Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
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In adults, prefrontal brain areas play an important role in modulating physical and social pain. During adolescence, these brain regions undergo crucial changes. It is unclear how this can influence the ability to regulate physical and social pain. In this dissertation I investigate cognitive and brain correlates of physical and social pain in adolescents and young adults. First, I conducted three studies to investigate the influence of conditioning on thermal discomfort. During the conditioning phase, differing visual cues were paired with either low or high temperatures applied to the participant’s forearm. During the testing phase, conditioned cues were paired with moderate temperatures. I investigated whether discomfort of moderate temperatures was higher when paired with the high conditioned cue (nocebo effect) and lower when paired with the low conditioned cue (placebo effect). In all three studies I found a significant conditioning effect, suggesting conditioned cues can modulate thermal discomfort in adolescents. Effect sizes were lower for youth compared to adults, and enhanced by engaging and personalized cues. (Chapter 2)Next, I investigated whether youth were able to up- and down-regulate thermal sensations and whether this ability was associated with structural integrity in pain modulation regions. Higher down-regulation magnitude was associated with structural integrity in ventromedial Prefrontal Cortex (vmPFC) to Periaqueductal Grey (PAG), and higher up-regulation magnitude with lower integrity dorsomedial Prefrontal Cortex (dmPFC) to PAG tracts. (Chapter 3)Lastly, using EEG I investigated brain dynamics associated with social pain, and whether mindset manipulation can influence these brain dynamics and negative mood in young adults. Negative social feedback was associated with early ERP components (lower P1, higher N1, higher P3) and higher parietal theta desynchronization. Processing self-related information was associated with higher LPP and higher right parietal theta desynchronization and higher left parietal alpha desynchronization. The mindset manipulation neither influenced participants mood, nor brain components associated with negative social feedback. (Chapter 4). The results suggest that developmental changes during adolescence reduce the modulation ability of physical pain. For social pain further studies are necessary to investigate how negative mood can be modulated effectively, and how this is related to adolescence.
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The first year of life is a period of dramatic structural changes in the brain. Along with structural changes, infants achieve significant behavioral milestones. The bridge between brain structure and behavior is strongly based on functional connections that enable intrinsic functioning and also develop emotion perception skills, both critical for early development. However, little is known about how these connections are functionally organized in infancy. Prenatal exposures to maternal mood disturbances and the use of selective serotonin reuptake inhibitor (SSRI) antidepressants play a crucial role in shaping infants’ development, although it remains unclear how these exposures are linked to infant developmental outcomes. In this thesis, I use task-based electroencephalography (EEG) and resting-state functional magnetic resonance imaging (rs-fMRI) combined with graph theory analysis to study the functional networks of emotion perception and the intrinsic functional connectivity of resting state networks (RSNs) in typically developing infants and in infants prenatally exposed to mood disturbances and SSRIs. I found that 8-to-10-month-old infants have network characteristics that are similar to adults when observing basic emotions (Chapter 3). Moreover, an increase in prenatal maternal mood symptoms was associated with reduced modularity only for negative emotions, while prenatal SSRI drug-exposure was associated with higher network modularity in observing both positive and negative emotions. In contrast, higher postnatal mood symptoms were associated with alterations in frontal hubs (Chapter 5). Prenatal mood disturbances were associated with alterations in intrinsic RSNs. Specifically, compared to the control group, infants exposed to prenatal maternal depression showed higher hub values of the left anterior-cingulate, insula, and caudate as well as higher hub values in the amygdala (Chapter 7). Prenatal SSRI exposure associated both with higher hub values in Heschel’s gyrus (Chapter 7) and with hyperconnectivity of the putative auditory network (Chapter 6) possibly support shifts in language perception previously reported in infants exposed to prenatal SSRI. Collectively, these data indicate that the core functional organization for observing basic emotions is in place at 8-to-10 months of age. Further, maternal mood disturbances and SSRI exposure may differently shape early intrinsic and emotion perception functional organization, possibly leading to different developmental trajectories.
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One in five women experience a depressive episode during pregnancy, with up to one in ten being treated with antidepressants. Despite an overall adverse developmental effect related to exposure to maternal depression and antidepressants during pregnancy, not all children are equally affected. Moreover, critical yet unanswered questions remain regarding the potential developmental risks and benefits of antidepressant treatment during pregnancy. The purpose of this thesis was to study the association between maternal depression and prenatal antidepressant exposure and child developmental outcomes while considering the role of key contextual factors that may influence these associations. Depression severity, patterns of depressive symptoms over time, and underlying genetic risk were investigated for their role in influencing child outcomes. Small yet consistent associations were found between prenatal antidepressant exposure and vulnerability for anxiety and lower physical independence at kindergarten age, after stringently adjusting for confounding by maternal mental health. Genetic differences were found to underlay associations between prenatal maternal depression symptom levels and genome-wide differences in DNA methylation at age 18 years. Looking longitudinally, increasing maternal depression symptoms across the first three postpartum years were associated with worse child behavioral problems and executive functions at ages three and six years; a pattern of decreasing maternal depression symptoms over the same time period, despite initially higher depressive symptoms during pregnancy, was associated with no impairments.Collectively, the findings presented herein help explain the heterogeneity of child outcomes that are observed in relation to early developmental exposure to maternal depression and its treatment with antidepressants. This thesis highlights the impact of factors underlying and related to maternal mental health on children’s developmental outcomes, and suggest that investments made to improve maternal depression have the potential to benefit the health of both mothers and their children.
