Heart rate and breathing effects on attention and memory (HeartBEAM): study protocol for a randomized controlled trial in older adults.

BACKGROUND: In healthy people, the "fight-or-flight" sympathetic system is counterbalanced by the "rest-and-digest" parasympathetic system. As we grow older, the parasympathetic system declines as the sympathetic system becomes hyperactive. In our prior heart rate variability biofeedback and emotion regulation (HRV-ER) clinical trial, we found that increasing parasympathetic activity through daily practice of slow-paced breathing significantly decreased plasma amyloid-ß (Aß) in healthy younger and older adults. In healthy adults, higher plasma Aß is associated with greater risk of Alzheimer's disease (AD). Our primary goal of this trial is to reproduce and extend our initial findings regarding effects of slow-paced breathing on Aß. Our secondary objectives are to examine the effects of daily slow-paced breathing on brain structure and the rate of learning. METHODS: Adults aged 50-70 have been randomized to practice one of two breathing protocols twice daily for 9 weeks: (1) "slow-paced breathing condition" involving daily cognitive training followed by slow-paced breathing designed to maximize heart rate oscillations or (2) "random-paced breathing condition" involving daily cognitive training followed by random-paced breathing to avoid increasing heart rate oscillations. The primary outcomes are plasma Aß40 and Aß42 levels and plasma Aß42/40 ratio. The secondary outcomes are brain perivascular space volume, hippocampal volume, and learning rates measured by cognitive training performance. Other pre-registered outcomes include plasma pTau-181/tTau ratio and urine Aß42. Recruitment began in January 2023. Interventions are ongoing and will be completed by the end of 2023. DISCUSSION: Our HRV-ER trial was groundbreaking in demonstrating that a behavioral intervention can reduce plasma Aß levels relative to a randomized control group. We aim to reproduce these findings while testing effects on brain clearance pathways and cognition. TRIAL REGISTRATION: ClinicalTrials.gov NCT05602220. Registered on January 12, 2023.

Noradrenaline: Can we now directly measure in humans?

Measuring noradrenergic activity in the human brain has been limited to indirect assessments through pupillometry and scalp-recorded event-related potentials. A novel study has demonstrated the capability to directly measure sub-second noradrenaline dynamics using surgically implanted electrodes.

Bicyclist-evoked arousal and greater attention to bicyclists independently promote safer driving.

While attention has consistently been shown to be biased toward threatening objects in experimental settings, our understanding of how attention is modulated when the observer is in an anxious or aroused state and how this ultimately affects behavior is limited. In real-world environments, automobile drivers can sometimes carry negative perceptions toward bicyclists that share the road. It is unclear whether bicyclist encounters on a roadway lead to physiological changes and attentional biases that ultimately influence driving behavior. Here, we examined whether participants in a high-fidelity driving simulator exhibited an arousal response in the presence of a bicyclist and how this modulated eye movements and driving behavior. We hypothesized that bicyclists would evoke a robust arousal and orienting response, the strength of which would be associated with safer driving behavior. The results revealed that encountering a bicyclist evoked negative arousal by both self-report and physiological measures. Physiological and eye-tracking measures were themselves unrelated, however, being independently associated with safer driving behavior. Our findings offer a real-world demonstration of how arousal and attentional prioritization can lead to adaptive behavior.

The influence of threat on the efficiency of goal-directed attentional control.

Anxiety has consistently been found to potentiate attentional capture by physically salient stimuli, which could be due to enhanced distractor processing, impaired goal-directed attention, or both. At the same time, a recent study demonstrated that a threat manipulation reduces attentional capture by reward-associated stimuli, suggesting that anxiety does not increase distractibility or, otherwise, interfere with the control of attention generally. Here, we experimentally induced anxiety via threat-of-shock in the adaptive choice visual search task to examine whether the experience of threat influences goal-directed attentional control. Participants chose to search through one of two task-relevant colors on each trial, where searching through the less abundant color would be optimal for maximizing performance. Performance was evaluated with and without the threat of unpredictable electric shock. Under threat, participants were more optimal in their visual search and missed fewer targets. Performance improvements were demonstrated on trials that the optimal target color switched, demonstrating that threat is beneficial in adapting to changing attentional demands. Our findings demonstrate that threat can facilitate the efficiency of goal-directed attentional control and are at odds with an antagonistic relationship between anxiety and the control of attention.

