Sex-specific behavioural deficits in adulthood following acute activation of the GABAA receptor in the neonatal mouse.

INTRODUCTION: Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between excitatory and inhibitory neurotransmission, leading to the question of whether males and females respond differently to altered neurotransmitter balance. We investigated whether pharmacological alteration of GABAA signalling in early development results in sex-dependent changes in adult behaviours associated with NDDs. METHODS: Male and female C57BL/6J mice received intraperitoneal injections of 0.5mg/kg muscimol or saline on postnatal days (P) 3-5 and were subjected to behavioural testing, specifically open field, light dark box, marble burying, sucralose preference, social interaction and olfactory habituation/dishabituation tests between P60-90. RESULTS: Early postnatal administration of muscimol resulted in reduced anxiety in the light dark box test in both male and female adult mice. Muscimol reduced sucralose preference in males, but not females, whereas female mice showed reduced social behaviours. Regional alterations in cortical thickness were observed in the weeks following GABAA receptor activation, pointing to an evolving structural difference in the brain underlying adult behaviour. CONCLUSIONS: We conclude that activation of the GABAA receptor in the first week of life resulted in long-lasting changes in a range of behaviours in adulthood following altered neurodevelopment. Sex of the individual affected the nature and severity of these abnormalities, explaining part of the varied pathophysiology and neurodevelopmental diagnosis that derive from excitatory/inhibitory imbalance.

Cross-sectional and longitudinal assessment of cognitive development in Williams syndrome.

Williams syndrome (WS) is a rare genetic syndrome. As with all rare syndromes, obtaining adequately powered sample sizes is a challenge. Here we present legacy data from seven UK labs, enabling the characterisation of cross-sectional and longitudinal developmental trajectories of verbal and non-verbal development in the largest sample of individuals with WS to-date. In Study 1, we report cross-sectional data between N = 102 and N = 209 children and adults with WS on measures of verbal and non-verbal ability. In Study 2, we report longitudinal data from N = 17 to N = 54 children and adults with WS who had been tested on at least three timepoints on these measures. Data support the WS characteristic cognitive profile of stronger verbal than non-verbal ability, and shallow developmental progression for both domains. Both cross-sectional and longitudinal data demonstrate steeper rates of development in the child participants than the adolescent and adults in our sample. Cross-sectional data indicate steeper development in verbal than non-verbal ability, and that individual differences in the discrepancy between verbal and non-verbal ability are largely accounted for by level of intellectual functioning. A diverging developmental discrepancy between verbal and non-verbal ability, whilst marginal, is not mirrored statistically in the longitudinal data. Cross-sectional and longitudinal data are discussed with reference to validating cross-sectional developmental patterns using longitudinal data and the importance of individual differences in understanding developmental progression.

Modulatory effects of SES and multilinguistic experience on cognitive development: a longitudinal data analysis of multilingual and monolingual adolescents from the SCAMP cohort.

Previous research has shown that cognitive development is sensitive to socio-economic status (SES) and multilinguistic experiences. However, these effects are difficult to disentangle and SES may modulate the effects of multilingualism. The present study used data from a large cohort of pupils who took part in the Study of Cognition, Adolescents and Mobile Phones (SCAMP) at ages 11-12 (T1) and 13-15 years old (T2). Cognitive measures were derived from tasks of cognitive flexibility, verbal, spatial and visuo-spatial working memory, speech processing and non-verbal reasoning. Using SES information collected through questionnaires (school type, level of deprivation, parental education and occupation), the sample was clustered into high/medium/low SES groups. Comparisons focused on 517 monolingual and 329 multilingual pupils in the high/low SES groups. Having controlled for multiple comparisons, the results indicated a significant beneficial effect of bilingualism in measures of working memory, visuo-spatial processing and non-verbal reasoning. These effects were present in both high and low SES individuals and sustained at both times of development, with a particularly significant improvement of working memory abilities in low SES bilinguals at T2 as compared to monolingual peers. Theoretical and practical implications of these findings are considered and guidance for educators is discussed.

