Beyond Neighborhood Disadvantage: Local Resources, Green Space, Pollution, and Crime as Residential Community Correlates of Cardiovascular Risk and Brain Morphology in Midlife Adults.

OBJECTIVE: Residing in communities characterized by socioeconomic disadvantage confers risk of cardiometabolic diseases. Residing in disadvantaged communities may also confer the risk of neurodegenerative brain changes via cardiometabolic pathways. This study tested whether features of communities-apart from conventional socioeconomic characteristics-relate not only to cardiometabolic risk but also to relative tissue reductions in the cerebral cortex and hippocampus. METHODS: Participants were 699 adults aged 30 to 54 years (340 women; 22.5% non-White) whose addresses were geocoded to compute community indicators of socioeconomic disadvantage, as well as air and toxic chemical pollutant exposures, homicide rates, concentration of employment opportunities, land use (green space), and availability of supermarkets and local resources. Participants also underwent assessments of cortical and hippocampal volumes and cardiometabolic risk factors (adiposity, blood pressure, fasting glucose, and lipids). RESULTS: Multilevel structural equation modeling demonstrated that cardiometabolic risk was associated with community disadvantage ( ß = 0.10, 95% confidence interval [CI] = 0.01 to 0.18), as well as chemical pollution ( ß = 0.11, 95% CI = 0.02 to 0.19), homicide rates ( ß = 0.10, 95% CI = 0.01 to 0.18), employment opportunities ( ß = -0.16, 95% CI = -0.27 to -0.04), and green space ( ß = -0.12, 95% CI = -0.20 to -0.04). Moreover, cardiometabolic risk indirectly mediated the associations of several of these community features and brain tissue volumes. Some associations were nonlinear, and none were explained by participants' individual-level socioeconomic characteristics. CONCLUSIONS: Features of communities other than conventional indicators of socioeconomic disadvantage may represent nonredundant correlates of cardiometabolic risk and brain tissue morphology in midlife.

Affective brain patterns as multivariate neural correlates of cardiovascular disease risk.

This study tested whether brain activity patterns evoked by affective stimuli relate to individual differences in an indicator of pre-clinical atherosclerosis: carotid artery intima-media thickness (CA-IMT). Adults (aged 30-54 years) completed functional magnetic resonance imaging (fMRI) tasks that involved viewing three sets of affective stimuli. Two sets included facial expressions of emotion, and one set included neutral and unpleasant images from the International Affective Picture System (IAPS). Cross-validated, multivariate and machine learning models showed that individual differences in CA-IMT were partially predicted by brain activity patterns evoked by unpleasant IAPS images, even after accounting for age, sex and known cardiovascular disease risk factors. CA-IMT was also predicted by brain activity patterns evoked by angry and fearful faces from one of the two stimulus sets of facial expressions, but this predictive association did not persist after accounting for known cardiovascular risk factors. The reliability (internal consistency) of brain activity patterns evoked by affective stimuli may have constrained their prediction of CA-IMT. Distributed brain activity patterns could comprise affective neural correlates of pre-clinical atherosclerosis; however, the interpretation of such correlates may depend on their psychometric properties, as well as the influence of other cardiovascular risk factors and specific affective cues.

The effects of omega-3 fatty acids on neuropsychological functioning and brain morphology in mid-life adults: a randomized clinical trial.

BACKGROUND: The diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation. METHODS: In a randomized, controlled trial, 271 mid-life adults (30-54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes. RESULTS: Capsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology. CONCLUSIONS: In healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.

Associations of immunometabolic risk factors with symptoms of depression and anxiety: The role of cardiac vagal activity.

