Publications by authors named "Marie-Laure Paillère Martinot"

100 Publications

Dynamic functional connectivity in adolescence-onset major depression: relationships with severity and symptom dimensions.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 May 26. Epub 2021 May 26.

INSERM U1299 "Trajectoires développementales & psychiatrie", University Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS; Centre Borelli, Gif-sur-Yvette, France; EPS Barthélémy Durand, Psychiatry Department, Etampes, France.

Background: The spatial functional chronnectome is an innovative mathematical model designed to capture dynamic features in the organization of brain function derived from resting-state functional magnetic resonance imaging (rs-fMRI) data. Measurements of dynamic functional connectivity (dFC) have been developed from this model to quantify the brain dynamical self-reconfigurations at different spatial and temporal scales. This study examined whether two spatiotemporal dFC quantifications were linked to late adolescence-onset major depressive disorder (AO-MDD), and scaled with depression and symptom severity measured with the Montgomery-Asberg depression rating scale (MADRS) Methods: Thirty-five AO-MDD patients (21±6y) and fifty-three age- and gender-matched healthy young participants (20±3y) underwent 3T MRI structural and rs-fMRI acquisitions. The chronnectome here comprised seven individualized functional networks portrayed along 132 temporal overlapping windows, each framing 110s of resting brain activity Results: Based on voxelwise analyses, AO-MDD patients demonstrated significantly reduced temporal variability within the bilateral prefrontal cortex in five functional networks including the limbic network, the default-mode network (DMN) and frontoparietal network (FPN). Furthermore, the limbic network appeared to be particularly involved in this sample, and was associated with MADRS scores, and its progressive dynamic inflexibility was linked to sadness. DMN and FPN dynamics scaled with negative thoughts and neurovegetative symptoms, respectively Conclusions: This triple-network imbalance could delay spatiotemporal integration, while across-subject symptom variability would be network-specific. Therefore, the present approach supports that brain network dynamics underlie patients' symptom heterogeneity in AO-MDD.
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http://dx.doi.org/10.1016/j.bpsc.2021.05.003DOI Listing
May 2021

Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts.

Front Psychiatry 2021 20;12:645746. Epub 2021 Apr 20.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study ( = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) ( = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 ( < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in (p =0.042, OR = 0.73) and rs507961 in (p = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 () and rs507961 () remained significantly associated with positive AUDIT screens ( < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction ( = 0.006) involving rs484061 (), rs4963307 (), and rs7766029 () predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.
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http://dx.doi.org/10.3389/fpsyt.2021.645746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093566PMC
April 2021

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

Biol Psychiatry 2021 Jan 30. Epub 2021 Jan 30.

Centre for Population Neuroscience and Stratified Medicine, Institute for Science and Technology of Brain-Inspired Intelligence, Fudan University, Shanghai, China; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.

Background: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues.

Methods: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels.

Results: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%.

Conclusions: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.
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http://dx.doi.org/10.1016/j.biopsych.2021.01.011DOI Listing
January 2021

Orbitofrontal control of conduct problems? Evidence from healthy adolescents processing negative facial affect.

Eur Child Adolesc Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany.

Conduct problems (CP) in patients with disruptive behavior disorders have been linked to impaired prefrontal processing of negative facial affect compared to controls. However, it is unknown whether associations with prefrontal activity during affective face processing hold along the CP dimension in a healthy population sample, and how subcortical processing is affected. We measured functional brain responses during negative affective face processing in 1444 healthy adolescents [M = 14.39 years (SD = 0.40), 51.5% female] from the European IMAGEN multicenter study. To determine the effects of CP, we applied a two-step approach: (a) testing matched subgroups of low versus high CP, extending into the clinical range [N = 182 per group, M = 14.44 years, (SD = 0.41), 47.3% female] using analysis of variance, and (b) considering (non)linear effects along the CP dimension in the full sample and in the high CP group using multiple regression. We observed no significant cortical or subcortical effect of CP group on brain responses to negative facial affect. In the full sample, regression analyses revealed a significant linear increase of left orbitofrontal cortex (OFC) activity with increasing CP up to the clinical range. In the high CP group, a significant inverted u-shaped effect indicated that left OFC responses decreased again in individuals with high CP. Left OFC activity during negative affective processing which is increasing with CP and decreasing in the highest CP range may reflect on the importance of frontal control mechanisms that counteract the consequences of severe CP by facilitating higher social engagement and better evaluation of social content in adolescents.
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http://dx.doi.org/10.1007/s00787-021-01770-1DOI Listing
April 2021

Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study.

