Biology subjects

Salami, A.

Publications and source records attributed to Salami, A..

16 recordsLinked to original sources

bioRxiv2026

Age-related reconfiguration of locus coeruleus-cortical functional organization

The locus coeruleus (LC) regulates attention, arousal, and adaptive behavior via widespread noradrenergic projections to cortex, yet its large-scale cortical organization and age-related vulnerability remain poorly understood. Using 7T MRI during naturalistic movie-viewing with neutral and negative emotional valence, study-specific LC delineation, and PET-derived receptor-transporter maps, we characterized LC-linked cortical organization in younger and older adults. Functional gradient analysis revealed two dominant axes: a stable primary gradient anchored by catecholaminergic receptor-transporter distributions, and a context-sensitive secondary gradient aligning with the visual-somatomotor (V-S) axis in neutral movie-viewing and the sensorimotor-association (S-A) axis in negative movie-viewing. During negative movie-viewing, older adults exhibited higher global and within-frontoparietal control network dispersion, indicating reduced functional differentiation, a pattern further associated with poorer emotional wellbeing. By revealing chemoarchitectural and context-sensitive LC-linked cortical organization, current work identifies mechanisms underlying age-related LC-linked cortical reorganization with consequences for mental health.

neuroscience↗

bioRxiv2026

Functional connectivity profile of the amygdala subfields associates with emotional well-being in aging

Amygdala-related functional connectivity plays a crucial role in human emotion, cognition, and mental well-being. The amygdala is a highly heterogeneous structure, with subregions that have both distinct and overlapping functions. However, the connectivity patterns of different amygdala subregions--and how these associations vary with age--remain poorly understood. Functional MRI data were analyzed from 68 younger adults and 66 older adults during movie watching in a 7T MRI scanner. Partial least squares (PLS) analysis was used to identify latent variables capturing variance associated with age-related differences in the functional connectivity patterns of three amygdala subregions: the basolateral (BLA), centromedial (CMA), and superficial (SFA) nuclei. In addition, covariance between behavioral measures, such as emotional resilience and cognitive function, and functional connectivity of these subregions was examined. We further explored the associated cognitive processes, correspondence with large-scale brain networks, and the underlying chemoarchitecture of the identified connectivity patterns of the BLA, CMA, and SFA. Multivariate analyses revealed age-related and subregion-specific functional connectivity patterns. Functional connectivity patterns of amygdala subregions were further associated with emotional resilience, which largely overlapped across widespread brain regions; however, their associations differed by age. Stronger coupling of amygdala subregions predicted higher resilience in older adults but lower resilience in younger adults. The identified connectivity patterns were linked to the salience, control, and default mode networks and showed spatial correspondence with mGluR5 and 5-HT6 receptor distributions. These findings highlight age-dependent reorganization of amygdala-related networks that support emotional resilience and provide novel insights into how functional and neurochemical changes of the amygdala subregions contribute to adaptive emotional and cognitive functions in aging.

neuroscience↗

bioRxiv2025

Frontoparietal functional dedifferentiation during naturalistic movie watching among older adults at risk of emotional vulnerability

Functional dedifferentiation, a hallmark of brain aging particularly evident within the frontoparietal network (FPN), has been extensively investigated in the context of cognitive decline, yet its implications for late-life mental health remain poorly understood. Leveraging naturalistic fMRI combined with gradient mapping techniques, the present study investigated FPN functional dedifferentiation--quantified by functional dispersion of FPN in the multidimension gradient manifold--during real-life emotional experiences and its link to affective outcomes. Here, we estimated functional dispersion during naturalistic movie watching in both younger (N=72, 34 female, 19-36 yrs) and older (N=68, 36 female, 65-82 yrs) adult groups with 7T MRI scanner and assessed their emotion regulation difficulties, anxiety, and depression symptoms as indicators of mental health status. The results demonstrated that greater FPN dispersion (i.e., more dissimilar connectivity) was linked to increased depressive symptoms in older adults and highlighted emotion regulation difficulties as a full mediator of this relationship. Moreover, FPN dispersion could distinguish emotionally resilient from vulnerable older individuals. These findings suggest that functional dedifferentiation of the FPN during ecologically valid emotional context constitutes a promising neural signature of affective vulnerability in older adults. By bridging age-related functional dedifferentiation to real-world emotional scenario, this work underscores the translational value of naturalistic paradigms in geriatric psychiatry and identifies potential intervention targets aimed at enhancing FPN specificity to promote mental health in aging population.

