Short-term blood pressure variability and brain functional network connectivity in older adults.

Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.

Aging impairs reactive attentional control but not proactive distractor inhibition.

Older adults tend to be more prone to distraction compared with young adults, and this age-related deficit has been attributed to a deficiency in inhibitory processing. However, recent findings challenge the notion that aging leads to global impairments in inhibition. To reconcile these mixed findings, we investigated how aging modulates multiple mechanisms of attentional control by tracking the timing and direction of eye movements. When engaged in feature-search mode and proactive distractor suppression, older adults made fewer first fixations to the target but inhibited the task-irrelevant salient distractor as effectively as did young adults. However, when engaged in singleton-search mode and required to reactively disengage from the distractor, older adults made significantly more first saccades toward the task-irrelevant salient distractor and showed increased fixation times in orienting to the target, longer dwell times on incorrect saccades, and increased saccadic reaction times compared with young adults. Our findings reveal that aging differently impairs attentional control depending on whether visual search requires proactive distractor suppression or reactive distractor disengagement. Furthermore, our oculomotor measures reveal both age-related deficits and age equivalence in various mechanisms of attention, including goal-directed orienting, selection history, disengagement, and distractor inhibition. These findings help explain why conclusions of age-related declines or age equivalence in mechanisms of attentional control are task specific and reveal that older adults do not exhibit global impairments in mechanisms of inhibition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Eye movements reveal age differences in how arousal modulates saliency priority but not attention processing speed.

The arousal-biased competition theory posits that inducing arousal increases attentional priority of salient stimuli while reducing priority of non-pertinent stimuli. However, unlike in young adults, older adults rarely exhibit shifts in priority under increased arousal, and prior studies have proposed different neural mechanisms to explain how arousal differentially modulates selective attention in older adults. Therefore, we investigated how the threat of unpredictable shock differentially modulates attentional control mechanisms in young and older adults by observing eye movements. Participants completed two oculomotor search tasks in which the salient distractor was typically captured by attention (singleton search) or proactively suppressed (feature search). We found that arousal did not modulate attentional priority for any stimulus among older adults nor affect the speed of attention processing in either age group. Furthermore, we observed that arousal modulated pupil sizes and found a correlation between evoked pupil responses and oculomotor function. Our findings suggest age differences in how the locus coeruleus-noradrenaline system interacts with neural networks of attention and oculomotor function.

The emotion paradox in the aging body and brain.

With age, parasympathetic activity decreases, while sympathetic activity increases. Thus, the typical older adult has low heart rate variability (HRV) and high noradrenaline levels. Younger adults with this physiological profile tend to be unhappy and stressed. Yet, with age, emotional experience tends to improve. Why does older adults' emotional well-being not suffer as their HRV decreases? To address this apparent paradox, I present the autonomic compensation model. In this model, failing organs, the initial phases of Alzheimer's pathology, and other age-related diseases trigger noradrenergic hyperactivity. To compensate, older brains increase autonomic regulatory activity in the pregenual prefrontal cortex (PFC). Age-related declines in nerve conduction reduce the ability of the pregenual PFC to reduce hyperactive noradrenergic activity and increase peripheral HRV. But these pregenual PFC autonomic compensation efforts have a significant impact in the brain, where they bias processing in favor of stimuli that tend to increase parasympathetic activity (e.g., stimuli that increase feelings of safety) and against stimuli that tend to increase sympathetic activity (e.g., threatening stimuli). In summary, the autonomic compensation model posits that age-related chronic sympathetic/noradrenergic hyperactivity stimulates regulatory attempts that have the side effect of enhancing emotional well-being.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Real-time heart rate variability biofeedback amplitude during a large-scale digital mental health intervention differed by age, gender, and mental and physical health.

