RESUMO
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.
RESUMO
BACKGROUND: Individuals who exhibit large-magnitude blood pressure (BP) reactions to acute psychological stressors are at risk for hypertension and premature death by cardiovascular disease. This study tested whether a multivariate pattern of stressor-evoked brain activity could reliably predict individual differences in BP reactivity, providing novel evidence for a candidate neurophysiological source of stress-related cardiovascular risk. METHODS AND RESULTS: Community-dwelling adults (N=310; 30-51 years; 153 women) underwent functional magnetic resonance imaging with concurrent BP monitoring while completing a standardized battery of stressor tasks. Across individuals, the battery evoked an increase systolic and diastolic BP relative to a nonstressor baseline period (M ∆systolic BP/∆diastolic BP=4.3/1.9 mm Hg [95% confidence interval=3.7-5.0/1.4-2.3 mm Hg]). Using cross-validation and machine learning approaches, including dimensionality reduction and linear shrinkage models, a multivariate pattern of stressor-evoked functional magnetic resonance imaging activity was identified in a training subsample (N=206). This multivariate pattern reliably predicted both systolic BP (r=0.32; P<0.005) and diastolic BP (r=0.25; P<0.01) reactivity in an independent subsample used for testing and replication (N=104). Brain areas encompassed by the pattern that were strongly predictive included those implicated in psychological stressor processing and cardiovascular responding through autonomic pathways, including the medial prefrontal cortex, anterior cingulate cortex, and insula. CONCLUSIONS: A novel multivariate pattern of stressor-evoked brain activity may comprise a phenotype that partly accounts for individual differences in BP reactivity, a stress-related cardiovascular risk factor.