Factual and counterfactual learning in major adolescent depressive disorder, evidence from an instrumental learning study.

BACKGROUND: The incidence of adolescent depressive disorder is globally skyrocketing in recent decades, albeit the causes and the decision deficits depression incurs has yet to be well-examined. With an instrumental learning task, the aim of the current study is to investigate the extent to which learning behavior deviates from that observed in healthy adolescent controls and track the underlying mechanistic channel for such a deviation. METHODS: We recruited a group of adolescents with major depression and age-matched healthy control subjects to carry out the learning task with either gain or loss outcome and applied a reinforcement learning model that dissociates valence (positive v. negative) of reward prediction error and selection (chosen v. unchosen). RESULTS: The results demonstrated that adolescent depressive patients performed significantly less well than the control group. Learning rates suggested that the optimistic bias that overall characterizes healthy adolescent subjects was absent for the depressive adolescent patients. Moreover, depressed adolescents exhibited an increased pessimistic bias for the counterfactual outcome. Lastly, individual difference analysis suggested that these observed biases, which significantly deviated from that observed in normal controls, were linked with the severity of depressive symoptoms as measured by HAMD scores. CONCLUSIONS: By leveraging an incentivized instrumental learning task with computational modeling within a reinforcement learning framework, the current study reveals a mechanistic decision-making deficit in adolescent depressive disorder. These findings, which have implications for the identification of behavioral markers in depression, could support the clinical evaluation, including both diagnosis and prognosis of this disorder.

Asymmetric valuation and belief updating over gain and loss in risky decision making: A behavioral and electrophysiological investigation.

Decisions under risk, either for gain or loss, are ubiquitous in our daily life. However, the extent to which the valence (gain or loss) of risky financial choices shapes outcome valuation and belief updating is a relatively overlooked research area. In the current study, we image neural activity using electroencephalography (EEG) combined with a financial decision task to investigate outcome valuation and belief updating. In the experimental task, subjects can either choose to take the risky gamble (stock) or the safe option (bond) and then report their belief over the quality of stock option in a trial-by-trial manner. Although the actual probabilities of the risky option are symmetric over gain and loss, we found an asymmetric effect of belief updating and risk preference, viz. the subjects tend to both report a higher probability for the stock to win and be more risk taking for potential gains compared to symmetric losses. The EEG data following feedback of stock payoff represents a parallel pattern which is resonant with the behavioral results. Notably, there is generally a greater FRN difference for feedback (correct vs. incorrect) in the gain condition compared to the loss condition, and the deflection of P300 is more prominent in gain condition than loss condition irrespective of the correctness. Lastly, while the P300 could be predictive for the subsequent probability estimate in both conditions (gain and loss), the FRN is only predictive for belief updating in the gain rather than loss condition. Therefore, both the behavioral and electrophysiological findings indicate an unbalanced processing of valence in shaping decisions under risk within financial learning in an experiential framework.

The heart-brain axis: A proteomics study of meditation on the cardiovascular system of Tibetan Monks.

BACKGROUND: There have been mixed reports on the beneficial effects of meditation in cardiovascular disease (CVD), which is widely considered the leading cause of death worldwide. METHODS: To clarify the role of meditation in modulating the heart-brain axis, we implemented an extreme phenotype strategy, i.e., Tibetan monks (BMI > 30) who practised 19.20 ± 7.82 years of meditation on average and their strictly matched non-meditative Tibetan controls. Hypothesis-free advanced proteomics strategies (Data Independent Acquisition and Targeted Parallel Reaction Monitoring) were jointly applied to systematically investigate and target the plasma proteome underlying meditation. Total cholesterol, low-density lipoprotein cholesterol  (LDL-C), apolipoprotein B (Apo B) and lipoprotein (a) [Lp(a)] as the potential cardiovascular risk factors were evaluated. Heart rate variability (HRV) was assessed by electrocardiogram. FINDINGS: Obesity, hypertension, and reduced HRV is offset by long-term meditation. Notably, meditative monks have blood pressure and HRV comparable to their matched Tibetan controls. Meditative monks have a protective plasma proteome, related to decreased atherosclerosis, enhanced glycolysis, and oxygen release, that confers resilience to the development of CVD. In addition, clinical risk factors in plasma were significantly decreased in monks compared with controls, including total cholesterol, LDL-C, Apo B, and Lp(a). INTERPRETATION: To our knowledge, this work is the first well-controlled proteomics investigation of long-term meditation, which opens up a window for individuals characterized by a sedentary lifestyle to improve their cardiovascular health with an accessible method practised for more than two millennia. FUNDING: See the Acknowledgements section.

