Biology subjects

Wirsching, P.

Publications and source records attributed to Wirsching, P..

6 recordsLinked to original sources

bioRxiv2026

Early life stress alters lifespan trajectories of amygdala development: a cross-species model of amygdala burnout

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. 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.

neuroscience↗

bioRxiv2026

Sex-specific associations of childhood adversity with frontostriatal network organization and anhedonia in young adulthood

IntroductionAnhedonia 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. MethodsIn 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. ResultsAt 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). ConclusionCompared 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.

neuroscience↗

bioRxiv2026

Protracted Maturation of Proactive and Reactive Systems Predicts Cognitive Stability and Psychopathology : A longitudinal multi-cohort study

Inhibitory control matures progressively from childhood to early adulthood, yet the neural mechanisms driving this development and their relevance to psychiatric risk remain poorly understood. Guided by the Dual Cognitive Control model, we leveraged longitudinal fMRI from two independent cohorts in the US (ABCD, ages 9-12) and Europe (IMAGEN, ages 14-22) to map the spatiotemporal dynamics of reactive and proactive control using novel single-trial modeling and representational similarity analysis. We found both reactive and proactive stopping networks stabilize after mid-adolescence, tracking the developmental patterns of inhibitory control and behavioral stability. By decoding trial-by-trial fluctuations along a speed-caution continuum, we demonstrate that brain-behavior coupling to a proactive "Safe state" tightens progressively with age. Furthermore, network-level representational coherence of this Safe state emerged as a scanner-invariant, trait-like biomarker that robustly predicted inhibitory control, behavioral stability, and transdiagnostic psychopathology across multiple developmental windows, providing a validated neural phenotype for precision psychiatry.

neuroscience↗

bioRxiv2026

Adversity and adolescent brain development: differential associations with grey and white matter across two longitudinal cohorts

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.

neuroscience↗

bioRxiv2026

Trajectories of brain organisation transition from predicting externalising to internalising symptoms across adolescence

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.

neuroscience↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