Neuro-environmental interactions: a time sensitive matter

Introduction: The assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). Methods: We implemented an interpretable XGBoost-shapley additive explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages, 13-25 years) enrolled in the public health impact of metals exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, copper, nickel, and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood, and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Results: Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated (p < 0.001, r = 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Discussion: Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity

Impact of COVID-19-Related Social Isolation on Behavioral Outcomes in Young Adults Residing in Northern Italy

: Social isolation affects our emotions, behavior and interactions. Worldwide, individuals experienced prolonged periods of isolation during the first wave of the COVID-19 pandemic when authorities-imposed restrictions to reduce the spread of the virus. In this study, we investigated the effects of social isolation on emotional and behavioral outcomes in young adults from Lombardy, Italy, a global hotspot of COVID-19. We leveraged baseline (pre-social isolation) and follow-up (mid- or post-isolation) data collected from young adults enrolled in the ongoing, longitudinal Public Health Impact of Metals Exposure (PHIME) study. At baseline, 167 participants completed the ASEBA questionnaires (ASR/YSR) by web link or in person; 65 completed the ASR 12-18 weeks after the onset of restrictions. Using the sign test and multiple linear regression models, we examined differences in ASR scores between baseline and follow-up adjusting for sex, age, pre-pandemic IQ and time with social restrictions (weeks). Further, we examined interactions between sex and time in social isolation. Participants completed the ASR after spending an average of 14 weeks in social isolation (range 12-18 weeks). Thought problems increased between baseline and follow-up (median difference 1.0; 1st, 3rd quartile: -1.0, 4.0; p = 0.049). Among males, a longer time in social isolation (≥14 weeks) was associated with increased rule-breaking behaviors of 2.8 points. These results suggest the social isolation related to COVID-19 adversely impacted mental health. In particular, males seem to externalize their condition. These findings might help future interventions and treatment to minimize the consequences of social isolation experience in young adults

Topological network properties of resting-state functional connectivity patterns are associated with metal mixture exposure in adolescents

IntroductionAdolescent exposure to neurotoxic metals adversely impacts cognitive, motor, and behavioral development. Few studies have addressed the underlying brain mechanisms of these metal-associated developmental outcomes. Furthermore, metal exposure occurs as a mixture, yet previous studies most often consider impacts of each metal individually. In this cross-sectional study, we investigated the relationship between exposure to neurotoxic metals and topological brain metrics in adolescents. MethodsIn 193 participants (53% females, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of four metals (manganese, lead, copper, and chromium) in multiple biological media (blood, urine, hair, and saliva) and acquired resting-state functional magnetic resonance imaging scans. Using graph theory metrics, we computed global and local efficiency (global:GE; local:LE) in 111 brain areas (Harvard Oxford Atlas). We used weighted quantile sum (WQS) regression models to examine association between metal mixtures and each graph metric (GE or LE), adjusted for sex and age. ResultsWe observed significant negative associations between the metal mixture and GE and LE [beta GE = -0.076, 95% CI (-0.122, -0.031); beta LE= -0.051, 95% CI (-0.095, -0.006)]. Lead and chromium measured in blood contributed most to this association for GE, while chromium measured in hair contributed the most for LE. DiscussionOur results suggest that exposure to this metal mixture during adolescence reduces the efficiency of integrating information in brain networks at both local and global levels, informing potential neural mechanisms underlying the developmental toxicity of metals. Results further suggest these associations are due to combined joint effects to different metals, rather than to a single metal

