Optimising brain age estimation through transfer learning: A suite of pre-trained foundation models for improved performance and generalisability in a clinical setting.

Estimated age from brain MRI data has emerged as a promising biomarker of neurological health. However, the absence of large, diverse, and clinically representative training datasets, along with the complexity of managing heterogeneous MRI data, presents significant barriers to the development of accurate and generalisable models appropriate for clinical use. Here, we present a deep learning framework trained on routine clinical data (N up to 18,890, age range 18-96 years). We trained five separate models for accurate brain age prediction (all with mean absolute error ≤4.0 years, R2 ≥ .86) across five different MRI sequences (T2 -weighted, T2 -FLAIR, T1 -weighted, diffusion-weighted, and gradient-recalled echo T2 *-weighted). Our trained models offer dual functionality. First, they have the potential to be directly employed on clinical data. Second, they can be used as foundation models for further refinement to accommodate a range of other MRI sequences (and therefore a range of clinical scenarios which employ such sequences). This adaptation process, enabled by transfer learning, proved effective in our study across a range of MRI sequences and scan orientations, including those which differed considerably from the original training datasets. Crucially, our findings suggest that this approach remains viable even with limited data availability (as low as N = 25 for fine-tuning), thus broadening the application of brain age estimation to more diverse clinical contexts and patient populations. By making these models publicly available, we aim to provide the scientific community with a versatile toolkit, promoting further research in brain age prediction and related areas.

Adolescent to young adult longitudinal development of subcortical volumes in two European sites with four waves.

Adolescent subcortical structural brain development might underlie psychopathological symptoms, which often emerge in adolescence. At the same time, sex differences exist in psychopathology, which might be mirrored in underlying sex differences in structural development. However, previous studies showed inconsistencies in subcortical trajectories and potential sex differences. Therefore, we aimed to investigate the subcortical structural trajectories and their sex differences across adolescence using for the first time a single cohort design, the same quality control procedure, software, and a general additive mixed modeling approach. We investigated two large European sites from ages 14 to 24 with 503 participants and 1408 total scans from France and Germany as part of the IMAGEN project including four waves of data acquisition. We found significantly larger volumes in males versus females in both sites and across all seven subcortical regions. Sex differences in age-related trajectories were observed across all regions in both sites. Our findings provide further evidence of sex differences in longitudinal adolescent brain development of subcortical regions and thus might eventually support the relationship of underlying brain development and different adolescent psychopathology in boys and girls.

Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

BACKGROUND: Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. METHODS: Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). RESULTS: We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. CONCLUSIONS: We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Covariation of preadult environmental exposures, adult brain imaging phenotypes, and adult personality traits.

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.

Self-blame in major depression: a randomised pilot trial comparing fMRI neurofeedback with self-guided psychological strategies.

BACKGROUND: Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown. METHOD: This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance (n = 43, n = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases. RESULTS: As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame v. other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life. CONCLUSIONS: These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888.

A prospective 5-year longitudinal study detects neurocognitive and imaging correlates of seizure remission in self-limiting Rolandic epilepsy.

OBJECTIVE: Self-limiting Rolandic epilepsy (RE) is the most common epilepsy in school-age children. Seizures are generally infrequent, but cognitive, language, and motor coordination problems can significantly impact the child's life. To better understand brain structure and function changes in RE, we longitudinally assessed neurocognition, cortical thickness, and subcortical volumes. METHODS: At baseline, we recruited 30 participants diagnosed with RE and 24-healthy controls and followed up for 4.94 ± 0.8 years when the participants with RE were in seizure remission. Measures included were as follows: T1-weighted magnetic resonance brain imaging (MRI) with FreeSurfer analysis and detailed neuropsychological assessments. MRI and neuropsychological data were compared between baseline and follow-up in seizure remission. RESULTS: Longitudinal MRI revealed excess cortical thinning in the left-orbitofrontal (p = 0.0001) and pre-central gyrus (p = 0.044). There is a significant association (p = 0.003) between a reduction in cortical thickness in the left-orbitofrontal cluster and improved processing of filtered words. Longitudinal neuropsychology revealed significant improvements in the symptoms of developmental coordination disorder (DCD, p = 0.005) in seizure remission. CONCLUSIONS: There is evidence for altered development of neocortical regions between active seizure state and seizure remission in RE within two clusters maximal in the left-orbitofrontal and pre-central gyrus. There is significant evidence for improvement in motor coordination between active seizures and seizure remission and suggestive evidence for a decline in fluid intelligence and gains in auditory processing.

