Browsing by Subject "Cognition"
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Item Anxiety and Anhedonia in Major Depressive Disorder: The Contributing Roles of Neuroticism, Cognitive Control, and Reward Learning(2017-07-19) Liao, Allen; Walker, Robrina; Trivedi, Madhukar; Carmody, Thomas; Cooper, Crystal; Shaw, MeredithHigher levels of anxiety and higher levels of anhedonia in Major Depressive Disorder (MDD) are two clinical presentations linked to poorer depression treatment outcomes. However, the mechanisms contributing to these symptom presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning have been suggested to be critical processes involved in MDD, and may help to explain symptoms of anxiety and anhedonia. Using baseline data from individuals with MDD (N=296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, we conducted a path analysis using structural equation modeling to model hypothesized relationships between the constructs of neuroticism, cognitive control, and reward learning and symptom levels of anxiety and anhedonia. Post-hoc model modifications were performed and relative model fit was compared. Findings indicate that neuroticism was significantly and positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001), whereas cognitive control was significantly and negatively associated with only anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with anxiety or anhedonia in the model. These findings suggest that neuroticism may be a potential predisposing factor to both anxiety and anhedonia in MDD, and that cognitive control may be a protective factor to anxiety in MDD. Reducing neuroticism and improving cognitive control through targeted interventions may improve treatment in MDD for those with anxiety and anhedonia.Item Assessing Approach Motivation in Depressed Individuals with a History of Concussion(2020-12-01T06:00:00.000Z) Cecil, Audrey Lorraine; Cullum, C. Munro; Trivedi, Madhukar; Cooper, Crystal; Greer, Tracy L.; Carmody, Thomas; Pop, RaduDepression is the leading cause of disability worldwide. Anhedonia, a core symptom of depression, has been described as a lack of pleasure or interest, though it is a much more complex process than simply lack of pleasure. Anhedonia is made up of anticipation, motivation, enjoyment, and learning related to rewards. When an individual's motivation is impaired, reward perception is blunted as the drive to work for it is reduced. This "approach motivation" is generally subserved by the ventral striatum and orbitofrontal cortex, two areas which can be affected in a variety of neurologic conditions, including traumatic brain injury, as these subcortical structures can be affected by pathophysiological sequalae of trauma. To explore this concept, we examined data from a large ongoing study of adult depression (Dallas 2K). A total of 110 participants with depression with (n=40) and without a history (n=70) of self-reported concussion were tested on a measure of approach motivation, the Energy Expenditure for Rewards Task (EEfRT). We also analyzed depression symptom severity and the relationship between anhedonia severity to approach motivation on the EEfRT. Results revealed no significant differences between depressed adults with and without a history of concussion on approach motivation. Exploratory analyses revealed differences between high and low depression severity groups, such that high depression severity participants were less likely to select low probability/high reward tasks, but this was irrespective of concussion history. Though the main study results were nonsignificant, exploratory analyses present an opportunity for future direction of studies related to approach motivation and cognition in co-morbid depression and concussion.Item Cell Type-Specific Roles of FoxP Transcription Factors in Vocalization and Cognition(2019-07-23) Co, Marissa; Tsai, Peter; Konopka, Genevieve; Johnson, Jane E.; Roberts, ToddMutations of the forkhead domain transcription factors FOXP2 and FOXP1 are highly associated with neurodevelopmental disorders affecting speech and language. Across vertebrate species, their conserved expression patterns in the developing and adult brain predict important functions in neural circuits mediating vocalization and sensorimotor learning. Their known gene targets regulate neuronal development, activity, and plasticity, and animal models of FoxP2 and FoxP1 function have linked some of these molecular functions with neurophysiological and behavioral phenotypes. Still, much remains unknown about molecular networks in the brain driven by these transcription factors, especially in specific regions and cell types. During my dissertation work, I sought to elucidate FoxP2 and FoxP1 functions in cortical, striatal, and cerebellar neurons in mice and zebra finches. This approach of combining comparative genomics with functional studies of salient genes has proven a powerful method for understanding higher cognitive functions such as language (Chapter Two). By characterizing mice lacking cortical Foxp2, I identified its roles in dopamine signaling, interneuron development, and cognitive behavior, but surprisingly not in vocalization (Chapter Three). I further studied