The role of context in verbal humor processing in autism.

Difficulties in processing humor have been associated with individuals with autism. The current study investigated whether humor comprehension and appreciation could be augmented in children with autism by providing contextual support suggesting that humor was to be expected. A verbally presented riddle task was used in which participants were assessed for their subjective ratings and comprehension of the materials. They were also filmed to record any smiling or laughing. Both riddles and control stimuli were presented with supporting verbal context and also without it. The results showed that (a) the greater subjective appreciation of riddles than of control stimuli was dependent on the provision of context for the participants with autism and that (b) context statistically equated these ratings of riddles between participants with autism and matched typically developing controls. However, context had no effect on comprehension or affective response. The results of the current study demonstrate that children with autism are, even in the most conservative interpretation, able to use verbal context to recognize verbal humor. This lays the foundation of possible interventions based on training sensitivity to context.

First demonstration of effective spatial training for near transfer to spatial performance and far transfer to a range of mathematics skills at 8 years.

There is evidence that spatial thinking is malleable, and that spatial and mathematical skills are associated (Mix et al. [2016] Journal of Experimental Psychology: General, 145, 1206; Mix et al. [2017] Journal of Cognition and Development, 18, 465; Uttal et al. [2013] Psychological Bulletin, 139, 352). However, few studies have investigated transfer of spatial training gains to mathematics outcomes in children, and no known studies have compared different modes of spatial instruction (explicit vs. implicit instruction). Based on a sample of 250 participants, this study compared the effectiveness of explicit and implicit spatial instruction in eliciting near transfer (to the specific spatial skills trained), intermediate transfer (to untrained spatial skills) and far transfer (to mathematics domains) at age 8. Spatial scaling and mental rotation skills were chosen as training targets as previous studies have found, and proposed explanations for, associations between these skills and mathematics in children of this age (Journal of Experimental Psychology: General, 145, 2016 and 1206). In this study, spatial training led to near, intermediate and far transfer of gains. Mental visualization and proportional reasoning were proposed to explain far transfer from mental rotation and spatial scaling skills respectively. For most outcomes, except for geometry, there was no difference in the effectiveness of implicit (practice with feedback) compared to explicit instruction (instructional videos). From a theoretical perspective, the study identified a specific causal effect of spatial skills on mathematics skills in children. Practically, the results also highlight the potential of instructional videos as a method of introducing spatial thinking into the classroom.

Evolving Connectionist Models to Capture Population Variability across Language Development: Modeling Children's Past Tense Formation.

Children's acquisition of the English past tense has been widely studied as a testing ground for theories of language development, mostly because it comprises a set of quasi-regular mappings. English verbs are of two types: regular verbs, which form their past tense based on a productive rule, and irregular verbs, which form their past tenses through exceptions to that rule. Although many connectionist models exist for capturing language development, few consider individual differences. In this article, we explore the use of populations of artificial neural networks (ANNs) that evolve according to behavioral genetics principles in order to create computational models capable of capturing the population variability exhibited by children in acquiring English past tense verbs. Literature in the field of behavioral genetics views variability in children's learning in terms of genetic and environmental influences. In our model, the effects of genetic influences are simulated through variations in parameters controlling computational properties of ANNs, and the effects of environmental influences are simulated via a filter applied to the training set. This filter alters the quality of information available to the artificial learning system and creates a unique subsample of the training set for each simulated individual. Our approach uses a population of twins to disentangle genetic and environmental influences on past tense performance and to capture the wide range of variability exhibited by children as they learn English past tenses. We use a novel technique to create the population of ANN twins based on the biological processes of meiosis and fertilization. This approach allows modeling of both individual differences and development (within the lifespan of an individual) in a single framework. Finally, our approach permits the application of selection on developmental performance on the quasi-regular task across generations. Setting individual differences within an evolutionary framework is an important and novel contribution of our work. We present an experimental evaluation of this model, focusing on individual differences in performance. The experiments led to several novel findings, including: divergence of population attributes during selection to favor regular verbs, irregular verbs, or both; evidence of canalization, analogous to Waddington's developmental epigenetic landscape, once selection starts targeting a particular aspect of the task domain; and the limiting effect on the power of selection in the face of stochastic selection (roulette wheel), sexual reproduction, and a variable learning environment for each individual. Most notably, the heritability of traits showed an inverse relationship to optimization. Selected traits show lower heritability as the genetic variation of the population reduces. The simulations demonstrate the viability of linking concepts such as heritability of individual differences, cognitive development, and selection over generations within a single computational framework.

