Neural Resilience Research Articles

Neuroprotective potential of paddy rice: Advancing nutritional and therapeutic strategies for brain health

Paddy rice has gained attention beyond its role as a staple food, now recognized for its neuroprotective properties due to its rich phytochemical content. Compounds like tocotrienols, gamma-oryzanol, and phenolic acids in paddy rice exhibit antioxidant, anti-inflammatory, and neuroregenerative properties. These compounds help reduce oxidative stress, manage neuroinflammation, balance neurotransmitter function, and promote neurogenesis, supporting overall brain health and potentially delaying neurodegenerative processes. Components like gamma-oryzanol and ferulic acid show promise in decreasing neuroinflammation and enhancing dopaminergic function, suggesting therapeutic potential for conditions like Parkinson's and Alzheimer's. Research indicates paddy rice bioactives can improve cognitive function and neural resilience, underscoring their therapeutic value for neurological disorders. Further studies are required to validate these findings in clinical settings, explore optimal dosages, and enhance bioavailability. This review summarizes recent research, highlighting the promising effects of paddy rice-derived nutraceuticals and emphasizing the importance of bridging lab discoveries with practical medical applications through comprehensive research efforts.

Maternal environmental enrichment protects neonatal brains from hypoxic-ischemic challenge by mitigating brain energetic dysfunction and modulating glial cell responses

There is evidence that maternal milieu and changes in environmental factors during the prenatal period may exert a lasting impact on the brain health of the newborn, even in case of neonatal brain hypoxia-ischemia (HI). The present study aimed to investigate the effects of maternal environmental enrichment (EE) on HI-induced energetic and metabolic failure, along with subsequent neural cell responses in the early postnatal period. Male Wistar pups born to dams exposed to maternal EE or standard conditions (SC) were randomly divided into Sham-SC, HI-SC, Sham-EE, and HI-EE groups. Neonatal HI was induced on postnatal day (PND) 3. The Na+,K+-ATPase activity, mitochondrial function and neuroinflammatory related-proteins were assessed at 24 h and 48 h after HI. MicroPET-FDG scans were used to measure glucose uptake at three time points: 24 h post-HI, PND18, and PND24. Moreover, neuronal preservation and glial cell responses were evaluated at PND18. After HI, animals exposed to maternal EE showed an increase in Na+,K+-ATPase activity, preservation of mitochondrial potential/mass ratio, and a reduction in mitochondrial swelling. Glucose uptake was preserved in HI-EE animals from PND18 onwards. Maternal EE attenuated HI-induced cell degeneration, white matter injury, and reduced astrocyte immunofluorescence. Moreover, the HI-EE group exhibited elevated levels of IL-10 and a reduction in Iba-1 positive cells. Data suggested that the regulation of AKT/ERK1/2 signaling pathways could be involved in the effects of maternal EE. This study evidenced that antenatal environmental stimuli could promote bioenergetic and neural resilience in the offspring against early HI damage, supporting the translational value of pregnancy-focused environmental treatments.

Neurobiology and Changing Ecosystems: Mechanisms Underlying Responses to Human-Generated Environmental Impacts.

Human generated environmental change profoundly affects organisms that reside across diverse ecosystems. Although nervous systems evolved to flexibly sense, respond, and adapt to environmental change, it is unclear whether the rapid rate of environmental change outpaces the adaptive capacity of complex nervous systems. Here, we explore neural systems mediating responses to, or impacted by, changing environments, such as those induced by global heating, sensory pollution, and changing habitation zones. We focus on rising temperature and accelerated changes in environments that impact sensory experience as examples of perturbations that directly or indirectly impact neural function, respectively. We also explore a mechanism involved in cross-species interactions that arises from changing habitation zones. We demonstrate that anthropogenic influences on neurons, circuits, and behaviors are widespread across taxa and require further scientific investigation to understand principles underlying neural resilience to accelerating environmental change.SIGNIFICANCE STATEMENT Neural systems evolved over hundreds of millions of years to allow organisms to sense and respond to their environments - to be receptive and responsive, yet flexible. Recent rapid, human-generated environmental changes are testing the limits of the adaptive capacity of neural systems. This presents an opportunity and an urgency to understand how neurobiological processes, including molecular, cellular, and circuit-level mechanisms, are vulnerable or resilient to changing environmental conditions. We showcase examples that range from molecular to circuit to behavioral levels of analysis across several model species, framing a broad neuroscientific approach to explore topics of neural adaptation, plasticity, and resilience. We believe this emerging scientific area is of great societal and scientific importance and will provide a unique opportunity to reexamine our understanding of neural adaptation and the mechanisms underlying neural resilience.

