International Journal of Psychophysiology

BackgroundAutonomous sensory meridian response (ASMR) and music-induced frisson are sensory-affective phenomena characterized by tingling, chills, and pronounced emotional responses. Previous research has mainly focused on physiological changes during these experiences, whereas much less is known about whether baseline physiological state is associated with subsequent susceptibility. ObjectiveTo examine whether baseline autonomic flexibility, indexed primarily by heart rate variability (HRV), is associated with later ASMR/frisson responsiveness. Resting EEG measures were included as secondary exploratory markers. MethodsFifteen participants were recruited by convenience sampling; after artifact-based exclusion, 10 participants were included in the analyses. A 5-minute resting baseline EEG and ECG was recorded prior to stimulus presentation. Participants were then exposed to auditory and audiovisual ASMR stimuli, classical music excerpts, and a control stimulus, and reported whether they had experienced ASMR-typical sensations or frisson. Main analyses examined associations between baseline physiological parameters and a combined response-positive outcome. Exploratory analyses included participant-level correlations, comparisons between susceptible and non-susceptible participants, and stimulus-specific effect sizes. ResultsHRV-related measures showed the clearest and most consistent pattern of association with responsiveness. Higher baseline total HRV power was associated with a greater number of response-positive stimuli (r = 0.756, p = 0.011), with similar positive associations for high-frequency HRV (HF; r = 0.672, p = 0.033) and baseline heart rate slope (r = 0.751, p = 0.012). Stimulus-specific analyses likewise showed the most consistent positive baseline effects for total HRV power, with HF and heart rate slope pointing in the same direction. Frontal alpha asymmetry (FAA) was negatively associated with responsiveness ({rho} = -0.862, p = 0.001), but EEG findings overall were less consistent than the HRV-related pattern and are best interpreted as secondary exploratory observations. ConclusionsIn this exploratory pilot sample, baseline HRV, particularly total HRV power, showed the most coherent physiological association with susceptibility to ASMR and music-induced frisson. The findings are consistent with the possibility that these experiences depend not only on stimulus properties, but also on pre-existing physiological state. Given the small sample and exploratory design, the results should be interpreted as hypothesis-generating and require replication in larger confirmatory studies.

Mental imagery is known to be accompanied by autonomic responses, traditionally viewed as merely downstream consequences of imagery. Recent theoretical work has challenged this view, proposing that mental imagery requires the integration of cortical sensory representations with ascending interoceptive signals supplied by the autonomic nervous system. These two views make opposite predictions: if autonomic activity is only a consequence of imagery, then the responsiveness of the autonomic nervous system should not predict imagery vividness. If instead autonomic input shapes the generation of mental images, individuals with greater autonomic responsiveness should experience more vivid imagery. The present study tested these competing predictions by examining whether individual differences in cardiac vagal reactivity (indexed by the magnitude of HRV change in response to a paced breathing manipulation) predict self-reported visual imagery vividness. Imagery vividness was assessed using the Vividness of Visual Imagery Questionnaire (VVIQ) at a separate time point from the paced breathing protocol, ensuring that any observed relationship between cardiac vagal capacity cannot reflect autonomic activation driven by imagery itself. The key result was that cardiac vagal reactivity (indexed by RMSSD change normalized by mean R-R interval), significantly predicted higher VVIQ scores (r = .30, p = .031). These findings demonstrate that vividness of mental imagery is not exclusively central in origin but also shaped by the capacity of the autonomic nervous system to enter a high-parasympathetic state. Imagery thus likely involves bidirectional autonomic-cortical interaction, with descending pathways triggering the intention to generate an image and ascending interoceptive signals contributing to its generation.

Emotions often occur within social interactions where affective cues are accessible or inferable by others. This raises questions regarding how and to which degree social context modulates subjective, physiological and behavioural affective responses, as well as their coherence, questions which remain points of tension in emotion research. To investigate this, we measured subjective affective ratings, autonomic sympathetic and parasympathetic activity, and facial behaviour while participants completed an emotion-induction task. In the social-context condition (but not control), participants believed that their video feed was accessible to a potential future interaction partner. Results show that even such "minimal social context" selectively and differentially modulated affective response modalities, characterised by both intensification of autonomic responses and dampening of overt facial and subjective affect. Multivariate dimensionality analysis further identified a cross-modal affective dimension Interestingly, social context reduced participants coupling with this shared affective response structure, indicating weaker cross-modal coherence. These findings suggest that emotional responding relies on a flexible, rather than rigid, configuration of affective features, likely recruited to meet the socioemotional demands of a given context. This has important implications for understanding the structure and function of emotion, as well as typical and atypical socioemotional responding.