OBJECTIVES: This study examined 1) the cross-sectional relationships between symptoms of depression/anxiety and immunometabolic risk factors, and 2) whether these relationships might be explained in part by cardiac vagal activity. METHODS: Data were drawn from the Adult Health and Behavior registries (n = 1785), comprised of community dwelling adults (52.8% women, aged 30-54). Depressive symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D) and the Beck Depression Inventory-II (BDI-II), and anxious symptoms with the Trait Anxiety scale of the State-Trait Anxiety Inventory (STAI-T). Immunometabolic risk factors included fasting levels of triglycerides, high-density lipoproteins, glucose, and insulin, as well as blood pressure, waist circumference, body mass index, C-reactive protein, and interleukin-6. Measures of cardiac autonomic activity were high- and low-frequency indicators of heart rate variability (HRV), standard deviation of normal-to-normal R-R intervals, and the mean of absolute and successive differences in R-R intervals. RESULTS: Higher BDI-II scores, in contrast to CES-D and STAI-T scores, were associated with increased immunometabolic risk and decreased HRV, especially HRV likely reflecting cardiac vagal activity. Decreased HRV was also associated with increased immunometabolic risk. Structural equation models indicated that BDI-II scores may relate to immunometabolic risk via cardiac vagal activity (indirect effect: ß = .012, p = .046) or to vagal activity via immunometabolic risk (indirect effect: ß = -.015, p = .021). CONCLUSIONS: Depressive symptoms, as measured by the BDI-II, but not anxious symptoms, were related to elevated levels of immunometabolic risk factors and low cardiac vagal activity. The latter may exhibit bidirectional influences on one another in a meditational framework. Future longitudinal, intervention, an nonhuman animal work is needed to elucidate the precise and mechanistic pathways linking depressive symptoms to immune, metabolic, and autonomic parameters of physiology that predispose to cardiovascular disease risk.

Socioeconomic Position and Age-Related Disparities in Regional Cerebral Blood Flow Within the Prefrontal Cortex.

OBJECTIVE: Socioeconomic position (SEP) is associated with cerebrovascular health and brain function, particularly in prefrontal cortex and medial temporal lobe regions that exhibit plasticity across the life course. However, it is unknown whether SEP associates with resting cerebral blood flow (CBF), an indicator of baseline brain function, in these regions in midlife, and whether the association is (a) period specific, with independent associations for childhood and adulthood SEP, or driven by life course SEP, and (b) explained by a persistent disparity, widening disparity, or the leveling of disparities with age. METHODS: To address these questions, we analyzed cerebral perfusion derived by magnetic resonance imaging in a cross-sectional study of healthy adults (N = 443) who reported on childhood and adult SEP. Main effects were examined as an index of persistent disparity and age by SEP interactions as reflecting widening or leveling disparities. RESULTS: Stable high SEP across the lifespan was associated with higher global CBF and regional CBF (rCBF) in inferior frontal gyrus. However, childhood SEP was associated with rCBF in middle frontal gyrus, as moderated by age (ß = 0.04, p = .035): rCBF was inversely associated with age only for those whose parents had a high school education or below. No associations were observed for the hippocampus or amygdala. CONCLUSIONS: Life course SEP associations with rCBF in prefrontal cortex are suggestive of persistent disparities, whereas the age by childhood SEP interaction suggests that childhood disadvantage relates to a widening disparity, independent of global differences. These differential patterns in midlife may relate to disparities in later-life cerebrovascular and neurocognitive outcomes.

Systemic inflammation and resting state connectivity of the default mode network.

The default mode network (DMN) encompasses brain systems that exhibit coherent neural activity at rest. DMN brain systems have been implicated in diverse social, cognitive, and affective processes, as well as risk for forms of dementia and psychiatric disorders that associate with systemic inflammation. Areas of the anterior cingulate cortex (ACC) and surrounding medial prefrontal cortex (mPFC) within the DMN have been implicated specifically in regulating autonomic and neuroendocrine processes that relate to systemic inflammation via bidirectional signaling mechanisms. However, it is still unclear whether indicators of inflammation relate directly to coherent resting state activity of the ACC, mPFC, or other areas within the DMN. Accordingly, we tested whether plasma interleukin (IL)-6, an indicator of systemic inflammation, covaried with resting-state functional connectivity of the DMN among 98 adults aged 30-54 (39% male; 81% Caucasian). Independent component analyses were applied to resting state fMRI data to generate DMN connectivity maps. Voxel-wise regression analyses were then used to test for associations between IL-6 and DMN connectivity across individuals, controlling for age, sex, body mass index, and fMRI signal motion. Within the DMN, IL-6 covaried positively with connectivity of the sub-genual ACC and negatively with a region of the dorsal medial PFC at corrected statistical thresholds. These novel findings offer evidence for a unique association between a marker of systemic inflammation (IL-6) and ACC and mPFC functional connectivity within the DMN, a network that may be important for linking aspects of immune function to psychological and behavioral states in health and disease.

Omega-3 Supplementation and the Neural Correlates of Negative Affect and Impulsivity: A Double-Blind, Randomized, Placebo-Controlled Trial in Midlife Adults.

