Browsing by Subject "Schizophrenia"
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Item Astrocytic Contribution to the Glutamatergic Transmission in Schizophrenia(2011-02-01) Stan, Ana Despina; Tamminga, CarolSchizophrenia is a chronic mental disorder encompassing an array of cognitive and behavioral manifestations. Although the disease molecular pathophysiology remains essentially unknown, evidence exists for abnormalities within all the main neurotransmitter systems and various cortical and subcortical brain structures, albeit with no unifying/overarching hypothesis connecting the existent knowledge. Moreover, no current animal model or biological construct reproduces the complexity of the disease with acceptable validity. In my work I have taken a multidisciplinary approach to study the live and postmortem human brains of people with schizophrenia, focusing specifically on the glutamatergic abnormalities in the hippocampus, one brain region repeatedly found to bear structural, molecular, and blood flow abnormalities in the disease. I have started with the in vivo measurement of glutamate and glutamine using magnetic resonance spectroscopy, thus getting a “high-level” sense of the glutamatergic transmission changes in the hippocampi of subjects with schizophrenia. Concretely, I have found that untreated people with schizophrenia have reduced levels of glutamate compared to their healthy counterparts, but this reduction can be partially reversed by antipsychotic medication. To allow for a more “small-scale” characterization of the glutamatergic transmission impairments, I have used postmortem brain tissue to zoom in on the glutamatergic synapse, viewed as a “tripartite synapse”. Apart from the pre- and postsynaptic neurons, the third component is represented by the astrocyte, the brain glial cell that is responsible for most of the glutamate recycling and that attunes the glutamatergic synapse to the overall energetic metabolism of the brain. I have found that glutamate recycling is impaired in schizophrenia, selectively in the dentate gyrus, one of vii the hippocampal subregions, and the specific abnormalities reside in the glutamate transporters, responsible clearing up synaptic glutamate.Item COMT Genotype, Schizophrenia, and Dopamine Transmission(2011-02-01) Birchfield, Thomas Richard; Ghose, SubrotoCatechol-o-methyltransferase (COMT) catabolism is the primary mechanism for dopamine signal deactivation in the dorsolateral prefrontal cortex, an area of the brain associated with working memory. Working memory deficits are found in persons with schizophrenia and their unaffected siblings. A single nucleotide polymorphism of the COMT gene results in a MET-->VAL shift at codon 158, increased enzyme thermostability, and increased enzymatic activity. The hypothesized result of this shift is decreased dopamine transmission in the brain area associated with working memory due to increased dopamine catabolism. The current study analyzed the effect of COMT genotype and schizophrenia on the mRNA expression of genes known to be influenced by dopamine signal transmission with qPCR of RNA extracted from high-quality, fresh-frozen postmortem dorsolateral prefrontal cortex tissue. While no significant difference was observed between genotypes, a significant effect of diagnosis was found for the D1 dopamine receptor, COMT, and tyrosine hydroxylase, the rate-limiting step of dopamine synthesis. The current findings support a model decreased dopamine synthesis and increased catabolism leading to deficient dopamine signal transmission in persons with schizophrenia.Item Do atypical antipsychotics cause diabetes?(2007-06-22) Wyne, KittieItem Hippocampal Subfield Transcriptome Analysis in Schizophrenia Psychosis(2018-11-29) Perez, Jessica Marie; Eisch, Amelia J.; Tamminga, Carol; Kim, Tae-Kyung; Zinn, Andrew R.Schizophrenia is one of the thirty most incapacitating conditions in the world and affects tens of millions of people worldwide. Devastatingly, suicide occurs in 10% of those diagnosed with schizophrenia. Symptoms are persistent and often severe and available treatments are not curative. In fact, 20-33% of people with schizophrenia are entirely resistant to treatment. The complex symptom manifestations of schizophrenia lack a molecular pathology. Consequently, advances in novel treatment directions are limited. Schizophrenia is recognized as a polygenic disorder influenced by environmental factors. This dissertation aims to examine this polygenic nature of this disorder. Genome wide association studies have identified hundreds of common genetic variants, which individually confer a small risk for schizophrenia. However, all identified genetic variants combined only account for a modest amount of the total heritability of schizophrenia. In this dissertation, I capitalize on the unique ability of next-generation sequencing to identify in a global and unbiased manner molecular changes, which have not been previously hypothesized, but may contribute to the origin of the missing heritability of schizophrenia and play a role in schizophrenia symptomatology. The Tamminga lab has particular interest in schizophrenia psychosis, conceptualizing it as a disorder of learning and memory, critically involving dentate gyrus (DG), CA3, and CA1 of the hippocampus. Therefore, this doctoral dissertation examines the transcriptome of all three