Maternal smoking during pregnancy has often been associated with numerous adverse outcomes for the offspring. However, its long-term effects are not well established. Given the high prevalence of maternal smoking during pregnancy, an understanding of these effects is essential. Therefore, the aim of the present dissertation was to shed light on the long-term neurophysiological effects of prenatal nicotine exposure on three different executive functioning processes by assessing participants in young adulthood, using functional magnetic resonance imaging (fMRI). Participants imaged were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables. The dissertation consists of three separate original manuscripts. In manuscript 1, participants completed a response inhibition task, in manuscript 2 participants completed a verbal working memory task and in manuscript 3 participants completed a visuospatial working memory task. Taken together, results from all three manuscripts showed that prenatal nicotine exposure leads to altered neural functioning during executive functioning processing that continues into young adulthood. These significant results highlight the need for education about the repercussions of women smoking during pregnancy.

Complaints of reduced cognitive abilities are frequent following chemotherapy. Research in the breast cancer population has revealed some patients may experience treatment-related decline in cognitive domains such as executive function, information processing speed, memory and learning, attention and concentration, and working memory. The extent and mechanism of action of this phenomenon remain poorly understood. Neuroimaging research can characterize the neural underpinnings of chemotherapy-related cognitive impairment; however, with few longitudinal studies, more prospective studies are needed to elucidate this important topic. The aim of this thesis was to use magnetic resonance imaging and contemporary analysis techniques to better understand the influence chemotherapy exerts on both the brain and cognition. This was achieved in two studies that measured cognitive function and brain structure and function at three time points: pre-treatment, one month post-chemotherapy, and at one-year follow-up. In the first study, the association between regions of brain structural changes and cognitive function was examined. The second study took a narrower approach and investigated the functional profile of brain activity during a working memory task. Patients had more pronounced structural and functional disruptions shortly after treatment, relative to both pre-treatment and one-year post-chemotherapy intervals. Regions of structural compromise were largely associated with information processing speed. Functional disruptions occurred in a frontoparietal network. Overall, this thesis provides more evidence of the injurious role chemotherapy plays on cognition, particularly in the short term. This thesis also provides the first longitudinal neuroimaging study to illustrate a complete resolution of working memory related brain disruption one year post-treatment.

Schizophrenia (SCZ) is a complex psychiatric disorder including various symptoms. Resting-state fMRI investigations mostly focused on functional connectivity alterations in SCZ reflecting the spontaneous activity’s spatial structure. Complementing its spatial structure, the brain’s spontaneous activity can be characterized by a complex temporal structure such as scale-free dynamics or long- range temporal correlations (LRTCs). However, it remains an open question whether the temporal structure of spontaneous brain activity, as indexed by the power-law exponent (PLE), can provide biomarkers specific to SCZ as distinguished from other psychiatric disorders like major depressive disorder (MDD) and bipolar disorder (BP). Here, we studied a large-scale cohort (n = 244) of two independent schizophrenic data sets (n = 45), MDD (n = 28), and BP patients (n = 73, in manic, depressed, and euthymic phases) and 98 healthy controls. We found significant PLE reduction in specifically the medial prefrontal cortex (mPFC) in SCZ. This was replicated in an independent sample and was shown to be specific when compared to MDD and different phases of BP. Due to its disease-specific nature, the mPFC PLE reduction may eventually serve as a biomarker for SCZ.

It is believed that with ageing comes a decline in many cognitive processes, ranging from memory, language and executive function to response inhibition and motor and visual processes. However, memory has attracted much attention and is of particular interest in ageing research. This is because it is a form of cognition that probably suffers the clearest decline with age, and can have a detrimental effect on day-to-day living. Additionally, as people are living longer these problems are affecting an increasing number of people and has therefore become an issue of concern. It is believed that these declines stem from neurophysiological changes that occur alongside ageing. It can be seen that research into this area is of particular importance to better understand the healthy ageing brain, and how illnesses such as Alzheimer's disease differ from this normal progression. The focus of this PhD project addresses this issue by exploring healthy age-related declines in recognition memory and their neural correlates, using brain imaging techniques to investigate underlying changes in brain structure. Novel recognition memory tasks were developed (Chapter 4) to tap underlying processes supporting scene recognition (recollection and familiarity), and were run alongside selected cognitive tasks taken from existing standardised batteries (Chapter 5). In addition to these behavioural measures, MR imaging datasets were collected relating to structural (Chapter 6), perfusion and functional (Chapter 7) as well as diffusion (Chapter 8) measures of the brain. The relationships between these imaging measures were investigated in Chapter 9, in addition to looking at how they related individually to a measure of recollection memory when accounting for the influence each imaging measure had on the others. Overall, age effects were found for the novel recognition memory tasks, in particular showing a significant decline in recollection performance with age. This was associated with a number of neurophysiological measures (functional, perfusion, diffusion and volume) which also showed age-related changes. After taking into account the relative contribution of these measures to task performance, no single imaging measure was found to be a significant predictor of recollection performance.

