Herta Flor

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.

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.

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.

Introduction: Anhedonia is a transdiagnostic psychiatric symptom linked to increased functional connectivity between the prefrontal cortex and striatum. Here, we examined how dimensions of early adversity contribute to this profile of connectivity. Methods: In a European community sample of young adults (IMAGEN), we examined cross-sectional (n=613) and longitudinal (n=332) associations of adversity dimensions with resting-state fMRI-derived connectivity. We selected 10 ROIs from anhedonia literature, defined in the functional images as 4mm-radius spheres. We then used network-based regression models to identify clusters of ROI-ROI connections associated with threat and deprivation scores, using interaction terms to examine sex and age-specific associations. We also examined associations between adversity and anhedonia, operationalized using factor analysis of six items from self-report surveys. Results: At age 18-22, we identified sex-specific associations between deprivation and connectivity for a cluster of 9 ROI-ROI connections ( p-FWE =0.038), primarily involving the nucleus accumbens. Specifically, we observed positive associations between deprivation and connectivity in males, and negative associations in females. In the longitudinal analysis, negative deprivation associations in females attenuated with age for a cluster of 14 connections ( p-FWE =0.009). A cluster of 17 connections also had initial positive associations with threat in females that attenuated with age ( p-FWE =0.008). No such longitudinal changes were observed in males. Higher deprivation was linked to increased later anhedonia in males but not females ( p =0.026). Conclusion: Compared to females, young adult males may be more vulnerable to developing anhedonia after experiencing deprivation in childhood. Dimensions of early adversity are linked to distinct pathways of frontostriatal development.

Globally, 60% of the population has experienced at least one type of adversity (e.g., emotional abuse, bullying) across infancy, childhood, and adolescence. Such experiences have been linked to an increased risk for mental health disorders. Changes in brain structure following experiences of childhood adversity have been hypothesised to be a mechanistic pathway explaining later mental health issues. However, to understand how changes in brain structure might mediate the effects of adversity, it is essential to identify which underlying neuronal processes may be affected by different types of adverse experiences. A key open question is whether grey or white matter is more vulnerable to adversity, as these two structures reflect distinct neurobiological mechanisms. This study investigated whether differences in trajectories of grey and white matter development during adolescence can be explained by exposure to different types of adversity. We applied the Adverse Adolescent Experiences Framework (Pollmann et al., 2025) categorising adversity into four levels: Intrapersonal (e.g., accidents), Caregiver (e.g., emotional neglect), Peer (e.g., bullying), and Community (e.g., neighbourhood safety). Exposure to each of the four factors was estimated through principal components analyses. We analysed two large longitudinal datasets: the Adolescent Brain Cognitive Development study (∼12,000 adolescents measured at ages 10, 12, and 14) and the IMAGEN study (∼1,400 adolescents measured at ages 14, 19, and 22). Using latent growth curve models, we captured individual differences in brain development by estimating baseline levels (intercepts) and rates of change (slopes) for total grey matter volume and mean white matter fractional anisotropy. In both cohorts, we found significant interindividual variability in baseline levels and rates of change for both grey matter volume and fractional anisotropy. Caregiver, Peer, and Community adversities were negatively associated only with the intercepts of grey matter volume and white matter fractional anisotropy. Importantly, associations differed between grey and white matter. In ABCD, Peer and Community adversities were more strongly associated with grey matter volume intercepts. In contrast, in IMAGEN, Caregiver, Peer and Community adversities were more strongly linked to white matter fractional anisotropy intercepts. This suggests that adversity has unique associations with grey and white matter, rather than exerting a uniform influence on brain structure. By demonstrating that different environments generate distinct biological associations with brain maturation, this work underscores the need to consider both grey and white matter when assessing the neurodevelopmental pathways to outcomes across the lifespan.

The biological mechanisms underlying major neuropsychiatric disorders remain largely elusive. Given the frequent association of immune dysregulation with these conditions, we used blood-derived multi-omics data from 1,274 healthy adolescents in the IMAGEN cohort to identify transdiagnostic biomarkers and mechanisms that could inform diagnosis and treatment. We first conducted genome-wide analyses to identify single nucleotide polymorphisms associated with DNA methylation and gene expression, with findings replicated in external datasets. These quantitative trait loci were further explored through Mendelian randomization analyses across 6 neuropsychiatric disorders (attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia and insomnia), leading to the identification of 73 putatively causal CpG sites and 62 genes that were either unique to individual disorders or, as in the case of MRPL2 , shared among the disorders. Notably, the identified genes were significantly enriched in pathways linked to both psychiatric and autoimmune diseases, suggesting a shared genomic architecture between autoimmune and neuropsychiatric disorders. Two-step Mendelian randomization and colocalization analyses revealed potential transdiagnostic regulatory pathways, in which the expression of three genes ( MAD1L1 , MRPL2 and HLA-DRB1 ) mediated the effects of CpG methylation on schizophrenia and insomnia. Specifically, DNA methylation at cg06770790 repressed MRPL2 , which was putatively causal for insomnia ( β = −0.38, P = 1.29 × 10 ⁻⁴ ) and schizophrenia ( β = −0.38, P = 1 × 10 ⁻⁴ ). Conversely, increased expression of MAD1L1 and HLA-DRB1 , driven by methylation at several CpG sites, was potentially causal for schizophrenia. Our findings highlight key molecular mechanisms and genes implicated in neuropsychiatric disorders, offering promising new targets for therapeutic intervention.

Pain is the leading cause of disability worldwide, yet no harmonised self-reported reference framework exists to characterise how its burden is distributed across the lifespan and world regions. Here, we harmonised individual-level self-reported pain data from 6,075,021 participants across 894 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 2.5% for facial pain to 45.0% for back pain, was consistently higher in women across all eleven anatomical sites (risk ratio range 1.09 to 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 nearly twice the late-life prevalence of any bodily pain compared with those in the highest (risk difference 31.8 percentage points [95% CI 30.1–33.6]). 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 drivers of pain in lower-HDI settings remain poorly characterised.