The enduring impact of childhood maltreatment on grey matter development

Childhood maltreatment doubles an individual’s risk of developing a psychiatric disorder, yet the neurobiological nature of the enduring impact of childhood maltreatment remains elusive. This thesis explores the long-term effect of childhood maltreatment on grey matter. The primary aims of this thesis are to discern the spatial extent, temporal profile and physiological breadth of the developmental impact of childhood maltreatment amongst young people with emerging mental disorder. Chapter II comprises of a meta-analysis of thirty-eight published articles and demonstrates that adults with a history of childhood maltreatment most commonly exhibit reduced grey matter in the hippocampus, amygdala and right dorsolateral prefrontal cortex, compared to non-maltreated adults. Chapters III-V contain three original studies, involving a cohort of 123 young people, aged 14-26, with emerging mental illness. Chapter III bridges a gap between cross-sectional child and adult studies by longitudinally mapping the developmental trajectory of the hippocampus and amygdala following childhood maltreatment. This study provided the first direct evidence that childhood maltreatment stunts hippocampal development into young adulthood. Chapter IV assesses the utility of the cumulative stress and mismatch hypotheses in understanding the contribution of childhood abuse and recent stress to the structure and function of the limbic system. Chapter V extends on recent advances in connectome research to examine the effect of childhood maltreatment on structural covariance networks. Investigation of the correspondence of structural covariance with structural connectivity and functional connectivity revealed that reduced grey matter across the network is likely related to deceased functional coactivation following childhood maltreatment. Chapter VI discusses the significance of these studies in understanding how maltreatment shapes brain development and increases the risk of psychiatric illness

BrainStat: A toolbox for brain-wide statistics and multimodal feature associations

Analysis and interpretation of neuroimaging datasets has become a multidisciplinary endeavor, relying not only on statistical methods, but increasingly on associations with respect to other brain-derived features such as gene expression, histological data, and functional as well as cognitive architectures. Here, we introduce BrainStat - a toolbox for (i) univariate and multivariate linear models in volumetric and surface-based brain imaging datasets, and (ii) multidomain feature association of results with respect to spatial maps of post-mortem gene expression and histology, task-based fMRI meta-analysis, as well as resting-state fMRI motifs across several common surface templates. The combination of statistics and feature associations into a turnkey toolbox streamlines analytical processes and accelerates cross-modal research. The toolbox is implemented in both Python and MATLAB, two widely used programming languages in the neuroimaging and neuroinformatics communities. BrainStat is openly available and complemented by an expandable documentation

Convergence of cortical types and functional motifs in the human mesiotemporal lobe

The mesiotemporal lobe (MTL) is implicated in many cognitive processes, is compromised in numerous brain disorders, and exhibits a gradual cytoarchitectural transition from six-layered parahippocampal isocortex to three-layered hippocampal allocortex. Leveraging an ultra-high-resolution histological reconstruction of a human brain, our study showed that the dominant axis of MTL cytoarchitectural differentiation follows the iso-to-allocortical transition and depth-specific variations in neuronal density. Projecting the histology-derived MTL model to in-vivo functional MRI, we furthermore determined how its cytoarchitecture underpins its intrinsic effective connectivity and association to large-scale networks. Here, the cytoarchitectural gradient was found to underpin intrinsic effective connectivity of the MTL, but patterns differed along the anterior-posterior axis. Moreover, while the iso-to-allocortical gradient parametrically represented the multiple-demand relative to task-negative networks, anterior-posterior gradients represented transmodal versus unimodal networks. Our findings establish that the combination of micro- and macrostructural features allow the MTL to represent dominant motifs of whole-brain functional organisation

Genetic and phylogenetic uncoupling of structure and function in human transmodal cortex

Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral flexibility. However, it remains unclear how a static, genetically controlled architecture supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and cognitive analyses to understand how the macroscale organization of structure-function coupling across the cortex can inform its role in cognition. In humans, structure-function coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-function uncoupling in macaques had a similar spatial distribution, but we observed an increased coupling between structure and function in association cortices relative to humans. Meta-analysis suggested regions with the least genetic control (low heritable correspondence and different across primates) are linked to social-cognition and autobiographical memory. Our findings suggest that genetic and evolutionary uncoupling of structure and function in different transmodal systems may support the emergence of complex forms of cognition

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals

A quantitative view of the transcriptome of Schistosoma mansoni adult-worms using SAGE

<p>Abstract</p> <p>Background</p> <p>Five species of the genus Schistosoma, a parasitic trematode flatworm, are causative agents of Schistosomiasis, a disease that is endemic in a large number of developing countries, affecting millions of patients around the world. By using SAGE (Serial Analysis of Gene Expression) we describe here the first large-scale quantitative analysis of the Schistosoma mansoni transcriptome, one of the most epidemiologically relevant species of this genus.</p> <p>Results</p> <p>After extracting mRNA from pooled male and female adult-worms, a SAGE library was constructed and sequenced, generating 68,238 tags that covered more than 6,000 genes expressed in this developmental stage. An analysis of the ordered tag-list shows the genes of F10 eggshell protein, pol-polyprotein, HSP86, 14-3-3 and a transcript yet to be identified to be the five top most abundant genes in pooled adult worms. Whereas only 8% of the 100 most abundant tags found in adult worms of S. mansoni could not be assigned to transcripts of this parasite, 46.9% of the total ditags could not be mapped, demonstrating that the 3 sequence of most of the rarest transcripts are still to be identified. Mapping of our SAGE tags to S. mansoni genes suggested the occurrence of alternative-polyadenylation in at least 13 gene transcripts. Most of these events seem to shorten the 3 UTR of the mRNAs, which may have consequences over their stability and regulation.</p> <p>Conclusion</p> <p>SAGE revealed the frequency of expression of the majority of the S. mansoni genes. Transcriptome data suggests that alternative polyadenylation is likely to be used in the control of mRNA stability in this organism. When transcriptome was compared with the proteomic data available, we observed a correlation of about 50%, suggesting that both transcriptional and post-transcriptional regulation are important for determining protein abundance in S. mansoni. The generation of SAGE tags from other life-cycle stages should contribute to reveal the dynamics of gene expression in this important parasite.</p

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While its neural substrates have been extensively investigated in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE, and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devise a multiscale approach to map brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems, and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE were broadly similar to those in TLE, but some patterns were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Functional abnormalities in FLE and TLE appeared overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies