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Effects of hormones, genetics, and sex on typical and atypical brain organization



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Bethlehem, Richard Alexander Ingmar  ORCID logo


The first part of this thesis discusses developmental influences on the human connectome in relation to autism and attention deficit hyperactivity disorder (ADHD), conditions associated with alterations in brain connectivity and marked by social impairments. It reports an experiment investigating whether the connectomes of individuals with autism or ADHD differ from the connectome of neurotypical individuals, and what the underlying genetic basis could be for any differences in neural architecture. Chapter 2 reports an analysis of networks in children with autism or ADHD, using structural covariance magnetic resonance imaging (scMRI). We found overlapping as well as distinct network features across both conditions. Chapter 3 reports an analysis of how gene expression might be associated with the basic building blocs of these structural covariance networks. We found that synaptic and transcriptionally downregulated genes were replicably associated with cortical thickness differences in children with autism, but not in children with ADHD.

In addition, the first part also aims to elucidate the potential modulation effects of sex on autism neurobiology. Chapter 4 reports an analysis of structural covariance networks in male and female adults with and without autism. We found that biological sex is a modulator of neurobiological heterogeneity in autism. Chapter 5 reports pilot data aiming to identify an electrophysiological signature of these network properties using electroencephalography (EEG). We find little evidence for theories about network asymmetry, but indications of altered frontal network integration. The second part of the thesis examines the acute effects of hormones on brain connectomics. Hormones are an integral part of the mechanism of social behaviour. In a series of hormone administration studies, we report experiments to test the acute effects of steroid and peptide hormones on brain functional connectivity (Chapters 6 and 7). Chapter 6 reports an oxytocin administration study that used a novel data-driven approach to assess resting-state fMRI connectivity in women. Although the number of fMRI studies on oxytocin have increased over past years, little is known about its effect on women. We found that oxytocin robustly enhances cortico-subcortical connectivity, and that this effect positively correlates with autistic traits. This is interesting given that oxytocin has been proposed as a potential therapeutic in autism. Chapter 7 reports an experiment testing if testosterone modulates connectivity in a specific social environment (a fear response). This was confirmed during the social task, but not during baseline resting-state, highlighting the role of testosterone in functional connectivity in this specific context.

Chapter 8 is the concluding chapter that integrates all the empirical findings in the thesis. We discuss their implications for our understanding of autism and ADHD, and of the role of steroid and peptide hormones in the typically and atypically developing connectome. Chapter 8 also reflects on the limitations of the experiments reported, and sets out future directions for research in this area.




Baron-Cohen, Simon


Autism, Neuroimaging, Genetics, Hormones


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Medical Research Council, Autism Research Trust, Pinsent Darwin Trust, Cambridge Trust