Cross-Hemispheric Collaboration and Segregation Associated with Task Difficulty as Revealed by Structural and Functional Connectivity

Although it is known that brain regions in one hemisphere may interact very closely with their corresponding contralateral regions (collaboration) or operate relatively independent of them (segregation), the specific brain regions (where) and conditions (how) associated with collaboration or segregation are largely unknown. We investigated these issues using a split field-matching task in which participants matched the meaning of words or the visual features of faces presented to the same (unilateral) or to different (bilateral) visual fields. Matching difficulty was manipulated by varying the semantic similarity of words or the visual similarity of faces. We assessed the white matter using the fractional anisotropy (FA) measure provided by diffusion tensor imaging (DTI) and crosshemispheric communication in terms of fMRI-based connectivity between homotopic pairs of cortical regions. For both perceptual and semantic matching, bilateral trials became faster than unilateral trials as difficulty increased (bilateral processing advantage, BPA). The study yielded three novel findings. First, whereas FA in anterior corpus callosum (genu) correlated with word-matching BPA, FA in posterior corpus callosum (splenium-occipital) correlated with face-matching BPA. Second, as matching difficulty intensified, crosshemispheric functional connectivity (CFC) increased in domain-general frontopolar cortex (for both word and face matching) but decreased in domain-specific ventral temporal lobe regions (temporal pole for word matching and fusiform gyrus for face matching). Last, a mediation analysis linking DTI and fMRI data showed that CFC mediated the effect of callosal FA on BPA. These findings clarify the mechanisms by which the hemispheres interact to perform complex cognitive tasks

Commissural white matter disconnectivity in normal ageing and Alzheimer’s disease

The network of commissural white matter fibres responsible for connecting the hemispheres of the brain is known as the corpus callosum (CC). Atrophy to the CC is evident in studies of aging and Alzheimer’s disease (AD), but patterns and functional implications of neurodegeneration are still somewhat unclear. In this thesis, neuroimaging methods were used to further examine how structural and functional CC properties are affected by normal ageing and AD. In Study 1, diffusion tensor imaging (DTI) was used to examine the posterior CC tract bundles in young and older adults. Parietal and temporal midsagittal CC segments were particularly impaired in older adults, while occipital tracts were relatively preserved. Study 2 applied this methodology to study Mild Cognitive Impairment (MCI) and AD. MCI patients exhibited reduced integrity in midsagittal parietal segments compared to controls. AD patients exhibited reductions in parietal and temporal segments, yielding high classification accuracy (95-98%) against controls. Study 3 assessed visual interhemispheric transfer in aging using electroencephalography (EEG). Transfer speed was elongated in older adults, but was driven by earlier activation of the input hemisphere rather than delayed activation of the receiving hemisphere. This was not interpreted as impairment in older age, in line with findings of preserved occipital tracts in Study 1. Study 5 examined EEG functional connectivity methodology. We showed that connectivity was strongest at the dominant EEG frequency, which experiences slowing in older age. Previous studies using conventional frequency bands may therefore be biased against older adults. Study 6 applied these findings to study interhemispheric functional connectivity in older adults, while controlling for age-related frequency slowing. Age-related disconnectivity between frontal sites was evident, reflecting typical anterior-posterior neurodegeneration in older adults (Bennett, Madden, Vaidya, Howard, & Howard, 2010). These studies provide novel spatial and methodological insight into the CC during ageing and AD

White Matter Degeneration in Huntington's Disease: A Study of Brain Structure and Cognition

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterised by devastating physical, behavioural and mental dysfunction. Accumulating evidence indicates that abnormal white matter (WM) is a major hallmark of the disease, with both macro- and microstructural changes apparent before manifest diagnosis. This thesis is an investigation of WM in HD and uses various imaging and cognitive techniques to address some key challenges. Firstly, the development of reliable structural measurement techniques sensitive to longitudinal change may aid characterisation of subtle abnormalities before disease onset. Secondly, optimised diffusion imaging techniques which incorporate superior image processing tools will further understanding as to why changes are harder to find in the premanifest stage and will increase sensitivity to detect them. Thirdly, the development of novel, hypothesis-driven neuropsychological tasks will help detect heterogeneous cognitive decline in individuals in the earliest disease stages. To address these challenges, firstly, a novel corpus callosum (CC) segmentation technique is developed and applied to a large clinical cohort revealing disease-related reduction in baseline CC volume and elevated rates of change over 24 months in both premanifest and manifest HD participants. Secondly, an investigation of template effects in diffusion image analysis reveals consistency between analyses using three customised templates and evidence of the superiority of tensor-based registration over scalar-based registration is demonstrated. An exploratory investigation into the association between brain volume and WM diffusivity is also presented and disease-specific changes in HD gene-carriers are reported. Lastly, two specially designed, pathology-targeted cognitive tasks are applied to a premanifest HD cohort. Abnormal interhemispheric transfer from the non-dominant to dominant hemisphere as well as altered attentional processing and impaired automaticity is revealed. By developing techniques to characterise WM pathology and explore cognitive deficits, this thesis improves our understanding of the role of WM degeneration in the premanifest and early stages of HD