The development of children's comprehension and appreciation of riddles.

Humor appreciation and understanding is important for children's social relationships. The current study examined the associations among riddle comprehension, riddle appreciation, and smiling/laughter in children from a wide age range (4-11 years) as well as how cognitive processing style relates to riddle comprehension. Style was distinguished between local and global language processing at the sentence level. The results showed that only children age 8 years or older showed a reliable relationship between humor comprehension and smiling/laughter. These findings show that laughter should not be taken as an automatic indicator of explicit understanding. In addition, higher vocabulary ability was independently associated with better humor comprehension. This demonstrates a separable role of language proficiency in humor comprehension and suggests avenues for future research in atypical populations known to have difficulties in this area.

Education, the science of learning, and the COVID-19 crisis.

In the COVID-19 crisis, the science of learning has two different responsibilities: first, to offer guidance about how best to deal with the impact of the current situation, including lockdown and home-schooling; and second, to consider bigger questions about what this large-scale educational experiment might mean for the future. The first part of this Viewpoint summarises advice for parents on mental health, and on becoming stand-in-teachers. The second part, taking the longer view, considers the potential negative impact of the COVID-19 crisis in increasing inequality in education; but also the potential positive impact of driving innovations in technology use for educating children.

Annual Research Review: Educational neuroscience: progress and prospects.

Educational neuroscience is an interdisciplinary research field that seeks to translate research findings on neural mechanisms of learning to educational practice and policy and to understand the effects of education on the brain. Neuroscience and education can interact directly, by virtue of considering the brain as a biological organ that needs to be in the optimal condition to learn ('brain health'); or indirectly, as neuroscience shapes psychological theory and psychology influences education. In this article, we trace the origins of educational neuroscience, its main areas of research activity and the principal challenges it faces as a translational field. We consider how a pure psychology approach that ignores neuroscience is at risk of being misleading for educators. We address the major criticisms of the field comprising, respectively, a priori arguments against the relevance of neuroscience to education, reservations with the current practical operation of the field, and doubts about the viability of neuroscience methods for diagnosing disorders or predicting individual differences. We consider future prospects of the field and ethical issues it raises. Finally, we discuss the challenge of responding to the (welcome) desire of education policymakers to include neuroscience evidence in their policymaking, while ensuring recommendations do not exceed the limitations of current basic science.

The developmental relations between spatial cognition and mathematics in primary school children.

Spatial thinking is an important predictor of mathematics. However, existing data do not determine whether all spatial sub-domains are equally important for mathematics outcomes nor whether mathematics-spatial associations vary through development. This study addresses these questions by exploring the developmental relations between mathematics and spatial skills in children aged 6-10 years (N = 155). We extend previous findings by assessing and comparing performance across Uttal et al.'s (2013), four spatial sub-domains. Overall spatial skills explained 5%-14% of the variation across three mathematics performance measures (standardized mathematics skills, approximate number sense and number line estimation skills), beyond other known predictors of mathematics including vocabulary and gender. Spatial scaling (extrinsic-static sub-domain) was a significant predictor of all mathematics outcomes, across all ages, highlighting its importance for mathematics in middle childhood. Other spatial sub-domains were differentially associated with mathematics in a task- and age-dependent manner. Mental rotation (intrinsic-dynamic skills) was a significant predictor of mathematics at 6 and 7 years only which suggests that at approximately 8 years of age there is a transition period regarding the spatial skills that are important for mathematics. Taken together, the results support the investigation of spatial training, particularly targeting spatial scaling, as a means of improving both spatial and mathematical thinking.