Blending oxytocin and dopamine with everyday creativity.

Converging evidence suggests that oxytocin (OT) is associated with creative thinking (CT) and that release of OT depends on ADP ribosyl-cyclases (CD38 and CD157). Neural mechanisms of CT and OT show a strong association with dopaminergic (DA) pathways, yet the link between CT and CD38, CD157, dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) peripheral gene expression remain inconclusive, thus limiting our understanding of the neurobiology of CT. To address this issue, two principal domains of CT, divergent thinking (AUT), were assessed. In men, both AUT is associated with gene expression of CD38, CD157, and their interaction CD38 × CD157. There were no significant associations for DA expression (DRD2, COMT, DRD2 × COMT) on both CT measures. However, analysis of the interactions of OT and DA systems reveal significant interactions for AUT in men. The full model explained a sizable 39% of the variance in females for the total CT score. The current findings suggest that OT and DA gene expression contributed significantly to cognition and CT phenotype. This provides the first empirical foundation of a more refined understanding of the molecular landscape of CT.

Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta-analysis.

Intranasal oxytocin has been shown to promote social functioning and has recently been applied as a treatment for autism spectrum disorders (ASD). The current meta-analysis aims to assess the crucial question of oxytocin's efficacy in the treatment of ASD. We performed a systematic literature search, including randomized, single- or double-blind/open-label and placebo-controlled clinical trials as well as single-arm, non-randomized and uncontrolled studies investigating exogenous oxytocin effect on ASD. A total of 28 studies (N = 726 ASD patients) met our predefined inclusion criteria. We used a multilevel meta-analytic model and found that oxytocin had beneficial effects on social functioning, but did not find strong evidence for symptoms improvement in the non-social domain. Our findings suggest that oxytocin administration can be regarded as an effective treatment for some core aspects of ASD, especially in the domain of social functioning, highlighting the promise of using oxytocin as a new-generation therapeutic to address core social impairments in ASD.

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior - a TPH2 imaging genetics approach.

BACKGROUND: Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. METHODS: The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). RESULTS: Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. CONCLUSIONS: The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

Effects of Mindfulness-Based Stress Reduction on Psychological Symptoms and Telomere Length: A Randomized Active-Controlled Trial.

Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term.

Molecular genetics in psychology and personality neuroscience: On candidate genes, genome wide scans, and new research strategies.

Despite the substantial heritability estimates for psychological traits, their precise genetic foundation from a molecular perspective remains elusive. We summarize findings and advances from more than twenty years of research into the molecular genetics of personality and other psychological traits. We describe how the candidate gene approach has - despite its appealing theoretical foundations - often (but not always) failed to point towards replicable associations between genetic polymorphisms and behavioral traits. The genome wide analysis approach on the contrary has become more fruitful in recent years and pointed towards reliable genetic associations. Results from genome wide scan studies (GWAS) are currently leveraged to explore gene-behavior associations through genetic correlation and polygenic score prediction which are important steps towards a precision medicine where treatment options are tailored to a patient's individual biology. But it is also true that future work needs to take a closer look at GWAS findings to link the growing list of statistical associations to biopsychological theory. We argue that research strategies from the candidate gene approach can be used to address these issues - given that necessary precautions are taken to avoid the problem of false-positive associations.

Correction to: Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.

An amendment to this paper has been published and can be accessed via the original article.

Cumulative Risk on Oxytocin-Pathway Genes Impairs Default Mode Network Connectivity in Trauma-Exposed Youth.

Background: Although the default mode network (DMN) is a core network essential for brain functioning, little is known about its developmental trajectory, particularly on factors associated with its coherence into a functional network. In light of adult studies indicating DMN's susceptibility to stress-related conditions, we examined links between variability on oxytocin-pathway genes and DMN connectivity in youth exposed to chronic war-related trauma Methods: Following a cohort of war-exposed children from early childhood, we imaged the brains of 74 preadolescents (age 11-13 years; 39 war-exposed) during rest using magnetoencephalography (MEG). A cumulative risk index on oxytocin-pathway genes was constructed by combining single nucleotide polymorphisms on five genes previously linked with social deficits and psychopathology; OXTR rs1042778, OXTR rs2254298, OXTRrs53576, CD38 rs3796863, and AVPR1A RS3. Avoidant response to trauma reminders in early childhood and anxiety disorders in late childhood were assessed as predictors of disruptions to DMN theta connectivity. Results: Higher vulnerability on oxytocin-pathway genes predicted greater disruptions to DMN theta connectivity. Avoidant symptoms in early childhood and generalized anxiety disorder in later childhood were related to impaired DMN connectivity. In combination, stress exposure, oxytocin-pathway genes, and stress-related symptoms explained 24.6% of the variance in DMN connectivity, highlighting the significant effect of stress on the maturing brain. Conclusions: Findings are the first to link the oxytocin system and maturation of the DMN, a core system sustaining autobiographical memories, alteration of intrinsic and extrinsic attention, mentalization, and sense of self. Results suggest that oxytocin may buffer the effects of chronic early stress on the DMN, particularly theta rhythms that typify the developing brain.

