Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester

Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this illness. Anatomical MRI scans from 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth of five major invariable primary sulci representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing the distinct developmental periods. A repeated-measure ANOVA with five sulci and two hemispheres as the within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134] = 14.8, p = 0.0002). Control subjects had deeper bilateral superior temporal, right inferior frontal and left calcarine sulci. A deeper superior frontal sulcus predicted better cognitive scores among patients. Our results suggest that the gestational disruption underlying schizophrenia is likely to predate, if not coincide with the appearance of calcarine sulcus (early second trimester). Nevertheless, the burden of cognitive deficits may relate specifically to the aberrant superior frontal development apparent in late second trimester

Neurobiological mechanisms of hallucinations in schizophrenia

All perception is a construct of the brain. Yet occasionally, sensory constructions emerge without origin in the physical world and are experienced as hallucinations. Hallucinations occur transdiagnostically, cross-culturally, and in all sensory modalities. They are common in people with schizophrenia, presenting in 60-80% of patients. Despite over 20 years of active neuroimaging research on hallucinations, the neural systems supporting these anomalous perceptual experiences remain disputed. This dissertation investigates the neurobiology of hallucinations, integrating research across structural and functional magnetic resonance imaging (MRI) to elucidate how hallucinations, chiefly in the context of schizophrenia, are supported by the brain, drawing on MRI indices of neurodevelopment. I introduce the phenomenon of hallucinations and motivate the utility of MRI for studying hallucinations. Considering their prevalence in other medical conditions, I conduct a meta-analysis and systematic review of the structural brain basis of hallucinations across diagnoses, primarily schizophrenia spectrum disorders and Parkinson’s disease. This illustrated distinct neuroanatomical organizations of grey matter associated with hallucinations that occur in neurodevelopmental compared to neurodegenerative disorders, which I hypothesise constitute at least two distinct mechanisms. Focussing on the neurodevelopmental mechanism characterized by fronto-temporal and insular grey matter reductions, I turn to the contribution of cortical sulcation, a product of second and third trimester neurodevelopmental processes, which has been robustly implicated in schizophrenia pathology, and, more recently, in hallucinations. Sulcal patterns derived from structural MRI provide a proxy in adulthood for early brain development. I studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MRI from the United Kingdom and Shanghai, China, stratified into those with and without hallucinations, and healthy controls from Shanghai. I first replicate the finding that left hemisphere paracingulate sulcus (PCS) length is reduced in patients who experience hallucinations, then demonstrate similar associations for superior temporal sulcus depth. Length and depth alterations occurred with focal deviations in sulcal geometry. The interindividual and interhemispheric variability of the PCS necessitated the development of semi-automated methods to characterize its morphology and validation to a manual protocol. I used structural covariance networks of the local gyrification index to investigate how specific sulcal deviations relate to global neurodevelopmental coordination, demonstrating that hallucinations correspond to increased covariance within and between salience and auditory networks. Hypothesizing structure-function relationships, I analyse resting-state functional MRI data from the same datasets described, finding significant interactions between PCS length and hallucinations status, but no main effects. There were no effects of hallucination status on salience and auditory network connectivity or in graph theoretical measures of connectivity, suggesting that resting-state connectivity is not a trait marker for hallucinations. Together, the discovery of neurodevelopmental alterations contributing to hallucinations provides mechanistic insight into the pathological consequences of prenatal origins. The interaction of sulcal alterations and hallucination status are associated with connectivity, which may have a role in the pathophysiology of hallucinations. I provide clear predictions and recommendations for future research.Gates Cambridge Scholarshi

Cognitive and Neurophysiological Models of Brain Asymmetry

Asymmetry is an inherent characteristic of brain organization in both humans and other vertebrate species, and is evident at the behavioral, neurophysiological, and structural levels. Brain asymmetry underlies the organization of several cognitive systems, such as emotion, communication, and spatial processing. Despite this ubiquity of asymmetries in the vertebrate brain, we are only beginning to understand the complex neuronal mechanisms underlying the interaction between hemispheric asymmetries and cognitive systems. Unfortunately, despite the vast number of empirical studies on brain asymmetries, theoretical models that aim to provide mechanistic explanations of hemispheric asymmetries are sparse in the field. Therefore, this Special Issue aims to highlight empirically based mechanistic models of brain asymmetry. Overall, six theoretical and four empirical articles were published in the Special Issue, covering a wide range of topics, from human handedness to auditory laterality in bats. Two key challenges for theoretical models of brain asymmetry are the integration of increasingly complex molecular data into testable models, and the creation of theoretical models that are robust and testable across different species

Early and Late Stage Mechanisms for Vocalization Processing in the Human Auditory System

