Browsing by Subject "Mental Disorders"
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Item Examining the Feasibility of a Resilience Mental Health Application in Adolescents(2020-08-01T05:00:00.000Z) Elledge, Daniel Kuroda; Hughes, Jennifer L.; Lee, Simon Craddock; Stewart, Sunita M.; Trivedi, Madhukar; Pop, RaduBACKGROUND: Resilience is defined as the ability to rely on internal characteristics and external strengths to adapt in the face of adverse events. While universal resilience-enhancing programs are effective for adolescents, there is still a need for interventions that are easily accessible and specific to the individual. Phone applications are easy to use, tailored to the individual, and have shown positive effects for mental health outcomes. This study will determine if a resilience application is feasible and acceptable for adolescents, evaluating whether or not short-term use leads to changes in resilience. METHODS: For Study 1, Phase 1, individual interviews and focus groups were conducted with adolescents, parents, teachers, and clinicians to discuss possible incentives for using a mental health application, the benefits of using an application, and what concerns would arise from using an application. For Study 1, Phase 2, individual interviews and focus groups were conducted with adolescents, parents, teachers, and clinicians to gather feedback about the resilience application prototype. For Study 2, 40 adolescents used the application for 30 days to gather more information about feasibility, acceptability, and if there were significant positive changes with resilience and other secondary mental health outcomes. RESULTS: Multiple themes were identified through Study 1 individual interviews and focus groups, including application content, features, engagement, benefits, concerns, and improvement. Study 1, Phase 2 adolescents and adults reported the prototype was feasible and acceptable through the Computer System Usability Questionnaire (M = 6.30, SD = 1.03) and Mobile Application Rating Scale (M = 4.08, SD = 0.61). For Study 2, there were no significant differences for resilience and mental health outcomes after using the application for 30 days. Users appeared to prefer the depression module and survey sections, which provided mental health feedback. CONCLUSION: Qualitative and quantitative data provide evidence that youth are interested in a resilience mental health application and found the current prototype to be feasible. Although there were no significant mental health changes for Study 2 users, clinical implications and future directions are discussed for mental health application research.Item The Functional Roles for SWI/SNF Chromatin Remodeling Complexes in Physiology and Disease(2020-12-01T06:00:00.000Z) Celen, Cemre; Wu, Jiang I.; Zhu, Hao; Olson, Eric N.; Xu, JianSequencing studies have implicated multiple subunits of SWI/SNF complexes in human neurodevelopmental and psychiatric disorders, as well as in cancers. Particularly haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, has been implicated in short stature, autism spectrum disorder, intellectual disability, and corpus callosum agenesis. In addition, ARID1B is the most common cause of Coffin-Siris Syndrome, a developmental delay syndrome characterized by some of the above abnormalities. However, its role in pathologies is not well characterized due to absence of in vivo models. Therefore, in the first part of this thesis, we generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified insulin-like growth factor deficiency with inadequate compensation by Growth Hormone Releasing Hormone and Growth Hormone, underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling. ARID1A is a paralogous subunit that is commonly mutated in cancers and plays critical roles in liver regeneration. Chromatin remodeling mechanisms could be generally important for regeneration in other tissues. Since dynamic regulation of β-cell proliferation in pancreatic islets is poorly understood and better understanding could lead to therapeutic approaches for replenishing β-cell mass in type 1 and type 2 diabetes, in the second part of this thesis we focused on the role of ARID1A in β-cells. Arid1a is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that β-cell specific Arid1a deletion could potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally, chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. Together, this work defined the role of ARID1A in β-cells and provided new insights into the molecular regulators of β-cell regeneration. Overall, we uncovered important roles of ARID1A and ARID1B-containing SWI/SNF complexes in physiological and disease states.Item Outcomes of Supported Employment for Individuals with Severe Mental Illness(2011-12-14) Pursley, Matthew Ray; Casenave, Gerald W.Individuals with severe mental illnesses such as severe Major Depressive Disorder, Bipolar I Disorder, Schizophrenia, and Schizoaffective Disorder face heavy barriers to employment, including the symptoms of the disorders themselves, medication side effects, and stigma and misconceptions about mental illness from coworkers and employers. Consistent employment has a strong positive impact on recovery prognosis for the severely mentally ill, but up to 90% are unemployed in spite of their own desire for competitive employment and the presence of federal legislation and incentive programs intended to reduce unemployment in this population. Literature shows that access to and participation in supported employment services is the most powerful predictor of competitive employment for those with severe mental illness, but the presence of differing models of rehabilitation contributes to inconsistent levels of service and results. The medical model and the recovery model are two of the most popular and widespread models of rehabilitation currently in use. Research comparing these models is necessary to determine which is more effective at helping the mentally ill achieve and maintain competitive employment. This thesis reviews relevant literature and presents a research design for a nonequivalent group study inspired by the Metroplex Employment Model, comparing the outcomes of the medical model of rehabilitation and placement with those of supported employment within the recovery model of rehabilitation. The goal is to determine which service format provides the desired results (prompt and sustained employment) more efficiently and consistently, making process-based and outcomes-based program evaluation a vital part of the design. Samples of program evaluation forms can be found in the Appendix. It is hypothesized that supported employment services following a biopsychosocial, recovery-based model will result in consumers with severe mental illness attaining employment significantly more quickly and sustaining it for longer than rehabilitation services that follow the traditional medical model. Following the literature review and basic design, there is discussion of the importance and implications of the results of such a study, potential improvements