The present thesis employed event-related potentials, the minute responses of the brain, to examine the differences in processing of increases and decreases in auditory intensity. The manner in which intensity was manipulated (i.e., whether it represented physical or psychological change) varied across the studies of the thesis. Study 1 investigated the processing of physical intensity change during wakefulness and natural sleep. An oddball paradigm (80 dB standard, 90 dB increment, 60 dB decrement) was presented to subjects during the waking state and during sleep. The increment elicited a larger deviant-related negativity and P3a than the decrement in the waking state. During sleep, only the increment deviant continued to elicit ERPs related to the detection of change. The waking and sleeping findings support the notion that increases in intensity are more salient to an observer. Studies 2 and 3 of this thesis determined the degree to which this differential salience could be attributed to the fact that intensity increments result in increased activation of the change and transient detection systems while intensity decrements result in greater activation of only the change detection system. In order to address this question, an alternating intensity pattern was employed (HLHLHLHL) with deviants created by the repetition of a tone in the sequence (HLHLHHHL) that violated the expectancy for a higher (psychological decrements) or lower intensity tone (psychological increments). Because deviant stimuli were physically identical to preceding standards, this manipulation should not have led to increased output of the transient detection system (N1 enhancement), permitting isolation of the output of the change detection system (Mismatch Negativity, MMN). The findings of these studies indicated that psychological increments resulted in shorter latency and larger amplitude MMNs than psychological decrements and that these differences could not be explained by the physical differences between deviant stimuli or temporal integration. This thesis provides convincing evidence that stimuli representing increments in intensity result in faster and more robust change detection. Further, the increased salience of increment stimuli cannot be solely explained by the contribution of transient detector activation, as it persists even when deviance-related processing is isolated to the change detection system.

This set of studies used event-related potentials (ERPs) to investigate the electrophysiology of face recognition as it may occur in real-life circumstances including eyewitness identification. Research using photographs has identified two ERP components as being associated with memory function, the N250 (an early indicator of perceptual recognition) and the P300 (associated with stimulus evaluation, task-relevance, and probability), however, there is no published research examining the relationship between these components and memory for live events, and recognizing a face seen briefly in real-life is somewhat different than recognizing a face only seen in a photograph. The present set of three studies employed a “target / non-target” paradigm that used a live interaction at each encoding stage. In Experiment 1, participants were introduced to and asked to identify their study experimenter as the target. In the second experiment, participants were introduced to the same experimenter and asked to imagine that they witnessed her committing a convenience-store robbery. Participants were asked to “cover” for the experimenter by choosing a different photo from the line-up to accuse as the culprit – they are asked to lie. In Experiment 3, participants witnessed a live simulated theft and were asked to identify the culprit from a line-up. In all three experiments the line-up paradigm was identical – participants were shown a repeated series of sequentially-presented photographs and were asked to correctly identify one target among nine foils (non-targets), while brainwaves were recorded. Results showed that across all three studies, both the N250 and P300 were attenuated for the person selected as the target, in comparison to correct rejections of foils. Additional results from Experiment 2 showed that, compared to rejections of foils, both the N250 and P300 were enhanced for rejections of the experimenter-photo when participants were “covering” for her. In Experiment 3, participants who were unable to correctly identify the culprit showed that the N250 to incorrect rejections of the culprit was larger than correct rejections of foils. Finally, a comparison of participants who correctly identified the culprit and those who incorrectly identified a foil showed that the amplitude of the N250 and P300 to the selected culprit were equivalent regardless of eyewitness accuracy. Collectively, results from Experiments 1, 2 and 3 provide support that the memory effects indicated by the N250 and P300 components reported in laboratory studies generalize to person memories acquired during live interactions.

