Stressor-evoked brain activity, cardiovascular reactivity, and subclinical atherosclerosis in midlife adults.

Background: Cardiovascular responses to psychological stressors have been separately associated with preclinical atherosclerosis and hemodynamic brain activity patterns across different studies and cohorts; however, what has not been established is whether cardiovascular stress responses reliably link indicators of stressor-evoked brain activity and preclinical atherosclerosis that have been measured in the same individuals. Accordingly, the present study used cross-validation and predictive modeling to test for the first time whether stressor-evoked systolic blood pressure (SBP) responses statistically mediated the association between concurrently measured brain activity and a vascular marker of preclinical atherosclerosis in the carotid arteries. Methods: 624 midlife adults (aged 28-56 years, 54.97% female) from two different cohorts underwent two information-conflict fMRI tasks, with concurrent SBP measures collected. Carotid artery intima-media thickness (CA-IMT) was measured by ultrasonography. A mediation framework that included harmonization, cross-validation, and penalized principal component regression was then employed, while significant areas in possible direct and indirect effects were identified through bootstrapping. Sensitivity analysis further tested the robustness of findings after accounting for prevailing levels of cardiovascular disease risk and brain imaging data quality control. Results: Task-averaged patterns of hemodynamic brain responses exhibited a generalizable association with CA-IMT, which was mediated by an area-under-the-curve measure of aggregate SBP reactivity. Importantly, this effect held in sensitivity analyses. Implicated brain areas in this mediation included the ventromedial prefrontal cortex, anterior cingulate cortex, insula and amygdala. Conclusions: These novel findings support a link between stressor-evoked brain activity and preclinical atherosclerosis accounted for by individual differences in corresponding levels of stressor-evoked cardiovascular reactivity.

A randomized, placebo-controlled, double-blinded mechanistic clinical trial using endotoxin to evaluate the relationship between insomnia, inflammation, and affective disturbance on pain in older adults: A protocol for the sleep and Healthy Aging Research for pain (SHARE-P) study.

Chronic pain is prevalent in older adults. Treatment, especially with opioids, is often ineffective and poses considerable negative consequences in this population. To improve treatment, it is important to understand why older adults are at a heightened risk for developing chronic pain. Insomnia is a major modifiable risk factor for chronic pain that is ubiquitous among older adults. Insomnia can also lead to heightened systemic inflammation and affective disturbance, both of which may further exacerbate pain conditions in older adults. Endotoxin exposure can be used as an experimental model of systemic inflammation and affective disturbance. The current study aims to understand how insomnia status and endotoxin-induced changes in inflammation and affect (increased negative affect and decreased positive affect) may interact to impact pain facilitatory and inhibitory processes in older adults. Longitudinal data will also assess how pain processing, affective, and inflammatory responses to endotoxin may predict the development of pain and/or depressive symptoms. The current study is a randomized, double-blinded, placebo-controlled, mechanistic clinical trial in men and women, with and without insomnia, aged 50 years and older. Participants were randomized to either 0.8ng/kg endotoxin injection or saline placebo injection. Daily diaries were used to collect variables related to sleep, mood, and pain at two-week intervals during baseline and 3-, 6-, 9-, and 12-months post-injection. Primary outcomes during the experimental phase include conditioned pain modulation, temporal summation, and affective pain modulation ∼5.5 hours after injection. Primary outcomes for longitudinal assessments are self-reported pain intensity and depressive symptoms. The current study uses endotoxin as an experimental model for pain. In doing so, it aims to extend the current literature by: (1) including older adults, (2) investigating insomnia as a potential risk factor for chronic pain, (3) evaluating the role of endotoxin-induced affective disturbances on pain sensitivity, and (4) assessing sex differences in endotoxin-induced hyperalgesia. Clinicaltrialsgov: NCT03256760. Trial sponsor: NIH R01AG057750-01.

The personality meta-trait of stability and carotid artery atherosclerosis.

