The role of white matter pathways in language networks has received much attention inrecent years. This is largely due to advances in diffusion imaging techniques, which haveenabled exploration of white matter properties in vivo. The emergent model from suchwork proposes that language processing is underpinned by a dorsal and a ventral pathwayconnecting anterior and posterior regions involved in language. This thesis aimed toexplore whether consideration of white matter measures could aid understanding ofperformance profiles in chronic stroke aphasia. To this end, a group of participants withchronic stroke aphasia were recruited and their performance on a large battery oflanguage assessments was related to their neuroimaging data. The neuroimaging datacomprised high resolution T1-weighted structural scans, fractional anisotropy (FA) maps,and data generated using a tractography-based technique called Anatomical ConnectivityMapping (ACM) which provides an index of long-range connectivity that has not yetbeen applied to chronic stroke aphasia.Chapter 3 established, in a small series of case examples, that connectivityinformation from ACM can help explain variations in performance in chronic strokeaphasia. Chapter 4 extended this work to a larger group of participants. Differencesbetween aphasic participants and controls, and between groups with different aphasicsubtypes and controls, were calculated and compared across imaging methods. ACMoffered insights into connectivity differences that were complementary to informationfrom T1-weighted and FA data. In addition to revealing areas where connectivity wasreduced relative to controls, ACM revealed an increase in connectivity in the righthemisphere dorsal route homologue of aphasic participants.Chapter 5 aimed to improve our ability to capture aphasic performance and torelate it to neuroimaging data. Principal components analysis (PCA) was used to derivefactors underlying performance on the language battery. Phonological, semantic, andcognitive factors emerged from the PCA and participants’ factor scores were used ascontinuous regressors in a voxel-level analysis of their T1-weighted images. Regions thatemerged as significantly related to language abilities aligned with those found usingother methodologies. Chapter 6 brought together work from the previous chapters byrelating PCA-derived factor scores to FA maps and ACM, in order to assess therelationship between behavioural performance and the status of key white matterpathways. In line with recent characterisations of the dual route system, phonologicalperformance related to dorsal route measures and semantic performance related to ventralroute measures. Better cognitive performance was found to relate to increasedconnectivity relative to controls in the right frontal lobe. Overall these results suggest thatconsideration of white matter abnormalities, both reductions and increases, can helpexplain patterns of performance in chronic stroke aphasia and that ACM can be a usefulsource of such information given its sensitivity to connectivity remote from the lesion.These findings both provide hypotheses for future research and could be used to informtherapeutic interventions.

Indiana University-Purdue University Indianapolis (IUPUI) / The pathway leading from soluble and monomeric to hyperphosphorylated, insoluble and filamentous tau protein is at the center of many human neurodegenerative diseases, collectively referred to as tauopathies, such as Alzheimer disease (AD). In this report, we discuss the role of neuroimaging, genetics, and biomarkers in better understanding the underlying brain changes in tauopathies. In Chapters 1 and 2, we review current knowledge of tauopathies, the protein tau and FDG PET studies in AD. In Chapter 3, we investigate glucose metabolism using [18F]FDG PET in a family with multiple systems tauopathy with presenile dementia (MSTD), a primary tauopathy cause by a mutation in MAPT. The results from this study suggest that mutation carriers have lower [18F]FDG uptake, which may precede clinical onset. In Chapter 4, we assessed brain glucose metabolism using [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) in individuals with Gerstmann–Sträussler–Scheinker Disease (GSS) with the PRNP F198S mutation. The results from this study suggest hypometabolism in the cerebellar and striatal regions, which may be preceded by hypermetabolism. This chapter also evaluated if [11C]Pittsburgh Compound B (PiB) PET is capable of detecting PrP-amyloid in GSS in individuals with the PRNP P102L and F198S mutations. The results from this study suggest that [11C]PiB is not suitable for in vivo assessment of PrP amyloid plaques in GSS. In Chapter 5, we examine a correlation between two peripheral markers of axonal degeneration, plasma tau and neurofilament light (NFL), and MRI. The results from this study suggest that plasma NFL may be a more specific marker for neurodegeneration relative to plasma tau. In Chapter 6, we attempted to create a tau biological network from gene and protein databases and literature search. We identified over 150 genes that are related to tau protein or MAPT that are involved in different biological functions. Overall, the results of this report support the notion that using a combination of techniques may help model progression of tau pathology. Future studies may establish additional markers that may be used in combination with some of these measures as tools for diagnosis and for the evaluation of treatment efficacy in therapeutic trials.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcoholism carries significant personal and societal burdens, and yet we still lack effective treatments for alcohol use disorders. Several lines of research have demonstrated disruption of major white matter (WM) tracts in the brains of detoxified alcoholics. Additionally, there are several reports of alterations in the dopaminergic system of alcoholics. A better understanding of the relationships of brain structure and function in the alcoholic brain is necessary to move toward more efficacious pharmacological interventions. In this dissertation, there are three main chapters. First, reduced WM integrity was reported in a sample of individuals with active alcohol use disorder (AUD). This is a relatively understudied population, which is believed to represent a less severe phenotype compared to the in-treatment samples that are typically studied. Second, higher WM integrity was reported in a sample of college-age, active AUD. In a subsample of these individuals, graph theory measures of structural brain network connectivity were shown to be altered in cigarette-smoking social-drinking controls and smoking AUD subjects, compared to nonsmoking healthy individuals. Finally, a novel multimodal approach that combines diffusion weighted imaging and [11C]raclopride positron emission tomography identified differential relationships between frontostriatal connectivity and striatal dopamine tone in active AUD versus social-drinking controls. This suggests that aberrations in frontostriatal connectivity may contribute to reported differences in dopaminergic function in AUD. In summary, these results show that similar to detoxified/in-treatment alcoholics, active AUD samples present with WM integrity alterations, and changes in both structural connectivity and frontostriatal structure/function relationships. / 2021-10-02

