To align the neuropsychological functioning of our adult euthymic patient group with that reported in previous studies on euthymic bipolar disorder (BD), we used a neuropsychological battery that examined sustained attention (Rapid Visual Information Processing Task), verbal memory (California Verbal Learning Task), executive functioning (Intradimensional-Extradimensional Shift Task, Barrett Impulsivity Task, and Framing Task), and emotion responsiveness/regulation (Positive Affect/Negative Affect Scales, Behavioral Inhibition/Behavioral Activation Scale, and Affective Lability/Affective Intensity Scales) in patients versus healthy volunteers (HV). Our results corroborated existing evidence of reduced sustained attention, impaired verbal memory and executive functioning, and abnormal emotional responsiveness and regulation in euthymic BD relative to healthy controls (Chapter 2). To investigate how abnormal development of brain function in BD leads to deficits in decision-making, motor inhibition, and response flexibility, we examined child and adult BD using a novel risky decision-making task, and used cross-sectional (age x diagnosis) functional magnetic resonance (fMRI) designs to examine neural activation associated with motor inhibition and response flexibility in BD relative to HV. During the risky decision-making task, adult euthymic BD patients were no different from healthy controls in their proportion of risky lottery choices over a range of competing lotteries. This matched behavioral performance was associated with similar prefrontal and striatal brain activation between the patient and control groups during response, anticipation, and outcome phases of decision-making (Chapter 3). These results are different from previous studies that have shown increased risk taking during decision-making in euthymic BD. Similarly, young BD patients were no different from age-matched healthy and patient controls in their pattern of decision making during the risky choice task. This was evidenced by a similar number of risky lottery selections over the range of changing expected values between the young BD group and control groups (Chapter 4). Using a cross-sectional, fMRI analytic design during the stop signal task, we found that child and adult BD showed similar behavioral performance to child and adult HV during motor inhibition. However, this matched behavioral performance was associated with abnormal neural activation in patients relative to controls. Specifically, during unsuccessful motor inhibition, there was an age group x diagnosis interaction, with BD youth showing reduced activity in left and right ACC compared to both age-matched HV and adult BD, and adult BD showing increased activation in left ACC compared to healthy adults. During successful motor inhibition there was a main effect of diagnosis, with HV showing greater activity in left VPFC and right NAc compared to BD (Chapter 5). These neuroimaging data support existing laboratory-based evidence of motor inhibition impairments in BD relative to HV, and indicate brain dysregulation during motor control is important to BD pathophysiology. A previous behavioral study showed impaired response flexibility in young BD patients relative to age-matched controls when using the change task. Here, we used the change task during fMRI to examine response flexibility in child and adult BD compared to child and adult HV. We found that patient and control groups showed similar change signal reaction times in response to change cues. However, this matched behavioral performance was associated with abnormal age group x diagnosis activations in brain regions important in signal detection, response conflict, response inhibition, and sustained attention. Specifically, during successful change trials, child BD participants showed frontal, parietal, and temporal hyperactivation relative to healthy children and adult BD, while adult BD showed hypoactivation in these regions relative to healthy adults. These novel fMRI findings during the change task indicate impaired neural activation during response flexibility may be important to the pathophysiology of BD development.