Adaptive Neuroplasticity in Brain Injury Recovery: Strategies and Insights.

This review addresses the relationship between neuroplasticity and recovery from brain damage. Neuroplasticity's ability to adapt becomes crucial since brain injuries frequently result in severe impairments. We begin by describing the fundamentals of neuroplasticity and how it relates to rehabilitation. Examining different forms of brain injuries and their neurological effects highlights the complex difficulties in rehabilitation. By revealing cellular processes, we shed light on synaptic adaptability following damage. Our study of synaptic plasticity digs into axonal sprouting, dendritic remodeling, and the balance of long-term potentiation. These processes depict neural resilience amid change. Then, after damage, we investigate immediate and slow neuroplastic alterations, separating reorganizations that are adaptive from those that are maladaptive. As we go on to rehabilitation, we evaluate techniques that use neuroplasticity's potential. These methods take advantage of the brain's plasticity for healing, from virtual reality and brain-computer interfaces to constraint-induced movement therapy. Ethics and individualized neurorehabilitation are explored. We scrutinize the promise of combination therapy and the difficulties in putting new knowledge into clinical practice. In conclusion, this analysis highlights neuroplasticity's critical role in brain injury recovery, providing sophisticated approaches to improve life after damage.

Maternal diet supplemented with African walnuts enhances cortico-hippocampal gene expression and histomorphology in rat offspring

ABSTRACT Background The brain is built up during pregnancy. How it functions afterwards depends on how the expectant mother's diet nourishes it. Walnuts contain significant quantities of polyunsaturated fatty acids (PUFAs) and bioactive phytochemicals, which enhance brain health and function even with advancing age. This study examined the effects of a walnut-enriched diet (WED) on corticohippocampal histoarchitecture and gene expression in rat offspring. Materials and methods Twenty-eight female adult Wistar rats (n= 7) averaging about 185 g in weight were used for this study. After mating, pregnant dams were split randomly into four groups: A (standard rat chow/control), B (WED from GD 0 – PND 21), C (WED from GD 0 – PND 1), D (WED from PND 1 – PND 21). Offspring of dams were sacrificed at adolescence (PND 35), with brain tissues of interest harvested for subsequent analyses. Results We observed no significant correlates in litter size, body, and brain weights across the experimental groups. Histomorphology revealed no distortion in cellular layering and delineation of cells in the PFC and dentate gyrus of both control and WED groups. Nissl staining intensity was enhanced in the offspring of dams exposed to WED versus the control, indicating improved proteostasis. Upregulated mRNA expression of DNMT3a, H2Ax, OPA1, and BDNF was observed in cortical and hippocampal tissues of WEDexposed offspring compared with the control group. Conclusion A diet enriched with African walnuts during early development induced changes predictive of cognitive improvements and enhanced stress-response signalling, plasticity, and neural resilience in rat offspring.

Genes Involved in Physiological Dysregulation and Decline in Resilience: Role in Alzheimer’s Disease

Our recent GWAS of a composite measure of physiological dysregulation (PD) in the Long Life Family Study (LLFS) found that the top genes associated with age-related changes in PD are involved in biological pathways relevant to maintaining neural networks and brain resilience. In our prior work, PD itself was linked to resilience-related traits. Alzheimer’s disease (AD) is a heterogeneous trait and it may involve an accelerated decline in resilience with age as a contributing factor. We proposed that genes associated with aging-changes in PD and brain resilience may contribute to AD risk. We investigated interactions between SNPs in such candidate genes with AD in LLFS and Health and Retirement Study (HRS). Our analysis revealed significant interactions between SNPs in UNC5C and other genes with AD, in both LLFS and HRS. These findings support roles of genetic interactions with UNC5C gene (implemented in axon growth and neuronal apoptosis) in AD.

Genes Involved in Physiological Dysregulation and Decline in Resilience: Role in Alzheimer’s Disease