the interaction between FoxP2 and its cortical binding partner TBR1, and I found synergistic gene regulation by these transcription factors in neural cells (Chapter Four). I contributed to identification of roles for cortico-hippocampal FoxP1 in cortical development and vocalization (Chapter Five), as well as roles for cerebellar FoxP2 in Purkinje cell morphology, vocalization, and gross motor function (Chapter Six). Finally, I generated tools and datasets to further our understanding of corticostriatal functions of FoxP2 and FoxP1 in vocal learning zebra finches (Chapter Seven). In light of these studies, I discuss their implications for understanding human disorders affecting speech and language, and I impart further hypotheses and recommendations for continuing their study (Chapter Eight). Together, these findings contribute to our knowledge of conserved roles for FoxP2 and FoxP1 in vocal behavior and cognition.Item Congruence of Parent-Report, Self-Report, and Performance-Based Neuropsychological Functioning in Pediatric Acute Lymphoblastic Leukemia Survivors(2017-07-28) Clem, Matthew Alan; Holland, Alice A.; Stavinoha, Peter L.; Cullum, C. Munro; Holm, Suzanne; Lampson, ErinAcute Lymphoblastic Leukemia (ALL) is thought to have long-term cognitive effects, and clinicians often rely on parent report to screen for cognitive impairment during survivorship, despite limited congruence with neuropsychological performance and susceptibility to parental factors such as stress. This study was the first to investigate the moderating effect of parental stress on the congruence between reported child functioning and neuropsychological performance in pediatric ALL. Based on prior literature, performance-based, parent-report, and self-report measures were expected to show significantly worse child functioning compared to norms, with parents expected to report elevated stress compared to norms. Parental stress was expected to moderate the congruence between parent report and neuropsychological performance or self-report, with more stressed parents overestimating child impairment. A relatively large (N=107) sample of pediatric ALL survivors treated on chemotherapy-only protocols completed neuropsychological screening and standardized questionnaires on cognitive, behavioral, and emotional functioning at an annual follow-up visit (minimum six months post-treatment completion). Parents completed standardized questionnaires on child cognitive, behavioral, and emotional functioning; and parental stress and mood. Independent t-tests showed average overall cognitive functioning compared with normative data, but higher-than-expected frequencies of impairment (≤ 2nd percentile) in attention and executive functioning. ANOVA/ANCOVA analyses showed greater methotrexate exposure and younger age of diagnosis are associated with worse attention and processing speed performances. Parental stress and depression were lower than expected, likely indicating good parental adjustment. Correlation analyses revealed low to moderate (r = .21 - .41) congruence between parent report and neuropsychological performance; parent- and self-reported behavioral/emotional functioning were weakly associated. Moderation analyses indicated ratings of parents reporting mild stress were more congruent with neuropsychological performance than ratings of parents reporting no stress (ΔR2 = .05, p < .05), suggesting parents reporting at least some stress are more attuned to subtle aspects of child functioning. Contemporary treatment protocols show generally intact child cognitive functioning, though some are vulnerable to late effects. Parental psychological factors may steer clinicians toward performance-based methods of child assessment. Longitudinal studies with healthy and matched controls are necessary to fully understand the variable course and expression of late cognitive effects in pediatric leukemia survivors.Item Connectivity within the Default Mode Network after Traumatic Axonal Injury(2011-12-12) Arenivas, Ana; Marquez de la Plata, CarlosTraumatic axonal injury (TAI) is a common consequence of TBI in which the brain’s white matter is mechanically torn by deceleration and rotational forces. Injury to axons after this type of injury causes significant impairments in cognitive functioning, but the association between disruption of structural connections (i.e., axons) and the brain’s functional connectedness is not well understood. Studies examining integrity of white matter after TAI have found significant compromise to structures likely involved in the connectivity of the default mode network (DMN), a reliably elicited functional neural network with clinical implications. The discriminant and prognostic utilities of the DMN following traumatic axonal injury (TAI) have not been previously investigated. This broad investigation was comprised of two related studies examining the utility of neuroimaging modalities as biomarkers of TAI. Resting-state magnetic resonance imaging (RS-MRI) and diffusion tensor imaging (DTI) sequences were acquired 6-11 months post-injury using a 3T scanner from 25 patients with TAI and 17 controls. Functional and neurocognitive outcomes were assessed the same day. The