The hippocampus plays an important role in the processing of spatial memory. During exploration, theta oscillations (4-12 Hz) are prominent in the hippocampus, whereas during sleep and rest irregular sharp wave/ripple (SWR) events occur spontaneously in the hippocampus and may support memory consolidation. To date, the ventral sub-region of the rodents hippocampus, has received less attention relative to the more accessible dorsal part. It has been suggested that spatial information decreases along the septo-temporal axis in favour of coding salient features and coordinated oscillatory activity might enable the binding of spatial and nonspatial information. The first goal of my research was to investigate how the spatial representation by dorsal and ventral neurons is organised by theta oscillations in the hippocampal network. The second goal was to investigate the role of the ventral hippocampus in spatial learning. Finally, the third goal examined to what extent the firing relationships established during spatial learning are replayed during subsequent sleep in the ventral CA1. I recorded the network activity of dorsal and ventral CA1 in rats performing a spatial memory task on the cheese board maze (Dupret et al., 2010). By using parallel multi-channel extracellular recordings in the dorsal and ventral portions of the hippocampus in behaving rats, I found that dorsal and ventral CA1 were theta coupled at particular times of the spatial learning. High coherence periods across the two regions were characterized by a strong speed-modulation of ventral theta oscillations, which was absent in other conditions. During sleep, it was found that SWR-related activity was presented in the ventral hippocampus as well, when the coordinated population activity established in spatial learning was reactivated within the two sub-regions. By contrast, reactivation across the two regions was observed outside the SWRs epochs. Overall, the data suggests that the ventral hippocampus might be involved in the processing of salient features of the environment such as rewards. On a temporal scale, this non-spatial information might be integrated to the spatial information provided by the dorsal hippocampus during theta oscillation. During sleep/rest periods, the coordinated communication of learned information might underlie the consolidation of memory traces.

Many psychotic patients fail to admit they are mentally ill. The current study evaluated the associations between insight, specific symptoms, and neurocognitive impairments. Thirty-three acute inpatients with a schizophrenia, schizoaffective disorder, or psychotic disorder NOS diagnosis were rated on the SAIE, Birchwood's IS, and the BPRS. Neurocognitive assessments of attention and frontal lobe functioning were also conducted. Stepwise multiple regression analyses found composites representing delusions, disorganization, and anxiety/depression, as well as CPT-IP shapes hit rate, served as significant predictors of total insight or the specific insight dimensions. At least for acute patients, symptoms tended to have stronger relationships with and were more regularly predictive of insight than neurocognitive measures, though the attentional task associated with right hemisphere functioning, contributed significantly.

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-TBI pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The studies in this dissertation were designed to test the efficacy of atomoxetine for treating cognitive deficits following experimental TBI and the potential mechanism for any beneficial effect. The first part of the study focused on behavioral recovery following atomoxetine treatment. Several important questions of dose, therapeutic window, and duration of treatment were addressed in these studies. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- .05). Four experiments were performed. In the first study, atomoxetine (.3 mg/kg, 1mg/kg, 3 mg/kg, or 9 mg/kg) or vehicle was administered daily on post injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (.3mg/kg, 1mg/kg, and 3mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In the next study atomoxetine was given daily on PID 1-7 and then treatment was terminated. The animals were tested in the MWM on PID 11-15. We found that atomoxetine treatment for 7 days post-injury provides an enhancement of cognitive deficits that is not significantly different from sham animals. We then investigated whether a single treatment of atomoxetine 24 h after brain injury could influence behavioral outcome on days 11-15. From this study, we found a single dose of atomoxetine is not as effective as chronic treatment. Finally, we investigated changes in the protein expression of brain-derived neurotrophic factor, growth-associated protein-43, and synaptophysin on day 7 PID to investigate what effect atomoxetine may have on brain plasticity and regeneration. We found that atomoxetine can enhance both GAP-43 and BDNF, but not synaptophysin at this time point. In conclusion, this is the first study to show that low doses of atomoxetine initiated early after experimental traumatic brain injury results in improved cognition. Furthermore, we show that enhancement of catecholamines via atomoxetine treatment during periods of postinjury-induced plasticity can provide long-term functional and structural benefits.