Adaptive decision making depends on multiple processes, including fast and efficient processing of stimulus events for effective responding and slow trial-to-trial learning of action values for optimization of the selection process. I applied the event-related brain potential (ERP) technique to investigate the involvement of two neuromodulatory systems in learning and decision making: The locus coeruleus-norepinephrine (LC-NE) system and the mesencephalic dopamine system (DA system). I present evidence that the "oddball" N2, a negative deflection in the ERP elicited by task-relevant events that begins approximately 200 ms after onset of the eliciting stimulus and that is sensitive to low-probability events, is a manifestation of cortex-wide noradrenergic modulation recruited to facilitate the processing of unexpected stimuli. Further, Holroyd and Coles (2002) proposed that the impact of DA reinforcement learning signals on the anterior cingulate cortex (ACC) produces a component of the ERP called the feedback-related negativity (FRN). I present electroencephalographic evidence that both the DA system and the LC-NE system act in concert when learning from rewards that vary in expectedness, but that the DA system is relatively more exercised when subjects are highly engaged/challenged by learning tasks, whereas the impact of the LC-NE system is attenuated by this manipulation. / Graduate

Current research in stuttering suggests that individuals who stutter (IWS) may have a hyperactive error-monitoring system, leading to the exacerbation and anticipation of verbal dysfluencies. Using a neurophysiological marker of error processing known as the feedback error-related negativity, the current thesis involved three studies. First, a pilot study was conducted to ensure that word feedback cues were usable in the current paradigm. Second, a classic virtual T-maze task was used to assess the generic error processing mechanism of IWS. Third, an adaptation of the T-maze was used to assess the integrity of the reinforcement learning system of IWS and their ability to associate reward and error information of personalized problem words with predictive cues. Results suggest preliminary evidence for functional generic error processing in IWS and disrupted error processing when conditioned predictive cues are needed to predict fluent versus dysfluent outcomes. / Graduate

Event-related potentials were recorded as subjects were presented with pairs of words, one word at a time, to examine the electrocortical manifestations of association formation and the effect of intra-list semantic similarity. Two types of lists were presented: Same – all pairs belonged to the same semantic category; Different – all pairs belonged to a different semantic category. Subjects were told to memorize the pairs for a following paired associate recall test. Recall was better for the Different than Same lists. Subsequent recall was predicted by the amplitudes of a potential lasting throughout the epoch and the P555 to each word of a pair (likely reflecting state- and item-related encoding activity, respectively), as well as a late positive wave that occurred after the offset of the second word, which is thought to reflect association formation. A larger N425 was elicited by pairs in the Different than Same lists, likely reflecting semantic integration.

Certain electrophysiological markers hold promise in distinguishing individuals with major depressive disorder (MDD) and in predicting antidepressant response, thereby assisting with assessment and optimizing treatment, respectively. This thesis examined resting brain activity via electroencephalographic (EEG) recordings, as well as EEG-derived event-related potentials (ERPs) to auditory stimuli and facial expression presentations in individuals with MDD and controls. Additionally, the utility of resting EEG as well as auditory ERPs (AEPs), and the associated loudness-dependence of AEPs (LDAEP) slope, were assessed in predicating outcome to chronic treatment with one of three antidepressant regimens [escitalopram (ESC); bupropion (BUP); ESC+BUP]. Relative to controls, depressed adults had lower pretreatment cortical activity in regions implicated in approach motives/positive processing. Increased anterior cingulate cortex (ACC)-localized theta was observed, possibly reflecting emotion/cognitive regulation disturbances in the disorder. AEPs and LDAEPs, putative indices of serotonin activity (implicated in MDD etiology), were largely unaltered in MDD. Assessment of ERPs to facial expression processing indicated slightly blunted late preconscious perceptual processing of expressions, and prolonged processing of intensely sad faces in MDD. Faces were rated as sadder overall in MDD, indicating a negative processing bias. Treatment responders (vs. non-responders) exhibited baseline cortical hypoactivity; after a week of treatment, cortical arousal emerged in responders. Increased baseline left fronto-cortical activity and early shifts towards this profile were noted in responders (vs. non-responders). Responders exhibited a steep, and non-responders shallow, baseline N1 LDAEP derived from primary auditory cortex activity. P2 LDAEP slopes (primary auditory cortex-derived) increased after a week of treatment in responders and decreased in non-responders. Consistent with overall findings, ESC responders displayed baseline cortical hypoactivity and steep LDAEP-sLORETA slopes (vs. non-responders). BUP responders also exhibited steep baseline slopes and high ACC theta. These results indicate that specific resting brain activity profiles appear to distinguish depressed from non-depressed individuals. Subtle ERP modulations to simple auditory and emotive processing also existed in MDD. Resting alpha power, ACC theta activity and LDAEP slopes predicted antidepressant response in general, but were limited in predicting outcome to a particular treatment, which may be associated with limited sample sizes.