Heart rate variability biofeedback (HRVB) is an efficacious treatment for depression and anxiety. However, translation to digital mental health interventions (DMHI) requires computing and providing real-time HRVB metrics in a personalized and user-friendly fashion. To address these gaps, this study validates a real-time HRVB feedback algorithm and characterizes the association of the main algorithmic summary metric-HRVB amplitude-with demographic, psychological, and health factors. We analyzed HRVB data from 5158 participants in a therapist-supported DMHI incorporating slow-paced breathing to treat depression or anxiety symptoms. A real-time feedback metric of HRVB amplitude and a gold-standard research metric of low-frequency (LF) power were computed for each session and then averaged within-participants over 2 weeks. We provide HRVB amplitude values, stratified by age and gender, and we characterize the multivariate associations of HRVB amplitude with demographic, psychological, and health factors. Real-time HRVB amplitude correlated strongly (r = .93, p < .001) with the LF power around the respiratory frequency (~0.1 Hz). Age was associated with a significant decline in HRVB (ß = -0.46, p < .001), which was steeper among men than women, adjusting for demographic, psychological, and health factors. Resting high- and low-frequency power, body mass index, hypertension, Asian race, depression symptoms, and trauma history were significantly associated with HRVB amplitude in multivariate analyses (p's < .01). Real-time HRVB amplitude correlates highly with a research gold-standard spectral metric, enabling automated biofeedback delivery as a potential treatment component of DMHIs. Moreover, we identify demographic, psychological, and health factors relevant to building an equitable, accurate, and personalized biofeedback user experience.

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.

Resting heart rate variability is associated with neural adaptation when repeatedly exposed to emotional stimuli.

Higher heart rate variability (HRV) at rest is associated with better emotion regulation ability. While the neurovisceral integration model explains this by postulating that HRV can index how the brain adaptively modulates responses to emotional stimuli, neuroimaging studies directly supporting this idea are scarce. We examined the neural correlates of regulating negative and positive emotion in relation to resting HRV based on the neuroimaging and heart rate data of one hundred young adults. The results showed that those with higher HRV better recruit the medial prefrontal cortex while intensifying positive compared to negative emotion. We also examined how individual differences in resting HRV are associated with adjusting brain activity to repeated emotional stimuli. During repeated viewing of emotional images, subjects with higher resting HRV better reduced activity in the medial prefrontal cortex, posterior cingulate gyrus, and angular gyrus, most of which overlapped with the default mode network. This HRV-DMN association was observed during passively viewing emotional images rather than during actively regulating emotion. While the regulating trials can better detect task-induced changes, the viewing trials might approximate resting state, better revealing individual differences. These findings suggest two possibilities: people with higher resting HRV might have a tendency to spontaneously engage with emotion regulation or possess a trait helping emotional arousal fade away.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

Daily biofeedback to modulate heart rate oscillations affects structural volume in hippocampal subregions targeted by the locus coeruleus in older adults but not younger adults.

Using data from a clinical trial, we tested the hypothesis that daily sessions modulating heart rate oscillations affect older adults' volume of a region-of-interest (ROI) comprised of adjacent hippocampal subregions with relatively strong locus coeruleus (LC) noradrenergic input. Younger and older adults were randomly assigned to one of two daily biofeedback practices for 5 weeks: 1) engage in slow-paced breathing to increase the amplitude of oscillations in heart rate at their breathing frequency (Osc+); 2) engage in self-selected strategies to decrease heart rate oscillations (Osc-). The interventions did not significantly affect younger adults' hippocampal volume. Among older adults, the two conditions affected volume in the LC-targeted hippocampal ROI differentially as reflected in a significant condition x time-point interaction on ROI volume. These condition differences were driven by opposing changes in the two conditions (increased volume in Osc+ and decreased volume in Osc-) and were mediated by the degree of heart rate oscillation during training sessions.

Daily biofeedback to modulate heart rate oscillations affects structural volume in hippocampal subregions targeted by the locus coeruleus in older adults but not younger adults.

Using data from a clinical trial, we tested the hypothesis that daily sessions modulating heart rate oscillations affect older adults' volume of a region-of-interest (ROI) comprised of adjacent hippocampal subregions with relatively strong locus coeruleus (LC) noradrenergic input. Younger and older adults were randomly assigned to one of two daily biofeedback practices for 5 weeks: (1) engage in slow-paced breathing to increase the amplitude of oscillations in heart rate at their breathing frequency (Osc+); (2) engage in self-selected strategies to decrease heart rate oscillations (Osc-). The interventions did not significantly affect younger adults' hippocampal volume. Among older adults, the two conditions affected volume in the LC-targeted hippocampal ROI differentially as reflected in a significant condition × time-point interaction on ROI volume. These condition differences were driven by opposing changes in the two conditions (increased volume in Osc+ and decreased volume in Osc-) and were mediated by the degree of heart rate oscillation during training sessions.