Selection History-Driven Signal Suppression.

The control of attention is influenced by current goals, physical salience, and selection history. Under certain conditions, physically salient stimuli can be strategically suppressed below baseline levels, facilitating visual search for a target. It is unclear whether such signal suppression is a broad mechanism of selective information processing that extends to other sources of attentional priority evoked by task-irrelevant stimuli, or whether it is particular to physically salient perceptual signals. Using eye movements, in the present study we highlight a case where a former-target-color distractor facilitates search for a target on a large percentage of trials. Our findings provide evidence that the principle of signal suppression extends to other sources of attentional priority beyond physical salience, and that selection history can be leveraged to strategically guide attention away from a stimulus.

Measuring attention to reward as an individual trait: the value-driven attention questionnaire (VDAQ).

Reward history is a powerful determinant of what we pay attention to. This influence of reward on attention varies substantially across individuals, being related to a variety of personality variables and clinical conditions. Currently, the ability to measure and quantify attention-to-reward is restricted to the use of psychophysical laboratory tasks, which limits research into the construct in a variety of ways. In the present study, we introduce a questionnaire designed to provide a brief and accessible means of assessing attention-to-reward. Scores on the questionnaire correlate with other measures known to be related to attention-to-reward and predict performance on multiple laboratory tasks measuring the construct. In demonstrating this relationship, we also provide evidence that attention-to-reward as measured in the lab, an automatic and implicit bias in information processing, is related to overt behaviors and motivations in everyday life as assessed via the questionnaire. Variation in scores on the questionnaire is additionally associated with a distinct biomarker in brain connectivity, and the questionnaire exhibits acceptable test-retest reliability. Overall, the Value-Driven Attention Questionnaire (VDAQ) provides a useful proxy-measure of attention-to-reward that is much more accessible than typical laboratory assessments.

Threat reduces value-driven but not salience-driven attentional capture.

What we direct our attention to is strongly influenced by both bottom-up and top-down processes. Moreover, the control of attention is biased by prior learning, such that attention is automatically captured by stimuli previously associated with either reward or threat. It is unknown whether value-oriented and threat-oriented mechanisms of selective information processing function independently of one another, or whether they interact with each other in the selection process. Here, we introduced the threat of electric shock into the value-driven attentional capture paradigm to examine whether the experience of threat influences the attention capturing quality of previously reward-associated stimuli. The results showed that value-driven attentional capture was blunted by the experience of threat. This contrasts with previous reports of threat potentiating attentional capture by physically salient stimuli, which we replicate here. Our findings demonstrate that threat selectively interferes with value-based but not salience-based attentional priority, consistent with a competitive relationship between value-based and threat-based information processing. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The Effects of Metformin on Obesity-Induced Dysfunctional Retinas.

Purpose: The purpose of this study was to determine the effects of metformin on dysfunctional retinas in obesity-induced type 2 diabetic mice. Methods: A high-fat diet (HFD)-induced diabetic mouse model (C57BL/6J) was used in this study. After 2 months of the HFD regimen, HFD mice were given daily metformin through oral gavage. Body weights, glucose tolerance, and retinal light responses were monitored regularly. Fluorescein angiography (FA) was used to assess changes in retinal vasculature. Ocular tissues (retina, vitreous, and lens) were harvested and analyzed for molecular changes as determined by immunofluorescent staining, Western blot analysis, and cytokine profiling. Results: Starting 1 month after the diet regimen, mice fed the HFD had mildly compromised retinal light responses as measured by electroretinography (ERG), which worsened over time compared to that in the control. In HFD mice treated with metformin, systemic glucose levels reverted back to normal, and their weight gain slowed. Metformin reversed HFD-induced changes in phosphorylated protein kinase B (pAKT), extracellular signal-regulated kinase (pERK), and 5'AMP-activated protein kinase (pAMPK) in the retina. However, metformin treatments for 3 months did not restore the retinal light responses nor lessen the HFD-induced retinal neovascularization, even though it did reduce intraocular inflammation. Conclusions: Although metformin was able to reverse systemic changes induced by HFD, it was not able to restore HFD-caused retinal light responses or deter neovascularization.