The human auditory system is able to rapidly process incoming acoustic information, actively filtering, categorizing, or suppressing different elements of the incoming acoustic stream. Vocalizations produced by other humans (conspecifics) likely represent the most ethologically-relevant sounds encountered by hearing individuals. Subtle acoustic characteristics of these vocalizations aid in determining the identity, emotional state, health, intent, etc. of the producer. The ability to assess vocalizations is likely subserved by a specialized network of structures and functional connections that are optimized for this stimulus class. Early elements of this network would show sensitivity to the most basic acoustic features of these sounds; later elements may show categorically-selective response patterns that represent high-level semantic organization of different classes of vocalizations. A combination of functional magnetic resonance imaging and electrophysiological studies were performed to investigate and describe some of the earlier and later stage mechanisms of conspecific vocalization processing in human auditory cortices. Using fMRI, cortical representations of harmonic signal content were found along the middle superior temporal gyri between primary auditory cortices along Heschl\u27s gyri and the superior temporal sulci, higher-order auditory regions. Additionally, electrophysiological findings also demonstrated a parametric response profile to harmonic signal content. Utilizing a novel class of vocalizations, human-mimicked versions of animal vocalizations, we demonstrated the presence of a left-lateralized cortical vocalization processing hierarchy to conspecific vocalizations, contrary to previous findings describing similar bilateral networks. This hierarchy originated near primary auditory cortices and was further supported by auditory evoked potential data that suggests differential temporal processing dynamics of conspecific human vocalizations versus those produced by other species. Taken together, these results suggest that there are auditory cortical networks that are highly optimized for processing utterances produced by the human vocal tract. Understanding the function and structure of these networks will be critical for advancing the development of novel communicative therapies and the design of future assistive hearing devices

Computational Unfolding of the Human Hippocampus

The hippocampal subfields are defined by their unique cytoarchitectures, which many recent studies have tried to map to human in-vivo MRI because of their promise to further our understanding of hippocampal function, or its dysfunction in disease. However, recent anatomical literature has highlighted broad inter-individual variability in hippocampal morphology and subfield locations, much of which can be attributed to different folding configurations within hippocampal (or archicortical) tissue. Inspired in part by analogous surface-based neocortical analysis methods, the current thesis aimed to develop a standardized coordinate framework, or surface-based method, that respects the topology of all hippocampal folding configurations. I developed such a coordinate framework in Chapter 2, which was initialized by detailed manual segmentations of hippocampal grey matter and high myelin laminae which are visible in 7-Tesla MRI and which separate different hippocampal folds. This framework was leveraged to i) computationally unfold the hippocampus which provided implicit topological inter-individual alignment, ii) delineate subfields with high reliability and validity, and iii) extract novel structural features of hippocampal grey matter. In Chapter 3, I applied this coordinate framework to the open source BigBrain 3D histology dataset. With this framework, I computationally extracted morphological and laminar features and showed that they are sufficient to derive hippocampal subfields in a data-driven manner. This underscores the sensitivity of these computational measures and the validity of the applied subfield definitions. Finally, the unfolding coordinate framework developed in Chapter 2 and extended in Chapter 3 requires manual detection of different tissue classes that separate folds in hippocampal grey matter. This is costly in the time and the expertise required. Thus, in Chapter 4, I applied state-of-the-art deep learning methods in the open source Human Connectome Project MRI dataset to automate this process. This allowed for scalable application of the methods described in Chapters 2, 3, and 4 to similar new datasets, with support for extensions to suit data of different modalities or resolutions. Overall, the projects presented here provide multifaceted evidence for the strengths of a surface-based approach to hippocampal analysis as developed in this thesis, and these methods are readily deployable in new neuroimaging work

Taxonomic Tapestries: The Threads of Evolutionary, Behavioural and Conservation Research

This volume explores the complexity, diversity and interwoven nature of taxonomic pursuits within the context of explorations of humans and related species. It also pays tribute to Professor Colin Groves, whose work has had an enormous impact on this field. Recent research into that somewhat unique species we call humankind, through the theoretical and conceptual approaches afforded by the discipline of biological anthropology, is showcased. The focus is on the evolution of the human species, the behaviour of primates and other species, and how humans affect the distribution and abundance of other species through anthropogenic impact. Weaving together these three key themes, through the considerable influence of Colin Groves, provides glimpses of how changes in taxonomic theory and methodology, including our fluctuating understanding of speciation, have recrafted the way in which we view animal behaviour, human evolution and conservation studies

Taxonomic Tapestries: The Threads of Evolutionary, Behavioural and Conservation Research

This volume explores the complexity, diversity and interwoven nature of taxonomic pursuits within the context of explorations of humans and related species. It also pays tribute to Professor Colin Groves, whose work has had an enormous impact on this field. Recent research into that somewhat unique species we call humankind, through the theoretical and conceptual approaches afforded by the discipline of biological anthropology, is showcased. The focus is on the evolution of the human species, the behaviour of primates and other species, and how humans affect the distribution and abundance of other species through anthropogenic impact. Weaving together these three key themes, through the considerable influence of Colin Groves, provides glimpses of how changes in taxonomic theory and methodology, including our fluctuating understanding of speciation, have recrafted the way in which we view animal behaviour, human evolution and conservation studies