Total recall in the SCAMP cohort: Validation of self-reported mobile phone use in the smartphone era.

Mobile phone use, predominantly smartphones, is almost ubiquitous amongst both adults and children. However adults and children have different usage patterns. A major challenge with research on mobile phone use is the reliability of self-reported phone activity for accurate exposure assessment. We investigated the agreement between self-reported mobile phone use data and objective mobile operator traffic data in a subset of adolescents aged 11-12 years participating in the Study of Cognition, Adolescents and Mobile Phones (SCAMP) cohort. We examined self-reported mobile phone use, including call frequency, cumulative call time duration and text messages sent among adolescents from SCAMP and matched these data with records provided by mobile network operators (n = 350). The extent of agreement between self-reported mobile phone use and mobile operator traffic data use was evaluated using Cohen's weighted Kappa (ĸ) statistics. Sensitivity and specificity of self-reported low (< 1 call/day, ≤ 5min of call/day or ≤ 5 text messages sent/day) and high (≥ 11 calls/day, > 30min of call/day or ≥ 11 text messages sent /day) use were estimated. Agreement between self-reported mobile phone use and mobile operator traffic data was highest for the duration spent talking on mobile phones per day on weekdays (38.9%) and weekends (29.4%) compared to frequency of calls and number of text messages sent. Adolescents overestimated their mobile phone use during weekends compared to weekdays. Analysis of agreement showed little difference overall between the sexes and socio-economic groups. Weighted kappa between self-reported and mobile operator traffic data for call frequency during weekdays was κ = 0.12, 95% CI 0.06-0.18. Of the three modes of mobile phone use measured in the questionnaire, call frequency was the most sensitive for low mobile phone users on weekdays and weekends (77.1, 95% CI: 69.3-83.7 and 72.0, 95% CI: 65.0-78.4, respectively). Specificity was moderate to high for high users with the highest for call frequency during weekdays (98.4, 95% CI: 96.4-99.5). Despite differential agreement between adolescents' self-reported mobile phone use and mobile operator traffic data, our findings demonstrate that self-reported usage adequately distinguishes between high and low use. The greater use of mobile smartphones over Wi-Fi networks by adolescents, as opposed to mobile phone networks, means operator data are not the gold standard for exposure assessment in this age group. This has important implications for epidemiologic research on the health effects of mobile phone use in adolescents.

A neurocomputational model of developmental trajectories of gifted children under a polygenic model: When are gifted children held back by poor environments?

From the genetic side, giftedness in cognitive development is the result of contribution of many common genetic variants of small effect size, so called polygenicity (Spain et al., 2016). From the environmental side, educationalists have argued for the importance of the environment for sustaining early potential in children, showing that bright poor children are held back in their subsequent development (Feinstein, 2003a). Such correlational data need to be complemented by mechanistic models showing how gifted development results from the respective genetic and environmental influences. A neurocomputational model of cognitive development is presented, using artificial neural networks to simulate the development of a population of children. Variability was produced by many small differences in neurocomputational parameters each influenced by multiple artificial genes, instantiating a polygenic model, and by variations in the level of stimulation from the environment. The simulations captured several key empirical phenomena, including the non-linearity of developmental trajectories, asymmetries in the characteristics of the upper and lower tails of the population distribution, and the potential of poor environments to hold back bright children. At a computational level, 'gifted' networks tended to have higher capacity, higher plasticity, less noisy neural processing, a lower impact of regressive events, and a richer environment. However, individual instances presented heterogeneous contributions of these neurocomputational factors, suggesting giftedness has diverse causes.

