Global topology of human connectome is insensitive to early life environments - A prospective longitudinal study of the general population.

The widely acknowledged detrimental impact of early adversity on child development has driven efforts to understand the underlying mechanisms that may mediate these effects within the developing brain. Recent efforts have begun to move beyond associating adversity with the morphology of individual brain regions towards determining if and how adversity might shape their interconnectivity. However, whether adversity effects a global shift in the organisation of whole-brain networks remains unclear. In this study, we assessed this possibility using parental questionnaire and diffusion imaging data from The Avon Longitudinal Study of Parents and Children (ALSPAC, N = 913), a prospective longitudinal study spanning more than 20 years. We tested whether a wide range of adversities-including experiences of abuse, domestic violence, physical and emotional cruelty, poverty, neglect, and parental separation-measured by questionnaire within the first seven years of life were significantly associated with the tractography-derived connectome in young adulthood. We tested this across multiple measures of organisation and using a computational model that simulated the wiring economy of the brain. We found no significant relationships between early exposure to any form of adversity and the global organisation of the structural connectome in young adulthood. We did detect local differences in the medial prefrontal cortex, as well as an association between weaker brain wiring constraints and greater externalising behaviour in adolescence. Our results indicate that further efforts are necessary to delimit the magnitude and functional implications of adversity-related differences in connectomic organization. RESEARCH HIGHLIGHTS: Diverse prospective measures of the early-life environment do not predict the organisation of the DTI tractography-derived connectome in young adulthood Wiring economy of the connectome is weakly associated with externalising in adolescence, but not internalising or cognitive ability Further work is needed to establish the scope and significance of global adversity-related differences in the structural connectome.

Evidence for separate backward recall and n-back working memory factors: a large-scale latent variable analysis.

Multiple studies have explored the factor structure of working memory (WM) tasks, yet few have done so controlling for both the domain and category of the memory items in a single study. In the current pre-registered study, we conducted a large-scale latent variable analysis using variant forms of n-back and backward recall tasks to test whether they measured a single underlying construct, or were distinguished by stimuli-, domain-, or paradigm-specific factors. Exploratory analyses investigated how the resulting WM factor(s) were linked to fluid intelligence. Participants (N = 703) completed a fluid reasoning test and multiple n-back and backward recall tasks containing memoranda that varied across (spatial or verbal material) and within (verbal digits or letters) domain, allowing the variance specific to task content and paradigm to be assessed. Two distinct but related backward recall and n-back constructs best captured the data, in comparison to other plausible model constructions (single WM factor, two-factor domain, and three-factor materials models). Common variance associated with WM was a stronger predictor of fluid reasoning than a residual n-back factor, but the backward recall factor predicted fluid reasoning as strongly as the common WM factor. These data emphasise the distinctiveness between backward recall and n-back tasks.

Transdiagnostic profiles of behaviour and communication relate to academic and socioemotional functioning and neural white matter organisation.

BACKGROUND: Behavioural and language difficulties co-occur in multiple neurodevelopmental conditions. Our understanding of these problems has arguably been slowed by an overreliance on study designs that compare diagnostic groups and fail to capture the overlap across different neurodevelopmental disorders and the heterogeneity within them. METHODS: We recruited a large transdiagnostic cohort of children with complex needs (N = 805) to identify distinct subgroups of children with common profiles of behavioural and language strengths and difficulties. We then investigated whether and how these data-driven groupings could be distinguished from a comparison sample (N = 158) on measures of academic and socioemotional functioning and patterns of global and local white matter connectome organisation. Academic skills were assessed via standardised measures of reading and maths. Socioemotional functioning was captured by the parent-rated version of the Strengths and Difficulties Questionnaire. RESULTS: We identified three distinct subgroups of children, each with different levels of difficulties in structural language, pragmatic communication, and hot and cool executive functions. All three subgroups struggled with academic and socioemotional skills relative to the comparison sample, potentially representing three alternative but related developmental pathways to difficulties in these areas. The children with the weakest language skills had the most widespread difficulties with learning, whereas those with more pronounced difficulties with hot executive skills experienced the most severe difficulties in the socioemotional domain. Each data-driven subgroup could be distinguished from the comparison sample based on both shared and subgroup-unique patterns of neural white matter organisation. Children with the most pronounced deficits in language, cool executive, or hot executive function were differentiated from the comparison sample by altered connectivity in predominantly thalamocortical, temporal-parietal-occipital, and frontostriatal circuits, respectively. CONCLUSIONS: These findings advance our understanding of commonly co-morbid behavioural and language problems and their relationship to behavioural outcomes and neurobiological substrates.

