Individual Differences in Cerebral Perfusion as a Function of Age and Loneliness.

Loneliness is defined as the subjective feeling that one's social needs are not satisfied by both quantity and quality of one's social relationships. Loneliness has been linked to a broad range of adverse physical and mental health consequences. There is an interest in identifying the neural and molecular processes by which loneliness adversely affects health. Prior imaging studies reported divergent networks involved in cognitive, emotional, and social processes associated with loneliness. Although loneliness is common among both younger and older adults, it is experienced differently across the lifespan and has different antecedents and consequences. The current study measured regional cerebral blood flow (CBF) using pulsed arterial spin labeling imaging. Forty-five older (Mage = 63.4) and forty-four younger adults (Mage = 20.9) with comparable degrees of loneliness were included. Whole-brain voxel-wise analysis revealed a main effect of age (in superior temporal and supramarginal gyri), but no main effect of loneliness. Furthermore, the age effect was only observed among people who reported higher level of loneliness. These regions have previously been implicated in social- and attention-related functions. The moderation of loneliness on age and regional CBF suggests that younger and older individuals present differential neural manifestations in response to loneliness, even with comparable levels of loneliness.

3D MRI of whole-brain water permeability with intrinsic diffusivity encoding of arterial labeled spin (IDEALS).

This work proposes a novel MRI method - Intrinsic Diffusivity Encoding of Arterial Labeled Spin (IDEALS) - for the whole-brain mapping of water permeability in the human brain without an exogenous contrast agent. Quantitative separation of the intravascular and extravascular labeled water MRI signal was achieved in arterial spin labeling experiments with segmented 3D-GRASE acquisition by modulating the relative sensitivity between relaxation, true diffusion, and pseudodiffusion. The intrinsic diffusivity encoding in k-space created different broadening of the image-domain point spread functions for intravascular and extravascular labeled spins, from which blood-brain barrier (BBB) water extraction fraction (Ew) and water permeability surface area product (PSw) were estimated. The feasibility and sensitivity of this method was evaluated in healthy subjects at baseline and after caffeine challenge. The estimated baseline Ew and PSw maps showed contrast among gray matter (GM) and white matter (WM). GM Ew was significantly lower than that of WM (78.8% ±â€¯3.3% in GM vs. 83.9% ±â€¯4.6% in WM; p < 0.05) and GM PSw was significantly higher than that of WM (131.7 ±â€¯29.5 mL/100  g/min in GM vs. 76.2 ±â€¯18.4 mL/100  g/min in WM; p < 0.05). BBB Ew was significantly lower for females than males (74.9% ±â€¯3.7% for females vs. 81.3% ±â€¯3.3% for males in GM; 80.5% ±â€¯4.7% for females vs. 86.1 ±â€¯3.0 for males in WM; p < 0.05 for both), while significant PSw differences were only observed in WM (143.8 ±â€¯34.4 mL/100  g/min for females vs. 123.6 ±â€¯24.4 mL/100  g/min for males in GM; 91.6 ±â€¯15.0 mL/100  g/min for females vs. 65.9 ±â€¯12.5 mL/100  g/min for males in WM; p = 0.20 and p < 0.05 for GM and WM respectively). Significant correlations between Ew and CBF (r = -0.32, p < 0.05) and between PSw and CBF (r = 0.89, p < 0.05) were observed, consistent with 15O-H2O PET findings. After caffeine challenge, reduced CBF, Ew and PSw were observed, demonstrating the sensitivity of IDEALS approach.

Early life stress and cortisol: A meta-analysis.