first study examined the utility of three approaches analyzing DMN integrity using RS-fMRI. The purpose was to identify the utility of each approach to distinguish between healthy and brain-injured individuals, and determine whether observed differences have clinical significance. The second study integrated functional and structural connectivity measures of the DMN to determine whether compromise to functional connectivity within this network can be explained by the degree of white matter compromise commonly observed after TAI. The first study concluded that connectivity within the DMN is compromised after TAI, as all three methods demonstrated good ability to discriminate between healthy and injured brains. The second study suggests the functional disconnectedness within the DMN is in part due to compromise in structural connections observed after TAI. Neither the degree of functional or structural compromise to the DMN has clinical implications in TAI. In general, the two investigations suggest the DMN undergoes compromise after TAI, and connectivity between nodes of the network are valid markers of axonal injury.Item Do Concussion History and Gender Influence Neurocognitive Testing Performance(2016-11-21) Borque, Brandy; Silver, Cheryl H.; Cullum, C. Munro; Resch, JacobBACKGROUND: To date, the literature regarding sport concussion (SC) has concentrated primarily on male athletes. Generally, as research on female athletics has increased, there is an overall agreement that female athletes show more impairment post-injury than males. However, more data are needed to determine how SC impacts the female athlete and if that impact is influenced by factors such as age or history of prior concussion. SUBJECTS: Subjects with and without a previous history of concussion at the high school and college level were included and carefully matched for age, gender, height, and weight. After careful matching, five high school athletes with a history of prior SC were compared with five high school athletes without a concussion history, and 14 college athletes with a history of prior SC were compared with 14 matched college athletes without a concussion history. METHOD: Data for this study were acquired from a larger study conducted at the University of Texas at Arlington that examined sport concussion in high school and college athletes. Variables included previous concussion history and baseline scores from the ImPACT test. It was hypothesized that female athletes with a previous SC would show more impairment on baseline neurocognitive measures and would report greater symptom severity at baseline testing compared to athletes without a prior SC. In addition, it was hypothesized that female athletes with a previous SC at the high school level would show more impairment on baseline neurocognitive measures than college athletes with prior SC and that high school players would show greater symptom severity compared to college athletes at baseline. RESULTS: No significant differences were seen on any ImPACT baseline composite scores between athletes with and without a reported history of prior concussion. Similarly, no differences on ImPACT baseline total symptom scores were seen between athletes with concussion versus without a history of prior concussion. Finally, there were no differences on ImPACT composite or total symptom scores between college and high school athletes.Item Dual Process Models of Decision Making: An fMRI Investigation of Framing Effects and Individual Differences(2010-11-02) Murch, Kevin Bertrand; Krawczyk, DanielWhile the manifestation of decisions can be explained in several ways, dual-process models provide a unique purview into the relationship between automatic and controlled components of the decision making process. Although dichotomies in processing can be observed utilizing different experimental paradigms, framing effects provide a unique reflection of these dichotomies. Framing effects have been studied behaviorally for quite some time; however, only recently have investigators begun to examine the neurobiological basis for these effects. Additionally, as these effects mirror dual-process accounts of decision making, the examination of concurrent task demands and individual differences in the manifestation of framing effects could serve to inform dual-process models. The current studies examined two different framing paradigms in the context of experimental manipulations, perspective taking and emotional priming, which were intended to facilitate processing within the subsystems of a dual-process account of social cognition. Framing manipulations included both a previously established risky-choice framing paradigm and a novel, socially relevant attribute framing paradigm. In addition to behavioral studies, an fMRI investigation of the attribute framing paradigm was conducted to examine the neural correlates associated with the observed framing effect within the neurobiological framework of the X- and C-System model of social cognition. Finally, the current studies sought to examine the role that individual differences (e.g., personality, intelligence, need for cognition, cognitive reflection, impulsivity, and attachment style) play