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.

Frontoparietal functional connectivity moderates the link between time spent on social media and subsequent negative affect in daily life.

Evidence on the harms and benefits of social media use is mixed, in part because the effects of social media on well-being depend on a variety of individual difference moderators. Here, we explored potential neural moderators of the link between time spent on social media and subsequent negative affect. We specifically focused on the strength of correlation among brain regions within the frontoparietal system, previously associated with the top-down cognitive control of attention and emotion. Participants (N = 54) underwent a resting state functional magnetic resonance imaging scan. Participants then completed 28 days of ecological momentary assessment and answered questions about social media use and negative affect, twice a day. Participants who spent more than their typical amount of time on social media since the previous time point reported feeling more negative at the present moment. This within-person temporal association between social media use and negative affect was mainly driven by individuals with lower resting state functional connectivity within the frontoparietal system. By contrast, time spent on social media did not predict subsequent affect for individuals with higher frontoparietal functional connectivity. Our results highlight the moderating role of individual functional neural connectivity in the relationship between social media and affect.

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.

Conscientiousness associated with efficiency of the salience/ventral attention network: Replication in three samples using individualized parcellation.

Conscientiousness, and related constructs impulsivity and self-control, have been related to structural and functional properties of regions in the prefrontal cortex (PFC) and anterior insula. Network-based conceptions of brain function suggest that these regions belong to a single large-scale network, labeled the salience/ventral attention network (SVAN). The current study tested associations between conscientiousness and resting-state functional connectivity in this network using two community samples (N's = 244 and 239) and data from the Human Connectome Project (N = 1000). Individualized parcellation was used to improve functional localization accuracy and facilitate replication. Functional connectivity was measured using an index of network efficiency, a graph theoretical measure quantifying the capacity for parallel information transfer within a network. Efficiency of a set of parcels in the SVAN was significantly associated with conscientiousness in all samples. Findings are consistent with a theory of conscientiousness as a function of variation in neural networks underlying effective prioritization of goals.

Hippocampus and temporal pole functional connectivity is associated with age and individual differences in autobiographical memory.

Recollection of one's personal past, or autobiographical memory (AM), varies across individuals and across the life span. This manifests in the amount of episodic content recalled during AM, which may reflect differences in associated functional brain networks. We take an individual differences approach to examine resting-state functional connectivity of temporal lobe regions known to coordinate AM content retrieval with the default network (anterior and posterior hippocampus, temporal pole) and test for associations with AM. Multiecho resting-state functional magnetic resonance imaging (fMRI) and autobiographical interviews were collected for 158 younger and 105 older healthy adults. Interviews were scored for internal (episodic) and external (semantic) details. Age group differences in connectivity profiles revealed that older adults had lower connectivity within anterior hippocampus, posterior hippocampus, and temporal pole but greater connectivity with regions across the default network compared with younger adults. This pattern was positively related to posterior hippocampal volumes in older adults, which were smaller than younger adult volumes. Connectivity associations with AM showed two significant patterns. The first dissociated connectivity related to internal vs. external AM across participants. Internal AM was related to anterior hippocampus and temporal pole connectivity with orbitofrontal cortex and connectivity within posterior hippocampus. External AM was related to temporal pole connectivity with regions across the lateral temporal cortex. In the second pattern, younger adults displayed temporal pole connectivity with regions throughout the default network associated with more detailed AMs overall. Our findings provide evidence for discrete ensembles of brain regions that scale with systematic variation in recollective styles across the healthy adult life span.

Age differences in the functional architecture of the human brain.

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience-dependent changes, or both, is uncertain. We employed a multimethod strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n = 181) and older (n = 120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multiscale, multimethod approaches to characterize the architecture of functional brain aging.

Neurocognitive aging data release with behavioral, structural and multi-echo functional MRI measures.

Central to understanding human behavior is a comprehensive mapping of brain-behavior relations within the context of lifespan development. Reproducible discoveries depend upon well-powered samples of reliable data. We provide to the scientific community two, 10-minute, multi-echo functional MRI (ME-fMRI) runs, and structural MRI (T1-MPRAGE), from 181 healthy younger (ages 18-34 y) and 120 older adults (ages 60-89 y). T2-FLAIR MRIs and behavioral assessments are available in a majority subset of over 250 participants. Behavioral assessments include fluid and crystallized cognition, self-reported measures of personality, and socioemotional functioning. Initial quality control and validation of these data is provided. This dataset will be of value to scientists interested in BOLD signal specifically isolated from ME-fMRI, individual differences in brain-behavioral associations, and cross-sectional aging effects in healthy adults. Demographic and behavioral data are available within the Open Science Framework project "Goal-Directed Cognition in Older and Younger Adults" ( http://osf.io/yhzxe/ ), which will be augmented over time; neuroimaging data are available on OpenNeuro ( https://openneuro.org/datasets/ds003592 ).

White matter lesion load is associated with lower within- and greater between- network connectivity across older age.

