The term working memory (WM) refers to a set of cognitive processes that allows for the temporary storage and manipulation of information. Neural correlates of the N- back task, a well-established WM measure used in neuroimaging, have been studied extensively in adults but less so in developmental populations. This thesis determines the effect of age on brain activations that mediate cognitive processes for remembering non- verbal/visual stimuli. Block-design fMRI was used to record activity in 84 subjects (6-35 years) during a visual-patterns 0- and 1-back task. Regions activated during the 1-back condition were largely common to all age groups, with adults displaying the largest extent of activations. Children and adolescents showed similar 0-back activations (distinct from 1-back) while adults engaged an analogous 1-back activation pattern during 0-back, suggesting that brain mechanisms underlying memory and attentional processes required for this task in children and adolescents are not yet mature and that strategy usage is still developing.

Emotion processing involves specialised brain regions allowing for effective evaluation of the social environment and for the acquisition of social skills that emerge over childhood. In humans, an important aspect of normal development is the ability to understand the facial expressions of others that signal the nature and safety of the environment. Existing functional data, however, have not characterised the developmental trajectories associated with the differing neural and cognitive-behavioural development. The current thesis investigates the functional specialisation and development of the spatial and temporal patterns in neural activities during implicit processing of facial emotions from early childhood through adulthood. The first study identified brain regions engaged in implicit processing of emotional expressions using a simple emotion-processing paradigm (target detection task) with fourteen healthy adults using magnetoencephalography (MEG) recordings. Participants responded to a non-face target (a scrambled pattern) while ignoring the emotional face presented in a different hemifield. Results showed ACC and right-lateralised amygdala activations in early latencies in response to the unattended emotional faces related to rapid and implicit attention to the task-irrelevant facial emotions, specifically during the processing of the fearful emotion. Based on the findings in the first study, the second study investigated the developmental patterns and age-related differences in brain activities associated with the rapid and automatic processing of the emotional expressions in MEG with twelve children 7 – 10 years old, twelve adolescents 12 – 15 years old and twelve young adults (mean age 24.4 years) using the same paradigm. The results showed that emotion processing developed early in childhood in the amygdalae, whereas the processing of fear had later maturation engaging the ACC. The results further demonstrated an age-correlated increase in development in ACC activity and an age-related laterality shift in the amygdalae related to fear processing. The present thesis provides new evidence contributing to the understanding of the protracted but differing normal development in the emotional brain over the childhood into adulthood, and offers critical insights into understanding possible dysfunctions of these brain regions during development.

Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder characterized by multiple motor and vocal tics, affecting approximately 1% of the population. The precise neuropathology of GTS has not yet been delineated, but current models implicate subcortical and cortical areas - the cortico-striato-thalamo-cortical (CSTC) circuit. The majority of studies in the literature have either dealt with GTS with comorbid conditions and/or children with GTS. As these factors are known to affect brain structure and function, it unknown what the neurobiological underpinnings of pure adult GTS are. The objective of this body of work was to use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize differences in brain function and structure in pure adult GTS patients versus age- and sex-matched controls. I employed a series of three distinct analyses for this purpose, based upon current models of CSTC circuit-related dysfunction in GTS. In the first, GTS patients and control participants executed three finger-tapping paradigms that varied in both complexity and memory requirements. These finger-tapping tasks were modeled after previous studies that showed CSTC circuit-related activity in healthy individuals. Using a multivariate statistical technique to assess task-related patterns of activation across the whole brain, I found that, while there was much overlap in brain activation patterns between groups, sensorimotor cortical regions were differentially recruited by GTS patients compared to controls. In the second fMRI analysis, I measured low-frequency spontaneous fluctuations of the blood oxygen level dependent signal during rest, and found that GTS patients exhibited greater resting state functional connectivity with the left putamen compared to controls. In the final analysis, DTI was used to provide a whole-brain assessment of regional diffusion anisotropy in GTS patients and healthy volunteers and to investigate the fractional anisotropy in predetermined ROIs. This analysis found no differences between GTS patients and controls. Overall, my findings indicated that several CSTC-related regions shown to be atypical in GTS patients previously, are also atypical in pure adult GTS, and that sensorimotor cortical regions and the putamen may be regions of functional disturbance in pure adult GTS.

