Differences in brain morphology and working memory capacity across childhood.

Working memory (WM) skills are closely associated with learning progress in key areas such as reading and mathematics across childhood. As yet, however, little is known about how the brain systems underpinning WM develop over this critical developmental period. The current study investigated whether and how structural brain correlates of components of the working memory system change over development. Verbal and visuospatial short-term and working memory were assessed in 153 children between 5.58 and 15.92 years, and latent components of the working memory system were derived. Fractional anisotropy and cortical thickness maps were derived from T1-weighted and diffusion-weighted MRI and processed using eigenanatomy decomposition. There was a greater involvement of the corpus callosum and posterior temporal white matter in younger children for performance associated with the executive part of the working memory system. For older children, this was more closely linked with the thickness of the occipitotemporal cortex. These findings suggest that increasing specialization leads to shifts in the contribution of neural substrates over childhood, moving from an early dependence on a distributed system supported by long-range connections to later reliance on specialized local circuitry. Our findings demonstrate that despite the component factor structure being stable across childhood, the underlying brain systems supporting working memory change. Taking the age of the child into account, and not just their overall score, is likely to be critical for understanding the nature of the limitations on their working memory capacity.The Centre for Attention Learning and Memory (CALM) research clinic at the MRC Cognition and Brain Sciences Unit in Cambridge (CBSU) is supported by funding from the Medical Research Council of Great Britain to Duncan Astle, Susan Gathercole and Tom Manly

Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DiSC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DiSC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DiSC1 led to dysregulation of DiSC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DiSC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DiSC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.</p

A generative network model of neurodevelopmental diversity in structural brain organization

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: James S. McDonnell Foundation (McDonnell Foundation); doi: https://doi.org/10.13039/100000913Funder: Cambridge Commonwealth, European and International Trust (Cambridge Commonwealth, European & International Trust); doi: https://doi.org/10.13039/501100003343Abstract: The formation of large-scale brain networks, and their continual refinement, represent crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. But how does this organization arise, and what mechanisms drive diversity in organization? We use generative network modeling to provide a computational framework for understanding neurodevelopmental diversity. Within this framework macroscopic brain organization, complete with spatial embedding of its organization, is an emergent property of a generative wiring equation that optimizes its connectivity by renegotiating its biological costs and topological values continuously over time. The rules that govern these iterative wiring properties are controlled by a set of tightly framed parameters, with subtle differences in these parameters steering network growth towards different neurodiverse outcomes. Regional expression of genes associated with the simulations converge on biological processes and cellular components predominantly involved in synaptic signaling, neuronal projection, catabolic intracellular processes and protein transport. Together, this provides a unifying computational framework for conceptualizing the mechanisms and diversity in neurodevelopment, capable of integrating different levels of analysis—from genes to cognition

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

Identifying Key Pathways into Sexual Offending for Juvenile Offenders and Exploring Possible Differences for the Aboriginal Community

Identifying the pathways that can contribute to offending behaviour can be useful to reduce offending and inform treatment development and improve therapeutic targeting for those who have offended. There are also some grounds for thinking that Aboriginal pathways might be different to those of non-Aboriginal offenders. This is because Australian Aboriginals face many additional adversities emanating from the experience of disadvantage, prejudice and ongoing genocidal pressures. In post-colonial societies, indigenous communities are generally overrepresented in both victim and offender populations. In New South Wales (NSW), Australia, where this study was conducted, this includes sexual offending, despite strong taboos against such behaviours within the Aboriginal community. The current study attempted to identify the key pathways into sexual offending for juveniles in general, and to see if the Aboriginal population of young sexual offenders differed in any way. Theory is sparse in this area so a multiple case study design utilising grounded theory methodology was implemented. Though similar models have been developed for adult male and female offenders (Gannon, Rose &amp; Ward., 2008), pathway models have not been previously developed for these groups of juvenile offenders. Data were collected via structured interviews with therapists and case managers who were working with this population. Fifty-six case studies were obtained from eight different therapists. From these, eight distinct pathways could be ascertained: complex trauma, poorly developed masculinities, disability, inappropriate sexualisation, dependent personality, deviant arousal, psychopathic nature and poor social skills without a trauma or disability background. Most juveniles displayed multiple pathways. Differences between the general and the Aboriginal offender groups were identified. Specifically, the Aboriginal offenders were more likely to have a trauma background, to have a disability and to have been inappropriately sexualised. These new data may help future theorising and intervention methods for this population

Changes in brain morphology and working memory capacity over childhood

1AbstractDevelopmental improvements in working memory are important in the acquisition of new skills, like reading and maths. Current accounts of the brain systems supporting working memory rarely take development into account. However, understanding the development of these skills, and in turn where this development can go awry, will require more sophsiticated neuropsychological accounts that fully consider the role of development. The current study investigated how structural brain correlates of components of the working memory system change over developmental time. Verbal and visuospatial short-term and working memory were assessed in 153 children between 6 and 16 years and latent components of the working memory system were derived using principal component analysis. Further, fractional anisotropy and cortical thickness maps were derived from T1-weighted and diffusion-weighted MRI and processed using eigenanatomy decomposition, an advanced dimensionality reduction method for neuroimaging data. We were then able to explore how the structural brain correlates of working memory gradually shifted across childhood. Regression modelling indicated greater involvement of the corpus callosum and posterior temporal white matter in younger children for performance associated with the executive part of the working memory system, while thickness of the occipitotemporal cortex was more predictive in older children. These findings are consistent with an account in which increasing specialisation leads to shifts in the contribution of neural substrates over developmental time, from early reliance on a distributed system supported by long-range connections to later reliance on specialised local circuitry. Furthemore, our findings emphasise the importance of taking development into account when considering the neural systems that support complex cognitive skills, like working memory.</jats:p