Eur Neuropsychopharmacol 2021 Mar 23;49:11-22. Epub 2021 Mar 23.

School of Psychology and Global Brain Health Institute, University College Dublin, Dublin, Ireland.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors.
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http://dx.doi.org/10.1016/j.euroneuro.2021.03.001DOI Listing
March 2021

Predicting depression onset in young people based on clinical, cognitive, environmental and neurobiological data.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 19. Epub 2021 Mar 19.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany.

Background: Adolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk-factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level.

Methods: A subsample of a multi-site longitudinal study in adolescents, the IMAGEN study, was used to predict future (subthreshold) major depressive disorder (MDD) onset in healthy adolescents. Based on 2-year and 5-year follow-up data, participants were grouped into: 1) developing an MDD diagnosis or subthreshold MDD and 2) healthy controls. Baseline measurements of 145 variables from different modalities (clinical, cognitive, environmental and structural magnetic resonance imaging [MRI]) at age 14 were used as input to penalized logistic regression (with different levels of penalization) to predict depression onset in a training dataset (N=407). The features contributing highest to the prediction were validated in an independent hold-out sample (3 independent IMAGEN sites; N=137).

Results: The area under the receiver operating characteristics curve (AUROC) for predicting depression onset ranged between 0.70-0.72 in the training dataset. Baseline severity of depressive symptoms, female sex, neuroticism, stressful life events and surface area of the supramarginal gyrus contributed most to the predictive model and predicted onset of depression with an AUROC between 0.68-0.72 in the independent validation sample.

Conclusions: This study showed that depression onset in adolescents can be predicted based on a combination multimodal data of clinical, life events, personality traits, brain structure variables.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.005DOI Listing
March 2021

Irregular sleep habits, regional grey matter volumes, and psychological functioning in adolescents.

PLoS One 2021 10;16(2):e0243720. Epub 2021 Feb 10.

National Institute of Health and Medical Research, INSERM U A10 "Trajectoires développementales & psychiatrie", University Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.

Changing sleep rhythms in adolescents often lead to sleep deficits and a delay in sleep timing between weekdays and weekends. The adolescent brain, and in particular the rapidly developing structures involved in emotional control, are vulnerable to external and internal factors. In our previous study in adolescents at age 14, we observed a strong relationship between weekend sleep schedules and regional medial prefrontal cortex grey matter volumes. Here, we aimed to assess whether this relationship remained in this group of adolescents of the general population at the age of 16 (n = 101; mean age 16.8 years; 55% girls). We further examined grey matter volumes in the hippocampi and the amygdalae, calculated with voxel-based morphometry. In addition, we investigated the relationships between sleep habits, assessed with self-reports, and regional grey matter volumes, and psychological functioning, assessed with the Strengths and Difficulties Questionnaire and tests on working memory and impulsivity. Later weekend wake-up times were associated with smaller grey matter volumes in the medial prefrontal cortex and the amygdalae, and greater weekend delays in wake-up time were associated with smaller grey matter volumes in the right hippocampus and amygdala. The medial prefrontal cortex region mediated the correlation between weekend wake up time and externalising symptoms. Paying attention to regular sleep habits during adolescence could act as a protective factor against the emergence of psychopathology via enabling favourable brain development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243720PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875363PMC
February 2021

Neural network involving medial orbitofrontal cortex and dorsal periaqueductal gray regulation in human alcohol abuse.

Sci Adv 2021 Feb 3;7(6). Epub 2021 Feb 3.

Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.

Prompted by recent evidence of neural circuitry in rodent models, functional magnetic resonance imaging and functional connectivity analyses were conducted for a large adolescent population at two ages, together with alcohol abuse measures, to characterize a neural network that may underlie the onset of alcoholism. A network centered on the medial orbitofrontal cortex (mOFC), as well as including the dorsal periaqueductal gray (dPAG), central nucleus of the amygdala, and nucleus accumbens, was identified, consistent with the rodent models, with evidence of both inhibitory and excitatory coregulation by the mOFC over the dPAG. Furthermore, significant relationships were detected between raised baseline excitatory coregulation in this network and impulsivity measures, supporting a role for negative urgency in alcohol dependence.
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http://dx.doi.org/10.1126/sciadv.abd4074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857680PMC
February 2021

Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?

Schizophr Res 2021 02 23;228:271-279. Epub 2021 Jan 23.

Department of Developmental Psychology, Adapt Lab, Research Priority Area Yield, University of Amsterdam, Nieuwe Achtergracht 129-B, 1018 WS Amsterdam, the Netherlands.