Depression in adolescence is a major health problem, associated with poor psychological function and key risk factors both for later illness and suicidal behaviours. The antidepressant fluoxetine is commonly used in this population and it is shown to have a favourable benefit-to-risk profile. However, controversy still exists about the use of antidepressants in young people and there is little research focusing on underlying mechanisms of wanted and unwanted actions in this group. This doctoral thesis aims to investigate, for the first time, the acute effects of fluoxetine on emotional processing, using a combination of behavioural and neuroimaging techniques. The aim is to achieve a greater understanding of the mechanisms underlying fluoxetine use in depressed adolescents, in light of differences seen in their clinical presentation and response to antidepressant drugs. In the first study (Chapter Two), a single dose of fluoxetine was shown to decrease the recognition of anger in a sample of young adult volunteers, an effect not previously seen in acute studies of older participants. This effect may be particularly relevant for the treatment of adolescent depression, in which symptoms of anger and irritability are often prominent. Beyond this, fluoxetine was shown to increase the recognition of positive vs. negative facial information, and also exerted an anxiolytic-like influence, eliminating the emotion-potentiated startle effect. However, no influence was seen in measures of attentional vigilance to threat. In an attempt to overcome methodological limitations of this study, a paradigm was developed that is particularly sensitive to the detection of automatic biases towards threatening information (Chapter Three). Chapter Four describes a neuroimaging study with depressed adolescents, in which a single dose of fluoxetine was found to reduce amygdala activity in response to anger. Early changes in amygdala activity to fear correlated with decreased symptoms of anxiety and depression in the first 7-10 days of treatment. Chapter Five explores the effects of acute fluoxetine in a sample of high trait anger males. This study replicated the finding that fluoxetine acts to increase the recognition of positive information, whilst showing preliminary evidence for a reduction in attentional vigilance to angry faces. Overall, fluoxetine was found to decrease the processing of anger across studies. This effect was seen alongside a broader influence on positive vs. negative information and anxiolytic-like properties. Together, these results indicate that fluoxetine has direct effects on processes that are especially relevant to adolescent depression and suggest a potential cognitive mechanism for the efficacy of this particular antidepressant in adolescent patients.

The subthalamic nucleus (STN), which is the most common target for deep brain stimulation for Parkinson's disease, is known to be crucially involved in motor control. Recent appreciation of the potential non-motor side effects of STN deep brain stimulation, however, has led to speculation that the importance of this nucleus may also relate to processes involved in decision- making, particularly during high conflict scenarios. This thesis concerns itself with investigating the STN's role in action selection during conflict. I begin by recording local field potentials directly from the STN of Parkinson's disease patients while they perform a flanker task that has been shown to elicit theta (4-8 Hz) band activity in areas of the prefrontal cortex involved in cognitive control. I report that like the prefrontal cortex, the STN demonstrates elevated theta activity during conflict. I then test whether STN theta activity is related to that of the prefrontal cortex by recording from both sites simultaneously while patients perform a novel task that temporally separates conflict from stimulus onset or movement. This reveals that theta activity indeed becomes synchronized during conflict, with cortical oscillations driving those of the STN. Thirdly, I investigate how STN oscillations may affect firing rate dynamics by intra-operatively recording local field potentials and single unit activity from patients performing the flanker task. I report that both theta and beta (15-30 Hz) oscillations entrain STN neurons, but only during conflict. Finally, I record cortical and STN activity while a fourth group of patients performs the flanker task. This experiment confirms that cortico-STN theta synchrony is elevated during conflict and may also relate to across-trial adaptations to conflict and errors. Taken together these studies shed light on the mechanisms by which cortical structures may influence the STN during conflict and why STN deep brain stimulation may result in impulsivity.

This study examined how attentional sub-processes contribute to binge-eating. Dense-array EEG and a version of the canonical attentional blink task were used to ascertain the neural correlates underlying the attentional sub-processes that comprise the Posner model of attention (alerting, orienting, and executive control) and how attentional activation differs for binge-eaters vs. non-binge eaters. Furthermore, we examined a number of the event-related potentials (ERP), including P2 activation, which has been linked with orientating of attention, and N2 activation which has been linked with attentional conflict. We found decreased P2 activation for binge-eaters, in the negative condition, for incorrect target 2 (T2) detection trials. We also found more N2 activation for binge-eaters than non-binge eaters, in negative trials when T2 was not detected. This pattern of results suggest that binge-eaters showed deficiencies in allocating attention to stimuli that followed negative images; this attention deficiency may be a key factor for binge-eating behavior.

