Biology subjects

Monaghan, A.

Publications and source records attributed to Monaghan, A..

6 recordsLinked to original sources

bioRxiv2026

Integrating Functional Transdiagnostic Dimensions of Psychopathology with Cortical Organization

Childhood and adolescence represent a critical period in which neurodevelopmental psychiatric conditions emerge; traditional case-control approaches often underestimate the complexity and co-occurrence of psychiatric conditions, calling for a transdiagnostic approach as a complementary measure. Open-access data sharing initiatives provide an opportunity to decipher structural- and functional-based organisational constraints on the relationship between brain connectivity and psychopathology. Using a highly heterogenous and comorbid neurodevelopmental sample of children and adolescents aged between 6 and 17 years old at-risk of neurodevelopmental conditions (N = 174, 114 males, mean age 10.72 {+/-} 2.21 years), and age-matched neurotypical controls (N = 27, 12 males, mean age 10.65 {+/-} 2.07 years), we identified a multivariate association, or latent variable, between resting-state functional connectivity and psychopathology. We extensively benchmarked this latent construct to develop a more parsimonious account of childhood psychopathology though an analytical framework spanning biological maps, brain connectivity, and behaviour. Participant-level expression of this latent brain-behaviour association differed by diagnostic burden and symptomatology, and pre-empted longitudinal psychopathology. Whilst diagnostic status was useful for interpretation, the latent construct transcended traditional diagnostic borders, revealing a neurotypical-neurodivergent continuum. The relationship between functional connectivity and neurodevelopmental psychopathology was circumscribed by functional connectivity networks (visual, fronto-parietal, and dorsal attention) and cytoarchitectonic class (primary/secondary sensory and primary sensory cortices). The latent variable aligned with magnetoencephalography-defined electrophysiological alpha (), high-gamma ({gamma}), and theta ({theta}) frequency bands, and was enriched across cortical distributions of astrocytes and excitatory neurones. The connectivity signature was significantly aligned with the archetypal sensorimotor-to-association axis and validated in an independent sample of pre-adolescents (N = 3504), with the strongest alignment with the principal component of gene expression and myelination and were relatively less enriched in cortical regions related to language, indicating a protective effect, and more positively enriched in regions related to executive functioning, conferring greater risk of psychopathology. Together, our findings suggest that the predictive link between functional connectivity and common symptoms of neurodevelopmental psychopathology are circumscribed by underlying macroscale anatomical, functional, and cognitive-related hierarchies.

neuroscience↗

bioRxiv2024

Canonical neurodevelopmental trajectories of structural and functional manifolds

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N = 390 with one observation, N = 163 with two observations, and N = 57 with three) and functional (512 participants, N = 340 with one observation, N = 128 with two observations, and N = 44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients exhibit sensitive periods and are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, such as working memory, are robust predictors of coupling. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These gradients are established early in life, refined through development, and their coupling is predicted by working memory.

neuroscience↗

bioRxiv2023

Population-level genetic variation shapes generative brain mechanisms

The structural organisation of the human brain emerges probabilistically as we develop. Due to the inherent complexity of the human brain, understanding the forces that shape this probabilistic emergence remains one of the central challenges of systems theory and neuroscience. Across 2153 children (9-11 years old) we used a computational model to simulate the formation of structural brain connectivity, conceptualised as a trade-off between the cost of new connections {eta} and their topological value {gamma}. We then triangulated this population-level neuroimaging and computational modelling with genomics. For each participant we assessed their genetic propensity for cognitive ability by calculating polygenic scores. Modelled parameters differed systematically for participants depending upon their genetic propensity. Those with the highest genetic propensity had a significantly weaker {eta} term - put simply, their networks emerged with a weaker distance penalty. Strikingly, this softer distance penalty produces more stochastic, diverse, and efficient networks. Furthermore, across the sample, overlapping biological and cellular pathways between polygenic scores and each childs optimal {eta}-{gamma} trade-off emerged. This application of computational modelling demonstrates a converging genomic basis for structural brain development and cognitive ability across the population, providing a mechanistic explanation of how and why characteristic network topologies emerge from children at the extreme distributions of polygenic scores, and why they might predict cognitive ability.

neuroscience↗

bioRxiv2020

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at Chr16q11.2 and on the MAPT H1 allele.

Parkinsons disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. We show that KAT8 and KANSL1 modulate PINK1 gene expression and subsequent PINK1-mitophagy. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data does not exclude a possible association between the MAPT gene and PD, it provides strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

neuroscience↗

bioRxiv2019

Intersecting vulnerabilities: Climatic and demographic contributions to future population exposure to Aedes-borne viruses in the United States

Understanding how climate change and demographic factors may shape future population exposure to viruses such as Zika, dengue, or chikungunya, transmitted by Aedes mosquitoes is essential to improving public health preparedness. In this study, we combine projections of cumulative monthly Aedes-borne virus transmission risk with spatially explicit population projections for vulnerable demographic groups (age and economic factors) to explore future county-level population exposure across the conterminous United States. We employ a scenario matrix - combinations of climate and socioeconomic scenarios (Representative Concentration Pathways and Shared Socioeconomic Pathways) - to assess the full range of uncertainty in emissions, socioeconomic development, and demographic change. Human exposure is projected to increase under most scenarios, up to +177% at the national scale in 2080 relative to 2010. Projected exposure changes are predominantly driven by population changes in vulnerable demographic groups, although climate change is also important, particularly in the western region where future exposure may decrease by >30% under the strongest climate change mitigation scenario. The results emphasize the crucial role that socioeconomic and demographic change play in shaping future population vulnerability and exposure to Aedes-borne virus transmission risk in the United States, and underscore the importance of including socioeconomic scenarios in projections of climate-related vector-borne disease impacts.

ecology↗

bioRxiv2017

Preliminary results of models to predict areas in the Americas with increased likelihood of Zika virus transmission in 2017.

Numerous Zika virus vaccines are being developed. However, identifying sites to evaluate the efficacy of a Zika virus vaccine is challenging due to the general decrease in Zika virus activity. We compare results from three different modeling approaches to estimate areas that may have increased relative risk of Zika virus transmission during 2017. The analysis focused on eight priority countries (i.e., Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Panama, and Peru). The models projected low incidence rates during 2017 for all locations in the priority countries but identified several subnational areas that may have increased relative risk of Zika virus transmission in 2017. Given the projected low incidence of disease, the total number of participants, number of study sites, or duration of study follow-up may need to be increased to meet the efficacy study endpoints.

epidemiology↗