Deletion of miR-150 Exacerbates Retinal Vascular Overgrowth in High-Fat-Diet Induced Diabetic Mice.

Diabetic retinopathy (DR) is the leading cause of blindness among American adults above 40 years old. The vascular complication in DR is a major cause of visual impairment, making finding therapeutic targets to block pathological angiogenesis a primary goal for developing DR treatments. MicroRNAs (miRs) have been proposed as diagnostic biomarkers and potential therapeutic targets for various ocular diseases including DR. In diabetic animals, the expression levels of several miRs, including miR-150, are altered. The expression of miR-150 is significantly suppressed in pathological neovascularization in mice with hyperoxia-induced retinopathy. The purpose of this study was to investigate the functional role of miR-150 in the development of retinal microvasculature complications in high-fat-diet (HFD) induced type 2 diabetic mice. Wild type (WT) and miR-150 null mutant (miR-150-/-) male mice were given a HFD (59% fat calories) or normal chow diet. Chronic HFD caused a decrease of serum miR-150 in WT mice. Mice on HFD for 7 months (both WT and miR-150-/-) had significant decreases in retinal light responses measured by electroretinograms (ERGs). The retinal neovascularization in miR-150-/--HFD mice was significantly higher compared to their age matched WT-HFD mice, which indicates that miR-150 null mutation exacerbates chronic HFD-induced neovascularization in the retina. Overexpression of miR-150 in cultured endothelial cells caused a significant reduction of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels. Hence, deletion of miR-150 significantly increased the retinal pathological angiogenesis in HFD induced type 2 diabetic mice, which was in part through VEGFR2.

A new role for AMP-activated protein kinase in the circadian regulation of L-type voltage-gated calcium channels in late-stage embryonic retinal photoreceptors.

AMP-activated protein kinase (AMPK) is a cellular energy sensor, which is activated when the intracellular ATP production decreases. The activities of AMPK display circadian rhythms in various organs and tissues, indicating that AMPK is involved in the circadian regulation of cellular metabolism. In vertebrate retina, the circadian clocks regulate many aspects of retinal function and physiology, including light/dark adaption, but whether and how AMPK was involved in the retinal circadian rhythm was not known. We hypothesized that the activation of AMPK (measured as phosphorylated AMPK) in the retina was under circadian control, and AMPK might interact with other intracellular signaling molecules to regulate photoreceptor physiology. We combined ATP assays, western blots, immunostaining, patch-clamp recordings, and pharmacological treatments to decipher the role of AMPK in the circadian regulation of photoreceptor physiology. We found that the overall retinal ATP content displayed a diurnal rhythm that peaked at early night, which was nearly anti-phase to the diurnal and circadian rhythms of AMPK phosphorylation. AMPK was also involved in the circadian phase-dependent regulation of photoreceptor L-type voltage-gated calcium channels (L-VGCCs), the ion channel essential for sustained neurotransmitter release. The activation of AMPK dampened the L-VGCC currents at night with a corresponding decrease in protein expression of the L-VGCCα1 pore-forming subunit, while inhibition of AMPK increased the L-VGCC current during the day. AMPK appeared to be upstream of extracellular-signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 (mTORC1) but downstream of adenylyl cyclase in regulating the circadian rhythm of L-VGCCs. Hence, as a cellular energy sensor, AMPK integrates into the cell signaling network to regulate the circadian rhythm of photoreceptor physiology. We found that in chicken embryonic retina, the activation of AMP-activated protein kinase (AMPK) is under circadian control and anti-phase to the retinal ATP rhythm. While ATP content is higher at night, phosphorylated AMPK (pAMPK) is higher during the day. AMPK appears to be upstream of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and mammalian target of rapamycin complex 1 (mTORC1) but downstream of adenylyl cyclase in regulating the circadian rhythm of L-VGCCs. Therefore, as a cellular energy sensor, AMPK integrates into the cell signaling network to regulate the circadian rhythm of photoreceptor physiology.