For methodological reasons, reward processing is commonly studied using random feedback and unlearnable tasks. It remains unclear whether task learnability influences reward-related brain activity, and whether this effect depends on individual differences such as reward responsiveness. We addressed this question by administering a behavioural activation system (BAS) scale before recording electroencephalography (EEG) while participants completed learnable and unlearnable versions of the "doors" task, a standard two-choice paradigm. Despite matched outcome likelihoods across conditions, participants reported greater motivation, enjoyment, and perceived performance in the learnable task. Contrary to our predictions, the amplitude of the reward positivity (RewP) - a frontocentral ERP index of reward processing - did not depend on task learnability and reward responsiveness. However, learnability and reward responsiveness effects became apparent when the analysis was restricted to high performers. Within this subgroup, participants low in reward responsiveness showed an enhanced RewP when the task was learnable. These findings suggest that contextual factors such as task learnability can interact with individual differences, informing ongoing efforts to identify the RewP as a biomarker of disordered reward processing.

Our responses to environmental inputs depend on the variations of our own physiological activity. However, the mechanisms by which the integration of sensory information with interoceptive signals shape bodily responses to external events remain debated. In this pre-registered study, we hypothesized three possible mechanisms underlying such exteroceptive-interoceptive integration: cardiac surprise, active inference, and dynamic coupling. To test them, we implemented a closed-loop stimulation procedure to play auditory deviations from sequences either synchronized or not with heartbeats which varied in type (omissions or rare tones) and predictability (random or regular intervals). First, we replicated previous findings that cardiac activity slows down in response to sound omissions only when sounds are synchronized with heartbeats. Second, we showed that this effect extends to rare tones, excluding the dynamic coupling hypothesis. Third, we demonstrated that these responses do not depend on the predictability of auditory deviations, excluding both cardiac surprise and active inference hypotheses. In a control experiment, we further observed that behavioral responses depend on the type and predictability of auditory deviants: participants can discriminate subjectively which sounds were synchronized with their own heartbeats without evidence of a relationship to interoception nor cardiac responses. Overall, these results demonstrate that auditory deviations slow down cardiac responses when locked to heartbeats but independently from their type and regularity, calling for novel hypotheses to account for the interoceptive-exteroceptive integration of sensory signals into cardiac activity. Impact statementUsing a cardio-audio synchrony task, we show that cardiac responses slow down upon heartbeat-locked auditory deviations independently from their type or regularity, suggesting a simple, fundamental mechanism of integration of internal and external signals into bodily responses to the environment. The heart may provide a straightforward way to study basic self-related processes, without depending on behavior or self-report, which is especially valuable for individuals who are unable to respond or communicate.

Flow, as defined by Mihalyi Csikszentmihalyi (1975), is a holistic sensation experienced when individuals are fully immersed in an activity, resulting in a mental state characterized by a diminished sense of self and altered perception of time. To investigate the global neural dynamics underlying flow, we employed EEG microstate analysis to capture the spatial and temporal properties of dominant transient global brain states (Lehmann et al., 1998). In a study involving 43 participants playing the video game Thumper for 25 minutes, we extracted three four-minute EEG segments from each session corresponding to reported experiences of flow, boredom, and frustration, as determined by self-reports and performance metrics. Across conditions, six distinct microstate topographies (A-F) accounted for most of the global variance. Given that reduced self-referential processing is a key feature of flow, we hypothesized that flow would modulate the properties of microstates C and E, which have been associated with brain regions resembling the default mode network (DMN). Compared to boredom and frustration, the flow condition showed significantly decreased global explained variance, mean duration, time coverage, and occurrence frequency of microstate E, as well as reduced mean duration and time coverage of microstate C. These findings suggest that microstates associated with self-referential processing are shorter and less frequent during flow than during boredom and frustration. This supports the notion that the flow experience modulates global brain dynamics, particularly within the DMN. Furthermore, our results align with previous research reporting reduced DMN activity during meditative and psychedelic states, reinforcing the idea of diminished self-awareness in such conditions.

