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ABSTRACTLearning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.

Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms in vivoto date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design. In vitrostandard and controlled modeling has played a significant role in predicting the behavior of dosage forms in vivo. However, discrepancies are reported between in vitroand in vivodisintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form in vivois a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms in vivoin healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal.

Perseverative negative thoughts, known as rumination, might arise from emotional challenges and preclude mental health when transitioning into adulthood. Due to its multifaceted nature, rumination can take several ruminative response styles, that diverge in manifestations, severity, and mental health outcomes. Still, prospective ruminative phenotypes remain elusive insofar. Longitudinal study designs are ideal for stratifying ruminative response styles, especially with resting-state functional MRI whose setup naturally elicits people’s ruminative traits. Here, we considered self-rated questionnaires on rumination and psychopathology, along with resting-state functional MRI data in 595 individuals assessed at age 18 and 22 from the IMAGEN cohort. We conducted independent component analysis to characterize eight single static resting-state functional networks in each subject and session and furthermore conducted a dynamic analysis, tackling the time variations of functional networks during the entire scanning time. We then investigated their longitudinal mediation role between changes in three ruminative response styles (reflective pondering, brooding, and depressive rumination) and changes in internalizing and co-morbid externalizing symptoms. Four static and two dynamic networks longitudinally differentiated these ruminative styles and showed complemental sensitivity to internalizing and co-morbid externalizing symptoms. Among these networks, the right frontoparietal network covaried with all ruminative styles but did not play any mediation role towards psychopathology. The default mode, the salience, and the limbic networks prospectively stratified these ruminative styles, suggesting that maladaptive ruminative styles are associated with altered corticolimbic function. For static measures, only the salience network played a longitudinal causal role between brooding rumination and internalizing symptoms. Dynamic measures highlighted the default-mode mediation role between the other ruminative styles and co-morbid externalizing symptoms. In conclusion, we identified the ruminative styles’ psychometric and neural outcome specificities, supporting their translation into applied research on young adult mental healthcare.

Leveraging ~10 years of prospective longitudinal data on 704 participants, we examined the effects of adolescent versus young adult cannabis initiation on MRI-assessed cortical thickness development and behavior. Data were obtained from the IMAGEN study conducted across eight European sites. We identified IMAGEN participants who reported being cannabis-naïve at baseline and had data available at baseline, 5-year, and 9-year follow-up visits. Cannabis use was assessed with the European School Survey Project on Alcohol and Drugs. T1-weighted MR images were processed through the CIVET pipeline. Cannabis initiation occurring during adolescence (14–19 years) and young adulthood (19–22 years) was associated with differing patterns of longitudinal cortical thickness change. Associations between adolescent cannabis initiation and cortical thickness change were observed primarily in dorso- and ventrolateral portions of the prefrontal cortex. In contrast, cannabis initiation occurring between 19 and 22 years of age was associated with thickness change in temporal and cortical midline areas. Follow-up analysis revealed that longitudinal brain change related to adolescent initiation persisted into young adulthood and partially mediated the association between adolescent cannabis use and past-month cocaine, ecstasy, and cannabis use at age 22. Extent of cannabis initiation during young adulthood (from 19 to 22 years) had an indirect effect on psychotic symptoms at age 22 through thickness change in temporal areas. Results suggest that developmental timing of cannabis exposure may have a marked effect on neuroanatomical correlates of cannabis use as well as associated behavioral sequelae. Critically, this work provides a foundation for neurodevelopmentally informed models of cannabis exposure in humans.