OBJECTIVE: In clinical trials, omega-3 fatty acid supplementation improves symptoms in psychiatric disorders involving dysregulated mood and impulse control, yet it is unclear whether in healthy adults, omega-3 fatty acid supplementation affects mood, impulse control, and the brain systems supporting these processes. Accordingly, this study tested the hypotheses that eciosapentaenoic (EPA) and docosahexaenoic (DHA) acid supplementation reduces negative affect and impulsive behaviors in healthy adults and that these changes correspond to alterations in corticolimbic and corticostriatal brain systems, which support affective and impulsive processes. METHODS: Healthy volunteers (N = 272) consuming 300 mg/d or less of EPA and DHA were enrolled in a double-blind, randomized, placebo controlled clinical trial. The participants received either capsules providing 1000 mg of EPA and 400 mg of DHA versus identical appearing soybean oil capsules per day for 18 weeks. Negative affect and impulsivity were measured by questionnaire and ecological momentary assessment, as well as functional alterations in corticolimbic and corticostriatal brain systems evoked by standardized functional magnetic resonance imaging tasks. RESULTS: There were no group by time interactions for any questionnaire or ecological momentary assessment measures of mood and impulsivity. Likewise, no group by time interactions were observed for functional magnetic resonance imaging responses evoked within corticolimbic and corticostriatal systems. CONCLUSIONS: In healthy adults with low intake of omega-3 fatty acids, moderate-dose supplementation for 18 weeks did not alter affect or impulsive behaviors nor alter corticolimbic and corticostriatal brain functionality. TRIAL REGISTRATION: Trial number NCT00663871.

Community Socioeconomic Disadvantage in Midlife Relates to Cortical Morphology via Neuroendocrine and Cardiometabolic Pathways.

Residing in communities of socioeconomic disadvantage confers risk for chronic diseases and cognitive aging, as well as risk for biological factors that negatively affect brain morphology. The present study tested whether community disadvantage negatively associates with brain morphology via 2 biological factors encompassing cardiometabolic disease risk and neuroendocrine function. Participants were 448 midlife adults aged 30-54 years (236 women) who underwent structural neuroimaging to assess cortical and subcortical brain tissue morphology. Community disadvantage was indexed by US Census data geocoded to participants' residential addresses. Cardiometabolic risk was indexed by measurements of adiposity, blood pressure, glucose, insulin, and lipids. Neuroendocrine function was indexed from salivary cortisol measurements taken over 3 days, from which we computed the cortisol awakening response, area-under-the-curve, and diurnal cortisol decline. Community disadvantage was associated with reduced cortical tissue volume, cortical surface area, and cortical thickness, but not subcortical morphology. Moreover, increased cardiometabolic risk and a flatter (dysregulated) diurnal cortisol decline mediated the associations of community disadvantage and cortical gray matter volume. These effects were independent of age, sex, and individual-level socioeconomic position. The adverse risks of residing in a disadvantaged community may extend to the cerebral cortex via cardiometabolic and neuroendocrine pathways.

Resting state connectivity of the medial prefrontal cortex covaries with individual differences in high-frequency heart rate variability.

Resting high-frequency heart rate variability (HF-HRV) relates to cardiac vagal control and predicts individual differences in health and longevity, but its functional neural correlates are not well defined. The medial prefrontal cortex (mPFC) encompasses visceral control regions that are components of intrinsic networks of the brain, particularly the default mode network (DMN) and the salience network (SN). Might individual differences in resting HF-HRV covary with resting state neural activity in the DMN and SN, particularly within the mPFC? This question was addressed using fMRI data from an eyes-open, 5-min rest period during which echoplanar brain imaging yielded BOLD time series. Independent component analysis yielded functional connectivity estimates defining the DMN and SN. HF-HRV was measured in a rest period outside of the scanner. Midlife (52% female) adults were assessed in two studies (Study 1, N = 107; Study 2, N = 112). Neither overall DMN nor SN connectivity strength was related to HF-HRV. However, HF-HRV related to connectivity of one region within mPFC shared by the DMN and SN, namely, the perigenual anterior cingulate cortex, an area with connectivity to other regions involved in autonomic control. In sum, HF-HRV does not seem directly related to global resting state activity of intrinsic brain networks, but rather to more localized connectivity. A mPFC region was of particular interest as connectivity related to HF-HRV was shared by the DMN and SN. These findings may indicate a functional basis for the coordination of autonomic cardiac control with engagement and disengagement from the environment.

Brain morphology links systemic inflammation to cognitive function in midlife adults.

