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My doctoral work has addressed the anatomy-function relationship by illustrating 1) the unique topology of brain anatomy for biologically plausible functional connectome to exist, 2) a higher vulnerability of neuroanatomy against the genetic control for a brain hub region, whereas lower genetic influence on its functional fingerprints, and 3) a global functional plasticity following a local injury beyond its anatomical boundaries. All together, the work here has demonstrated the interplay between brains structure and function, as well as the impact of familial relatedness (heritability) on these measures.

<p>The human brain is possibly the most complicated structure in the known world. It contains 100 billion neurons, each making contact with 1,000 to 10,000 other neurons. The neurons themselves have hundreds of excitatory and inhibitory neurotransmitters / receptors with which to use to activate or de-activate other neighbouring neurons. Ultimately these neurons are organized into locally defined functional neural networks, which in turn connect with other neural networks to create non-localized highly-complex brain circuits. These brain circuits are responsible for the higher order functions such as perception, emotions, learning, language and conscious thought. In healthy brain states, these networks and circuits are communicating and signalling appropriately. With mental illness, or in an intoxicated brain state, however, this network and circuit functioning can become disrupted: either in a very specific manner, or in a generalized form. Alcohol (in the form of ethanol) is one of the oldest and most widely used psychoactive drugs in the world. In recreational doses, it can have drastic effects on how a person thinks and behaves. Small doses will lead to feelings of euphoria, increased sociability, and impaired judgement, while larger doses will lead to impaired memory and comprehension, and at extreme doses will lead from confusion and stupor to coma and death. The current understanding of alcohol’s effects on the brain is that it acts in a very specific way on a variety of brain enzymes and receptors. This in turn affects specific brain circuitries, making alcohol intoxication a promising model of pharmacological neural network and brain circuit modulation. Obsessive-compulsive disorder (OCD) is a major psychiatric disorder that affects many (lifetime prevalence of between 1-2.5%) and can cause significant disability and impairment in one’s life. The onset of OCD is usually during childhood and adolescence, with more than 50% of adults with OCD reporting its onset occurring before the age of 18. The etiological origin of OCD lies ultimately in specific neuropathological processes, with current theories postulating either a neurochemical model that emphasizes the dysfunction of the serotonergic and possibly dopaminergic systems; or a neuroanatomical model that emphasizes the dysfunction of a specific corticostriatal pathway; or both. Magnetic resonance imaging (MRI), with its safe, non-invasive ability to image both anatomy, brain function and brain metabolism, provides a unique tool with which to probe brain circuit changes, such as in healthy subjects under a pharmacological challenge (ethyl alcohol), or in medication naïve children with OCD. In the ethanol intoxicated brain, functional MRI can be used to probe specific resting state networks (RSN; functionally connected networks that exhibit low frequency blood oxygen level dependent (BOLD) fluctuations), measure brain BOLD time-signal complexity using fractal analysis, and to correlate these findings with measured alcohol levels in the brain in vivo using magnetic resonance spectroscopy (MRS). In subjects with OCD, functional MRI can be used to once again probe RSNs, and as well, MRS can be used to look at potential differences in brain metabolites in axonal projections that connect OCD relevant brain circuits. It is the purpose of this thesis to show how brain circuits and neural networks in atypical brain states (such as intoxication or mental illness) can be probed and better understood using advanced MRI techniques, such as resting state fMRI. Over a series of three studies, one involving MRI scans of healthy male adults before and after drinking a substantial amount of ethanol, and two others comparing RSNs in children with OCD versus healthy matched controls, and MRS differences in prefrontal white matter between the same two groups, we examined brain circuit changes using advanced MRI techniques. In the alcohol study, evidence was found of brain signal complexity decreasing after 60min and 90min post alcohol consumption. Simultaneously, a mixture of increased and decreased functional connectivity in the default mode network was found after 60min post alcohol consumption, which became general decreased functional connectivity after 90min post alcohol consumption. These changes took place while alcohol in the brain increased substantially after 60min. These findings may help provide insight into the neurofunctional underpinnings of the cognitive and behavioural changes observed during acute alcohol intoxication. In the first study on medication naïve children with OCD, we observed increased connectivity (OCD>control) in the right section of Brodmann area 43 of the auditory cortex, as well as decreased connectivity in the right section of Brodmann area 8 and Brodmann area 40 in the cingulate network. In the second study looking at medication naïve children with OCD, we observed higher levels of N-acetyl-aspartate (NAA) and choline in the right prefrontal white matter (RPFWM) in children with OCD compared to healthy controls, as well as a positive correlation of creatine, NAA, and myo-inositol levels in the RPFWM and OCD symptom severity. Both studies lend further support to the cortico-striatal-thalamiccortical hypothesis of OCD, while the first study further implicates other regions of the brain outside of the CSTC. Both of these OCD studies further demonstrated the differences in brain circuits of neuropsychiatric disorders between children and adults.</p> / Doctor of Philosophy (PhD)