in susceptibility to framing phenomena. Results indicated the framing manipulations utilized in these studies were successful in eliciting a bias in decision making behavior. The effects of additional experimental manipulations were mixed, with some evidence for influences on the manifestation of the framing effects. fMRI data generally showed changes in brain activity in a manner consistent with the neurobiological divisions included within the X-and C-System model and provided preliminary evidence suggesting differences in the way frames and counterframes are processed. Individual differences, both in terms of psychological constructs and brain activity, appeared to be associated with susceptibility to framing phenomena. In total, the current series of studies provide several novel contributions to the existing literature on framing effects, and by extension, dual-process accounts of decision making.Item Effects of Alcohol Use on Cognition During Later Adulthood(2020-12-01T06:00:00.000Z) Becker, Joshua Eric; Brown, E. Sherwood; Rossetti, Heidi; Denney, David; Palka, Jayme; Cullum, C. Munro; Adinoff, Byron H.Alcohol is one of the most widely used psychoactive substance in the world, yet there are conflicting findings related to its long-term effect on cognition. Some research has identified a U-shaped relationship between alcohol consumption and cognition, while negative relationships have been identified in other studies. Methodological issues, particularly the time at which alcohol consumption was measured relative to when cognition was measured, wide variability in definitions of "moderate" alcohol consumption, and selecting appropriate comparison groups, have made exploring the effects of alcohol on cognition during aging difficult. The current study examined the relationship between drinking at three separate time points (between the ages of 50 and 74) and cognition in older adulthood. Results revealed that the quantity of self-reported drinks over the three time points was a significant predictor of cognition in older adulthood (b=0.001; p<.001), although the effect sizes were very small and not meaningful. Subsequent analyses examined this relationship among heavy drinkers and binge drinkers compared to moderate drinkers and non-binge drinkers, but heavy and binge drinking were not significant predictors of cognition in older adulthood (all ps>0.05). Overall, the results suggest no that there is not a meaningful relationship between alcohol consumption and cognitive functioning in older adulthood in this sample. There were few consistent heavy drinkers (n=71), but a large number of consistent moderate drinkers (n=1,847), although even the moderate drinkers did not consume much alcohol (mean alcohol consumption = 15.3 drinks/month; median alcohol consumption = 5.0 drinks/month). This may have limited the ability to detect clinically meaningful differences. Future studies should rely on more standardized alcohol measures, large, diverse samples, and inclusion of cognitive measures assessing visuospatial abilities and executive functioning, in order to better explore the relationship of alcohol in the aging brain.Item Elucidating the Impact of Previous Head Injury on Cognition, Brain Structure, and Pathophysiology in Cognitively Normal Individuals Across the Adult Lifespan(2020-08-01T05:00:00.000Z) Munro, Catherine Elizabeth; Cullum, C. Munro; Park, Denise C.; Davenport, Elizabeth; Didehbani, Nyaz; Rodrigue, KarenMild traumatic brain injury (mTBI), or concussion, is a common experience and awareness of mTBI has been increasing. There has been growing concern regarding potential long-term effects of concussion on cognition and risk for neurodegenerative disorders. This concern is heightened for athletic populations, particularly in high-contact sports, at risk for repetitive mTBI. Short-term effects of mTBI are heterogeneous, but well-documented, and the majority of individuals recover from post-concussive symptoms within several months. However, long-term effects of mTBI on brain structure and function are more poorly understood. The current studies sought to determine potential long-term effects of mTBI history and history of sports participation on 1) cognitive performance and change and 2) white matter hyperintensities (WMH) and hyperphosphorylated tau (pTau) burden, a protein associated with neurodegenerative disorders. Participants from the Dallas Lifespan Brain Study (DLBS) (aged 20-90 at baseline) completed two assessments related to head injury: the novel Head Injury Exposure and Assessment Data (HEAD) questionnaire and the current "gold standard," the Ohio State University TBI Identification Method (OSU TBI-ID). MTBI exposure variables were: number of mTBI and HEAD Total Index Score (overall seriousness of mTBI history) from the HEAD questionnaire and history of "concerning" head injury per OSU TBI-ID criteria. The HEAD questionnaire assessed history of participation in sports and average number of years played across no, limited, and high contact sports. Participants underwent longitudinal neuropsychological testing and magnetic resonance imaging, and cross-sectional positron emission tomography. Composite indices were created to