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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
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The white matter connectome as an individualized biomarker of language impairment in temporal lobe epilepsy.
ObjectiveThe distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment.MethodsT1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results.ResultsThe SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p < .001; accuracy: 70%, p < .001) and the CV-model (AUC: .59, p < .001; accuracy: 64%, p < .001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance.ConclusionThe SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance
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