This dissertation proposes to combine magnetic resonance imaging (MRI), positron emission tomography (PET) and a neuropsychological test, Mini-Mental State Examination (MMSE), as input to a multidimensional space for the classification of Alzheimer’s disease (AD) and it’s prodromal stages including amnestic MCI (aMCI) and non-amnestic MCI (naMCI). An assessment is provided on the effect of different MRI normalization techniques on the prediction of AD. Statistically significant variables selected for each combination model were used to construct the classification space using support vector machines. To combine MRI and PET, orthogonal partial least squares to latent structures is used as a multivariate analysis to discriminate between AD, early and late MCI (EMCI and LMCI) from cognitively normal (CN)s. In addition, this dissertation proposes a new effective mean indicator (EMI) method for distinguishing stages of AD from CN. EMI utilizes the mean of specific top-ranked measures, determined by incremental error analysis, to achieve optimal separation of AD and CN. For AD vs. CN, the two most discriminative volumetric variables (right hippocampus and left inferior lateral ventricle), when combined with MMSE scores, provided an average accuracy of 92.4% (sensitivity: 84.0%; specificity: 96.1%). MMSE scores were found to improve classification accuracy by 8.2% and 12% for aMCI vs. CN and naMCI vs. CN, respectively. Brain atrophy was almost evenly seen on both sides of the brain for AD subjects, which was different from right side dominance for aMCI and left side dominance for naMCI. Findings suggest that subcortical volume need not be normalized, whereas cortical thickness should be normalized either by intracranial volume or the mean thickness. Furthermore, MRI and PET had comparable predictive power in separating AD from CN. For the EMCI prediction, cortical thickness was found to be the best predictor, even better than using all features together. Validation with an external test set demonstrated that best of feature-selected models for the LMCI group was able to classify 83% of the LMCI subjects. The EMI-based method achieved an accuracy of 92.7% using only MRI features. The performance of the EMI-based method along with its simplicity suggests great potential for its use in clinical trials.

The last decade has seen a surge in the development of Brain-Machine Interfaces (BMI) as assistive neural devices for paralysis patients. Current BMI research typically involves a subject performing movements by controlling a robotic prosthesis. The neural signal that we consider for analysis is the Local Field Potential (LFP). The LFP is a low frequency neural signal recorded from intra-cortical electrodes, and has been recognized as one containing movement information. This thesis investigates hand-movement prediction using LFP data as input. In Chapter 1, we give an overview of Brain Machine Interfaces. In Chapter 2, we review the necessary concepts in time series analysis and pattern recognition. In the final chapter, we discuss classification accuracies when considering Summed power and Coherence as feature vectors.

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Dissociated neuronal cell cultures grown on substrate integrated microelectrode arrays (MEAs) generate spontaneous activity that can be recorded for up to several weeks. The signature wave shapes from extracellular recording of neuronal activity display a great variety of shapes with triphasic signals predominating. I characterized extracellular recordings from over 600 neuronal signals. I have preformed a categorical study by dividing wave shapes into two major classes: (type 1) signals in which the large positive peak follows the negative spike, and (type 2) signals in which the large positive peak precedes the negative spike. The former are hypothesized to be active signal propagation that can occur in the axon and possibly in soma or dendrites. The latter are hypothesized to be passive which is generally secluded to soma or dendrites. In order to verify these hypotheses, I pharmacologically targeted ion channels with tetrodotoxin (TTX), tetraethylammonium (TEA), 4-aminopyridine (4-AP), and monensin.

This thesis will address the mechanisms underlying amphetamine addiction, as well as the psychosis that may develop with amphetamine use.

Male survivors of abuse who become fathers themselves face challenges different from female survivors, such as conceptualizing their roles as providers and heads of households after the traumatic and often belittling experiences of abuse. However, very few researchers have studied the connection between child abuse and fatherhood, and none specific to young African American fathers. An interpretative phenomenological approach enabled exploration of how African American fathers who were abused as children, conceptualized and perceived their own experiences with fatherhood. The theoretical framework for this study was identity theory, which indicates that how people conceptualize a social role influences their actions in that role. Research questions centered on how young African American fathers, who were abused as children, conceptualized fatherhood and carried out their roles as fathers. Data collected from 11 young African American fathers came through in-depth, semistructured interviews. Key findings showed participants conceptualized fatherhood as being present for, providing for, and protecting their children. These fathers worked to break the cycle of abuse they had experienced and to show support for their children. Implications to promote social change include use of study findings to develop parenting programs that address childhood trauma. Other benefits may come from developing groups for father with children in the foster care system, helping these men to understand why they parent the way they do and to break the destructive cycle of parenting they had experienced. Findings may also contribute to the establishment of fatherhood programs that match fathers with supportive role models who help in navigating the father role.

Male survivors of abuse who become fathers themselves face challenges different from female survivors, such as conceptualizing their roles as providers and heads of households after the traumatic and often belittling experiences of abuse. However, very few researchers have studied the connection between child abuse and fatherhood, and none specific to young African American fathers. An interpretative phenomenological approach enabled exploration of how African American fathers who were abused as children, conceptualized and perceived their own experiences with fatherhood. The theoretical framework for this study was identity theory, which indicates that how people conceptualize a social role influences their actions in that role. Research questions centered on how young African American fathers, who were abused as children, conceptualized fatherhood and carried out their roles as fathers. Data collected from 11 young African American fathers came through in-depth, semistructured interviews. Key findings showed participants conceptualized fatherhood as being present for, providing for, and protecting their children. These fathers worked to break the cycle of abuse they had experienced and to show support for their children. Implications to promote social change include use of study findings to develop parenting programs that address childhood trauma. Other benefits may come from developing groups for father with children in the foster care system, helping these men to understand why they parent the way they do and to break the destructive cycle of parenting they had experienced. Findings may also contribute to the establishment of fatherhood programs that match fathers with supportive role models who help in navigating the father role.