Verbal and non-verbal intelligence changes in the teenage brain.

Intelligence quotient (IQ) is a standardized measure of human intellectual capacity that takes into account a wide range of cognitive skills. IQ is generally considered to be stable across the lifespan, with scores at one time point used to predict educational achievement and employment prospects in later years. Neuroimaging allows us to test whether unexpected longitudinal fluctuations in measured IQ are related to brain development. Here we show that verbal and non-verbal IQ can rise or fall in the teenage years, with these changes in performance validated by their close correlation with changes in local brain structure. A combination of structural and functional imaging showed that verbal IQ changed with grey matter in a region that was activated by speech, whereas non-verbal IQ changed with grey matter in a region that was activated by finger movements. By using longitudinal assessments of the same individuals, we obviated the many sources of variation in brain structure that confound cross-sectional studies. This allowed us to dissociate neural markers for the two types of IQ and to show that general verbal and non-verbal abilities are closely linked to the sensorimotor skills involved in learning. More generally, our results emphasize the possibility that an individual's intellectual capacity relative to their peers can decrease or increase in the teenage years. This would be encouraging to those whose intellectual potential may improve, and would be a warning that early achievers may not maintain their potential.

The over-pruning hypothesis of autism.

This article outlines the over-pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub-type (Thomas, Knowland & Karmiloff-Smith, 2011a, 2011b). Here we develop a more general version of the over-pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co-inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at-risk of ASD. We review evidence consistent with the over-pruning hypothesis, its relation to other current theories (including C. Frith's under-pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.

Audio-visual speech perception: a developmental ERP investigation.

Being able to see a talking face confers a considerable advantage for speech perception in adulthood. However, behavioural data currently suggest that children fail to make full use of these available visual speech cues until age 8 or 9. This is particularly surprising given the potential utility of multiple informational cues during language learning. We therefore explored this at the neural level. The event-related potential (ERP) technique has been used to assess the mechanisms of audio-visual speech perception in adults, with visual cues reliably modulating auditory ERP responses to speech. Previous work has shown congruence-dependent shortening of auditory N1/P2 latency and congruence-independent attenuation of amplitude in the presence of auditory and visual speech signals, compared to auditory alone. The aim of this study was to chart the development of these well-established modulatory effects over mid-to-late childhood. Experiment 1 employed an adult sample to validate a child-friendly stimulus set and paradigm by replicating previously observed effects of N1/P2 amplitude and latency modulation by visual speech cues; it also revealed greater attenuation of component amplitude given incongruent audio-visual stimuli, pointing to a new interpretation of the amplitude modulation effect. Experiment 2 used the same paradigm to map cross-sectional developmental change in these ERP responses between 6 and 11 years of age. The effect of amplitude modulation by visual cues emerged over development, while the effect of latency modulation was stable over the child sample. These data suggest that auditory ERP modulation by visual speech represents separable underlying cognitive processes, some of which show earlier maturation than others over the course of development.

Associations between Socioeconomic Status, Cognition, and Brain Structure: Evaluating Potential Causal Pathways Through Mechanistic Models of Development.

Differences in socioeconomic status (SES) correlate both with differences in cognitive development and in brain structure. Associations between SES and brain measures such as cortical surface area and cortical thickness mediate differences in cognitive skills such as executive function and language. However, causal accounts that link SES, brain, and behavior are challenging because SES is a multidimensional construct: correlated environmental factors, such as family income and parental education, are only distal markers for proximal causal pathways. Moreover, the causal accounts themselves must span multiple levels of description, employ a developmental perspective, and integrate genetic effects on individual differences. Nevertheless, causal accounts have the potential to inform policy and guide interventions to reduce gaps in developmental outcomes. In this article, we review the range of empirical data to be integrated in causal accounts of developmental effects on the brain and cognition associated with variation in SES. We take the specific example of language development and evaluate the potential of a multiscale computational model of development, based on an artificial neural network, to support the construction of causal accounts. We show how, with bridging assumptions that link properties of network structure to magnetic resonance imaging (MRI) measures of brain structure, different sets of empirical data on SES effects can be connected. We use the model to contrast two possible causal pathways for environmental influences that are associated with SES: differences in prenatal brain development and differences in postnatal cognitive stimulation. We then use the model to explore the implications of each pathway for the potential to intervene to reduce gaps in developmental outcomes. The model points to the cumulative effects of social disadvantage on multiple pathways as the source of the poorest response to interventions. Overall, we highlight the importance of implemented models to test competing accounts of environmental influences on individual differences.