Neurocognitive models of speech comprehension generally outline either the spatial or temporal organisation of speech processing and rarely consider combining the two to provide a more complete model. Simultaneous EEG-fMRI recordings have the potential to link these domains, due to the complementary high spatial (fMRI) and temporal (EEG) sensitivities. Although the neural basis of speech comprehension has been investigated intensively during the past few decades there are still some important outstanding questions. For instance, there is considerable evidence from neuropsychology and other convergent sources that the anterior temporal lobe (ATL) should play an important role in accessing meaning. However, fMRI studies do not usually highlight this area, possibly because magnetic susceptibility artefacts cause severe signal loss within the ventral ATL (vATL). In this thesis EEG and fMRI were used to refine the spatial and temporal components of neurocognitive models of speech comprehension, and to attempt to provide a combined spatial and temporal model. Chapter 2 describes an EEG study that was conducted while participants listened to intelligible and unintelligible single words. A two-pass processing framework best explained the results, which showed comprehension to proceed in a somewhat hierarchical manner; however, top-down processes were involved during the early stages. These early processes were found to originate from the mid-superior temporal gyrus (STG) and inferior frontal gyrus (IFG), while the late processes were found within ATL and IFG regions. Chapter 3 compared two novel fMRI methods known to overcome signal loss within vATL: dual-echo and spin-echo fMRI. The results showed dual-echo fMRI outperformed spin-echo fMRI in vATL regions, as well as extra temporal regions. Chapter 4 harnessed the dual-echo method to investigate a speech comprehension task (sentences). Intelligibility related activation was found in bilateral STG, left vATL and left IFG. This is consistent with converging evidence implicating the vATL in semantic processing. Chapter 5 describes how simultaneous EEG-fMRI was used to investigate word comprehension. The results showed activity in superior temporal sulcus (STS), vATL and IFG. The temporal profile showed that these nodes were most active around 400 ms (specifically the anterior STS and vATL), while the vATL was consistently active across the whole epoch. Overall, these studies suggest that models of speech comprehension need to be updated to include the vATL region, as a way of accessing semantic meaning. Furthermore, the temporal evolution is best explained within a two-pass framework. The early top-down influence of vATL regions attempt to map speech-like sounds onto semantic representations. Successful mapping, and therefore comprehension, is achieved around 400 ms in the vATL and anterior STS.

In everyday settings, spatial attention helps listeners isolate and understand individual sound sources. However, the neural mechanisms of auditory spatial attention (ASpA) are only partially understood. This thesis uses within-subject analysis of functional magnetic resonance imaging (fMRI) data to address fundamental questions regarding cortical mechanisms supporting ASpA by applying novel multi-voxel pattern analysis (MVPA) and resting-state functional connectivity (rsFC) approaches. A series of fMRI studies of ASpA were conducted in which subjects performed a one-back task in which they attended to one of two spatially separated streams. Attention modulated blood oxygenation level-dependent (BOLD) activity in multiple areas in the prefrontal, temporal, and parietal cortex, including non-visuotopic intraparietal sulcus (IPS), but not the visuotopic maps in IPS. No spatial bias was detected in any cortical area using standard univariate analysis; however, MVPA revealed that activation patterns in a number of areas, including the auditory cortex, predicted the attended direction. Furthermore, we explored how cognitive task demands and the sensory modality of the inputs influenced activity with a visual one-back task and a visual multiple object tracking (MOT) task. Activity from the visual and auditory one-back tasks overlapped along the fundus of IPS and lateral prefrontal cortex (lPFC). However, there was minimal overlap of activity in the lPFC between the visual MOT task and the two one-back tasks. Finally, we endeavored to identify visual and auditory networks using rsFC. We identified a dorsal visual attention network reliably within individual subjects using visuotopic seeds. Using auditory seeds, we found a prefrontal area nested between segments of the dorsal visual attention network. These findings mark fundamental progress towards elucidating the cortical network controlling ASpA. Our results suggest that similar lPFC structures support both ASpA and its visual counterpart during a spatial one-back task, but that ASpA does not drive visuotopic IPS in the parietal cortex. Furthermore, rsFC reveals that visual and auditory seed regions are functionally connected with non-overlapping lPFC regions, possibly reflecting spatial and temporal cognitive processing biases, respectively. While we find no evidence for a spatiotopic map, the auditory cortex is sensitive to direction of attention in its patterns of activation.