Complexity-modulated tasks elicit differential hemodynamic activations in the primary motor cortex for upper limb motor representations. However, much is yet to be learned regarding lower limb complexity modulation, as most fNIRS complexity modulation studies focus on the upper limb. It is currently unknown whether hemodynamic activations from single-joint lower limb motor tasks are detectable by fNIRS, and further, if fNIRS can detect differences between activations from simple and complex lower limb motor tasks. An fNIRS study was conducted to investigate the effects of an unpredictable, complex force-tracking task vs. a predictable, simple force-tracking task on hemodynamic activations in the TA motor representation. No significant TA motor cortex activations were found for 4/5 participants, with one participant showing a significant activation in one channel. Lack of activation in the TA motor representation was attributed to the depth of the area within the central sulcus. Significant hemodynamic activations were also found in areas assumed to overly STG/SII, and pre-SMA/SMA. These activations were attributed to sensory integration and motor learning, respectively. An fNIRS processing review was also conducted to inform processing decisions in the first experiment and to further fNIRS usage in our lab. Common techniques were identified as low-pass, band-pass, and high-pass filters, smoothing filters, wavelet filters, and the GLM. More appropriate alternative techniques were provided, including short-separation regression, pre-whitening, and spline interpolation with a Savitsky-Golay filter. Future studies may elucidate the lack of activity in the TA motor representation, and will further basic neuroscience regarding fNIRS. / Thesis / Master of Science in Kinesiology

Neuroimaging techniques are likely to continue to improve our understanding of the brain in health and disease, but studies tend to be small, based in one imaging centre and of uncertain generalisability. Multicentre imaging studies therefore have great appeal but it is not yet clear under which circumstances data from different scanners can be combined. The successful harmonisation of multiple Magnetic Resonance Imaging (MRI) machines will increase study power, flexibility and generalisability. I have conducted a detailed study of the performance of three research MRI scanners in Scotland under the name CaliBrain, with the aims of developing reliable, valid image acquisition and analysis techniques that will facilitate multicentre MRI studies in Scotland and beyond. Fourteen healthy volunteers had two brain scans on each of three 1.5T MRI research machines in Aberdeen, Edinburgh and Glasgow. The scans usually took place 2-3 weeks apart. Each scan was performed using an identical scanning protocol consisting of a detailed structural MRI (sMRI) and a range of functional MRI (fMRI) paradigms. The quality assurance (QA) of scanner performance was monitored in all three sites over the duration of the study using a three-part protocol comprising a baseline assessment, regular measures and session specific measures. The analyses have demonstrated that the data are comparable but also that within- and between-scanner variances are evident and that harmonisation work could enhance the level of agreement. The QA data suggest that scanner performance was similar between and within machines over the course of the study. For the structural MRI scans an optimised methodology was utilised to minimise variation in brain geometry between scanners and fit all the scanned brains into a common stereotactic space, such that repeated measures analyses yielded no significant differences over time for any of the three scanners. I examined the reproducibility of the fMRI motor task within and between the three sites. Similar results were obtained in all analyses; areas consistently activated by the task include the premotor, primary motor and supplementary motor areas, the striatum and the cerebellum. Reproducibility of statistical parametric maps was evaluated within and between sites comparing the activation extent and spatial agreement of maps at both the subject and the group level. The results were within the range reported by studies examining the reproducibility of similar tasks on one scanner and reproducibility was found to be comparable within and between sites, with between site comparisons often exceeding the within site measures. A components of variance analysis showed a relatively small contribution of the factor site with subject being the main source of variation. Similar results were obtained for the working memory task. The analysis of the emotional face processing task showed poor reproducibility both within and between sites. These findings suggest that multicentre structural and functional MRI studies are feasible, at least on similar machines, when a consistent protocol is followed in all participating scanning sites, a suitable fMRI task is employed and appropriate analysis methods are used.