Neurobiological theories of bipolar spectrum disorder (BSD) propose that the emotional dysregulation characteristic of BSD stems from disrupted prefrontal control over subcortical limbic structures (Strakowski et al., 2012; Depue & Iacono, 1989). However, existing neuroimaging research on functional connectivity between frontal and limbic brain regions remains inconclusive, and is unable to adequately characterize global functional network dynamics. Graph theoretical analysis provides a framework for understanding the local and global connections of the brain and comparing these connections between groups (Sporns et al., 2004). The purpose of this study was to investigate resting state functional connectivity in individuals at low and high risk for BSD based on moderate versus high reward sensitivity, both with and without a BSD diagnosis, using graph theoretical network analysis. Results demonstrated decreased connectivity in a cognitive control region (dorsolateral prefrontal cortex), but increased connectivity of a brain region involved in the detection and processing of reward (bilateral orbitofrontal cortex), among participants at high risk for BSD. Participants with BSD showed increased inter-module connectivity of the dorsal anterior cingulate cortex (ACC). Reward sensitivity was associated with decreased global and local efficiency, and interacted with BSD risk group status to predict inter-module connectivity. Findings are discussed in relation to neurobiological theories of BSD. / Psychology

<p> Hypertension is a modifiable risk factor for cardiovascular disease. The current treatment options are drug therapy and lifestyle modifications. A promising lifestyle modification therapy for the management of hypertension is isometric exercise, as several studies have demonstrated that isometric handgrip (IHG) training reduces resting arterial blood pressure (ABP) (Peters et al., 2006; Taylor et al., 2003; Wiley et al., 1992). The purpose of the present investigation was two-fold: 1) to examine the effectiveness of IHG training in reducing resting ABP in newly diagnosed hypertensive patients, in comparison to matched controls receiving advice from a physician about lifestyle modifications; and 2) to examine markers of autonomic function, specifically, heart rate variability (HRV) to determine if changes in the autonomic nervous system (ANS) existed between the two groups of hypertensive adults.</p> <p> Resting blood pressure and heart rate were assessed with an automated acquisition system before, during and after the 6-week intervention period. Also, power spectral analysis of HRV was used to assess changes in modulation of the ANS. Participants in both groups (n=14) were given lifestyle modification recommendations regarding diet, exercise and stress reduction, while participants in the training group (n=8) also completed a bilateral IHG training protocol 3 times/week at 30% maximum voluntary contraction (MVC).</p> <p> Our results demonstrate that contrary to our hypothesis, isometric exercise in combination with lifestyle modification recommendations did not result in a reduction of resting ABP or change indices of HRV. Possible explanations for these results are that unlike previous IHG training, the present study was the first to use home-based training and the small sample size of this investigation would limit our ability to identify alterations in resting ABP or HRV.</p> / Thesis / Master of Science (MSc)

