Dimitri Papadopoulos Orfanos

Background: Chronic pain and internalising disorders such as anxiety and depression frequently co-occur during adolescence. Although prospective associations between internalising symptoms and later pain have been reported previously, the biological mechanisms underlying individual differences in this relationship remain poorly understood. Immune- and oxidative stress-related pathways, including the NRF2 gene, may contribute to such variability. This study investigated whether polymorphisms in the NRF2 gene (rs6721961 and rs35652124) are related to the association between anxiety and depression symptoms at age 14-15 and pain complaints two years later at age 16-17. Methods: Data were drawn from the IMAGEN longitudinal study ( N = 724). Anxiety and depression symptoms were assessed using the Development and Well-Being Assessment (DAWBA), and pain complaints were measured via the Children’s Somatization Inventory (CSI). Genotyping was conducted for NRF2 SNPs rs6721961 and rs35652124. Regression analyses tested main effects, followed by genotype-stratified analyses. Results: Consistent with previous literature, higher levels of anxiety and depression at age 14-15 predicted increased pain complaints at age 16-17. Carriers of the TG/TT genotype of rs6721961 had significantly lower anxiety scores and reported fewer pain complaints compared to those carrying the GG genotype of rs6721961. Notably, the association between anxiety and later pain was significant only among individuals with the GG genotype. Conclusion: While replicating established associations between adolescent early internalising symptoms and later pain, this study suggests that genetic variation in NRF2 is related to the anxiety-pain association. Specifically, rs6721961 is associated with differences in susceptibility to pain among adolescents with elevated anxiety symptoms.

Addiction stands as a critical public health concern, contributing substantially to morbidity, mortality and societal burden worldwide. It can be conceptualized along a developmental continuum, from risky substance use in adolescence to compulsive use and addiction in adulthood, yet the neural changes underlying this continuum remain poorly understood. Here we show age-specific brain structural trajectories along this continuum by harmonizing multimodal data across large population cohorts spanning adolescence to late adulthood. We identified three life stages with distinct patterns of problematic substance use (PSU). Before age 25, PSU was associated with neurodevelopmental differences, alongside greater impulsivity and rule-breaking, suggesting a key window for early prevention. Between ages 25 and 45, PSU was linked to structural differences in brain regions linked to craving and reward processing, supporting early detection and intervention during the reinforcement and maintenance of substance use. After age 45, PSU-related brain differences may reflect cumulative effects of prolonged substance exposure, emphasizing broader health monitoring. These stage-specific patterns also differed by sex, particularly earlier in life. Together, our findings map structural brain changes across the addiction continuum and provide a lifespan framework for stage-specific prevention, intervention and health monitoring.

Pain is the leading cause of disability worldwide, yet no harmonized self-reported reference framework exists to characterize how its burden is distributed across the lifespan and world regions. In this study, we harmonized individual-level self-reported pain data from 6,125,459 participants across 902 population-based data sources in 118 countries to establish global reference trajectories of pain. We implemented these trajectories in an open-access benchmarking platform for positioning external datasets against global pain norms. Pain prevalence ranged from roughly 2% for facial pain to 40% for back pain, was consistently higher in women across all 11 anatomical sites (risk ratio range: 1.08−1.83) and increased most steeply before age 55 years. Contrary to existing estimates that generally project higher prevalence of pain conditions in higher Human Development Index (HDI) regions, we found that individuals in the lowest HDI countries experienced a substantially higher late-life prevalence of any bodily pain than those in the highest (risk difference: 30.6 percentage points (95% confidence interval: 26.9−34.3)), with low back pain approaching twice the prevalence at the oldest ages. Globally, 18.3% of pain burden across anatomical sites was attributable to three modifiable risk factors (smoking, obesity and low income), but this varied from 12.6% in sub-Saharan Africa to 27.1% in eastern Europe, indicating that the factors underlying pain in lower-HDI settings remain poorly characterized. Together, these reference trajectories provide a common framework for defining and comparing pain burden and informing more equitable global surveillance and prevention.

The translation of abstract cognitive intention into localised physical action is a defining feature of voluntary behaviour1,2. To achieve this, the brain must maintain a highly regulated preparatory state, yet the macroscopic architecture of this interface remains elusive. Historically, the primary motor cortex has been viewed simply as a strictly contralateral kinematic relay3, making its robust bilateral activation during single-limb preparation a long-standing functional paradox4,5. Here, we show that human motor preparation is driven by two distinct, superimposed neural processes operating across the cerebral cortex and cerebellum. By mathematically decomposing neuroimaging signals from over six thousand sessions, we identified a broadly distributed cognitive readiness network that dictates the precise timing of an action, and an independent, highly localised kinematic preparation network that controls execution speed. This macroscopic duality maps human whole-brain dynamics onto the neural subspaces and circuits previously observed only at the microscopic level in animal models6-9. Furthermore, we reveal that genetic risk for Parkinson’s disease selectively impairs this cognitive readiness network during healthy adolescence. Ultimately, these findings redefine the cortico-cerebellar axis as an active computational interface integrating abstract thought with physical embodiment, offering a generalisable framework for understanding mind-body synchronisation and early neurodegenerative vulnerability.

