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.

Poor inhibitory control and decision-making are often considered as risks for substance use and other adverse psychiatric outcomes. The Stop-Signal Task (SST) is a widely used protocol, from which inhibitory control is indexed by stop signal reaction time (SSRT). However, heretofore models of SSRT may be too simplistic to capture complex processes underlying task performance. In contrast, the Racing Diffusion Ex-Gaussian ABCD (RDEX-ABCD) model provides a more mechanistic framework, capturing both inhibitory control and task-general decision-making processes during the SST. Here, we applied the RDEX-ABCD model to SST data from the IMAGEN cohort (n > 1000) at ages 19 and 23, and examined model parameters in relation to substance use via Elastic Net regression. Connectome-based predictive modeling was then performed to identify brain networks predicting parameters, and the association between these networks and substance use was examined. We found that parameters indexing inhibitory control had no associations with substance use and were only weakly associated with brain connectivity. In contrast, parameters reflecting general decision-making processes - such as efficiency of evidence accumulation, decision threshold (response caution), probability of go failure - and their associated brain activity were significant predictors of cannabis and cigarette use. These findings suggested that efficiency of evidence accumulation, a neurocognitive mechanism that facilitates adaptive decision making across many contexts, emerged as a robust predictor of substance use vulnerability. Overall, general decision-making mechanisms may act as more reliable indicators of vulnerability to substance use than the conventional inhibitory control measures.

Abstract Pain is the leading cause of disability worldwide, yet no population-based reference exists against which individual cohorts, clinical populations, or countries can be benchmarked. 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 across the lifespan, implemented in an open-access benchmarking platform. 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 site-specific pain burden 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.

ABSTRACT Understanding the dynamics of brain–behaviour relationships during adolescence is critical for elucidating the neurodevelopmental basis of mental health. Leveraging two large-scale longitudinal cohorts—the Adolescent Brain Cognitive Development (ABCD) and IMAGEN studies, comprising over 10,000 participants aged 10 to 22 years with six waves of multimodal neuroimaging and behavioural data, we applied multi-view sparse canonical correlation analysis to investigate evolving associations between structural MRI, resting-state functional connectivity, and multi-domain behavioural measures. Our findings reveal four fundamental patterns of developmental reorganisation in brain-psychopathology relationships. First, symptom profiles evolved from predominantly externalising features (aggression, attention problems) at ages 10-12 toward global psychopathology by age 14, then transitioned toward internalising features (e.g., anxiety, depression) by ages 19-22, reflecting fundamental shifts in vulnerability from behavioural dysregulation to affective disturbance. Second, cortical thickness exhibited negative associations with externalising symptom profiles throughout development. During early adolescence (ages 10-14) this was driven by broadly distributed decreases across sensorimotor, temporal, visual, and cingulate regions alongside overall mean cortical thickness. After 14, this diffuse pattern shifted towards late maturing association cortices, notably the dorsolateral prefrontal and lateral temporal cortices. Third, this was accompanied by subcortical effects that exhibited greater age-specificity: whilst cerebellar volume contributions were evident at most timepoints, basal ganglia volume influence was principally evident in early development (ages 10-12), with thalamic structures and global subcortical grey matter volume becoming dominant at age 14, marking a transition in which subcortical structures mediate psychopathology associations. Fourth, functional connectivity showed a more dynamic developmental trajectory. During early adolescence, symptom associations were driven by positive connectivity between cognitive control and sensorimotor networks, whereas late adolescence exhibited predominantly positive connectivity patterns, transitioning from dense sensorimotor-frontoparietal configurations to more specific patterns involving the central executive and default-mode networks. These findings fundamentally challenge static biomarker models, demonstrating that adolescent psychopathology reflects developmentally contingent brain-behaviour relationships rather than static neural markers. Age 14 emerges as a critical inflection point marked by convergent thalamic reconfiguration, global subcortical grey matter dominance, and symptom profile transitions. This work provides an empirical foundation for precision mental health strategies tailored to specific developmental windows, with implications for reducing psychiatric burden in youth.