Exposure to preadult environmental exposures may have long-lasting effects on mental health by affecting the maturation of the brain and personality, two traits that interact throughout the developmental process. However, environment-brain-personality covariation patterns and their mediation relationships remain unclear. In 4297 healthy participants (aged 18–30 years), we combined sparse multiple canonical correlation analysis with independent component analysis to identify the three-way covariation patterns of 59 preadult environmental exposures, 760 adult brain imaging phenotypes, and five personality traits, and found two robust environment-brain-personality covariation models with sex specificity. One model linked greater stress and less support to weaker functional connectivity and activity in the default mode network, stronger activity in subcortical nuclei, greater thickness and volume in the occipital, parietal and temporal cortices, and lower agreeableness, consciousness and extraversion as well as higher neuroticism. The other model linked higher urbanicity and better socioeconomic status to stronger functional connectivity and activity in the sensorimotor network, smaller volume and surface area and weaker functional connectivity and activity in the medial prefrontal cortex, lower white matter integrity, and higher openness to experience. We also conducted mediation analyses to explore the potential bidirectional mediation relationships between adult brain imaging phenotypes and personality traits with the influence of preadult environmental exposures and found both environment-brain-personality and environment-personality-brain pathways. We finally performed moderated mediation analyses to test the potential interactions between macro- and microenvironmental exposures and found that one category of exposure moderated the mediation pathways of another category of exposure. These results improve our understanding of the effects of preadult environmental exposures on the adult brain and personality traits and may facilitate the design of targeted interventions to improve mental health by reducing the impact of adverse environmental exposures.

The presence of a ‘magenstrasse’, a central ‘stomach road’ for flow and mixing of foods and drinks in the stomach had been predicted from hydrodynamic modelling. Here a magnetic resonance imaging (MRI) tagging technique was used to gain novel insights on the intragastric motion of breakfast porridges in 17 healthy humans. They consumed two similar breakfast porridge meals on separate days and tagging images with two different delay times were acquired 15 and 45 minutes postprandially, generating 128 data sets. Motion of the gastric contents was assessed by coefficient of variation (CoV) analysis across timeframes. The data showed that postprandial movement occurred already at the first imaging point after feeding. The motion of the gastric contents occurred along the central axis of the stomach appearing as a central ‘magenstrasse’ reaching the stomach body/fundus region in 73% of cases. Only in 10% of cases the displacement and smearing of the tag lines was detected close to the stomach walls. Seven % of data sets showed antegrade (towards the antrum) motion whilst a much larger percentage of motion was observed to be only retrograde (43%) or mixed antegrade and retrograde (50%). In conclusion, the MRI tagging method allowed novel insights into the movement of stomach contents using real model porridge meals and confirmed the existence of a central ‘stomach road’ for intragastric flow and mixing of food.

Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years (n= 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years (n= 114) and in an independent sample at 22 years (n= 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology.

On a theoretical level, impulsivity represents a multidimensional construct associated with acting without foresight, inefficient inhibitory response control, and alterations in reward processing. On an empirical level, relationships and changes in associations between different measures of impulsivity from adolescence into young adulthood and their relation to neural activity during inhibitory control and reward anticipation have not been fully understood.

Owing to its role in glucose homeostasis, liver glycogen concentration ([LGly]) can be a marker of altered metabolism seen in disorders that impact the health of children. However, there is a paucity of normative data for this measure in children to allow comparison with patients, and time-course assessment of [LGly] in response to feeding has not been reported. In addition, carbon-13 magnetic resonance spectroscopy (13C-MRS) is used extensively in research to assess liver metabolites in adult health and disease noninvasively, but similar measurements in children are lacking.

Recent longitudinal studies in youth have reported MRI correlates of prospective anxiety symptoms during adolescence, a vulnerable period for the onset of anxiety disorders. However, their predictive value has not been established. Individual prediction through machine-learning algorithms might help bridge the gap to clinical relevance. A voting classifier with Random Forest, Support Vector Machine and Logistic Regression algorithms was used to evaluate the predictive pertinence of gray matter volumes of interest and psychometric scores in the detection of prospective clinical anxiety. Participants with clinical anxiety at age 18–23 (N= 156) were investigated at age 14 along with healthy controls (N= 424). Shapley values were extracted for in-depth interpretation of feature importance. Prospective prediction of pooled anxiety disorders relied mostly on psychometric features and achieved moderate performance (area under the receiver operating curve = 0.68), while generalized anxiety disorder (GAD) prediction achieved similar performance. MRI regional volumes did not improve the prediction performance of prospective pooled anxiety disorders with respect to psychometric features alone, but they improved the prediction performance of GAD, with the caudate and pallidum volumes being among the most contributing features. To conclude, in non-anxious 14 year old adolescents, future clinical anxiety onset 4–8 years later could be individually predicted. Psychometric features such as neuroticism, hopelessness and emotional symptoms were the main contributors to pooled anxiety disorders prediction. Neuroanatomical data, such as caudate and pallidum volume, proved valuable for GAD and should be included in prospective clinical anxiety prediction in adolescents.

Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the Stratify Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities.

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.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1and KCNS2with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37overexpression, and cg26741686 hypermethylation favored ANKRD37overexpression, and ANKRD37overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37expression, and ANKRD37expression with hippocampal volume could be replicated in an independent healthy young (n= 443) dataset and observed in elderly people (n= 194), and were more significant in patients with late-onset Alzheimer’s disease (n= 76). This study revealed a novel causal molecular association mechanism of ANKRD37with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.

ObjectiveHealth-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would reduce gas production.DesignA randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an in vitrofermentation model. Primary endpoint was colonic gas assessed by MRI.ResultsColonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC(0–360 min)3145 (848–6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62–2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC(0–360 min)were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC(0–360 min)from 7230 (3255–17910) ppm·hour to 1035 (360–4320) ppm·hour, p=0.007.Fermentation in vitroproduced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production.ConclusionsPsyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study.Trial registration numberNCT03265002.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1and APOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

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 rrange: 0.30–0.65, all PFDR< 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.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r= 0.10, n= 874, p= 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r= 0.17, n= 874, p= 6.5 × 10−6FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b=0.006, 90% CIs = 0.001, 0.019) and BMI (b=0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b=0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b=0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Exposure to maltreatment during childhood is associated with structural changes throughout the brain. However, the structural differences that are most strongly associated with maltreatment remain unclear given the limited number of whole-brain studies. The present study used machine learning to identify if and how brain structure distinguished young adults with and without a history of maltreatment. Young adults (ages 18–21, n= 384) completed an assessment of childhood trauma exposure and a structural MRI as part of the IMAGEN study. Elastic net regularized regression was used to identify the structural features that identified those with a history of maltreatment. A generalizable model that included 7 cortical thicknesses, 15 surface areas, and 5 subcortical volumes was identified (area under the receiver operating characteristic curve = 0.71, p< 0.001). Those with a maltreatment history had reduced surface areas and cortical thicknesses primarily in fronto-temporal regions. This group also had larger cortical thicknesses in occipital regions and surface areas in frontal regions. The results suggest childhood maltreatment is associated with multiple measures of structure throughout the brain. The use of a large sample without exposure to adulthood trauma provides further evidence for the unique contribution of childhood trauma to brain structure. The identified regions overlapped with regions associated with psychopathology in adults with maltreatment histories, which offers insights as to how these disorders manifest.

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Attention-Deficit/Hyperactivity Disorder (ADHD) and conduct disorder (CD) exemplify top-down dysregulation conditions that show a large comorbidity and shared genetics. At the same time, they entail two different types of symptomology involving mainly non-emotional or emotional dysregulation. Few studies have tried to separate the specific biology underlying these two dimensions. It has also been suggested that both types of conditions consist of extreme cases in the general population where the symptoms are widely distributed. Here we test whether brain structure is specifically associated to ADHD or CD symptoms in a general population of adolescents (n?=?1093) being part of the IMAGEN project. Both ADHD symptoms and CD symptoms were related to similar and overlapping MRI findings of a smaller structure in prefrontal and anterior cingulate cortex. However, our regions of interest (ROI) approach indicated that gray matter volume (GMV) and surface area (SA) in dorsolateral/dorsomedial prefrontal cortex and caudal anterior cingulate cortex were negatively associated to ADHD symptoms when controlling for CD symptoms while rostral anterior cingulate cortex GMV was negatively associated to CD symptoms when controlling for ADHD symptoms. The structural findings were mirrored in performance of neuropsychological tests dependent on prefrontal and anterior cingulate regions, showing that while performance on the Stop Signal test was specifically related to the ADHD trait, delayed discounting and working memory were related to both ADHD and CD traits. These results point towards a partially domain specific and dimensional capacity in different top-down regulatory systems associated with ADHD and CD symptoms.

Chronic peer victimization has long-term impacts on mental health; however, the biological mediators of this adverse relationship are unknown. We sought to determine whether adolescent brain development is involved in mediating the effect of peer victimization on psychopathology. We included participants (n?=?682) from the longitudinal IMAGEN study with both peer victimization and neuroimaging data. Latent profile analysis identified groups of adolescents with different experiential patterns of victimization. We then associated the victimization trajectories and brain volume changes with depression, generalized anxiety, and hyperactivity symptoms at age 19. Repeated measures ANOVA revealed time-by-victimization interactions on left putamen volume (F?=?4.38, p?=?0.037). Changes in left putamen volume were negatively associated with generalized anxiety (t?=?-2.32, p?=?0.020). Notably, peer victimization was indirectly associated with generalized anxiety via decreases in putamen volume (95% CI?=?0.004–0.109). This was also true for the left caudate (95% CI?=?0.002–0.099). These data suggest that the experience of chronic peer victimization during adolescence might induce psychopathology-relevant deviations from normative brain development. Early peer victimization interventions could prevent such pathological changes.

The regular overnight migrating motor complex (MMC) ensures that the normal fasting small-bowel water content (SBWC) is minimised. We have applied our recently validated non-invasive magnetic resonance technique to assess SBWC in newly diagnosed coeliac disease (CD), scleroderma (SCD) and irritable bowel syndrome (IBS), conditions possibly associated with small intestinal bacterial overgrowth (SIBO). A total of 20 CD and 15 SCD patients with gastrointestinal symptoms were compared to 20 healthy volunteers (HV) and 26 IBS with diarrhoea (IBS-D) patients, as previously reported. All underwent a fasting magnetic resonance imaging (MRI) scan on a 1.5?T Philips Achieva MRI scanner to assess fasting SBWC and colonic volumes. Stool and symptom diaries were completed for one week. Compared to HV, all patients had significantly increased stool frequency and Bristol stool form score. SBWC was significantly increased in CD (median 109?mL; interquartile range (IQR) 53–224?mL) compared to HV (median 53?mL; IQR 31–98?mL; p?

Few studies have investigated the link between putative biomarkers of attention-deficit/hyperactivity disorder (ADHD) symptomatology and genetic risk for ADHD. To address this, we investigate the degree to which ADHD symptomatology is associated with white matter microstructure and cerebral cortical thickness in a large population-based sample of adolescents. Critically, we then test the extent to which multimodal correlates of ADHD symptomatology are related to ADHD polygenic risk score (PRS). Neuroimaging, genetic, and behavioral data were obtained from the IMAGEN study. A dimensional ADHD composite score was derived from multi-informant ratings of ADHD symptomatology. Using tract-based spatial statistics, whole brain voxel-wise regressions between fractional anisotropy (FA) and ADHD composite score were calculated. Local cortical thickness was regressed on ADHD composite score. ADHD PRS was based on a very recent genome-wide association study, and calculated using PRSice. ADHD composite score was negatively associated with FA in several white matter pathways, including bilateral superior and inferior longitudinal fasciculi (p< 0.05, corrected). ADHD composite score was negatively associated with orbitofrontal cortical thickness (p< 0.05, corrected). The ADHD composite score was correlated with ADHD PRS (p< 0.001). FA correlates of ADHD symptomatology were significantly associated with ADHD PRS, whereas cortical thickness correlates of ADHD symptomatology were unrelated to ADHD PRS. Variation in hyperactive/inattentive symptomatology was associated with white matter microstructure, which, in turn, was related to ADHD PRS. Results suggest that genetic risk for ADHD symptomatology may be tied to biological processes affecting white matter microstructure.

Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or “pockets”. Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivoperformance of controlled release formulations targeted to the colon. The in vivoquantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitroperformance tools predictive of the in vivoenvironment.

OBJECTIVES:Non-invasive biomarkers which identify different mechanisms of disease in subgroups of irritable bowel syndrome (IBS) could be valuable. Our aim was to seek useful magnetic resonance imaging (MRI) parameters that could distinguish each IBS subtypes.METHODS:34 healthy volunteers (HV), 30 IBS with diarrhea (IBS-D), 16 IBS with constipation (IBS-C), and 11 IBS with mixed bowel habit (IBS-M) underwent whole-gut transit and small and large bowel volumes assessment with MRI scans from t=0 to t=360 min. Since the bowel frequency for IBS-M were similar to IBS-D, IBS-M and IBS-D were grouped together and labeled as IBS non-constipation group (IBS-nonC).RESULTS:Median (interquartile range): fasting small bowel water content in IBS-nonC was 21 (10–42), significantly less than HV at 44 ml (15–70), P<0.01 as was the postprandial area under the curve (AUC) P<0.01. The fasting transverse colon volumes in IBS-C were significantly larger at 253 (200–329) compared with HV, IBS-nonC whose values were 165 (117–255) and 198 (106–270) ml, respectively, P=0.02. Whole-gut transit time for IBS-C was prolonged at 69 (51–111), compared with HV at 34 (4–63) and IBS-D at 34 (17–78) h, P=0.03. Bloating score (VAS 0–10 cm) correlated with transverse colon volume at t=405 min, Spearman r=0.21, P=0.04.CONCLUSIONS:The constricted small bowel in IBS-nonC and the dilated transverse colon in IBS-C point to significant differences in underlying mechanisms of disease.

Endotoxemia is common in advanced chronic kidney disease and is particularly severe in those receiving dialysis. In hemodialysis patients, translocation from the bowel occurs as a consequence of recurrent circulatory stress leading to a reduction in circulating splanchnic volume and increased intestinal permeability. Peritoneal dialysis (PD) patients are often volume expanded and have continuous direct immersion of bowel in fluid; these may also be important factors in endotoxin translocation and would suggest different therapeutic strategies to improve it. The mechanisms leading to endotoxemia have never been specifically studied in PD. In this study, 17 subjects (8 PD patients, 9 healthy controls) underwent detailed gastrointestinal and cardiac magnetic resonance imaging during fasted and fed states. Gross splanchnic perfusion was assessed by quantification of superior mesenteric artery flow. Magnetic resonance imaging findings were correlated to endotoxemia, markers of hydration status and cardiac structure and function.

The onset of substance use mostly occurs during adolescence. The aim of the present study is to investigate the relevance of personality on the basis of the NEO-Five-Factor Inventory (NEO-FFI) to future experiences with tobacco, alcohol and cannabis. The test data were derived from the baseline assessment and first follow-up of the IMAGEN study, a European multicenter and multidisciplinary research project on adolescent mental health. In the present study 1004 participants were tested. The characterization of personality was conducted with the NEO-FFI at the age of 14 (T1). The data on substance use were collected with the European School Survey Project on Alcohol and Other Drugs (ESPAD) questionnaire at the age of 16 (T2). For the statistical analysis, t-tests and univariate analyses of variance were performed. The scores of Conscientiousness at T1 were significantly lower for adolescents with tobacco, alcohol and cannabis experiences at T2. We found lower scores of Agreeableness at T1 in participants with tobacco and cannabis use at T2. Extraversion at T1 was significantly higher for adolescents with smoking experiences at T2. No significant associations between Neuroticism or Openness and future substance use were observed. Low scores of Conscientiousness and Agreeableness seem to have the greatest value for a prediction of later experiences with substance use. As the present study is the first one to examine the predictive value of the NEO-FFI for future substance use in an adolescent sample, further studies are necessary to enable a better applicability in a clinical context.