Objective: To assess changes in cannabis use in young adults as a function of psychotic-like experiences.

Method: Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19.

Results: Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22.

Conclusion: Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use.
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http://dx.doi.org/10.1016/j.schres.2021.01.002DOI Listing
February 2021

The Human Brain Is Best Described as Being on a Female/Male Continuum: Evidence from a Neuroimaging Connectivity Study.

Cereb Cortex 2021 May;31(6):3021-3033

Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, 200433, China.

Psychological androgyny has long been associated with greater cognitive flexibility, adaptive behavior, and better mental health, but whether a similar concept can be defined using neural features remains unknown. Using the neuroimaging data from 9620 participants, we found that global functional connectivity was stronger in the male brain before middle age but became weaker after that, when compared with the female brain, after systematic testing of potentially confounding effects. We defined a brain gender continuum by estimating the likelihood of an observed functional connectivity matrix to represent a male brain. We found that participants mapped at the center of this continuum had fewer internalizing symptoms compared with those at the 2 extreme ends. These findings suggest a novel hypothesis proposing that there exists a neuroimaging concept of androgyny using the brain gender continuum, which may be associated with better mental health in a similar way to psychological androgyny.
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http://dx.doi.org/10.1093/cercor/bhaa408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107794PMC
May 2021

Functional Connectivity Predicts Individual Development of Inhibitory Control during Adolescence.

Cereb Cortex 2021 Mar;31(5):2686-2700

School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin 2, Ireland.

Derailment of inhibitory control (IC) underlies numerous psychiatric and behavioral disorders, many of which emerge during adolescence. Identifying reliable predictive biomarkers that place the adolescents at elevated risk for future IC deficits can help guide early interventions, yet the scarcity of longitudinal research has hindered the progress. Here, using a large-scale longitudinal dataset in which the same subjects performed a stop signal task during functional magnetic resonance imaging at ages 14 and 19, we tracked their IC development individually and tried to find the brain features predicting their development by constructing prediction models using 14-year-olds' functional connections within a network or between a pair of networks. The participants had distinct between-subject trajectories in their IC development. Of the candidate connections used for prediction, ventral attention-subcortical network interconnections could predict the individual development of IC and formed a prediction model that generalized to previously unseen individuals. Furthermore, we found that connectivity between these two networks was related to substance abuse problems, an IC-deficit related problematic behavior, within 5 years. Our study reveals individual differences in IC development from mid- to late-adolescence and highlights the importance of ventral attention-subcortical network interconnections in predicting future IC development and substance abuse in adolescents.
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http://dx.doi.org/10.1093/cercor/bhaa383DOI Listing
March 2021

Association of Genetic and Phenotypic Assessments With Onset of Disordered Eating Behaviors and Comorbid Mental Health Problems Among Adolescents.

JAMA Netw Open 2020 12 1;3(12):e2026874. Epub 2020 Dec 1.

Technische Universität Dresden, Faculty of Medicine Carl Gustav Carus, Department of Psychiatry and Psychotherapy, Section of Systems Neuroscience, Dresden, Germany.

Importance: Eating disorders are serious mental disorders with increasing prevalence. Without early identification and treatment, eating disorders may run a long-term course.

Objective: To characterize any associations among disordered eating behaviors (DEBs) and other mental health disorders and to identify early associations with the development of symptoms over time.

Design, Setting, And Participants: This multicenter, population-based, longitudinal cohort study used data from baseline (collected in 2010), follow-up 1 (collected in 2012), and follow-up 2 (collected in 2015) of the IMAGEN Study, which included adolescents recruited from 8 European sites. The present study assessed data from 1623 healthy adolescents, aged 14 years at baseline, recruited from high schools. Data analyses were performed from January 2018 to September 2019.

Main Outcomes And Measures: Body mass index (BMI), mental health symptoms, substance use behaviors, and personality variables were investigated as time-varying associations of DEBs (dieting, binge eating, and purging) or change in BMI over time. Polygenic risk scores were calculated to investigate genetic contributions associated with BMI, attention-deficit/hyperactivity disorder (ADHD) and neuroticism to DEBs.

