Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)-the rhythmic heart rate modulation accompanying respiration-has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 ± 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working-memory and associative-memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging.

Background: What social consequences do older adults anticipate experiencing after learning their apolipoprotein E test result, a genetic risk factor for Alzheimer's dementia in later life? We contrasted these anticipations with the experiences of people who knew their apolipoprotein E test result. Methods: Adults (N=291) who underwent apolipoprotein E testing when screening for a clinical trial completed a 23-item Social Impact Scale, a measure of AD stigma. Some (n=180) answered based on their expectations of social impact if they learned a heightened risk for Alzheimer's. Others (n=111) answered based on knowing their apolipoprotein E ε4 carrier status. We compared Social Impact Scale responses cross-sectionally and within-groups defined by apolipoprotein E carrier status, sex, and age over 6 months. Findings: Anticipated stigma was greater than experienced stigma; participants who did not know their apolipoprotein E result reported a significantly higher mean Social Impact Scale score (26.1%) than the group that knew they were ε4 carriers (2.3%, p<0.05). The largest between-group discrepancies were: "People act like I am less competent" (Δ63.0%) and "I need greater reassurance from loved ones" (Δ41.4%). Social Impact Scale scores decreased in individuals learning they were apolipoprotein E non-carriers (Δ19.8%) between the 6-week and 6-month assessments. Interpretation: Individuals tend to anticipate more adverse social consequences of genetic risk disclosure than are reported by those who know they are at higher genetic risk for dementia. Findings suggest clinicians should identify patients' anticipatory worries and address the concerns as part of pre-disclosure counseling for learning an Alzheimer's disease genetic result. Funding: This study is funded by a grant from the Alzheimer's Association to Banner Alzheimer's Institute and philanthropic support from the Banner Alzheimer's Foundation. This study leverages data and resources from the Generation Program funded by Novartis Pharma AG, Basel, Switzerland and Amgen, Thousand Oaks, CA, USA, in collaboration with the Banner Alzheimer's Institute located in Phoenix, AZ, USA. Generation Study 1 is supported by funding from the National Institute on Aging (1UF1AG046150), part of the National Institutes of Health, as well as the Alzheimer's Association, FBRI, GHR Foundation and Banner Alzheimer's Foundation. Dr. Stites is supported by the Alzheimer's Association (AARF-17-528934) and the National Institute on Aging (1K23AG065442, 1K23AG065442-03S1). Mehek Dedhia is supported by the University Scholars program at the University of Pennsylvania.Declaration of Interest: The authors have no conflicts of interest to report.Ethical Approval: All participants provided informed consent and all procedures involving human subjects were approved by the Western Institutional Review Board (Protocol #20180837).

The locus coeruleus (LC) and substantia nigra (SN) have attracted attention in the search for early biomarkers and new therapeutic targets in neurodegenerative and psychiatric diseases. MRI methods that provide contrast in the LC and SN are commonly described as “neuromelanin-sensitive.” This terminology originated from early observations linking the MRI signal topography to apparent spatial correspondence with pigmented regions at autopsy. However, converging evidence from MRI physics, modelling, and animal studies indicates that the observed contrast cannot be attributed specifically to neuromelanin. Instead, it reflects a complex interplay of different MRI physical properties that can yield diverse biological interpretations depending on the context, age, region, and disease. Continued use of the term therefore risks conflating MRI measurement properties with biological interpretation, leading to overattributing MRI-signal changes to neuromelanin accumulation and loss across the lifespan and with disease. We argue that the term “neuromelanin-sensitive” should be abandoned, and propose instead a descriptive reporting framework with terminology that separates acquisition (“type”), the visible signal (“contrast”), quantification (“derivative”), and biological interpretation (“inference”). This new approach will improve interpretability, comparability, and conceptual rigor in locus coeruleus and substantia nigra research.

