Brain networks exist within the confines of resource limitations. As a result, a brain network must overcome the metabolic costs of growing and sustaining the network within its physical space, while simultaneously implementing its required information processing. Here, to observe the effect of these processes, we introduce the spatially embedded recurrent neural network (seRNN). seRNNs learn basic task-related inferences while existing within a three-dimensional Euclidean space, where the communication of constituent neurons is constrained by a sparse connectome. We find that seRNNs converge on structural and functional features that are also commonly found in primate cerebral cortices. Specifically, they converge on solving inferences using modular small-world networks, in which functionally similar units spatially configure themselves to utilize an energetically efficient mixed-selective code. Because these features emerge in unison, seRNNs reveal how many common structural and functional brain motifs are strongly intertwined and can be attributed to basic biological optimization processes. seRNNs incorporate biophysical constraints within a fully artificial system and can serve as a bridge between structural and functional research communities to move neuroscientific understanding forwards.

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.

Economic efficiency has been a popular explanation for how networks self-organize within the developing nervous system. However, the precise nature of the economic negotiations governing this putative organizational principle remains unclear. Here, we address this question further by combining large-scale electrophysiological recordings, to characterize the functional connectivity of developing neuronal networks in vitro , with a generative modeling approach capable of simulating network formation. We find that the best fitting model uses a homophilic generative wiring principle in which neurons form connections to other neurons which are spatially proximal and have similar connectivity patterns to themselves. Homophilic generative models outperform more canonical models in which neurons wire depending upon their spatial proximity either alone or in combination with the extent of their local connectivity. This homophily-based mechanism for neuronal network emergence accounts for a wide range of observations that are described, but not sufficiently explained, by traditional analyses of network topology. Using rodent and human monolayer and organoid cultures, we show that homophilic generative mechanisms can accurately recapitulate the topology of emerging cellular functional connectivity, representing an important wiring principle and determining factor of neuronal network formation in vitro .

Dynamic connectivity in functional brain networks is a fundamental aspect of cognitive development, but we have little understanding of the mechanisms driving variability in these networks. Genes are likely to influence the emergence of fast network connectivity via their regulation of neuronal processes, but novel methods to capture these rapid dynamics have rarely been used in genetic populations. The current study redressed this by investigating brain network dynamics in a neurodevelopmental disorder of known genetic origin, by comparing individuals with a ZDHHC9‐associated intellectual disability to individuals with no known impairment. We characterised transient network dynamics using a Hidden Markov Model (HMM) on magnetoencephalography (MEG) data, at rest and during auditory oddball stimulation. The HMM is a data‐driven method that captures rapid patterns of coordinated brain activity recurring over time. Resting‐state network dynamics distinguished the groups, with ZDHHC9 participants showing longer state activation and, crucially, ZDHHC9 gene expression levels predicted the group differences in dynamic connectivity across networks. In contrast, network dynamics during auditory oddball stimulation did not show this association. We demonstrate a link between regional gene expression and brain network dynamics, and present the new application of a powerful method for understanding the neural mechanisms linking genetic variation to cognitive difficulties.

Previous studies have identified localized associations between childhood environment - namely their socio-economic status (SES) - and particular neural structures. The primary aim of the current study was to test whether associations between SES and brain structure are widespread or limited to specific neural pathways. We employed advances in whole-brain structural connectomics to address this. Diffusion tensor imaging was used to construct whole-brain connectomes in 113 6-12 year olds. We then applied an adapted multi-block partial-least squares (PLS) regression to explore how connectome organisation is associated with childhood SES (parental income, education levels, and neighbourhood deprivation). The Fractional Anisotropy (FA) connectome was significantly associated with childhood SES and this effect was widespread. We then pursued a secondary aim, and demonstrated that the connectome mediated the relationship between SES and cognitive ability (matrix reasoning and vocabulary). However, the connectome did not significantly mediate SES relationships with academic ability (maths and reading) or internalising and externalising behavior. This multivariate approach is important for advancing our theoretical understanding of how brain development may be shaped by childhood environment, and the role that it plays in predicting key outcomes. We also discuss the limitations with this new methodological approach.

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.