Results: In this cohort study of 1623 adolescents (829 girls [51.1%]) recruited at a mean (SD) age of 14.5 (0.4) years and followed up at ages 16 and 19 years, 278 adolescents (17.1%) reported binge eating, 334 adolescents (20.6%) reported purging, and 356 adolescents (21.9%) reported dieting at 14, 16, or 19 years. Among the precursors of DEBs, high BMI was associated with future dieting (OR, 3.44; 95% CI, 2.09-5.65). High levels of neuroticism (OR, 1.04; 95% CI, 1.01-1.06), conduct problems (OR, 1.41; 95% CI, 1.17-1.69), and deliberate self-harm (OR, 2.18; 95% CI, 1.37-3.45) were associated with future binge eating. Low agreeableness (OR, 0.95; 95% CI, 0.92-0.97), deliberate self-harm (OR, 2.59; 95% CI, 1.69-3.95), conduct problems (OR, 1.42; 95% CI, 1.20-1.68), alcohol misuse (OR, 1.31; 95% CI, 1.10-1.54), and drug abuse (OR, 2.91; 95% CI, 1.78-4.74) were associated with future purging. Polygenetic risk scores for BMI were associated with dieting (at 14 years: OR, 1.27; lower bound 95% CI, 1.08; at 16 years: OR, 1.38; lower bound 95% CI, 1.17); ADHD, with purging (at 16 years: OR, 1.25; lower bound 95% CI, 1.08; at 19 years, OR, 1.23; lower bound 95% CI, 1.06); and neuroticism, with binge eating (at 14 years: OR, 1.32; lower bound 95% CI, 1.11; at 16 years: OR, 1.24; lower bound 95% CI, 1.06), highlighting distinct etiologic overlaps between these traits. The DEBs predated other mental health problems, with dieting at 14 years associated with future symptoms of depression (OR, 2.53; 95% CI, 1.56-4.10), generalized anxiety (OR, 2.27; 95% CI, 1.14-4.51), deliberate self-harm (OR, 2.10; 95% CI, 1.51-4.24), emotional problems (OR, 1.24; 95% CI, 1.08-1.43), and smoking (OR, 2.16; 95% CI, 1.36-3.48). Purging at 14 years was also associated with future depression (OR, 2.87; 95% CI, 1.69-5.01) and anxiety (OR, 2.48; 95% CI, 1.49-4.12) symptoms.

Conclusions And Relevance: The findings of this study delineate temporal associations and shared etiologies among DEBs and other mental health disorders and emphasize the potential of genetic and phenotypical assessments of obesity, behavioral disorders, and neuroticism to improve early and differential diagnosis of eating disorders.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711322PMC
December 2020

Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 03 10;6(3):259-269. Epub 2020 Sep 10.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.

Background: The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.

Methods: Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14.

Results: The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003).

Conclusions: Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.
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http://dx.doi.org/10.1016/j.bpsc.2020.08.017DOI Listing
March 2021

Association between childhood trauma and risk for obesity: a putative neurocognitive developmental pathway.

BMC Med 2020 10 15;18(1):278. Epub 2020 Oct 15.

Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, People's Republic of China.

Background: Childhood trauma increases the risk for adult obesity through multiple complex pathways, and the neural substrates are yet to be determined.

Methods: Participants from three population-based neuroimaging cohorts, including the IMAGEN cohort, the UK Biobank (UKB), and the Human Connectome Project (HCP), were recruited. Voxel-based morphometry analysis of both childhood trauma and body mass index (BMI) was performed in the longitudinal IMAGEN cohort; validation of the findings was performed in the UKB. White-matter connectivity analysis was conducted to study the structural connectivity between the identified brain region and subdivisions of the hypothalamus in the HCP.

Results: In IMAGEN, a smaller frontopolar cortex (FPC) was associated with both childhood abuse (CA) (β = - .568, 95%CI - .942 to - .194; p = .003) and higher BMI (β = - .086, 95%CI - .128 to - .043; p < .001) in male participants, and these findings were validated in UKB. Across seven data collection sites, a stronger negative CA-FPC association was correlated with a higher positive CA-BMI association (β = - 1.033, 95%CI - 1.762 to - .305; p = .015). Using 7-T diffusion tensor imaging data (n = 156), we found that FPC was the third most connected cortical area with the hypothalamus, especially the lateral hypothalamus. A smaller FPC at age 14 contributed to higher BMI at age 19 in those male participants with a history of CA, and the CA-FPC interaction enabled a model at age 14 to account for some future weight gain during a 5-year follow-up (variance explained 5.8%).

Conclusions: The findings highlight that a malfunctioning, top-down cognitive or behavioral control system, independent of genetic predisposition, putatively contributes to excessive weight gain in a particularly vulnerable population, and may inform treatment approaches.
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http://dx.doi.org/10.1186/s12916-020-01743-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559717PMC
October 2020

Neuroimaging Association Scores: reliability and validity of aggregate measures of brain structural features linked to mental disorders in youth.

