Soon after the advent of signal-recording techniques in the brain, functional connectivity (FC), a measure of interregional neural interactions, became an important tool to assess brain function and its relation to structure. It was discovered that certain groups of regions in the brain corresponding to behavioural domains are organized into intrinsic networks of connectivity (ICNs). These networks were shown to exhibit high FC during rest, and also during task. ICNs are not only delineated by areas which correspond to various behaviours, but can be modulated in the long and short-term in their connectivity by disease conditions, learning, and task performance. The significance of changes in FC, permanent and transient, is poorly understood with respect to even the simplest ICNs corresponding to motor and visual regions. A better grasp on how to interpret these changes could elucidate the mechanisms and implications of patterns in FC changes during therapy and basic tasks. The aim of this work is to examine long-term changes in the connectivity of several ICNs as a result of modulation by stroke and rehabilitation, and to assess short term changes due to simple, continuous task performance in healthy volunteers. To explore long-term changes in ICN connectivity, fifteen hemiparetic stroke patients underwent resting state scanning and behavioural testing before and after a two-week session of Constraint Induced Movement Therapy (CIMT). It was found that therapy led to localized increases in FC within the sensorimotor ICN. To assess transient changes in FC with task, sixteen healthy volunteers underwent a series of scans during rest, continuous performance of a non-demanding finger-tapping task, viewing of a continuous visual stimulus, and a combined (but uncoupled) visual and motor task. Group Independent Component Analysis (ICA) revealed that canonical ICNs remained robustly connected during task conditions as well as during rest, and dual regression/seed analyses showed that visual and sensorimotor ICNs showed divergent patterns of changes in FC, with the former showing increased intra-network connectivity and the latter decreased intra-network connectivity. Additionally, it was found that task activation within ICNs has a relationship to these changes in FC. Overall, these results suggest that modulation of functional connectivity is a valuable and informative tool in the study of disease recovery and task performance.

Explorations into the organisation of spontaneous activity within the brain have demonstrated the existence of networks of temporally correlated activity, consisting of brain areas that share similar cognitive or sensory functions. These so-called resting state networks (RSNs) emerge spontaneously during rest and disappear in response to overt stimuli or cognitive demands. In recent years, the study of RSNs has emerged as a valuable tool for probing brain function, both in the healthy brain and in disorders such as schizophrenia, Alzheimer’s disease and Parkinson’s disease. However, analyses of these networks have so far been limited, in part due to assumptions that the patterns of neuronal activity that underlie these networks remain constant over time. Moreover, the majority of RSN studies have used functional magnetic resonance imaging (fMRI), in which slow fluctuations in the level of oxygen in the blood are used as a proxy for the activity within a given brain region. In this thesis we develop the use of magnetoencephalography (MEG) to study resting state functional connectivity. Unlike fMRI, MEG provides a direct measure of neuronal activity and can provide novel insights into the temporal dynamics that underlie resting state activity. In particular, we focus on the application of non- stationary analysis methods, which are able to capture fast temporal changes in activity. We first develop a framework for preprocessing MEG data and measuring interactions within different RSNs (Chapter 3). We then extend this framework to assess temporal variability in resting state functional connectivity by applying time- varying measures of interactions and show that within-network functional connectivity is underpinned by non-stationary temporal dynamics (Chapter 4). Finally we develop a data driven approach based on a hidden Markov model for inferring short lived connectivity states from resting state and task data (Chapter 5). By applying this approach to data from multiple subjects we reveal transient states that capture short lived patterns of neuronal activity (Chapter 6).