neuroscience↗

bioRxiv2025

Compression of functional gradients from rest to naturalistic processing: Moderation effect of age

The functional cortical hierarchy of the human brain, a fundamental principle of brain organization, has been extensively characterized during resting state for healthy younger adults. However, functional re-organization during naturalistic settings, such as movie-watching, and its alterations across the adult lifespan remains poorly understood. Using resting-state and movie fMRI data from two large datasets, Cam-CAN (N=416) and DyNAMiC (N=156), this study conducted a comprehensive comparison of brain organization across two states. We identified a robust reorganization with compression of functional gradients from rest to movie-watching states, which is mediated by changes in functional integration and segregation of brain networks. The extent of compression from rest to movie was significantly greater in older adults and predicted worse cognitive performance among the elderly population. Our findings provide novel insights into how macroscale brain hierarchy is reorganized during naturalistic processing, and how this reorganization during aging impacts cognitive processes, offering a deeper understanding of the neural basis of aging and cognition.

neuroscience↗

bioRxiv2025

Global brain maintenance predicts well-preserved cognitive function: A pooled analysis of three longitudinal population-based Swedish cohorts

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is lacking. We pooled data from three population-based Swedish cohorts (Betula, N = 196; SNAC-K, N = 472; H70, N = 688; aged 60-93 years at baseline, follow-up duration up to 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles (adjusted for total intracranial volume), and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., aged) versus high (i.e., youth-like) brain integrity based on ventricular volume estimates available for a younger reference sample in one of the cohorts (Betula, 25-55 years, N = 60). Subgroup differences in cognition at baseline and over the follow-up were assessed with ANCOVAs and linear mixed effects models. Logistic regressions were used to examine lifestyle predictors of brain maintenance. Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition (p < .001) and less cognitive decline longitudinally (p < .001). Moreover, lower cardiovascular disease (CVD) risk and the absence of diabetes predicted brain maintenance at baseline (CVD risk, OR = 0.80, 95% CI [0.68, 0.93]; diabetes, OR = 0.39, 95% CI [0.26, 0.59]) and over the follow-up (CVD risk, OR = 0.79, 95% CI [0.64, 0.96]; diabetes, OR = 0.53, 95% CI [0.29, 0.94]). These findings underscore brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

neuroscience↗

bioRxiv2024

Brain-Cognitive Gaps in relation to Dopamine and Health-related Factors: Insights from AI-Driven Functional Connectome Predictions

A key question in human neuroscience is to understand how individual differences in brain function relate to cognitive differences. However, the optimal condition of brain function to study between-person differences in cognition remains unclear. While many studies have developed objective biomarkers to accurately predict intelligence and general cognition, consensus on domain-specific markers has not yet emerged. Brain age has been proposed as a potential candidate, but recent research suggests that brain age offers minimal additional information on cognitive decline beyond what chronological age provides, prompting a shift toward approaches focused directly on cognitive prediction. Using a deep learning approach, we evaluated the predictive power of the functional connectome during various states (resting state, movie-watching, and n-back) on episodic memory and working memory performance. Our findings show that while connectomes during task, especially during movie watching, better predict both episodic and working memory, resting state connectomes are equally effective in predicting episodic memory. Furthermore, individuals with a negative brain-cognition gap (where brain predictions underestimate actual performance) exhibited lower physical activity and higher cardiovascular risk compared to those with a positive gap. This shows that knowledge of the brain-cognition gap provides insights into factors contributing to cognitive resilience. Further lower PET-derived measures of dopamine binding were linked to a greater brain-cognition gap, mediated by regional functional variability. Together, our findings highlight the importance of brain state in connectome-based cognitive prediction and introduce the brain cognitive gap as a potentially informative, dopamine-modulated marker of vulnerability to compromise brain function.

neuroscience↗

bioRxiv2024

Multiple neural pathways to successful visual short-term memory across the adult lifespan