Stressors are commonly used in rats to induce models of anxiety or depression. The effectiveness of these stressors is often evaluated using specific behavioural tests. In a previous meta-analysis of chronic variable stress (CVS) procedures, we predicted that longer and more intensive stress procedures would result in larger effect sizes in behavioural tests. However, we found that the duration or intensity of CVS procedures did not correlate strongly with the magnitude of the effect sizes reported in behaviouraltests. In that study, we were concerned that the large and unexplained diversity in CVS procedure design, both in terms of duration and the types of stressors used, made it challenging to detect the factors that were influencing effect size. In an effort to address this, we explore here the use of a much simpler stress procedure - chronic restraint stress (CRS) - to study the relationship between the duration of CRS procedures and the effect sizes obtained in subsequent behavioural tests. We searched PubMed for articles using CRS procedures with rats, systematically documented the total duration of restraint, and carried out a meta-analysis of the effect sizes obtained in four behavioural tests: the forced swim test (FST), the sucrose preference test (SPT), the elevated plus maze (EPM) and the open field test (OFT). We found that chronic restraint stress increased immobility in the FST, decreased sucrose preference in the SPT, decreased time spent in the open arms of the EPM but had no effect on time spent in the centre of the OFT. However, the effect sizes in all behavioural tests, except the SPT, were not moderated by the duration of the CRS procedure, indicating that longer CRS procedures are associated with larger effect sizes in the SPT but not in the FST or EPM.

The identification of objective, dimensional indices of mental health is of central importance in the pursuit of transdiagnostic multi-dimensional frameworks of psychopathology. Altered visual processing occupies a specific domain of interest and motivated the present investigation aimed to quantify the visuocortical impact of affective naturalistic distractor cues on limited capacity attentional resources in obsessive-compulsive disorder (OCD). The current investigation examined the extent to which attentional resources are allocated toward task cues under affective and disorder-relevant distraction in participants with OCD (N = 33) and control participants (N = 31). Steady-state visual evoked potentials (ssVEPs) in response to task-relevant cues were examined using a foreground task where participants detected coherent motion in a flickering random dot kinematogram (RDK) overlaid on naturalistic distractor pictures ranging in emotional content (pleasant, neutral, unpleasant, and OCD-evoking pictures). Amplitude envelopes of ssVEPs in response to the motion stimulus served as an index of visuocortical engagement with task-relevant cues. Data were also fitted to the distraction under competition model (DUC), a computational framework of attention selection. Group differences emerged with stronger visuocortical competition effects (attenuated task engagement) for the OCD group, driven largely by the unpleasant pictures, followed by the OCD-evoking pictures. Furthermore, the DUC model fit well in both groups, demonstrated the dominance of the visuocortical competition observed in response to the unpleasant pictures, and revealed the presence of substantial competition in response to the OCD-evoking pictures in the OCD group.

Pleasurable urge to move to music is often referred to as groove. Although previous studies have shown an association between the supplementary motor area (SMA) and the groove experience, its causal role remains unclear. Here, we investigated whether the SMA is causally involved in groove experience during music listening using repetitive transcranial magnetic stimulation. Fifteen healthy participants completed three sessions on separate days: excitatory stimulation (intermittent theta burst stimulation; iTBS) over the SMA, inhibitory stimulation (continuous theta burst stimulation; cTBS) over the SMA, and sham stimulation (iTBS or cTBS) over the vertex. After each stimulation session, participants listened to five high-groove and five low-groove musical excerpts and rated urge-to-move and pleasure on a 0-100 scale. Heart rate was additionally recorded as an exploratory physiological measure during music listening. Linear mixed-effects models (LMM) showed that pleasure ratings, but not urge-to-move ratings, were higher following both iTBS and cTBS compared with sham stimulation. In exploratory LMMs, reduced log-transformed heart rate variability (HRV) significantly predicted higher pleasure ratings. These findings suggest that SMA stimulation modulates the pleasurable component of the groove experience, likely via network-level mechanisms rather than a simple linear relationship between SMA excitability and pleasure. They also raise the possibility that reduced parasympathetic activity, reflected by lower HRV, mediates the stimulation-related increase in musical pleasure. Future studies should investigate the causal roles of other brain regions as well as clarify the directionality between autonomic changes and the groove experience.