Heart rate variability biofeedback (HRVB) has been confirmed to enhance cardiovagal activation and alleviate depressive symptoms in patients with major depressive disorder (MDD). However, it remains unknown which dimensions of depression predict better treatment outcomes following HRVB. This study utilized a randomized controlled trial design. A total of 59 patients with depressive disorder were enrolled and randomly assigned to either the HRVB group or the relaxation training (RT) group. Both groups receive 60-min training sessions twice weekly for 10 sessions over five weeks. Psychological variables (depression and anxiety) and lead II electrocardiogram (ECG) were collected at pre-test and post-test. ECG data were converted into HRV indices. Two-way mixed-design analyses of variances were conducted to examine the Group (HRVB vs. RT) × Time (pre-test vs. post-test transfer) interaction effects on psychological outcomes and HRV indices. In addition, participants in the HRVB group were classified as responders (n = 10) or non-responders (n = 14) based on change in the root mean square of successive differences between normal heartbeats (RMSSD) following HRVB. Differences in demographic and psychological variables between these subgroups were further examined. (1) Both groups showed significant reductions in depression and anxiety over time; however, no significant differences between groups were observed. (2) At the transfer stage, the HRVB group demonstrated significant increases in HRV indices from pre-test rest stage to post-test transfer stage. (3) Within the HRVB group, responders exhibited significantly lower levels of depressive symptoms (including loss of pleasure, loss of interest, worthlessness, and loss of energy) and lower parasympathetic activity compared with non-responders. HRVB not only alleviated depression and anxiety symptoms but also enhanced autonomic nervous system activity. Moreover, patients who derived the greatest benefit from HRVB tended to exhibit more favorable psychological features at pre-test. These findings may inform the development of personalized and evidence-based psychological interventions for patients with depressive disorders.

Compared to younger adults, older adults seem to prioritize processing positive information and deprioritize processing negative information. Known as the positivity effect, its mechanisms remain debated. One explanation of the positivity effect is that older adults are influenced by a sense of limited time left in life to focus more on emotional well-being compared with younger adults. Previous research shows that experimentally manipulating time perspective can mimic the positivity effect in younger adults, however such findings have relied on designs where participants can reflect on emotional images they are viewing. In the current study, we examined if time perspective manipulations would similarly elicit positivity effect patterns in younger adults using an emotion-attention task with rapid stimuli display. Across two experiments (N = 236 and N = 431), we found that time perspective had no influence on biases toward positive over negative emotional stimuli in younger adults. We instead found effects driven by time-related trait biases. We discuss these results as they relate to theories about mechanisms underlying the positivity effect and in the way that time-related biases may change the way individuals perceptually prioritize positive and negative information.

Agitation is a common, distressing and difficult-to-treat symptom in dementia, linked to emotional dysregulation and interpersonal stress. Degenerative and compensatory changes in the locus coeruleus-noradrenergic (LC-NA) system have been implicated in agitation in Alzheimer’s disease. However, neuropathology alone does not fully explain why some individuals are more prone to agitation than others. We explore how premorbid mentalizing capacity (the ability to understand one’s own and others’ mental states) in both care recipients and caregivers may influence agitation propensity. Mentalizing, rooted in early attachment experiences, supports emotion regulation but may be compromised under stress in the context of neurodegeneration and neuropsychiatric symptoms, and this could increase the likelihood of escalation of care. We propose a neurorelational framework for understanding and addressing agitation, integrating neurobiological and socio-emotional perspectives. Targeting both care recipients’ LC-NA system and caregivers’ mentalizing capacity may represent a personalized intervention strategy to mitigate effects of neurodegeneration on ‘neuropsychiatric reserve’.

How aging affects brain-body connections can be investigated through changes in the coupling between functional magnetic resonance imaging (fMRI) signals and bodily autonomic processes across the adult lifespan. Recent studies using univariate approaches have identified age-related changes in the association between fMRI signals from multiple individual brain regions and low-frequency respiratory and cardiac activity. Here, we investigate if whole-brain spatial fMRI patterns associated with low-frequency physiological processes (heart rate and respiratory volume fluctuations) present generalizable changes with age. Data from human participants of both sexes are included in the analysis. We find that chronological age can be predicted statistically beyond chance from patterns of low-frequency fMRI-physiology coupling, even after accounting for individual differences in physiological signal characteristics and brain anatomy. Notably, brain areas implicated in central autonomic regulation, including nodes within salience and ventral attention networks (e.g., insula and middle cingulate cortex), are amongst the strongest contributors to age prediction. Further, we observe that after removing physiological effects from fMRI data, the residual blood oxygen level-dependent (BOLD) signal variability is still a reliable indicator of age. Together, these findings underscore the close integration between brain and body physiology, and highlight this interaction as a potential biomarker of the aging process.