upon the design, and variations on how the data may be computed.Item The Role of SHANK3 at the Synapse and Its Implications in Autism-Associated Behaviors and Synaptic Transmission(2015-04-10) Kouser, Mehreen; Rothenfluh, Adrian; Huber, Kimberly M.; Bibb, James A.; Powell, Craig M.Autism is a neurodevelopmental disorder characterized by an increase in repetitive behaviors and impairments in social interaction and communication. Since its discovery, a multitude of studies have linked SHANK3 to autism. Moreover, deletion of SHANK3 has been shown to cause Phelan McDermid Syndrome (22q13 Deletion Syndrome) by several human studies. Shank3 is a multi domain post-synaptic scaffolding proteins that is found in excitatory synapses and plays a critical role in forming the post-synaptic density by connecting the necessary machinery together. In this study, I have characterized a homozygous Shank3 mutation in mice that deletes exon 21(Shank3ΔC) including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major, naturally occurring Shank3 protein bands. Shank3ΔC/ΔC mice exhibit an increased localization of mGluR5 to the synapses in the hippocampus, a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. I also report on a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G) which causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse like the Shank3ΔC/ΔC mice. Shank3G/G mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, and altered response to novelty. Shank3G/G mice also exhibit impaired hippocampal excitatory transmission and plasticity. Finally, Shank3G/G mice were designed to be genetically rescued to wild-type at various times during development. In this study, I also report on the biochemical and behavioral results of the genetic rescue in Shank3G/G mice after the completion of neurodevelopment. I was able to achieve a biochemical rescue in the Shank3G/G mice. Interestingly, not all the behavioral impairments observed in Shank3G/G mice were replicated in the Reversible-Shank3G/G mutation mice making the interpretation of the data more challenging which is discussed in detail in this thesis.Item Two Psychological Survey Studies: (1) Understanding the Stigma Toward Lung Cancer and (2) Using Research Domain Criteria Project (RDoC) to Predict Remission Rates of Major Depressive Disorder Patients(2017-11-22) Ma, Tsung-wei; Zhan, Xiaowei; Xie, Yang; Xiao, Guanghua; Schiller, Joan H.; Gazdar, AdiThis dissertation is composed of two psychological survey studies. In the first study, people's negative attitudes toward lung cancer are assessed and discussed. The second topic is about predicting the remission rates of major depressive disorder patients with patients' self-reported questionnaires. In the first topic, I analyzed data from The Lung Cancer Project, an online survey study, to assess both explicit and implicit attitudes expressed by the four participant groups: health care professionals, cancer patients, caregivers and the general public. Negative attitudes toward lung cancer were detected among all these participant groups. I also discovered several demographic factors significantly associated with negative attitudes toward lung cancer. Furthermore, I investigated the association between state-level perceptions of lung cancer (including both explicit and implicit attitudes) and rates of treatment (drug treatment rates or total treatment rates, including surgery, chemotherapy, radiation, and immunotherapy) for lung cancer patients in the corresponding states. In the second topic, existing data from the Combining Medications to Enhance Depression Outcomes (CO-MED) trial were utilized to develop a data-driven method for mapping the behavioral factors to the constructs defined in Research Domain Criteria (RDoC). And I used the defined behavioral factors from CO-MED to discover patient subgroups. In further analysis, I found that the discovered patient subgroups have significantly different remission rates to the antidepressant treatment, which indicates that there are three endo-phenotypes in major depression disorder.Item Understanding Autism Pathology: Insights from Genetic Mouse Model Manipulation of KCTD13 and SHANK3(2017-07-19) Ochoa Escamilla, Christine; Konopka, Genevieve; Powell, Craig M.; Huber, Kimberly M.; Eisch, Amelia J.; Tsai, PeterCopy number variations (CNVs) contribute to the etiology of Autism Spectrum Disorders (ASDs). Deletions/duplications in human chromosomal region 16p11.2 are frequently associated with ASD and other neurodevelopmental disorders. Specific genes within this region may be important for determining autism risk, though none has been individually linked to ASD. To understand how single 16p11.2 genes contribute to CNV deletion pathology, we delete a candidate among the 16p11.2 genes, Kctd13, in mice to examine its function in mammalian brain. We report that our Kctd13 deletion mouse model results in decreased synaptic transmission (input/output curves and mEPSC and mIPSC frequency) in area CA1 of the hippocampus with normal paired-pulse ratio, normal mEPSC/IPSC amplitude, and no change in another correlate of presynaptic release probability, suggesting a decrease in the number of functional synapses. Consistent with these results, reduced synaptic transmission correlates with increased levels of RhoA, the KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, confirming increased RhoA as one important molecular mechanism. These changes correlate with a decrease in total dendritic length and spine density in area CA1 of the hippocampus, confirming the decrease in synapse number. This genetic mouse model also displays increased locomotor activity, a robust behavioral phenotype in 16p11.2 deletion mouse models. These results suggest that KCTD13 regulates neuronal morphology and synapse number and likely does so via alteration of RhoA signaling pathways. Together, these data implicate Kctd13 in regulation of neuronal function relevant to neuropsychiatric disorders and reveal a potential role for RhoA as a future preclinical therapeutic target with potential to benefit patients containing KCTD13 deletions. SHANK3 (also known as PROSAP2) functions as a postsynaptic scaffolding protein at excitatory synapses. Mutations and deletions within SHANK3 are known to cause idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. We create a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight SHANK3 isoforms at the synapse. At the cellular level, Shank3G/G mice exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. Changes in NMDA receptor function correlate with decreased phosphorylation of the GluN2BR Tyr 1472 site in the Shank3G/G mice. These results identify clear alterations in synaptic function and in the biochemistry of NMDA receptors in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. These findings reveal a potential role for NMDA receptors as a preclinical therapeutic target for patients with SHANK3 mutations.Item [UT News](1985-09-23) Harrell, AnnItem [UT News](1986-05-22) Cason, VickiItem [UT Southwestern Medical Center News](2006-11-07) McKenzie, Aline