provide initial considerations and recommendations from the workgroup. This perspective piece includes a selective review of challenges to this enterprise, including (1) network scale, resolution, and hierarchies; (2) interindividual variability of networks; (3) dynamics and nonstationarity of networks; (4) consideration of network affiliations of subcortical structures; and (5) consideration of multimodal information. We close with minimal reporting guidelines for the cognitive and network neuroscience communities to adopt.

Functional connectome fingerprinting across the lifespan.

Systematic changes have been observed in the functional architecture of the human brain with advancing age. However, functional connectivity (FC) is also a powerful feature to detect unique "connectome fingerprints," allowing identification of individuals among their peers. Although fingerprinting has been robustly observed in samples of young adults, the reliability of this approach has not been demonstrated across the lifespan. We applied the fingerprinting framework to the Cambridge Centre for Ageing and Neuroscience cohort (n = 483 aged 18 to 89 years). We found that individuals are "fingerprintable" (i.e., identifiable) across independent functional MRI scans throughout the lifespan. We observed a U-shape distribution in the strength of "self-identifiability" (within-individual correlation across modalities), and "others-identifiability" (between-individual correlation across modalities), with a decrease from early adulthood into middle age, before improving in older age. FC edges contributing to self-identifiability were not restricted to specific brain networks and were different between individuals across the lifespan sample. Self-identifiability was additionally associated with regional brain volume. These findings indicate that individual participant-level identification is preserved across the lifespan despite the fact that its components are changing nonlinearly.

Age differences in functional brain networks associated with loneliness and empathy.

Loneliness is associated with differences in resting-state functional connectivity (RSFC) within and between large-scale networks in early- and middle-aged adult cohorts. However, age-related changes in associations between sociality and brain function into late adulthood are not well understood. Here, we examined age differences in the association between two dimensions of sociality-loneliness and empathic responding-and RSFC of the cerebral cortex. Self-report measures of loneliness and empathy were inversely related across the entire sample of younger (mean age = 22.6y, n = 128) and older (mean age = 69.0y, n = 92) adults. Using multivariate analyses of multi-echo fMRI RSFC, we identified distinct functional connectivity patterns for individual and age group differences associated with loneliness and empathic responding. Loneliness in young and empathy in both age groups was related to greater visual network integration with association networks (e.g., default, fronto-parietal control). In contrast, loneliness was positively related to within- and between-network integration of association networks for older adults. These results extend our previous findings in early- and middle-aged cohorts, demonstrating that brain systems associated with loneliness, as well as empathy, differ in older age. Further, the findings suggest that these two aspects of social experience engage different neurocognitive processes across human life-span development.