BackgroundLow frequency oscillations in blood-oxygen-level-dependent signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs shed light on cerebrovascular dysfunction and preclinical Alzheimer's disease, but the mechanisms remain unclear. No investigations have assessed the relationship between BOLD-LFOs and plasma pTau217, or how it differs in apolipoprotein ε4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD.ObjectiveTo study the relationship between BOLD-LFOs and plasma p-Tau217 in APOE4 carriers compared to non-carriers.MethodsIndependently living older adults (N = 118) were recruited and underwent resting-state fMRI and venipuncture. BOLD-LFOs were quantified as signal power within the 0.01-0.10 Hz frequency range. Plasma pTau217 was assessed and linear regression quantified the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau217. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.ResultsThe interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau217 (β = -0.78, p = 0.001). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau217 in APOE4 carriers (β = -0.57, p = 0.0007). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (-) APOE4 carriers (p = 0.008) and amyloid-β (+) non-carriers (p = 0.03). Models were adjusted for age, sex, vascular risk factors, and total intracranial volume.ConclusionsFindings suggests BOLD-LFOs are implicated in preclinical AD in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.

The neurovisceral integration model posits that the reciprocal interaction between the amygdala and prefrontal cortex (PFC) influences heart rate variability (HRV) and emotion modulation. Emerging evidence also suggests that HRV influences brain regions involved in emotion regulation. Building on previous functional magnetic resonance (fMRI) studies, the present study aimed to provide neuroanatomical evidence by employing structural covariance analysis to examine the effects of HRV biofeedback intervention on the structural covariance between the amygdala and cortical regions. Investigating the covariation between the amygdala and cortical regions during a biofeedback intervention can provide insight into how HRV regulatory attempts influence neural structures involved in HRV and emotion regulation. Baseline and post-intervention MRI scans were collected from 151 participants (100 younger and 51 older adults) who completed 5 weeks of daily biofeedback sessions to either increase (Osc+ condition) or decrease (Osc- condition) HRV. Across both age groups, the two intervention conditions were associated with opposing patterns of structural covariance between the right amygdala and the left medial prefrontal cortex (mPFC). In the Osc+ condition, volume changes in the left amygdala showed an inverse association with volume changes in the right orbitofrontal cortex (OFC), while no association was observed in the Osc- condition. These findings provide support for the neurovisceral integration model perspective that the PFC exerts inhibitory influence over subcortical structures and that HRV influences brain regions involved in emotion regulation.

Numerous studies have reported brain correlates of autonomic activity. However, ambiguity exists regarding whether those correlates reflect receiving or sending out autonomic signals. Additionally, little is known about how emotion and aging interact with brain-autonomic coordination. Based on time-varying heart rate variability (HRV) and blood oxygenation level dependent (BOLD) data (N = 104 younger; N = 51 older adults), we found that insular and cingulate activity was negatively correlated with HRV during emotion regulation. We further examined the afferent and efferent nature of HRV-BOLD correlations during rest (N = 102 younger; N = 51 older adults). Functionally afferent regions where increased BOLD activity was associated with preceding decreases in HRV included the posterior insula, postcentral gyrus, and frontal pole. Functionally efferent regions where increased BOLD activity was associated with subsequent increases in HRV included the anterior insula and cingulate cortex. Information appeared to flow in one direction as the afferent regions' activity Granger-predicted the efferent regions' activity. Together, our findings suggest a feedback loop where decreased HRV increases the afferent regions' activity, which activates the efferent regions, leading to increased HRV. Aging appears to affect this system as the efferent and afferent regions scarcely overlapped in younger adults but overlapped in older adults.