Social isolation is commonly reported in individuals with isolated cleft lip and palate (ICLP), and is often cited as due to secondary factors of living with a facial malformation. However, the data are mixed, and the literature is biased to self-report studies. This study aimed to go beyond self-report data, and various components of social functioning were examined in a group of males with and without ICLP. The main aim of the study was to assess and compare social motivation in ICLP, and to relate social adjustment to brain structure. It was predicted that males with ICLP would be more likely to be socially isolated; however, self-concept was predicted to be similar to the comparison group (NC). Additionally, males with ICLP were predicted to have reduced social motivation (i.e., social abulia). Finally, volumes of the medial orbitofrontal cortex (mOFC) and the cerebellum were predicted to be related to social outcomes. The sample's age range was 13 - 25 years old, and 20 males with ICLP were compared to a group of 20 NC males. MRI scans were obtained from all the participants. As expected, males with ICLP were more likely to be socially isolated. Against predictions, they also had lower self-concept relative to the NC group. However, self-concept was not related to the extent of facial abnormality in the ICLP group. In line with predictions, the study did provide evidence for social abulia as a mechanism for social isolation, as males with ICLP had a more positive attitude after being socially excluded relative to excluded NC males. Unexpectedly however, the groups responded the same to social pressure, as all participants were more likely to take riskier turns in a driving simulator experiment when someone behind them was honking. Finally, social adjustment was significantly correlated with the volume of the mOFC, and posterior cerebellum white matter. Both correlations suggested that individuals with larger volumes were more likely to be better socially adjusted. In conclusion, the study provided evidence for a potentially different mechanism of social isolation in ICLP, and showed that brain morphology may at least partly underlie social dysfunction as well.

Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy severely injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection, as they develop neuropathology, including cerebellar injuries, similar to those seen in humans. The goal of this thesis was to determine what underlies brain injury and the differential immune response and to determine the role of T-cells in LCMV induced pathology. First, I examined whether cytokine and chemokine expression after LCMV infection was higher in the cerebellum and olfactory bulbs, which undergo destruction, compared to the hippocampus and septum, which undergo no acute destruction. Second, I used T-cell deficient and T-cell competent animals to evaluate the role of T-lymphocytes in LCMV-induced cerebellar and hippocampus pathology. Finally, I characterized the migration abnormality that develops in the cerebellum after LCMV infection. My results showed that cytokine and chemokine expression is higher in the cerebellum and olfactory bulb than in the hippocampus and septum. Using astrocyte cultures, I determined that astrocytes isolated from the cerebellum have a more robust cytokine response to infection compared to astrocytes from the hippocampus. Furthermore, inoculation of congenitally athymic (rnu/rnu) rats, which are deficient in T-lymphocytes, demonstrated that cerebellar hypoplasia is T-cell independent while cerebellar destruction and abnormal neuron migration is T-cell dependent. In the hippocampus, T-cells protect against loss of dentate granule cells. A study of the migration abnormality determined that LCMV infection disrupts radial glia fibers and extends proliferation of granule cells in a T-cell dependent manner. The findings reported here support a pivotal role of the immune system in regional brain pathology as well as in the disruption of migration.

Cigarette smoking is an addictive behavior. There are two learned emotional responses to smoking that may be particularly important for promoting addiction to smoking: the pleasure obtained from the airway sensory effects of smoking (airway sensory pleasure) and the urge to smoke that is elicited by environmental smoking cues (cue-induced urge). The ventromedial prefrontal cortex (VMPFC) has been implicated in a variety of learned emotional and motivational responses to drug-associated sensory cues. This project set out to address the role of the VMPFC and related areas in airway sensory pleasure and cue-induced urge, as well as the role of this region in promoting smoking behavior in real life, by examining the effects of focal lesions within the VMPFC and related areas in human cigarette smokers. It was found that lesions of the VMPFC itself were associated with a marked impairment of cue-induced urge in the laboratory, which was paralleled by a reported reduction in the difficulty of abstaining from smoking in real life. At the same time, VMPFC lesions led to a relative sparing of airway sensory pleasure in the laboratory, which was paralleled by no change in the enjoyment from smoking in real life. In addition, it was found that VMPFC lesions were not associated with changes in real-life measures of smoking dependence. It was found that lesions of the insula, a region that is functionally related to the VMPFC, were associated with an ability to quit smoking easily, immediately, without relapses and without a lasting urge to smoke. However, among patients with insula lesions who continued to smoke after lesion onset, there were no appreciable impairments of airway sensory pleasure or cue-induced urge. The results suggest that, while VMPFC lesions may disrupt cue-induced urges, they do not disrupt dependence upon smoking. This may be because VMPFC lesions spare more implicit motivational processes, such as "habits" and "incentive salience," that can drive smoking behavior in the absence of a conscious desire to smoke. The results also suggest that the insula functions in psychological processes that may contribute to the difficulty of quitting smoking.