Cognitive difficulties following adversity are not related to mental health: Findings from the ABCD study.

Early life adversity is associated with differences in cognition and mental health that can impact on daily functioning. This study uses a hybrid machine-learning approach that combines random forest classification with hierarchical clustering to clarify whether there are cognitive differences between individuals who have experienced moderate-to-severe adversity relative to those have not experienced adversity, to explore whether different forms of adversity are associated with distinct cognitive alterations and whether these such alterations are related to mental health using data from the ABCD study (n = 5,955). Cognitive measures spanning language, reasoning, memory, risk-taking, affective control, and reward processing predicted whether a child had a history of adversity with reasonable accuracy (67%), and with good specificity and sensitivity (>70%). Two subgroups were identified within the adversity group and two within the no-adversity group that were distinguished by cognitive ability (low vs high). There was no evidence for specific associations between the type of adverse exposure and cognitive profile. Worse cognition predicted lower levels of mental health in unexposed children. However, while children who experience adversity had elevated mental health difficulties, their mental health did not differ as a function of cognitive ability, thus providing novel insight into the heterogeneity of psychiatric risk.

Dimensions of internalizing symptoms are stable across early adolescence and predicted by executive functions: Longitudinal findings from the Adolescent Brain and Cognitive Development (ABCD) study.

Early adolescence is characterized by rapid changes in executive function and increased vulnerability to internalizing difficulties. The aim of this study was to explore whether internalizing symptoms are stable across early adolescence and to identify possible links with executive function. Using data from the Adolescent Brain and Cognitive Development Study (ABCD), we identified four dimensions of internalizing symptoms from item-level ratings on the Child Behavior Checklist at ages 10 (n = 10,841) and 12 (n = 5,846), with an invariant factor structure across time. These dimensions corresponded to anxiety, depression, withdrawal, and somatic problems. We then examined associations between these dimensions and three aspects of executive function at age 10 measured by the NIH Toolbox: inhibition, shifting and working memory. Worse shifting and inhibition at age 10 was associated with elevated symptoms of anxiety and withdrawal cross-sectionally, while poor inhibition was also uniquely associated with symptoms of depression. Longitudinal associations were more limited: Worse inhibition at age 10 predicted greater symptoms of withdrawal at age 12, while worse shifting predicted fewer symptoms of anxiety 2 years later. These findings suggest that poor executive function in early adolescence is associated with greater internalizing difficulties and poor inhibition may contribute to later social withdrawal.

Early adversity changes the economic conditions of mouse structural brain network organization.

Early adversity can change educational, cognitive, and mental health outcomes. However, the neural processes through which early adversity exerts these effects remain largely unknown. We used generative network modeling of the mouse connectome to test whether unpredictable postnatal stress shifts the constraints that govern the organization of the structural connectome. A model that trades off the wiring cost of long-distance connections with topological homophily (i.e., links between regions with shared neighbors) generated simulations that successfully replicate the rodent connectome. The imposition of early life adversity shifted the best-performing parameter combinations toward zero, heightening the stochastic nature of the generative process. Put simply, unpredictable postnatal stress changes the economic constraints that reproduce rodent connectome organization, introducing greater randomness into the development of the simulations. While this change may constrain the development of cognitive abilities, it could also reflect an adaptive mechanism that facilitates effective responses to future challenges.