Echo-planar magnetic resonance imaging of a fetus may not adversely affect its hearing. Echo-planar imaging is faster than conventional magnetic resonance imaging and gives a clearer image. There is concern, however, that the acoustic noise levels due to the changing magnetic field gradients may cause hearing loss in the fetus. Echo-planar imaging was performed on 20 pregnant women whose fetuses had been diagnosed as abnormal. Of the 18 infants who were followed, 16 passed their eight-month hearing distraction test. The two infants who did not pass were later found to have normal hearing. A larger study is needed to confirm the safety of echo-planar imaging.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivoin an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitrotesting methods and in silicotransport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.

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.

This study assessed whether high-resolution 7 T MRI allowed direct in vivo visualization of nigrosomes, substructures of the substantia nigra pars compacta (SNpc) undergoing the greatest and earliest dopaminergic cell loss in Parkinson disease (PD), and whether any disease-specific changes could be detected in patients with PD.

Functional magnetic resonance imaging (fMRI) is a non-invasive imaging technique that maps the brain's response to neuronal activity based on the blood oxygenation level dependent (BOLD) effect. This work proposes a novel method for fMRI data analysis that enables the decomposition of the fMRI signal in its sources based on morphological descriptors. Beyond traditional fMRI hypothesis-based or blind data-driven exploratory approaches, this method allows the detection of BOLD responses without prior timing information. It is based on the deconvolution of the neuronal-related haemodynamic component of the fMRI signal with paradigm free mapping and also furnishes estimates of the movement-related effects, instrumental drifts and physiological fluctuations. Our algorithm is based on an overcomplete representation of the fMRI voxel time series with an additive linear model that is recovered by means of a L1-norm regularized least-squares estimators and an adapted block coordinate relaxation procedure. The performance of the technique is evaluated with simulated data and real experimental data acquired at 3T.

Liquid Gaviscon and Gaviscon Advance are established reflux suppressant formulations. This study describes the use of echo‐planar magnetic resonance imaging (EPI) to visualise non‐invasively intragastric alginate rafts of Liquid Gaviscon and Gaviscon Advance in healthy subjects. Secondly, the feasibility of using relaxation rate (T2−1) measurements to monitor changes in the physicochemical properties of the rafts in‐vivo is evaluated. Six subjects ingested 500 mL of a liquid meal and received a single dose of 20 mL Liquid Gaviscon or 10 mL Gaviscon Advance on 2 separate visits each and were imaged every 15 min. An alginate raft was observed in the stomach for all subjects and both treatments. The raft was observed to consist of a few large fragments on the majority of the scans for both products. At t = 60 min a raft was still present in all cases. Three‐dimensional volume reconstructions showed, for the first time, the spatial distribution of the rafts within the gastric lumen. The T2−1data showed potential for assessment of dynamic changes in the physicochemical properties of the alginate rafts in‐vivo. We conclude that EPI shows great potential in assessing alginate rafts formation in‐vivo.

Objective:To quantify longitudinal increses in fetal, fetal liver, and fetal brain volume using echo-planar magnetic resonance imaging and to quantify the results using appropriate statistical modeling.Methods:Fifty-six singleton fetuses were studied using echo-planar (snap-shot) magnetic resonance imaging, between 19 weeks and term. They were assessed at a variety of different gestations and on a different number of occasions, thereby requiring multilevel statistical modeling to analyze the pattern of fetal growth.Results:Fetal volume varied according to the following equation: square root (√) [fetal volume] = -37.71 + 2.17·gestational age (GA) - 0.004·GA2. The equation for fetal liver volume was √[fetal liver volume] = 9.47 + 0.56·GA - 0.02·GA2, for fetal brain volume was √[fetal brain volume] = 15.50 + 0.69·GA - 0.014·GA2, and for placental volume √[placental volume] = 28.54 + 0.95·GA - 0.039·GA2, where GA is the gestational age in weeks -30.Conclusion:The assessment of fetal, fetal organ, and placental volume was feasible using echo-planar magnetic resonance imaging from 20 weeks to term. Multilevel statistical modeling can be applied to analyze sets of data with different measurements on different occasions. This information is useful clinically to assess abnormal fetal growth.