This study investigated associations between bullying victimization and brain development using longitudinal structural MRI data from the IMAGEN cohort (n = 2,094; 1,009 females) across three time points (~14, ~19, and ~22 years). A data-driven analysis revealed that higher bullying victimization was significantly associated with accelerated volumetric growth in subcortical and limbic regions, including the putamen (β = 0.12, 95% CI: 0.10-0.15), amygdala (β = 0.07, 95% CI: 0.05-0.09), hippocampus (β = 0.06, 95% CI: 0.04-0.08), and anterior cingulate cortex (caudal: β = 0.05, 95% CI: 0.03-0.07; rostral: β = 0.06, 95% CI: 0.04-0.08). In contrast, bullying victimization was also significantly associated with reduced volumetric growth in the cerebellum (β = -0.09, 95% CI: -0.11 to -0.07), entorhinal cortex (β = -0.10, 95% CI: -0.13 to -0.07), and insula (β = -0.08, 95% CI: -0.11 to -0.06). Exploratory analyses indicated that females exhibited more pronounced changes in emotional processing regions, while males showed greater changes in motor and sensory areas. Overall, the findings indicate that bullying victimization is associated with widespread structural differences in brain development from adolescence to early adulthood, with sex-specific trajectories.

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.

Adolescence represents a developmental phase marked by profound and rapidly shifting emotional states. While some adolescents exhibit pronounced, day-to-day mood variability, others remain comparatively stable. Although emotional fluctuation has long been considered a core feature with implications for health and well-being, the determinants underlying these substantial individual differences remain insufficiently understood. To address this, we conducted a longitudinal study using daily app-based assessments, aiming to explore whether perceived stress and self-esteem dynamics help explain why some adolescents show greater mood variability than others. We asked N = 70 adolescents to rate their self-esteem, positive, and negative mood once per day for 15 days. For data analyses, we used path analytic mediation modeling. Fluctuation of self-esteem (FSE) significantly predicted both fluctuation of positive mood (FPM; b = 0.282, 95% CI [0.101, 0.464], p = .0.002) and fluctuation of negative mood (FNM; b = 0.395, 95% CI [0.147, 0.644], p = 0.002) indicating that greater variability in self-esteem is associated with greater mood fluctuation. Moreover, perceived stress (PS) significantly predicted FSE (b = 0.057, 95% CI [0.012, 0.102], p = 0.013), suggesting that higher perceived stress was associated with greater self-esteem fluctuation. Significant indirect effect emerged for PS on FPM (b = 0.016, 95% CI [0.003, 0.030], p = 0.019) and on FNM (b = 0.023, 95% CI [0.002, 0.043], p = 0 .028) via FSE, confirming a mediating role of self-esteem fluctuations. This study showed that perceived stress was associated with fluctuations in self-esteem, which were related to mood variability among adolescents. These findings suggest that stress reduction could be explored as a potential avenue for future interventions.

Chess-based cognitive remediation therapy (CB-CRT) is a group intervention that adapts elements of the classic game of chess in a supportive group setting to help improve cognitive functions in individuals with mental disorders. The program is supported by structured and freely available training materials. We applied this method during a smoking cessation program and used psychoeducative elements tailored to tobacco use disorder.

ABSTRACT Individual variability in pain perception raises fundamental questions about how biological and experiential factors shape pain processing. Cognitive-demanding motor training is a key driver of use-dependent brain plasticity and may contribute to differences in pain responses. Using musicians as a model of cognitive-motor expertise, we examined how such experience influences cortical dynamics and pain perception during experimentally induced prolonged musculoskeletal pain. Resting-state electroencephalography (EEG) was recorded in musicians and non-musicians before (Day 1) and during pain development (Days 3 and 8) following intramuscular nerve growth factor (NGF) administration. We parameterized periodic (alpha peak frequency, power, frontal asymmetry) and aperiodic (exponent, offset) components of the EEG signal to characterize intrinsic cortical activity. During pain development, non-musicians exhibited slowing of peak alpha frequency, a neural marker associated with ongoing pain. In contrast, musicians showed preserved alpha dynamics and greater left frontal asymmetry, reflecting resilient top-down pain regulation. Musicians also displayed higher aperiodic exponent across sessions, suggesting that musical training shapes the excitation-to-inhibition (E:I) balance potentially reflecting a shift toward greater inhibitory activity. Notably, across all participants, only aperiodic features improved the prediction of pain severity, with higher exponents and higher offsets associated with lower pain ratings. These findings demonstrate that cognitive-motor training shapes cortical dynamics during sustained pain, supporting more stable, resilient cortical responses to pain. Such training also contributes to inter-individual variability in pain processing. Moreover, this study identifies aperiodic EEG components as predictors of pain severity and resilience.