Amnestic mild cognitive impairment (aMCI) has been established as a significant risk factor for Alzheimer‟s disease (AD) and in many cases this state appears to represent an early or incipient stage of AD. Due to difficulties with the diagnosis and prognosis of aMCI and AD, as well as with the projected significant socioeconomic ramifications of AD, there is a need to establish sensitive and reliable biomarkers. The application of event related potentials (ERPs) has been recommended in this context due to their reliability, non-invasive nature, inexpense and relatively widespread availability. This thesis aims to further assess the potential efficacy of ERP markers for such applications. These aims are pursued via investigations of ERPs in healthy ageing, MCI and AD utilising an explicit recognition task that requires the use of key cognitive/memory processes which are often impaired in aMCI and AD. Two ERP effects were analysed: the N400effect which is assumed to index familiarity or trace strength, and the Late Positive Complex (LPC) which appears to index recollection or decision-related factors such as accuracy. Chapter 3 reports ERP and recognition accuracy comparisons between samples of 15 young (mean age = 21.73 years) and 15 older, cognitively healthy adults (mean age = 66.67 years). ERP data were acquired during performance of a word recognition task with high and low memory load conditions (long and short encoding lists, respectively). At test, participants were required to make old/new judgements to visually presented words. There was a trend for young participants to perform more accurately than the older sample, especially on the long list; although these differences only approached significance. However, the N400 old/new effect was found to be significantly reduced in the old compared with the young participants across memory load conditions. LPC old/new effects were generally not observed and this is likely due to the nature of the task which generally places minimal demands on controlled retrieval processes. These results indicate that the N400 effect may be more sensitive to the deleterious effects of ageing on recognition memory-related process(s) than behavioural measures of memory accuracy. Consistent with the view that the N400 indexes familiarity, these results are in accordance with other evidence that familiarity is affected in healthy ageing. The same methodology was used to compare ERPs between aMCI (n = 11) and healthy older adults (n = 11) in Chapter 4. The aMCI participants performed significantly worse than vi healthy elderly participants in discriminating „old‟ from „new‟ words. In the corresponding ERP data, healthy control sample demonstrated significant N400 old/new effects at parietal electrode locations, whereas aMCI participants failed to demonstrate significant N400 old/new effects at any electrode location. Again, LPC effects were not observed in either sample. The absence of significant N400 effects in aMCI participants may reflect a disruption of familiarity-based recognition in aMCI. These results converge with other evidence that the N400 effect may be a sensitive ERP marker useful for detecting, monitoring and/or predicting amnestic related cognitive decline. There are reported variations in underlying causes and sequelae of aMCI (e.g., not all progress to AD). Chapter 5 reports an exploratory investigation aimed at determining whether baseline ERPs differentiate between aMCI participants on the basis of their clinical diagnosis at follow-up. Baseline ERP data were compared in a small sample (n = 7) of aMCI participant who remained cognitively stable at 12-month follow-up (SMCI) with two aMCI participants who progressed to meet an AD diagnosis (PMCI) at the latter time-point. There was a trend for PMCI participants to display smaller old/new effects. However, only one participant displayed significantly smaller N400 old/new effects under low memory load conditions. Interestingly, this participant was also more impaired in baseline cognitive functioning. Chapter 6 examines the relationship between baseline ERPs and performance on neuropsychological assessment at 12-month follow-up in a sample of aMCI and AD participants (n =13) in order to investigate whether ERPs may prove informative for prognoses regarding general trajectories of cognitive decline, irrespective of diagnostic status. Smaller N400 old/new effects (at Fz and CPz) were associated with poorer performance on tasks assessing global cognitive functioning and auditory attention span. Reduced LPC old/new differences were related to poorer performance on tasks assessing global cognitive functioning, verbal learning and memory and better performance on a task assessing working memory at follow-up. In contrast to these results, no relationships were observed between ERP effects and concurrent performance on neuropsychological assessment in this sample, or in 42 elderly participants (including healthy, aMCI and AD), as described in Chapter 7. Taken together these results suggest that ERPs may be more sensitive in predicting future rather than concurrent cognitive functioning and may provide a more objective measure/classification of cognitive impairment vii irrespective of diagnosis. These outcomes are particularly novel as the relationship between baseline ERP data and follow-up neuropsychological measures does not appear to have been systematically reported in the literature to date. Collectively these findings indicate that ERP measure(s), particularly the N400 old/new effect, are sensitive to neurocognitive changes associated with ageing and aMCI, and may prove a useful biomarker for the early detection of AD. This is interesting as the effects of healthy ageing and pathological decline on the N400 from explicit recognition tasks have not been thoroughly explored. Moreover, the N400 (and perhaps, to a lesser degree, LPC) effect(s) appear to have substantial value for informing future prognoses of subsequent cognitive trajectories, at least for persons with amnestic impairment. These results may have significant clinical implications pertaining to the selection and application of efficacious therapeutic interventions in aMCI and AD.