Eur Child Adolesc Psychiatry 2020 Oct 8. Epub 2020 Oct 8.

Section On Negative Affect and Social Processes, Departamento de Psiquiatria e Medicina Legal, Hospital de Clínicas de Porto Alegre, Universidade Federal Do Rio Grande Do Sul, Ramiro Barcelos, 2350, Room 2202, Porto Alegre, 90035-003, Brazil.

In genetics, aggregation of many loci with small effect sizes into a single score improved prediction. Nevertheless, studies applying easily replicable weighted scores to neuroimaging data are lacking. Our aim was to assess the reliability and validity of the Neuroimaging Association Score (NAS), which combines information from structural brain features previously linked to mental disorders. Participants were 726 youth (aged 6-14) from two cities in Brazil who underwent MRI and psychopathology assessment at baseline and 387 at 3-year follow-up. Results were replicated in two samples: IMAGEN (n = 1627) and the Healthy Brain Network (n = 843). NAS were derived by summing the product of each standardized brain feature by the effect size of the association of that brain feature with seven psychiatric disorders documented by previous meta-analyses. NAS were calculated for surface area, cortical thickness and subcortical volumes using T1-weighted scans. NAS reliability, temporal stability and psychopathology and cognition prediction were analyzed. NAS for surface area showed high internal consistency and 3-year stability and predicted general psychopathology and cognition with higher replicability than specific symptomatic domains for all samples. They also predicted general psychopathology with higher replicability than single structures alone, accounting for 1-3% of the variance, but without directionality. The NAS for cortical thickness and subcortical volumes showed lower internal consistency and less replicable associations with behavioural phenotypes. These findings indicate the NAS based on surface area might be replicable markers of general psychopathology, but these links are unlikely to be causal or clinically useful yet.
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http://dx.doi.org/10.1007/s00787-020-01653-xDOI Listing
October 2020

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

J Am Acad Child Adolesc Psychiatry 2021 05 1;60(5):623-636. Epub 2020 Oct 1.

Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Objective: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.

Method: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.

Results: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).

Conclusion: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.
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http://dx.doi.org/10.1016/j.jaac.2020.08.443DOI Listing
May 2021

Brain structure and habitat: Do the brains of our children tell us where they have been brought up?

Neuroimage 2020 11 13;222:117225. Epub 2020 Aug 13.

Lise Meitner Group for Environmental Neuroscience, Max Planck Institute for Human Development, Berlin, Germany.

Recently many lifestyle factors have been shown to be associated with brain structural alterations. At present we are facing increasing population shifts from rural to urban areas, which considerably change the living environments of human beings. To investigate the association between rural vs. urban upbringing and brain structure we selected 106 14-year old adolescents of whom half were exclusively raised in rural areas and the other half who exclusively lived in cities. Voxel-based morphometry revealed a group difference in left hippocampal formation (Rural > City), which was positively associated with cognitive performance in a spatial processing task. Moreover, significant group differences were observed in spatial processing (Rural > City). A mediation analysis revealed that hippocampal formation accounted for more than half of the association between upbringing and spatial processing. The results are compatible with studies reporting earlier and more intense opportunities for spatial exploration in children brought up in rural areas. The results are interesting in the light of urban planning where spaces enabling spatial exploration for children may deserve more attention.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117225DOI Listing
November 2020

Development of Disordered Eating Behaviors and Comorbid Depressive Symptoms in Adolescence: Neural and Psychopathological Predictors.

Biol Psychiatry 2020 Jun 10. Epub 2020 Jun 10.

Department of Psychiatry and Neuroimaging Center, Technische Universitat Dresden, Dresden, Germany.

Background: Eating disorders are common in adolescence and are devastating and strongly comorbid with other psychiatric disorders. Yet little is known about their etiology, knowing which would aid in developing effective preventive measures.

Methods: Longitudinal assessments of disordered eating behaviors (DEBs)-binge-eating, purging, and dieting-and comorbid psychopathology were measured in 1386 adolescents from the IMAGEN study. Development of DEBs and associated mental health problems was investigated by comparing participants who reported symptoms at ages 16 or 19 years, but not at age 14 years, with asymptomatic control participants. Voxel-based morphometry and psychopathological differences at age 14 were investigated to identify risk factors for the development of DEBs and associated mental health problems.

