In the aerobic cell, oxygen can be converted into a series of reactive metabolites, together called as "reactive oxygen species" (ROS). This large group include both radical and non-radical species such as superoxide anion (02"), hydroxyl radical ("0H), H202, nitric oxide (N0') and lipid hydroperoxides (LOOH). ROS are generated in very small amounts at all stages of aerobic life, and probably have a role in cellular regulation. However, their formation in excess leads to toxicity and damage to tissues. This situation, called 'oxidative stress', is responsible, atleast in part, to the pathophysioiogy of a number of disease states such as inflammation, arthritis, cancer, ageing, ischemia-reperfusion and several neurodegenerative disorders. Compared to other organs in the animal body, brain tissue is more vulnerable to oxidative stress. This is due to three major reasons; (1) brain has a high oxygen consumption (2) high content of polyunsaturated fatty acids and iron, that can promote lipid peroxidation, and (3) low levels of antioxidant enzymes such as catalase and glutathione peroxidase. The inability of neurons to regenerate also contributes to exacerbate an oxidant damage in the brain. The main objective of this investigation was to identify biochemical systems in the brain that are susceptible to ROS, on the following two issues: 1. What are the targets for the action of H2O2 and NO in the glycolytic cycle, the major route for the oxidation of glucose in brain? 2. What are the targets for the action of polyunsaturated fatty acids and their oxidative metabolites among the enzymes of phosphoinositide cycle (PI cycle), the ubiquitous signal transduction event in the brain? Using sheep brain cytosol , it was found that among the various glycolytic enzymes, only glyceraldehyde 3-phosphate dehydrogenase (GAPD) was inhibited by H2O2. The enzyme was purified to homogeneity from sheep brain and its inactivation with H202 was studied in detail. Commercial preparations of rabbit skeletal muscle GAPD was also used in this study. An unusual requirement of glutathione for the complete inactivtion of the enzyme by H2O2 was observed. The H2O2-inactivated GAPD was partially reactivated by prolonged treatment with thiol compounds. Using CD-spectral analysis, a significant change was found in the secondary structure in H2O2-treated GAPD. GAPD was inactivated by NO only in presence of high concentrations of DTT and after prolonged incubation. The N0-inactivated GAPD was partially reactivated by treatment with thiol compounds. A new activity, namely ADP-ribosylation (ADPR) emerged in the NO-treated mammalian, but not in yeast. GAPD, ADPR activity could be generated in GAPD through NO-independent treatments such as incubation with NADPH and aerobic dialysis. During NADPH treatment no loss of dehydrogenase activity occurred. Thus, it was concluded that loss of dehydrogenase activity and emergence of ADPR in NO-treated GAPD were not correlated but coincidental, and that NO treatment yielded small amounts of modified-GAPD that had ADPR activity. In the brain, onset of ischemia is characterized by a significant elevation in free fatty acid (FFA) levels, predominantly, arachidonic acid (AA). It is suggested that AA can be oxidised to its metabolites like prostaglandins and 15-hydroperoxy arachidonic acid (15-HPETE) and some of these might exert toxic effects during reperfusion. Using whole membranes or tissue slices prepared from rat brain, effects of polyunsaturated fatty acids and their oxidative metabolites on five enzymes of PI cycle namely PI synthase, PI and PIP kinases, agonist-stimulated PLC and DG kinase was studied. Hydroperoxides of linoleic- and arachidonic acids inactivated PI synthase selectively among the PI cycle enzymes. Interestingly, AA selectively stimulated DG kinase in neural membranes. Docasahexaenoic acid (DHA) a highly unsaturated fatty acid found in the brain, also stimulated DG kinase activity while saturated, mono-and di-unsaturated fatty acids were ineffective. It was concluded that AA and DHA have a role in modulating neural DG kinase. The data presented in the thesis indicate that ROS have selective targets in cells and the consequent protein modifications can be used to modulate cellular functions under normal and oxidative stress conditions.

Sutherland, Sparks and Lehmann (2010) proposed a new theory of memory consolidation, termed Distributed Reinstatement Theory (DRT), where the hippocampus (HPC) is needed for initial encoding but some types of memories are established in non-HPC systems through post-learning HPC activity. An evaluation of the current methodology of temporary inactivation was conducted experimentally. By permanently implanting two bilateral guide cannulae in the HPC and infusing ropivacaine cellular activity could be reduced by 97%. Rats were trained in a context-fear paradigm. Six learning episodes distributed across three days made the memory resistant to HPC inactivation while three episodes did not. Blocking post-learning HPC activity following three of six training sessions failed to reduce the rat’s memory of the fearful context. These results fail to support DRT and indicate that one or more memory systems outside the HPC can acquire context memory without HPC post-event activity. / x, 85 leaves : ill. ; 29 cm