Aging is the strongest known risk factor for Alzheimer's disease (AD), and elevated plasma amyloid-β (Aβ) levels in healthy adults are associated with increased AD risk. Aging is also associated with autonomic imbalance, characterized by increased sympathetic and decreased parasympathetic activity. In our previous randomized clinical trial, we found that four weeks of daily slow-paced breathing designed to enhance parasympathetic activity reduced plasma Aβ42 and Aβ40 levels in younger and older adults and showed a trend toward increasing Aβ42/Aβ40 ratio only in older adults. The primary goal of the current study was to extend these findings in 62 adults aged 50 to 70 years using randomized assignment to 10 weeks of slow-paced breathing or a random-paced breathing control with three assessment time points. Secondary objectives included examining the effects of slow-paced breathing on brain structure (i.e., perivascular space and hippocampal volumes) and cognitive performance. Consistent with prior findings, the slow-paced breathing group showed greater decreases in plasma Aβ42 than the control group. However, group differences were not significant for Aβ40 or Aβ42/Aβ40 ratios, and no significant effects were observed for the secondary outcomes. The non-significant findings may be due to changes we made to both intervention and control condition methods relative to our previous trial. Further research is needed to explore the underlying mechanisms and potential effects of slow-paced breathing on Aβ accumulation in the brain.

The neurovisceral integration model posits that the reciprocal interaction between the amygdala and prefrontal cortex (PFC) influences heart rate variability (HRV) and emotion modulation. Emerging evidence also suggests that HRV influences brain regions involved in emotion regulation. Building on previous functional magnetic resonance (fMRI) studies, the present study employed structural covariance analysis to examine the effects of HRV biofeedback intervention on the structural covariance between the amygdala and cortical regions. Investigating the covariation between the amygdala and cortical regions during a biofeedback intervention can provide insight into how HRV regulatory attempts influence neural structures involved in HRV and emotion regulation. Baseline and post-intervention MRI scans were collected from 151 participants (100 younger and 51 older adults) who completed 5 weeks of daily biofeedback sessions to either increase (Osc + condition) or decrease (Osc- condition) HRV. Across both age groups, the two intervention conditions were associated with opposing patterns of structural covariance between the right amygdala and the left medial prefrontal cortex (mPFC). In the Osc + condition, volume changes in the left amygdala showed an inverse association with volume changes in the right orbitofrontal cortex (OFC), while no association was observed in the Osc- condition. These findings are consistent with the neurovisceral integration model perspective that the PFC exerts inhibitory influence over subcortical structures and that HRV influences brain regions involved in emotion regulation.

BackgroundBlood pressure variability (BPV) is associated with neurodegeneration and cognitive decline independent of average pressure. The effect of parasympathetic central autonomic network (CAN) impairment on this relationship has not been assessed.ObjectiveDetermine whether parasympathetic CAN network function affects the relationship between BPV and neurodegenerative markers.Methods100 independently living older adults (55-89 years) underwent continuous blood pressure monitoring, neuropsychological testing, venipuncture, and brain MRI. Hippocampal volumes and entorhinal cortex thicknesses were assessed. Functional connectivity within a parasympathetic cardiovascular control network was used as a measure of parasympathetic CAN function. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were used as measures of glial and neuronal injury, respectively.ResultsElevated BPV was associated with left hippocampal atrophy (p = 0.03) and elevated plasma GFAP (p = 0.005) independent of age, sex, vascular risk factor burden, total intracranial volume (when applicable) and average blood pressure. These relationships were not mediated by parasympathetic central autonomic network impairment. Instead, parasympathetic CAN impairment conferred a vulnerability to elevated BPV. In participants with decreased parasympathetic CAN connectivity elevated BPV was associated with left entorhinal cortex atrophy (p = 0.0001), elevated plasma GFAP (p = 0.0001), elevated plasma NfL (p = 0.001), and memory impairment (p = 0.007).ConclusionsFindings suggest elevated beat-to-beat BPV is directly related to brain injury, and this effect is not mediated by CAN dysfunction. Instead, CAN impairment may confer a susceptibility to glial and neuronal injury in older adults with elevated beat-to-beat blood pressure variability. Mechanisms underlying increased susceptibility to BPV elevation in those with CAN dysfunction warrants further study.