Social cognition and social brain in developmental disorders during childhood

Les troubles du spectre autistique (TSA) sont des troubles neuro-développementaux caractérisés notamment par des anomalies des interactions sociales. Des études en eye-tracking ont permis de mettre en évidence de façon objective des anomalies de la perception sociale dans les TSA, caractérisées par une diminution du regard vers des stimuli sociaux. Des études sur le fonctionnement cérébral, par des méthodes TEP et SPECT, ont mis en évidence une diminution du débit sanguin cérébral (DSC) au repos au niveau des régions temporales, notamment au niveau du sillon temporal supérieur (STS), chez des enfants avec TSA. Nous avons aujourd’hui la possibilité de mesurer le DSC au repos en IRM avec la séquence arterial spin labelling (ASL). Dans cette thèse nous avons confirmé la diminution du DSC au repos au niveau du STS chez des enfants avec TSA par la méthode IRM-ASL, ce qui pourraient permettre son utilisation en tant que biomarqueur dans les TSA. Nous suggérons également que le DSC au repos pourrait être un indice plus pertinent pour l’étude du fonctionnement cérébral de base dans les TSA. De plus, par une étude transversale en eye-tracking utilisant les mêmes stimuli sur une large tranche d’âge, nous avons montré l’impact de l’âge sur la perception sociale chez des participants avec TSA et des témoins. Enfin, nous avons mis en évidence des anomalies de perception sociale par l’eye-tracking et de fonctionnement cortical au niveau du STS par l’IRM-ASL, chez des enfants ayant un kyste arachnoïdien de la fosse postérieure. Une meilleure connaissance des difficultés sociales subjacentes à ce trouble peut avoir un impact majeur sur la prise en charge de ces enfants.Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by abnormal social interactions. Eye-tracking studies have objectively reported social perception abnormalities in ASD, characterized by a decrease of gaze towards social stimuli. Brain imaging studies, using PET and SPECT methods, have revealed a decrease in cerebral blood flow (CSF) at rest in the temporal regions, particularly in the superior temporal sulcus (STS), in children with ASD. Nowadays, it is possible to measure rest CBF with MRI using arterial spin labeling (ASL) sequence. In this thesis, we confirmed the decreased in rest CBF within the STS in children with ASD using MRI-ASL, which could allow its use as a biomarker in ASD. We also suggest that rest CBF could be a more relevant index for studying basic brain function in ASD. In addition, we performed a cross-sectional eye-tracking study using the same stimuli over a wide age-range and showed the impact of age on social perception in ASD and in typical development. Finally, we showed social perception abnormalities, using eye-tracking, and cortical functioning abnormalities within the STS using MRI-ASL, in children with posterior fossa arachnoid cyst. A better understanding of the social difficulties underlying this disorder could have a major impact on patient outcome

Cognition sociale et cerveau social dans les troubles du développement de l’enfant

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by abnormal social interactions. Eye-tracking studies have objectively reported social perception abnormalities in ASD, characterized by a decrease of gaze towards social stimuli. Brain imaging studies, using PET and SPECT methods, have revealed a decrease in cerebral blood flow (CSF) at rest in the temporal regions, particularly in the superior temporal sulcus (STS), in children with ASD. Nowadays, it is possible to measure rest CBF with MRI using arterial spin labeling (ASL) sequence. In this thesis, we confirmed the decreased in rest CBF within the STS in children with ASD using MRI-ASL, which could allow its use as a biomarker in ASD. We also suggest that rest CBF could be a more relevant index for studying basic brain function in ASD. In addition, we performed a cross-sectional eye-tracking study using the same stimuli over a wide age-range and showed the impact of age on social perception in ASD and in typical development. Finally, we showed social perception abnormalities, using eye-tracking, and cortical functioning abnormalities within the STS using MRI-ASL, in children with posterior fossa arachnoid cyst. A better understanding of the social difficulties underlying this disorder could have a major impact on patient outcome.Les troubles du spectre autistique (TSA) sont des troubles neuro-développementaux caractérisés notamment par des anomalies des interactions sociales. Des études en eye-tracking ont permis de mettre en évidence de façon objective des anomalies de la perception sociale dans les TSA, caractérisées par une diminution du regard vers des stimuli sociaux. Des études sur le fonctionnement cérébral, par des méthodes TEP et SPECT, ont mis en évidence une diminution du débit sanguin cérébral (DSC) au repos au niveau des régions temporales, notamment au niveau du sillon temporal supérieur (STS), chez des enfants avec TSA. Nous avons aujourd’hui la possibilité de mesurer le DSC au repos en IRM avec la séquence arterial spin labelling (ASL). Dans cette thèse nous avons confirmé la diminution du DSC au repos au niveau du STS chez des enfants avec TSA par la méthode IRM-ASL, ce qui pourraient permettre son utilisation en tant que biomarqueur dans les TSA. Nous suggérons également que le DSC au repos pourrait être un indice plus pertinent pour l’étude du fonctionnement cérébral de base dans les TSA. De plus, par une étude transversale en eye-tracking utilisant les mêmes stimuli sur une large tranche d’âge, nous avons montré l’impact de l’âge sur la perception sociale chez des participants avec TSA et des témoins. Enfin, nous avons mis en évidence des anomalies de perception sociale par l’eye-tracking et de fonctionnement cortical au niveau du STS par l’IRM-ASL, chez des enfants ayant un kyste arachnoïdien de la fosse postérieure. Une meilleure connaissance des difficultés sociales subjacentes à ce trouble peut avoir un impact majeur sur la prise en charge de ces enfants