subfields, DG, CA3, and CA1 in human postmortem tissue of controls and individuals diagnosed with schizophrenia, using RNA-seq to identify additional psychosis-mediating molecular candidates and produce plausible targets for therapeutic treatment. After Chapters 1, 2, and 3 introduce the significance and contribution of this dissertation to the field of neuroscience in psychiatry, I show (Chapter 4) that each hippocampal subfield in schizophrenia has a unique molecular identity based on its transcriptome profile. As well, I show only slight effects of antipsychotic medication on schizophrenia-dependent gene changes in DG, CA3, and CA1. Taken together, my data identify molecular candidates and specific cell populations that we previously did not hypothesize as potential contributors to schizophrenia pathology. Finally, in Chapter 5, I outline future directions based on the contributions of my doctoral dissertation to the field.Item Long Term Cognitive Sequelae of Adolescent Cannabis Use in Individuals with Psychosis(2014-08-28) Shalvoy, Alexandra Miller; Ghose, Subroto; Tamminga, Carol; Cullum, C. MunroBACKGROUND: Cognitive deficits are well established in schizophrenia and there is evidence of an association between adolescent cannabis use and cognitive function in schizophrenia. This study examined the relationship between age of cannabis use and cognition in individuals within the psychosis domain, including those with schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. SUBJECTS: Archival data from the University of Texas Southwestern Medical Center (UTSW) site of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Participants included probands with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, and healthy controls with and without a history of cannabis use. METHOD: The psychosis (N=97) and control (N=64) groups were divided into six groups: control with no cannabis use (CCB-; N=38), control with adolescent cannabis use (CCB+; N=16), control with late cannabis use (N=10), psychosis with no cannabis use (PCB-; N=48), psychosis with adolescent cannabis use (PCB+; N=33), and psychosis with late cannabis use (N=16). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery, the Birchwood Social Functioning Scale, Structured Clinical Interview for DSM-IV diagnosis, Positive and Negative Symptom Scale, as well as a detailed record of patterns of substance use including age of onset, period and frequency of greatest consumption, and most recent use. RESULTS: Regarding cognitive function, this thesis found that age of cannabis use impacted the BACS total score. Specifically, the control and psychosis adolescent cannabis use groups were not significantly different in cognitive functioning. PCB+ performed better than the other psychosis groups, and CCB+ performed worse than the other control groups. Additionally, PCB+ and PCB- were significantly different, with the PCB+ performing better cognitively. DISCUSSION: There is previous evidence suggesting that individuals with schizophrenia and adolescent cannabis have less neuropsychological impairment compared to individuals with schizophrenia who do not have a cannabis use history. In this thesis, we extended these findings to psychosis as a spectrum, finding that individuals with psychosis and adolescent cannabis use had better overall cognition as measured by a brief neurocognitive test battery compared to those with psychosis and no cannabis use history.Item [News](1972-10-18) Fenley, Bob; Weeks, John; Harrell, AnnItem [News](1984-08-31) Harrell, AnnItem Psychometric Properties and Clinical Utility of the Texas Functional Living Scale Short Form in Individuals with Schizophrenia(2013-09-10) Rogers, Kathryn Rayne; Casenave, Gerald W.; Hester, Andrea; Chiu, Chung-YiBACKGROUND: Schizophrenia is a chronic mental disorder presenting with psychotic and cognitive symptoms that lead to impairments in independent living and psychosocial functioning. Individuals with schizophrenia demonstrate cognitive deficits in areas of attention, executive functioning, memory, and language. Additionally, schizophrenia has been associated with impairments in activities of daily living (ADLs) such as toileting and the ability to feed one’s self and instrumental activities of daily living (IADLs) such as taking medication, financial management, communication, and transportation. METHODS: Twenty-six participants diagnosed with schizophrenia or schizoaffective disorders were recruited from the University of Texas Southwestern Medical Center’s Division of Translational Neuroscience of Schizophrenia’s IRB approved Database Registry for Psychotic Disorders and completed a neuropsychological test battery which included the Texas Functional Living Scale (TFLS) and University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA). IBM SPSS Statistics (SPSS v. 19.0) was used to perform Pearson correlation coefficients and multiple regression analyses to identify which subscale(s) of the TFLS had the highest predictive ability for examining IADLs to create a possible short form and to identify which subscales of the TFLS long form have the strongest correlation to neurocognitive measures used in the study. The present pilot study used the Type I error rate at .10; a 90% confidence interval. RESULTS: Results of the analysis indicated that the Time and Money Calculation subscales of the TFLS long form significantly