Given the high prevalence of early life stress (ELS) and the potential physiological dysregulation such experiences can lead to, this meta-analysis tested the relationship between ELS and cortisol. Search terms related to ELS and cortisol were entered in to PsycINFO and PubMed. Effect sizes were extracted for four outcomes variables: cortisol awakening response (CAR), baseline cortisol (cortisol at one time point), non-stressed cortisol over time (cortisol captured at two or more time points), and cortisol reactivity to an acute stressor. The articles were additionally coded for potential confounding variables, population-related, ELS-related and cortisol-related moderators. There was no significant relationship between ELS and the CAR (g=0.19, p=0.268), ELS and baseline cortisol (g=-0.072, p=0.328), ELS and non-stressed cortisol over time (g=0.09, p=0.292) or ELS and cortisol reactivity (g=-0.089, p=0.363). However, there was a significant amount of heterogeneity amongst relationships. Within the ELS-CAR relationship, in those who had experienced ELS that was sexually, physically or emotionally abusive, the CAR was heightened. Within the ELS-Baseline relationship, if blood samples were collected the ELS was associated with a blunting effect of cortisol. The non-significant main effects challenge the commonly held belief in the literature that ELS affects cortisol later in life. However, the high degree of heterogeneity uncovered by this analysis and significant moderators suggest that the literature may benefit from consistent operationalizations of ELS and standardized methods of how cortisol is measured.

Emotion regulation and amygdala-precuneus connectivity: Focusing on attentional deployment.

Attentional deployment is an emotion regulation strategy that involves shifting attentional focus. Deploying attention to non-arousing, compared to arousing, regions of unpleasant images has been associated with reduced negative affect, reduced amygdala activation, and increased activity in fronto-parietal control networks. The current study examined neural correlates and functional connectivity associated with using attentional deployment to increase negative affect (deploying attention towards arousing unpleasant information) or to decrease negative affect (deploying attention away from arousing unpleasant information), compared to naturally viewing unpleasant images, in 42 individuals while concurrently monitoring eye movements. Directing attention to both arousing and non-arousing regions resulted in enhanced fronto-parietal activation compared to natural viewing, but only directing attention to non-arousing regions was associated with changes in amygdala activation. There were no significant differences in connectivity between naturally viewing unpleasant images and focusing on arousing regions. However, naturally viewing unpleasant images, relative to focusing on non-arousing regions, was associated with increased connectivity between the amygdala and visual cortex, while focusing on non-arousing regions of unpleasant images, compared to natural viewing, was associated with increased connectivity between the amygdala and the precuneus. Amygdala-precuneus connectivity correlated positively with eye-tracking measures of attentional deployment success and with trait reappraisal. Deploying attention away from arousing unpleasant information, then, may depend upon functional relationships between the amygdala and parietal regions implicated in attentional control. Furthermore, these relationships might relate to the ability to successfully implement attentional deployment, and the predisposition to utilize adaptive emotion regulation strategies.

Digital Media and Developing Brains: Concerns and Opportunities.

Purpose of Review: The incorporation of digital technologies and their use in youth's everyday lives has been increasing rapidly over the past several decades with possible impacts on youth development and mental health. This narrative review aimed to consider how the use of digital technologies may be influencing brain development underlying adaptive and maladaptive screen-related behaviors. Recent Findings: To explore and provide direction for further scientific inquiry, an international group of experts considered what is known, important gaps in knowledge, and how a research agenda might be pursued regarding relationships between screen media activity and neurodevelopment from infancy through childhood and adolescence. While an understanding of brain-behavior relationships involving screen media activity has been emerging, significant gaps exist that have important implications for the health of developing youth. Summary: Specific considerations regarding brain-behavior relationships involving screen media activity exist for infancy, toddlerhood, and early childhood; middle childhood; and adolescence. Transdiagnostic frameworks may provide a foundation for guiding future research efforts. Translating knowledge gained into better interventions and policy to promote healthy development is important in a rapidly changing digital technology environment.

Neural correlates of attentional deployment within unpleasant pictures.

Attentional deployment is an emotion regulation strategy that involves shifting attentional focus towards or away from particular aspects of emotional stimuli. Previous studies have highlighted the prevalence of attentional deployment and demonstrated that it can have a significant impact on brain activity and behavior. However, little is known about the neural correlates of this strategy. The goal of the present studies was to examine the effect of attentional deployment on neural activity by directing attention to more or less arousing portions of unpleasant images. In Studies 1 and 2, participants passively viewed counterbalanced blocks of unpleasant images without a focus, unpleasant images with an arousing focus, unpleasant images with a non-arousing focus, neutral images without a focus, and neutral images with a non-arousing focus for 4000 ms each. In Study 2, eye-tracking data were collected on all participants during image acquisition. In both studies, affect ratings following each block indicated that participants felt significantly less negative affect after viewing unpleasant images with a non-arousing focus compared to unpleasant images with an arousing focus. In both studies, the unpleasant non-arousing focus condition compared to the unpleasant arousing focus condition was associated with increased activity in frontal and parietal regions implicated in inhibitory control and visual attention. In Study 2, the unpleasant non-arousing focus condition compared to the unpleasant arousing focus condition was associated with reduced activity in the amygdala and visual cortex. Collectively these data suggest that attending to a non-arousing portion of an unpleasant image successfully reduces subjective negative affect and recruits fronto-parietal networks implicated in inhibitory control. Moreover, when ensuring task compliance by monitoring eye movements, attentional deployment modulates amygdala activity.