The third generation of hip resurfacing commenced in the U.K. in the 1990’s with the Birmingham Hip Resurfacing system and is now becoming more commonplace as an attractive alternative for young and active patients due to premature failure in total hip replacement in this patient group. However the Swedish National Hip Arthroplasty Register (2010) suggests that premature failure of resurfacing arthroplasty may be more prevalent than first expected. The aim of this study is to investigate, through Finite Element Analysis, the short, medium and long term performance of Poly Methyl Methacrylate (PMMA) bone cement of the femoral component in hip resurfacing arthroplasty. The study takes a forensic engineering approach, analysing the performance of PMMA bone cement in order to provide understanding, awareness and an insight into lifestyle options. Finite Element Analysis explores and models the effect of resting periods during daily activities, patients’ bone quality and PMMA bone cement Young’s modulus on the PMMA bone cement stresses within the femoral hip resurfacing component. Mechanical tests are used to illustrate the use of the Finite Element Analysis results. Contributing to knowledge, this study verifies the significance of high metal-on-metal friction due to resting periods, developing a dynamic FEA model to quantify the premature fatigue failure of PMMA bone cement, within the femoral component of hip resurfacing arthroplasty. A decrease in bone quality added to the effect of resting periods increase the risk of PMMA fatigue failure and PMMA-metal interface failure due to an increase of PMMA tensile and shear stresses, suggesting that patients with low bone quality should avoid hip resurfacing procedures. The use of low PMMA Young’s modulus could greatly enhance the long term success of hip resurfacing arthroplasty generally and specifically reduce the risk of interface failure and PMMA bone cement failure due to resting periods and patient bone quality. Moreover, this study shows that the consequence of PMMA fatigue failure and PMMA-metal interface failure must be included in the design, patient selection, screening process, post-operative rehabilitation and long term lifestyle attributes. This study suggests that occupational therapists and patients with hip resurfacing arthroplasty should be aware of high metal-on-metal friction situations, which could lead to early failure indicated by this research. The deleterious effect of resting periods indicated by this research could be alleviated by appropriate re-initiation of synovial lubrication by movement prior to full loading. Recommendations for further work include the compilation of a PMMA bone-cement fatigue properties database and further development of the FEA modelling technique for application upon other arthroplasty procedures.

Grasslands are the most threatened terrestrial ecosystem in the world, and as they decline the species that depend on them also decline. Variable stocking rates and resting rangeland could be used by range managers to manipulate plant cover and create wildlife habitat. I used generalized linear mixed-models to evaluate how effects of rest on vegetation and songbirds varied based stocking rates previously applied from 2006-2014 in Grasslands National Park, Canada. My results indicate, in the mixed-grass prairie, succession is retrogressive following rest, and both vegetation and songbirds are resilient to grazing. Recovery of songbirds was linked to the recovery of habitat structure. Songbirds with flexible habitat requirements, such as Savannah and grasshopper sparrows, responded rapidly to livestock exclusion. The retrogressive nature of succession in mixed-grass prairie offers managers an opportunity to take chances when attempting to create wildlife habitat with livestock grazing, as risk of irreversible change is relatively low. / October 2016

Despite the success of available medical and psychosocial treatments, a sizable subgroup of individuals with commonly co-occurring disorders, generalized anxiety disorder (GAD) and major depressive disorder (MDD), fail to make sufficient treatment gains thereby prolonging their deficits in life functioning and satisfaction. Clinically, these patients often display temperamental features reflecting heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss (e.g., somatic anxiety) as well as inordinate negative self-referential processing (e.g., worry, rumination). This profile may reflect disruption in two important neural networks associated with emotional/motivational salience (e.g., salience network) and self-referentiality (e.g., default network, DN). Emotion Regulation Therapy (ERT) was developed to target this hypothesized profile and its neurobehavioral markers. In the present study, 22 GAD patients (with and without MDD) completed resting state MRI scans before receiving 16 sessions of ERT. To test study these hypotheses, we examined the associations between baseline patterns of intrinsic functional connectivity (iFC) of the insula and of hubs within the DN (anterior and dorsal medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]) and treatment-related changes in worry, somatic anxiety symptoms and decentering. Results suggest that greater treatment linked reductions in worry were associated with iFC clusters in both the insular and parietal cortices. Greater treatment linked gains in decentering, a metacognitive process that involves the capacity to observe items that arise in the mind with healthy psychological distance that is targeted by ERT, was associated with iFC clusters in the anterior and posterior DN. The current study adds to the growing body of research implicating disruptions in the default and salience networks as promising targets of treatment for GAD with and without co-occurring MDD.