correlated with more neurocognitive measures than the UPSA. Specifically, these two subscales had a higher number of moderate to strong correlations with the neurocognitive measures compared to the UPSA. Results also indicated the TFLS short form to have a stronger correlation with the UPSA (r =.59, p < .003) compared to baseline correlations of the TFLS long form and the UPSA (r = .34, p < .112), which suggests that the Time and Money Calculations subscales of the TFLS can be used as a valid short form of the TFLS in the assessment of IADLS in schizophrenia. DISCUSSION: Overall, the short form of the TFLS appears to be a valuable addition to standard neuropsychological assessment batteries given its numerous correlations with neurocognitive measures. Results also suggest that the TFLS short form is a stronger measure for detecting IADL impairments compared to its original long form and the UPSA.Item Resting State Functional Magnetic Resonance Imaging Alterations In Psychosis Spectrum Disorders(2015-03-20) Samudra, Niyatee; Tamminga, CarolBACKGROUND: Many psychiatric disorders, especially those on the psychosis spectrum, are as yet without good diagnostic and treatment options. Neuroimaging research, most recently research into brain functional connectivity via resting-state fMRI, may provide a window into this problem, creating possibilities for discovering disease state-specific biomarkers important for diagnosis or to follow treatment efficacy. Hippocampal hyperactivity is known to be a feature of schizophrenia. The anterior hippocampus in particular, because of its structural connectivity relationships to frontal and limbic areas, may have specific connectivity alterations in psychosis spectrum disorders. In addition, it is important to understand whether putative changes in hippocampal functional connectivity are unique to a particular conventional (Diagnostic and Statistical Manual) psychosis disorder or whether they are present in multiple psychosis spectrum disorders, as this helps establish a biological foundation for psychosis. This work examines hippocampal functional connectivity changes in psychosis spectrum disorders in light of a possible imaging signature for psychosis. It is best understood in light of the work done by the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, a multi-site study group to establish imaging and molecular biomarkers across the psychosis dimension. OBJECTIVES: 1) To understand abnormal hippocampal connectivity and its targets in the rest of the brain in psychosis spectrum disorders. 2) To assess whether hippocampal connectivity changes are specific to one DSM diagnostic group or common across the psychosis spectrum. 3) To correlate hippocampal connectivity alterations with specific cognitive and clinical outcomes. METHODS: We tested resting state connectivity in 88 participants with psychosis disorders (21 schizophrenia; 40 schizoaffective disorder; 27 psychotic bipolar I disorder) and 65 healthy controls. Image processing and seed-based, voxel-wise connectivity analyses were carried out in the Analysis of Functional Neuroimaging (AFNI) software package to understand differential connectivity in psychosis spectrum vs. healthy controls using whole, anterior, and posterior hippocampal seeds. Connectivity measures for psychosis participants, as assessed by z-scores, were correlated with multiple clinical and cognitive measures. RESULTS: We found no significant differences in hippocampal functional connectivity across the three DSM diagnoses tested, thus justifying combining the groups for an analysis versus healthy controls. For the whole psychosis group, there were strong reductions in anterior hippocampal connectivity to anterior neocortical regions, including medial frontal and anterior cingulate cortices, as well as to superior temporal gyrus, precuneus, thalamus and cerebellum. Posterior hippocampal seeds also demonstrated decreased connectivity in psychosis subjects, with fewer regions of altered connectivity and a predominantly posterior/cerebellar distribution. Whole hippocampal outcomes were consistent with anterior/posterior hippocampal connectivity changes. These changes did not correspond to measures of cognition, medication effect, or clinical symptoms. CONCLUSION: This research underlines the possibility of a neuroimaging signature for psychosis spectrum disorders consisting of decreased predominantly anterior hippocampal connectivity with frontal and temporal regions, among others. The changes observed do not seem to correspond to medication effect or demographic variables in our analysis, thereby suggesting a primary disease effect. Further research is necessary to establish a hippocampal network in psychosis which may serve as a biomarker, with implications for more definitive diagnosis and treatment response prediction.Item A Reverse Translation Mouse Model for Schizophrenic Psychosis: Contribution of Hippocampal Subfield Pathology(2016-11-30) Southcott, Sarah Ann; Hsieh, Jenny; Huber, Kimberly M.; Rothenfluh, Adrian; Tamminga, CarolSchizophrenia is a serious and lifelong psychotic illness that affects all aspects of cognitive and affective function and whose etiology and brain mechanisms remain elusive. Schizophrenia affects not only those who express the condition, but also their family members, friends, and society as a whole. There is a worldwide prevalence