Declining locus coeruleus-dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer's disease.

Memory is essential in defining our identity by guiding behavior based on past experiences. However, aging leads to declining memory, disrupting older adult's lives. Memories are encoded through experience-dependent modifications of synaptic strength, which are regulated by the catecholamines dopamine and noradrenaline. While cognitive aging research demonstrates how dopaminergic neuromodulation from the substantia nigra-ventral tegmental area regulates hippocampal synaptic plasticity and memory, recent findings indicate that the noradrenergic locus coeruleus sends denser inputs to the hippocampus. The locus coeruleus produces dopamine as biosynthetic precursor of noradrenaline, and releases both to modulate hippocampal plasticity and memory. Crucially, the locus coeruleus is also the first site to accumulate Alzheimer's-related abnormal tau and severely degenerates with disease development. New in-vivo assessments of locus coeruleus integrity reveal associations with Alzheimer's markers and late-life memory impairments, which likely stem from impaired dopaminergic and noradrenergic neurotransmission. Bridging research across species, the reviewed findings suggest that degeneration of the locus coeruleus results in deficient dopaminergic and noradrenergic modulation of hippocampal plasticity and thus memory decline.

Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults in a randomized clinical trial.

As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance.

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra-ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Short-term blood pressure variability is inversely related to regional amplitude of low frequency fluctuations in older and younger adults.

Blood pressure variability (BPV), independent of mean blood pressure levels, is associated with cerebrovascular disease burden on MRI and postmortem evaluation. However, less is known about relationships with markers of cerebrovascular dysfunction, such as diminished spontaneous brain activity as measured by the amplitude of low frequency fluctuations (ALFF), especially in brain regions with vascular and neuronal vulnerability in aging. We investigated the relationship between short-term BPV and concurrent regional ALFF from resting state fMRI in a sample of community-dwelling older adults (n = 44) and healthy younger adults (n = 49). In older adults, elevated systolic BPV was associated with lower ALFF in widespread medial temporal regions and the anterior cingulate cortex. Higher systolic BPV in younger adults was also related to lower ALFF in the medial temporal lobe, albeit in fewer subregions, and the amygdala. There were no significant associations between systolic BPV and ALFF across the right/left whole brain or in the insular cortex in either group. Findings suggest a possible regional vulnerability to cerebrovascular dysfunction and short-term fluctuations in blood pressure. BPV may be an understudied risk factor for cerebrovascular changes in aging.

Multimodal neuroimaging data from a 5-week heart rate variability biofeedback randomized clinical trial.

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy (1H MRS). During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO2) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests and ten questionnaires related to emotional well-being. A subset (N = 104) provided plasma samples pre- and post-intervention that were assayed for amyloid and tau. Data is publicly available via the OpenNeuro data sharing platform.

Sex Differences in Neural Correlates of Emotion Regulation in Relation to Resting Heart Rate Variability.

Prior studies suggest that sex differences in emotion regulation (ER) ability contribute to sex disparities in affective disorders. In behavioral studies, females rely more on maladaptive strategies to cope with emotional distress than males. Neuroimaging studies suggest that males more efficiently regulate emotion than females by showing less prefrontal cortex activity (suggesting less effort) for similar amygdala activity (similar regulation outcome). However, physiological studies involving heart rate variability (HRV) indicated that, compared with males, females have higher resting HRV, indicative of parasympathetic dominance and better control of emotion. To help resolve these apparently inconsistent findings, we examined sex differences in how resting HRV relates to brain activity while using cognitive reappraisal, one of the adaptive strategies. Based on 51 males and 49 females, we found that females showed different levels of self-rated emotional intensity and amygdala activity for negative versus positive emotions, while males did not. Females also showed greater overall prefrontal cortex activity but similar levels of amygdala activity compared to males. Sex differences in how resting HRV related to brain activity during ER were evident only during viewing or regulating positive emotion. The results suggest that sex differences in the neural correlates of ER and resting HRV might lie in valence more than arousal modulation.