Emotion Downregulation Targets Interoceptive Brain Regions While Emotion Upregulation Targets Other Affective Brain Regions.

Researchers generally agree that when upregulating and downregulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating brain areas. However, the "affective dial hypothesis" that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We tested this hypothesis by examining the overlap between the regions activated during upregulation and those deactivated during downregulation in 54 male and 51 female humans. We found that upregulation and downregulation both recruit regulatory regions, such as the inferior frontal gyrus and dorsal anterior cingulate gyrus, but act on distinct affect-generating regions. Upregulation increased activity in regions associated with emotional experience, such as the amygdala, anterior insula, striatum, and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity, such as periventricular white matter, while downregulation decreased activity in regions receiving interoceptive input, such as the posterior insula and postcentral gyrus. Nevertheless, participants' subjective sense of emotional intensity was associated with activity in overlapping brain regions (dorsal anterior cingulate, insula, thalamus, and frontal pole) across upregulation and downregulation. These findings indicate that upregulation and downregulation rely on overlapping brain regions to control and assess emotions but target different affect-generating brain regions.SIGNIFICANCE STATEMENT Many contexts require modulating one's own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: both emotion upregulation and downregulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation might differ more than previously appreciated for upregulation versus downregulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention.

Increasing coordination and responsivity of emotion-related brain regions with a heart rate variability biofeedback randomized trial.

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.

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.

Changes in Medial Prefrontal Cortex Mediate Effects of Heart Rate Variability Biofeedback on Positive Emotional Memory Biases.

Previous research suggests that implicit automatic emotion regulation relies on the medial prefrontal cortex (mPFC). However, most of the human studies supporting this hypothesis have been correlational in nature. In the current study, we examine how changes in mPFC-left amygdala functional connectivity relate to emotional memory biases. In a randomized clinical trial examining the effects of heart rate variability (HRV) biofeedback on brain mechanisms of emotion regulation, we randomly assigned participants to increase or decrease heart rate oscillations while receiving biofeedback. After several weeks of daily biofeedback sessions, younger and older participants completed an emotional picture memory task involving encoding, recall, and recognition phases as an additional measure in this clinical trial. Participants assigned to increase HRV (Osc+) (n = 84) showed a relatively higher rate of false alarms for positive than negative images than participants assigned to decrease HRV (Osc-) (n = 81). Osc+ participants also recalled relatively more positive compared with negative items than Osc- participants, but this difference was not significant. However, a summary bias score reflecting positive emotional memory bias across recall and recognition was significantly higher in the Osc+ than Osc- condition. As previously reported, the Osc+ manipulation increased left amygdala-mPFC resting-state functional connectivity significantly more than the Osc- manipulation. This increased functional connectivity significantly mediated the effects of the Osc+ condition on emotional bias. These findings suggest that, by increasing mPFC coordination of emotion-related circuits, daily practice increasing heart rate oscillations can increase implicit emotion regulation.

Effects of a Randomised Trial of 5-Week Heart Rate Variability Biofeedback Intervention on Cognitive Function: Possible Benefits for Inhibitory Control.

Previous research suggests that higher heart rate variability (HRV) is associated with better cognitive function. However, since most previous findings on the relationship between HRV and cognitive function were correlational in nature, it is unclear whether individual differences in HRV play a causal role in cognitive performance. To investigate whether there are causal relationships, we used a simple breathing manipulation that increases HRV through a 5-week HRV biofeedback intervention and examined whether this manipulation improves cognitive performance in younger and older adults (N = 165). The 5-week HRV biofeedback intervention did not significantly improve inhibitory control, working memory and processing speed across age groups. However, improvement in the Flanker score (a measure of inhibition) was associated with the amplitude of heart rate oscillations during practice sessions in the younger and older intervention groups. Our results suggest that daily practice to increase heart rate oscillations may improve inhibitory control, but future studies using longer intervention periods are warranted to replicate the present finding.

Effects of a randomised trial of 5-week heart rate variability biofeedback intervention on mind wandering and associated brain function.

Previous research suggests that excessive negative self-related thought during mind wandering involves the default mode network (DMN) core subsystem and the orbitofrontal cortex (OFC). Heart rate variability (HRV) biofeedback, which involves slow paced breathing to increase HRV, is known to promote emotional well-being. However, it remains unclear whether it has positive effects on mind wandering and associated brain function. We conducted a study where young adults were randomly assigned to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations via slow paced breathing (Osc+ condition) or had little effect on heart rate oscillations (active control or Osc- condition). The two intervention conditions did not differentially affect mind wandering and DMN core-OFC functional connectivity. However, the magnitude of participants' heart rate oscillations during daily biofeedback practice was associated with pre-to-post decreases in mind wandering and in DMN core-OFC functional connectivity. Furthermore, the reduction in the DMN core-OFC connectivity was associated with a decrease in mind wandering. Our results suggested that daily sessions involving high amplitude heart rate oscillations may help reduce negative mind wandering and associated brain function.

Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans.

Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits.SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline.

Age-related differences in BOLD modulation to cognitive control costs in a multitasking paradigm: Global switch, local switch, and compatibility-switch costs.

It is well documented that older adults recruit additional brain regions compared to those recruited by younger adults while performing a wide variety of cognitive tasks. However, it is unclear how such age-related over-recruitment interacts with different types of cognitive control, and whether this over-recruitment is compensatory. To test this, we used a multitasking paradigm, which allowed us to examine age-related over-activation associated with three types of cognitive costs (i.e., global switch, local switch, compatibility-switch costs). We found age-related impairments in global switch cost (GSC), evidenced by slower response times for maintaining and coordinating two tasks vs. performing only one task. However, no age-related declines were observed in either local switch cost (LSC), a cognitive cost associated with switching between the two tasks while maintaining two task loads, or compatibility-switch cost (CSC), a cognitive cost associated with incompatible vs. compatible stimulus-response mappings across the two tasks. The fMRI analyses allowed for identification of distinct cognitive cost-sensitive brain regions associated with GSC and LSC. In fronto-parietal GSC and LSC regions, older adults' increased activations were associated with poorer performance (greater costs), whereas a reverse relationship was observed in younger adults. Older adults also recruited additional fronto-parietal brain regions outside the cognitive cost-sensitive areas, which was associated with poorer performance or no behavioral benefits. Our results suggest that older adults exhibit a combination of inefficient activation within cognitive cost-sensitive regions, specifically the GSC and LSC regions, and non-compensatory over-recruitment in age-sensitive regions. Age-related declines in global switching, compared to local switching, was observed earlier in old age at both neural and behavioral levels.

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 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.

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.

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.

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.

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.

Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults.

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αß40, Αß42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc-). They practiced 20-40 min daily. Four weeks of practicing the Osc+ and Osc- conditions produced large effect size differences in change in plasma Aß40 and Aß42 levels. The Osc+ condition decreased plasma Αß while the Osc- condition increased Αß. Decreases in Αß were associated with decreases in gene transcription indicators of ß-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc- interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.

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.

Differential brain activity during emotional versus nonemotional reversal learning.

The ability to change an established stimulus-behavior association based on feedback is critical for adaptive social behaviors. This ability has been examined in reversal learning tasks, where participants first learn a stimulus-response association (e.g., select a particular object to get a reward) and then need to alter their response when reinforcement contingencies change. Although substantial evidence demonstrates that the OFC is a critical region for reversal learning, previous studies have not distinguished reversal learning for emotional associations from neutral associations. The current study examined whether OFC plays similar roles in emotional versus neutral reversal learning. The OFC showed greater activity during reversals of stimulus-outcome associations for negative outcomes than for neutral outcomes. Similar OFC activity was also observed during reversals involving positive outcomes. Furthermore, OFC activity is more inversely correlated with amygdala activity during negative reversals than during neutral reversals. Overall, our results indicate that the OFC is more activated by emotional than neutral reversal learning and that OFC's interactions with the amygdala are greater for negative than neutral reversal learning.

Age differences in brain activity during emotion processing: reflections of age-related decline or increased emotion regulation?

Despite the fact that physical health and cognitive abilities decline with aging, the ability to regulate emotion remains stable and in some aspects improves across the adult life span. Older adults also show a positivity effect in their attention and memory, with diminished processing of negative stimuli relative to positive stimuli compared with younger adults. The current paper reviews functional magnetic resonance imaging studies investigating age-related differences in emotional processing and discusses how this evidence relates to two opposing theoretical accounts of older adults' positivity effect. The aging-brain model [Cacioppo et al. in: Social Neuroscience: Toward Understanding the Underpinnings of the Social Mind. New York, Oxford University Press, 2011] proposes that older adults' positivity effect is a consequence of age-related decline in the amygdala, whereas the cognitive control hypothesis [Kryla-Lighthall and Mather in: Handbook of Theories of Aging, ed 2. New York, Springer, 2009; Mather and Carstensen: Trends Cogn Sci 2005;9:496-502; Mather and Knight: Psychol Aging 2005;20:554-570] argues that the positivity effect is a result of older adults' greater focus on regulating emotion. Based on evidence for structural and functional preservation of the amygdala in older adults and findings that older adults show greater prefrontal cortex activity than younger adults while engaging in emotion-processing tasks, we argue that the cognitive control hypothesis is a more likely explanation for older adults' positivity effect than the aging-brain model.