Chronic Childhood Peer Rejection is Associated with Heightened Neural Responses to Social Exclusion During Adolescence

This functional Magnetic Resonance Imaging (fMRI) study examined subjective and neural responses to social exclusion in adolescents (age 12-15) who either had a stable accepted (n = 27; 14 males) or a chronic rejected (n = 19; 12 males) status among peers from age 6 to 12. Both groups of adolescents reported similar increases in distress after being excluded in a virtual ball-tossing game (Cyberball), but adolescents with a history of chronic peer rejection showed higher activity in brain regions previously linked to the detection of, and the distress caused by, social exclusion. Specifically, compared with stably accepted adolescents, chronically rejected adolescents displayed: 1) higher activity in the dorsal anterior cingulate cortex (dACC) during social exclusion and 2) higher activity in the dACC and anterior prefrontal cortex when they were incidentally excluded in a social interaction in which they were overall included. These findings demonstrate that chronic childhood peer rejection is associated with heightened neural responses to social exclusion during adolescence, which has implications for understanding the processes through which peer rejection may lead to adverse effects on mental health over time.Pathways through Adolescenc

Longitudinal links between childhood peer acceptance and the neural correlates of sharing

Childhood peer acceptance is associated with high levels of prosocial behavior and advanced perspective taking skills. Yet, the neurobiological mechanisms underlying these associations have not been studied. This functional magnetic resonance imaging study examined the neural correlates of sharing decisions in a group of adolescents who had a stable accepted status (n = 27) and a group who had a chronic rejected status (n = 19) across six elementary school grades. Both groups of adolescents played three allocation games in which they could share money with strangers with varying costs and profits to them and the other person. Stably accepted adolescents were more likely to share their money with unknown others than chronically rejected adolescents when sharing was not costly. Neuroimaging analyses showed that stably accepted adolescents, compared to chronically rejected adolescents, exhibited higher levels of activation in the temporo-parietal junction, posterior superior temporal sulcus, temporal pole, pre-supplementary motor area, and anterior insula during costly sharing decisions. These findings demonstrate that stable peer acceptance across childhood is associated with heightened activity in brain regions previously linked to perspective taking and the detection of social norm violations during adolescence, and thereby provide insight into processes underlying the widely established links between peer acceptance and prosocial behavior

Sticky criticism? Affective and neural responses to parental criticism and praise in adolescents with depression

Background Parent-adolescent interactions, particularly parental criticism and praise, have previously been identified as factors relevant to self-concept development and, when negative, to adolescent depression. Yet, whether adolescents with depression show aberrant emotional and neural reactivity to parental criticism and praise is understudied. Methods Adolescents with depression (n = 20) and healthy controls (n = 59) received feedback supposedly provided by their mother or father in the form of negative ('untrustworthy'), neutral ('chaotic'), and positive ('respectful') personality evaluations while in an MRI-scanner. After each feedback word, adolescents reported their mood. Beforehand, adolescents had rated whether these personality evaluations matched their self-views. Results In both groups, mood decreased after criticism and increased after praise. Adolescents with depression reported blunted mood responses after praise, whereas there were no mood differences after criticism. Neuroimaging analyses revealed that adolescents with depression (v. healthy controls) exhibited increased activity in response to criticism in the subgenual anterior cingulate cortex, temporal pole, hippocampus, and parahippocampal gyrus. Praise consistent with adolescents' self-views improved mood independent of depression status, while criticism matching self-views resulted in smaller mood increases in adolescents with depression (v. healthy controls). Exploratory analyses indicated that adolescents with depression recalled criticism (v. praise) more. Conclusions Adolescents with depression might be especially attentive to parental criticism, as indexed by increased sgACC and hippocampus activity, and memorize this criticism more. Together with lower positive impact of praise, these findings suggest that cognitive biases in adolescent depression may affect how parental feedback is processed, and may be fed into their self-views.</p

Sticky criticism? Affective and neural responses to parental criticism and praise in adolescents with depression