Introduction:Phantom limb pain (PLP) is a common complication after amputation, yet its underlying mechanisms and longitudinal course remain incompletely understood. Alterations in peripheral sensory processing, as assessed using Quantitative Sensory Testing (QST), have been associated with PLP; however, most existing studies are cross-sectional, and little is known about how sensory function changes over time. To address this research question, the present longitudinal study aimed to characterize changes in sensory sensitivity during the first year after amputation and to examine their association with the presence and intensity of PLP. Methods:This study adopted a longitudinal within-subject design, examining 11 persons with unilateral lower limb amputation (mean age 47 years, n = 7 men, n = 4 women) within the first six months after amputation (T1) and at a follow-up assessment at least six months later (T2). To control for potential day-to-day variability in sensory assessments, we additionally collected data from 11 age- and sex-matched control subjects without amputation at both measurements. Sensory function was assessed using the standardized DFNS QST protocol. Outcome measures included warm detection threshold (WDT), heat pain threshold (HPT), mechanical detection threshold (MDT), mechanical pain threshold (MPT), pressure pain threshold (PPT), wind-up ratio (WUR), mechanical pain sensitivity (MPS) and the presence of mechanical allodynia (DMA). Measurements were conducted at the residual limb and the homologous contralateral body site. Group comparisons were conducted using paired and independent t-tests or their non-parametric equivalents (Wilcoxon signed-rank and Mann-Whitney U-tests), and correlations were assessed using Spearman's rank correlation. Results:PLP prevalence increased in our cohort from T1 to T2, with three additional amputees classified as having PLP at T2. At T1, amputees with PLP showed a significantly higher WDT and MDT at the residual limb compared to the contralateral body site (resp. p = 0.026, 95% CI [0.08, 0.68]); (p = 0.003, 95% CI [0.37, 0.92]). At T2, MDT at the residual limb in the PLP+ group was significantly higher than in non-amputated controls (p = 0.049, 95% CI [-0.91, -0.002]). Furthermore, within the PLP+ group, higher PLP intensity was positively correlated with MDT at the residual limb at T2 (p = 0.638, p = 0.047). In addition, signs of central sensitization were observed in amputees with PLP compared to Controls and included allodynia at T1 and T2 (resp. T1: p = 0.010, 95% CI [-0.31, -0.06]; T2: p = 0.043, 95% CI [-0.14, -0.01]) as well as a higher wind-up ratio in amputees with PLP compared to amputees without PLP at T2 (p = 0.037, 95% CI [-0.03, 0.5]) indicating enhanced temporal summation of pain. Conclusion:These findings suggest that PLP is associated with dynamic alterations in peripheral sensory processing at the residual limb and increasing signs of central sensitization over time. Together, the results support the notion that PLP is not solely a consequence of peripheral deafferentation but may reflect an interaction between evolving sensory abnormalities and centrally mediated pain amplification processes.

Human cognitive processing involves dynamic interactions across brain regions, evolving over time. Traditional neuroimaging analysis often overlooks this temporal aspect, limiting insights into how functional network connectivity (FNC) supports ongoing cognition and behaviour. Using sliding window analysis, we captured FNC changes during tasks, reflecting network reconfiguration in cognitive processes. We further determined behavioural relevance of time-varying FNC by relating network measurements with task performances and psychopathology. We found that several whole-brain FNC patterns, or states, persist across resting and task-based fMRI, with state occurrences fluctuating with the most prominent task stimuli. Regional FNC distinguishes specific task conditions, and time-varying FNC explains more variance in psychopathology symptoms compared to static connectivity. These findings highlight that cognitive tasks reshape regional and whole-brain connectivity. By considering the different FNC states, time-varying connectivity provides a more comprehensive representation of brain interactions and thus may represent a better neural proxy for cognition and behaviour.

