Adolescents’ neural reactivity to acute psychosocial stress: dysfunctional regulation habits are linked to temporal gyrus response

Mid-adolescence is a critical time for the development of stress-related disorders and it is associated with significant social vulnerability. However, little is known about normative neural processes accompanying psychosocial stress at this time. Previous research found that emotion regulation strategies critically influence the relationship between stress and the development of psychiatric symptoms during adolescence. Using functional magnetic resonance imaging (fMRI), we examined neural responses to acute stress and analyzed whether the tendency to use adaptive or maladaptive emotion regulation strategies is related to neural and autonomic stress responses. Results show large linear activation increases from low to medium to high stress levels mainly in medial prefrontal, insulae and temporal areas. Caudate and subgenual anterior cingulate cortex, neural areas related to reward and affective valuations, showed linearly decreasing activation. In line with our hypothesis, the current adolescent neural stress profile resembled social rejection and was characterized by pronounced activation in insula, angular and temporal cortices. Moreover, results point to an intriguing role of the anterior temporal gyrus. Stress-related activity in the anterior temporal gyrus was positively related to maladaptive regulation strategies and stress-induced autonomic activity. Maladaptive coping might increase the social threat and reappraisal load of a stressor, relating to higher stress sensitivity of anterior temporal cortices

Does Feedback-Related Brain Response during Reinforcement Learning Predict Socio-motivational (In-)dependence in Adolescence?

This multi-methodological study applied functional magnetic resonance imaging to investigate neural activation in a group of adolescent students (N = 88) during a probabilistic reinforcement learning task. We related patterns of emerging brain activity and individual learning rates to socio-motivational (in-)dependence manifested in four different motivation types (MTs): (1) peer-dependent MT, (2) teacher-dependent MT, (3) peer-and-teacher-dependent MT, (4) peer-and-teacher-independent MT. A multinomial regression analysis revealed that the individual learning rate predicts students’ membership to the independent MT, or the peer-and-teacher-dependent MT. Additionally, the striatum, a brain region associated with behavioral adaptation and flexibility, showed increased learning-related activation in students with motivational independence. Moreover, the prefrontal cortex, which is involved in behavioral control, was more active in students of the peer-and-teacher-dependent MT. Overall, this study offers new insights into the interplay of motivation and learning with (1) a focus on inter-individual differences in the role of peers and teachers as source of students’ individual motivation and (2) its potential neurobiological basis

Distinct Functional Connectivity Signatures of Impaired Social Cognition in Multiple Sclerosis

Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions

A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity

The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC50 of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Neurobiologische Mechanismen der Emotionsinhibition unter Stress bei Personen mit schwerer früher Traumatisierung