White matter hyperintensities (WMH) are among the most prominent structural changes observed in older adulthood. These changes coincide with functional changes to the intrinsic network organization of the aging brain. Yet little is known about how WMH are associated with changes to the whole-brain functional connectome in normal aging. We used a lesion prediction algorithm to quantify WMH as well as resting-state multiecho functional magnetic resonance imaging to characterize resting-state functional connectivity in a cross-sectional sample of healthy older adults (N = 105, 60-83 years of age). In a multivariate analysis, we found that higher lesion load was associated with a global pattern of network dedifferentiation, marked by lower within- and greater between- network connectivity. Network specific changes included greater visual network integration and greater posterior-anterior connectivity. The relationship between WMH and resting-state functional connectivity was negatively associated with fluid IQ as well as Blood Oxygen Level Dependent signal dimensionality. Reduced functional network segregation is a widely observed pattern of age-related change. Our findings show that these functional changes are associated with the accumulation of WMH in older adulthood.

Age differences in intuitive moral decision-making: Associations with inter-network neural connectivity.

Positions of power involving moral decision-making are often held by older adults (OAs). However, little is known about age differences in moral decision-making and the intrinsic organization of the aging brain. In this study, younger adults (YAs; n = 117, Mage = 22.11) and OAs (n = 82, Mage = 67.54) made decisions in hypothetical moral dilemmas and completed resting-state multi-echo functional magnetic resonance imaging (fMRI) scans. Relative to YAs, OAs were more likely to endorse deontological decisions (i.e., decisions based on adherence to a moral principle or duty), but only when the choice was immediately compelling or intuitive. By contrast, there was no difference between YAs and OAs in utilitarian decisions (i.e., decisions aimed at maximizing collective well-being) when the utilitarian choice was intuitive. Enhanced connections between the posterior medial core of the default network (pmDN) and the dorsal attention network, and overall reduced segregation of pmDN from the rest of the brain, were associated with this increased deontological-intuitive moral decision-making style in OAs. The present study contributes to our understanding of age differences in decision-making styles by taking into account the intuitiveness of the moral choice, and it offers further insights as to how age differences in intrinsic brain connectivity relate to these distinct moral decision-making styles in YAs and OAs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Inter-regional BOLD signal variability is an organizational feature of functional brain networks.

Neuronal variability patterns promote the formation and organization of neural circuits. Macroscale similarities in regional variability patterns may therefore be linked to the strength and topography of inter-regional functional connections. To assess this relationship, we used multi-echo resting-state fMRI and investigated macroscale connectivity-variability associations in 154 adult humans (86 women; mean age = 22yrs). We computed inter-regional measures of moment-to-moment BOLD signal variability and related them to inter-regional functional connectivity. Region pairs that showed stronger functional connectivity also showed similar BOLD signal variability patterns, independent of inter-regional distance and structural similarity. Connectivity-variability associations were predominant within all networks and followed a hierarchical spatial organization that separated sensory, motor and attention systems from limbic, default and frontoparietal control association networks. Results were replicated in a second held-out fMRI run. These findings suggest that macroscale BOLD signal variability is an organizational feature of large-scale functional networks, and shared inter-regional BOLD signal variability may underlie macroscale brain network dynamics.

Social exclusion reliably engages the default network: A meta-analysis of Cyberball.

Social exclusion refers to the experience of being disregarded or rejected by others and has wide-ranging negative consequences for well-being and cognition. Cyberball, a game where a ball is virtually tossed between players, then leads to the exclusion of the research participant, is a common method used to examine the experience of social exclusion. The neural correlates of social exclusion remain a topic of debate, particularly with regards to the role of the dorsal anterior cingulate cortex (dACC) and the concept of social pain. Here we conducted a quantitative meta-analysis using activation likelihood estimation (ALE) to identify brain activity reliably engaged by social exclusion during Cyberball task performance (Studies = 53; total N = 1,817 participants). Results revealed consistent recruitment in ventral anterior cingulate and posterior cingulate cortex, inferior and superior frontal gyri, posterior insula, and occipital pole. No reliable activity was observed in dACC. Using a probabilistic atlas to define dACC, fewer than 15% of studies reported peak coordinates in dACC. Meta-analytic connectivity mapping suggests patterns of co-activation are consistent with the topography of the default network. Reverse inference for cognition associated with reliable Cyberball activity computed in Neurosynth revealed social exclusion to be associated with cognitive terms Social, Autobiographical, Mental States, and Theory of Mind. Taken together, these findings highlight the role of the default network in social exclusion and warns against interpretations of the dACC as a key region involved in the experience of social exclusion in humans.

The default network of the human brain is associated with perceived social isolation.

Humans survive and thrive through social exchange. Yet, social dependency also comes at a cost. Perceived social isolation, or loneliness, affects physical and mental health, cognitive performance, overall life expectancy, and increases vulnerability to Alzheimer's disease-related dementias. Despite severe consequences on behavior and health, the neural basis of loneliness remains elusive. Using the UK Biobank population imaging-genetics cohort (n = ~40,000, aged 40-69 years when recruited, mean age = 54.9), we test for signatures of loneliness in grey matter morphology, intrinsic functional coupling, and fiber tract microstructure. The loneliness-linked neurobiological profiles converge on a collection of brain regions known as the 'default network'. This higher associative network shows more consistent loneliness associations in grey matter volume than other cortical brain networks. Lonely individuals display stronger functional communication in the default network, and greater microstructural integrity of its fornix pathway. The findings fit with the possibility that the up-regulation of these neural circuits supports mentalizing, reminiscence and imagination to fill the social void.

