Robert Whelan

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.

Objective: Methylphenidate is the first-line treatment for ADHD, yet its neurocognitive mechanisms remain incompletely understood. Electroencephalography (EEG) has been used to examine methylphenidate’s effects on brain function and has been proposed as a potential tool for monitoring treatment response. This systematic review addressed whether EEG can (a) clarify methylphenidate’s neurocognitive mechanisms and (b) serve as a biomarker of treatment response. Methods: A PRISMA-compliant systematic review (PROSPERO: CRD42024538039) searched six databases for English-language studies published after 1994. Included studies involved individuals with ADHD, used within-subject designs with acute methylphenidate administration, and collected resting-state or task-based EEG. Assessment of study quality and risk of bias assessment was conducted. Results: Forty-four studies were included. The most consistent finding was an increase in P3 amplitude following methylphenidate administration, observed in eleven of twenty P3 studies. In contrast, there was little evidence to support effects on early sensory processing, movement planning or response monitoring event-related potentials. Findings from quantitative EEG and event-related spectral perturbation analyses were limited, with either no effect observed, or a paucity of studies in some frequency bands. Discussion: Methylphenidate reliably increased P3 amplitude across tasks, suggesting an improvement in higher order cognitive functioning. However, the P3 does not meet criteria for a pharmacodynamic or surrogate endpoint biomarker in this context, and the current evidence does not support EEG as a treatment-response biomarker for MPH in ADHD. Based on our findings, we make 10 recommendations for future research in this area.

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.

Optically pumped magnetometer magnetoencephalography (OPM-MEG) offers a wearable, movement-tolerant alternative to conventional cryogenic MEG, placing sensors closer to the scalp and, in principle, improving sensitivity to deep sources. This is advantageous for examining subcortical structures that are affected by ageing, disorders and disease, such as the hippocampus. However, it remains unclear whether previously reported activity (such as the attenuation of theta oscillations during the imagination of novel scenes) can be recovered from the medial temporal lobe (MTL) with OPM-MEG, and whether an individual structural MRI is required for accurate source localisation. Here, fifteen adults completed a scene imagination task. Initially we applied a 12-parameter template warping coregistration pipeline to the full sample. Following source reconstruction, we recovered the expected attenuation of theta (4-8 Hz) power during scene imagination compared to a counting baseline, with a significant cluster of activity peaking in the left parahippocampal gyrus. The cluster’s centre of mass was localised to the left hippocampus ( t = -3.55, p = 0.048, whole-brain FWE-corrected) and was mostly confined to the left medial temporal lobe. We further supported our findings by using an individual T1-weighted MRI reconstruction pipeline in six participants who had these scans available. The two approaches produced similar whole-brain topographies and localised the peak MTL theta effect to left hippocampus, with temporal-lobe conjunction centroids 3-mm apart. These findings provide evidence that the theta attenuation of the scene construction network can be recovered at the group level with OPM-MEG, without an individual MRI.

Psychiatric pharmacotherapy is often effective for patients. For example, symptoms of attention deficit hyperactivity disorder (ADHD) are typically ameliorated by stimulant medications. However, identifying the best medication for an individual or their optimal dose can be difficult because clinical visits and retrospective symptom reports only capture snapshots of the underlying dynamic, context-dependent treatment trajectories. Real-world data approaches, obtained from smartphones and wearable technologies, can potentially provide a rich source of information for individual optimization of pharmacotherapy, yet they are infrequently used. First, these tools enable remote, high-frequency monitoring of medication efficacy and side effects, tracking core symptoms plus comorbid psychopathology, sleep, and autonomic function throughout titration. Second, densely sampled cognitive task data and ecological momentary assessment offer a route to understanding changes to neurocognitive mechanisms in response to medication. Third, real-world data can help redress the persistent sex disparities in pharmacotherapeutic research and practice by characterizing how symptoms and treatment response interact with sex-specific life events. We conclude with recommendations for future research and practice.

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.