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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. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is a major source of medical comorbidity for patients with mood and anxiety disorders, and it remains the leading public health burden for the general population in industrialized nations. Indirect neurobiological evidence suggests that preclinical risk for atherosclerosis, the main contributor to CVD, may be conferred by interindividual variation in the functionality of the amygdala, a brain system jointly involved in processing behaviorally salient stimuli and regulating the cardiovascular system. Methods: In a neuroimaging study of 36 middle-aged adults (18 women) who were screened for confounding clinical cardiovascular and psychiatric disorders, we examined the direct covariation between a marker of preclinical atherosclerosis, carotid artery intima-media thickness (IMT), and interindividual variation in amygdala reactivity and functional connectivity assessed during the processing of behaviorally salient stimuli (angry and fearful facial expressions). Results: After accounting for traditional CVD risk factors, a thickening of carotid IMT across individuals covaried with greater amygdala reactivity and a more positive functional connectivity between the amygdala and perigenual anterior cingulate cortex, a corticolimbic area also implicated in behavioral salience processing and cardiovascular regulation. Conclusions: Individual differences in amygdala reactivity and functional connectivity may reflect facets of a novel, systems-level neural phenotype conferring risk for atherosclerosis and CVD. [Copyright &y& Elsevier]

Objective: To characterize the functional neuroanatomy of late-life depression (LLD) by probing for both episodic and persistent alterations in the executive-control circuit of elderly adults. Design: Event-related functional magnetic resonance imaging (fMRI) data were collected while participants performed an executive-control task. Setting: Participants were recruited through a depression-treatment study within the Pittsburgh, PA, Intervention Research Center for Late-Life Mood Disorders. Participants: Thirteen nondepressed elderly comparison participants and 13 LLD patients. Intervention: The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine. Measurements: Regional fMRI activity was assessed in the dorsolateral prefrontal cortex (dLPFC: BA9 and BA46 bilaterally) and the dorsal anterior cingulate cortex (dACC). Functional connectivity was assessed by correlating the fMRI time-series in the dLPFC and dACC. Results: Both depressed and comparison participants performed the task as expected, with greater response latency during high versus low-load trials. The response-latency load-effect did not differ between groups. In contrast to the null findings for behavioral data, pretreatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25) = 1.9, p = 0.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25) = 2.17, p <0.02) showed increased activity after treatment. Conclusions: These results support a model of both episodic and persistent neurobiologic components of LLD. The altered functional connectivity, perhaps due to vascular damage to frontal white matter, appears to be persistent. Further, at least some of the prefrontal hypoactivity (in the right dLPFC) seems to be an episodic characteristic of acute depression amenable to treatment. [ABSTRACT FROM AUTHOR]

Background: Converging animal findings suggest that higher peripheral levels of inflammation are associated with activation of central inflammatory mechanisms that result in hippocampal neurodegeneration and related impairment of memory function. We have recently shown, consistent with animal findings, an inverse association between peripheral levels of interleukin-6 (IL-6), a relatively stable marker of systemic inflammation, and memory function in mid-life adults. In the current study, we extend this work to test whether systemic inflammation is associated with reduced grey matter volume of the hippocampus. Methods: For this purpose, we used a computational structural neuroimaging method (optimized voxel-based morphometry) to evaluate the relationship between plasma IL-6 levels and hippocampal grey matter volume in a sample of 76 relatively healthy community volunteers ages 30–54. Results: Peripheral levels of IL-6 covaried inversely with hippocampal grey matter volume, and this relationship persisted after accounting for several possible confounders, including age, gender, race, years of education, percent body fat, blood pressure, smoking, physical activity, hours of sleep, alcohol use, and total grey matter volume. Conclusions: To our knowledge, this is the first report of a relationship between a peripheral marker of IL-6 and hippocampal grey matter volume, raising the possibility that low-grade systemic inflammation could plausibly presage subclinical cognitive decline in part via structural neural pathways. [Copyright &y& Elsevier]

Abstract: Background: In animals, dendritic arborization and levels of brain derived neurotrophic factor are positively associated with intake of the omega-3 fatty acids. Here, we test whether omega-3 fatty acid intake in humans varies with individual differences in gray matter volume, an in vivo, systems-level index of neuronal integrity. Methods: Fifty-five healthy adults completed two 24h dietary recall interviews. Intake of long-chain omega-3 fatty acids was categorized by tertiles. Regional gray matter volumes in a putative emotional brain circuitry comprised of the anterior cingulate cortex (ACC), amygdala and hippocampus were calculated using optimized voxel-based morphometry on high-resolution structural magnetic resonance images. Results: Region of interest analyses revealed positive associations between reported dietary omega-3 intake and gray matter volume in the subgenual ACC, the right hippocampus and the right amygdala, adjusted for total gray matter volume of brain. Unconstrained whole-brain analyses confirmed that higher intake of omega-3 fatty acids was selectively associated with increased greater gray matter volume in these and not other regions. Conclusions: Higher reported consumption of the long-chain omega-3 fatty acids is associated with greater gray matter volume in nodes of a corticolimbic circuitry supporting emotional arousal and regulation. Such associations may mediate previously observed effects of omega-3 fatty acids on memory, mood and affect regulation. [Copyright &y& Elsevier]