"Nothing to see here": No structural brain differences as a function of the Big Five personality traits from a systematic review and meta-analysis.

Personality reflects social, affective, and cognitive predispositions that emerge from genetic and environmental influences. Contemporary personality theories conceptualize a Big Five Model of personality based on the traits of neuroticism, extraversion, agreeableness, conscientiousness, and openness to experience. Starting around the turn of the millennium, neuroimaging studies began to investigate functional and structural brain features associated with these traits. Here, we present the first study to systematically evaluate the entire published literature of the association between the Big Five traits and three different measures of brain structure. Qualitative results were highly heterogeneous, and a quantitative meta-analysis did not produce any replicable results. The present study provides a comprehensive evaluation of the literature and its limitations, including sample heterogeneity, Big Five personality instruments, structural image data acquisition, processing, and analytic strategies, and the heterogeneous nature of personality and brain structures. We propose to rethink the biological basis of personality traits and identify ways in which the field of personality neuroscience can be strengthened in its methodological rigor and replicability.

Long story short: the serotonin transporter in emotion regulation and social cognition.

The gene encoding the serotonin transporter (5-HTT) contains a regulatory variation that has been associated with anxiety-related traits and susceptibility for depression. Here we highlight recent discoveries related to allelic variation of 5-HTT function with respect to emotion regulation and social behavior, drawing from an interdisciplinary perspective of behavioral genetics and cognitive neuroscience. Following a reductionistic path that leads from gene-behavior association studies to neuroimaging and epigenetic studies, we compare two models of 5-HTT-dependent modulation of brain activity and discuss the role of life stress experience in modifying 5-HTT function in the brain. Integration of these findings suggests that the impact of the 5-HTT gene on behavior is much broader than is commonly appreciated and may have a role in social cognition.

Integrated microRNA and mRNA gene expression in peripheral blood mononuclear cells in response to acute psychosocial stress: a repeated-measures within-subject pilot study.

OBJECTIVE: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with current research efforts directed at possible mechanisms. Here, we focused on a potential mechanism involving differential expression of mRNA and microRNA in response to acute psychosocial stress. We utilized a validated behavioral paradigm, the Trier Social Stress Test (TSST), to induce acute psychosocial stress in a cohort of volunteers. Stress reactivity was assessed repeatedly during the TSST using saliva samples that were analyzed for levels of cortisol. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. Total RNA was extracted, and mRNA and microRNA microarrays were utilized to assess within-subject changes in gene expression between baseline and the two post-stressor time points. RESULTS: For microarray gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, as an indicator of robust HPA-axis activation. We discovered a set of mRNAs and miRNAs that exhibited dynamic expression change in response to the TSST in peripheral blood mononuclear cells, further characterizing the link between psychosocial stress and cellular response mechanisms.

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218.

Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twenty postmortem samples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA-protein-miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed that SV2A is associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278). Postmortem amygdala expression profiling implicated three putative regulatory miRNAs to target SV2A: miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from the SV2A dual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenous SV2A mRNA and protein levels, confirming miRNA targeting of the SV2A gene. This study illustrates the utility of combining postmortem gene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology.

Emotional memory function, personality structure and psychopathology: a neural system approach to the identification of vulnerability markers.