A meta-analytic review of the impact of ADHD medications on anxiety and depression in children and adolescents.

Anxiety and depression are listed as common side effects for medications licensed for treating ADHD in children and adolescents. This meta-analytic review of randomised controlled trials aimed to explore the effect of medications on symptoms of anxiety and depression in children and adolescents with ADHD. A meta-analytic review of ADHD drug trials in children and adolescents was conducted. Random effects meta-analyses were conducted on anxiety and depression outcomes measured by validated psychological scales or side effect rating scales. Only 11% of eligible trials in this review reported anxiety and/or depression as an outcome or side effect, limiting the conclusions of the meta-analyses. Relative to placebo control, no significant effect of medication was found for symptoms of anxiety or depression in randomised controlled trials of ADHD medication in children and adolescents. This review highlights the systemic lack of mental health outcome reporting in child and adolescent ADHD drug trials. The importance of widespread implementation of standardised measurement of mental health outcomes in future trials is discussed.

Testing Deprivation and Threat: A Preregistered Network Analysis of the Dimensions of Early Adversity.

Despite abundant evidence of the detrimental effects of childhood adversity, its nature and underlying mechanisms remain contested. One influential theory, the dimensional model of adversity and psychopathology, proposes deprivation and threat as distinct dimensions of early experience. In this preregistered analysis of data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we used a network and clustering approach to assess the dimensionality of relationships between childhood adversity and adolescent cognition and emotional functioning, and we used recursive partitioning to identify timing effects. We found evidence that deprivation and threat are separate dimensions of adversity and that early experiences of deprivation cluster with later measures of cognition and emotional functioning. This cluster varies by age of exposure; it includes fewer forms of deprivation as children grow from infancy to middle childhood. Our measures did not form a specific cluster linking threat to emotional functioning.

Annual Research Review: The transdiagnostic revolution in neurodevelopmental disorders.

Practitioners frequently use diagnostic criteria to identify children with neurodevelopmental disorders and to guide intervention decisions. These criteria also provide the organising framework for much of the research focussing on these disorders. Study design, recruitment, analysis and theory are largely built on the assumption that diagnostic criteria reflect an underlying reality. However, there is growing concern that this assumption may not be a valid and that an alternative transdiagnostic approach may better serve our understanding of this large heterogeneous population of young people. This review draws on important developments over the past decade that have set the stage for much-needed breakthroughs in understanding neurodevelopmental disorders. We evaluate contemporary approaches to study design and recruitment, review the use of data-driven methods to characterise cognition, behaviour and neurobiology, and consider what alternative transdiagnostic models could mean for children and families. This review concludes that an overreliance on ill-fitting diagnostic criteria is impeding progress towards identifying the barriers that children encounter, understanding underpinning mechanisms and finding the best route to supporting them.

Age-related differences in adults' ability to follow spoken instructions.

A growing body of research illustrates that working memory capacity is a crucial limiting factor in our ability to follow spoken instructions. Despite the ubiquitous nature of instruction following throughout the lifespan, how the natural ageing process affects the ability to do so is not yet fully understood. In this study, we investigated the consequences of action at encoding and recall on the ability to follow spoken instructions. Younger (< 30 y/o) and older (> 65 y/o) adults recalled sequences of spoken action commands under presentation and recall conditions that either did or did not involve their physical performance. Both groups showed an enacted-recall advantage, with superior recall by physical performance than oral repetition. When both encoding and recall were purely verbal, older adults' recall accuracy was comparable to that of their younger counterparts. When action was involved at either encoding or recall, however, the difference in performance between the two age groups became pronounced: enactment-based encoding significantly improved younger adults' ability to follow spoken instructions; there was no such advantage for older adults. These data show that spatial-motoric representations disproportionately benefit younger adults' memory performance. We discuss the practical implications of these findings in the context of lifelong learning.