Risk clustering and psychopathology from a multi-center cohort of Indian children, adolescents, and young adults.

Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8-2.3], externalizing (RR = 4.8, 95% CI 3.6-6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2-2.9), and suicidality (2.3, 95% CI 1.8-2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.

Reliability of structural MRI measurements: The effects of scan session, head tilt, inter-scan interval, acquisition sequence, FreeSurfer version and processing stream.

BACKGROUND: Large-scale longitudinal and multi-centre studies are used to explore neuroimaging markers of normal ageing, and neurodegenerative and mental health disorders. Longitudinal changes in brain structure are typically small, therefore the reliability of automated techniques is crucial. Determining the effects of different factors on reliability allows investigators to control those adversely affecting reliability, calculate statistical power, or even avoid particular brain measures with low reliability. This study examined the impact of several image acquisition and processing factors and documented the test-retest reliability of structural MRI measurements. METHODS: In Phase I, 20 healthy adults (11 females; aged 20-30 years) were scanned on two occasions three weeks apart on the same scanner using the ADNI-3 protocol. On each occasion, individuals were scanned twice (repetition), after re-entering the scanner (reposition) and after tilting their head forward. At one year follow-up, nine returning individuals and 11 new volunteers were recruited for Phase II (11 females; aged 22-31 years). Scans were acquired on two different scanners using the ADNI-2 and ADNI-3 protocols. Structural images were processed using FreeSurfer (v5.3.0, 6.0.0 and 7.1.0) to provide subcortical and cortical volume, cortical surface area and thickness measurements. Intra-class correlation coefficients (ICC) were calculated to estimate test-retest reliability. We examined the effect of repetition, reposition, head tilt, time between scans, MRI sequence and scanner on reliability of structural brain measurements. Mean percentage differences were also calculated in supplementary analyses. RESULTS: Using the FreeSurfer v7.1.0 longitudinal pipeline, we observed high reliability for subcortical and cortical volumes, and cortical surface areas at repetition, reposition, three weeks and one year (mean ICCs>0.97). Cortical thickness reliability was lower (mean ICCs>0.82). Head tilt had the greatest adverse impact on ICC estimates, for example reducing mean right cortical thickness to ICC=0.74. In contrast, changes in ADNI sequence or MRI scanner had a minimal effect. We observed an increase in reliability for updated FreeSurfer versions, with the longitudinal pipeline consistently having a higher reliability than the cross-sectional pipeline. DISCUSSION: Longitudinal studies should monitor or control head tilt to maximise reliability. We provided the ICC estimates and mean percentage differences for all FreeSurfer brain regions, which may inform power analyses for clinical studies and have implications for the design of future longitudinal studies.

Accurate brain-age models for routine clinical MRI examinations.

Convolutional neural networks (CNN) can accurately predict chronological age in healthy individuals from structural MRI brain scans. Potentially, these models could be applied during routine clinical examinations to detect deviations from healthy ageing, including early-stage neurodegeneration. This could have important implications for patient care, drug development, and optimising MRI data collection. However, existing brain-age models are typically optimised for scans which are not part of routine examinations (e.g., volumetric T1-weighted scans), generalise poorly (e.g., to data from different scanner vendors and hospitals etc.), or rely on computationally expensive pre-processing steps which limit real-time clinical utility. Here, we sought to develop a brain-age framework suitable for use during routine clinical head MRI examinations. Using a deep learning-based neuroradiology report classifier, we generated a dataset of 23,302 'radiologically normal for age' head MRI examinations from two large UK hospitals for model training and testing (age range = 18-95 years), and demonstrate fast (< 5 s), accurate (mean absolute error [MAE] < 4 years) age prediction from clinical-grade, minimally processed axial T2-weighted and axial diffusion-weighted scans, with generalisability between hospitals and scanner vendors (Δ MAE < 1 year). The clinical relevance of these brain-age predictions was tested using 228 patients whose MRIs were reported independently by neuroradiologists as showing atrophy 'excessive for age'. These patients had systematically higher brain-predicted age than chronological age (mean predicted age difference = +5.89 years, 'radiologically normal for age' mean predicted age difference = +0.05 years, p < 0.0001). Our brain-age framework demonstrates feasibility for use as a screening tool during routine hospital examinations to automatically detect older-appearing brains in real-time, with relevance for clinical decision-making and optimising patient pathways.

Motion corrected silent ZTE neuroimaging.