Cognitive task performance can be supported through multiple brain activation patterns, a concept referred to as brain degeneracy. We used a novel approach to consider brain degeneracy during a visual short-term memory task (VSTM) across the adult lifespan in the cross-sectional Cam-CAN study (n = 113, 23-87 years old). Our main goal was to identify subgroups of participants whose VSTM performance was characterized by distinct brain activation patterns. First, we identified seven brain modules that responded similarly to the VSTM task across participants, and resembled previously identified functional networks. Subsequently, latent profile analysis revealed four distinct subgroups of participants. Each subgroup was characterized by different recruitment patterns of these brain modules, predominantly in the frontal control module (FCM), visual module (VM), and default mode module (DMM). Subgroups did not differ in demographics or task performance. However, associations between brain activity and performance varied across subgroups, particularly in the FCM, suggesting that individuals may use different cognitive operations to perform the VSTM task. Further analyses revealed group differences in white matter integrity, mostly in the uncinate fasciculus, suggesting that individual differences in structural brain properties may shape the different brain activation patterns. Altogether, our study contributes to our understanding of how multiple brain activation patterns could underlie cognitive performance.

neuroscience↗

bioRxiv2024

Dedifferentiation of caudate-cortical connectivity is linked to reduced D1 dopamine receptor availability and poorer memory function in aging

Age-related alterations in cortico-striatal function have been highlighted as an important determinant of declines in flexible, higher-order, cognition in older age. However, the mechanisms underlying such alterations remain poorly understood. Computational accounts propose age-related dopaminergic decreases to impoverish neural gain control, possibly contributing to reduced specificity of cortico-striatal circuits, that are modulated by dopamine, in older age. Using multi-modal neuroimaging data (fMRI, PET) from a large lifespan cohort (n = 180), we assessed the relationship between dopamine D1-like receptors (D1DRs) and cortico-striatal function during rest and an n-back working memory task. The results revealed gradual age-related decreases in the specificity of functional coupling between the centrolateral caudate and cortical association networks during both rest and working memory, which in turn was associated with poorer short and long-term memory performance with older age. Critically, reduced D1DR availability in the caudate and the prefrontal cortex predicted less differentiated caudate-cortical coupling across the lifespan, in part accounting for the age-related declines observed on this metric. These findings provide novel empirical evidence for a key role of dopamine in maintaining functional specialization of cortico-striatal circuits as individuals age, aligning with computational models that propose deficient catecholaminergic neuromodulation to underpin age-related dedifferentiation of brain function.

neuroscience↗

bioRxiv2024

Evaluating the position of the uncal apex as a predictor of episodic memory across the adult lifespan

Structural decline of the hippocampus follows heterogeneous spatial patterns, and is an important determinant of episodic memory dysfunction in aging. However, evidence indicate that the anatomical landmark uncal apex, used to demarcate anterior and posterior hippocampal subregions, changes position as the hippocampus atrophies. This risks misclassifying gray matter into the incorrect subregion when using standard demarcation methods, potentially contributing to over- and underestimation of age-related anterior and posterior hippocampal volume loss, respectively. Yet, it remains unexplored whether inter-individual differences in uncal apex position itself predict episodic memory performance. Here, we manually identified the uncal apex in anatomical MRI data from a healthy adult-lifespan sample (n=180; 20-79 years), analyzed age differences in its position, and examined associations with word recall performance. Increasing age was linked to a more anteriorly located uncal apex (retracting [~]0.04 mm/year), and this anterior shift was linked to lower memory performance. Using the manually identified uncal apex for subregion segmentation in native space revealed a lower proportion of anterior hippocampal volume compared to segmentation in MNI space (y = -21), with effects of age on volumes differing between methods. Memory performance was not predicted by hippocampal subregion volumes, but the ratio of posterior to anterior volume was significantly linked to memory when accounting for tissue misclassification due to uncal apex variation. These results indicate that uncal apex position may provide an estimate of hippocampal integrity sensitive to inter-individual differences in memory, independent of limitations associated with different segmentation methods.

neuroscience↗

bioRxiv2023

Resilience-driven neural synchrony during naturalistic movie watching: an ultra-high field fMRI study