BACKGROUND: Inflammation is linked to cognitive decline in midlife, but the neural basis for this link is unclear. One possibility is that inflammation associates with adverse changes in brain morphology, which accelerates cognitive aging and later dementia risk. Clear evidence is lacking, however, regarding whether inflammation relates to cognition in midlife via changes in brain morphology. Accordingly, the current study examines whether associations of inflammation with cognitive function are mediated by variation in cortical gray matter volume among midlife adults. METHODS: Plasma levels of interleukin (IL)-6 and C-reactive protein (CRP), relatively stable markers of peripheral systemic inflammation, were assessed in 408 community volunteers aged 30-54 years. All participants underwent structural neuroimaging to assess global and regional brain morphology and completed neuropsychological tests sensitive to early changes in cognitive function. Measurements of brain morphology (regional tissue volumes and cortical thickness and surface area) were derived using Freesurfer. RESULTS: Higher peripheral inflammation was associated with poorer spatial reasoning, short term memory, verbal proficiency, learning and memory, and executive function, as well as lower cortical gray and white matter volumes, hippocampal volume and cortical surface area. Mediation models with age, sex and intracranial volume as covariates showed cortical gray matter volume to partially mediate the association of inflammation with cognitive performance. Exploratory analyses of body mass suggested that adiposity may be a source of the inflammation linking brain morphology to cognition. CONCLUSIONS: Inflammation and adiposity might relate to cognitive decline via influences on brain morphology.

An inflammatory pathway links atherosclerotic cardiovascular disease risk to neural activity evoked by the cognitive regulation of emotion.

BACKGROUND: Cognitive reappraisal is a form of emotion regulation that alters emotional responding by changing the meaning of emotional stimuli. Reappraisal engages regions of the prefrontal cortex that support multiple functions, including visceral control functions implicated in regulating the immune system. Immune activity plays a role in the preclinical pathophysiology of atherosclerotic cardiovascular disease (CVD), an inflammatory condition that is highly comorbid with affective disorders characterized by problems with emotion regulation. Here, we tested whether prefrontal engagement by reappraisal would be associated with atherosclerotic CVD risk and whether this association would be mediated by inflammatory activity. METHODS: Community volunteers (n = 157; 30-54 years of age; 80 women) without DSM-IV Axis-1 psychiatric diagnoses or cardiovascular or immune disorders performed a functional neuroimaging task involving the reappraisal of negative emotional stimuli. Carotid artery intima-media thickness and inter-adventitial diameter were measured by ultrasonography and used as markers of preclinical atherosclerosis. Also measured were circulating levels of interleukin-6 (IL-6), an inflammatory cytokine linked to CVD risk and prefrontal neural activity. RESULTS: Greater reappraisal-related engagement of the dorsal anterior cingulate cortex was associated with greater preclinical atherosclerosis and IL-6. Moreover, IL-6 mediated the association of dorsal anterior cingulate cortex engagement with preclinical atherosclerosis. These results were independent of age, sex, race, smoking status, and other known CVD risk factors. CONCLUSIONS: The cognitive regulation of emotion might relate to CVD risk through a pathway involving the functional interplay between the anterior cingulate region of the prefrontal cortex and inflammatory activity.

Parental education predicts corticostriatal functionality in adulthood.

Socioeconomic disadvantage experienced in early development predicts ill health in adulthood. However, the neurobiological pathways linking early disadvantage to adult health remain unclear. Lower parental education-a presumptive indicator of early socioeconomic disadvantage-predicts health-impairing adult behaviors, including tobacco and alcohol dependencies. These behaviors depend, in part, on the functionality of corticostriatal brain systems that 1) show developmental plasticity and early vulnerability, 2) process reward-related information, and 3) regulate impulsive decisions and actions. Hence, corticostriatal functionality in adulthood may covary directly with indicators of early socioeconomic disadvantage, particularly lower parental education. Here, we tested the covariation between parental education and corticostriatal activation and connectivity in 76 adults without confounding clinical syndromes. Corticostriatal activation and connectivity were assessed during the processing of stimuli signaling monetary gains (positive feedback [PF]) and losses (negative feedback). After accounting for participants' own education and other explanatory factors, lower parental education predicted reduced activation in anterior cingulate and dorsomedial prefrontal cortices during PF, along with reduced connectivity between these cortices and orbitofrontal and striatal areas implicated in reward processing and impulse regulation. In speculation, adult alterations in corticostriatal functionality may represent facets of a neurobiological endophenotype linked to socioeconomic conditions of early development.