BACKGROUND: Several personality traits increase the risk for atherosclerotic cardiovascular disease. Because many of these traits are correlated, their associations with disease risk could reflect shared variance, rather than unique contributions of each trait. We examined a higher-order personality trait of Stability as related to preclinical atherosclerosis and tested whether any such relationship might be explained by correlated variation in cardiometabolic risk factors. METHOD: Among 798 community volunteers, lower-order traits of Neuroticism, Agreeableness, and Conscientiousness were modeled as latent variables (from self- and informant ratings) and used to estimate the second-order factor, Stability. Cardiometabolic risk was similarly modeled from indicators of glycemic control, blood pressure, adiposity, and lipids. Carotid artery atherosclerosis was measured as intima-media thickness (IMT) by duplex ultrasonography. RESULT: A structural equation model incorporating direct and indirect effects showed lower Stability associated with greater IMT, and this relationship was accounted for by the indirect pathway via cardiometabolic risk. Secondary analyses showed that: (1) Neuroticism, Agreeableness, and Conscientiousness were unrelated to IMT independent of Stability; and (2) Stability predicted variation in IMT when estimated from informant-, but not self-rated, traits. CONCLUSION: Personality traits may associate with atherosclerotic burden through their shared, rather than unique, variance, as reflected in Stability.

Does an Online Positive Psychological Intervention Improve Positive Affect in Young Adults During the COVID-19 Pandemic?

Meta-analyses indicate that positive psychological interventions are effective at increasing positive affect, as well as reducing anxiety and depression; however, it is unclear how well these effects generalize during periods of high stress. Therefore, the current study tested whether a 2-week online positive psychological intervention delivered during the COVID-19 pandemic, a naturalistic stressor, (1) increased positive affect; (2) improved psychological well-being, optimism, life satisfaction, perceived social support, and loneliness; (3) and reduced negative affect in college students, a group known to have high pandemic distress. Participants (N = 250; 76.9% female) ages 18-45 were recruited from the University of Pittsburgh undergraduate subject pool between September and November of 2020. Participants were randomized to the online positive psychological intervention or active control condition and stratified by trait positive affect, sex, and year in college. Participants in both conditions completed one writing activity every other day for two consecutive weeks. Control participants documented their activities for that day (e.g., meals, going to gym). Intervention participants chose from six positive psychology activities. All outcome variables were assessed pre- and post-intervention by validated questionnaires. Across both conditions, positive and negative affect decreased from pre- to post-intervention. No other psychological factor differed by condition, time, or their interaction. The current null findings are in line with a more recent meta-analysis indicating that positive psychological interventions may have smaller effects on psychological well-being and depressive symptoms than was reported pre-pandemic. Study findings may suggest reduced efficacy of virtual positive psychological interventions under highly stressful circumstances. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-022-00148-z.

Multivariate Brain Activity while Viewing and Reappraising Affective Scenes Does Not Predict the Multiyear Progression of Preclinical Atherosclerosis in Otherwise Healthy Midlife Adults.

Cognitive reappraisal is an emotion regulation strategy that is postulated to reduce risk for atherosclerotic cardiovascular disease (CVD), particularly the risk due to negative affect. At present, however, the brain systems and vascular pathways that may link reappraisal to CVD risk remain unclear. This study thus tested whether brain activity evoked by using reappraisal to reduce negative affect would predict the multiyear progression of a vascular marker of preclinical atherosclerosis and CVD risk: carotid artery intima-media thickness (CA-IMT). Participants were 176 otherwise healthy adults (50.6% women; aged 30-51 years) who completed a functional magnetic resonance imaging task involving the reappraisal of unpleasant scenes from the International Affective Picture System. Ultrasonography was used to compute CA-IMT at baseline and a median of 2.78 (interquartile range, 2.67 to 2.98) years later among 146 participants. As expected, reappraisal engaged brain systems implicated in emotion regulation. Reappraisal also reduced self-reported negative affect. On average, CA-IMT progressed over the follow-up period. However, multivariate and cross-validated machine-learning models demonstrated that brain activity during reappraisal failed to predict CA-IMT progression. Contrary to hypotheses, brain activity during cognitive reappraisal to reduce negative affect does not appear to forecast the progression of a vascular marker of CVD risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-021-00098-y.

An online Trier social stress paradigm to evoke affective and cardiovascular responses.

In response to the COVID-19 pandemic, prior studies have modified the Trier Social Stress Test to be conducted remotely. The current study aimed to extend these studies to test whether a remote Trier Social Stress Test (rTSST) can elicit (a) affective, (b) blood pressure, and (c) heart rate responses relative to a control condition and whether these responses were reliable when assessed 1 week later. Participants (N = 99, 19.7 ± 3.5 years, 55% female) were randomized to a control or stress condition. Participants received blood pressure monitors in person. Controls completed easier versions of the tasks with a single, friendly researcher. Stress participants performed more difficult versions of the task in front of two judges who participants believed were rating their performance. Blood pressure and heart rate were measured every 2 min throughout, while affect was assessed at baseline, after the final task, and following recovery. The rTSST was feasible to administer with minimal technical issues reported. Participants reported lower positive affect and higher negative affect during the tasks in the stress condition relative to controls. Similarly, stress participants had higher cardiovascular responses during the tasks relative to controls, except that blood pressure was not elevated during mental arithmetic in stress participants relative to controls. Cardiovascular responses demonstrated good test-retest reliability when assessed 1 week later, especially when computed using area under the curve methods. Overall, a rTSST can be used to elicit affective and cardiovascular reactivity and provides an opportunity to increase the accessibility of research participation among diverse populations.