A Novel Role of CD38 and Oxytocin as Tandem Molecular Moderators of Human Social Behavior.

Oxytocin is an important modulator of human affiliative behaviors, including social skills, human pair bonding, and friendship. CD38 will be discussed as an immune marker and then in more detail the mechanisms of CD38 on releasing brain oxytocin. Mention is made of the paralogue of oxytocin, vasopressin, that has often overlapping and complementary functions with oxytocin on social behavior. Curiously, vasopressin does not require CD38 to be released from the brain. This review discusses the social salience hypothesis of oxytocin action, a novel view of how this molecule influences much of human social behaviors often in contradictory ways. The oxytocinergic-vasopressinergic systems are crucial modulators of broad aspects of human personality. Of special interest are studies of these two hormones in trust related behavior observed using behavioral economic games. This review also covers the role of oxytocin in parenting and parental attachment. In conclusion, the effects of oxytocin on human behavior depend on the individual's social context and importantly as well, the individual's cultural milieu, viz. East and West. ACRONYMS: ACC = Anterior Cingulate ADP = Adenosine diphosphate AQ = Autism Quotient cADPR = Cyclic ADP-ribose CNS = Central nervous system DA = Dopamine eQTLC = Expression Quantitative Trait Loci LC-NE = Locus Coeruleus-Norepinephrine MRI = Magnetic Resonance Imaging OFC = Orbitofrontal cortices OXT = Oxytocin RAGE = Receptor for advanced glycation end-products SARM1 = Sterile Alpha and toll/interleukin-1 receptor motif-containing 1 TRPM2= Transient Receptor Potential Cation Channel Subfamily M Member 2 AVP = Vasopressin.

To Reveal or Not to Reveal? Observation of Social Outcomes Facilitates Reward Processing.

Motivation is a key topic that comprises considerable theoretical and practical implications, and its study is gaining increasing traction in recent years. Employing both behavioral and neural techniques, previous studies examined the extent to which intrinsic and extrinsic motivations collectively shape individual decision making. Investigations found that both processes play indispensable and interactive roles in choice behavior. However, despite its importance, little is known respecting the role of extrinsic social factors in contributing to individual variations in intrinsic motivation. Toward elucidating the role of extrinsic social factors in motivated decision making, the current study implements the stop watch task, combined with hyper-recording electrophysiological measurements. With the electrophysiological toolkit, our goal is to bring to light how extrinsic social signals impact intrinsic motivation and shape the reward processing over success and failure at the succeeding stage. Empirically, we show that, following social outcome presentation, there is an increased divergent feedback-related negativity (FRN), which reflects the failure/success discrepancy at the outcome stage of choice behavior. In summary, this study demonstrates the saliency of social information in intrinsic motivational processes that underpin success-failure outcomes.

To run with the herd or not: Electrophysiological dynamics are associated with preference change in crowdfunding.

The herd instinct is a common feature of human society and is frequently encountered in a myriad of other human social interaction including entertainment, fashion, and the adoption of new gadgets. Indeed, social influence, taking account of others' actions in one's decisions, is ubiquitous in our daily life. With the growing prevalence of crowdfunding investments, an increasing number of studies are currently focused on how social influences impact such behavior. Moreover, only a few studies have examined its neural correlates and the value of evaluating social influence as a possible predictor of herd behavior especially regarding crowdfunding. The present study aims to parse the neural processing of social influences on crowdfunding investment and examine whether neural signals can be correlated with an individuals' willingness to invest. Our results demonstrate that the greater ones' choice deviates from the overall group judgement, there is a resulting increased deflection of the feedback related negativity (FRN). However, the averaged and single trial analysis reveal that the subsequent P300, rather than the feedback related negativity, reflects the magnitude of social influence on individual behavior. Single trial analysis of the EEG data shows that, in addition to the behavioral manipulation, the deflection of the P300 is a robust signal, which is associated with the behavioral adjustment following an individual's awareness of the group opinion at the trial-by-trial level. The current study freshly extends the growing literature on social influences on decision making stemming from another's action to the new investment possibilities of crowdfunding investment and notably observes that the P300 component at the outcome stage evidently is associated with the behavioral-decision making shift evoked by following the herd.