Results: DEBs and depressive symptoms developed together. Emotional and behavioral problems, including symptoms of attention-deficit/hyperactivity disorder and conduct disorder, predated their development. Alterations in frontostriatal brain areas also predated the development of DEBs and depressive symptoms. Specifically, development of binge-eating was predicted by higher gray matter volumes in the right putamen/globus pallidus at age 14. Conversely, development of purging and depressive symptoms was predicted by lower volumes in the medial orbitofrontal, dorsomedial, and dorsolateral prefrontal cortices. Lower gray matter volumes in the orbitofrontal and anterior cingulate cortices mediated the relationship between attention-deficit/hyperactivity disorder and conduct disorder symptoms and future purging and depressive symptoms.

Conclusions: These findings suggest that alterations in frontal brain circuits are part of the shared etiology among eating disorders, attention-deficit/hyperactivity disorder, conduct disorder, and depression and highlight the importance of a transdiagnostic approach to treating these conditions.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.003DOI Listing
June 2020

Longitudinal associations between amygdala reactivity and cannabis use in a large sample of adolescents.

Psychopharmacology (Berl) 2020 Nov 8;237(11):3447-3458. Epub 2020 Aug 8.

Vermont Center on Behavior and Health, University of Vermont, Burlington, VT, 05401, USA.

Rationale: The amygdala is a key brain structure to study in relation to cannabis use as reflected by its high-density of cannabinoid receptors and functional reactivity to processes relevant to drug use. Previously, we identified a correlation between cannabis use in early adolescence and amygdala hyper-reactivity to angry faces (Spechler et al. 2015).

Objectives: Here, we leveraged the longitudinal aspect of the same dataset (the IMAGEN study) to determine (1) if amygdala hyper-reactivity predicts future cannabis use and (2) if amygdala reactivity is affected by prolonged cannabis exposure during adolescence.

Methods: First, linear regressions predicted the level of cannabis use by age 19 using amygdala reactivity to angry faces measured at age 14 prior to cannabis exposure in a sample of 1119 participants. Next, we evaluated the time course of amygdala functional development from age 14 to 19 for angry face processing and how it might be associated with protracted cannabis use throughout this developmental window. We compared the sample from Spechler et al. 2015, the majority of whom escalated their use over the 5-year interval, to a matched sample of non-users.

Results: Right amygdala reactivity to angry faces significantly predicted cannabis use 5 years later in a dose-response fashion. Cannabis-naïve adolescents demonstrated the lowest levels of amygdala reactivity. No such predictive relationship was identified for alcohol or cigarette use. Next, follow-up analyses indicated a significant group-by-time interaction for the right amygdala.

Conclusions: (1) Right amygdala hyper-reactivity is predictive of future cannabis use, and (2) protracted cannabis exposure during adolescence may alter the rate of neurotypical functional development.
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http://dx.doi.org/10.1007/s00213-020-05624-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572697PMC
November 2020

The IMAGEN study: a decade of imaging genetics in adolescents.

Mol Psychiatry 2020 11 29;25(11):2648-2671. Epub 2020 Jun 29.

Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.

Imaging genetics offers the possibility of detecting associations between genotype and brain structure as well as function, with effect sizes potentially exceeding correlations between genotype and behavior. However, study results are often limited due to small sample sizes and methodological differences, thus reducing the reliability of findings. The IMAGEN cohort with 2000 young adolescents assessed from the age of 14 onwards tries to eliminate some of these limitations by offering a longitudinal approach and sufficient sample size for analyzing gene-environment interactions on brain structure and function. Here, we give a systematic review of IMAGEN publications since the start of the consortium. We then focus on the specific phenotype 'drug use' to illustrate the potential of the IMAGEN approach. We describe findings with respect to frontocortical, limbic and striatal brain volume, functional activation elicited by reward anticipation, behavioral inhibition, and affective faces, and their respective associations with drug intake. In addition to describing its strengths, we also discuss limitations of the IMAGEN study. Because of the longitudinal design and related attrition, analyses are underpowered for (epi-) genome-wide approaches due to the limited sample size. Estimating the generalizability of results requires replications in independent samples. However, such densely phenotyped longitudinal studies are still rare and alternative internal cross-validation methods (e.g., leave-one out, split-half) are also warranted. In conclusion, the IMAGEN cohort is a unique, very well characterized longitudinal sample, which helped to elucidate neurobiological mechanisms involved in complex behavior and offers the possibility to further disentangle genotype × phenotype interactions.
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http://dx.doi.org/10.1038/s41380-020-0822-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577859PMC
November 2020

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study.

Mol Psychiatry 2020 May 22. Epub 2020 May 22.

Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all P < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.
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http://dx.doi.org/10.1038/s41380-020-0757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981783PMC
May 2020

Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment.

Proc Natl Acad Sci U S A 2020 06 19;117(22):12411-12418. Epub 2020 May 19.

Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, 01087, Germany.

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated ( = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.
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http://dx.doi.org/10.1073/pnas.2001228117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275733PMC
June 2020

Neural Correlates of the Dual-Pathway Model for ADHD in Adolescents.

Am J Psychiatry 2020 09 7;177(9):844-854. Epub 2020 May 7.

Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Shanghai, China (Shen, Luo, Jia, Feng, Sahakian); State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science and Human Phenome Institute, Fudan University, Shanghai, China (Luo); Departments of Psychology and Psychiatry and the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, U.K. (Sahakian); Medical Research Council-Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Desrivières, Quinlan, Schumann); School of Mathematical Sciences, Fudan University, Shanghai, China (Zhao); Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (Banaschewski, Millenet, Nees); Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin (Bokde); University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Büchel); Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (Flor, Nees); Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany (Flor); Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany (Nees); NeuroSpin, Commissariat à l'Énergie Atomique, Université Paris-Saclay, Gif-sur-Yvette, France (Frouin, Orfanos); Departments of Psychiatry and Psychology, University of Vermont, Burlington (Garavan); Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, U.K. (Gowland); Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité, Universitätsmedizin Berlin (Heinz, Walter); Physikalisch-Technische Bundesanstalt Braunschweig and Berlin (Ittermann); Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1000, Neuroimaging and Psychiatry, University Paris Sud-Paris Saclay, University Paris Descartes, Paris (Martinot, Artiges, Paillère-Martinot); Service Hospitalier Frédéric Joliot, Orsay, France (Martinot, Artiges); Maison de Solenn, Paris (Martinot); Groupe Hospitalier Nord Essonne, Department of Psychiatry, Orsay, France (Artiges); Assistance Publique-Hôpitaux de Paris, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris (Paillère-Martinot); Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto (Paus); Departments of Psychology and Psychiatry, University of Toronto, Toronto (Paus); Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany (Poustka); Clinic for Child and Adolescent Psychiatry, Medical University of Vienna, Vienna (Poustka); Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany (Fröhner, Smolka); School of Psychology and Global Brain Health Institute, Trinity College Dublin (Whelan); Developmental and Behavioral Pediatric Department and Child Primary Care Department, Ministry of Education-Shanghai Key Lab for Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China (Li, Sahakian); Department of Computer Science, University of Warwick, Coventry, U.K. (Feng); and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (Feng).

Objective: The dual-pathway model has been proposed to explain the heterogeneity in symptoms of attention deficit hyperactivity disorder (ADHD) by two independent psychological pathways based on distinct brain circuits. The authors sought to test whether the hypothesized cognitive and motivational pathways have separable neural correlates.

Methods: In a longitudinal community-based cohort of 1,963 adolescents, the neuroanatomical correlates of ADHD were identified by a voxel-wise association analysis and then validated using an independent clinical sample (99 never-medicated patients with ADHD, 56 medicated patients with ADHD, and 267 healthy control subjects). The cognitive and motivational pathways were assessed by neuropsychological tests of working memory, intrasubject variability, stop-signal reaction time, and delay discounting. The associations were tested between the identified neuroanatomical correlates and both ADHD symptoms 2 years later and the polygenic risk score for ADHD.

Results: Gray matter volumes of both a prefrontal cluster and a posterior occipital cluster were negatively associated with inattention. Compared with healthy control subjects, never-medicated patients, but not medicated patients, had significantly lower gray matter volumes in these two clusters. Working memory and intrasubject variability were associated with the posterior occipital cluster, and delay discounting was independently associated with both clusters. The baseline gray matter volume of the posterior occipital cluster predicted the inattention symptoms in a 2-year follow-up and was associated with the genetic risk for ADHD.

Conclusions: The dual-pathway model has both shared and separable neuroanatomical correlates, and the shared correlate in the occipital cortex has the potential to serve as an imaging trait marker of ADHD, especially the inattention symptom domain.
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http://dx.doi.org/10.1176/appi.ajp.2020.19020183DOI Listing
September 2020

Neurobehavioural characterisation and stratification of reinforcement-related behaviour.

Nat Hum Behav 2020 05 20;4(5):544-558. Epub 2020 Apr 20.

Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.

