Depressive Symptoms, Neuropsychological Functioning, and Self-Management in Youth with Spina Bifida: Direct, Mediating, and Reciprocal Pathways

Although successful self-management of health care responsibilities is critical to meeting the developmental demands associated with the transition to adulthood in youth with spina bifida (SB), research on individual factors impacting self-management in this population is sparse. Given the increased risk for cognitive deficits and development of depressive symptoms in this population, this study utilized a longitudinal, multi-method, multi-informant design to examine two pathways through which depressive symptoms and neuropsychological dysfunction may be associated with medical autonomy and adherence in youth with SB. Bootstrapped mediation analyses revealed that teacher-reported depressive symptoms significantly mediated the respective relationships between attention and working memory, and medical responsibility (all p\u27s \u3c .05), but that neuropsychological dysfunction did not mediate the relationship between depressive symptoms and medical responsibility. It is hoped that this research will inform the development of evidence-based interventions aimed at improving and fostering the development of self-management in youth with SB

Elucidating Genetic and Environmental Influences on Alcohol-Related Phenotypes

Decades of work has led researchers to believe that risk for complex behavioral phenotypes, such as alcohol use disorders, is likely influenced by multiple genes of small effect acting in conjunction with each other and the environment. Currently, the field of psychiatric genetics is developing methodologies for the identification of genetic risk variants that predispose individuals to the development of complex behavioral disorders. Several challenges related to the complex and polygenic nature of these phenotypes, must be considered. This dissertation study attempts to address these important challenges in the context of alcohol use disorders and related phenotypes. A rich twin and family study literature has indicated that 40-70% of the variance in alcohol use disorders (AUDs) is influenced by genetics. Recent attempts to identify specific x genetic risk variants associated with AUDs have been met with limited success. Meanwhile, evidence of the moderating effects of the environment on AUDs has been mounting, providing a strong rationale for examining gene-environment interaction. In the following chapters several studies will be described that integrate established twin methodologies into gene identification projects in an effort to reduce heterogeneity (both phenotypic and genotypic), elucidate environmental constructs that moderate genetic influences, and to enhance statistical power to detect the subtle genetic influences on alcohol related phenotypes

Using Genetic Information in Risk Prediction for Alcohol Dependence

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history has not yet been reported. These studies aim to explore the aggregate impact of multiple genetic variants with small effect sizes on risk prediction in order to provide a clinical interpretation of genetic contributions to AD. Data simulations showed that given AD’s prevalence and heritability, a risk prediction model incorporating all genetic contributions would have an area under the receiver operating characteristic curve (AUC) approaching 0.80, which is often a target AUC for screening. Adding additional environmental factors could increase the AUC to 0.95. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we used several different sources to capture genetic information associated with AD in discovery samples, and then tested genetic sum scores created based on this information for predictive accuracy in validation samples. Scores were assessed separately for single nucleotide polymorphisms (SNPs) associated in candidate gene studies and in GWAS analyses. Candidate gene sum scores did not exhibit significant predictive accuracy, but SNPs meeting less stringent p-value thresholds in GWAS analyses did, ranging from mean estimates of 0.549 for SNPs meeting p\u3c0.01 to 0.565 for SNPs meeting p\u3c0.50. Variants associated with subtypes of AD showed that there is similarly modest and significant predictive ability for an externalizing subtype. Scores created based on all individual SNP effects in aggregate across the entire genome accounted for 0.46%-0.57% of the variance in AD symptom count, and have AUCs of 0.527 to 0.549. Additional covariates and environmental factors that are correlated with AD increased the AUC to 0.865. Family history was a better classifier of case-control status than genetic sum scores, with an AUC of 0.686 in COGA and 0.614 in SAGE. This project suggests that SNPs from candidate gene studies and genome-wide association studies currently have limited clinical validity, but there is potential for enhanced predictive ability with better detection of genetic factors contributing to AD

Executive Dysfunction as a Trait Marker for Depression in Children and Adolescents

Perinatal depression has been recognized as a public health problem in the United States, which is important because of the demonstrated wide-reaching negative effects of maternal depression on child outcomes. Some evidence suggests that maternal depression is a risk factor for executive dysfunction in children. By contrast, there is abundant evidence that maternal depression is a risk factor for later child depression. Therefore, this study focuses on executive dysfunction in children as a potential trait marker for later depression in childhood and adolescence, utilizing data from the NICHD Study of Early Child Care and Youth Development. Participants were from 10 locations around the United States. Measures assessed postnatal depressive symptoms (Center of Epidemiologic Studies Depression Scale, CES-D), inhibition in children (Conners Continuous Performance Test, CPT), inhibition and information updating in children (Tower of Hanoi, TOH, and Tower of London, TOL), inhibition and set shifting in children (Stroop Test), and internalizing behaviors in children (Child Behavior Checklist, CBCL). Maternal depression was grouped based on trajectory: no depression, postpartum depression, early childhood depression, and chronic depression. A series of ANCOVAs and MANCOVAs were conducted to examine: a) whether early chronic maternal depression would be associated with lower scores on measures of executive function among children in 1st grade, 4th grade, 5th grade, and at 15 years of age; and b) whether children with depressed mothers who experience executive dysfunction would be more likely to experience subsequent depressive symptoms; that is, whether the relationship between maternal depression and later child internalizing behaviors would be mediated by child executive dysfunction. Overall, findings revealed that all courses of maternal depression were associated with later child depression and child inhibition and information updating deficits at grade 1 in males only. Additionally, early childhood and chronic depression were associated with inhibition and information updating deficits at grade 5 in males. Other exploratory analyses are discussed