BackgroundUnscheduled emergency department (ED) revisits leading to acute hospital admission (RVA) are tantamount to a failed discharge, associated with physician error, mis-prognosis, and inadequate care planning. Previous research has shown RVA to be associated with adverse outcomes such as ICU admissions, long hospitalizations and mortality. Given the limited impact of pre-existing screening tools for older adults, we developed and validated a machine learning model to predict individual patient risk of RVA within 72 hours and 9 days of index ED visits. Method: A machine learning model was applied to retrospective electronic health record (EHR) data of patients presenting to 2 geographically and demographically divergent urban EDs in 2019. 478 clinically meaningful EHR data variables were included: socio-demographics, ED and comorbidity diagnoses, therapeutics, laboratory test orders and test results, diagnostic imaging test orders, vital signs, and utilization and operational data. Multiple machine learning algorithms were constructed; models were compared against a pre-existing adult ED-RVA risk score as a baseline.ResultsA total of 62,154 patients were included in the analysis, with 508 (0.82%) and 889 (1.4%) having 72-hour and 9-day RVA. The best-performing model, combining deep significance clustering (DICE) and regularized logistic regression, achieved AUC of 0.86 and 0.79 for 72-hour and 9-day ED-RVA for older adult patients, respectively, outperforming the pre-existing RVA risk score (0.704 and 0.694).DiscussionMachine learning models to screen for and predict older adults at high-risk for ED-RVA may be useful in directing interventions to reduce adverse events in older adults discharged from the ED.

Virgin coconut oil abrogates depression-associated cognitive deficits by modulating hippocampal antioxidant balance, GABAergic and glutamatergic receptors in mice.

GABA and glutamate neurotransmission play critical roles in both the neurobiology of depression and cognition; and Virgin coconut oil (VCO) is reported to support brain health. The present study investigated the effect of VCO on depression-associated cognitive deficits in mice. Thirty male mice divided into five groups were either exposed to chronic unpredicted mild stress (CUMS) protocol for 28days or pre-treated with 3mL/kg b. wt. of VCO for 21days or post-treated with 3mL/kg b. wt. of VCO for 21days following 28days of CUMS exposure. Mice were subjected to behavioural assessments for depressive-like behaviours and short-term memory, and thereafter euthanised. Hippocampal tissue was dissected from the harvested whole brain for biochemical and immunohistochemical evaluations. Our results showed that CUMS exposure produced depressive-like behaviours, cognitive deficits and altered hippocampal redox balance. However, treatment with VCO abrogated depression-associated cognitive impairment, and enhanced hippocampal antioxidant concentration. Furthermore, immunohistochemical evaluation revealed significant improvement in GABAA and mGluR1a immunoreactivity following treatment with VCO in the depressed mice. Therefore, findings from this study support the dietary application of VCO to enhance neural resilience in patients with depression and related disorders.

Neural Network Approach to Modelling Transport System Resilience for Major Cities: Case Studies of Lagos and Kano (Nigeria)

Congestion has become part of everyday urban life, and resilience is very crucial to traffic vulnerability and sustainable urban mobility. This research employed a neural network as an adaptive artificially-intelligent application to study the complex domains of traffic vulnerability and the resilience of the transport system in Nigerian cities (Kano and Lagos). The input criteria to train and check the models for the neural resilience network are the demographic variables, the geospatial data, traffic parameters, and infrastructure inventories. The training targets were set as congestion elements (traffic volume, saturation degree and congestion indices), which are in line with the relevant design standards obtained from the literature. A multi-layer feed-forward and back-propagation model involving input–output and curve fitting (nftool) in the MATLAB R2019b software wizard was used. Three algorithms—including Levenberg–Marquardt (LM), Bayesian Regularization (BR), and a Scaled Conjugate Gradient (SCG)—were selected for the simulation. LM converged easily with the Mean Squared Error (MSE) (2.675 × 10−3) and regression coefficient (R) (1.0) for the city of Lagos. Furthermore, the LM algorithm provided a better fit for the model training and for the overall validation of the Kano network analysis with MSE (4.424 × 10−1) and R (1.0). The model offers a modern method for the simulation of urban traffic and discrete congestion prediction.

Reduced postpartum hippocampal volume is associated with positive mother-infant caregiving behavior

BackgroundMaternal caregiving is a complex set of behaviors that can be impacted by early life stress (ELS), yet human neurobiological mechanisms are not well understood. MethodsYoung mothers (n=137) were enrolled into a neuroimaging substudy of the longitudinal Pittsburgh Girls Study (PGS). Using data collected annually while subjects were ages 8-16, ELS was calculated as a composite score of poverty, trauma, and difficult life circumstances. At 4 months postpartum, mothers underwent neuroimaging and filmed mother-infant interaction. Maternal caregiving was coded along 6 dimensions yielding “positive” and “negative” components of caregiving. Participants’ MPRAGE images were subjected to preprocessing and voxel-based morphometry (VBM) to quantify vmPFC, amygdala and hippocampus gray matter (GM) volume. We used hierarchical linear regression to investigate the relationship between GM volume and maternal caregiving, covarying for ELS as well as maternal age, weeks postpartum, race and postpartum depression score. ResultsHippocampal GM volume was inversely associated with independent observations of positive maternal caregiving. Similar findings in the vmPFC did not remain significant after correction for multiple comparisons. ELS, particularly physical assault, was associated with reduced GM volumes but was unrelated to observed maternal caregiving. LimitationsOur single-timepoint MRI-based GM volume method was not able to demonstrate time-related intra-individual perinatal neuroplasticity, nor could it resolve neural subregions involved in caregiving-related plasticity. ConclusionsOur findings shed light on the putative plasticity of the human maternal extra-hypothalamic stress-circuitry underlying positive maternal caregiving behavior. Whether reduced hippocampal GM volume represents pruning or represents neural resilience in the face of ELS, remains to be studied.