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Background: Given that individuals with subjective cognitive decline (SCD) report a change that is not yet measurable with standard neuropsychological assessment measures, they are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD). The current study used a neuroimaging approach to examine differences in brain function and structure between individuals with SCD and healthy controls (HC). Method: 3T resting state functional MRI and high resolution anatomical images were retrieved from 23 individuals with SCD (mean age = 72.9 years, SD = 5.4, 12 females) and 23 HC (mean age = 74.3 years, SD = 5.0, 12 females) from the screening time point from the AD Neuroimaging Initiative database. All data were processed using the FMRIB Software Library. Seed-based analyses of the default mode network (DMN) were used to compare differences in brain function between SCD and HC groups (Z > 2.3; cluster significance: p < 0.05, corrected). Voxel-based morphometry (VBM) was used to examine differences in grey matter volume between the SCD and HC groups. Results: The SCD and HC groups were not significantly different in age or education level. Results revealed significantly greater activity in the DMN including the bilateral precuneus cortex, bilateral thalamus, and right hippocampal regions in individuals with SCD relative to controls. Conversely, those with SCD showed decreased activation in the bilateral frontal pole, caudate, angular gyrus, lingual gyrus, right superior frontal gyrus, right occipital pole, right superior temporal gyrus, left superior temporal gyrus in the posterior division, left precuneus cortex, left precentral gyrus, left occipital fusiform gyrus, left temporal pole, and left cerebellum compared to HC. Finally, VBM results did not show significant differences in grey matter volume between the groups. Conclusion: Findings revealed changes in brain function but not structure between individuals with SCD and HC. Overall, this study represents a crucial step in characterizing individuals with SCD, a group recognized to be at increased risk for AD. It is imperative to identify biomarkers prior to significant decline on clinical assessment, so that disease-delaying interventions may be delivered at the earliest possible time point. / Graduate / 2020-08-15

The first part of this thesis discusses developmental influences on the human connectome in relation to autism and attention deficit hyperactivity disorder (ADHD), conditions associated with alterations in brain connectivity and marked by social impairments. It reports an experiment investigating whether the connectomes of individuals with autism or ADHD differ from the connectome of neurotypical individuals, and what the underlying genetic basis could be for any differences in neural architecture. Chapter 2 reports an analysis of networks in children with autism or ADHD, using structural covariance magnetic resonance imaging (scMRI). We found overlapping as well as distinct network features across both conditions. Chapter 3 reports an analysis of how gene expression might be associated with the basic building blocs of these structural covariance networks. We found that synaptic and transcriptionally downregulated genes were replicably associated with cortical thickness differences in children with autism, but not in children with ADHD. In addition, the first part also aims to elucidate the potential modulation effects of sex on autism neurobiology. Chapter 4 reports an analysis of structural covariance networks in male and female adults with and without autism. We found that biological sex is a modulator of neurobiological heterogeneity in autism. Chapter 5 reports pilot data aiming to identify an electrophysiological signature of these network properties using electroencephalography (EEG). We find little evidence for theories about network asymmetry, but indications of altered frontal network integration. The second part of the thesis examines the acute effects of hormones on brain connectomics. Hormones are an integral part of the mechanism of social behaviour. In a series of hormone administration studies, we report experiments to test the acute effects of steroid and peptide hormones on brain functional connectivity (Chapters 6 and 7). Chapter 6 reports an oxytocin administration study that used a novel data-driven approach to assess resting-state fMRI connectivity in women. Although the number of fMRI studies on oxytocin have increased over past years, little is known about its effect on women. We found that oxytocin robustly enhances cortico-subcortical connectivity, and that this effect positively correlates with autistic traits. This is interesting given that oxytocin has been proposed as a potential therapeutic in autism. Chapter 7 reports an experiment testing if testosterone modulates connectivity in a specific social environment (a fear response). This was confirmed during the social task, but not during baseline resting-state, highlighting the role of testosterone in functional connectivity in this specific context. Chapter 8 is the concluding chapter that integrates all the empirical findings in the thesis. We discuss their implications for our understanding of autism and ADHD, and of the role of steroid and peptide hormones in the typically and atypically developing connectome. Chapter 8 also reflects on the limitations of the experiments reported, and sets out future directions for research in this area.

Anatomical variability of the human insula has not been well studied because the structure of the insula is difficult to image. Thus, the aim of this study was to apply a novel method to reconstruct insular topology in order to assess the anatomic variation within a population. An analysis of 60 healthy male and female subjects revealed a significant amount of anatomic variation. Some structures, such as the central sulcus were extremely stable and showed little inter-individual variability, while other structures such as the middle short gyrus were highly variable, being more conspicuous in the left hemisphere and in males. Grey matter in the cortex was found to be thinner in the left posterior and dorsal insular subregions in older female subjects but not males. This work shows that the insula is an anatomically complex and variable structure and that some of the variability is related to sex and laterality.

Anatomical variability of the human insula has not been well studied because the structure of the insula is difficult to image. Thus, the aim of this study was to apply a novel method to reconstruct insular topology in order to assess the anatomic variation within a population. An analysis of 60 healthy male and female subjects revealed a significant amount of anatomic variation. Some structures, such as the central sulcus were extremely stable and showed little inter-individual variability, while other structures such as the middle short gyrus were highly variable, being more conspicuous in the left hemisphere and in males. Grey matter in the cortex was found to be thinner in the left posterior and dorsal insular subregions in older female subjects but not males. This work shows that the insula is an anatomically complex and variable structure and that some of the variability is related to sex and laterality.