Background Parent-adolescent interactions, particularly parental criticism and praise, have previously been identified as factors relevant to self-concept development and, when negative, to adolescent depression. Yet, whether adolescents with depression show aberrant emotional and neural reactivity to parental criticism and praise is understudied. Methods Adolescents with depression (n = 20) and healthy controls (n = 59) received feedback supposedly provided by their mother or father in the form of negative ('untrustworthy'), neutral ('chaotic'), and positive ('respectful') personality evaluations while in an MRI-scanner. After each feedback word, adolescents reported their mood. Beforehand, adolescents had rated whether these personality evaluations matched their self-views. Results In both groups, mood decreased after criticism and increased after praise. Adolescents with depression reported blunted mood responses after praise, whereas there were no mood differences after criticism. Neuroimaging analyses revealed that adolescents with depression (v. healthy controls) exhibited increased activity in response to criticism in the subgenual anterior cingulate cortex, temporal pole, hippocampus, and parahippocampal gyrus. Praise consistent with adolescents' self-views improved mood independent of depression status, while criticism matching self-views resulted in smaller mood increases in adolescents with depression (v. healthy controls). Exploratory analyses indicated that adolescents with depression recalled criticism (v. praise) more. Conclusions Adolescents with depression might be especially attentive to parental criticism, as indexed by increased sgACC and hippocampus activity, and memorize this criticism more. Together with lower positive impact of praise, these findings suggest that cognitive biases in adolescent depression may affect how parental feedback is processed, and may be fed into their self-views.</p

Concentration of Plasmodium falciparum gametocytes in whole blood samples by magnetic cell sorting enhances parasite infection rates in mosquito feeding assays.

BACKGROUND: Mosquito-feeding assays are important tools to guide the development and support the evaluation of transmission-blocking interventions. These functional bioassays measure the sporogonic development of gametocytes in blood-fed mosquitoes. Measuring the infectivity of low gametocyte densities has become increasingly important in malaria elimination scenarios. This will pose challenges to the sensitivity and throughput of existing mosquito-feeding assay protocols. Here, different gametocyte concentration methods of blood samples were explored to optimize conditions for detection of positive mosquito infections. METHODS: Mature gametocytes of Plasmodium falciparum were diluted into whole blood samples of malaria-naïve volunteers. Standard centrifugation, Percoll gradient, magnetic cell sorting (MACS) enrichment were compared using starting blood volumes larger than the control (direct) feed. RESULTS: MACS gametocyte enrichment resulted in the highest infection intensity with statistically significant increases in mean oocyst density in 2 of 3 experiments (p = 0.0003; p ≤ 0.0001; p = 0.2348). The Percoll gradient and standard centrifugation procedures resulted in variable infectivity. A significant increase in the proportion of infected mosquitoes and oocyst density was found when larger volumes of gametocyte-infected blood were used with the MACS procedure. CONCLUSIONS: The current study demonstrates that concentration methods of P. falciparum gametocyte-infected whole blood samples can enhance transmission in mosquito-feeding assays. Gametocyte purification by MACS was the most efficient method, allowing the assessment of gametocyte infectivity in low-density gametocyte infections, as can be expected in natural or experimental conditions

Multi-Round Trust Game Quantifies Inter-Individual Differences in Social Exchange from Adolescence to Adulthood

Investing in strangers in a socio-economic exchange is risky, as we may be uncertain whether they will reciprocate. Nevertheless, the potential rewards for cooperating can be great. Here, we used a cross sectional sample (n = 784) to study how the challenges of cooperation versus defection are negotiated across an important period of the lifespan: from adolescence to young adulthood (ages 14 to 25). We quantified social behaviour using a multi round investor-trustee task, phenotyping individuals using a validated model whose parameters characterise patterns of real exchange and constitute latent social characteristics. We found highly significant differences in investment behaviour according to age, sex, socio-economic status and IQ. Consistent with the literature, we showed an overall trend towards higher trust from adolescence to young adulthood but, in a novel finding, we characterized key cognitive mechanisms explaining this, especially regarding socio-economic risk aversion. Males showed lower risk-aversion, associated with greater investments. We also found that inequality aversion was higher in females and, in a novel relation, that socio-economic deprivation was associated with more risk averse play

An inter-laboratory comparison of standard membrane-feeding assays for evaluation of malaria transmission-blocking vaccines.

BACKGROUND: An effective malaria transmission-blocking vaccine may play an important role in malaria elimination efforts, and a robust biological assay is essential for its development. The standard membrane-feeding assay (SMFA) for Plasmodium falciparum infection of mosquitoes is considered a "gold standard" assay to measure transmission-blocking activity of test antibodies, and has been utilized widely in both non-clinical and clinical studies. While several studies have discussed the inherent variability of SMFA within a study group, there has been no assessment of inter-laboratory variation. Therefore, there is currently no assurance that SMFA results are comparable between different studies. METHODS: Mouse anti-Pfs25 monoclonal antibody (mAb, 4B7 mAb), rat anti-Pfs48/45 mAb (85RF45.1 mAb) and a human polyclonal antibody (pAb) collected from a malaria-exposed adult were tested at the same concentrations (6-94 μg/mL for 4B7, 1.2-31.3 μg/mL for 85RF45.1 and 23-630 μg/mL for human pAb) in two laboratories following their own standardized SMFA protocols. The mAbs and pAb, previously shown to have strong inhibition activities in the SMFA, were tested at three or four concentrations in two or three independent assays in each laboratory, and percent inhibition in mean oocyst intensity relative to a control in the same feed was determined in each feeding experiment. RESULTS: Both monoclonal and polyclonal antibodies dose-dependently reduced oocyst intensity in all experiments performed at the two test sites. In both laboratories, the inter-assay variability in percent inhibition in oocyst intensity decreased at higher levels of inhibition, regardless of which antibody was tested. At antibody concentrations that led to a >80 % reduction in oocyst numbers, the inter-laboratory variations were in the same range compared with the inter-assay variation observed within a single laboratory, and the differences in best estimates from multiple feeds between the two laboratories were <5 percentage points. CONCLUSIONS: This study confirms previous reports that the precision of the SMFA increases with increasing percent inhibition. Moreover, the variation between the two laboratories is not greater than the variation observed within a laboratory. The findings of this study provide guidance for comparison of SMFA data from different laboratories