SUMMARY Introduction: There has recently been a great deal of interest in the role of synchronous high-frequency gamma oscillations in brain function. This interest has been motivated by an increasing body of evidence, that oscillations which are synchronous in phase across separated neuronal populations, may represent an important mechanism by which the brain binds or integrates spatially distributed processing activity which is related to the same object. Many models of schizophrenia suggest an impairment in the integration of brain processing, such as a loosening of associations, disconnection, defective multiple constraint organization, or cognitive dysmetria. This has led to recent speculation that abnormalities of high-frequency gamma synchronization may reflect a core dimension of the disturbance underlying this disorder. However, examination of the phase synchronization of gamma oscillations in patients with schizophrenia has never been previously undertaken. Method: In this thesis a new method of analysis of gamma synchrony was introduced, which enables the phase relationships of oscillations in a specific frequency band to be examined across multiple scalp sites as a function of time. This enabled, for the first time, the phase synchronization of gamma oscillations across widespread regions, to be studied in electrical brain activity measured at the scalp in humans. Gamma synchrony responses were studied in electroencephalographic (EEG) data acquired during a commonly employed conventional auditory oddball paradigm. The research consisted of two sets of experiments. In the first set of experiments, data from 100 normal subjects, consisting of 10 males and 10 females in each age decade from 20 to 70, was examined. These experiments were designed to characterize the gamma synchonizations that occurred in response to target and background stimuli and their functional significance in normal brain activity, and to exclude the possibility of these findings being due to electromyogram (EMG) or volume conduction artifact. The examination of functional significance involved the development of an additional new analysis technique. In the second set of experiments, data acquired from 35 patients with schizophrenia and 35 matched normal controls was analyzed. The purpose of these experiments was to determine whether patients showed disturbances of gamma synchrony compared to controls, and to establish the relationship of any such disturbances to medication levels, symptom profiles, duration of illness, and a range of psychophysiological variables. Results: In the 100 normals, responses to target stimuli were characterized by two bursts of synchronous gamma oscillations, an early (evoked) and a late (induced) synchronization, with different topographic distributions. Only the early gamma synchronization was seen in response to background stimuli. The main variable modulating the magnitude of these gamma synchronizations from epoch to epoch was pre-stimulus EEG theta (3-7 Hz) and delta (1-3 Hz) power. Early and late gamma synchrony were also associated with N1 and P3 ERP component amplitude across epochs. Across subjects, the early gamma synchronization was associated with shorter latency of the ERP components P2, N2 and P3, smaller amplitude of N1 and P2, and smaller pre-stimulus beta power. The control analyses showed that these gamma responses were specific to a narrow frequency range (37 to 41 Hz), and were not present in adjacent frequency bands. The responses were not generated by EMG contamination or volume conduction. In the 35 patients with schizophrenia, significant abnormalities of both the early and late synchronizations were observed compared to the 35 normal controls, with distinctive topographic characteristics. In general, early gamma synchrony was increased in patients compared to controls, and late gamma synchrony was decreased. These gamma synchrony disturbances were not related to medication level or the four summed symptom profile scores (positive, negative, general and total). They were, however, associated with duration of illness, becoming less severe the longer the patient had suffered from the disorder. The disordered gamma synchrony in patients was not secondary to abnormalities in other psychophysiological variables, but appeared to represent a primary disturbance. Discussion: The early synchronization may relate to the binding of object representations in early sensory processing, or, given that a constant inter-stimulus interval was employed, may be anticipatory and related to active memory. The late response is probably involved in binding in relation to activation of the internal contextual model involved in late expectancy/contextual processing (context updating or context closure) for target stimuli. The across epochs effects may relate to whether the focus of attention immediately prior to stimulus presentation is internal or is directed at the task. The across subjects effects suggest that a larger magnitude of the early gamma synchronization might indicate that the subject maintains a more stable and less ambiguous internal representation of the environment, that reduces the complexity of input and facilitates