Machine Learning Assisted Discovery of Interactions between Pesticides, Phthalates, Phenols, and Trace Elements in Child Neurodevelopment.

A growing body of literature suggests that developmental exposure to individual or mixtures of environmental chemicals (ECs) is associated with autism spectrum disorder (ASD). However, investigating the effect of interactions among these ECs can be challenging. We introduced a combination of the classical exposure-mixture Weighted Quantile Sum (WQS) regression and a machine-learning method termed Signed iterative Random Forest (SiRF) to discover synergistic interactions between ECs that are (1) associated with higher odds of ASD diagnosis, (2) mimic toxicological interactions, and (3) are present only in a subset of the sample whose chemical concentrations are higher than certain thresholds. In a case-control Childhood Autism Risks from Genetics and Environment (CHARGE) study, we evaluated multiordered synergistic interactions among 62 ECs measured in the urine samples of 479 children in association with increased odds for ASD diagnosis (yes vs no). WQS-SiRF identified two synergistic two-ordered interactions between (1) trace-element cadmium (Cd) and the organophosphate pesticide metabolite diethyl-phosphate (DEP); and (2) 2,4,6-trichlorophenol (TCP-246) and DEP. Both interactions were suggestively associated with increased odds of ASD diagnosis in the subset of children with urinary concentrations of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates a novel method that combines the inferential power of WQS and the predictive accuracy of machine-learning algorithms to discover potentially biologically relevant chemical-chemical interactions associated with ASD

Neural basis of interindividual variability in social perception in typically developing children and adolescents using diffusion tensor imaging

International audienceHumans show great interindividual variability in the degree they engage in social relationship. The neural basis of this variability is still poorly understood, particularly in children. In this study, we aimed to investigate the neural basis of interindividual variability in the first step of social behavior, that is social perception, in typically developing children. For that purpose, we first used eye-tracking to objectively measure eye-gaze processing during passive visualization of social movie clips in 24 children and adolescents (10.5 ± 2.9 y). Secondly, we correlated eye-tracking data with measures of fractional anisotropy, an index of white matter microstructure, obtained using diffusion tensor imaging MRI. The results showed a large interindividual variability in the number of fixations to the eyes of characters during visualization of social scenes. In addition, whole-brain analysis showed a significant positive correlation between FA and number of fixations to the eyes,mainly in the temporal part of the superior longitudinal fasciculi bilaterally, adjacent to the posterior superior temporal cortex. Our results indicate the existence of a neural signature associated with the interindividual variability in social perception in children, contributing for better understanding the neural basis of typical and atypical development of a broader social expertise

Tuning Eye-Gaze Perception by Transitory STS Inhibition

International audienceProcessing eye-gaze information is a key step to human social interaction. Neuroimaging studies have shown that superior temporal sulcus (STS) is highly implicated in eye-gaze perception. In autism, a lack of preference for the eyes, as well as anatomo-functional abnormalities within the STS, has been described. To date, there are no experimental data in humans showing whether it is possible to interfere with eye-gaze processing by modulating STS neural activity. Here, we measured eye-gaze perception before and after inhibitory transcranial magnetic stimulation (TMS) applied over the posterior STS (pSTS) in young healthy volunteers. Eye-gaze processing, namely overt orienting toward the eyes, was measured using eye tracking during passive visualization of social movies. Inhibition of the right pSTS led participants to look less to the eyes of characters during visualization of social movies. Such effect was specific for the eyes and was not observed after inhibition of the left pSTS nor after placebo TMS. These results indicate for the first time that interfering with the right pSTS neural activity transitorily disrupts the behavior of orienting toward the eyes and thus indirectly gaze perception, a fundamental process for human social cognition. These results could open up new perspectives in therapeutic interventions in autism