Gastric emptying, frequency of antral contractions, and speed of antral contraction propagation were assessed in four patients using echoplanar imaging techniques. The results obtained and their impact on the diagnosis and management of the patients are presented and discussed. This shows that echoplanar evaluation of gastric function is noninvasive, well-tolerated by patients, detects clinically relevant abnormalities, and has the potential of becoming a valuable examination in the clinical gastrointestinal practice. J. Magn. Reson. Imaging 2000;12:343–346. © 2000 Wiley-Liss, Inc.

This paper presents a steady‐state method of arterial spin labelling using continuous saturation in conjunction with echo‐planar imaging (EPI), which has been implemented at 3 T. The continuous saturation technique has the advantage of having high sensitivity compared to transient labelling techniques, when long repetition times are used. It is also easy to implement and requires minimal data to be acquired for quantitation. Like other arterial spin labelling techniques, continuous saturation is potentially prone to overestimation of perfusion rates due to the effect of tagged blood in vessels within the image slice. Using a simple model of the vasculature, the degree of diffusion weighting required to suppress the arterial signal has been determined, with the results indicating that a value of 2 s/mm2is adequate. Histogram analysis of the experimental data has been used to evaluate the effect of diffusion weighting. Using a b‐value of 2 s/mm2, the mean perfusion‐related signal change in grey matter on continuous saturation was found to be 1.5 ± 0.2%, yielding a mean perfusion rate of 87 ± 9 ml/100 g/min. Brain activation studies using the diffusion weighted continuous saturation technique gave a mean increase in perfusion of 36 ± 12% in activated motor cortex. Copyright © 1999 John Wiley & Sons, Ltd.

Objective To measure magnetic resonance parameters T1 and T2 of the fetal lungs and investigate the relationship of these parameters to changes in volume and gestation.

This paper presents the first in vivomeasurements of perfusion in the human placenta from 20 weeks gestational age until term, using the non‐selective/selective inversion recovery echo‐planar imaging sequence, in which data is alternately acquired following a selective and non‐selective inversion pulse. Twenty pairs of images were collected, two each at the following inversion times: 20, 310, 610, 910, 1110, 1410, 1910, 2810, 3310, and 4510 ms with the sequence being repeated with a repetition time (TR) of 10 s. The results of these measurements were used to suggest the optimum sequence for future work in terms of the signal to noise ratio in the measured perfusion rate in a given measurement time. The sequence was also analyzed to determine the expected variability in the measurements. In normal pregnancies the average value of perfusion rate was found to be 176 (standard error = ±24) ml/100 mg/min. (n= 16, standard deviation = 96 ml/100 mg/min). The expected variability in the measured parameters due to signal to noise ratio considerations alone was calculated to be 71%. For a maximum scanning time of 400 s, the optimum sequence for measuring placental perfusion was found to require 8 repetitions at each of 10 inversion times which were geometrically spaced (given by a0a0r0a0r2a0r3,…), with a0= 850 ms, r = 1.073 and TR = 5 s, giving a pixel variability of 38%. Other timing schemes are recommended for measuring perfusion in other anatomical regions with different values of perfusion rate and longitudinal relaxation time.

Gamma-aminobutyric acid (GABA) and glutamate are the primary neurotransmitters responsible for modulating excitatory and inhibitory signalling within the human brain. Dysfunctional GABAergic and glutamatergic signalling has been identified as a key factor in a range of neuropsychiatric conditions; hence measurement and modulation of these neurometabolites is important for improving our understanding of neuropsychiatric conditions and treatment options. Gabapentin (GBP) is one of several drugs developed to increase GABA levels and is routinely prescribed for conditions such as epilepsy and neuralgia. While animal and human studies indicate that GBP can elevate GABA levels, its exact mechanisms of action are not fully understood, although animal studies indicate that GBP does not have a direct effect upon GABAergic receptors.