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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Background:Antibiotics are among the most used medications during pregnancy, and while their short-term benefits are clear, their potential long-term effects are underexplored. Antibiotic exposure induces changes in the maternal microbiome, which could in turn influence the development of the infant’s microbiome with implications for neurodevelopment. This thesis examined the associations of 1) intrapartum antibiotic exposure and 2) prenatal antibiotic exposure with autism spectrum disorder (ASD) in offspring.Methods:Using multiple linked population-level datasets, we examined everyone who delivered a live singleton term infant in British Columbia, Canada between April 1st 2000 and December 31st 2014. To examine the associations among pregnant individuals treated for the same indication, we studied sub-cohorts of those diagnosed 1) as group B streptococcus-positive, and 2) with urinary tract infections. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios. Sensitivity analyses were conducted to examine the impact of different classes of antibiotics, and to assess for dose-response and temporal relationships. Additionally, potential effect modification was examined based on sex and mode of delivery. To account for unmeasured confounding, we ran a conditional logistic regression of discordant sibling pairs.Results:We found no association between intrapartum antibiotic administration and ASD in offspring. In contrast, we observed a small statistically significant increase in risk of ASD associated with prenatal antibiotic exposure. In particular, highest risk was observed if exposure took place during the second trimester, to penicillins or other beta lactams, and for 15 days or longer. Among the cohort restricted to pregnant individuals diagnosed with UTIs, findings showed a positive association between prenatal antibiotics and ASD with an increased effect size; yet, this association was no longer statistically significant, possibly due to a reduced sample size. Therelationship between prenatal antibiotic exposure and ASD was no longer significant in the conditional logistic regression.Conclusions:Overall, our findings suggest that the risk of ASD should not factor into clinical decisions on whether to administer antibiotics both prenatally and during labour and delivery. Results may suggest a hypothesized role of impaired fetal metabolic programming by the maternal microbiome and metabolome in ASD development.
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Chronic pain is a common and costly condition in youth. 20-30% report recurrent pain that is not disabling, but still interferes with academic, social, and recreational functioning, and has significant effects on mental health (e.g. higher rates of anxiety, depression, and post-traumatic stress symptoms). Existing digital applications to help patients self-manage chronic pain often report low engagement and typically focus narrowly on either symptom tracking (emphasis on user providing data), or intervention delivery (translating an in-person intervention into a digital format).We hypothesize that if youth with chronic pain could actively explore data from their lived experiences, they could better relate their symptoms to other areas of their lives and improve their general functioning. Our approach novelly uses interactive visualization of self-reported data as an intervention. We contribute design principles for engaging youth-centered visualizations of personal health data, and discuss metrics that can be used to measure their efficacy. Both were derived through the development of myWeekInSight, a visualization-based web application for teens to interactively explore personal health data, using data collected via thrice-daily surveys (Ecological Momentary Assessments) to capture in-the-moment a youth’s everyday circumstances, symptoms and experiences. We developed these visualizations iteratively with guidance from pediatric chronic pain clinicians, a patient partner, and experts in information visualization and human-computer interaction. We evaluated them in two phases, both with members of the target population: (1) design evaluation (N=10): assessment of comprehensibility, usability, and engagement through semi-structured interviews and questionnaires, followed by a qualitative analysis using affinity diagramming; and (2) utility evaluation (N=50): through a 2-week clinical deployment of a fully-functioning prototype developed in collaboration with a health tech firm, followed by semi-structured interviews and questionnaires with a subset of the participants (N=10) analyzed using affinity diagramming. Youth found the visualizations to be reflective of their experiences, interesting and useful, and were able to extract actionable insights; they also confirmed their interest in using the application in their daily lives, and described possible usage scenarios. We close by discussing our learnings from the evaluation studies, and implications for next steps.
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Depression is the leading cause of disability worldwide, where women are twice as likely to be diagnosed than men. Pregnancy and early postpartum is an especially vulnerable period, where approximately 15% of birthing individuals are diagnosed with perinatal depression (PND). Approximately 40% of PND cases occur in the postpartum period. Overwhelmingly, most of these cases are the first depressive episode in the birthing individual’s life. Concerningly, selective serotonin reuptake inhibitors (SSRIs), the first line antidepressant treatment for PND, show decreased efficacy in treating postpartum depression symptoms compared to antepartum depression symptoms. Previous research using an animal model of de novo postpartum depression indicates that SSRI inefficacy may be related to increased levels of the proinflammatory cytokine interleukin-1β (IL-1β). This thesis aims to further investigate the relationship between inflammation and the postpartum onset of depression, by targeting the IL-1 receptor using an animal model of postpartum depression. In this model, high corticosterone (primary rat glucocorticoid) is given to the rat dam postpartum. Rat dams received either daily injections of corticosterone, fluoxetine and/or the IL-1 receptor antagonist, anakinra, or their vehicles. Anakinra competitively binds to the IL-1 receptor to block IL-1β activity. Our results indicate anakinra treatment has mixed effects on PND endophenotypes, depending on co-treatment with fluoxetine. With and without fluoxetine co-treatment, anakinra decreases microglia in the hippocampus, indicating an overall dampening of neuroinflammation through IL-1 receptors. Without fluoxetine co-treatment, anakinra decreases maternal care behaviour, whereas anakinra with fluoxetine treatment returned to control levels. Co-treatment of anakinra and fluoxetine resulted in increased active coping behaviours during the Forced Swim Test and increased hippocampal neurogenesis in the ventral dentate gyrus. Notably, fluoxetine with anakinra co-treatment increased ventral hippocampal neurogenesis, while fluoxetine treatment alone was ineffective in these outcome variables. These results suggest a possible therapeutic benefit of anakinra when used as an adjuvant with fluoxetine. Further research is critical to build upon this foundation and continue to explore the connection between neuroinflammation and antidepressant efficacy.
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