Decision making can be a complicated process involving perception of the present situation, past experience and knowledge necessary to foresee a better future. This cognitive process is one of the essential human ability that is required from everyday walk of life to making major life choices. Although it may seem ambiguous to translate such a primitive process into quantifiable science, the goal of this thesis is to break it down to signal processing and quantifying the thought process with prominence of EEG signal power variance. This paper will discuss the cognitive science, the signal processing of brain signals and how brain activity can be quantifiable through data analysis. An experiment is analyzed in this thesis to provide evidence that theta frequency band activity is associated with stress and stress is negatively correlated with concentration and problem solving, therefore hindering decision making skill. From the results of the experiment, it is seen that theta is negatively correlated to delta and beta frequency band activity, thus establishing the fact that stress affects internal focus while carrying out a task.

Text in English / This work is organised around two main objectives: a) the formulation of a new conceptual framework as the basis for a new scientific aesthetic; and (b) an attempt to explain the possibilities and current limitations of neuroscience in aesthetics. The first part of the work is devoted to the conceptual foundations of aesthetics. In the first chapter, I analyse the philosophical assumptions reflected in neuroaesthetics. In particular, I would like to show that the concept of art on which neuroaesthetics is based is both conceptually and empirically untenable. In the second chapter, I propose a new conceptual framework for a theory of aesthetics; in particular, I present new definitions of key concepts in aesthetics, such as 'art', 'artistic system', 'artistic movement', 'artwork', and so forth. Furthermore, in the second chapter, I advance the view that—even though the neurosciences are an essential part of aesthetics—not every aesthetic problem requires a neuroscientific solution. In other words, there are aesthetic problems that cannot be answered satisfactorily by neuroscience using only its special concepts and terminology. Some questions may require additional sociological, physical and/or semiotic concepts, and explanatory devices. The second part of this thesis deals with the experimental aspects of the neuroscience of artistic appreciation. First, I argue that the conceptual foundations underlying much of the current approaches to neuroaesthetics are still problematic and that the experimental approach cannot be applied in any straightforward manner to conduct neuroaesthetic research. I then review some of the most important results of experimental aesthetics and cognitive neurosciences with regard to the mechanisms of aesthetic appreciation before proposing a new neurocognitive model of artistic appreciation based on the notion of an artistic 'task-set' Finally, I end the second part with a theoretical postulate and a neurocognitive framework pertaining to the interactions between mental images and emotions and their possible role in the process of appreciating literary artworks. In the third and final part of the work, I briefly discuss the central ontological preconditions of the neurocognitive studies of art, namely, the neural hypothesis of identity, ‘mind = brain’, and compare it to other approaches of the mind-brain relationship. I also offer a hierarchical model of mental functions based on both the anatomical and the functional aspects of the brain. / Psychology / Ph. D. (Psychology)

The facial width-to-height ratio (fWHR) is a measure of the cheekbone width divided by the height of the face from the upper lip to the brows. The metric is hypothesised to have evolved as an intra-sexual competition mechanism in males, where large fWHRs are thought to signal both threat and aggression. The fWHR is suggested to subtly resemble angry facial expressions, which, in turn, also signal threat. The late positive potential (LPP) and the vertex positive potential (VPP) are two event-related potentials (ERPs) especially sensitive to emotional content. Studies have also found that viewing angry compared to neutral facial expressions elicit a stronger response on the LPP. However, no study has tested how responses to the fWHR and angry facial expressions elicit changes in the LPP or VPP. In this study, participants firstly rated how threatening faces were with either low or high fWHRs with neutral or angry facial expressions. Secondly, EEG-activity was recorded during a picture-viewing task of the same faces. In the first task, participants rated the faces with angry facial expressions as more threatening compared to all other faces, regardless of fWHR, although the high fWHRs were rated as more threatening than the low fWHRs. In the second task, LPP and VPP mean amplitudes were significantly higher for the angry, high fWHR face compared to all other faces tested. This suggests that an additive effect of both angry facial expressions and high fWHRs together creates the highest threat level in both subjective ratings as well as in ERP mean amplitudes. Further ERP research is needed on the relationship between fWHRs and anger to establish how the two features work both separately and together.