AimsDue to the multifaceted nature of "impulsivity", its measurement remains fragmented. Here, we developed the Risky Social Choices task to provide evidence for its validity and reliability, while testing the hypothesis that impaired access to implicit knowledge of negative long-term consequences is of distinct importance for "impulsive" decision-making in a general population sample. MethodsForty participants chose whether to engage in risk-taking behaviors, which combined web-based AI-generated videos with narrated hypothetical scenarios and measured worries related to negative long-term consequences, approach-related motivation for short-term rewards, response time to and accuracy of recognizing degraded auditory prime words denoting negative long-term consequences. ResultsA pre-registered multi-step regression model was constructed with worry, motivation, response time and accuracy as predictors and percentage of risky choices as the outcome. Among all predictors, only prime word recognition accuracy was significantly negatively associated with risky choices, confirming our hypothesis of the role of reduced implicit access to negative long-term consequences in risk-taking decisions. In contrast, approach-related motivation for rewards was the only predictor significantly positively related to percentage of risky choices. DiscussionAs predicted, the negative association between risky choices and implicit access to negative long-term consequences supports its role as a distinct aspect of "impulsivity". The novel task successfully captured this aspect, paving the way for a more precise neurocognitive characterization of clinical conditions where "impulsivity" plays a key role. The findings unveil the importance of implicit social sequential knowledge for impulsivity in neurotypical populations, so far only investigated in patients with brain lesions.

Abstract Background: Biological systems exhibit dynamic patterns over multiple temporal scales -from minutes to months- that are poorly captured by conventional cross-sectional or low-frequency longitudinal studies. These patterns, including circadian and ultradian rhythms, may be critical determinants of health, resilience, and disease risk in aging. Existing longitudinal studies in older adults lack high-frequency, multimodal measurements that integrate molecular, physiological, and digital health data streams. Objectives: The TIME Study aims to: (i) Characterize temporal patterns in molecular, physiological, and digital health measures in healthy older adults; (ii) determine how these patterns vary across biological domains and relate to each other; and (iii) assess how physiological systems respond to defined perturbations (oral glucose tolerance and maximal exercise). Methods: TIME is a single-site, observational, longitudinal study enrolling up to 150 adults aged [≥] 55 years. Over an 11-week main phase, participants complete seven weekly low-frequency visits, two perturbation challenge visits, and two, two-day high-frequency sampling epochs. Biospecimens, clinical measures, cognitive and physical performance tests, and continuous digital health data are collected. Follow-up visits occur at 6 and 12 months. Expected Impact: By integrating multimodal, temporally resolved data, TIME will provide a foundational dataset for understanding the role of biological rhythms in aging and inform future precision health strategies.

Summary paragraphA hallmark of learning is the need for sensory stimuli (Ginns, 2015; McGraw et al., 2009; Reinwein, 2012; Spence, 1950) so that learning is fundamentally based on sensory input signals affecting behaviour, physiology, and neurology. If behavioural measures of learning can be causally linked to physiological and neurological variables, a broader understanding of the mechanisms related to learning in schools, learning disabilities, and learning and health issues may emerge (McGraw et al., 2009). Despite decades of research on the physiological/neurological variable of sympathetic activation, learning, and achievement (Horvers et al., 2021), any causal relation remains unclear (Cowley et al., 2014; Mason et al., 2020; Pijeira-Diaz et al., 2016; Sung et al., 2023; Yu et al., 2024) and issues with instrument validation remain (Costantini et al., 2023; Hu et al., 2024; Milstein & Gordon, 2020; Van Der Mee et al., 2021). Here we investigate the effect of sensory input on sympathetic activation by using validated instruments for skin conductance measurement (Batista et al., 2019) and whether sympathetic activation is connected to learning in a cognitive laboratory context and an ecologically valid classroom context. In both contexts, we found a physiological variable which correlated with learning and that sensory input affected this variable while student movement did not. These sensory inputs varied depending on the different instructional activities the students participated in. Together, these findings bring us one step closer to a model linking sensory input to behavioural, physiological, and neurological variables.

