Partial‐volume modeling reveals reduced gray matter in specific thalamic nuclei early in the time course of psychosis and chronic schizophrenia

The structural complexity of the thalamus, due to its mixed composition of gray and white matter, make it challenging to disjoint and quantify each tissue contribution to the thalamic anatomy. This work promotes the use of partial-volume-based over probabilistic-based tissue segmentation approaches to better capture thalamic gray matter differences between patients at different stages of psychosis (early and chronic) and healthy controls. The study was performed on a cohort of 23 patients with schizophrenia, 41 with early psychosis and 69 age and sex-matched healthy subjects. Six tissue segmentation approaches were employed to obtain the gray matter concentration/probability images. The statistical tests were applied at three different anatomical scales: whole thalamus, thalamic subregions and voxel-wise. The results suggest that the partial volume model estimation of gray matter is more sensitive to detect atrophies within the thalamus of patients with psychosis. However all the methods detected gray matter deficit in the pulvinar, particularly in early stages of psychosis. This study demonstrates also that the gray matter decrease varies nonlinearly with age and between nuclei. While a gray matter loss was found in the pulvinar of patients in both stages of psychosis, reduced gray matter in the mediodorsal was only observed in early psychosis subjects. Finally, our analyses point to alterations in a sub-region comprising the lateral posterior and ventral posterior nuclei. The obtained results reinforce the hypothesis that thalamic gray matter assessment is more reliable when the tissues segmentation method takes into account the partial volume effect

Motor and higher‐order functions topography of the human dentate nuclei identified with tractography and clustering methods

Deep gray matter nuclei are the synaptic relays, responsible to route signals between specific brain areas. Dentate nuclei (DNs) represent the main output channel of the cerebellum and yet are often unexplored especially in humans. We developed a multimodal MRI approach to identify DNs topography on the basis of their connectivity as well as their microstructural features. Based on results, we defined DN parcellations deputed to motor and to higher-order functions in humans in vivo. Whole-brain probabilistic tractography was performed on 25 healthy subjects from the Human Connectome Project to infer DN parcellations based on their connectivity with either the cerebral or the cerebellar cortex, in turn. A third DN atlas was created inputting microstructural diffusion-derived metrics in an unsupervised fuzzy c-means classification algorithm. All analyses were performed in native space, with probability atlas maps generated in standard space. Cerebellar lobule-specific connectivity identified one motor parcellation, accounting for about 30% of the DN volume, and two non-motor parcellations, one cognitive and one sensory, which occupied the remaining volume. The other two approaches provided overlapping results in terms of geometrical distribution with those identified with cerebellar lobule-specific connectivity, although with some differences in volumes. A gender effect was observed with respect to motor areas and higher-order function representations. This is the first study that indicates that more than half of the DN volumes is involved in non-motor functions and that connectivity-based and microstructure-based atlases provide complementary information. These results represent a step-ahead for the interpretation of pathological conditions involving cerebro-cerebellar circuits

Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas

The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing segmentation of 25 thalamic labels per hemisphere informed by both modalities. We present an improved probabilistic atlas, incorporating thalamic nuclei identified from histology and 45 white matter tracts surrounding the thalamus identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclear groups versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer’s disease (AUROC 81.98%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer

Multimodal MRI analysis using deep learning methods

Magnetic resonance imaging (MRI) has been widely used in scientific and clinical research. It is a non-invasive medical imaging technique that reveals anatomical structures and provides useful information for investigators to explore aging and pathological processes. Different MR modalities offer different useful properties. Automatic MRI analysis algorithms have been developed to address problems in many applications such as classification, segmentation, and disease diagnosis. Segmentation and labeling algorithms applied to brain MRIs enable evaluations of the volumetric changes of specific structures in neurodegenerative diseases. Reconstruction of fiber orientations using diffusion MRI is beneficial to obtain better understanding of the underlying structures. In this thesis, we focused on development of deep learning methods for MRI analysis using different image modalities. Specifically, we applied deep learning techniques on different applications, including segmentation of brain structures and reconstruction of tongue muscle fiber orientations. For segmentation of brain structures, we developed an end-to-end deep learning algorithm for ventricle parcellation of brains with ventriculomegaly using T1-w MR images. The deep network provides robust and accurate segmentation results in subjects with high variability in ventricle shapes and sizes. We developed another deep learning method to automatically parcellate the thalamus into a set of thalamic nuclei using T1-w MRI and features from diffusion MRI. The algorithm incorporates a harmonization step to make the network adapt to input images with different contrasts. We also studied the strains associated with tongue muscles during speech production using multiple MRI modalities. To enable this study, we first developed a deep network to reconstruct crossing tongue muscle fiber orientations using diffusion MRI. The network was specifically designed for the human tongue and accounted for the orthogonality property of the tongue muscles. Next, we proposed a comprehensive pipeline to analyze the strains associated with tongue muscle fiber orientations during speech using diffusion MRI, and tagged and cine MRI. The proposed pipeline provides a solution to analyze the cooperation between muscle groups during speech production

