32 research outputs found
Characterising population variability in brain structure through models of whole-brain structural connectivity
Models of whole-brain connectivity are valuable for understanding neurological function. This thesis
seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically
acquired diffusion data. We propose new approaches for studying these models. The aim is to
develop techniques which can take models of brain connectivity and use them to identify biomarkers
or phenotypes of disease.
The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified
to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections
are traced between 77 regions of interest, automatically extracted by label propagation from
multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract
are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data.
These are compared in subsequent studies.
To date, most whole-brain connectivity studies have characterised population differences using graph
theory techniques. However these can be limited in their ability to pinpoint the locations of differences
in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include
a spectral clustering approach for comparing population differences in the clustering properties of
weighted brain networks. In addition, machine learning approaches are suggested for the first time.
These are particularly advantageous as they allow classification of subjects and extraction of features
which best represent the differences between groups.
One limitation of the proposed approach is that errors propagate from segmentation and registration
steps prior to tractography. This can cumulate in the assignment of false positive connections, where
the contribution of these factors may vary across populations, causing the appearance of population
differences where there are none. The final contribution of this thesis is therefore to develop a common
co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject
into a single probabilistic model of diffusion for the population. This allows tractography to be
performed only once, ensuring that there is one model of connectivity. Cross-subject differences can
then be identified by mapping individual subjects’ anisotropy data to this model. The approach is
used to compare populations separated by age and gender
Quantification of cortical folding using MR image data
The cerebral cortex is a thin layer of tissue lining the brain where neural circuits perform important high level functions including sensory perception, motor control and language processing. In the third trimester the fetal cortex folds rapidly from a smooth sheet into a highly convoluted arrangement of gyri and sulci. Premature birth is a high risk factor for poor neurodevelopmental outcome and has been associated with abnormal cortical development, however the nature of the disruption to developmental processes is not fully understood. Recent developments in magnetic resonance imaging have allowed the acquisition of high quality brain images of preterms and also fetuses in-utero. The aim of this thesis is to develop techniques which quantify folding from these images in order to better understand cortical development in these two populations. A framework is presented that quantifies global and regional folding using curvature-based measures. This methodology was applied to fetuses over a wide gestational age range (21.7 to 38.9 weeks) for a large number of subjects (N = 80) extending our understanding of how the cortex folds through this critical developmental period. The changing relationship between the folding measures and gestational age was modelled with a Gompertz function which allowed an accurate prediction of physiological age. A spectral-based method is outlined for constructing a spatio-temporal surface atlas (a sequence of mean cortical surface meshes for weekly intervals). A key advantage of this method is the ability to do group-wise atlasing without bias to the anatomy of an initial reference subject. Mean surface templates were constructed for both fetuses and preterms allowing a preliminary comparison of mean cortical shape over the postmenstrual age range 28-36 weeks. Displacement patterns were revealed which intensified with increasing prematurity, however more work is needed to evaluate the reliability of these findings.Open Acces
Construction and validation of a database of head models for functional imaging of the neonatal brain
The neonatal brain undergoes dramatic structural and functional changes over the last trimester of gestation. The accuracy of source localisation of brain activity recorded from the scalp therefore relies on accurate age-specific head models. Although an age-appropriate population-level atlas could be used, detail is lost in the construction of such atlases, in particular with regard to the smoothing of the cortical surface, and so such a model is not representative of anatomy at an individual level. In this work, we describe the construction of a database of individual structural priors of the neonatal head using 215 individual-level datasets at ages 29-44 weeks postmenstrual age from the Developing Human Connectome Project. We have validated a method to segment the extra-cerebral tissue against manual segmentation. We have also conducted a leave-one-out analysis to quantify the expected spatial error incurred with regard to localising functional activation when using a best-matching individual from the database in place of a subject-specific model; the median error was calculated to be 8.3 mm (median absolute deviation 3.8 mm). The database can be applied for any functional neuroimaging modality which requires structural data whereby the physical parameters associated with that modality vary with tissue type and is freely available at www.ucl.ac.uk/dot-hub
Functional network correlates of language and semiology in epilepsy
Epilepsy surgery is appropriate for 2-3% of all epilepsy diagnoses. The goal of the presurgical workup is to delineate the seizure network and to identify the risks associated with surgery. While interpretation of functional MRI and results in EEG-fMRI studies have largely focused on anatomical parameters, the focus of this thesis was to investigate canonical intrinsic connectivity networks in language function and seizure semiology. Epilepsy surgery aims to remove brain areas that generate seizures. Language dysfunction is frequently observed after anterior temporal lobe resection (ATLR), and the presurgical workup seeks to identify the risks associated with surgical outcome. The principal aim of experimental studies was to elaborate understanding of language function as expressed in the recruitment of relevant connectivity networks and to evaluate whether it has value in the prediction of language decline after anterior temporal lobe resection. Using cognitive fMRI, we assessed brain areas defined by parameters of anatomy and canonical intrinsic connectivity networks (ICN) that are involved in language function, specifically word retrieval as expressed in naming and fluency. fMRI data was quantified by lateralisation indices and by ICN_atlas metrics in a priori defined ICN and anatomical regions of interest. Reliability of language ICN recruitment was studied in 59 patients and 30 healthy controls who were included in our language experiments. New and established language fMRI paradigms were employed on a three Tesla scanner, while intellectual ability, language performance and emotional status were established for all subjects with standard psychometric assessment. Patients who had surgery were reinvestigated at an early postoperative stage of four months after anterior temporal lobe resection. A major part of the work sought to elucidate the association between fMRI patterns and disease characteristics including features of anxiety and depression, and prediction of postoperative language outcome. We studied the efficiency of reorganisation of language function associated with disease features prior to and following surgery. A further aim of experimental work was to use EEG-fMRI data to investigate the relationship between canonical intrinsic connectivity networks and seizure semiology, potentially providing an avenue for characterising the seizure network in the presurgical workup. The association of clinical signs with the EEG-fMRI informed activation patterns were studied using the data from eighteen patients’ whose seizures and simultaneous EEG-fMRI activations were reported in a previous study.