represent the domains of Memory, Executive Functioning, and Processing Speed. The results did not find any evidence to suggest mTBI negatively affects cognitive performance, cognitive change, or perceived memory capacity. Longer participation in high-contact sports was not predictive of cognitive performance and there was no difference in mean cognitive index scores across highest level of contact sport played. There was also no evidence to support any relationship between history of mTBI/participation in high-contact sports and increased cerebral WMH volume or regional pTau burden. Thus, prior history of mTBI/participation in high-contact sports does not appear to be related to changes in brain structure or function in these otherwise healthy adults.Item Identifying Predictors of Reversion from Mild Cognitive Impairment to Normal Cognition(2015-07-15) Pandya, Seema Yogendra; Woon, Fu Lye; Lacritz, Laura H.; Weiner, Myron F.; Deschner, Martin; Jeon-Slaughter, HaekyungStudies on mild cognitive impairment (MCI) have focused on identifying predictors of progression to dementia, yet relatively few studies have examined predictors of reversion from MCI to normal cognition. This retrospective study incorporated data from the National Alzheimer's Coordinating Center Uniform Data Set to examine baseline predictors of MCI reversion. A total of 1,208 participants meeting MCI criteria were evaluated at baseline visit and three subsequent annual visits. Of these, 175 (14%) reverted to normal cognition, 612 (51%) remained MCI, and 421 (35%) progressed to dementia at two-years, with sustained diagnoses at three-years. This study only examined MCI participants who reverted to normal cognition (175) and progressed to dementia (421) for a final total of 596 participants. Baseline predictors of MCI reversion were categorized into the clusters of demographic/genetic data, global functioning, neuropsychological functioning, medical health/dementia risk score, and neuropsychiatric symptoms. Binary stepwise logistic regression models were used to identify significant predictors of MCI reversion compared to MCI progression for each cluster, which were then entered into a final comprehensive model to find the overall significant predictor(s). Receiver operating characteristic (ROC) curves were then used to determine cut-off scores for the continuous predictors most significant for MCI reversion. The variables most significantly associated with MCI reversion were younger age, being unmarried, having zero copies of the APOE ε4 allele, lower Clinical Dementia Rating Sum of Boxes scores, and higher test scores on Logical Memory Delayed Recall, Vegetable Fluency, and Boston Naming Test at baseline. ROC curve results revealed a standard z-score of -1.16 or better on Logical Memory Delayed Recall as an accurate classification of the MCI reversion group from the MCI progression group, with 89% sensitivity and 73% specificity. Results suggest that demographic, global functioning, and neuropsychological factors are significantly associated with MCI reversion. Future longitudinal studies on MCI reversion, with a multifactorial approach, are necessary to increase understanding of MCI reversion. Findings could help educate patients and families on clinical outcomes of MCI, better inform healthcare providers on treatment management and clinical prognosis, and increase precision of findings in early intervention studies of dementia.Item Lifestyle Factors Related to Cognitive Aging(2020-08-01T05:00:00.000Z) Smith, Emily Elaine; Rossetti, Heidi; Lacritz, Laura; Hynan, Linda S.; Lamar, Melissa; Smernoff, Eric; Valvano, AbbeyCognitive changes are a hallmark feature of Alzheimer's disease (AD) and lifestyle behaviors have been associated with a reduced risk of disease onset and slower rate of cognitive decline. Research examining the relationship of lifestyle factors (LFs) to brain health has typically focused on individual factors in isolation (more physical activity (PA) and reduced risk of AD); however, few studies have examined the combined effects of multiple LFs on cognition. The current study aimed to 1) determine which LFs best predict cognition cross-sectionally; 2) derive and compare different approaches to developing a Health Score (HS) to help predict cognition; and 3) discern if a healthy lifestyle was associated with slower rate of cognitive decline. This study included 467 older adults (Mage=83; No Cognitive Impairment=361, Mild Cognitive Impairment (MCI=94), Alzheimer's dementia (AD=12)) enrolled in a longitudinal (Myears=3.72) aging study with yearly evaluations, including neuropsychological testing, clinical evaluation, and detailed assessment of lifestyle behaviors: diet, PA, sleep, social activities, stress, depression, alcohol, smoking, body mass index (BMI), and APOE genotyping. Cognitive z-scores were derived for global cognition, verbal memory, processing speed, and working memory. HS based on a Scientific (i.e., data driven), Lifestyle/Health (i.e., only healthy lifestyle behaviors), Risk/Disease (i.e., only unhealthy behaviors), or Comprehensive (i.e., all healthy/unhealthy behaviors) approaches were calculated and categorized (Unfavorable, Minimally Favorable, Moderately