target/background discrimination and subsequent processing. The early gamma synchronization findings in patients with schizophrenia suggest that anticipatory processing involving active memory and forward-prediction of the environment is subject to over-binding or the formation of inappropriate associations. The late synchronization disturbances may reflect a fragmentation of contextual processing, and an inability to maintain contextual models of the environment intact over time. Conclusion: This research demonstrates the potential importance of integrative network activity as indexed by gamma phase synchrony in relation to normal cognition, and the possible broad relevance of such activity in psychiatric disorders. In particular, the application in this study to patients with schizophrenia showed that an impairment of brain integrative activity (missing links) might be a key feature of this illness.

Research Doctorate - Doctor of Philosophy (PhD) / This thesis investigates mechanisms of brain maturation by utilising the special advantages offered by the protracted maturation of neural circuits in chicken forebrain. Biochemical, behavioural and electrophysiological techniques are used in behaving animals to investigate the functional consequences of maturation changes at the molecular, behavioural and physiological levels. Two issues are addressed: (1) do immature (2 week) and mature (8 week) chickens employ different molecular mechanisms to produce changes in neuronal function after learning a behavioural task; and (2) can quantitative non-invasive measures of neuronal function be used to monitor maturation changes in chicken forebrain? Biochemical investigation of subcellular fractions using antibodies and western blots of chicken forebrain and intermediate medial mesopallium (IMM) revealed regional differences in expression levels of a number of components of the glutamatergic neurotransmitter system. The discriminative taste aversion learning (DTAL) task was used to assess whether an animal learns the same task at different ages using different intracellular signalling pathways. The patterns of biochemical change seen in the IMM after DTAL training was very different at 2 weeks and 8 weeks. Two major differences were observed. Firstly, the same type of training induced changes occurred at both ages in GluR1 and CaMKII but they occurred faster at 8 weeks. Secondly the difference in ERK and CREB responses is consistent with a change in the relative contribution made by the ERK signalling pathway and CREB requirement to learning at these two ages. These results imply that the molecular changes induced by learning a behavioural task are faster in mature than immature brain and may involve a different balance of intracellular signalling pathways. In order to be able to investigate biological mechanisms controlling maturation and to use the chicken as an animal model in which pharmacological and/or environmental agents can be screened for potentially harmful effects on brain maturation two non-invasive measures of neuronal function were investigated. One was behavioural (prepulse inhibition: PPI) and the other was electrophysiological (auditory evoked related potentials: AERP). PPI in the chicken was examined electromyographically and via whole body movement with a stabilimeter apparatus. In two strains of chicken (a meat breed and a laying breed) PPI was identified but shown to be small and variable compared to that in the rat. The results indicate that the phenomenon of PPI in the chicken is too small and variable to be used as a quantitative measure of neural circuit maturation. Quantitative analysis of the chicken AERP revealed a significant decrease in amplitude of the positive AERP component and a decrease in latency of the negative AERP component with maturation. These maturation changes were comparable to developmental changes seen in human and other mammal AERPs. Such changes may reflect changes in the intracortical synaptic organisation of the auditory cortex. This technique allowed for repeated measures to be undertaken on the same animal over a number of weeks and enabled developmental changes to be monitored. This technique was extended to investigate perturbed maturation via the induction of chemically induced hypothyroidism. Results from this study showed that the induction of late onset hypothyroidism produces measurable effects on the chicken AERP consistent with perturbation in maturation of neuronal circuits and synapses. This suggests that AERPs may be useful non-invasive functional measures of brain maturation that can be used to study the effects of endogenous or exogenous factors on brain maturation in the chicken. Since human brain also exhibits a protracted maturation period the availability of a well characterised animal model for protracted brain maturation provides an opportunity to identify molecules, genes and environmental factors that are important in the regulation of maturation. Such a model may provide the basis for developing rational therapies or prevention strategies for some neurodevelopmental disorders. The protracted maturation of neuronal circuits observed in chicken forebrain offers such a model.