The field of neuroimaging has truly become data rich, and as such, novel analytical methods capable of gleaning meaningful information from large stores of imaging data are in high demand. Those methods that might also be applicable on the level of individual subjects, and thus potentially useful clinically, are of special interest. In this dissertation we introduce just such a method, called nonlinear functional mapping (NFM), and demonstrate its application in the analysis of resting state fMRI (functional Magnetic Resonance Imaging) from a 242-subject subset of the IMAGEN project, a European study of risk-taking behavior in adolescents that includes longitudinal phenotypic, behavioral, genetic, and neuroimaging data. Functional mapping employs a computational technique inspired by biological evolution to discover and mathematically characterize interactions among ROI (regions of interest), without making linear or univariate assumptions. Statistics of the resulting interaction relationships comport with recent independent work, constituting a preliminary cross-validation. Furthermore, nonlinear terms are ubiquitous in the models generated by NFM, suggesting that some of the interactions characterized here are not discoverable by standard linear methods of analysis. One such nonlinear interaction is discussed in the context of a direct comparison with a procedure involving pairwise correlation, designed to be an analogous linear version of functional mapping. Another such interaction suggests a novel distinction in brain function between drinking and non-drinking adolescents: a tighter coupling of ROI associated with emotion, reward, and interceptive processes such as thirst, among drinkers. Finally, we outline many improvements and extensions of the methodology to reduce computational expense, complement other analytical tools like graph-theoretic analysis, and possibly allow for voxel level functional mapping to eliminate the necessity of ROI selection.

This thesis investigated transcranial direct current stimulation (tDCS) as applied to the motor system, and its ability to modulate underlying cortical processes and resultant motor behaviours. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) were employed to assess the extent to which tDCS induces quantifiable changes in neural structure and function in controls and stroke patients. Modifications in the connectivity of intrinsic functional networks following tDCS application were examined using resting state fMRI. Polarity-specific changes were found: cathodal (inhibitory) tDCS increased the strength of the default mode network and increased functional coupling between major nodes within the motor network. No significant effects were found following anodal (excitatory) tDCS. Although anodal tDCS elicited only subtle changes in resting activity, it is known to produce robust modifications of behaviour. Single and paired-pulse TMS were used to investigate the neurophysiological underpinnings of these changes. Consistent with the theory of homeostatic plasticity, anodal tDCS applied prior to task performance increased GABAA-mediated cortical inhibition and worsened behaviour. The specificity of these changes suggests a central role for the mechanism of surround inhibition. A longitudinal clinical trial in chronic stroke patients was conducted to determine the utility of tDCS as an adjunct in motor rehabilitation. Serial MRI scans revealed that, when combined with motor training, anodal tDCS increased functional activity and grey matter in primarily ipsilesional motor areas. These brain changes were correlated with behavioural improvements in the stroke-affected upper limb. The laterality of connectivity at baseline, as measured by resting state activity and corticospinal tract integrity, was predictive of response to the rehabilitation program, particularly in those stroke patients who received tDCS. Asymmetry favouring the contralesional hemisphere predicted greater behavioural gains. Such results underscore the importance of re-normalisation of structure and functional activity toward the lesioned hemisphere in stroke rehabilitation.

The development of functional connectivity is often described as changing from local to distributed connections which give rise to the functional brain networks observed in adulthood. In contrast to the well-explored pattern found in functional connectivity, no research has been published describing effective connectivity development. Also, there is a plethora of literature describing functional connectivity patterns in a variety of neurodevelopmental and internalizing disorders, but there is little consistency in the connectivity patterns discovered for each disorder. Hence, this study aimed to describe functional and effective resting-state connectivity during adolescent development in a typically developing adolescent (TDA) group (n = 128) and to determine how adolescents with comorbid neurodevelopmental disorders (CND) (n = 46) differed. This was accomplished through functional and effective connectivity analysis within and between four networks: the Default Mode Network (DMN), the Salience Network (SN), the Dorsal Attention Network (DAN), and the Frontal Parietal Control Network (FPCN). The results from this study indicate that within-network connectivity decreased across age in the TDA group, which is in opposition to previous work which suggests strengthening within-network connectivity. The CND group displayed hyper-connectivity compared to the TDA group in between-network connectivity with no effect of age. The effective connectivity in the TDA group displayed decreasing connectivity within networks with increasing age, a novel effect not previously reported in the literature. The CND group’s effective connectivity was overall hyper-connected (for within- and between-networks). The functional connectivity patterns in the TDA group suggest that functional connectivity has subtle developmental change during adolescence. Further, the CND group consistently displayed hyper-connectivity in functional and effective connectivity. The CND group, and perhaps similar comorbid groups, may have less efficient networks which could contribute to their disorder(s).

Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Moreover, potent postnatal brain plasticity engenders increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Recently, resting-state functional magnetic resonance imaging (fMRI) emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Its application has expanded to infant populations in the past decade, providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal/ disease states. However, rapid extension of the resting-state technique to infant populations leaves many methodological issues need to be resolved prior to standardization of the technique. The purpose of this thesis is to describe a protocol for intrinsic functional connectivity analysis, and extraction of resting-state networks in infants <12 months of age using the data-driven approach independent component analysis (ICA). To begin, we review the evolution of resting-state fMRI application in infant populations, including the biological premise for neural networks. Next, we present a protocol designed such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature. Presented protocol provides detailed, albeit basic framework for RSN analysis, with interwoven discussion of basic theory behind each technique, as well as the rationale behind selecting parameters. The overarching goal is to catalyze efforts towards development of robust, infant-specific acquisition and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used. Finally, we review the literature, current methodological challenges and potential future directions for the field of infant resting-state fMRI.

Objectives: Most weight loss medications target reductions in energy intake while neglecting energy expenditure, a critical predictor of weight loss/regain. This pilot study examined the effect of short-acting methylphenidate (MPH) on resting energy expenditure (REE), thermic effect of food (TEF), physical activity energy expenditure (PAEE), and how changes in energy expenditure relate to changes in body composition in youth and adults living with obesity. Methods: This study was a randomized, double-blind, placebo-controlled two-parallel arm study. In total, 19 participants were screened, of which 14 participants were randomized into the study, but complete data was only collected for 12, and only analyzed for 10 participants. Those 10 participants aged 28.8 ± 6.9 yrs. (5 Male, 5 Female) were randomized to receive either MPH (0.5 mg/kg) (n = 5) or placebo (n =5) twice daily for 60 days. Participants’ REE and TEF (indirect calorimetry), were measured at baseline (no drug/placebo), and day 60 post-treatment (drug/placebo). Participants’ PAEE (Actical) was measured between screening and baseline for a 1-week period (no drug/placebo), and on day 53 for a 1-week period (drug/placebo). Participants’ anthropometrics were measured using DEXA at baseline, and day 60 post-treatment. Results: From baseline to day 60, MPH showed a relative difference to placebo in relative REE (Relative REE: F(1, 8) = 4.235, p = 0.074, d = 0.83, 2 = 0.346) of 10%, evidenced by a 6% increase in relative REE kcal/kg (18.53 ± 1.97 Kcal/day/kg at baseline, 19.71 ± 2.52 Kcal/day/kg at final) for the MPH group, and a 4% decrease (19.08 2.36 Kcal/day/kg at baseline, 18.26 ± 2.04 Kcal/day/kg at final) in placebo, translating to moderate-effect size (Cohen’s d=0.63) favouring MPH. From baseline to day 60, there were no significant differences between groups on changes in TEF (TEF AUC: F(1, 8) = 0.079, p = 0.785, d = 0.15, 2 = 0.010) or any PAEE variables such as sedentary behavior (SB: F (1, 8) = 0.455, p = 0.52, d = 0.02, 2 = 0.054), light physical activity (LPA: F (1, 8) = 0.504, p = 0.50, d = 0.16, 2 = 0.059), moderate physical activity (MPA: F (1, 8) = 0.281, p = 0.61, d = 0.19, 2 = 0.034), moderate-to-vigorous physical activity (MVPA: F (1, 8) = 0.120, p = 0.74, d = 0.15, 2 = 0.015), or vigorous physical activity (VPA: F (1, 8) = 3.495, p = 0.098, d = 0.91, 2 = 0.304) . Mean change in body weight (kg) resulted in a weight loss of roughly -2.66 ± 2.00 kg in the MPH group and -1.64 ± 1.41 kg in the placebo group, differences that were not statistically significant. Mean change in both groups for body fat% of -0.33 ± 2.08 %, mean change in fat mass of -1.05 ± 2.59 kg, and finally a mean change in fat-free mass of -0.06 ± 1.19 kg was reported. Changes in relative REE were inversely correlated with changes in body weight (r = -0.599, p = 0.067), body fat (r = -0.524, p = 0.12) and fat mass (r = -0.599, p = 0.096). These associations were stronger in the MPH group. Conclusions: Our data suggests that MPH administration may lead to a meaningful increase in relative REE, and these suggested changes were associated with reductions in adiposity among individuals with obesity. These preliminary findings suggest that MPH should be further examined using a larger sample size and study duration to determine its effectiveness in promoting weight loss and maintenance of weight loss in individuals with obesity, a population at high risk of morbidity and premature mortality.