BACKGROUND: Immersive virtual reality (VR) distraction reduces procedural pain. The current study explores whether immersive VR also reduces how much people can remember about a painful experience: anterograde amnesia for pain. METHODS: A within-subject, crossover design was used. Sixteen healthy adult volunteers participated. Each participant received 5 thermal stimuli (some hot, some cold) during no-VR and 5 stimuli during immersive VR distraction (treatment order randomized). They were instructed to memorize the order of hot and cold stimuli for a later memory test. After a brief delay after each stimulus set, participants completed a memory recall test for the order of stimuli (the primary measure) and also provided ratings of pain, distraction, anxiety, and nausea using standardized graphic rating scales (GRS; 0-10). RESULTS: Within-subject Wilcoxon signed-rank tests revealed that immersive VR significantly reduced how accurately participants could recall the hot/cold order of thermal stimuli, mean accuracy: 96% correct (standard deviation [SD] = 8.06) in no-VR, versus 59% (SD = 25.79) in VR, Z = 3.09, P = .002, r = 0.77. On a rating scale from 0 to 10, immersive VR was significantly more distracting (mean = 7.60, very distracting, SD =1.72) compared to the control condition (mean = 2.07, mildly distracting, SD = 2.16, Z = 3.42, P < .001, r = 0.86), and on GRS mean pain perception ratings, participants reported significantly lower pain intensity during VR, mean = 4.03 (SD = 1.61) during VR, versus no-VR = 6.30 (SD = 1.81), Z = 3.47, P < .001, r = 0.87. CONCLUSIONS: Results of this study provide preliminary evidence that immersive VR reduces memory for a painful experience. Conscious/episodic memory formation and storage of memories about specific experiences requires attentional resources. VR distraction pain intervention significantly disrupts memory for painful stimuli, leading to what we term "VR amnesia." Our study provides preliminary laboratory evidence that immersive VR during pain induces anterograde amnesia for pain, disrupting the formation of memory for painful events. Further studies exploring the mechanism of how VR reduces memory for painful events are needed. These results suggest the utility of future studies in clinical pain contexts. If VR can reduce the formation of adverse memories associated with painful clinical procedures, VR may serve as an effective nonpharmacological adjunct to reduce postoperative distress and medications and may reduce risk of developing chronic pain.

BACKGROUND:Chronic postsurgical pain is a significant medical concern, particularly in cancer patients. However, most previous studies overlooked the psychological mechanisms contributing to this risk. The present study aimed to identify baseline predictive factors for chronic postsurgical pain in order to build and validate a predictive algorithm based on somatic and psychological predictors in a highly phenotyped longitudinal cohort of adult patients with breast or lung cancer from two European centres. METHODS:Comprehensive preoperative data, including patient characteristics and clinical, psychological, and social variables, were collected between 2017 and 2018. Four distinct machine learning models were trained and validated. Patients were examined at baseline and re-evaluated in face-to-face interviews 1 yr later. RESULTS:The sample included 255 patients (mean age 62.3 [range, 28-83] yr, 89.4% female). Chronic postsurgical pain was present in 83 patients (32.5%), of whom 72 (28% of the total sample) had neuropathic pain. We developed a predictive algorithm based on three independent variables: younger age (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.32-0.69), preoperative pain outside of the surgical area (OR, 2.45; 95% CI, 1.46-4.10), and a specific anxiety symptom (overwhelming worries) (OR, 1.81; 95% CI, 1.05-3.13). CONCLUSIONS:This simple algorithm, requiring only three easily accessible inputs, offers a practical tool in routine preoperative settings, supporting timely, targeted interventions to improve pain management in cancer patients at risk of chronic postsurgical pain. CLINICAL TRIAL REGISTRATION:NCT02368275, NCT03124511, NCT02960971.