The noradrenergic locus coeruleus and its neuromodulatory cortical projections are critical for adaptive behavior, yet their contributions to implicit learning in novel environments remain incompletely understood, due to challenges in non-invasive assessment. Here, we combined multimodal neuroimaging-including locus-coeruleus-sensitive structural MRI, concurrent pupillometry-fMRI, and PET-derived noradrenergic transporter maps-with repeated behavioral assessments to investigate noradrenergic contributions to implicit learning across younger and older adults (n = 77). Salient expectation-violating stimuli elicited pupil dilation, indicating enhanced neuromodulation, activated the action-mode network and deactivated the default-mode network. Pupil-linked BOLD responses suggested a functional coupling between the locus coeruleus and action-mode network, further supported by spatial overlap of activation patterns with PET-derived noradrenergic transporter maps. Locus coeruleus MRI-guided functional connectivity analyses demonstrated that locus coeruleus activity is coupled to anterior insula activation, suggesting a noradrenergic role in shifting cortical dynamics toward action-oriented processing. Behaviorally, participants implicitly learned the statistical task structure over time, as evidenced by reaction time adjustments based on stimulus probabilities. Critically, stronger locus coeruleus integrity, greater task-related anterior insula activation, and more pronounced pupil dilation were associated with enhanced implicit learning, highlighting the behavioral relevance of noradrenergic neuromodulation. Notably, noradrenergic responses and their link to learning were preserved across age groups, suggesting a robust noradrenergic role in supporting adaptive behavior throughout adulthood. These findings provide novel insights into the neuromodulatory mechanisms underlying learning and cognitive flexibility, emphasizing the pivotal role of locus coeruleus-action-mode network interactions in behavioral adaptation.

Cognitive reappraisal is a fundamental emotion regulation strategy for mental and physical well-being, but how its neural mechanisms relate to individual differences remains poorly understood. In a consortium effort analyzing 40 fMRI datasets ( N =2,175), we examined the relationship between neural activation during reappraisal tasks and three core individual difference indices of reappraisal capabilities: (1) trait questionnaires, (2) task-based affective ratings, and (3) amygdala down-regulation. Strikingly, there was no shared overlap across these three common indices. Only a very weak correlation emerged between amygdala down-regulation and task-based affective ratings. Whole-brain analyses revealed no reliable neural associations with trait questionnaires, and associations with task-based affective ratings fell outside canonical emotion regulation networks (e.g., prefrontal circuitry). Moreover, amygdala down-regulation, often interpreted as a stable individual marker, was confounded by person-specific whole-brain responses — a limitation extending to fMRI research beyond the emotion regulation domain. These findings challenge the assumption that an individual’s prefrontal activity is a valid indicator of their reappraisal capabilities and suggest that common trait, behavioral, and neural measures might capture distinct facets of emotion regulation. More broadly, our results highlight concrete methodological challenges for fMRI research on individual differences, with implications extending beyond emotion regulation to the neuroscience of personality, psychopathology, and general well-being. ### Competing Interest Statement The authors have declared no competing interest.

In addition to their more studied cognitive and motor effects, neurodegenerative diseases are also associated with impairments in autonomic function — the regulation of involuntary physiological processes. These autonomic impairments manifest in different ways and at different stages depending on the specific disease. The neural networks responsible for autonomic regulation in the brain and body have characteristics that render them particularly susceptible to the prion-like spread of protein aggregation involved in neurodegenerative diseases. Specifically, the axons of these neurons — in both peripheral and central networks — are long and poorly myelinated axons, which make them preferential targets for pathological protein aggregation. Moreover, cortical regions integrating information about the internal state of the body are highly connected with other brain regions, which increases the likelihood of intersection with pathological pathways and prion-like spread of abnormal proteins. This leads to an autonomic ‘signature’ of dysfunction, characteristic of each neurodegenerative disease, that is linked to the affected networks and regions undergoing pathological aggregation. Neurodegenerative disorders are commonly associated with autonomic dysfunction as well as the more well-known cognitive and motor effects. In this Review, Mather describes how properties of neurons in the brain and periphery regulating autonomic activity render them more vulnerable to prion-like spread of pathological protein and subsequent neurodegeneration.

Many studies of the human brain using functional magnetic resonance imaging (fMRI) lack physiological measurements, which substantially impacts the interpretation and richness of fMRI studies. Natural fluctuations in autonomic physiology, such as breathing and heart rate, provide windows into critical functions, including cognition, emotion, and health, and can heavily influence fMRI signals. Here, we developed DeepPhysioRecon, a Long-Short-Term-Memory (LSTM)-based network that decodes continuous variations in respiration amplitude and heart rate directly from whole-brain fMRI dynamics. Through systematic evaluations, we investigate the generalizability of this approach across datasets and experimental conditions. We also demonstrate the importance of including these measures in fMRI analyses. This work highlights the importance of studying brain-body interactions, proposes a tool that may enhance the efficacy of fMRI as a biomarker, and provides widely applicable open-source software.