The accuracy of ICN_atlas was validated and the ICN construct upheld in the language maps of TLE patients. The ICN construct was not evident in ictal fMRI maps and simulated ICN_atlas data. Intrinsic connectivity network recruitment was stable between sessions in controls. Amodal linguistic processing and the relevance of temporal intrinsic connectivity networks for naming and that of frontal intrinsic connectivity networks for word retrieval in the context of fluency was evident in intrinsic connectivity networks regions. The relevance of intrinsic connectivity networks in the study of language was further reiterated by significant association between some disease features and language performance, and disease features and activation in intrinsic connectivity networks. However, the anterior temporal lobe (ATL) showed significantly greater activation compared to intrinsic connectivity networks – a result which indicated that ATL functional language networks are better studied in the context of the anatomically demarked ATL, rather than its functionally connected intrinsic connectivity networks. Activation in temporal lobe networks served as a predictor for naming and fluency impairment after ATLR and an increasing likelihood of significant decline with greater magnitude of left lateralisation.
Impairment of awareness served as a significant classifying feature of clinical expression and was significantly associated with the inhibition of normal brain functions. Canonical intrinsic connectivity networks including the default mode network were recruited along an anterior-posterior anatomical axis and were not significantly associated with clinical signs
High-throughput transgenic mouse phenotyping using microscopic-MRI
With the completion of the human genome sequence in 2003, efforts have shifted towards elucidating gene function. Such phenotypic investigations are aided by advances in techniques for genetic modification of mice, with whom we share ~99% of genes. Mice are key models for both examination of basic gene function and translational study of human conditions. Furthering these efforts, ambitious programmes are underway to produce knockout mice for the ~25,000 mouse genes. In the coming years, methods to rapidly phenotype mouse morphology will be in great demand. This thesis demonstrates the development of non-invasive microscopic magnetic resonance imaging (\muMRI) methods for high-resolution ex-vivo phenotyping of mouse embryo and mouse brain morphology. It then goes on to show the application of computational atlasing techniques to these datasets, enabling automated analysis of phenotype. First, the issue of image quality in high-throughput embryo MRI was addressed. After investigating preparation and imaging parameters, substantial gains in signal- and contrast-to-noise were achieved. This protocol was applied to a study of Chd7+/- mice (a model of CHARGE syndrome), identifying cardiac defects. Combining this protocol with automated segmentation-propagation techniques, phenotypic differences were shown between three groups of mice in a volumetric analysis involving a number of organ systems. Focussing on the mouse brain, the optimal preparation and imaging parameters to maximise image quality and structural contrast were investigated, producing a high-resolution in-skull imaging protocol. Enhanced delineation of hippocampal and cerebellar structures was observed, correlating well to detailed histological comparisons. Subsequently this protocol was applied to a phenotypic investigation of the Tc1 model of Down syndrome. Using both visual inspection and automated, tensor based morphometry, novel phenotypic findings were identified in brain and inner ear structures. It is hoped that a combination of \muMRI with computational analysis techniques, as presented in this work, may help ease the burden of current phenotyping efforts
In-vivo digital volume correlation via magnetic resonance imaging: Application to positional brain shift and deep tissue injury
This thesis aims to investigate the complexity of the physiological mechanical response
of soft tissues, providing rich datasets for the verification of clinical systems limiting or
preventing tissue injury. A thorough understanding of the sagging of the brain tissue
under the effect of gravity (positional brain shift, PBS) is paramount for the design of
an effective intra-operative correction of surgical trajectories; rich measurements of the
response of the buttock to sitting loads can help the verification of computational models
to couple with clinical measures for the prevention and control of pressure ulcers.
Digital volume correlation (DVC) consists in measuring the local differences between
scans depicting the deformed and undeformed stages of a sample under load, facilitating
the characterisation of the mechanical response of the sample. The use of DVC in-vivo
is limited, due to the limited quality of the scans constrained by the acquisition setting.
Accuracy of three deformable registration methods was first assessed after optimisation
against biomechanically plausible ground truths generated via finite element simulations.
Against the simulation of PBS, the best accuracy achieved was of one order of magnitude
smaller than the resolution of the images. For the simulation of deformations of the
buttock due to sitting, optimal accuracy was around 10% of the average deformation
fields applied.
The best performing methods alongside their optimal parameter sets were then used
to perform in-vivo measurements on real magnetic resonance scans of two separate
datasets of healthy subjects. For PBS, the study revealed the need for intervention- and
Abstract iv
patient-specific correction of surgical trajectories given the effect of head geometry and
orientation on the shift. For the deformation of the buttock due to sitting, the measure�ments gave a three-dimensional depiction of the local and global pattern of deformation,
which results were previously limited to thickness or surface measurements