<p> Hypertension and reduced arterial distensibility are independent risk factors for cardiovascular disease. Previous research has found that isometric training reduces resting blood pressure (RBP) (Wiley et al. 1992; Taylor et al. 2003) yet the mechanisms responsible remain elusive. Improved arterial distensibility may contribute to this reduction in RBP. The purpose of the present study was threefold: 1) to replicate the RBP lowering effect of isometric handgrip (IHG) exercise; 2) to compare IHG and isometric leg press (ILP) based in their RBP lowering effects; and 3) to determine if central or peripheral arterial distensibility improved with IHG or ILP. The population examined was people whom were medicated for hypertension.</p> <p> RBP, as assessed by brachial oscillometry, and arterial distensibility, as assessed by Doppler ultrasound and applanation tonometry in the carotid, brachial and femoral arteries, were measured pre training, after 4 weeks of training, and post training. Participants performed unilateral IHG exercise (n=10) or ILP exercise (n=9) 3 times/week for 8 weeks at 30% MVC or acted as a non-exercising control group (n=5).</p> <p> Results indicated that the present study was unable to reproduce the RBP reductions noted in previous studies using IHG exercise. Also, the ILP exercise group did not experience reductions in RBP. Finally, neither central nor peripheral arterial distensibility improved in the IHG or ILP group when compared to the control group.</p> <p> Although these findings are contrary to our hypotheses one must consider that the control group examined contained very few subjects. This may have limited our ability to detect statistically significant changes in RBP and arterial distensibility.</p> / Thesis / Master of Science (MSc)

This study examined the effects of isometric handgrip (IHG) training on resting blood pressure (RBP), heart rate variability (HRV) and blood pressure variability (BPV) in older adults with hypertension. Nine subjects performed four 2-minute IHG contractions at 30% maximal voluntary contraction (MVC) 3 days/week for 10 weeks and 8 subjects served as controls. Power spectral analysis (PSA) of HRV and BPV was used to assess changes in modulation of the autonomic nervous system. After training, there was a marked attenuation in arterial pressure and evidence for a shift in HR.V and BPV sympathovagal balance. There was a reduction in systolic blood pressure (156 ± 9.4 to 137 ± 7.8 mm Hg; p<0.05), diastolic blood pressure (82 ± 9.3 to 75 ± 10.9 mm Hg; N.S), mean arterial pressure (107 ± 8.53 to 96 ± 8.7 mm Hg; p<0.05) and resting heart rate (RHR) (70 ± 14.2 to 68 ± 12.1 beats/min). In addition, PSA of HRV showed a decrease in sympathetic modulation represented by low frequency (LF) area, an increase in parasympathetic modulation represented by high frequency (HF) area (p<0.05) and a decrease in LF:HF area ratio. After training, BPV PSA showed a decrease in systolic blood pressure LF area (p<0.05), an increase in HF area (p<0.05) and decrease in LF:HF area (p<0.05). Similar, but non-significant changes occurred in diastolic BPV. It is concluded that isometric training at a moderate intensity can elicit a hypotensive response and can potentially alter sympathovagal balance of HRV and BPV in older adults with hypertension. / Thesis / Master of Science (MS)

The default mode network (DMN) is active in the absence of task demands and during self-referential thought. Considerable evidence suggests that the DMN is involved in normative aspects of social cognition, and as such, disruptions in the function of DMN would be expected in disorders characterized by alterations in social function. Consistent with this notion, work in autism spectrum disorder (ASD) and social anxiety disorder (SAD) has demonstrated altered activation of several core regions of the DMN relative to neurotypical controls. Despite emergent evidence for alterations within the same brain systems in SAD and ASD, as well as a behavioral continuum of social impairments, no study to date has examined what is unique and what is common to the brain systems within these disorders. Therefore, the primary aim of the current study is to precisely characterize the topology of neural connectivity within the DMN in SAD and ASD and neurotypical controls in order to test the following hypotheses through functional and structural connectivity analyses of the DMN. Our analyses demonstrate increased coavtivation of the dorsomedial prefrontal cortex in ASD and SAD compared to controls, as well as over and under connectivity in structural brain connectivity in ASD. These results may reflect general deficits in social function at rest, and disorder specific alterations in structural connectivity in ASD. / Master of Science