Cerebrospinal fluid (CSF) transport is crucial for waste clearance and the maintenance of healthy brain function. Various factors, including respiration, have been proposed to drive CSF pulsation. Despite the close relationship between CSF movement and respiration, the impact of different slow respiratory frequencies on CSF oscillations remains unclear. Utilizing a fast neuroimaging technique, we investigated the effects of four different paced respiratory conditions on CSF oscillations. Our findings indicate that all paced respiratory conditions resulted in increased CSF oscillatory power and BOLD global signal amplitude, factors previously associated with increased CSF pulsations. Additionally, we observed that, compared to rest, paced sighing at the 0.02-0.03 Hz frequency range significantly increased the coupling between CSF oscillations and the negative derivative of the BOLD signal. Our study provides a novel perspective on how the frequency of breathing can influence CSF oscillations during wakefulness. Highlights:Breathing manipulations affect CSF oscillatory power during wakefulnessPaced sighing at frequency lower than breathing led to stronger dynamic between CSF and BOLDBreathing and sighing manipulations lower the BOLD signal proxy of arousal.

Healthy cognitive aging emphasizes preserving cognitive functions essential for independence and well-being. Developing interventions that promote cognition and resilience in older individuals is crucial. Social playfulness, characterized by spontaneity and mutual enjoyment, allows individuals to step away from routine roles and engage in novel and surprising exchanges. Emerging evidence suggests that social playfulness is a promising approach for supporting cognitive functions in aging in a joyful and engaging way. In this theory and hypothesis manuscript, we propose a neurobiological pathway mediating the effects of social playfulness on cognition. Playful interactions generate high levels of uncertainty, requiring continuous adaptation and exploration. We suggest that these demands engage the locus coeruleus-noradrenaline (LC-NA) system, which is crucial for navigating uncertainty and sustaining arousal and flexibility needed to adapt to the dynamic and unpredictable nature of playful interactions. Importantly, the collaborative and safe environment of playfulness transforms this uncertainty-driven noradrenergic activation into an engaging and rewarding experience, enhancing focus, positive affect, and flexibility. In older adults, where LC-NA functionality may decline with age, social playfulness could counteract cognitive decline by upregulating this system. We review evidence linking LC-NA integrity to cognitive health and explore how playfulness might mitigate the deterioration of cognitive functioning by training executive functions and promoting novelty and exploration. This framework bridges neuroscience, cognitive psychology, and creative-arts therapies, highlighting social playfulness as a tool for healthy aging. We emphasize the need for further research to validate this hypothesis and explore its implications for designing interventions that leverage social playfulness to enhance cognitive resilience in older populations.

Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampering the development of targeted preventative interventions. In this study, we acquired electrophysiological, pupillometric, and behavioral measures in a passive and active auditory oddball paradigm to test the hypothesis that cognitively healthy older adults experience tonic LC hyperactivity. We leveraged the LC-NA system’s role in arousal regulation and manipulated state arousal and noradrenergic activity using the unpredictable threat of electric shock. Based on older adults' hypothesized tonic LC hyperactivity, we predicted that increased arousal would evoke weaker phasic (stimulus-evoked) noradrenergic responses in older adults compared with young adults. Consistent with this hypothesis, arousal differentially modulated behavioral responses and resting-state alpha power across age groups, and older adults showed smaller pupil dilation responses than young adults. Furthermore, linear mixed models revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors across age groups, with older adults exhibiting less behavioral slowing and longer P300 latency delays under threat of shock than did young adults. Together these findings provide convergent multi-modal evidence that aging is associated with tonic LC-NA system hyperactivity in humans, with consequences for mechanisms supporting attentional control. This research highlights the utility of non-invasive physiological markers to determine when across the adult lifespan the LC-NA system becomes hyperactive and to identify adults who may be at elevated risk for neurodegenerative progression due to emerging changes in LC-NA system function.