Flow is a mental state characterised by a feeling of energised focus, complete involvement and success when fully immersed in an activity. The dimensions of and the conditions required for flow to occur have been explored in a broad spectrum of situational contexts. The close relationship between flow and peak performance sparked an interest in ways to induce flow. However, any process of flow induction requires a measure to trace the degree to which flow is in fact occurring. Self-reports of the flow experience are subjective and provide ad hoc information. Psycho-physiological measures, such as EEG, can provide objective and continuous indications of the degree to which flow is occurring. Unfortunately few studies have explored the relationships between psycho-physiological measures and flow. The present study was an attempt to determine the EEG correlates of flow under conditions of peak performance. Twenty participants were asked to perform a continuous visuomotor task 10 times. Time taken per task was used as an indicator of task performance. EEG recordings were done concurrently. Participants completed an Abbreviated Flow Questionnaire (AFQ) after each task and a Game Flow Inventory (GFI) after having finished all 10 tasks. On completion, performance times and associated flow scores were standardised where after the sample was segmented into a high flow - peak performance and a low flow - low performance level. Multi-variate analysis of variance (MANOVA) was conducted on the performance, flow and EEG data to establish that a significant difference existed between the two levels. In addition, a one-way analysis of variance between high and low flow data was conducted for all variables and main effects were established. Inter-correlations of all EEG data at both levels were then conducted across four brain sites (F3, C3, P3, O1). In high flow only, results indicated increased lobeta power in the sensorimotor cortex together with a unique EEG pattern showing beta band synchronisation between the prefrontal and sensori-motor areas and de-synchronisation between all other areas, while all other frequencies (delta, theta, alpha, lobeta, hibeta, and gamma) remained synchronised across all scalp locations. These findings supported a theoretical neuropsychological model of flow. / Psychology / D. Com. (Consulting Psychology)

Stress-related cognitive changes are still a matter of debate. In some particular neuropathological conditions such as focal ischemia, cognitive functions have been shown to be significantly impaired. These conditions, however, may be improved by some factors such as steroid hormones. The purpose of the current thesis was to assess the structural and functional effects of corticosterone-related experiences on the hippocampus before and after endothelin-1 (ET-1)-induced stroke. We found corticosterone-related experiences enhance the hippocampal recovery, and improve its function in both wet and dryland tasks after ET-1-induced focal stroke. Structural and functional effects of such experiences prior to the focal ischemia in the hippocampus, however, showed that stress, not corticosterone is a strong inhibitor for hippocampal recovery. / xii, 252 leaves : ill. ; 29 cm. --

This dissertation is devoted to study of complex systems in human physiology particularly heartbeats and brain dynamics. We have studied the dynamics of heartbeats that has been a subject of investigation of two independent groups. The first group emphasized the multifractal nature of the heartbeat dynamics of healthy subjects, whereas the second group had established a close connection between healthy subjects and the occurrence of crucial events. We have analyzed the same set of data and established that in fact the heartbeats are characterized by the occurrence of crucial and Poisson events. An increase in the percentage of crucial events makes the multifractal spectrum broader, thereby bridging the results of the former group with the results of the latter group. The crucial events are characterized by a power index that signals the occurrence of 1/f noise for complex systems in the best physiological condition. These results led us to focus our analysis on the statistical properties of crucial events. We have adopted the same statistical analysis to study the statistical properties of the heartbeat dynamics of subjects practicing meditation. The heartbeats of people doing meditation are known to produce coherent fluctuations. In addition to this effect, we made the surprising discovery that meditation makes the heartbeat depart from the ideal condition of 1/f noise. We also discussed how to combine the wave-like nature of the dynamics of the brain with the existence of crucial events that are responsible for the 1/f noise. We showed that the anomalous scaling generated by the crucial events could be established by means of a direct analysis of raw data. The efficiency of the direct analysis procedure is made possible by the fact that periodicity and crucial events is the product of a spontaneous process of self-organization. We argue that the results of this study can be used to shed light into the nature of this process of self-organization.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual loss of brain functions, usually preceded by memory impairments. It has been widely affecting aging Americans over 65 old and listed as 6th leading cause of death. More importantly, unlike other diseases, loss of brain function in AD progression usually leads to the significant decline in self-care abilities. And this will undoubtedly exert a lot of pressure on family members, friends, communities and the whole society due to the time-consuming daily care and high health care expenditures. In the past decade, while deaths attributed to the number one cause, heart disease, has decreased 16 percent, deaths attributed to AD has increased 68 percent. And all of these situations will continue to deteriorate as the population ages during the next several decades. To prevent such health care crisis, substantial efforts have been made to help cure, slow or stop the progression of the disease. The massive data generated through these efforts, like multimodal neuroimaging scans as well as next generation sequences, provides unprecedented opportunities for researchers to look into the deep side of the disease, with more confidence and precision. While plenty of efforts have been made to pull in those existing machine learning and statistical models, the correlated structure and high dimensionality of imaging and genetics data are generally ignored or avoided through targeted analysis. Therefore their performances on imaging genetics study are quite limited and still have plenty to be improved. The primary contribution of this work lies in the development of novel prior knowledge-guided regression and association models, and their applications in various neurobiological problems, such as identification of cognitive performance related imaging biomarkers and imaging genetics associations. In summary, this work has achieved the following research goals: (1) Explore the multimodal imaging biomarkers toward various cognitive functions using group-guided learning algorithms, (2) Development and application of novel network structure guided sparse regression model, (3) Development and application of novel network structure guided sparse multivariate association model, and (4) Promotion of the computation efficiency through parallelization strategies.