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a gradual deterioration of the patients’ ability to independently perform day to day activities. Researchers have discovered significant changes in neuroanatomy, cognition and behavior that are related to the disease process of AD and researchers continue to uncover new variables, such as the presence of vascular risk factors, which may further increase our ability to understand and characterize the disease. The purpose of this study is to identify the neuroanatomical, cognitive and behavioral variables that best predict impairment of instrumental activities of daily living in individuals with probable AD. Reduced white matter integrity in the dorsolateral prefrontal cortex as well as the presence of vascular risk factors significantly predicted impairments in activities of daily living (ADLs). Executive functioning skills, typically described as frontal lobe system behaviors, were positively associated with ADLs. Further, executive functions fully mediated the relationship between frontal lobe white matter integrity and ADLs. A better understanding of the variables responsible for diminished ADLs in AD will allow researchers and clinicians to better target prevention and intervention strategies and ultimately help individuals with AD to maintain their independence for a longer duration.

This research is primarily focused on laser-based non-invasive photoacoustic tomography of small animal brains. Photoacoustic tomography, a novel imaging modality, was applied to visualize the distribution of optical absorptions in small-animal brains through the skin and skull. This technique combines the high-contrast advantage of optical imaging with the high-resolution advantage of ultrasonic imaging. Based on the intrinsic optical contrast, this imaging system successfully visualized three-dimensional tissue structures in intact brains, including lesions and tumors in brain cerebral cortex. Physiological changes and functional activities in brains, including cerebral blood volume and blood oxygenation in addition to anatomical information, were also satisfactorily monitored. This technique successfully imaged the dynamic distributions of exogenous contrast agents in small-animal brains. Photoacoustic angiography in small-animal brains yielding high contrast and high spatial resolution was implemented noninvasively using intravenously injected absorbing dyes. In the appendix, the theory of Monte Carlo simulation of polarized light propagation in scattering media was briefly summarized.

Real-world decision making is challenging due, in part, to changes in the underlying reward structure: the best option last week may be less rewarding today. Determining the best response is even more challenging when feedback validity is low. Presented here are the results of two experiments designed to determine the degree to which midbrain reward processing is responsible for detecting reward contingency changes when feedback validity is low. These results suggest that while midbrain reward systems may be involved in detecting unexpected uncertainty in non-stationary environments, other systems are likely involved when feedback validity is low – namely, the locus-coeruleus-norepinephrine system. Finally, a computational model that combines these systems is described and tested. Taken together, these results downplay the role of the midbrain reward system when feedback validity is low, and highlight the importance of the locus-coeruleus-norepinephrine system in detecting reward contingency changes.

Visual processing, though seemingly automatic, is complex. Typical humansprocess objects and faces routinely. Yet, when a disease or disorder disrupts face andobject recognition, the effects are profound. Because of its importance and complexity,visual processing has been the subject of many adult functional imaging studies.However, relatively little is known about the development of the neural organization andunderlying cognitive mechanisms of face and object recognition. The current projectused functional magnetic resonance imaging (fMRI) to identify maturational changes inthe neural substrates of face and object recognition in 5-8 year olds, 9-11 year olds, andadults. A passive face and object viewing task revealed cortical shifts in the faceresponsiveloci of the ventral processing stream (VPS), an inferior occipito-temporalregion known to function in higher visual processing. Older children and adults recruitedmore anterior regions of the ventral processing stream than younger children. Toinvestigate the potential cognitive basis for these developmental changes, researchersimplemented a shape-matching task with parametric variations of shape overlap,structural similarity (SS), in stimulus pairs. VPS regions sensitive to high SS emerged inolder children and adults. Younger children recruited no structurally-sensitive regions inthe VPS. Two right hemisphere VPS regions were sensitive to maturational changes inSS. A comparison of face-responsive regions from the passive viewing task and the VPSSS regions did not reveal overlap. Though SS drives organization of the VPS, it did notexplain the cortical shifts in the neural substrates for face processing. In addition to VPSregions, results indicated additional maturational SS changes in frontal, parietal, andcerebellar regions. Based on these findings, further analyses were conducted to quantifyand qualify maturational changes in face and object processing throughout the brain.Results indicated developmental changes in activation extent, signal magnitude, andlateralization of face and object recognition networks. Collectively, this project supportsa developmental change in visual processing between 5-8 years and 9-11 years of age.Chapters Four through Six provide an in-depth discussion of the implications of thesefindings.