PURPOSE: To develop self-navigated motion correction for 3D silent zero echo time (ZTE) based neuroimaging and characterize its performance for different types of head motion. METHODS: The proposed method termed MERLIN (Motion Estimation & Retrospective correction Leveraging Interleaved Navigators) achieves self-navigation by using interleaved 3D phyllotaxis k-space sampling. Low resolution navigator images are reconstructed continuously throughout the ZTE acquisition using a sliding window and co-registered in image space relative to a fixed reference position. Rigid body motion corrections are then applied retrospectively to the k-space trajectory and raw data and reconstructed into a final, high-resolution ZTE image. RESULTS: MERLIN demonstrated successful and consistent motion correction for magnetization prepared ZTE images for a range of different instructed motion paradigms. The acoustic noise response of the self-navigated phyllotaxis trajectory was found to be only slightly above ambient noise levels (<4 dBA). CONCLUSION: Silent ZTE imaging combined with MERLIN addresses two major challenges intrinsic to MRI (i.e., subject motion and acoustic noise) in a synergistic and integrated manner without increase in scan time and thereby forms a versatile and powerful framework for clinical and research MR neuroimaging applications.

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions.

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1 , T2 , myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord.

Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks.

Inflammation is associated with depressive symptoms and innate immune mechanisms are likely causal in some cases of major depression. Systemic inflammation also perturbs brain function and microstructure, though how these are related remains unclear. We recruited N = 46 healthy controls, and N = 83 depressed cases stratified by CRP (> 3 mg/L: N = 33; < 3 mg/L: N = 50). All completed clinical assessment, venous blood sampling for C-reactive protein (CRP) assay, and brain magnetic resonance imaging (MRI). Micro-structural MRI parameters including proton density (PD), a measure of tissue water content, were measured at 360 cortical and 16 subcortical regions. Resting-state fMRI time series were correlated to estimate functional connectivity between individual regions, as well as the sum of connectivity (weighted degree) of each region. Multiple tests for regional analysis were controlled by the false discovery rate (FDR = 5%). We found that CRP was significantly associated with PD in precuneus, posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC); and with functional connectivity between pC/pCC, mPFC and hippocampus. Depression was associated with reduced weighted degree of pC/pCC, mPFC, and other nodes of the default mode network (DMN). Thus CRP-related increases in proton density-a plausible marker of extracellular oedema-and changes in functional connectivity were anatomically co-localised with DMN nodes that also demonstrated significantly reduced hubness in depression. We suggest that effects of peripheral inflammation on DMN node micro-structure and connectivity may mediate inflammatory effects on depression.

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

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 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.

3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3 T.

OBJECTIVE: Clinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. Here, we investigated APT- and NOE-weighted imaging based on advanced CEST metrics to map tumor heterogeneity of non-enhancing glioma at 3 T. MATERIALS AND METHODS: APT- and NOE-weighted maps based on Lorentzian difference (LD) and inverse magnetization transfer ratio (MTRREX) were acquired with a 3D snapshot CEST acquisition at 3 T. Saturation power was investigated first by varying B1 (0.5-2 µT) in 5 healthy volunteers then by applying B1 of 0.5 and 1.5 µT in 10 patients with non-enhancing glioma. Tissue contrast (TC) and contrast-to-noise ratios (CNR) were calculated between glioma and normal appearing white matter (NAWM) and grey matter, in APT- and NOE-weighted images. Volume percentages of the tumor showing hypo/hyperintensity (VPhypo/hyper,CEST) in APT/NOE-weighted images were calculated for each patient. RESULTS: LD APT resulting from using a B1 of 1.5 µT was found to provide significant positive TCtumor,NAWM and MTRREX NOE (B1 of 1.5 µT) provided significant negative TCtumor,NAWM in tissue differentiation. MTRREX-based NOE imaging under 1.5 µT provided significantly larger VPhypo,CEST than MTRREX APT under 1.5 µT. CONCLUSION: This work showed that with a rapid CEST acquisition using a B1 saturation power of 1.5 µT and covering the whole tumor, analysis of both LD APT and MTRREX NOE allows for observing tumor heterogeneity, which will be beneficial in future studies using CEST-MRI to improve imaging diagnostics for non-enhancing glioma.

Mapping tumour heterogeneity with pulsed 3D CEST MRI in non-enhancing glioma at 3 T.