Background: Early life trauma significantly increases the risk for most psychiatric disorders. Across disorders, a diminished capacity to regulate emotions and inhibit impulses has been observed in exposed individuals. While it is now becoming increasingly clear that early life trauma can have a lasting effect on the brain, direct comparisons between healthy individuals exposed to early trauma, but without a history of psychiatric disorder, to trauma-naive individuals are scarce. Moreover, it has remained challenging to understand pathways from early trauma to adulthood psychopathology. However, recent studies suggest that altered reactivity to stress during adulthood might play an important connective function. Methods: We conducted an experiment to examine response inhibition towards emotional facial expressions under a condition of psychosocial (non-traumatic) stress compared to baseline. Twenty-five healthy women (mean age 31.5 ± 9.7 years) who were exposed to severe and multiple traumatic experiences before the age of 18 but never developed any psychiatric disorder and 25 age- and education-matched trauma-naïve women were included. In both groups, functional magnetic resonance imaging (fMRI) was used to assess brain activity, which was subsequently linked to behavioural performance and subsyndromal psychiatric symptoms. Endocrine (salivary cortisol and α-amylase), autonomic (heart rate) and self-report measurements were used to validate and compare acute stress responses. Results: Stress reduced inhibition towards fearful, but not towards happy or neutral facial expressions in both groups. However, compared to trauma-naïve women, trauma-exposed women showed blunted activation of the left inferior frontal gyrus (IFG) and slightly increased activation of the right anterior insula (aIns) during response inhibition towards fearful facial expressions. Furthermore, divergent brain-behaviour correlations could be identified. In controls only, IFG activation was linked to better inhibitory performance related to fearful facial expressions. In turn, exclusively in trauma-exposed women, aIns activation was linked to decreased inhibitory performance related to fearful facial expressions. Across groups, lower IFG activation was negatively linked to more subsyndromal posttraumatic symptoms. Discussion and Conclusion: These results suggest that early life trauma has a lasting effect on the brain, even in the absence of lifetime psychopathology. Dysregulation of IFG-initiated top-down control, in concert with heightened aIns-initiated salience detection may point to imbalances in neural resource allocation after acute stress in trauma-exposed individuals. This imbalance likely raises vulnerability to everyday stress and, in the long term to posttraumatic psychopathology. Our results therefore have implications for approaches to early intervention and prevention.Lebensgeschichtlich frühe Traumata erhöhen das Risiko für die meisten psychiatrischen Erkrankungen. Bei Personen, die frühe Traumata erlitten haben, wird häufig über verschiedene Störungsbilder hinweg eine verminderte Fähigkeit beobachtet, Emotionen zu regulieren und Impulse zu inhibieren. Wenngleich erste Erkenntnisse der jüngeren Forschung nun nahelegen, dass sich frühe Traumatisierung dauerhaft auf das Gehirn auswirken kann, fehlt es an direkten Vergleichen zwischen gesunden Personen ohne und gesunden Personen mit früher Traumaerfahrung. Darüber hinaus bleiben die Mechanismen, die frühe Traumata mit der Entwicklung von Psychopathologie im Erwachsenenalter verbinden, weitgehend unklar. Aktuelle Studien lassen vermuten, dass eine veränderte Stressreaktivität im Erwachsenenalter hier eine wichtige verbindende Funktion darstellen könnte. Methoden: Wir haben ein Experiment durchgeführt, um die Inhibition von Reaktionen (response inhibition) auf emotionale Gesichtsausdrücke sowohl unter Standardbedingungen als auch nach psychosozialem (nichttraumatischem) Stress, zu untersuchen. 25 gesunde Frauen (durchschnittliches Alter 31,5 ± 9,7 Jahre), die vor ihrem 18. Lebensjahr schweren und multiplen traumatischen Ereignissen ausgesetzt waren, aber nie eine psychiatrische Erkrankung entwickelt haben, wurden mit 25 im Hinblick auf Alter und Bildung parallelisierten, traumanaiven Kontrollprobandinnen verglichen. Mithilfe von funktioneller Magnetresonanztomografie (fMRT) wurde die Hirnaktivität in beiden Gruppen erfasst und diese daraufhin in Beziehung zur Inhibitionsleistung und zu subsyndromalen psychiatrischen Symptomen gesetzt. Um akute Stressreaktionen zu validieren und zu vergleichen, wurden endokrine (Cortisol- und α-Amylasekonzentrationen im Speichel) und autonome (Herzraten-) Werte gemessen sowie Selbstbeurteilungen erhoben. Ergebnisse: In beiden Gruppen reduzierte Stress die Inhibitionsleistung bezogen auf ängstliche, jedoch nicht auf fröhliche oder neutrale Gesichtsausdrücke. Verglichen mit der Kontrollgruppe zeigte sich in der Traumagruppe eine verminderte Aktivierung des linken Gyrus Frontalis Inferior (IFG) zusammen mit einer leicht erhöhten Aktivierung des rechten anterioren Lobus Insularis (aIns) während der Response Inhibition auf ärgerliche Gesichtsausdrücke. Zudem konnten divergierende Hirn-Verhaltens-Korrelate identifiziert werden. Anders als bei traumaexponierten Probandinnen hing die IFG-Aktivierung bei den Kontrollprobandinnen mit verbesserter Inhibitionsleistung zusammen. Ausschließlich in der Traumagruppe korrelierte wiederum die aIns-Aktivierung mit reduzierter Inhibitionsleistung. In der Gesamtgruppe hing die IFG-Aktivierung negativ mit subklinischen posttraumatischen Symptomen zusammen. Diskussion: Diese Ergebnisse weisen darauf hin, dass biografisch frühe Traumata selbst ohne psychiatrische Erkrankungen in der Lebensgeschichte einen dauerhaften Effekt auf das Gehirn haben. Dysregulation von IFG-initiierter top-down Kontrolle zusammen mit erhöhter aIns-initiierter Salienzerkennung könnte auf Ungleichgewichte in der neuronalen Ressourcenverteilung nach akutem Stress in traumaexponierten Personen deuten. Diese Ungleichverteilung erhöht mit großer Wahrscheinlichkeit die Stressvulnerabilität und damit auf lange Sicht die Anfälligkeit für posttraumatische Psychopathologie. Die vorliegenden Ergebnisse haben Implikationen für Frühinterventions- und Präventionsansätze