Mental fatigue is induced by prolonged engagement in cognitively demanding tasks and impairs endurance performance. The neuropsychophysiological mechanisms underlying this decreased performance remain unclear, with suggestion that mental fatigue may disrupt motor command and consequently muscle activation. We aimed to test this hypothesis in a repeated cross-over design study in which 18 participants completed two experimental sessions involving a time-to-exhaustion cycling test at 80% of peak power output. Each cycling task was preceded by 1h of a prolonged Stroop task (Stroop session) or a neutral control task (Control session). Perception of effort and surface electromyography from ten lower-limb muscles of the right leg were recorded at regular intervals during cycling. Mental fatigue was higher in the Stroop compared to the Control session (p = .002). Endurance cycling time was 111 {+/-} 160 s shorter in the Stroop than in the Control session (p = .009). No significant differences in electromyography parameters were observed between Stroop and Control sessions, for any muscle (p > .05). Perception of effort was higher in the Stroop session from the onset of the cycling task (p = .006), and the rate of increase in perception of effort was significantly higher in the Stroop than Control session (p = .031). Our findings do not support the hypothesis that mental fatigue alters motor control or increases central motor command, as no changes in muscle activation were detected. Conversely, our results reinforce the notion that prolonged cognitive engagement impairs endurance performance primarily through an increased perception of effort. Future research should consider combining surface electromyography with more sensitive neurophysiological techniques to investigate potential subtle changes in motor drive during dynamic, whole-body tasks under mental fatigue. Impact statementOur study confirms that mental fatigue induced by prolonged cognitive exertion impairs cycling endurance performance. By combining measurements of perceptual responses and multi-muscle surface EMG during the endurance task, we observed that the decreased endurance performance is related to an increased perceived effort in the presence of mental fatigue, not related to alterations in motor command.

Exercise is a positive health behaviour associated with improved mood. However, the mechanisms underlying the benefits of exercise on affective health are unclear, particularly with respect to type of exercise and sex. Chronic exercise decreases neuroinflammation, which is linked to improvements in mood and anxiety. However, exercise is also a physiological stressor that can transiently upregulate systemic inflammation, and its effects on neuroinflammation are not well understood. This study examined how acute and chronic exercise affect circulating and brain cytokine levels and anxiety-related behaviour in young healthy male and female mice. In Experiment 1, mice were placed on a treadmill for a two-hour bout of moderate exercise. Two hours after exercise, animals were either tested in the open field or euthanized for measurement of cytokines (IL-1{beta}, TNF, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IFN-{gamma}, KC/GRO). In Experiment 2, mice underwent an 8-week moderate treadmill exercise paradigm followed by open field testing and tissue collection. Acute exercise decreased time spent in the centre of the open field in males only, suggesting increased anxiety-like behaviour in males. Acute exercise increased IL-6 and decreased TNF in serum, and increased amygdala principal component 1 (loading IL-12p70, IL-10, IFN-{gamma}, and TNF) in both sexes. Chronic exercise increased open field centre entries, increased IL-6 in the prefrontal cortex, decreased TNF in the dorsal hippocampus, and had minimal effects on circulating cytokines in both sexes. These results demonstrate that the effects of exercise on anxiety-related behaviour and cytokine levels depend on recurrence, tissue, and brain region. New & NoteworthyOur work highlights the contrast between anxiogenic and anxiolytic effects of acute versus chronic exercise, respectively, in healthy mice. Acute and chronic exercise differentially affected circulating and brain cytokines, providing insight into physiological adaptations to exercise. Both sexes demonstrated similar cytokine responses to exercise. These similarities are novel with respect to exercise research and noteworthy given sex differences in anxiety with respect to acute exercise.

Historically, neural variability observed during task was interpreted as "noise," assumed to obscure meaningful signal and thus something to be minimized both analytically by researchers and functionally by the brain. Changes to this signal-to-noise ratio have been proposed as a possible neural mechanism behind the increased reaction-time variability (RTV) in attention deficit hyperactivity disorder (ADHD). However, not all variability is the same - in some cases, variability can have some underlying "statistical structure" that can be beneficial to information processing. The challenge lies in distinguishing meaningful variability from random noise. The edge-of-synchrony critical point, which describes a system poised between synchronous and asynchronous regimes, could be a good theoretical framework to study these different types of neural variability. In this study, we investigate whether changes in criticality and oscillatory dynamics preceded slower behavioral responses during a bimodal continuous performance task in ADHD. We find evidence that, prior to slower responses, neural dynamics shift toward criticality in both ADHD and control groups, suggesting that increase variability in ADHD and during attention lapses are related to structured variability and not necessarily random noise. Notably, these findings run counter predictions based on the proposed model and previous literature on neural noise in this population, challenging predictions of edge-of-synchrony criticality as a unifying account of neural variability and behavioral performance. Furthermore, this effect did not emerge at the between-subject level, underscoring the limitations of relying on between-subject correlations to infer neural mechanisms. Impact StatementOur findings add new perspective to the hypothesis that links neural variability to reaction time variability in adults with and without ADHD. We found that neural dynamics shift towards criticality prior to slow reaction times in adults with and without ADHD, but in ADHD, dynamics lie closer to criticality regardless of response type, suggesting a different "attractor" state.