How Repair-or-Dispose Decisions Under Stress Can Initiate Disease Progression.

SummaryGlia, the helper cells of the brain, are essential in maintaining neural resilience across time and varying challenges: By reacting to changes in neuronal health glia carefully balance repair or disposal of injured neurons. Malfunction of these interactions is implicated in many neurodegenerative diseases. We present a reductionist model that mimics repair-or-dispose decisions to generate a hypothesis for the cause of disease onset. The model assumes four tissue states: healthy and challenged tissue, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. We discuss analogies to progression stages observed in the most common neurodegenerative conditions and to experimental observations of cellular signaling pathways of glia-neuron crosstalk. The model suggests that the onset of neurodegeneration can result as a compromise between two conflicting goals: short-term resilience to stressors versus long-term prevention of tissue damage.

Bilingualism and aging: A focused neuroscientific review

Abstract Research has suggested that using two or more languages on a daily basis helps older adults maintain a heightened functional state and improves neurocomputational efficiency. In this review, we discuss studies that have examined the effect of life-long bilingualism on age-related cognitive and neural decline, with a focus on discrepancies between different sources of evidence. We intend to outline and characterize factors which might explain inconsistencies between studies claiming that bilingualism has neurocognitive benefits and those that failed to find such evidence. We argue that individual variation in language proficiency and exposure, especially language switching frequency and daily frequency of use of the two languages, likely account for a significant chunk of the inconsistencies found in the literature and constrain the effectiveness of bilingualism as a cognitive and brain reserve factor. Finally, we briefly review studies of cognitive intervention and speculate on the potential of developing language training protocols to increase cognitive and neural resilience in older adults.

Developmental opioid exposures: Neurobiological underpinnings, behavioral impacts, and policy implications.

The devastating impact of opioid abuse and dependence on the individual, family, and society are well known but extremely difficult to combat. During pregnancy, opioid drugs and withdrawal also affect fetal brain development and newborn neural functions, in addition to maternal effects. Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) rates have drastically increased in the US in the past decade. Solutions to this complex problem must be multi-faceted, which would be greatly enhanced by a translational, multidisciplinary understanding. Therefore, this mini-review incorporates biomedical, clinical, and policy aspects of opioid use during pregnancy. We review the known roles for endogenous opioids in mediating circuit formation and function in the developing brain, discuss how exogenous opioid drug use and addiction impact these processes in animal models and humans, and discuss the implications of these data on public policy. We suggest that some current policy initiatives produce unintended harm on both mothers and their children and delineate recommendations for how legislation could better contribute to addiction recovery and increase neural resilience in affected children. Impact statement Opioid abuse is a critical epidemic affecting individuals, families, and communities. This mini-review summarizes current literature on the impact of opioid drugs—including prescription pain relievers and illicit opioids—on neurobiological and neurobehavioral development. Using concepts related to the medical model of addiction as a brain disease, we review the public policy implications of these data and identify needs for future investigations.

Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice

SUMMARYCognitive dysfunction and decreased mobility from aging and neurodegenerative conditions, such as Parkinson and Alzheimer diseases, are major biomedical challenges in need of more effective therapies. Increasing brain resilience may represent a new treatment strategy. Klotho, a longevity factor, enhances cognition when genetically and broadly overexpressed in its full, wild-type form over the mouse lifespan. Whether acute klotho treatment can rapidly enhance cognitive and motor functions or induce resilience is a gap in our knowledge of its therapeutic potential. Here, we show that an α-klotho protein fragment (αKL-F), administered peripherally, surprisingly induced cognitive enhancement and neural resilience despite impermeability to the blood-brain barrier in young, aging, and transgenic α-synuclein mice. αKL-F treatment induced cleavage of the NMDAR subunit GluN2B and also enhanced NMDAR-dependent synaptic plasticity. GluN2B blockade abolished αKL-F-mediated effects. Peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans.

Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging

Cognitive decline is a major biomedical challenge as the global population ages. Elevated levels of the longevity factor klotho suppress aging, enhance cognition, and promote synaptic plasticity and neural resilience against aging and Alzheimer’s disease (AD)-related pathogenic proteins. Here, we examined the relationship between human genetic variants of KLOTHO and systemic klotho levels – and assessed neuroanatomic correlates of serum klotho in a cohort of healthy older adults. Serum klotho levels were increased with KL-VS heterozygosity, as anticipated. We report, for the first time, that serum klotho levels were paradoxically decreased with KL-VS homozygosity. Further, we found that higher serum klotho levels were associated with measures of greater intrinsic connectivity in key functional networks of the brain vulnerable to aging and AD such as the fronto-parietal and default mode networks. Our findings suggest that elevated klotho promotes a resilient brain, possibly through increased network connectivity of critical brain regions.

Pathway to neural resilience: Self-esteem buffers against deleterious effects of poverty on the hippocampus.

Human neuroimaging studies have shown that people living in poverty tend to suffer hippocampal atrophy, which leads to impaired memory and learning throughout life. However, behavioral studies demonstrate that poor people with high self-esteem are often exempt from the deleterious effect of poverty and instead possess a happy and successful life. Here we investigated whether high self-esteem can buffer against the deleterious effects of poverty, as indicated by low subjective socioeconomic status (SSS), on the hippocampal gray matter volume (GMV) in a large cohort of young participants (N = 280). As expected, findings revealed that although low (vs. high) SSS was linked with a smaller hippocampal GMV, the deleterious effect of low SSS on hippocampal GMV was alleviated when the participants have high self-esteem. Commonality analyses further confirmed this observation. The current study suggests that positive psychological resources such as self-esteem may provide protection for the hippocampal atrophy in adversity. Hum Brain Mapp 37:3757-3766, 2016. © 2016 Wiley Periodicals, Inc.

Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology. Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

Lifespan behavioural and neural resilience in a social insect.

Analyses of senescence in social species are important to understanding how group living influences the evolution of ageing in society members. Social insects exhibit remarkable lifespan polyphenisms and division of labour, presenting excellent opportunities to test hypotheses concerning ageing and behaviour. Senescence patterns in other taxa suggest that behavioural performance in ageing workers would decrease in association with declining brain functions. Using the ant Pheidole dentata as a model, we found that 120-day-old minor workers, having completed 86% of their laboratory lifespan, showed no decrease in sensorimotor functions underscoring complex tasks such as alloparenting and foraging. Collaterally, we found no age-associated increases in apoptosis in functionally specialized brain compartments or decreases in synaptic densities in the mushroom bodies, regions associated with integrative processing. Furthermore, brain titres of serotonin and dopamine--neuromodulators that could negatively impact behaviour through age-related declines--increased in old workers. Unimpaired task performance appears to be based on the maintenance of brain functions supporting olfaction and motor coordination independent of age. Our study is the first to comprehensively assess lifespan task performance and its neurobiological correlates and identify constancy in behavioural performance and the absence of significant age-related neural declines.

Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet

Quality nutrition during the period of brain formation is a predictor of brain functional capacity and plasticity during adulthood; however it is not clear how this conferred plasticity imparts long-term neural resilience. Here we report that early exposure to dietary omega-3 fatty acids orchestrates key interactions between metabolic signals and Bdnf methylation creating a reservoir of neuroplasticity that can protect the brain against the deleterious effects of switching to a Western diet (WD). We observed that the switch to a WD increased Bdnf methylation specific to exon IV, in proportion to anxiety-like behavior, in Sprague Dawley rats reared in low omega-3 fatty acid diet, and these effects were abolished by the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Blocking methylation also counteracted the reducing action of WD on the transcription regulator CTCF binding to Bdnf promoter IV. In vitro studies confirmed that CTCF binding to Bdnf promoter IV is essential for the action of DHA on BDNF regulation. Diet is also intrinsically associated to cell metabolism, and here we show that the switch to WD downregulated cell metabolism (NAD/NADH ratio and SIRT1). The fact that DNA methyltransferase inhibitor did not alter these parameters suggests they occur upstream to methylation. In turn, the methylation inhibitor counteracted the action of WD on PGC-1α, a mitochondrial transcription co-activator and BDNF regulator, suggesting that PGC-1α is an effector of Bdnf methylation. Results support a model in which diet can build an “epigenetic memory” during brain formation that confers resilience to metabolic perturbations occurring in adulthood.

Neuropsychosocial profiles of current and future adolescent alcohol misusers.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.