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|Title:||Magnetic Resonance Imaging Analysis of Neural Circuit Abnormalities in: Medication Naive Children with Obsessive-Compulsive Disorder, and Normal Healthy Adults During Acute Alcohol Intoxication|
|Authors:||Weber, Alexander M.|
|Advisor:||Noseworthy, Michael D.|
|Keywords:||resting state networks;mri;brain circuits;neural networks;obsessive-compulsive disorder;alcohol|
|Abstract:||<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>|
|Appears in Collections:||Open Access Dissertations and Theses|
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