Loneliness and meaning in life are reflected in the intrinsic network architecture of the brain.

Social relationships imbue life with meaning, whereas loneliness diminishes one's sense of meaning in life. Yet the extent of interdependence between these psychological constructs remains poorly understood. We took a multivariate network approach to examine resting-state fMRI functional connectivity's association with loneliness and meaning in a large cohort of adults (N = 942). Loneliness and meaning in life were negatively correlated with one another. In their relationship with individually parcelled whole-brain measures of functional connectivity, a significant and reliable pattern was observed. Greater loneliness was associated with dense, and less modular, connections between default, frontoparietal, attention and perceptual networks. A greater sense of life meaning was associated with increased, and more modular, connectivity between default and limbic networks. Low loneliness was associated with more modular brain connectivity, and lower life meaning was associated with higher between-network connectivity. These findings advance our understanding of loneliness and life meaning as distinct, yet interdependent, features of sociality. The results highlight a potential role of the default network as a central hub, providing a putative neural mechanism for shifting between feelings of isolation and purpose.

Gain Control in the Auditory Cortex Evoked by Changing Temporal Correlation of Sounds.

Natural sounds exhibit statistical variation in their spectrotemporal structure. This variation is central to identification of unique environmental sounds and to vocal communication. Using limited resources, the auditory system must create a faithful representation of sounds across the full range of variation in temporal statistics. Imaging studies in humans demonstrated that the auditory cortex is sensitive to temporal correlations. However, the mechanisms by which the auditory cortex represents the spectrotemporal structure of sounds and how neuronal activity adjusts to vastly different statistics remain poorly understood. In this study, we recorded responses of neurons in the primary auditory cortex of awake rats to sounds with systematically varied temporal correlation, to determine whether and how this feature alters sound encoding. Neuronal responses adapted to changing stimulus temporal correlation. This adaptation was mediated by a change in the firing rate gain of neuronal responses rather than their spectrotemporal properties. This gain adaptation allowed neurons to maintain similar firing rates across stimuli with different statistics, preserving their ability to efficiently encode temporal modulation. This dynamic gain control mechanism may underlie comprehension of vocalizations and other natural sounds under different contexts, subject to distortions in temporal correlation structure via stretching or compression.

Bidirectional Regulation of Innate and Learned Behaviors That Rely on Frequency Discrimination by Cortical Inhibitory Neurons.

The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination.

Complementary control of sensory adaptation by two types of cortical interneurons.

Reliably detecting unexpected sounds is important for environmental awareness and survival. By selectively reducing responses to frequently, but not rarely, occurring sounds, auditory cortical neurons are thought to enhance the brain's ability to detect unexpected events through stimulus-specific adaptation (SSA). The majority of neurons in the primary auditory cortex exhibit SSA, yet little is known about the underlying cortical circuits. We found that two types of cortical interneurons differentially amplify SSA in putative excitatory neurons. Parvalbumin-positive interneurons (PVs) amplify SSA by providing non-specific inhibition: optogenetic suppression of PVs led to an equal increase in responses to frequent and rare tones. In contrast, somatostatin-positive interneurons (SOMs) selectively reduce excitatory responses to frequent tones: suppression of SOMs led to an increase in responses to frequent, but not to rare tones. A mutually coupled excitatory-inhibitory network model accounts for distinct mechanisms by which cortical inhibitory neurons enhance the brain's sensitivity to unexpected sounds.

Selective Impairment in Frequency Discrimination in a Mouse Model of Tinnitus.

Tinnitus is an auditory disorder, which affects millions of Americans, including active duty service members and veterans. It is manifested by a phantom sound that is commonly restricted to a specific frequency range. Because tinnitus is associated with hearing deficits, understanding how tinnitus affects hearing perception is important for guiding therapies to improve the quality of life in this vast group of patients. In a rodent model of tinnitus, prolonged exposure to a tone leads to a selective decrease in gap detection in specific frequency bands. However, whether and how hearing acuity is affected for sounds within and outside those frequency bands is not well understood. We induced tinnitus in mice by prolonged exposure to a loud mid-range tone, and behaviorally assayed whether mice exhibited a change in frequency discrimination acuity for tones embedded within the mid-frequency range and high-frequency range at 1, 4, and 8 weeks post-exposure. A subset of tone-exposed mice exhibited tinnitus-like symptoms, as demonstrated by selective deficits in gap detection, which were restricted to the high frequency range. These mice exhibited impaired frequency discrimination both for tones in the mid-frequency range and high-frequency range. The remaining tone exposed mice, which did not demonstrate behavioral evidence of tinnitus, showed temporary deficits in frequency discrimination for tones in the mid-frequency range, while control mice remained unimpaired. Our findings reveal that the high frequency-specific deficits in gap detection, indicative of tinnitus, are associated with impairments in frequency discrimination at the frequency of the presumed tinnitus.