Cognitive Dimensions of Learning in Children With Problems in Attention, Learning, and Memory.

A data-driven, transdiagnostic approach was used to identify the cognitive dimensions linked with learning in a mixed group of 805 children aged 5 to 18 years recognised as having problems in attention, learning and memory by a health or education practitioner. Assessments included phonological processing, information processing speed, short-term and working memory, and executive functions, and attainments in word reading, spelling, and maths. Data reduction methods identified three dimensions of phonological processing, processing speed and executive function for the sample as a whole. This model was comparable for children with and without ADHD. The severity of learning difficulties in literacy was linked with phonological processing skills, and in maths with executive control. Associations between cognition and learning were similar across younger and older children and individuals with and without ADHD, although stronger links between learning-related problems and both executive skills and processing speed were observed in children with ADHD. The results establish clear domain-specific cognitive pathways to learning that distinguish individuals in the heterogeneous population of children struggling to learn.

The effects of transcranial direct current stimulation on within- and cross-paradigm transfer following multi-session backward recall training.

Transcranial direct current stimulation (tDCS) has been shown to enhance the efficacy and generalisation of working memory (WM) training, but there has been little systematic investigation into how coupling task-specific WM training with stimulation impacts more specifically on transfer to untrained tasks. This randomised controlled trial investigated the boundary conditions to transfer by testing firstly whether the benefits of training on backward digit recall (BDR) extend to untrained backward recall tasks and n-back tasks with different materials, and secondly which, if any, form of transfer is enhanced by tDCS. Forty-eight participants were allocated to one of three conditions: BDR training with anodal (10 min, 1 mA) or sham tDCS, or visual search training with sham tDCS, applied over the left dorsolateral prefrontal cortex. Transfer was assessed on within- (backward recall with digits, letters, and spatial locations) and cross-paradigm (n-back with digits and letters) transfer tests following three sessions of training and stimulation. On-task training gains were found, with transfer to other backward span but not n-back tasks. There was little evidence that tDCS enhanced on-task training or transfer. These findings indicate that training enhances paradigm-specific processes within WM, but that tDCS does not enhance these gains.

Remapping the cognitive and neural profiles of children who struggle at school.

Our understanding of learning difficulties largely comes from children with specific diagnoses or individuals selected from community/clinical samples according to strict inclusion criteria. Applying strict exclusionary criteria overemphasizes within group homogeneity and between group differences, and fails to capture comorbidity. Here, we identify cognitive profiles in a large heterogeneous sample of struggling learners, using unsupervised machine learning in the form of an artificial neural network. Children were referred to the Centre for Attention Learning and Memory (CALM) by health and education professionals, irrespective of diagnosis or comorbidity, for problems in attention, memory, language, or poor school progress (n = 530). Children completed a battery of cognitive and learning assessments, underwent a structural MRI scan, and their parents completed behavior questionnaires. Within the network we could identify four groups of children: (a) children with broad cognitive difficulties, and severe reading, spelling and maths problems; (b) children with age-typical cognitive abilities and learning profiles; (c) children with working memory problems; and (d) children with phonological difficulties. Despite their contrasting cognitive profiles, the learning profiles for the latter two groups did not differ: both were around 1 SD below age-expected levels on all learning measures. Importantly a child's cognitive profile was not predicted by diagnosis or referral reason. We also constructed whole-brain structural connectomes for children from these four groupings (n = 184), alongside an additional group of typically developing children (n = 36), and identified distinct patterns of brain organization for each group. This study represents a novel move toward identifying data-driven neurocognitive dimensions underlying learning-related difficulties in a representative sample of poor learners.

Transdiagnostic associations across communication, cognitive, and behavioural problems in a developmentally at-risk population: a network approach.