OBJECTIVE: Amide proton transfer (APT) weighted chemical exchange saturation transfer (CEST) imaging is increasingly used to investigate high-grade, enhancing brain tumours. Non-enhancing glioma is currently less studied, but shows heterogeneous pathophysiology with subtypes having equally poor prognosis as enhancing glioma. Here, we investigate the use of CEST MRI to best differentiate non-enhancing glioma from healthy tissue and image tumour heterogeneity. MATERIALS & METHODS: A 3D pulsed CEST sequence was applied at 3 Tesla with whole tumour coverage and 31 off-resonance frequencies (+6 to -6 ppm) in 18 patients with non-enhancing glioma. Magnetisation transfer ratio asymmetry (MTRasym) and Lorentzian difference (LD) maps at 3.5 ppm were compared for differentiation of tumour versus normal appearing white matter. Heterogeneity was mapped by calculating volume percentages of the tumour showing hyperintense APT-weighted signal. RESULTS: LDamide gave greater effect sizes than MTRasym to differentiate non-enhancing glioma from normal appearing white matter. On average, 17.9 % ± 13.3 % (min-max: 2.4 %-54.5 %) of the tumour volume showed hyperintense LDamide in non-enhancing glioma. CONCLUSION: This works illustrates the need for whole tumour coverage to investigate heterogeneity in increased APT-weighted CEST signal in non-enhancing glioma. Future work should investigate whether targeting hyperintense LDamide regions for biopsies improves diagnosis of non-enhancing glioma.

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

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.

The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults.

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.

In vivo Glx and Glu measurements from GABA-edited MRS at 3 T.

In vivo quantification of glutamate (Glu) and γ-aminobutyric acid (GABA) using MRS is often achieved using two separate sequences: a short-echo point resolved spectroscopy (PRESS) acquisition for Glu and a Mescher-Garwood PRESS (MEGA-PRESS) acquisition for GABA. The purpose of this study was to examine the agreement of Glu and Glx (the combined signal of glutamate + glutamine) quantified from two different GABA-edited MEGA-PRESS acquisitions (GABA plus macromolecules, GABA+, TE = 68 ms, and macromolecule suppressed, MMSup, TE = 80 ms) with Glu and Glx quantified from a short-echo PRESS (PRESS-35, TE = 35 ms) acquisition. Fifteen healthy male volunteers underwent a single scan session, in which data were acquired using the three acquisitions (GABA+, MMSup and PRESS-35) in both the sensorimotor and anterior cingulate cortices using a voxel size of 3 × 3 × 3 cm3 . Glx and Glu were quantified from the MEGA-PRESS data using both the OFF sub-spectra and the difference (DIFF) spectra. Agreement was assessed using correlation analyses, Bland-Altman plots and intraclass correlation coefficients. Glx quantified from the OFF sub-spectra from both the GABA+ and MMSup acquisitions showed poor agreement with PRESS-35 in both brain regions. In the sensorimotor cortex, Glu quantified from the OFF sub-spectra of GABA+ showed moderate agreement with PRESS-35 data, but this finding was not replicated in the anterior cingulate cortex. Glx and Glu quantified using the DIFF spectra of either MEGA-PRESS sequence were in poor agreement with the PRESS-35 data in both brain regions. In conclusion, Glx and Glu measured from MEGA-PRESS data generally showed poor agreement with Glx and Glu measured using PRESS-35.

Identifying biological markers for improved precision medicine in psychiatry.

Mental disorders represent an increasing personal and financial burden and yet treatment development has stagnated in recent decades. Current disease classifications do not reflect psychobiological mechanisms of psychopathology, nor the complex interplay of genetic and environmental factors, likely contributing to this stagnation. Ten years ago, the longitudinal IMAGEN study was designed to comprehensively incorporate neuroimaging, genetics, and environmental factors to investigate the neural basis of reinforcement-related behavior in normal adolescent development and psychopathology. In this article, we describe how insights into the psychobiological mechanisms of clinically relevant symptoms obtained by innovative integrative methodologies applied in IMAGEN have informed our current and future research aims. These aims include the identification of symptom groups that are based on shared psychobiological mechanisms and the development of markers that predict disease course and treatment response in clinical groups. These improvements in precision medicine will be achieved, in part, by employing novel methodological tools that refine the biological systems we target. We will also implement our approach in low- and medium-income countries to understand how distinct environmental, socioeconomic, and cultural conditions influence the development of psychopathology. Together, IMAGEN and related initiatives strive to reduce the burden of mental disorders by developing precision medicine approaches globally.

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

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.