Psychological resilience protects individuals against the negative consequences of exposure to adversity. Despite increasing attention given to resilience for its role in maintaining mental health, a clear conceptualization of resilience remains elusive, and the intricacies of its neural correlates are poorly understood. Here, we recorded brain activity in healthy young adults using a 7T MRI scanner while they naturally watched movies. Stronger and more extensive resilience-driven neural synchrony, as estimated by inter-subject correlation, was observed in a wider set of brain regions in response to the negative movie compared to the neutral movie. Moreover, we found that high-resilience individuals had similar neural activities to their peers, while low-resilience individuals showed more variable neural activities. Intolerance of uncertainty (IU), a personality trait that shapes biased perception and cognition, damped the resilience-driven brain synchrony in regions related to attention, indicating IU may compromise resilience by affecting attentional functions. We propose that similarity of neural responses among resilient individuals highlights adaptive emotional processing. Conversely, the variability in neural responses indicates vulnerability to adverse psychological outcomes. These insights shed light on the mechanisms of resilience, highlighting that it operates as a system encompassing multiple neuropsychological processes crucial for adapting to external stimuli.

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bioRxiv2023

Dopamine D1-receptor Organization Contributes to Functional Brain Architecture

Decades of research on functional brain mapping have highlighted the importance of understanding the functional organization of the cerebral cortex. Recent advances have revealed a gradient of functional organization spanning from primary sensory to transmodal cortices. This gradient-like axis of connectivity has been hypothesized to be aligned with regional differences in the density of neuromodulatory receptors. Recent work in non-human primates supports this notion, revealing a gradient of dopamine D1-like receptor (D1DR) density along the cortical hierarchy. Given the importance of dopaminergic modulation for synaptic activity and neural gain, we tested whether D1DRs shares the same organizational principles as brain function in humans, and whether inter-regional relationships in D1 expression modulate functional crosstalk. Using the worlds largest combined dopamine D1DR-PET and MRI database, we provided empirical support for the first time in humans that the landscape of D1DR availability follows a unimodal-transmodal cortical hierarchy, with greater D1DR expression in associative cortical regions. We found an organization of inter-regional D1DR co-expression spanning unimodal to transmodal brain regions, expressing a high spatial correspondence to the principal macroscale gradient of functional connectivity. Critically, we found that individual differences in D1DR density between unimodal and transmodal regions was associated with greater differentiation of default-mode and somatosensory networks. Finally, inter-regional D1DR co-expression was found to modulate couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain. Significance StatementWe found a high correspondence between the organization of the most abundantly expressed dopamine receptor subtype and a macroscale unimodal-to-transmodal functional gradient. Differences in D1 density between unimodal and transmodal regions were related to the shape of the functional gradient, contributing to greater differentiation of somatomotor and default mode networks. Finally, we observed that the covariance structure of dopamine D1 receptors is associated with the strength of connectivity within functional networks. The discovery of a dopaminergic layer of brain organization represents a crucial first step towards an understanding of how dopamine, with close ties to behavior and neuropsychiatric conditions, potentially contribute to the emergence of functional brain organization.

neuroscience↗

bioRxiv2023

Two long-axis dimensions of hippocampal cortical integration support memory function across the adult lifespan

The hippocampus is a complex structure critically involved in numerous behavior-regulating systems. In young adults, multiple overlapping spatial modes along its longitudinal and transverse axes describe the organization of its functional integration with neocortex, extending the traditional framework emphasizing functional differences between sharply segregated hippocampal subregions. Yet, it remains unknown whether these modes (i.e., gradients) persist across the adult human lifespan, and relate to memory and molecular markers associated with brain function and cognition. In two independent samples, we demonstrate that the principal anteroposterior and second-order, mid-to-anterior/posterior hippocampal modes of neocortical functional connectivity, representing distinct dimensions of macroscale cortical organization, manifest across the adult lifespan. Specifically, individual differences in topography of the second-order gradient predicted episodic memory and mirrored dopamine D1 receptor distribution, capturing shared functional and molecular organization. Older age was associated with less distinct transitions along gradients (i.e., increased functional homogeneity). Importantly, a youth-like gradient profile predicted preserved episodic memory - emphasizing age-related gradient dedifferentiation as a marker of cognitive decline. Our results underscore a critical role of mapping multidimensional hippocampal organization in understanding the neural circuits that support memory across the adult lifespan.

