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.

Brain activity during a post-stress working memory task differs between the hormone-present and hormone-absent phase of hormonal contraception.

Taking hormonal contraceptives (HCs) affects the magnitude of the hormonal stress response and cognition. HCs are usually administered in a monthly cycle with both synthetic-hormone-containing and synthetic-hormone-absent phases. The synthetic hormones contained in HCs affect a wide range of neurophysiological systems, suggesting that effects of the medication might only be observed during the synthetic-hormone-containing phase of the HC cycle. To test this, women were seen twice, once during the hormone-present phase and once during the hormone-absent phase of the HC cycle. In each session, women performed an n-back working memory task to assess pre-stress performance outside of the magnetic resonance imaging scanner, were then exposed to cold pressor stress, and again completed the n-back task during functional magnetic resonance imaging. The free cortisol response to stress remained the same across the HC cycle. Women also performed comparably on the n-back task after stress exposure across the two phases. However, despite these similarities, women displayed greater disengagement of default mode network as task demands increased during the hormone-present phase only, a pattern more in line with working memory-related brain activation under non-stressful conditions reported in other studies. The results suggest that the synthetic hormones contained in HCs may mitigate stress-related disruptions of typical brain activation patterns during the hormone-present phase of the HC cycle, despite exhibiting comparable cortisol responses across the HC cycle. Additional research is required to determine the mechanisms contributing to, and the extent of, such mitigating effects.

Hormonal contraceptive phases matter: Resting-state functional connectivity of emotion-processing regions under stress.

Hormonal contraceptives (HCs) affect various processes related to emotion processing, including emotional memory, fear extinction, and the cortisol response to stress. Despite the modulating role of HCs on the stress response in women and variance in synthetic hormone levels across the HC cycle, little is known about the phase-related effects of HCs on the brain's response to stress. We investigated the effect of HC cycle phase on functional connectivity of memory- and emotion-related regions at rest after exposure to a stressor. Twenty HC users completed two sessions of resting-state functional magnetic resonance imaging after exposure to the cold pressor test, one during the hormone-present HC phase (when synthetic hormones are taken) and one during the hormone-absent HC phase (when synthetic hormones are not taken). Women showed higher functional connectivity between left amygdala and ventromedial prefrontal cortex during the hormone-present phase. During the hormone-absent phase, women showed higher coupling between left parahippocampus and right superior lateral occipital cortex. Our results suggest that the synthetic hormones contained in HCs may protect against the negative effects of stress on functional connectivity of emotional processing regions.

Effects of hormonal contraceptive phase and progestin generation on stress-induced cortisol and progesterone release.

The stress response differs between women using hormonal contraception and naturally cycling women. Yet, despite ample evidence showing that the stress response differs across the menstrual cycle in naturally cycling women, limited work has investigated whether the stress response differs across the hormonal contraceptive cycle, during which synthetic hormones are taken most of the month but not all of it. To induce a stress response, women using hormonal contraception completed the cold pressor test during either the active phase, when hormones are present, or during the inactive phase, when hormones are not present. Saliva was collected and assayed for free cortisol and progesterone levels prior to stress onset, immediately after stress termination, and 15-min post stress onset. Free cortisol and progesterone increased to a similar degree across both hormonal contraceptive phases in response to the cold pressor test. Post-hoc investigation indicates that the progestin "generation" (classification of synthetic progestins based on the compounds they are derived from) can differentially affect the free steroid response to cold pressor test stress, with the largest effects observed in women using formulations containing second-generation progestins. These findings indicate that progestin generation, particularly second-generation progestins, may have a more impactful influence on the stress response than hormonal contraceptive cycle phase. Potential mechanisms driving this effect and need for additional research are discussed.

Estradiol Therapy After Menopause Mitigates Effects of Stress on Cortisol and Working Memory.

Context: Postmenopausal estradiol therapy (ET) can reduce the stress response. However, it remains unclear whether such reductions can mitigate effects of stress on cognition. Objective: Investigate effects of ET on cortisol response to a physical stressor, cold pressor test (CPT), and whether ET attenuates stress effects on working memory. Design: Women completed the CPT or control condition across two sessions and subsequently completed a sentence span task. Setting: General community: Participants were recruited from the Early vs Late Intervention Trial with Estradiol (ELITE). Participants: ELITE participants (mean age = 66, standard deviation age = 6.8) in this study did not suffer from any major chronic illness or use medications known to affect the stress response or cognition. Interventions: Participants had received a median of randomized 4.7 years of estradiol (n = 21) or placebo (n = 21) treatment at time of participation in this study. Main Outcome Measures: Salivary cortisol and sentence span task performance. Results: Women assigned to estradiol exhibited blunted cortisol responses to CPT compared with placebo (P = 0.017) and lesser negative effects of stress on working memory (P = 0.048). Conclusions: We present evidence suggesting ET may protect certain types of cognition in the presence of stress. Such estrogenic protection against stress hormone exposure may prove beneficial to both cognition and the neural circuitry that maintains and propagates cognitive faculties.

Stress-induced increases in progesterone and cortisol in naturally cycling women.

Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test) had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release.