Favorable, Favorable) based on quartiles. Rate of cognitive change was also calculated. Multiple linear regression analyses in the full sample revealed demographic and lifestyle (i.e., social activities, diet) factors consistently predicted cognition cross-sectionally. In the MCI/AD group, diet, PA and BMI were significant predictors with minimal demographic predictors. HS comparisons via Meng's test revealed a Lifestyle/Health approach as the best predictor of cognition compared to the other approaches. In addition, individuals with HSs in the Favorable category had significantly slower rates of cognitive decline than individuals in other categories. Overall, LFs better predicted cognition than risk factors commonly used in clinical and research settings. Results from this study corroborate prior findings and encourage continued support and resources for lifestyle research and intervention programs to help prevent and slow cognitive decline and AD.Item The MMPI-2 Restructured Clinical (RC) Scales and Personality Assessment in Multiple Sclerosis(2011-02-01) Rosvall, Traci; Lacritz, Laura H.Multiple sclerosis (MS) is a demyelinating central nervous system disease commonly accompanied by mood changes and cognitive deficits. The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is frequently used in MS but has been criticized for its inclusion of items referring to neurologic content. MS patients may accurately endorse physical symptoms, which may lead to multiple scale elevations due to the extensive item overlap across the MMPI-2 Clinical Scales. Many published studies have documented elevations on Scales 1, 2, 3, 7, and 8 in MS. In 2003, Tellegen et al. used factor analysis and a construct validity-guided approach to adapt the MMPI-2 and create a set of Restructured Clinical (RC) Scales that included 388 items. The RC scales have attracted significant attention, with evidence of improved psychometric properties, but also criticism about their conceptual foundations and applications. This study had three broad goals. The first was to compare psychometric properties in the RC and Clinical Scales in an MS sample. Secondly, profiles were examined to compare the association between somatic symptoms and the RC and Clinical Scales. Third, the relationship between cognitive dysfunction and the RC and Clinical Scales was investigated. Scores from the RC and Clinical Scales and several cognitive measures were examined from 84 patients in an outpatient neuropsychology clinic. Results showed higher item-total correlations and lower inter-scale correlations for the RC Scales compared to the Clinical Scales, although internal consistency coefficients were comparable or better for the Clinical Scales. Thus, internal consistency findings were mixed with regard to improvement for the RC Scales, while some evidence of higher discriminant validity was found. Somatic and cognitive symptoms were associated with higher Clinical Scale elevations compared to their RC counterparts, particularly on Scales 1, 2, 3, 7, and 8, which were clinically significant in this sample. Mean RC Scale scores were within normal limits with the exception of RC1 (Somatic Complaints), indicating less psychopathology in the sample than the Clinical Scales would suggest. Findings support the need for cautious interpretation of Clinical Scale profiles in MS and suggest that the RC Scales may be a useful measure with this population.Item Molecular Pathogenesis of Autism: A Role for Neurexin and Neuroligin(2012-08-15) Etherton, Mark Richard; Südhof, Thomas C.The Autism Spectrum Disorders (ASDs) represent a clinically heterogeneous group of diseases that share deficits in three core domains: social interaction, communication, and repetitive behaviors and/or restricted interests. The strong genetic basis of these disorders, which was demonstrated by multiple twin and family studies, has prompted the search for candidate genes. Neurexin and neuroligin, trans-synaptic ligands for each other, are two families of synaptic cell-adhesion molecules that have been linked to ASD pathogenesis. I found that three different mouse models for ASDs, the neurexin-1α deletion, the neuroligin-3 (NL3) R451C mutation, and the NL3 R704C mutation all aberrantly alter synaptic transmission. First, I showed that deletion of neurexin-1α in a mouse, which induced behavioral abnormalities consistent with increased repetitive behaviors, significantly reduced AMPA-receptor mediated synaptic transmission in the hippocampus. Next, I demonstrated that the NL3 R451C mutation, which has impaired social interaction, has circuit-specific abnormalities in synaptic transmission. In the somatosensory cortex, inhibitory transmission is enhanced, while in the hippocampus, excitatory transmission is increased. I went on to demonstrate that in the hippocampus, the NL3 R451C mutation appears to deleteriously impair synapse morphogenesis. Lastly, I found that the NL3 R704C mouse model also had a significant reduction in AMPA-receptor mediated transmission in the hippocampus. Taken together, these findings suggest several points. First, each of these mouse models has abnormalities in synaptic transmission, indicative of a synaptic pathology