Abstract Changes in personality during adolescence may shape future alcohol use, especially in times of societal crisis. The COVID-19 pandemic disrupted social norms and stress regulation, making it a natural experiment to examine how early-life personality trajectories predict later substance use. Using longitudinal data from the European IMAGEN cohort (N = 968), we investigated whether intra-individual personality changes during adolescence predicted alcohol use at three timepoints: pre-pandemic, immediately after COVID-19 onset (T1), and several months into the pandemic (T2). Generalized Additive Mixed Models (GAMMs) were used to model non-linear relationships between adolescent personality change (e.g., in anxiety sensitivity and openness) and alcohol use frequency across time. Participants were drawn from the IMAGEN cohort (N = 968; 54.4% female), assessed longitudinally from early adolescence (BL: M = 13.93, SD = 0.41) through middle (FU1: M = 16.04, SD = 0.60) and late adolescence (FU2: M = 18.41, SD = 0.65) to early adulthood (FU3: M = 22.00, SD = 0.66), with additional follow-ups during the COVID-19 pandemic (COVID-T1: M = 25.00, SD = 0.81; COVID-T2: M = 25.56, SD = 0.75). Assessments were conducted at approximately 2-year intervals during adolescence and at shorter intervals (several months) during the COVID-19 period. Analyses controlled for sex and country-level lockdown stringency. Intra-individual fluctuations in anxiety sensitivity significantly predicted increased alcohol use several months into the pandemic (T2; EDF = 1.86, p < 0.05), but not immediately after lockdown (T1). Pre-pandemic alcohol use was instead associated with changes in openness (EDF = 1.00, p < 0.05). Exploratory analyses suggested gender differences in anxiety-related drinking risk. Our findings suggest that personality dynamics in adolescence shape alcohol use responses during societal crises. Different traits appear to matter depending on the temporal and emotional context of the stressor. These findings have implications for personalized prevention efforts targeting stress-related substance use in youth.

BACKGROUND:Although the initiation of alcohol consumption is common during adolescence, some individuals engage in binge drinking behavior that could lead to harmful consequences such as developing alcohol use disorder later in life. Evidence suggests a relationship between depressive symptoms and harmful alcohol consumption that seems to vary depending on sex. Furthermore, it has been suggested that amygdala activation in response to negative emotional stimuli influences drinking due to depressive mood states. Therefore, we expected a sex-dependent effect of neuronal activation and depressive symptoms on risky drinking. METHODS:Here, we tested our hypothesis using a large dataset of 19-year-old participants (n = 958) in the IMAGEN study. Amygdala activation during an emotional faces task was extracted and entered into sex-moderated mediation models that also included scores from the Alcohol Use Disorders Identification Test and the Adolescent Depression Rating Scale. RESULTS:Moderated mediation models indicated that amygdala activation was associated with hazardous drinking through enhanced depressive symptoms in males, while amygdala reactivity in females was associated with decreased risky drinking. CONCLUSIONS:Taken together, our findings reveal sex differences in negative emotional processing in at-risk adolescents. These associations have the potential to inform the development of sex-specific strategies as well as the detection of early neuronal risk factors to effectively curtail alcohol risk behavior.

Brain charts have emerged as a highly useful approach for understanding brain development and aging on the basis of brain imaging and have shown substantial utility in describing typical and atypical brain development with respect to a given reference model. However, all existing models are fundamentally cross-sectional and cannot capture change over time at the individual level. We address this using velocity centiles, which directly map change over time and can be overlaid onto cross-sectionally derived population centiles. We demonstrate this by modelling rates of change for 24,062 scans from 10,795 healthy individuals with up to 8 longitudinal measurements across the lifespan. We provide a method to detect individual deviations from a stable trajectory, generalising the notion of 'thrive lines', which are used in pediatric medicine to declare 'failure to thrive'. Using this approach, we predict transition from mild cognitive impairment to dementia more accurately than by using either time point alone, replicated across two datasets. Last, by taking into account multiple time points, we improve the sensitivity of velocity models for predicting the future trajectory of brain change. This highlights the value of predicting change over time and makes a fundamental step towards precision medicine.