BackgroundVitamins are important modulators of intestinal health and may affect the gut-brain axis through microbial metabolites such as short-chain fatty acids (SCFAs). However, the neurocognitive effects of colon-delivered vitamins in older adults remain unexplored - a critical gap given the gut-brain axiss emerging role in cognitive aging. ObjectiveWe investigated the effect of a colon-delivered multivitamin (CDMV) supplement on intestinal health and neurocognitive outcomes in older adults at risk of cognitive decline. MethodsWithin the double-blind randomized placebo-controlled trial COMBI (ClinicalTrials.govID: NCT05675007), we included 75 older adults (60-75 years) at risk of cognitive decline based on lifestyle-related factors. Participants consumed a colon-delivered capsule with vitamins B2, B3, B6, B9, C and D3, or a placebo, daily for six weeks. Pre- and post-intervention, we employed neuroimaging, feces- and blood collection. Primary outcomes were fecal SCFA concentrations, working memory (WM)-related fMRI responses, and WM performance measured with the n-back task. ResultsAfter adjusting for baseline values, we found no significant between-group differences in total fecal SCFA levels (p=0.30) and WM performance (p=0.50). Post-intervention WM-related fMRI responses in the hippocampus (p=0.01; p{superscript 2}=0.09) and dorsolateral prefrontal cortex (dlPFC) (p=0.06; p{superscript 2}=0.04), driven by the right dlPFC (p=0.02), were higher in the CDMV group compared to placebo. Independent of intervention group, post-pre increases in fecal SCFA levels were significantly correlated to increases in dlPFC fMRI responses ({rho}=0.31; p=0.02) and WM performance ({rho}=0.43; p=0.001). ConclusionsOur findings suggest that CDMV supplementation increases WM-related responses of the dlPFC and hippocampus in older adults, but this effect was not accompanied by changes in fecal SCFA levels or WM performance. The positive correlation of within-subject changes in fecal SCFAs with changes in WM dlPFC responses and performance across intervention groups provides human evidence for gut-brain communication in cognitive aging beyond cross-sectional associations.

Reaction time is a measure of the speed of our response to stimuli in the environment. Even for a well-trained task, a subjects reaction time varies. One source of this variability is internal state fluctuations (such as changes in arousal). There are few studies that systematically quantify the extent to which reaction time varies across different timescales and link this to measures of systemic physiology associated with arousal. In much of the literature, it is assumed but not demonstrated that behavioral and systemic measurements associated with arousal will be consistently linked because both estimate a common underlying arousal process. In this work, we examined this assumption by simultaneously measuring reaction time, heart rate, and pupil diameter in rhesus macaque monkeys performing several visual tasks over hours and across hundreds of sessions. We found a portion of the variability in reaction time could be linked to systemic physiological signatures of arousal on fast timescales from second to second and slower timescales from minute to minute. This link between reaction time and systemic physiology was also present for different biomarkers of arousal (heart rate and pupil). However, the strength of this relationship varied depending on the arousal biomarker. Our findings support the conclusion that there are multiple arousal mechanisms that act simultaneously to influence behavior and multiple timescales at which they operate.