Melanopsin-driven pupil response in summer and winter in unipolar seasonal affective disorder.

A retinal subsensitivity to environmental light may trigger Seasonal Affective Disorder (SAD) under low wintertime light conditions. The main aim of this study was to assess the responses of melanopsin-containing retinal ganglion cells in participants (N= 65) diagnosed with unipolar SAD compared to controls with no history of depression. Participants attended a summer visit, a winter visit, or both. Retinal responses to light were measured using the post-illumination pupil response (PIPR) to assess melanopsin-driven responses in the non-visual light input pathway. Linear mixed-effects modeling was used to test a group*season interaction on the Net PIPR (red minus blue light response, percent baseline). We observed a significant group*season interaction such that the PIPR decreased from summer to winter significantly in the SAD group while not in the control group. The SAD group PIPR was significantly lower in winter compared to controls but did not differ between groups in summer. Only 60% of the participants underwent an eye health exam, although all participants reported no history of retinal pathology, and eye exam status was neither associated with outcome nor different between groups. This seasonal variation in melanopsin driven non-visual responses to light may be a risk factor for SAD, and further highlights individual differences in responses to light for direct or indirect effects of light on mood.

Dual impedance cardiography: An inexpensive and reliable method to assess arterial stiffness.

Pulse wave velocity (PWV) is a common measure of arterial stiffness. Non-invasive methods to measure PWV are widely used in biomedical studies of aging and cardiovascular disease, but they are rarely used in psychophysiology. Barriers to wider use include the prohibitive costs of specialized equipment and need for trained technicians (e.g., ultrasonographers). Here, we describe an impedance cardiography method to measure PWV. By this method, impedance signals are dually collected from the thorax and calf. Combined with ensemble averaging of vascular signals, this dual impedance cardiography (d-ICG) method allows for the measurement of aortic flow onset and the arrival time of peripheral pulse waveforms to compute PWV. In a community sample of adults (aged 19-78 years), PWV measured with d-ICG exhibited a strong positive correlation with age. Moreover, age-specific mean PWV values were within the normative reference intervals established by large scale studies using other techniques. PWV derived from d-ICG exhibited high test-retest reliability across several days, as well as excellent inter-rater reliability. Last, PWV exhibited expected associations with known cardiovascular disease risk factors and indicators of autonomic cardiovascular control. d-ICG is an inexpensive and reliable method to assess arterial stiffness.

Is stressor-evoked cardiovascular reactivity a pathway linking positive and negative emotionality to preclinical cardiovascular disease risk?

Stressor-evoked cardiovascular reactivity, trait positive emotionality, and negative emotionality are all associated with cardiovascular disease. It is unknown, however, whether cardiovascular reactivity may constitute a pathway by which trait positive or negative emotionality relates to disease risk. Accordingly, this study modeled the cross-sectional relationships between trait positive and negative emotionality, stressor-evoked cardiovascular reactivity, and severity of a subclinical vascular marker of cardiovascular risk, carotid artery intima-media thickness (CA-IMT). The sample consisted of healthy, midlife adults free from clinical cardiovascular disease (N = 286; ages 30-54; 50% female). Trait positive and negative emotionality were measured by three questionnaires. Heart rate and blood pressure reactivity were assessed across three stressor tasks. CA-IMT was assessed by ultrasonography. Latent factors of positive and negative emotionality, blood pressure reactivity, heart rate reactivity, and CA-IMT were created using structural equation modeling. Greater negative emotionality was marginally associated with more CA-IMT (ß = .21; p = .049), but lower blood pressure reactivity (ß = -.19; p = .03). However, heightened blood pressure (ß = .21; p = .03), but not heart rate reactivity (ß = -.05; p = .75), associated with greater CA-IMT. Positive emotionality was uncorrelated with cardiovascular reactivity (blood pressure: ß = -.04; p = .61; heart rate: ß = .16; p = .11) and CA-IMT (ß = .16; p = .07). Although trait negative emotionality associates with a known marker of cardiovascular disease risk, independent of positive emotionality, it is unlikely to occur via a stressor-evoked cardiovascular reactivity pathway.