High-Fat Diet-Induced Retinal Dysfunction.

PURPOSE: The purpose of this study was to investigate the impact of obesity-induced prediabetes/early diabetes on the retina to provide new evidence on the pathogenesis of type 2 diabetes-associated diabetic retinopathy (DR). METHODS: A high-fat diet (HFD)-induced obesity mouse model (male C57BL/6J) was used in this study. At the end of the 12-week HFD feeding regimen, mice were evaluated for glucose and insulin tolerance, and retinal light responses were recorded by electroretinogram (ERG). Western immunoblot and immunohistochemical staining were used to determine changes in elements regulating calcium homeostasis between HFD and control retinas, as well as unstained human retinal sections from DR patients and age-appropriate controls. RESULTS: Compared to the control, the scotopic and photopic ERGs from HFD mice were decreased. There were significant decreases in molecules related to cell signaling, calcium homeostasis, and glucose metabolism from HFD retinas, including phosphorylated protein kinase B (pAKT), glucose transporter 4, L-type voltage-gated calcium channel (L-VGCC), and plasma membrane calcium ATPase (PMCA). Similar changes for pAKT, PMCA, and L-VGCC were also observed in human retinal sections from DR patients. CONCLUSIONS: Obesity-induced hyperglycemic and prediabetic/early diabetic conditions caused detrimental impacts on retinal light sensitivities and health. The decrease of the ERG components in early diabetes reflects the decreased neuronal activity of retinal light responses, which may be caused by a decrease in neuronal calcium signaling. Since PI3K-AKT is important in regulating calcium homeostasis and neural survival, maintaining proper PI3K-AKT signaling in early diabetes or at the prediabetic stage might be a new strategy for DR prevention.

Peptide Lv augments L-type voltage-gated calcium channels through vascular endothelial growth factor receptor 2 (VEGFR2) signaling.

We previously identified peptide Lv, a novel bioactive peptide that enhances the activity of L-type voltage-gated calcium channels (L-VGCCs) in cone photoreceptors. In this study, we verified that peptide Lv was able to augment L-VGCC currents in cardiomyocytes, as well as promote proliferation of endothelial cells. We used a proteomics approach to determine the specific receptors and binding partners of peptide Lv and found that vascular endothelial growth factor receptor 2 (VEGFR2) interacted with peptide Lv. Peptide Lv treatment in embryonic cardiomyocytes stimulated tyrosine autophosphorylation of VEGFR2 and activated its downstream signaling. Peptide Lv activity was blocked by DMH4, a VEGFR2 specific blocker, but not by SCH202676, an allosteric inhibitor of G protein-coupled receptors, suggesting that the activity of peptide Lv was mediated through VEGFR2 signaling. Inhibition of VEGFR tyrosine kinase or its downstream signaling molecules abolished the augmentation of L-VGCCs elicited by peptide Lv in cardiomyocytes. In addition, peptide Lv promoted cell proliferation of cultured human endothelial cells. Calcium entry through L-VGCCs is essential for excitation-contraction coupling in cardiomyocytes. Since peptide Lv was able to augment L-VGCCs through activation of VEGF signaling in cardiomyocytes and promote proliferation of endothelial cells, peptide Lv may play an important role in regulating the cardiovascular system.