The Neural Correlates of Visual Hallucinations in Parkinson's Disease

Visual hallucinations are common in Parkinson’s disease (PD) and linked to worse outcomes: increased mortality, higher carer burden, cognitive decline, and worse quality of life. Recent functional studies have aided our understanding, showing large-scale brain network imbalance in PD hallucinations. Imbalance of different influences on visual perception also occurs, with impaired accumulation of feedforward signals from the eyes and visual parts of the brain. Whether feedback signals from higher brain control centres are also affected is unknown and the mechanisms driving network imbalance in PD hallucinations remain unclear. In this thesis I will clarify the computational and structural changes underlying PD hallucinations and link these to functional abnormalities and regional changes at the cellular level. To achieve this, I will employ behavioural testing, diffusion weighted imaging, structural and functional MRI in PD patients with and without hallucinations. I will quantify the use of prior knowledge during a visual learning task and show that PD with hallucinations over-rely on feedback signals. I will examine underlying structural connectivity changes at baseline and longitudinally and will show that posterior thalamic connections are affected early, with frontal connections remaining relatively preserved. I will show that PD hallucinations are associated with a subnetwork of reduced structural connectivity strength, affecting areas crucial for switching the brain between functional states. I will assess the role of the thalamus as a potential driver of network-level changes and show preferential medial thalamus involvement. I will utilise data from the Allen Institute transcription atlas and show how differences in regional gene expression in health contributes to the selective vulnerability of specific white matter connections in PD hallucinations. These findings reveal the structural correlates of visual hallucinations in PD, link these to functional and behavioural changes and provide insights into the cellular mechanisms that drive regional vulnerability, ultimately leading to hallucinations

Examining the development of brain structure in utero with fetal MRI, acquired as part of the Developing Human Connectome Project

The human brain is an incredibly complex organ, and the study of it traverses many scales across space and time. The development of the brain is a protracted process that begins embryonically but continues into adulthood. Although neural circuits have the capacity to adapt and are modulated throughout life, the major structural foundations are laid in utero during the fetal period, through a series of rapid but precisely timed, dynamic processes. These include neuronal proliferation, migration, differentiation, axonal pathfinding, and myelination, to name a few. The fetal origins of disease hypothesis proposed that a variety of non-communicable diseases emerging in childhood and adulthood could be traced back to a series of risk factors effecting neurodevelopment in utero (Barker 1995). Since this publication, many studies have shown that the structural scaffolding of the brain is vulnerable to external environmental influences and the perinatal developmental window is a crucial determinant of neurological health later in life. However, there remain many fundamental gaps in our understanding of it. The study of human brain development is riddled with biophysical, ethical, and technical challenges. The Developing Human Connectome Project (dHCP) was designed to tackle these specific challenges and produce high quality open-access perinatal MRI data, to enable researchers to investigate normal and abnormal neurodevelopment (Edwards et al., 2022). This thesis will focus on investigating the diffusion-weighted and anatomical (T2) imaging data acquired in the fetal period, between the second to third trimester (22 – 37 gestational weeks). The limitations of fetal MR data are ill-defined due to a lack of literature and therefore this thesis aims to explore the data through a series of critical and strategic analysis approaches that are mindful of the biophysical challenges associated with fetal imaging. A variety of analysis approaches are optimised to quantify structural brain development in utero, exploring avenues to relate the changes in MR signal to possible neurobiological correlates. In doing so, the work in this thesis aims to improve mechanistic understanding about how the human brain develops in utero, providing the clinical and medical imaging community with a normative reference point. To this aim, this thesis investigates fetal neurodevelopment with advanced in utero MRI methods, with a particular emphasis on diffusion MRI. Initially, the first chapter outlines a descriptive, average trajectory of diffusion metrics in different white matter fiber bundles across the second to third trimester. This work identified unique polynomial trajectories in diffusion metrics that characterise white matter development (Wilson et al., 2021). Guided by previous literature on the sensitivity of DWI to cellular processes, I formulated a hypothesis about the biophysical correlates of diffusion signal components that might underpin this trend in transitioning microstructure. This hypothesis accounted for the high sensitivity of the diffusion signal to a multitude of simultaneously occurring processes, such as the dissipating radial glial scaffold, commencement of pre-myelination and arborization of dendritic trees. In the next chapter, the methods were adapted to address this hypothesis by introducing another dimension, and charting changes in diffusion properties along developing fiber pathways. With this approach it was possible to identify compartment-specific microstructural maturation, refining the spatial and temporal specificity (Wilson et al., 2023). The results reveal that the dynamic fluctuations in the components of the diffusion signal correlate with observations from previous histological work. Overall, this work allowed me to consolidate my interpretation of the changing diffusion signal from the first chapter. It also serves to improve understanding about how diffusion signal properties are affected by processes in transient compartments of the fetal brain. The third chapter of this thesis addresses the hypothesis that cortical gyrification is influenced by both underlying fiber connectivity and cytoarchitecture. Using the same fetal imaging dataset, I analyse the tissue microstructural change underlying the formation of cortical folds. I investigate correlations between macrostructural surface features (curvature, sulcal depth) and tissue microstructural measures (diffusion tensor metrics, and multi-shell multi-tissue decomposition) in the subplate and cortical plate across gestational age, exploring this relationship both at the population level and within subjects. This study provides empirical evidence to support the hypotheses that microstructural properties in the subplate and cortical plate are altered with the development of sulci. The final chapter explores the data without anatomical priors, using a data-driven method to extract components that represent coordinated structural maturation. This analysis aims to examine if brain regions with coherent patterns of growth over the fetal period converge on neonatal functional networks. I extract spatially independent features from the anatomical imaging data and quantify the spatial overlap with pre-defined neonatal resting state networks. I hypothesised that coherent spatial patterns of anatomical development over the fetal period would map onto the functional networks observed in the neonatal period. Overall, this thesis provides new insight about the developmental contrast over the second to third trimester of human development, and the biophysical correlates affecting T2 and diffusion MR signal. The results highlight the utility of fetal MRI to research critical mechanisms of structural brain maturation in utero, including white matter development and cortical gyrification, bridging scales from neurobiological processes to whole brain macrostructure. their gendered constructions relating to women