The Dynamics of Naturally Acquired Immune Responses to Plasmodium falciparum Sexual Stage Antigens Pfs230 & Pfs48/45 in a Low Endemic Area in Tanzania

BACKGROUND: Naturally acquired immune responses against sexual stages of P. falciparum can reduce the transmission of malaria from humans to mosquitoes. These antigens are candidate transmission-blocking vaccines but little is known about the acquisition of sexual stage immunity after exposure to gametocytes, or their longevity and functionality. We conducted a longitudinal study on functional sexual stage immune responses. METHODOLOGY/PRINCIPAL FINDINGS: Parasitaemic individuals (n = 116) were recruited at a health centre in Lower Moshi, Tanzania. Patients presented with gametocytes (n = 16), developed circulating gametocytes by day 7 (n = 69) or between day 7 and 14 (n = 10) after treatment or did not develop gametocytes (n = 21). Serum samples were collected on the first day of gametocytaemia and 28 and 84 days post-enrolment (or d7, 28, 84 after enrolment from gametocyte-negative individuals). Antibody responses to sexual stage antigens Pfs230 and Pfs48/45 were detected in 20.7% (72/348) and 15.2% (53/348) of the samples, respectively, and were less prevalent than antibodies against asexual stage antigens MSP-1(19) (48.1%; 137/285) and AMA-1 (52.4%; 129/246)(p<0.001). The prevalence of anti-Pfs230 (p = 0.026) and anti-Pfs48/45 antibodies (p = 0.017) increased with longer duration of gametocyte exposure and had an estimated half-life of approximately 3 months. Membrane feeding experiments demonstrated a strong association between the prevalence and concentration of Pfs230 and Pfs48/45 antibodies and transmission reducing activity (TRA, p<0.01). CONCLUSIONS/SIGNIFICANCE: In a longitudinal study, anti-Pfs230 and Pfs48/45 antibodies developed rapidly after exposure to gametocytes and were strongly associated with transmission-reducing activity. Our data indicate that the extent of antigen exposure is important in eliciting functional transmission-reducing immune responses

Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity

Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes

Neurocomputational mechanisms underpinning aberrant social learning in young adults with low self-esteem

Funder: UCLH NIHR BRCAbstract: Low self-esteem is a risk factor for a range of psychiatric disorders. From a cognitive perspective a negative self-image can be maintained through aberrant learning about self-worth derived from social feedback. We previously showed that neural teaching signals that represent the difference between expected and actual social feedback (i.e., social prediction errors) drive fluctuations in self-worth. Here, we used model-based functional magnetic resonance imaging (fMRI) to characterize learning from social prediction errors in 61 participants drawn from a population-based sample (n = 2402) who were recruited on the basis of being in the bottom or top 10% of self-esteem scores. Participants performed a social evaluation task during fMRI scanning, which entailed predicting whether other people liked them as well as the repeated provision of reported feelings of self-worth. Computational modeling results showed that low self-esteem participants had persistent expectations that others would dislike them, and a reduced propensity to update these expectations in response to social prediction errors. Low self-esteem subjects also displayed an enhanced volatility in reported feelings of self-worth, and this was linked to an increased tendency for social prediction errors to determine momentary self-worth. Canonical correlation analysis revealed that individual differences in self-esteem related to several interconnected psychiatric symptoms organized around a single dimension of interpersonal vulnerability. Such interpersonal vulnerability was associated with an attenuated social value signal in ventromedial prefrontal cortex when making predictions about being liked, and enhanced dorsal prefrontal cortex activity upon receipt of social feedback. We suggest these computational signatures of low self-esteem and their associated neural underpinnings might represent vulnerability for development of psychiatric disorder