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.

"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.

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.

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.

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.

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.

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.

Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex.

Subjective social isolation, loneliness, is associated with poor mental and physical health, but the underlying molecular mechanisms are poorly understood. Here we analyzed loneliness data collected on average 5 years ante-mortem and RNA gene expression at death in postmortem dorsolateral prefrontal cortex (DLPFC) from 181 participants in the Rush Memory and Aging Project (MAP), a longitudinal, prospective cohort study of common chronic conditions of aging. Our analytic protocol controlled for biographical variables (age, sex, education), psychological and health variables (depressive symptoms, interval between assessment and autopsy, slope of cognitive decline, AD pathology, presence of infarcts) and RNA integrity. Our results are based on a pre-ranked Gene Set Enrichment Analysis (GSEA) at FDR-corrected q-values <0.05, using these collections from the Molecular Signatures Database (v6.0 MSigDB): (1) Hallmarks, (2) Canonical, (3) Gene Ontology (GO), (4) Chemical and Genetic Perturbations, (5) Immunologic Signatures, (6) Oncogenic Signatures, and (7) Cancer Modules. We now report on 337 up-regulated and 43 down-regulated gene sets, among which the most significant ones were associated with Alzheimer's disease, psychiatric illness, immune dysfunction, and cancer. These gene sets constitute attractive targets for future studies into the molecular mechanisms by which loneliness exacerbates a wide range of neurodegenerative, psychiatric, and somatic illnesses.

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.

Stressing over anxiety: A novel interaction of 5-HTTPLR genotype and anxiety-related phenotypes in older adults.

Variation within the serotonin transporter gene-linked polymorphic region (5-HTTPLR) contributes to individual differences in trait neuroticism and increases risk for the development of psychopathology in the context of stressful life events. The underlying mechanisms may involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress-related hormones. Yet, observed effects are small, possibly because they occur against the background of many other, mostly unknown, genetic and environmental variables. In this study, we removed much of the variance contributed by such background factors by including complex trait and behavioral measures in our analyses, to isolate the unique contributions of 5-HTTLPR genotype to cortisol baseline, reactivity, and recovery during the Trier Social Stress Test. We recruited 82 community-dwelling older adults (55 and older), an under-studied population, and measured salivary cortisol levels at baseline and following the TSST. As a comparison group we also recruited 88 younger adults (males only, 18-51 years old). Neuroticism, trait anxiety, perceived stress levels, and early childhood trauma experiences were measured using self-report questionnaires. An exploratory factor analysis revealed a latent anxiety trait. Cortisol baseline levels were significantly elevated in older adult S-allele carriers (but not in LL-homozygotes) who scored higher on the latent anxiety trait, relative to S-allele carriers. No such differences were found among younger adults, nor amongst measures obtained during the reactivity or recovery periods. These results highlight the utility of taking into account background variables that may otherwise obscure associations between genetic variables and endophenotypes.

Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males.

BACKGROUND: Previous research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response. RESULTS: Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = -.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040). CONCLUSIONS: Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.

Neurogenethics: An emerging discipline at the intersection of ethics, neuroscience, and genomics.

The analysis of ethical, legal, and social implications (ELSI) associated with genetics ("genethics") has focused on traditional concerns in bioethics, such as privacy and informed consent. The analysis of ELSI associated with neuroscience ("neuroethics") has focused on concerns related to personhood, such as free will or cognitive enhancement. With neurogenomics coming of age, this is an appropriate time to attend to the set of novel concerns that arises when we consider the confluence of these two lines of research. I call this area of ethics inquiry "neurogenethics", map out the problem space, and highlight future areas of inquiry related to genome editing and gene therapy, optogenetics and memory manipulation, and genomic identity and online communities.

'Purpose in Life' as a psychosocial resource in healthy aging: an examination of cortisol baseline levels and response to the Trier Social Stress Test.

'Purpose in Life' (Purpose) is associated with healthy aging, but it is unknown whether this association is causal. Conceptualizing Purpose as a form of psychosocial resource, one mechanism promoting health could be the regulation of stress hormones. To test this hypothesis, we recruited 44 older community-dwelling adults to examine the association between Purpose and cortisol at baseline, in response to, and recovery from, an acute social laboratory stressor. Purpose did not predict cortisol baseline or reactivity, but did predict a faster recovery to pre-stress baseline levels. The health benefits of Purpose in aging may therefore reflect the combination of a normal stress response, which serves an adaptive benefit of allostasis, with an accelerated stress recovery, which reduces the burden of allostatic load. This model should be tested in future studies using larger samples, multiple related constructs, and longitudinal designs that include participants' health records.

Reconceptualizing major depressive disorder as an infectious disease.

In this article, I argue for a reconceptualization of major depressive disorder (major depression) as an infectious disease. I suggest that major depression may result from a parasitic, bacterial, or viral infection and present examples that illustrate possible pathways by which these microorganisms could contribute to the etiology of major depression. I also argue that the reconceptualization of the human body as an ecosystem for these microorganisms and the human genome as a host for non-human exogenous sequences may greatly amplify the opportunity to discover genetic links to the illness. Deliberately speculative, this article is intended to stimulate novel research approaches and expand the circle of researchers taking aim at this vexing illness.

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.

Measurement and reliability of response inhibition.

Response inhibition plays a critical role in adaptive functioning and can be assessed with the Stop-signal task, which requires participants to suppress prepotent motor responses. Evidence suggests that this ability to inhibit a prepotent motor response (reflected as Stop-signal reaction time (SSRT)) is a quantitative and heritable measure of interindividual variation in brain function. Although attention has been given to the optimal method of SSRT estimation, and initial evidence exists in support of its reliability, there is still variability in how Stop-signal task data are treated across samples. In order to examine this issue, we pooled data across three separate studies and examined the influence of multiple SSRT calculation methods and outlier calling on reliability (using Intra-class correlation). Our results suggest that an approach which uses the average of all available sessions, all trials of each session, and excludes outliers based on predetermined lenient criteria yields reliable SSRT estimates, while not excluding too many participants. Our findings further support the reliability of SSRT, which is commonly used as an index of inhibitory control, and provide support for its continued use as a neurocognitive phenotype.