Alzheimers disease (AD) is characterized by the mis-aggregation of amyloid {beta} (A{beta}) and tau, which is proposed to be driven by impaired A{beta} and tau clearance. While sleep-active glymphatic transport contributes to the clearance of A{beta} and tau in humans, studies have yet to demonstrate that it is possible to enhance glymphatic transport in humans and that augmenting glymphatic transport improves the clearance of A{beta} and tau from the human brain. In two cross-over clinical trials in healthy older adults, we demonstrated that a fixed-dose combination therapy of intravenous dexmedetomidine (0.7 g/kg/h) and 10 mg oral midodrine (ACX-02), that suppressed central noradrenergic tone while maintaining systemic arterial pressure, increased EEG slow waves, enhanced cerebrovascular pulsatility, and reduced parenchymal resistance to perivascular fluid flow, that have shown to be key determinants of glymphatic transport. Dynamic shifts in plasma mass balance indices of clearance within the brain demonstrated that pharmacological enhancement of glymphatic transport increased A{beta} and tau clearance by approximately 9%-10% during a single 4h 15min sleep opportunity. Bayesian mediation analysis demonstrated that increasing EEG slow waves and declining parenchymal resistance were key mediators, and cerebrovascular compliance was a moderator, of the effect of ACX-02 on plasma AD biomarker dynamics. These findings demonstrate that pharmacologic enhancement of glymphatic transport increased brain-to-blood clearance of A{beta} and tau in human participants. This suggests that enhancement of A{beta} and tau clearance may serve as a complementary approach to existing disease-modifying therapies, and as a therapeutic approach in AD and AD-related proteinopathies.

To evaluate whether hemodynamic responses to acute cognitive stress, measured via pulse-wave harmonic analysis, can characterize cardiovascular regulatory coherence and differentiate older adults with mild cognitive impairment (MCI) from cognitively intact individuals, this exploratory cross-sectional observational study utilized a within-session pre-post cognitive task design. A total of 101 community-dwelling older adults in southern Taiwan were stratified by Montreal Cognitive Assessment (MoCA) scores into Reference (MoCA [&ge;]26; n=12, paired n=10), MCI (MoCA 18-25; n=50, paired n=45), and dementia-level (MoCA <18; n=39) groups, the latter being excluded from task-evoked analyses. The primary outcome was the Harmonic Response Consistency Score (HRCS), quantifying the directional uniformity of cardiovascular regulatory responses, alongside secondary measures of harmonic amplitudes (Cn) and phase angles (Pn). Although mean pre-post changes were subtle, response organization differed by cognitive status. The Reference group exhibited high response consistency (mean HRCS = 9.00), characterized by coordinated harmonic down-modulation. Conversely, the MCI group showed attenuated, directionally heterogeneous responses. Compared to the Reference group, the MCI group demonstrated significantly lower HRCS values for the Cn domain (Mean difference: 2.60, 95% CI 0.29-4.91; p=0.020) and PnSD domain (Mean difference: 1.98, 95% CI 0.04-3.92; p=0.030), indicating a breakdown in regulatory coherence. These findings suggest that acute cognitive stimulus reveals coherent harmonic down-modulation in cognitively intact older adults but fragmented responses in MCI. Pulse-harmonic profiling thus serves as a robust physiological index of cardiovascular regulatory coherence, which, when integrated with neuropsychological assessments, may enhance the sensitivity of non-invasive, community-based screening frameworks for early cognitive aging.

Singing is an innate human behaviour present across cultures and the lifespan. Despite lacking direct biological advantages, its ubiquity suggests that it is intrinsically rewarding. This research aimed to investigate the underlying factors that explain variability in sensitivity to deriving reward and enjoyment from natural singing in the general population. In Study 1 (n = 606), an initial pool of items describing daily, non-professional singing behaviours were administered to an international adult sample. Exploratory factor analysis revealed a unidimensional structure of 20 items with acceptable model fit, organized into five facets representing distinct domains of singing-related rewards: 1) pleasure and emotional evocation, 2) social singing reward, 3) singing frequency, 4) mood regulation through singing, and 5) inattentional singing during routine tasks. In Study 2 (n = 430), confirmatory factor analysis in a new sample supported this structure. When both samples were combined (n = 1036), the unidimensional model defined by these five facets showed acceptable to excellent goodness-of-fit indices, supporting the conceptualization of singing reward as a multidimensional construct with differentiated facets. This led to the Barcelona-Aarhus Natural Singing Engagement Questionnaire (BANSEQ), which demonstrated excellent reliability ( = .94) and population-level stability. Study 3 (n = 1036) tested the convergent validity of BANSEQ with measures of music reward and engagement and identified sociodemographic and psychological correlates across the five facets of singing reward. Overall, these findings characterize the sources of individual differences in the hedonic experience of natural singing and propose BANSEQ as a robust psychometric tool for its assessment in the general population.