Browsing by Subject "Endophenotype"

Now showing 1 - 3 of 3
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    The Effects of Alcohol and Cannabis Use on Inhibitory Control Brain Networks In Emerging Adulthood: Causal Inferences From A Cotwin Control Study
    (2020-06) Harper, Jeremy
    The overarching theme of this dissertation was to separate the causal influences of familial risk toward substance misuse (e.g., genetic liability) from the potential effects of alcohol and cannabis exposure on multi-method indicators of the (pre)frontal inhibitory control brain network in a sample of 24-year-old twins. Deficits in inhibitory control and measures of its underlying brain circuitry have been implicated as core phenotypes of substance misuse. Research often assumes an exposure effect of alcohol or cannabis misuse on the still-developing emerging adult (ages 18-25) brain, but these individual differences may reflect the familial (e.g., genetic) risk toward both substance use and brain deviations. This remains largely unknown as the vast majority of prior work used research designs that could not disentangle exposure from risk. To address this and other limitations in the literature at large, this dissertation was designed to study how alcohol and cannabis use during emerging adulthood affect the structure and function of the inhibitory control network. We used a large (N = 673) genetically informative population-based twin sample, careful phenotyping of alcohol and cannabis use, multi-method brain assessment (EEG; structural MRI; resting-state fMRI connectivity), and a quasi-experimental research design (cotwin control analysis) to draw causal inferences regarding the effect of alcohol/cannabis use on the brain in a field where true experimentation is often unfeasible. Across the three studies in this dissertation, we found evidence that alcohol and/or cannabis use were associated with deviations in EEG theta-band rhythms, cortical thickness, and resting-state functional connectivity measures of the (pre)frontal inhibitory control network. The cotwin control analyses offered evidence that some of the anomalies can be attributed to consequences of alcohol and cannabis exposure, while others primarily reflect the liability to misuse alcohol or cannabis. Interestingly, deviations in the frontal medial cortex, a key hub of the control-related circuit, were implicated across all three studies, suggesting that it may play a crucial role in substance-related disinhibition. The work collectively suggests that substance-related variations in the inhibitory control brain network reflect a mixture of premorbid brain-based characteristics of familial risk and the deleterious effects of alcohol/cannabis exposure. Findings have implications for informing and shaping policy, public messaging, and prevention efforts to curb the alarmingly high rates of alcohol and cannabis use in emerging adults.
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    Neurometric Encoding and Decoding: Using Multivariate Functional Connectivity Methods to Describe Cognitive States, Traits and Clinical Endophenotypes
    (2014-10) Moodie, Craig
    This research was undertaken for the purpose of demonstrating the neurometric utility of functional connectivity methods by combining metrics that utilize information derived from independent component analyses (ICAs) with traditional fMRI and graph theory analyses. The combination of these methodologies was used to establish traits and evaluate cognitive states from a behavioral genetics perspective, as well as to posit connectivity endophenotypes related to psychiatric and neurological diseases. The studies described below demonstrate that the metrics used to study intrinsic connectivity networks (ICNs) are useful tools for studying the in vivo brain in states of normalcy and disease. For instance, by examining ICNs across tasks and monozygotic twins, it was possible to establish these brain networks as traits. The ICNs were stable across cognitive states, while still exhibiting sensitivity to specific demands. In addition, the state- dependent modulation of these ICNs, as well as their other characteristics, was shown to be influenced by genetic factors in two separate twin samples. In the second twin sample, and a study of connectivity phenotypes related to schizophrenia, ICNs were useful for establishing the relationships between ICNs and tasks in both cases. The task-related characteristics and resting state profiles of ICNs were also useful for establishing novel endophenotypes of the disease states of schizophrenia and Parkinson's disease. Overall, this research serves to establish the study of the brain's intrinsic connectivity across the domains of both cognitive and clinical neuroscience and this work serves a contribution to the understanding of the dimensions along which normal and abnormal neurobiological functioning lie, and how intrinsic connectivity networks can be examined in both spheres.
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    Testing the effects of adolescent alcohol use on adult conflict-related theta dynamics
    (2017-02) Harper, Jeremy
    While adolescent alcohol use (AAU) has been associated with poor neurocognitive outcomes, few studies have utilized prospective samples, leaving uncertain any potential long-term neurocognitive effects of AAU. In addition, despite theoretical models linking AAU to diminished cognitive control, empirical work testing the relationship between AAU and specific neural correlates of cognitive control remains scarce. Recent work indicates that demands of cognitive control (e.g., response conflict) involve EEG theta-band dynamics, including medial frontal cortex (MFC) power and MFC-dorsal prefrontal cortex (dPFC) functional connectivity, which may be related to AAU-related neurocognitive dysfunction. The present study tested the hypothesis that greater AAU is associated with diminished adult conflict-related EEG theta-band dynamics in a large (N = 718) population-based prospective twin sample assessed at the target ages of 11, 14, 17, and 29. Two complementary analytic methods (cotwin control design; bivariate biometric modeling) were used to disentangle the genetic/shared environmental premorbid risk towards AAU from the potentially causal nonshared environmental effects of alcohol exposure. AAU was negatively associated with adult (age 29) theta MFC power and MFC-dPFC connectivity during a flanker task, suggesting that early drinking is associated with diminished cognitive control-related theta dynamics in adulthood. Both the CTC and biometric modeling results indicated that genetic influences primarily accounted for the association between AAU and reduced theta-band dynamics. Taken together, these findings suggest that the link between AAU and diminished adult cognitive control-related theta dynamics is likely a consequence of heritable genetic factors, rather than causal nonshared environmental effects.