Compared to others, individuals living in communities of socioeconomic disadvantage experience more atherosclerotic cardiovascular disease (CVD) and a greater extent of preclinical atherosclerosis. Although the mechanisms underlying these associations remain unclear, it is widely hypothesized that alterations in normative cortisol release from the Hypothalamic Pituitary Adrenal (HPA) axis may play a role in linking lower community socioeconomic position (C-SEP) to CVD risk. The current study examined this hypothesis in relation to a marker of preclinical atherosclerosis among 488 healthy midlife adults (30–54 years, Mean age= 43, 52% Female, 81% White). All participants were employed and without clinical CVD. C-SEP was estimated from census tract data, and atherosclerosis was measured as intima-medial thickness of the carotid arteries (cIMT) by duplex ultrasonography. Four indicators of HPA activity [cortisol at awakening and the cortisol awakening response (CAR), rate of diurnal decline in cortisol (diurnal slope), and total output expressed as area under the curve (AUC)] were derived from salivary cortisol measurements obtained from 5 samples on each of 3 working days. Path analyses were used to examine associations of C-SEP with cIMT and HPA activity and to test whether individual differences in HPA activity could account for any association of C-SEP with cIMT using bootstrapping (5000 iterations). All models were adjusted for age, sex, race, and composite measures of both individual-level socioeconomic position (income, education, occupation), and cardiometabolic risk (systolic and diastolic blood pressure, waist circumference, fasting lipids and glucose). Lower C-SEP was related to both greater cIMT (b = −0.004, p =.021) and a flatter diurnal slope of cortisol (b = −0.001, p =.039). An indirect effect showed attenuated diurnal slope to partially mediate the relationship between C-SEP and cIMT (95% CI = −0.0018 to −0.0001), and a residual direct effect of C-SEP on cIMT remained significant (95% CI = −0.0097 to −0.004). These results suggest that low C-SEP associations with preclinical atherosclerosis may be due in part to correlated variation in adrenocortical activity. • Individual residing in communities of lower socioeconomic position show greater atherosclerosis and alterations in typical HPA dynamics. • A flatter diurnal decline in cortisol partially mediates associations of community level socioeconomic position and atherosclerosis. • This relationship persists after accounting for individual-level socioeconomic position and standard cardiometabolic risk factors. [ABSTRACT FROM AUTHOR]

Purpose: The present study examined whether susceptibility to nausea and other symptoms of vection-induced motion sickness vary as a function of phase of the menstrual cycle, as research findings in this area are sparse and contradictory. Design: Ninety young women (42 current users of oral contraceptives) were exposed to a rotating optokinetic drum during the peri-menses or peri-ovulatory phase of the menstrual cycle in an independent-groups, quasi-experimental design. Nausea and motion sickness symptoms were assessed using the Nausea Profile (NP) and the Subjective Symptoms of Motion Sickness (SSMS) questionnaire. Results: Among women not on oral contraceptives, reports of nausea and motion sickness by women in the peri-menses phase were more severe than reports by women in the peri-ovulatory phase. By contrast, among women taking oral contraceptives, reports of nausea and motion sickness did not differ by the same categorical phase of the menstrual cycle. Conclusions: We speculate that fluctuating estrogen levels over the course of the menstrual cycle may influence the experience of or susceptibility to nausea and motion sickness during illusory self-motion and other nauseogenic contexts. [Copyright &y& Elsevier]

Highlights • Review of brain regions and networks associated with peripheral inflammation. • Meta-analysis of 24 neuroimaging studies revealed consistently reported regions. • Some regions were specific to study design and task. • Patterns of regions resembled intrinsic brain networks and corticostriatal loops. • Co-activated regions formed prefrontal-brainstem and insula-brainstem ensembles. Abstract Communication between the brain and peripheral mediators of systemic inflammation is implicated in numerous psychological, behavioral, and physiological processes. Functional neuroimaging studies have identified brain regions that associate with peripheral inflammation in humans, yet there are open questions about the consistency, specificity, and network characteristics of these findings. The present systematic review provides a meta-analysis to address these questions. Multilevel kernel density analysis of 24 studies (37 statistical maps; 264 coordinates; 457 participants) revealed consistent effects in the amygdala, hippocampus, hypothalamus, striatum, insula, midbrain, and brainstem, as well as prefrontal and temporal cortices. Effects in some regions were specific to particular study designs and tasks. Spatial pattern analysis revealed significant overlap of reported effects with limbic, default mode, ventral attention, and corticostriatal networks, and co-activation analyses revealed functional ensembles encompassing the prefrontal cortex, insula, and midbrain/brainstem. Together, these results characterize brain regions and networks associated with peripheral inflammation in humans, and they provide a functional neuroanatomical reference point for future neuroimaging studies on brain-body interactions. [ABSTRACT FROM AUTHOR]