It is well established that emotional events are ingrained stronger into memory relative to neutral events. Facilitated emotional memory is highly variable between individuals within the normal population and is particularly exacerbated in those diagnosed with mood and anxiety disorders. In order to elucidate how variation of enhanced emotional memory within the normal population may manifest into psychopathological states, we explored the convergence between studies investigating the neural systems engaged in emotional memory facilitation and studies investigating how these systems differ from person to person. Converging evidence highlights the roles of three neural systems (1. Amygdala function and attention, 2. Neuroendocrine function, 3. Interactive effects with mood) that all govern emotional memory facilitation and are highly variable between individuals as a function of personality. We applied this neural system approach to models of vulnerability of three forms of psychopathology that are particularly characterized by atypical emotional memory function (depression, generalized anxiety disorder and post-traumatic stress disorder). This application suggests that the incorporation of known vulnerability markers across psychological, neuroimaging and neuroendocrinological domains is cardinal to how susceptibility is conceptualized and assessed in these disorders.

A model of human endogenous retrovirus (HERV) activation in mental health and illness.

Despite strong evidence for the heritability of major depressive disorder (MDD), efforts to identify causal genes have been disappointing. Furthermore, although there is strong support for life stress as a major predictor of MDD, there are also considerable individual differences in susceptibility and resilience that remain poorly understood. Efforts to identify specific gene-by-environment risk factors produced results that were initially encouraging, but that were not supported by later large-scale studies. Here I propose a novel mechanism that could address the "missing heritability" of MDD, the role of environmental risk factors, and individual differences in susceptibility and resilience. This mechanism focuses on a class of transposable elements, Human Endogenous Retroviruses (HERVs), which make up approximately 8% of the human genome as the result of ancient retroviral infections that entered mammalian germ lines throughout the course of evolution. My primary hypothesis is that exposure to either exogenous viruses or traumatic experiences can activate HERVs in the brain to cause depressive (and possibly other psychiatric) symptoms. My secondary hypothesis is that individual differences in vulnerability or resilience result from the balance of activated HERVs with pathogenic versus protective functions in the brain. Future research can test these hypotheses by analysis of postmortem human brain tissue from donors with known viral or trauma histories; animal studies manipulating HERV expression; cell culture studies examining regulatory mechanisms of HERV expression; and from brain imaging studies of individuals with known HERV-expression. Such research may reveal novel functions of HERVs in neural tissue and may lead to a new generation of psychiatric interventions designed to target aberrant HERV activation.

Early Life Stress, Physiology, and Genetics: A Review.

Early life stress (ELS) is a widely studied concept due to both its prevalent nature and its (presumed) detrimental consequences. In this review, we discuss the relationship between ELS and its underlying physiology spanning the sympathetic nervous system, hypothalamic-pituitary-adrenal axis, and markers of inflammation related to immune function in both human and animal literature. We also consider the potential role of genetic and epigenetic factors on the ELS-health outcome relationship. We conclude with recommendations to overcome identified shortcomings in a field that seeks to address the health consequences of ELS.

An fMRI study of loneliness in younger and older adults.

Loneliness, the subjective experience of social isolation, may reflect, in part, underlying neural processing of social signals. Aging may exacerbate loneliness due to decreased social networks and increased social isolation, or it may reduce loneliness due to preferential attentional processing of positive information and increased interactions with emotionally close partners. Here, we conducted a functional magnetic resonance imaging (fMRI) study of loneliness in younger (N = 50, 26 female, Mage = 20.4) and older (N = 49, 30 female, Mage = 62.9) adults. Compared to younger adults, older adults were less lonely and dwelled longer on faces, regardless of valence. Previous studies in younger adults found that loneliness was negatively correlated with ventral striatal (VS) activation to pleasant social pictures of strangers yet positively correlated with VS activation to faces of close others. In the present study, we observed no association between loneliness and VS activation to social pictures of strangers in either age group. Further, unlike previous studies, we observed no association between social network size and amygdala activation to social stimuli. Additional research is needed to examine the effect of loneliness and social network size on neural processing of different dimensions of social stimuli.

Stop the sadness: Neuroticism is associated with sustained medial prefrontal cortex response to emotional facial expressions.