Cognitive and Neural Correlates of Coping and Resilience in Depression

Depression is one of the most prevalent and devastating psychological disorders, often with a chronic or remitting/reoccurring course. The inability to effectively cope with stress and negative life events has been strongly linked to the development and maintenance of depression symptoms; yet, the cognitive and biological processes underlying the complex and multidimensional behavioral construct of coping are not well understood. Using a combination of self-report measures, computerized cognitive tasks, and scalp electroencephalography (EEG) methodologies, the present study investigated associations between specific executive function abilities (i.e., inhibition and set-shifting), underlying neural activity, coping strategy and flexibility, and depression symptoms. Results did not support the primary study hypotheses predicting coping to mediate the relation between executive dysfunction and depression symptoms. Post-hoc correlational analyses elucidated relations between various components of coping strategy and depression symptomatology, and further demonstrated associations with frontocentral N200/P300 and parietal P300 peak latencies

SEX-SPECIFIC EFFECTS OF PSYCHEDELIC DRUG ADMINISTRATION ON STRESS-RELATED BRAIN REGION REACTIVITY AND BEHAVIORAL RESPONDING

Psychedelics have experienced renewed interest following studies suggesting rapid-acting and long-lasting therapeutic effects in patients with affective psychiatric disorders. While clinical results look promising, the circuit-level neurobiological mechanisms underlying acute and prolonged effects remain unclear. Many psychiatric disorders involve dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The central amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), and paraventricular nucleus of the thalamus (PVT) are all key regions in orchestrating the neural and endocrine stress response. Here, we aimed to test how a single administration of psilocin, the psychoactive metabolite of psilocybin, alters reactivity of these regions at both acute and prolonged time points in Sprague Dawley rats. We found that a single dose of psilocin (2mg/kg) produces acute increases in reactivity within the PVT and CeA in females, and acute increases in PVN reactivity and prolonged decreases in CeA reactivity in males. The effects in both CeA and PVN seen in males were driven by those employing an active threat responding behavior strategy. We also observed an effect of psilocin administration on maintenance of reactivity within PVTCeA circuitry in both males and females. All together, these data provide intriguing new insight into the region-specific alterations following a single dose of a psychedelic and may serve as a foundation in uncovering the circuit-level mechanisms underlying the acute and persistent effects of psychedelic drug action.Doctor of Philosoph

Androgens and the Female Brain: The Relationship between Testosterone Levels, Depression, Anxiety, Cognitive Function, and Emotion Processing in Females with Polycystic Ovarian Syndrome

Background: Polycystic Ovarian Syndrome (PCOS) is the most common endocrine disorder in reproductive-aged females, with the main hormonal abnormality being androgen (testosterone) excess. Although it is well-established that there is a higher prevalence of depression in PCOS, little research has examined the direct relationship between androgen levels, depression and associated cognitive impairment. The current study conducted a simultaneous investigation of the relationship between androgen levels, mood, cognitive function and emotion processing in females with PCOS, before and after 12 weeks of anti-androgen treatment. Elucidating the relationship between androgens and mood in females could have significant benefit in determining optimal treatment for the subset of females whose symptoms of depression may be related to an underlying androgen excess. Objectives: • To describe differences between the PCOS (n = 53) and non-PCOS control (n = 54) groups on measures of mood, anxiety, cognitive function and emotion processing, • To determine whether correlations exist between androgen levels and symptoms of depression and anxiety, cognitive function, and emotion processing in the entire sample with varying androgen levels, • To determine whether symptoms of depression relate to aspects of cognitive function and emotion processing, • To determine whether anti-androgen treatment is associated with changes in mood, anxiety, cognitive function and emotion processing in the PCOS group. Methods: Fifty-three females with PCOS and 54 age-matched females without PCOS completed an assessment of androgen levels from blood samples, depression-rating scales, and cognitive and emotion processing measures at two-time points; baseline and 12 weeks. The PCOS group commenced anti-androgen treatment following baseline assessment. Results: • Females with PCOS had more symptoms of depression but not anxiety, and showed worse performance on the cognitive domains of psychomotor speed and emotion processing compared with the control group. • Higher testosterone levels were significantly associated with worse mood and worse cognitive function in sub-tests within the domains of verbal and visuospatial learning and memory, psychomotor speed and emotion processing across the entire sample. • Significant correlations were found between worse mood and anxiety and poorer cognitive performance on aspects of verbal and visuospatial learning and memory, and attention and executive function measures. • Anti-androgen treatment was associated with significant improvements in psychomotor speed and aspects of emotion processing in the PCOS group. • Following anti-androgen treatment, a significant improvement was observed in symptoms of depression and anxiety and on performance on verbal and visuospatial learning and memory and emotion processing measures within the PCOS group. • Improvement in symptoms of mood was associated with improved performance on measures of psychomotor speed, attention and executive function and improved recognition accuracy of fearful and disgusted faces within the PCOS group. Conclusions: Females with PCOS showed greater symptoms of depression and worse cognitive function compared with non-PCOS control participants. Additionally, higher testosterone levels were associated with greater symptoms of depression and worse cognitive performance. Anti-androgen treatment appeared to have a significantly beneficial effect on mood and aspects of cognitive function in the PCOS group. Results from the current study thus provide preliminary evidence that testosterone excess in females with PCOS is associated with greater depressive symptoms and worse cognitive function, which may be benefited by anti-androgen treatment