This dissertation focuses on two specific problems related to the design of parametric signal classifiers: dimensionality reduction to overcome the curse of dimensionality and information fusion to improve classification by exploiting complementary information from multiple sensors or multiple classifiers. Dimensionality reduction is achieved by introducing a strategy to rank and select a subset of principal component transform (PCT) coefficients that carry the most useful discriminatory information. The criteria considered for ranking transform coefficients include magnitude, variance, inter-class separation, and classification accuracies of individual transform coefficients. The ranking strategy not only facilitates overcoming the dimensionality curse for multivariate classifier implementation but also provides a means to further select, out of a rank-ordered set, a smaller set of features that give the best classification accuracies. Because the class-conditional densities of transform feature vectors are often assumed to be multivariate Gaussian, the dimensionality reduction strategy focuses on overcoming the specific problems encountered in the design of practical multivariate Gaussian classifiers using transform feature vectors. Through experiments with event related potentials (ERPs) and ear pressure signals, it is shown that the dimension of the feature space can be decreased quite significantly by means of the feature ranking and selection strategy. Furthermore, the resulting Gaussian classifiers yield higher classification accuracies than those reported in previous classification studies on the same signal sets. Amongst the four feature selection criteria, Gaussian classifiers using the maximum magnitude and maximum variance selection criteria gave the best classification accuracies across the two sets of classification experiments. For the multisensor case, dimensionality reduction is achieved by introducing a spatio-temporal array model to observe the signals across channels and time, simultaneously. A two-step process which uses the Kolmogrov-Smirnov test and the Lilliefors test is formulated to select the array elements which have different Gaussian densities across all signal categories. Selecting spatio-temporal elements that fit the assumed model and also statistically differ across the signal categories not only decreases the dimensionality significantly but also ensures high classification accuracies. The selection is dynamic in the sense that selecting spatio-temporal array elements corresponds to selecting samples of different sensors at different time-instants. Each selected array element is classified using a univariate Gaussian classifier and the resulting decisions are fused into a decision fusion vector which is classified using a discrete Bayes classifier. The application of the resulting dynamic channel selection-based classification strategy is demonstrated by designing and testing classifiers for multi-channel ERPs and it is shown that strategy yields high classification accuracies. Most noteworthy of the two dimensionality reduction strategies is the fact that the multivariate Gaussian signal classifiers developed can be implemented without having to collect a prohibitively large number of training signals simply to satisfy the dimensionality conditions. Consequently, the classification strategies can be beneficial for designing personalized human-machine-interface (HMI) signal classifiers for individuals from whom only a limited number of training signals can reliably be collected due to severe disabilities. The information fusion strategy introduced is aimed at improving the performance of signal classifiers by combining signals from multiple sensors or by combining decisions of multiple classifiers. Fusion classifiers with diverse components (classifiers or data sets) outperform those with less diverse components. Determining component diversity, therefore, is of the utmost importance in the design of fusion classifiers which are often employed in clinical diagnostic and numerous other pattern recognition problems. A new pairwise diversity-based ranking strategy is introduced to select a subset of ensemble components, which when combined, will be more diverse than any other component subset of the same size. The strategy is unified in the sense that the components can be either polychotomous classifiers or polychotomous data sets. Classifier fusion and data fusion systems are formulated based on the diversity selection strategy and the application of the two fusion strategies are demonstrated through the classification of multi-channel ERPs. From the results it is concluded that data fusion outperforms classifier fusion. It is also shown that the diversity-based data fusion system outperforms the system using randomly selected data components. Furthermore, it is demonstrated that the combination of data components that yield the best performance, in a relative sense, can be determined through the diversity selection strategy.