Clinical heterogeneity in the symptom trajectories of attention deficit hyperactivity disorder (ADHD) is well documented, but their neurodevelopmental mechanisms remain unclear. We used a longitudinal cohort of adolescents (ABCD; n = 7,436) to show that persistent, remitting and emergent ADHD symptom trajectories correlated with persistent, improving and worsening behavioral changes, respectively. Each trajectory had distinct brain signatures: faster cortical thinning (persistence), slower thinning (emergence) and faster subcortical expansion (remission). Slower cortical thinning in the right posterior cingulate was associated with inattention symptom increase, whereas faster hippocampal expansion was associated with inattention symptom decrease. These signatures enhance ADHD symptom prediction at age 13 and generalize to young adults (age 23) in the IMAGEN cohort. The hippocampal signature for remitting symptoms was replicated in IMAGEN and two clinical cohorts (ADHD-200 and ADHD-1000). Given that baseline ADHD medication use was not significantly associated with the remitting trajectory, our findings suggest that current treatments may not facilitate sustained remission, highlighting the potential for new interventions.

Abstract Human reward processing varies along cue-centric and outcome-centric axes, but a reproducible mechanistic account of individual variation in incentive salience attribution has been lacking. Using fMRI across five cohorts (N-total=1,251; N1=890; N2=245; N3=34; N4=48; N5=34), we identified two robust 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 D 2 /D 3 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, D 2 /D 3 partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D 2 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.

Childhood trauma (CT) is associated with cognitive impairment across major psychiatric disorders. We tested a novel transdiagnostic hypothesis that atypical connectivity of the default mode network (DMN) mediates the association between childhood trauma (CT) and cognitive impairment. The sample of 1851 individuals aged 18-25 included 433 patients with depression, eating disorders, alcohol use disorder, psychosis and ADHD) and were recruited as part of the ESTRA/STRATIFY/IMAGEN studies. CT was measured using the Childhood Trauma Questionnaire (CTQ). The CANTAB spatial working memory task was administered to assess cognition. Four a priori seeds of the default mode network (DMN) were measured during face processing, namely the medial prefrontal cortex (PFC), right lateral parietal (LP), left lateral parietal (LP) and posterior cingulate cortex (PCC), according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN. Patients had significantly reduced DMN connectivity between the four chosen DMN seeds and the rest of the brain. Reduced DMN connectivity mediated the association between higher CT and worse cognitive performance. Our findings are transdiagnostic in nature with stronger effects in some regions observed in depression, and suggest one transdiagnostic cortical network via which CT's effects on cognition are transmitted.

Introduction:Exposure to adverse life experiences (ALEs) renders individuals vulnerable to the emergence of pain, depression, and anxiety. It remains unclear to what extent these symptom categories share common ALEs, especially in cases of comorbidity, and how these relationships manifest in developmental trajectories and neural pathways. Objectives:In this study, we investigated the impact of ALEs, considering their timing, quality, and quantity, as well as structural brain changes, on pain, depression, and anxiety symptoms, and their comorbidity from adolescence to young adulthood. Methods:We used prospective and retrospective questionnaires and magnetic resonance imaging data from a large European longitudinal cohort (N = 1700) spanning from 14 to 25 years. We conducted Latent-Class-Growth-Analysis for symptom levels of pain, depression, and anxiety, subsequent logistic regressions to explore prediction of ALEs on symptom classes, and mediation analysis to examine the role of insula in this association. Results:Physical illness unrelated to pain, bullying, and abuse-maltreatment were associated with pain; sexual abuse, bullying, parental violence, and deprivation with depression; bullying and deprivation with anxiety; substance abuse in the household and abuse-maltreatment with pain-depression comorbidity; deprivation with pain-anxiety comorbidity. Smaller insula volume in late adolescence was a significant mediator for the association between deprivation-related ALEs and the pain-anxiety, but not the pain-depression comorbidity. Conclusion:Together, although various and mainly different types of ALEs strongly impact pain, depression, and anxiety symptoms and their comorbidity, insula volume impacts are specific for pain-anxiety comorbidity. These findings may inform early screening and prevention for individuals affected by ALEs.