BACKGROUND: Communication, behavioural, and executive function problems often co-occur in childhood. Previous attempts to identify the origins of these comorbidities have typically relied on comparisons of different deficit groups and/or latent variable models. Here we apply a network approach to a heterogeneous sample of struggling learners to conceptualise these comorbidities as a dynamic system of interacting difficulties. METHODS: 714 children struggling with attention, learning, and/or memory were included. The sample consisted of children with both diagnosed (41%) and undiagnosed difficulties. The conditional independence network of parent ratings of everyday behaviour, cognition, and communication was estimated. RESULTS: A clustering coefficient identified four interconnected areas of difficulty: (1) structural language and learning; (2) pragmatics and peer relationships; (3) behavioural and emotional problems; and (4) cognitive skills. Emotional and behavioural symptoms shared multiple direct connections with pragmatic abilities and cognitive problems, but not with structural language skills or learning problems. Poor structural language and cognitive skills were associated with learning problems. Centrality indices highlighted working memory and language coherence as symptoms bridging different problem areas. CONCLUSION: The network model identified four areas of difficulty and potential bridging symptoms. Although the current analytic framework does not provide causal evidence, it is possible that bridging symptoms may be the origins of comorbidities observed on a dimensional level; problems in these areas may cascade and activate problems in other areas of the network. The potential value of applying a dynamic systems network approach to symptoms of developmental disorders is discussed.

Protocol for a transdiagnostic study of children with problems of attention, learning and memory (CALM).

BACKGROUND: A substantial proportion of the school-age population experience cognitive-related learning difficulties. Not all children who struggle at school receive a diagnosis, yet their problems are sufficient to warrant additional support. Understanding the causes of learning difficulties is the key to developing effective prevention and intervention strategies for struggling learners. The aim of this project is to apply a transdiagnostic approach to children with cognitive developmental difficulties related to learning to discover the underpinning mechanisms of learning problems. METHODS: A cohort of 1000 children aged 5 to 18 years is being recruited. The sample consists of 800 children with problems in attention, learning and / memory, as identified by a health or educational professional, and 200 typically-developing children recruited from the same schools as those with difficulties. All children are completing assessments of cognition, including tests of phonological processing, short-term and working memory, attention, executive function and processing speed. Their parents/ carers are completing questionnaires about the child's family history, communication skills, mental health and behaviour. Children are invited for an optional MRI brain scan and are asked to provide an optional DNA sample (saliva). Hypothesis-free data-driven methods will be used to identify the cognitive, behavioural and neural dimensions of learning difficulties. Machine-learning approaches will be used to map the multi-dimensional space of the cognitive, neural and behavioural measures to identify clusters of children with shared profiles. Finally, group comparisons will be used to test theories of development and disorder. DISCUSSION: Our multi-systems approach to identifying the causes of learning difficulties in a heterogeneous sample of struggling learners provides a novel way to enhance our understanding of the common and complex needs of the majority of children who struggle at school. Our broad recruitment criteria targeting all children with cognitive learning problems, irrespective of diagnoses and comorbidities, are novel and make our sample unique. Our dataset will also provide a valuable resource of genetic, imaging and cognitive developmental data for the scientific community.

Do actions speak louder than words? Examining children's ability to follow instructions.

The ability to encode, retain, and implement instructions within working memory is central to many behaviours, including classroom activities which underpin learning. The three experiments presented here explored how action-planned, enacted, and observed-impacted 6- to 10-year-old's ability to follow instructions. Experiment 1 (N = 81) found enacted recall was superior to verbal recall, but self-enactment at encoding had a negative effect on enacted recall and verbal recall. In contrast, observation of other-enactment (demonstration) at encoding facilitated both types of recall (Experiment 2a: N = 81). Further, reducing task demands through a reduced set of possible actions (Experiment 2b; N = 64) led to a positive effect of self-enactment at encoding for later recall (both verbal and enacted). Expecting to enact at recall may lead to the creation of an imaginal spatial-motoric plan at encoding that boosts later recall. However, children's ability to use the additional spatial-motoric codes generated via self-enactment at encoding depends on the demands the task places on central executive resources. Demonstration at encoding appears to reduce executive demands and enable use of these additional forms of coding.