<p>Few aspects of human cognition are more personal than the choices we make. Our decisions &mdash; from the mundane to the impossibly complex &mdash; continually shape the courses of our lives. In recent years, researchers have applied the tools of neuroscience to understand the mechanisms that underlie decision making, as part of the new discipline of decision neuroscience. A primary goal of this emerging field has been to identify the processes that underlie specific decision variables, including the value of rewards, the uncertainty associated with particular outcomes, and the consequences of social interactions. Here, across three independent studies, I focus on the neural circuitry supporting social valuation &mdash; which shapes our social interactions and interpersonal choices. In the first study (Chapter 2), I demonstrate that social valuation relies on the posterior ventromedial prefrontal cortex (pVMPFC). Extending these findings, I next show that idiosyncratic responses within pVMPFC predict individual differences in complex social decision scenarios (Chapter 3). In addition, I also demonstrate that decisions involving other people (e.g., donations to a charitable organization) produce increased activation in brain regions associated with social cognition, particularly the temporal-parietal junction (TPJ). Finally, in my last study (Chapter 4), I employ functional connectivity analyses and show that social cognition regions &mdash; including the TPJ &mdash; exhibit increased connectivity with pVMPFC during social valuation, an effect that depends upon individual differences in preferences for social stimuli. Collectively, these results demonstrate that the computation of social value relies on distributed neural circuitry, including both value regions and social cognition regions. Future research on social valuation and interpersonal choice must build upon this emerging theme by linking neural circuits and behavior.</p> / Dissertation

While studies have examined risk factors and consequences of child maltreatment in general, relatively few have focused specifically on neglect, especially maternally perpetrated child neglect. This is despite evidence that neglect is the most common and most rapidly increasing form of maltreatment, with some of the most serious long-term effects on child development. Maternal neglect constitutes a substantial disturbance in the mother-child relationship. For this reason, after establishing the epidemiology of neglect at a population level, this thesis examines the neurobiology of patterns of mother-infant attachment using functional MRI. Disturbance in mother-infant attachment, in conjunction with family, social and societal risk and protective factors, constitutes the likely pathway to maternal neglect. Specific objectives were: 1) to describe the magnitude of the problem of maternal neglect in Australia, using longitudinal population-based studies; 2) to identify risk and protective factors associated with neglect, both in a high risk population of extremely low birth weight (ELBW) infants and a representative birth cohort; 3) to specifically explore whether breastfeeding was protective against maternally perpetrated neglect; 4) to examine the consequences of child neglect on infant cognitive development and head growth; and 5) to determine how maternal brain and endocrine responses differ according to patterns of adult attachment security. In Part A, two cohort studies examined the epidemiology of child abuse and neglect among mothers and their infants born at the Mater Mothers’ Hospital in Brisbane, Australia. Cohort databases were confidentially linked with official notifications of child abuse and neglect. The first cohort included 353 ELBW infants who were assessed at birth and at 1, 2 and 4 years of age. The second cohort included 7223 children whose mothers were enrolled prenatally into the Mater-University of Queensland Study of Pregnancy (MUSP), where data were collected at birth, 6 months, and 5 and 14 years. The initial ELBW study examined all reported notifications of neglect, while the MUSP study focused particularly on substantiated maternally perpetrated neglect and the protective effect of breastfeeding. These studies examined a broad range of social and biological predictors. Outcome variables for child neglect were examined in the ELBW cohort using cognitive z-scores and growth parameters. Analytic techniques included multivariate modelling. In Part B, the neurobiology of mother-infant attachment was examined by monitoring a cohort of 61 first-time mothers from Houston, Texas, over 4 study visits. The mothers’ attachment classifications were determined during pregnancy using the Adult Attachment Interview. At 6 months, mother-infant pairs were videotaped, and serum oxytocin measures collected before, during and after interaction. At 10 months, the mothers viewed pictures of their own and unknown infants during functional MRI scanning. The first report examined the brain responses of 28 mothers to happy, neutral and sad infant face cues. The next compared brain responses of 15 mothers with “secure” attachment patterns to 15 “insecure/dismissing” mothers, and also examined differences in peripheral oxytocin response to mother-infant interaction. Data were analysed using a general linear model and repeated measures ANOVA. Overall, more than 1 in 10 children were reported for suspected child maltreatment, 3-5% as a result of substantiated neglect and 3% with maternally perpetrated neglect, with higher rates seen in the ELBW cohort. Duration of breastfeeding was inversely associated with the odds of maternal neglect, with non-breastfeeding mothers almost 4 times more likely to neglect their child compared to mothers who breastfed for 4 or more months, after adjusting for covariates. Other significant risk factors for substantiated maternal neglect included low education, young maternal age, and race, which were also significant univariate predictors in the ELBW population. ELBW children exposed to neglect showed a progressive decline in cognitive functioning over the first 4 years of life, as well as a significantly reduced head circumference at 2 and 4 years. When mothers viewed their own infant’s faces, compared with an unknown infant, key dopamine-associated reward processing regions of the brain were activated, including the midbrain’s ventral tegmental area/substantia nigra, striatum and prefrontal cortex. Mothers with an insecure/dismissing type of attachment showed significantly less activation of these reward regions in response to both happy and sad own-infant faces. On viewing their own infant’s crying faces, these mothers showed activation of the anterior insula, a region involved in feelings of unfairness, pain and disgust. “Secure” mothers showed greater peripheral oxytocin responses during mother-infant interaction, which were correlated with activation of the pituitary/hypothalamic region of the brain, where oxytocin is produced and secreted. These findings confirm the magnitude of neglect as a public health concern, with identifiable consequences and specific risk and protective factors. The neurobiological studies identify neuroendocrine systems associated with mother-infant responses and patterns of adult attachment. Together, these studies theoretically link secure mother-infant attachment with brain reward activation and oxytocin response, breastfeeding success, and a reduced risk for maternal neglect. Implications for prevention and intervention, and future research plans, are discussed.

Current thinking suggests that specialised modules process visual information in a hierarchical manner, using local circuitry in order to maximise efficiency both in terms of wiring costs and stimulus coverage (Reichl et al. (2012)). The resulting organisation has been shown to contain structure in the form of stripes, columns and pinwheels, which in animal models have been linked to functional segregation and specificity. In human cortex, post-mortem investigations have assisted in the visualisation of two such key features: ocular dominance columns (ODC) within V1, and a stripe system within V2 (Adams et al. (2007); Hockfield et al. (1990)). However, functional observations in humans have until recently been beyond the investigatory scope of in-vivo methodology, and as such, a role of these networks has yet to be conclusively determined. In the small number of instances of in-vivo investigations of human ODC and V2 stripes (Cheng et al. (2001); Yacoub et al. (2001); Nasr et al. (2016)), data have been acquired for a small number of carefully selected participants over long scan durations. I aimed to overcome these limitations and explore the functional similarities further, employing a novel, ultra-high resolution fMRI sequence to do so. I measured the cortical response to monocular stimulation and recorded a robust response within V1. However, the regular and repeating functional patterns of ODCs were not observed. Using multivariate techniques I concluded, based on robust classification, that reliable monocular signals were present but that they were subtle and difficult to differentiate from noise. I then investigated the segregation of colour, form and motion within V2, where I found evidence for spatially segregated signals in response to colour and motion, but not to form. I hypothesised that the form stimulus was sub-optimal in driving the neural population of the associated stripes. Based on a limited number of samples, activity in response to colour and motion stimulation conformed on average to the neuroanatomical profile of the V2 stripe system. I suggest that my results offer encouragement for in-vivo investigations of small-scale functional organisation in visual cortex.