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bioRxiv2023

The iron-dopamine D1 coupling modulates neural signatures of working memory across adulthood

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention. HighlightsO_LIFirst study demonstrating the association between regional iron and dopamine D1DR in adult humans. C_LIO_LIThe interplay between age-related elevated iron and diminished D1DR explained lower task-related brain activity, which in turn was related to poorer task performance. C_LIO_LIOur findings iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration. C_LI

neuroscience↗

bioRxiv2023

Hub connectivity in the human connectome: Links to aging and processing speed

The human structural brain network, or connectome, has a rich-club organization with a small number of brain regions showing high network connectivity, called hubs. Hubs are centrally located in the network, energy costly, and critical for human cognition. Aging has been associated with changes in brain structure, function, and cognitive decline, such as processing speed. At a molecular level, the aging process is a progressive accumulation of oxidative damage, which leads to subsequent energy depletion in the neuron and causes cell death. However, it is still unclear how age affects hub connections in the human connectome. The current study aims to address this research gap by utilizing a novel measure of structural connectivity strength, fiber bundle capacity (FBC), which is derived from Constrained Spherical Deconvolution (CSD) modeling of white-matter fiber bundles. FBC represents the capacity of a fiber bundle to transfer information and is a less biased measure for quantifying connection strength within biological pathways. We found that hubs exhibit longer-distance connections and higher metabolic rates compared to peripheral brain regions, suggesting that hubs are biologically costly. Although the landscape of structural hubs was relatively age-invariant, there were wide-spread age effects on FBC in the connectome. Critically, these age effects were larger in connections within hub compared to peripheral brain connections. These findings were supported by both a cross-sectional sample with wide age-range (N=137) and a longitudinal sample across 5 years (N=83). Moreover, our results demonstrated that associations between FBC and processing speed were more concentrated in hub connections than chance level, and FBC in hub connections mediated the age-effects on processing speed. Overall, our findings indicate that structural connections of hubs, which demonstrate greater energy demands, are particular vulnerable to aging. The vulnerability may contribute to age-related impairments in processing speed among older adults.

neuroscience↗

bioRxiv2022

Bi-phasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan

The dopamine (DA) system, particularly D1-like DA receptors (D1DR), declines across the adult life. The functional consequences of reduced D1DR has been hypothesized to vary across life periods, but the precise timing of these periods is unknown. To examine distinct phases in age-related D1DR reductions, we studied 180 healthy adults (90 females, 20-80 years), who underwent D1DR PET assessment using [11C]SCH23390. A bi-phasic pattern of age-related D1DR differences was revealed, with an inflection point at approximately 40 years of age. Notably, D1DR levels before and after the inflection showed opposing relations to neurocognitive functions, in concordance with distinct consequences of D1DR differences during development and in old age. Furthermore, D1DR reductions in later life were linked to age-related cerebrovascular consequences. These results support a distinction between D1DR reductions in early adulthood from those later in life, and suggest less dramatic and more malleable DA losses in aging than previously suggested.

neuroscience↗

bioRxiv2022

Dynamic regulation of neural variability during working memory reflects dopamine, functional integration, and decision-making

The regulation of moment-to-moment neural variability may permit effective responses to changing cognitive demands. However, the mechanisms that support variability regulation are unknown. In the context of working memory, we leverage the largest available PET and fMRI dataset to jointly consider three lenses through which neural variability regulation could be understood: dopamine capacity, network-level functional integration, and flexible decision processes. We show that with greater working memory load, upregulation of variability was associated with elevated dopamine capacity and heightened functional integration, effects dominantly expressed in the striato-thalamic system rather than cortex. Strikingly, behavioral modeling revealed that working memory load evoked substantial decision biases during evidence accumulation, and those who jointly expressed a more optimal decision bias and higher dopamine capacity were most likely to upregulate striato-thalamic variability under load. We argue that the ability to align striato-thalamic variability to level of demand may be a hallmark of a well-functioning brain.

neuroscience↗