to ASD. Secondly, each of the dysfunctions in synaptic transmission are different, suggesting that comparable to the disease presentation, the pathology may also be heterogeneous. Lastly, for one mouse model, the NL3 R451C, the synaptic deficits were circuit specific, highlighting the observation that ASDs may be an manifestation of variable dysfunctions in multiple brain regions.Item Neurocognitive Functioning in Severe Depression(2006-12-19) McClintock, Shawn Michael; Cullum, C. MunroResearch has suggested that major depressive disorder can negatively impact neurocognitive functioning. Depression has been implicated in affecting many cognitive domains, including executive function, attention, memory, and psychomotor and processing speed. However, there has been limited examination of the relationship between neurocognitive functioning and depressive characteristics such as depression severity, depressive subtypes, number of depressive episodes, and episode duration. The primary goal of this study was to explore the relationship between neurocognitive functioning and depressive characteristics in severe unipolar major depressive disorder. Baseline socio-demographic, clinical, and neuropsychological information was examined in 145 inpatients enrolled in a large electroconvulsive therapy study (the Consortium for Research in ECT). Results revealed that depression severity was unrelated to global cognitive functioning and executive functioning. However, performance on certain neurocognitive variables accounted for 25% of the variability in the magnitude of depression severity. Various clinical dimensions of depression, including depressive subtype, number of episodes, and episode duration did not show a systematic relationship to neurocognitive functioning. Patients with psychotic depression performed similarly to patients without psychosis, and the ability to predict the presence of psychosis by neuropsychological performance was low. Those with atypical depression performed similarly to patients with typical depression, although patients with atypical depression showed better performance on a measure of verbal memory. No significant differences were found between subjects with multiple versus single episodes of depression, and the number of depressive episodes was unrelated to neurocognitive performance. These data indicate that the depressive characteristics examined were not systematically related to neurocognitive functioning among severely depressed patients in this well characterized and carefully selected sample.Item Quality of Life Is Associated with Survival in Patients with Cirrhosis and Hepatocellular Carcinoma(2014-04-11) Meier, Adam Thomas; Singal, Amit G.; Yopp, Adam; Beg, MuhammadBACKGROUND: Prior studies assessing quality of life (QOL) in patients with hepatocellular carcinoma (HCC) primarily included patients with preserved liver function and/or early HCC, leading to overestimation of QOL. OBJECTIVE: To characterize QOL among a diverse cohort of cirrhotic patients with HCC and evaluate its association with survival. METHODS: We conducted a prospective cohort study among cirrhotic patients with HCC from a large urban safety-net hospital between April 2011 and September 2013. Patients completed two self-administered surveys, the EORTC QLQ-C30, and QLQ-HCC18, prior to HCC-directed treatment. We used generalized linear models to identify correlates of QOL. Survival curves were generated using Kaplan-Meier analysis and compared using log rank test to determine if QOL is associated with survival. RESULTS: 130 treatment-naïve patients were enrolled and completed both surveys. Patients reported fair global QOL (median score 50%), high cognitive and social function (median scores 67%), but poor role function (median score 50%). QOL was associated with both cirrhosis-related (p=0.02) and tumor-related (p=0.02) components of Barcelona Clinic Liver Cancer (BCLC) stage. QOL was associated with survival on univariate analysis (HR 0.37, 95%CI 0.16-0.85) but became non-significant (HR 0.82, 95%CI 0.37-1.80) after adjusting for BCLC stage and treatment. Role functioning was significantly associated with survival (HR 0.40, 95%CI 0.20-0.81), after adjusting for Caucasian race (HR 0.31, 95%CI 0.16-0.59), BCLC stage (HR 1.51, 95%CI 0.21-1.89), and treatment (HR 0.57, 95%CI 0.33-0.97). CONCLUSION: QOL and role function have prognostic significance and are important to assess in cirrhotic patients with HCC.Item The Relationship of Coronary Atherosclerosis Progression to Cognition(2014-07-25) Carter, Kirstine Renee; Rossetti, Heidi; Lacritz, Laura H.; Cullum, C. Munro; Hynan, Linda S.; Khera, Amit; Weiner, Myron F.Subclinical atherosclerosis has been linked to poorer cognitive performance. Most of the literature investigating the relationship between atherosclerosis and cognitive functioning has utilized the carotid artery as an indicator. Few studies have examined the association between cognitive performance and atherosclerosis in areas where it accumulates early in the progression process, such as the coronary artery. This project aimed to examine the relationship between change in subclinical coronary atherosclerosis and cognitive performance in a