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.

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-β (Aβ) in healthy younger and older adults. In healthy adults, higher plasma Aβ is associated with greater risk of Alzheimers disease (AD). Our primary goal of this trial is to reproduce and extend our initial findings regarding effects of slow-paced breathing on Aβ. 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 Aβ40 and Aβ42 levels and plasma Aβ42/40 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 Aβ42. 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 Aβ 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.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also enhance brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression, or mood. These findings indicate that modulating heart rate oscillatory activity changes emotion network coordination in the brain.

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.