Reinforcement-related cognitive processes, such as reward processing, inhibitory control and social-emotional regulation are critical components of externalising and internalising behaviours. It is unclear to what extent the deficit in each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes and whether neural activation profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing emotional faces in the European IMAGEN cohort of 2,000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattentive behaviour and conduct symptoms, and we describe neural signatures across cognitive tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns underling different externalising symptoms and identify neural stratification markers, while accounting for clinically observed comorbidity.
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http://dx.doi.org/10.1038/s41562-020-0846-5DOI Listing
May 2020

Examination of the neural basis of psychotic-like experiences in adolescence during processing of emotional faces.

Sci Rep 2020 03 20;10(1):5164. Epub 2020 Mar 20.

Cognition Schizophrenia and Imaging Laboratory, Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, United Kingdom.

Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal/amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential 'aberrant' neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.
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http://dx.doi.org/10.1038/s41598-020-62026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083946PMC
March 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Predicting change trajectories of neuroticism from baseline brain structure using whole brain analyses and latent growth curve models in adolescents.

Sci Rep 2020 Jan 27;10(1):1207. Epub 2020 Jan 27.

University Medical Center Hamburg-Eppendorf, Department of Psychiatry and Psychotherapy, Martinistrasse 52, 20246, Hamburg, Germany.

Adolescence is a vulnerable time for personality development. Especially neuroticism with its link to the development of psychopathology is of interest concerning influential factors. The present study exploratorily investigates neuroanatomical signatures for developmental trajectories of neuroticism based on a voxel-wise whole-brain structural equation modelling framework. In 1,814 healthy adolescents of the IMAGEN sample, the NEO-FFI was acquired at three measurement occasions across five years. Based on a partial measurement invariance second-order latent growth curve model we conducted whole-brain analyses on structural MRI data at age 14 years, predicting change in neuroticism over time. We observed that a reduced volume in the pituitary gland was associated with the slope of neuroticism over time. However, no relations with prefrontal areas emerged. Both findings are discussed against the background of possible genetic and social influences that may account for this result.
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http://dx.doi.org/10.1038/s41598-020-58128-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985226PMC
January 2020

Association of Gray Matter and Personality Development With Increased Drunkenness Frequency During Adolescence.

JAMA Psychiatry 2020 04;77(4):409-419

Department of Psychiatry and Addictology, Medical Faculty, University of Montreal, Montréal, Québec, Canada.

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown.

Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents.

Design, Setting, And Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points.

Main Outcomes And Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses.

Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P = .01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10 624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; β = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P = .004), the association of drunkenness increase with gray matter volume at age 14 years (β = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (β = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (β = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P = .01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness.

Conclusions And Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990803PMC
April 2020

Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence.

Cereb Cortex 2020 04;30(4):2707-2718

Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, Bloorview Research Institute, University of Toronto, Toronto, Ontario, M6A 2E1, Canada.

Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2-94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0-21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.
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http://dx.doi.org/10.1093/cercor/bhz270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175009PMC
April 2020

Sex effects on structural maturation of the limbic system and outcomes on emotional regulation during adolescence.

Neuroimage 2020 04 4;210:116441. Epub 2019 Dec 4.

Inserm, UMR 1000, Research Unit NeuroImaging and Psychiatry, Univ Paris Sud, Université Paris-Saclay, Université Paris Descartes, Digiteo Labs, Bâtiment 660, Gif-sur-Yvette, France; Groupe d'Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives, CNRS UMR 5293, Université de Bordeaux, Centre Broca Nouvelle-Aquitaine, Bordeaux, France. Electronic address:

Though adolescence is a time of emerging sex differences in emotions, sex-related differences in the anatomy of the maturing brain has been under-explored over this period. The aim of this study was to investigate whether puberty and sexual differentiation in brain maturation could explain emotional differences between girls and boys during adolescence. We adapted a dedicated longitudinal pipeline to process structural and diffusion images from 335 typically developing adolescents between 14 and 16 years. We used voxel-based and Regions of Interest approaches to explore sex and puberty effects on brain and behavioral changes during adolescence. Sexual differences in brain maturation were characterized by amygdala and hippocampal volume increase in boys and decrease in girls. These changes were mediating the sexual differences in positive emotional regulation as illustrated by positive attributes increase in boys and decrease in girls. Moreover, the differential maturation rates between the limbic system and the prefrontal cortex highlighted the delayed maturation in boys compared to girls. This is the first study to show the sex effects on the differential cortico/subcortical maturation rates and the interaction between sex and puberty in the limbic system maturation related to positive attributes, reported as being protective from emotional disorders.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116441DOI Listing
April 2020