large, community-based sample. Participants included 1,386 individuals with Dallas Heart Study data for coronary artery calcium (CAC) levels obtained at two time points (DHS-1 and DHS-2, approximately 7 years later) and Montreal Cognitive Assessment (MoCA) scores at DHS-2 (mean age in years (SD)=52 (9.0); 57% female, 48% Black). A subset of DHS participants (N=101, mean age (SD)= 66 (5.1), 58% female, 38% Black) returned 5 years later for comprehensive neuropsychological testing as part of the Dallas Heart and Brain Aging Study (DHBAS) at the UT Southwestern Alzheimer Disease Center. CAC progression was examined as an increase from baseline calcium levels and based on CAC progression groups (i.e., None, Incidence, Non-Progressor, Progressor) in relationship to MoCA Total Score using linear multiple regression and ANOVA to compare MoCA performance between groups. Neuropsychological test data were aggregated into functional domains, and then into a Global Composite Score. The relationship between CAC progression and this global score was examined using linear multiple regression and MANOVA. ANCOVA and MANCOVA were also used to control for sociodemographic variables, traditional vascular risk factors, and baseline CAC. In the DHS sample, CAC progression was weakly but significantly associated with MoCA scores, but this relationship was attenuated by sociodemographic factors. Membership in the CAC Progressor group was significantly associated with poorer MoCA scores after controlling for baseline CAC, race, age, sex, education, hypertension, diabetes, hypercholesterolemia, and waist to hip ratio; however, when participants with stroke were excluded Progressor group membership was no longer a predictor. There was no relationship between CAC change and subsequent cognitive performance on comprehensive neuropsychological testing. Overall, there was minimal relationship between CAC progression and global cognitive performance in a large, relatively young, community-based sample.Item The Role of KIBRA in Synaptic Plasticity Across Age(2021-05-01T05:00:00.000Z) Mendoza, Matthew Lee; Meeks, Julian P.; Huber, Kimberly M.; Green, Carla B.; Terman, Jonathan R.; Volk, Lenora J.Over the last four decades, neurobiology has gained valuable insight into the cellular and molecular mechanisms of learning and memory. However, a complete understanding of how we learn and remember information remains at the frontier of neuroscience research. In particular, the molecular bases for age-dependent changes in our capacity to learn and remember are poorly understood. Identifying the neural basis of age-dependent changes in learning and memory will not only provide crucial insights into the pathological mechanisms underlying progressive neurological disorders but also guide neurodevelopmentally informed educational strategies and legal policies. Synaptic plasticity, expressed as persistent increases (long-term potentiation, LTP) or decreases (long-term depression, LTD) in synaptic strength is thought to be a key cellular mechanism underlying cognitive functions such as learning and memory. AMPA-type glutamate receptors mediate the vast majority of fast-excitatory synaptic transmission in the central nervous system, and dynamic AMPA receptor trafficking is critical for many forms of synaptic plasticity. The coordinated movement of AMPA receptors into and out of a synapse is regulated by interactions with multiple proteins including the synaptic scaffold KIBRA (Kidney and Brain Protein). Previous evidence indicates that KIBRA and it's respective binding partners are associated with age-emergent neurological diseases such as Tourette, Schizophrenia, Alzheimer's, and Autism Spectrum Disorders. While there is a growing body of human literature implicating KIBRA in learning and memory, KIBRA's molecular function and contribution to cognitive maturation remains poorly understood. Therefore, this dissertation was designed to focus on the role of KIBRA in synaptic plasticity and AMPA receptor trafficking across the juvenile and adult brain. In Chapter 1, I review the pertinent literature to frame the overall trajectory of this dissertation. Next, in Chapter 2, using novel inducible and conditional KIBRA knock mice, I show that KIBRA acutely influences hippocampal LTP selectively in the adult brain, but not the juvenile brain. These adult-specific deficits in LTP were associated with a reduction in the basal and activity-dependent expression of AMPA receptors and AMPA receptor complex interactors. In Chapter 3, I examine KIBRA's role in LTD. Contrary to published results in conventional KIBRA KO mice on a hybrid C57Bl6N/FVB background, we show that acute manipulation of KIBRA on a C57Bl6N background does not influence hippocampal LTD. Lastly, I show that acute reduction of KIBRA influences GluA2 phosphorylation at S880, which might restrict the recycling of internalized AMPA receptors. Taken together, my data suggest that KIBRA preferentially influences LTP as opposed to LTD. KIBRA's role in LTP is selective to the adult hippocampus and loss of KIBRA reduces the expression and trafficking of AMPA receptors. In Chapter 4, I discuss the implication of this work and layout future directions.