Research suggests that patients with social anxiety disorder (SAD) have an attentional bias toward socially threatening stimuli, and recent studies have shown that computerized interventions designed to train attention away from such stimuli decrease attentional bias and SAD symptomatology. The current study sought to replicate findings from previous attention retraining studies and to examine neural mechanisms underlying attentional biases in SAD using functional magnetic resonance imaging (fMRI). Thirty-two SAD patients were randomized to complete either eight 15-minute sessions of a probe detection task designed to train attention away from disgust faces (n=16), or a placebo control task (n=16). Before and after these sessions, patients completed an fMRI probe detection task. Sixteen matched healthy controls also completed this fMRI task on one occasion. Study hypotheses were as follows: (a) post-intervention, SAD patients in the retraining condition would show greater reductions in attentional bias and SAD symptomatology compared to patients in the placebo condition; (b) SAD patients would show greater amygdala activation, and less prefrontal cortex (PFC) activation, when viewing negative faces than healthy controls; and (c) post-intervention, SAD patients in the retraining condition would show less amygdala activation, and greater PFC activation, when viewing negative faces than patients in the placebo condition. Results showed no between-group differences in attentional bias or SAD symptomatology post-intervention, with both groups showing significant symptom reduction. However, attentional bias change was significantly correlated with symptom change across the entire SAD sample (N=32) and was predictive of Liebowitz Social Anxiety Scale scores at post-intervention. Neuroimaging results showed hypo-activation in the orbitofrontal cortex and anterior cingulate cortex at pre-treatment for the SAD group compared to healthy controls. At post-treatment, this difference was no longer significant across the entire SAD group (N=32). Finally, results indicated that activation at pre-treatment in the posterior cingulate cortex/precuneus was significantly correlated with symptom change across the entire SAD sample. These results suggest that SAD patients may not be engaging higher-level cortical regions as readily as healthy controls and add to the recent growing body of research suggesting that attention retraining may not be an effective treatment for patients with SAD.

Adolescence is a unique period of development. This life phase seems to entail being sensitive to aversive and social cues. However, adolescents' performances have been seen as equivalent to that of adults in nonemotional contexts. For this reason, questions remain regarding adolescents’ sensitivity to, and cognitive regulation of, emotional content. In line with this, the following paper aimed to provide a literature review of the successful use of an emotion regulation (ER) strategy, known as reappraisal, and its normative development during adolescence. Specifically, the main focus ofthis paper was to review studies investigating age differences of adolescents' reappraisal capacity in association with related functional activity, as measured by functional magnetic resonance imaging (fMRI). Reappraisal, i.e., to rethink the appraisal of an emotionally eliciting stimulus as to change one’s emotional response, is a well-studied psychological phenomenon. Research of reappraisal ability has mainly been studied on adults when viewing aversive images. Therefore, such findings in the field that are of relevance for the more in-depth review a represented. The studies reviewed suggest that reappraisal may account more for age differences in emotional responding than emotional reactivity. Generally, reappraisal ability shows increased success with increasing age. The paper ends with a discussion of results and limitations within the field, such as regarding the various terminology and instructions used for reappraisal tactics.

Trait mindfulness refers to the tendency of being mindful in everyday life. Individuals characterized with high trait mindfulness have reported high subjective wellbeing and are less prone to depression and stress. The aim with this systematic review was to investigate the neural correlates of trait mindfulness. Also, to compare the neural correlates underlying trait mindfulness with those related to mindfulness practices. A systematic search, screening and selection was conducted, resulting in twelve articles included for data extraction and discussion. All studies investigated resting state brain activity or brain structure, measured by fMRI or MRI, in relation to individual scores in trait mindfulness measures. Trait mindfulness was characterized by reduced connectivity within the DMN (between the PCC, the medial PFC, the STG and the thalamus e.g.) and increased functional connectivity between the insula and the ACC within the SN. Further, decreased functional connectivity between the DMN and the SN was observed. No consistent structural correlates characterizing trait mindfulness were reported. Reduced connectivity within the DMN is thought to associate with reduced vulnerability to rumination and depression. Increased connectivity within the SN has been linked to enhanced body awareness and interoception. Decreased functional connectivity between the DMN and the SN has been suggested to facilitate enhanced attention. Trait mindfulness appears to share some neural characteristics with those linked to mindfulness practices: weaker functional connectivity within the DMN, increased involvement of the insula and the ACC within the SN, and weaker connectivity between the DMN and the SN.

Indiana University-Purdue University Indianapolis (IUPUI) / Negative urgency, defined as a tendency to act rashly under extreme negative emotion, is strongly associated with tobacco use. Despite the robust cross-sectional and experimental evidence linking negative urgency and tobacco use, neural correlates of negative urgency in tobacco use have not been studied. The purpose of the current study was to 1) identify neural circuits that differ between tobacco users and non-tobacco users and 2) explore the relationship between resting-state seed-based functional connectivity (rsFC) and negative urgency, both in the overall group and between tobacco users and non-tobacco users. Using negative urgency-related brain regions as seed regions (voxel level p = .005, cluster-level a < .05), compared to non-tobacco users (n = 21; mean age = 36.57, 62% female, 76% white), tobacco users (n = 22; mean age = 37.50, 64% female, 77% white) had stronger rsFC strengths in the right amygdala – left medial orbitofrontal cortex/ventromedial prefrontal cortex circuit and the right nucleus accumbens – right temporoparietal junction circuit. Additionally, rsFC in the bilateral temporal pole – left supramarginal gyrus circuits was positively correlated with negative urgency (Left temporal pole: r = .55, p < .001; Right temporal pole: r = .51, p < .001). The current study extends previous neuroimaging findings, which have mainly focused on how negative urgency is related to brain responses in localized, segregated brain regions, by examining the network-level interactions between different brain regions. This study provides prime preliminary data for future neuroimaging studies of negative urgency by providing potential target networks that would aid the development of novel intervention strategies for negative urgency-based maladaptive behaviors.