Early-life stress is associated with alterations in amygdala volume, but findings vary across studies and species. Rodent models typically report increased amygdala volume, whereas human studies often find reductions or mixed effects. We propose the amygdala burnout hypothesis, which suggests that early-life stress alters amygdala developmental trajectories, producing initial volumetric increases that are followed by reductions later in life. To test this hypothesis, we examined amygdala development across rodent and human cohorts spanning adolescence to older adulthood. In rodents, chronic stress was associated with increased amygdala nuclei volumes during adolescence. Comparable increases were observed in adolescents from the IMAGEN consortium, with evidence of a dose-dependent association between childhood stress and amygdala developmental trajectories. In contrast, analyses of older adults from the UK Biobank revealed reduced bilateral amygdala volume associated with early-life stress. Together, these findings support a developmental model that reconciles previously conflicting observations across species and age groups.

Human reward processing varies along cue-centric and outcome-centric axes, but the mechanistic basis of individual variation in incentive salience attribution remains incompletely characterized. Here we show, using fMRI across five cohorts (N-total = 1251; N1 = 890; N2 = 245; N3 = 34; N4 = 48; N5 = 34), two reproducible imaging phenotypes mirroring sign- and goal-tracking (ST-like, GT-like). ST-like individuals showed dominant ventral striatal responses to reward-anticipation cues and sustained incentive salience attribution; GT-like individuals showed heightened responses to reward outcomes. This distinction was replicable across sites and independent samples. Single-dose and repeated-dose D₂/D₃ antagonism (risperidone, haloperidol, amisulpride) selectively reduced anticipatory ventral striatal activity in ST, with single-dose antagonism additionally producing a parallel drop in self-reported energy. Instead, D₂/D₃ partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D₂ affinity was associated with blunted anticipatory signals and higher negative symptom burden, offering a neuroimaging-driven basis for stratifying patients and predicting response to dopaminergic agents.

Exposure to early life adversity is associated with elevated risk for psychopathology, including internalising disorders, that often endure into adulthood, yet the neurodevelopmental processes linking adversity to symptom emergence remain unclear. Longitudinal analyses of brain development may clarify whether adversity-related structural alterations contribute to this vulnerability. Structural MRI data were analysed from 2,021 participants in the IMAGEN cohort assessed at approximately ages 14, 19, and 22 years. Higher-order mixed-effects modelling examined associations between adversity and volumetric trajectories of 88 brain regions. Regions showing significant adversity effects were further analysed to test whether related brain changes explained or modified later symptom risk and to examine temporal dynamics. Early life adversity was associated with variations in 19 regional volumes, spanning prefrontal (rostral anterior cingulate, orbitofrontal, caudal middle frontal), parietal (superior and supramarginal), and subcortical (thalamus, ventral diencephalon) systems, reflected in both stable differences and adversity-by-age interactions. Greater adversity exposure predicted higher total and emotional symptoms in early adulthood. Regional brain volume change did not mediate the association between adversity and later symptoms. However, moderation analyses indicated that developmental change in select regions amplified vulnerability to symptom emergence, suggesting that brain structure influenced individual susceptibility rather than explaining symptom risk. Adversity-related brain differences do not explain later psychopathology through simple mediation. Instead, findings support a dynamic, bidirectional framework in which adversity, brain maturation, and symptoms interact dynamically across adolescence, highlighting the need for network-level and multivariate approaches sensitive to developmental timing.

Early detection and prevention of psychiatric disorders, particularly depression, remain as major global health challenges, yet reliable tools for identifying individuals before symptom onset are lacking. Here, we combine functional neuroimaging with computational modeling to identify a mechanistic biomarker of depression risk. In a population-based adolescent cohort (IMAGEN, N = 1332), we found that weakened neural representations of emotional signals were linked to depressive symptoms. Perturbation experiments in a brain-aligned deep learning model showed that this deficit reflects overregularized emotion perception, producing a negative perceptual bias. A neurocomputational signature of this mechanism predicted depression symptom onset up to 4 years later at the IMAGEN follow-up ( N = 725), was associated with both a genetic-risk variant and polygenic risk for depression, and improved depression classification in a patient cohort (STRATIFY, N = 411). These findings suggest a possible mechanism linking genetic vulnerability to altered emotion perception and future depression, and propose a predictive computational marker with potential for early detection and prevention.

The STRATIFY (Brain Network-Based Stratification of Reinforcement-Related Disorders) and ESTRA (Eating Disorders Stratification) studies were established as harmonised “sibling” cohorts to develop a mechanistically informed framework for stratifying psychiatric disorders. Here, we describe the study design, methodology, and cohort characteristics. Both studies investigate how network properties of brain structure and function, together with biological markers derived from blood-based genomics, epigenetics, and proteomics, relate to reinforcement-related behaviours that cut across major depressive disorder, alcohol use disorder, psychosis, and eating disorders. A further objective is to identify discriminative multimodal features that predict disease onset, symptom course, and functional outcomes, thereby supporting the development of targeted interventions. STRATIFY and ESTRA recruited 674 patients and 70 healthy controls aged 18–30 years (76% females), supplemented by 199 age- and sex-matched healthy controls from the population-based IMAGEN cohort assessed at the same sites using harmonised protocols. Multimodal assessment included structured clinical interviews, self-report measures, cognitive testing, biosamples for molecular analyses, and multimodal MRI (structural, diffusion, resting-state, and task-based fMRI). ESTRA participants additionally completed longitudinal follow-up, and all cohorts were assessed during the COVID-19 pandemic. STRATIFY and ESTRA together constitute a large-scale, open-science resource integrating multimodal brain, behavioural, and biological data across transdiagnostic patient cohorts in early adulthood. The anonymised dataset is available to the research community through managed access, supporting international collaboration and accelerating the development of mechanistically informed classification systems and predictive tools in psychiatry.