Validation of the 40 Hz Auditory Steady State Response as a Pharmacodynamic Biomarker of Evoked Neural Synchrony

Schizophrenia is a troubling and severe mental illness that is only incompletely treated by currently available drugs. New drug development is hindered by a scarcity of functionally relevant pharmacodynamic biomarkers that are translatable across preclinical and human subjects. Although psychosis is a major feature of schizophrenia, cognitive and negative symptoms determine the long-term functional outcomes for patients. Stimulus-evoked neural synchrony at gamma (~ 40 Hz) frequency plays an important role in the processing and integration of sensory information. Not surprisingly, schizophrenia patients show deficits in gamma oscillations. NMDA receptor (NMDAR) activation on fast-spiking parvalbumin-positive interneurons is deemed important for the generation of gamma oscillations. NMDA hypofunction has been proposed as an alternative hypothesis to the well-known dopamine dysregulation to explain the neurochemical abnormalities associated with schizophrenia. For this dissertation, we validated a preclinical model to pharmacologically probe NMDA-mediated gamma oscillations by further characterizing the auditory-steady state response (ASSR) in female Sprague Dawley rats. The ASSR is a measure of cortical neural synchrony evoked in response to periodic auditory stimuli. ASSR at 40 Hz is consistently disrupted in patients. First, we established the reliability of click train-evoked 40 Hz ASSR and tone-evoked gamma oscillations in 6 separate sessions, spread over a 3-week period. Then we established the sensitivity of these neural synchrony measures to acute NMDAR blockade using the high affinity NMDA channel blocker MK-801, using a repeated measures design. Next, we compared the reliability and sensitivity of the 40 Hz ASSR from two distinct recording sites. Results from this study showed that as compared to vertex, temporal recording showed a greater gamma synchrony. However, the temporal recording had poor test-retest reliability and lower sensitivity to MK-801-induced disruption. Lastly, we characterized the dose-response profiles of an NMDA co-agonist D-serine, an atypical (clozapine) and a typical (haloperidol) antipsychotic, on the 40 Hz ASSR. Results from these studies showed that only clozapine was effective in robustly augmenting 40 Hz ASSR. Furthermore, only clozapine pretreatment had partial protective effect against MK-801 induced ASSR disruption. Overall, this work establishes that vertex recorded 40 Hz ASSR is a reliable neural synchrony biomarker in female SD rats that is amenable for bidirectional pharmacodynamic modulation

Discovering the molecular mechanisms underlying schizophrenia

290 p.Schizophrenia is a chronic, disabling illness that affects about 0.32% of the world's population (Institute for Health Metrics and Evaluation (IHME), 2020). It typically begins in adolescence and worsens over time, reducing life expectancy by approximately 14.5 years (Hjorthøj et al., 2017). Due to its early onset, chronic nature, and associated deficits, schizophrenia ranks among the top ten causes of disability worldwide (Marder & Cannon, 2019). In addition, it is estimated to be the seventh most costly disease in terms of care and loss of productivity (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators et al., 2018). This entails an estimated annual cost of around 3.5 billion dollars in countries such as Spain and up to 102 billion dollars, according to the most pessimistic studies, in countries such as the United States (Chong et al., 2016) taking into account direct costs (treatments, damages, accidents, etc.) and indirect costs (loss of human capital). Additionally, in 2022 the most commonly used atypical antipsychotics in Spain (risperidone and olanzapine) were among the top 8 drugs that generated the highest expenditure, with an economic cost of around 347 million euros (Ministerio de Sanidad, 2022). This explains why research on this disease is a priority objective of global health systems