Complex cognition and individual variability: a mixed methods study of the relationship between creativity and executive control.

One of the methodological challenges of educational neuroscience is understanding real world cognition in the multifaceted environment of the classroom. Complex cognition does not simplify to processes (which might be satisfactorily measured in the lab) but to sets of activities, likely to vary between individuals, which involve the iterative use of multiple processes, as well as the environment, over an extended period of time. As such, studying complex cognition requires methodological flexibility; any single method is unlikely to provide complete answers. We illustrate this idea with our research exploring the relationship between executive control (EC) and creativity in primary school age children; in it, we used both qualitative and quantitative tools and a novel approach to bringing both sets of findings together. Quantitative findings helped inform 'how much' a participant could deploy EC or creative thinking, while qualitative findings told us more about 'how' they deployed EC in their creativity. Through triangulating findings, we gained insights which would have remained obscure using either approach alone; namely, first, that wide variation in how children deploy EC in creativity means that the same creative results can be achieved with very different levels of EC involvement, and second, that high levels of EC can limit creativity. We argue that, beyond the specific findings of this study, there might be useful broader methodological lessons for educational neuroscience. We also attempt to demystify mixed methods by showing that a multi-pronged approach is more feasible than many assume; for example, by using existing, familiar tools in novel ways. In our work, we redeployed well-established quantitative tests used in creativity research as stimuli for qualitative investigation. For educational neuroscience to evolve its understanding of complex cognition, we suggest it might benefit from being innovative, open-minded and ambitious in how it exploits the diversity of methodological tools available.

A systematic review of cognitive interventions for adult patients with brain tumours.

BACKGROUND: Neurocognitive impairments are common in patients with current or previously treated brain tumours, and such impairments can negatively affect patient outcomes including quality of life and survival. This systematic review aimed to identify and describe interventions used to ameliorate (improve) or prevent cognitive impairments in adults with brain tumours. METHODS: We performed a literature search of the Ovid MEDLINE, PsychINFO and PsycTESTS databases from commencement until September 2021. RESULTS: In total, 9998 articles were identified by the search strategy; an additional 14 articles were identified through other sources. Of these, 35 randomised and nonrandomised studies were deemed to meet the inclusion/exclusion criteria of our review and were subsequently included for evaluation. A range of interventions were associated with positive effects on cognition, including pharmacological agents such as memantine, donepezil, methylphenidate, modafinil, ginkgo biloba and shenqi fuzheng, and nonpharmacological interventions such as general and cognitive rehabilitation, working memory training, Goal Management Training, aerobic exercise, virtual reality training combined with computer-assisted cognitive rehabilitation, hyperbaric oxygen therapy and semantic strategy training. However, most identified studies had a number of methodological limitations and were judged to be at moderate-to-high risk of bias. In addition, it remains unclear whether and to what extent the identified interventions lead to durable cognitive benefits after cessation of the intervention. CONCLUSION: The 35 studies identified in this systematic review have indicated potential cognitive benefits for a number of pharmacological and nonpharmacological interventions in patients with brain tumours. Study limitations were identified and further studies should focus on improved study reporting, methods to reduce bias and minimise participant drop-out and withdrawal where possible, and consider standardisation of methods and interventions across studies. Greater collaboration between centres could result in larger studies with standardised methods and outcome measures, and should be a focus of future research in the field.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".