Negative and positive self-beliefs in social anxiety: The strength of believing mediates the affective response

Background and objectives Current cognitive models of social anxiety disorder (SAD) propose that individual, situation-specific self-beliefs are central to SAD. However, the role of differences in the degree to which individuals with social anxiety are convinced of self-beliefs, in particular positive ones, is still not fully understood. We compared how much high and low socially anxious individuals agree with their own negative and positive self-beliefs. Furthermore, we investigated whether agreeing with one’s self-belief can explain the relation between negative affect in response to self-beliefs and social anxiety. Specifically, we were interested whether social anxiety increases negative affect in response to self-beliefs through an increase in agreement. Methods We developed a new experimental self-belief task containing positive and negative semi-idiosyncratic, situation specific self-beliefs typical of high social anxiety and included a direct measure of agreement with these beliefs. Using extreme group sampling, we a-priori selected high (n = 51) and low (n = 50) socially anxious individuals. By multi-level mediation analysis, we analyzed agreement with self-beliefs in both groups and its association with affect. Results High and low socially anxious individuals chose similar self-beliefs. However, high socially anxious individuals (HSA) agreed more with negative self-beliefs and less with positive self-beliefs compared to low socially anxious individuals (LSA). HSA individuals reported increased negative affect after both, exposition to negative and positive self-beliefs compared to LSA. We found that social anxiety increases affective responses towards negative-self beliefs through an increase in agreeing with these self-beliefs. Conclusions These findings suggest that cognitive models of social anxiety can be improved by including not only the content of a self-belief but also the strength of such a belief. In addition, they emphasize the relevance of positive self-beliefs in social anxiety, which has frequently been overlooked

Association between childhood trauma and brain anatomy in women with post-traumatic stress disorder, women with borderline personality disorder, and healthy women

Background: Childhood trauma (CT) is associated with altered brain anatomy. These neuroanatomical changes might be more pronounced in individuals with a psychiatric disorder. Post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) are more prevalent in individuals with a history of CT. Objective: In this study, we examined limbic and total brain volumes in healthy women with and without a history of CT and in females with PTSD or BPD and a history of CT to see whether neuroanatomical changes are a function of psychopathology or CT. Method: In total, 128 women (N = 70 healthy controls without CT, N = 25 healthy controls with CT, N = 14 individuals with PTSD, and N = 19 individuals with BPD) were recruited. A T1- weighted anatomical MRI was acquired from all participants for Freesurfer-based assessment of total brain, hippocampus, and amygdala volumes. Severity of CT was assessed with a clinical interview and the Childhood Trauma Questionnaire. Group differences in hippocampal and amygdala volumes (adjusted for total brain volume) and total brain volume (adjusted for height) were characterized by analysis of covariance. Results: Volume of the total brain, hippocampus, and amygdala did not differ between the four groups (p > .05). CT severity correlated negatively with total brain volume across groups (r = −0.20; p = .029). Conclusions: CT was associated with reduced brain volume but PTSD or BPD was not. The association between CT and reduced brain volume as a global measure of brain integrity suggests a common origin for vulnerability to psychiatric disorders later in life

Do Belonging and Social Exclusion at School Affect Structural Brain Development During Adolescence?

Students’ sense of belonging presents an essential resource for academic and health outcomes, whereas social exclusion at school negatively impacts students’ well‐being and academic performance. Aiming to understand how feelings of school‐related belonging and exclusion shape the structural brain development, this study applied longitudinal questionnaire‐based data and MRI data from 71 adolescent students (37 females, Mage at t1 = 15.0; t2 = 16.1 years). All were white participants from Germany. Voxel‐based morphometry revealed only an association of social exclusion (and not of belonging) and gray matter volume in the left anterior insula: From t1 to t2, there was less gray matter decrease, the more social exclusion students perceived. School‐related social exclusion and disturbed neurodevelopment are thus significantly associated