Psychologically stressful experiences evoke changes in cardiovascular physiology that may influence risk for cardiovascular disease (CVD). But what are the neural circuits and intermediate physiological pathways that link stressful experiences to cardiovascular changes that might in turn confer disease risk? This question is important because it has broader implications for our understanding of the neurophysiological pathways that link stressful and other psychological experiences to physical health. This review highlights selected findings from brain imaging studies of stressor-evoked cardiovascular reactivity and CVD risk. Converging evidence across these studies complements animal models and patient lesion studies to suggest that a network of cortical, limbic, and brainstem areas for central autonomic and physiological control are important for generating and regulating stressor-evoked cardiovascular reactivity via visceromotor and viscerosensory mechanisms. Emerging evidence further suggests that these brain areas may play a role in stress-related CVD risk, specifically by their involvement in mediating metabolically-dysregulated or extreme stressor-evoked cardiovascular reactions. Contextually, the research reviewed here offers an example of how brain imaging and health neuroscience methods can be integrated to address open and mechanistic questions about the neurophysiological pathways linking psychological stress and physical health. [ABSTRACT FROM AUTHOR]

Background Mindfulness meditation training interventions have been shown to improve markers of health, but the underlying neurobiological mechanisms are not known. Building on initial cross-sectional research showing that mindfulness meditation may increase default mode network (DMN) resting-state functional connectivity (rsFC) with regions important in top-down executive control (dorsolateral prefrontal cortex [dlPFC]), here we test whether mindfulness meditation training increases DMN-dlPFC rsFC and whether these rsFC alterations prospectively explain improvements in interleukin (IL)-6 in a randomized controlled trial. Methods Stressed job-seeking unemployed community adults ( n = 35) were randomized to either a 3-day intensive residential mindfulness meditation or relaxation training program. Participants completed a 5-minute resting-state scan before and after the intervention program. Participants also provided blood samples at preintervention and at 4-month follow-up, which were assayed for circulating IL-6, a biomarker of systemic inflammation. Results We tested for alterations in DMN rsFC using a posterior cingulate cortex seed-based analysis and found that mindfulness meditation training, and not relaxation training, increased posterior cingulate cortex rsFC with left dlPFC ( p < .05, corrected). These pretraining to posttraining alterations in posterior cingulate cortex-dlPFC rsFC statistically mediated mindfulness meditation training improvements in IL-6 at 4-month follow-up. Specifically, these alterations in rsFC statistically explained 30% of the overall mindfulness meditation training effects on IL-6 at follow-up. Conclusions These findings provide the first evidence that mindfulness meditation training functionally couples the DMN with a region known to be important in top-down executive control at rest (left dlPFC), which, in turn, is associated with improvements in a marker of inflammatory disease risk. [ABSTRACT FROM AUTHOR]

We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70–79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (β = −0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.Methods: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls).Findings: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline.Interpretation: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease.Funding: National Institutes of Health and Howard Hughes Medical Institute. [ABSTRACT FROM AUTHOR]

Abstract: The metabolic syndrome (MetS) is a clustering of cardiovascular and cerebrovascular risk factors that are often comorbid with depressive symptoms. Individual components of the MetS also covary with the morphology of basal ganglia regions that are altered by depression. However, it remains unknown whether the covariation between the MetS and depressive symptomatology can be accounted for in part by morphological changes in the basal ganglia. Accordingly, we tested the hypothesis that increased depressive symptoms among individuals with the MetS might be statistically mediated by reduced gray matter volume in basal ganglia regions. The presence of the MetS was determined in 147 middle-aged adults using the criteria of the National Cholesterol Education Program, Adult Treatment Panel III. Basal ganglia volumes were determined on an a priori basis by automated segmentation of high-resolution magnetic resonance images. Depressive symptoms were assessed using the Patient Health Questionnaire. Even after controlling for demographic and other confounding factors, having the MetS and meeting more MetS criteria covaried with reduced globus pallidus volume. Meeting more MetS criteria and reduced pallidal volume were also related to depressive symptoms. Moreover, the MetS-depression association was statistically mediated by pallidal volume. In summary, reduced globus pallidus volume is a neural correlate of the MetS that may partly account for its association with depressive symptoms. [Copyright &y& Elsevier]

Aims: To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications. Methods: Regional GMV was computed using 3 T MRI of 104 adults with a childhood onset of T1D (mean age: 49 ± 7 and duration: 41 ± 6 years) and 151 adults without diabetes (mean age: 40 ± 6). A Bonferroni threshold (n = 45, p ≤ 0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n = 44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively). Results: Compared to controls, T1D patients had smaller GMV in the frontal lobe (6% to 19% smaller) and adjacent supramarginal and postcentral gyri (8% to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant. Conclusions: These findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age. [ABSTRACT FROM AUTHOR]

The integration of behavioral processes with changes in vagally-controlled heart rate has been the focus of our investigations. A series of studies is reviewed showing that central and peripheral response inhibition is a primary source of transient, vagally-induced cardiac slowing during information processing. Individual differences in such responses are then shown to relate to the amplitude of cardiovascular responses to stressors. Overall, the specificity and sensitivity of vagal responses to higher level cortical function is supported by our research. [Copyright &y& Elsevier]