Transcranial Random Noise Stimulation Does Not Enhance the Effects of Working Memory Training.

Transcranial random noise stimulation (tRNS), a noninvasive brain stimulation technique, enhances the generalization and sustainability of gains following mathematical training. Here it is combined for the first time with working memory training in a double-blind randomized controlled trial. Adults completed 10 sessions of Cogmed Working Memory Training with either active tRNS or sham stimulation applied bilaterally to dorsolateral pFC. Training was associated with gains on both the training tasks and on untrained tests of working memory that shared overlapping processes with the training tasks, but not with improvements on working memory tasks with distinct processing demands or tests of other cognitive abilities (e.g., IQ, maths). There was no evidence that tRNS increased the magnitude or transfer of these gains. Thus, combining tRNS with Cogmed Working Memory Training provides no additional therapeutic value.

Following instructions from working memory: Why does action at encoding and recall help?

Two experiments investigated the consequences of action at encoding and recall on the ability to follow sequences of instructions. Children ages 7-9 years recalled sequences of spoken action commands under presentation and recall conditions that either did or did not involve their physical performance. In both experiments, recall was enhanced by carrying out the instructions as they were being initially presented and also by performing them at recall. In contrast, the accuracy of instruction-following did not improve above spoken presentation alone, either when the instructions were silently read or heard by the child (Experiment 1), or when the child repeated the spoken instructions as they were presented (Experiment 2). These findings suggest that the enactment advantage at presentation does not simply reflect a general benefit of a dual exposure to instructions, and that it is not a result of their self-production at presentation. The benefits of action-based recall were reduced following enactment during presentation, suggesting that the positive effects of action at encoding and recall may have a common origin. It is proposed that the benefits of physical movement arise from the existence of a short-term motor store that maintains the temporal, spatial, and motoric features of either planned or already executed actions.

Following instructions in a virtual school: Does working memory play a role?

Accumulating evidence that working memory supports the ability to follow instructions has so far been restricted to experimental paradigms that have greatly simplified the practical demands of performing actions to instructions in everyday tasks. The aim of the present study was to investigate whether working memory is involved in maintaining information over the longer periods of time that are more typical of everyday situations that require performing instructions to command. Forty-two children 7-11 years of age completed assessments of working memory, a real-world following-instructions task employing 3-D objects, and two new computerized instruction-following tasks involving navigation around a virtual school to complete a sequence of practical spoken commands. One task involved performing actions in a single classroom, and the other, performing actions in multiple locations in a virtual school building. Verbal working memory was closely linked with all three following-instructions paradigms, but with greater association to the virtual than to the real-world tasks. These results indicate that verbal working memory plays a key role in following instructions over extended periods of activity.

Does working memory training promote the use of strategies on untrained working memory tasks?

Adaptive computerized training has been associated with significant enhancements in untrained working memory tasks, but the nature of the cognitive changes that underpin these improvements are not yet fully understood. Here, we investigate the possibility that training stimulates the use of memory-related strategies. In a randomized controlled trial, participants completed four tests of working memory before receiving adaptive working memory training, nonadaptive working memory training with low memory loads, or no training. Open-ended interviews about strategy use were conducted after the administration of untrained working memory tasks at two time points. Those in the adaptive and nonadaptive groups completed the assessments before (T1) and after (T2) 10 training sessions. The no-training group completed the same set of tasks at T1 and T2, without any training between assessment points. Adaptive training was associated with selective improvements in untrained tests of working memory, accompanied by a significant increase in the use of a grouping strategy for visuospatial short-term memory and verbal working memory tasks. These results indicate that training-related improvements in working memory may be mediated by implicit and spontaneous changes in the use of strategies to subsegment sequences of information into groups for recall when the tasks used at test overlap with those used during training.