Neuroticism is a personality trait associated with negative mood states, sensitivity to negative information, negative appraisal and vulnerability to psychopathology. Previous studies have associated the sustained processing of negative information (words) with individual differences such as rumination and depression but not with personality. In the current study, we aimed to investigate the relationship between neuroticism and changes in sustained patterns of activity within a brain region implicated in emotional self-evaluation and appraisal, the Medial Prefrontal Cortex (MedPFC), when responding to emotional facial expressions (happy, fearful, and sad). We tested whether higher scores of neuroticism are associated with greater sustained patterns of brain activity in the MedPFC when responding to blocks of negative facial expressions. We found that higher scores of neuroticism were associated with greater sustained MedPFC activity throughout blocks of sad facial expressions, but not fearful or happy facial expressions. Based on the relationship between neuroticism and sensitivity to negative information, the current finding identifies a sustained temporal mechanism to this relationship.

Toward a neurogenetic theory of neuroticism.

Recent advances in neuroscience and molecular biology have begun to identify neural and genetic correlates of complex traits. Future theories of personality need to integrate these data across the behavioral, neural, and genetic level of analysis and further explain the underlying epigenetic processes by which genes and environmental variables interact to shape the structure and function of neural circuitry. In this chapter, I will review some of the work that has been conducted at the cognitive, neural, and molecular genetic level with respect to one specific personality trait-neuroticism. I will focus particularly on individual differences with respect to memory, self-reference, perception, and attention during processing of emotional stimuli and the significance of gene-by-environment interactions. This chapter is intended to serve as a tutorial bridge for psychologists who may be intrigued by molecular genetics and for molecular biologists who may be curious about how to apply their research to the study of personality.

Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing.

Individual differences in brain response to emotional stimuli have previously been associated with gene variations within the serotonin transporter (5-HTT) and tryptophan hydroxylase-2 (TPH2) genes. We recently reported that these two genes exhibit an additive effect, based on recordings of event-related potentials (ERPs) from individuals viewing emotional scenes. The current study was designed to replicate and extent this initial report in an independent study sample, and use functional magnetic resonance imaging (fMRI) to identify specific neural loci that may mediate the 5-HTT-TPH2 additive effect. Furthermore, we sought to obtain convergent evidence for a gene-gene additive effect by collecting fMRI data from the same individuals engaged in two different cognitive-affective tasks, using emotional and neutral facial expressions and word stimuli. We found evidence for an additive effect of 5-HTT-TPH2 genotype, which was most robust in the putamen, a region rich in both 5-HTT and TPH2 protein, but was also observed in the amygdala at a less stringent threshold, and in other cortical regions. The additive effect was more robust effect for visuospatial than for verbal stimuli, and more robust for negatively than for positively valenced stimuli. These findings confirm and extend the additive effect of two critical genes in the serotonergic regulation of neural processing of affective stimuli, and identify the striatum as a critical site where is gene-gene regulation takes place.

A neurogenetic approach to impulsivity.

Impulsivity is a complex and multidimensional trait that is of interest to both personality psychologists and to clinicians. For investigators seeking the biological basis of personality traits, the use of neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) revolutionized personality psychology in less than a decade. Now, another revolution is under way, and it originates from molecular biology. Specifically, new findings in molecular genetics, the detailed mapping and the study of the function of genes, have shown that individual differences in personality traits can be related to individual differences within specific genes. In this article, we will review the current state of the field with respect to the neural and genetic basis of trait impulsivity.

Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: implications for impulsivity.

Impulsivity, a highly prevalent symptom in multiple psychiatric disorders, is a partially heritable trait influenced by specific biological mechanisms. In particular, dopamine is proposed to play a role in impulsive behaviors and recent studies have implicated functional polymorphisms of dopamine-related genes in impulsive behaviors across different clinical and behavioral classifications. However, most have not isolated the impulsivity construct per se as a biologically based and measurable endophenotype. The present study was therefore undertaken in a sample of healthy adults to investigate the influence of two candidate dopaminergic gene polymorphisms (DRD4 and DAT) on the endophenotype of impulsivity, which we operationalized as behavioral inhibition during the Stop-signal task. We recruited an ethnically diverse sample of 119 healthy adults to complete a self-report questionnaire of impulsivity and to perform a Stop-signal task. We report significant differences in inhibitory control between individuals with at least one 7-repeat allele of the DRD4 polymorphism, as well as an interaction between DRD4 and DAT genotypes, on inhibitory control. Results of the present study support the influence of dopaminergic variation on impulsive-related measures, as well as the advantage of using measures which are likely more sensitive to the effects of such genetic variation.