Human Extinction Learning Is Accelerated by an Angiotensin Antagonist via Ventromedial Prefrontal Cortex and Its Connections With Basolateral Amygdala.

BACKGROUND: Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. METHODS: Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. RESULTS: LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. CONCLUSIONS: Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.

Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.

BACKGROUND: Whereas meditation training has been purported to support slower cellular aging, little work has explored the association among different facets of dispositional mindfulness, self-compassion, and cellular aging. The present study aimed to examine the relationship between leukocyte telomere length (LTL), an index of cellular aging, dispositional mindfulness, and self-compassion in a sample of Singaporean Chinese adults. METHODS: One hundred and fifty-eight Chinese adults (mean age = 27.24 years; 63.3% female) were recruited from the community and completed self-report measures assessing dispositional mindfulness, self-compassion, and psychological symptoms, as well as provided blood samples for analyses of LTL. Multiple regression analyses were conducted to examine the role of trait mindfulness and self-compassion in predicting LTL, taking into consideration potential covariates such as chronological age and psychological symptoms. RESULTS: Results showed that nonreactivity, one of the five facets of dispositional mindfulness, was significantly associated with LTL, after controlling for chronological age. There was also a trend for dispositional mindfulness, self-compassion, and their selected facets (i.e., nonjudging, common humanity, and de-identification) to each be associated with longer LTL. CONCLUSIONS: Overall, the findings provide preliminary support for the association among aspects of dispositional mindfulness, self-compassion, and aging. In particular, individuals high on nonreactivity experience slower aging at the cellular level, likely through engaging in more adaptive coping mechanisms.

Correction: AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance.

[This corrects the article DOI: 10.1371/journal.pgen.0010042.].

Successful aging, cognitive function, socioeconomic status, and leukocyte telomere length.

In a rapidly greying world, the notion that some individuals maintain successful aging trajectories, viz. high physical, cognitive, emotional, and social functioning in older age, is increasingly germane. Biomarkers of such successful aging are increasingly sought. Leukocyte telomere length (LTL), an emerging yardstick of cellular aging that is influenced by but distinct from chronological age, may also be associated to successful aging. Furthermore, given that socio-economic status (SES) influences successful aging trajectories, socioeconomic status may also moderate the association between chronological age and LTL. The goals of this study are to examine 1) whether successful aging is associated with LTL; 2) whether successful aging accounts for age-related LTL and 3) whether SES moderates the effect of age on LTL. Singaporean Chinese (n = 353) aged 65-80 completed a multidimensional assessment of successful aging and provided blood samples for LTL analysis. Results show that LTL negatively correlates with chronological age and positively correlates with successful aging. Successful aging mediates the association between chronological age and LTL. Moderated mediation analyses show that lower SES is associated with stronger negative associations of chronological age with successful aging and LTL. Moreover, the cognitive functioning dimension of successful aging is uniquely associated with LTL and its association with chronological age is moderated by SES. This study provides evidence that among older Singaporean Chinese with lower SES, declines in successful aging and in cognitive functioning are linked to age-related LTL shortening and hence to accelerated aging at the cellular level.

The role of the Oxytocin-Neurophysin I gene in contributing to human personality traits promoting sociality.

Oxytocin (OT) plays a salient role in contributing to the high levels of human sociality that characterize our species. Across the lifespan this nonapeptide promotes prosocial behaviors and modulates stress responses. Curiously, the OXT-Neurophysin I gene has been little studied despite the fact this is the structural gene for the OT nonapeptide. In a large group of Han Chinese undergraduate students (n = 1593) we examined associations of two single nucleotide polymorphisms of the OXT- Neurophysin I gene with personality traits. Results indicated that the OXT-Neurophysin I rs2770378 was related to extraversion, agreeableness, and neuroticism. AA homozygous individuals reported more prosocial personality traits, compared to participants carrying the G allele. These results indicate that variants of the OXT-Neurophysin-I gene resonate with phenotypes that foster positive social interactions, which may in turn facilitate the social regulation of stress responses.