Does well-being associate with stress physiology? A systematic review and meta-analysis.

OBJECTIVE: The current meta-analysis tested whether trait indicators of well-being associate with stressor-evoked physiological reactivity and recovery in healthy adults. METHOD: Medline, PsycINFO, and PubMed were used to identify relevant articles. Articles were included if they (a) measured cardiovascular or neuroendocrine (but not immune) physiology during or after an acute laboratory stress paradigm (b) measured indicators of hedonic well-being, eudaimonic well-being, or optimism, and (c) included healthy adult participants. Laboratory stress tasks included frustrating cognitive tasks, emotional recall tasks, and tasks involving social evaluation. Physiological variables were aggregated across cardiac (heart rate and cardiac output), hemodynamic (mean arterial pressure, systolic blood pressure, and diastolic blood pressure), HPA (cortisol), and autonomic (high frequency heart rate variability, skin conductance, and catecholamines) markers. Twenty-seven studies were included (n = 3,390; 54.6% women). Effect sizes and confidence intervals were estimated using a random-effects model with pooled variance. RESULTS: Contrary to expectations, optimism was associated with greater cardiac reactivity to cognitive stressors but did not associate with stress recovery. By contrast, hedonic well-being was associated with enhanced hemodynamic recovery following laboratory stressors but was not associated with stress reactivity. CONCLUSIONS: Hedonic well-being, but not optimism, could potentially buffer against the effects of psychological stressors on physiological responding by relating to more complete recovery. Identifying the mechanisms contributing to these patterns of association may provide insights into psychological interventions for well-being and stress-related disease risk. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Rest-activity rhythms characteristics and seasonal changes in seasonal affective disorder.

Identifying objectively measurable seasonal changes in 24-h activity patterns (rest-activity rhythms or RARs) that occur in seasonal affective disorder (SAD) could help guide research and practice towards new monitoring tools or prevention targets. We quantified RARs from actigraphy data using non-parametric and extended cosine based approaches, then compared RARs between people with SAD and healthy controls in the summer (n = 70) and winter seasons (n = 84). We also characterized the within-person seasonal RAR changes that occurred in the SAD (n = 19) and control (n = 26) participants who contributed repeated measures. Only controls had significant winter increases in RAR fragmentation (intra-daily variability; in controls mean winter-summer changes (log scale) = 0.05, 0.21 standard deviation, p = 0.03). In SAD participants only, estimated evening settling times (down-mesor) were an average of 30 min earlier in the winter compared with the summer (1-h standard deviation, p = 0.045). These RAR characteristics correlated with greater fatigue (Spearman r = 0.36) but not depression symptom severity. Additional research is needed to ascertain why healthy controls, but not people with SAD, appear to have increased RAR fragmentation in the winter. People with SAD lacked this increase in RAR fragmentation, and instead had earlier evening setting in the winter. Prospective and intervention studies with greater temporal resolution are warranted to ascertain how these seasonal behavioral differences relate to fatigue pathophysiology in SAD. Future research is needed to determine whether extending the winter active period, even in relatively fragmented bouts, could help reduce the fatigue symptoms common in SAD.

Disturbances in the FGFR1-5-HT1A Heteroreceptor Complexes in the Raphe-Hippocampal 5-HT System Develop in a Genetic Rat Model of Depression.

The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.

Hippocampal-Dependent Antidepressant Action of the H3 Receptor Antagonist Clobenpropit in a Rat Model of Depression.

BACKGROUND: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission. METHODS: Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons. RESULTS: Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment. Clobenpropit enhanced hippocampal plasticity, but did not affect EPSCs. H1R and H2R antagonists prevented the clobenpropit-induced increase in LTP and, injected locally into the hippocampus, blocked clobenpropit's effect in the forced swim test. CONCLUSIONS: Clobenpropit's antidepressant effects and the enhanced synaptic plasticity require hippocampal H1R and H2R activation, suggesting that clobenpropit acts through disinhibition of histamine release. Clobenpropit reverses memory deficits and increases hippocampal GluN2A expression without modifying anxiety-related phenotypes or EPSCs in CA1 pyramidal neurons.

Impaired trace fear conditioning and diminished ERK1/2 phosphorylation in the dorsal hippocampus of adult rats administered alcohol as neonates.

Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N-methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec.

Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory-enhancing effect of reboxetine.

Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D1/5 receptors.