of 1%, and the illness in 2012 alone, cost the USA an estimated $62.7 billion in medical care cost and lost wages. Schizophrenia is an extremely complex disease with a heterogeneous mixture of symptoms, including cognitive dysfunction, mood dysfunction, negative symptoms, and the defining symptom set, positive psychotic symptoms. The antipsychotic effects of dopamine receptor antagonists led people to hypothesize that schizophrenia is a disorder of dopamine hyperfunction, but considerable research has generated no strong evidence to support such a simple mechanistic hypothesis. Most recently, the glutamate system has become an etiologic focus in schizophrenia research and its research is proving more promising. We have studied the molecular basis of psychosis in human post mortem hippocampus in schizophrenia, and its related proteins important for learning and memory, especially the n-methyl-d-aspartate (NMDA) glutamate receptor system. Based on our findings we have developed a testable hypothesis of psychosis, formulated as a learning and memory disorder. In order to fully test this hypothesis we first needed to create a dynamic animal model based on our tissue findings that could be manipulated and probed. We found that knocking out the obligate subunit (GluN1) of the NMDA receptor selectively in the dentate gyrus paradoxically led to an increase in neuronal activity in the CA3 and several behavioral changes parallel to those we observe in schizophrenia. Furthermore we combined a pharmacological risk factor (phencyclidine) and a genetic risk factor (DISC1) with the knockout mouse that we believed would have the highest probability of interacting in a manner reminiscent of schizophrenia. These particular combinations did not exacerbate the symptoms of the dentate gyrus-specific GluN1 knockout mouse. Now we plan to use this dynamic mouse preparation to study the mechanisms whereby the reduction in GluN1 protein in dentate gyrus sensitizes and stimulates neuronal activity downstream within the hippocampus to better understand psychosis processes.Item [Southwestern News](1993-09-20) Harrell, AnnItem [Southwestern News](2000-08-08) Harrell, AnnItem [Southwestern News](2005-08-17) McKenzie, AlineItem Using Multimodal MRI Techniques to Understand the Role of Hippocampus in Schizophrenia(2013-07-29) Fang, Yan; Lenkinski, Robert; Tamminga, Carol; Choi, Changho; Lu, Hanzhang; Maher, ElizabethAccording to our hippocampal metaplasticity model for schizophrenia (SZ), reduced glutamate signaling in dentate gyrus could lower the LTP threshold in its target region CA3, thus generates increased associative function in CA3, resulting in memories with psychotic content. The loss of mnemonic functions in dentate gyrus could decrease its pattern separation function. Multimodal MRI techniques including proton magnetic resonance spectroscopy (1H-MRS), cerebral blood volume (CBV), cerebral blood flow (CBF) and functional MRI at 3T were used to examine the metaplasticity model and probe the role of hippocampus in schizophrenia both with (SZ-on) and without (SZ-off) antipsychotic drug treatment. Single-voxel localized scalar (J) difference editing sequence was used in 1H MRS to measure glutamate (Glu), GABA and N-acetylaspartate (NAA) concentrations in the left hippocampus in normal control (NC), SZ-on and SZ-off groups. Significant decreases in Glu and NAA concentrations relative to creatine (Cr) were found in SZ group, which confirms our hypothesis of decreased dentate gyrus glutamatergic output in SZ. High resolution vascular-space occupancy (VASO) technique using Gd-DTPA as contrast agent acquired CBV maps with resolution of 0.78mm x 0.78 mm x 4 mm, and found increased CA3+CA1+Sub relative CBV value normalized by thalamus CBV in SZ group compared to NC group, which suggests a basal hypermetabolic state in these hippocampal subregions in SZ. Pseudo-continuous arterial spin labeling (pCASL) was used to measure whole brain CBF at standard resolution, and we found hippocampal CBF had positive correlation with PANSS total scores. In the acquired equivalence (AE) fMRI study, reduced midbrain and hippocampal activity was found in both trained and transfer tasks in SZ-on group compared to NC group. The behavior data also support this finding although lacking statistical significance, which may indicate a hyperactivity-induced inefficiency in memory processing in hippocampus. Some of our results support while some modify our original hypotheses. The reduced glutamate concentration in left hippocampus can be interpreted as deriving from the putative NMDA receptor lesion in dentate gyrus in SZ. And that the hypoglutamatergic lesion in dentate gyrus would be sufficient to generate reduced hippocampal glutamate detected by MRS is demonstrated in our NR1-KO mouse study. The increased basal neuronal activity in CA3 and CA1 is supposed to decrease the efficiency of the pattern completion function within CA3, resulting in hyperassociative memory. The positive correlation between hippocampal CBF and PANSS total reveals that the increased CBF in hippocampus is related to psychosis. The AE fMRI result also gives a support to our hypothesis. We could not distinguish the SZ-on and SZ-off groups in our 1H MRS and VASO studies. This might be due to the limited sample sizes of these studies. In the AE fMRI study, the SZ-off group had better performance than the SZ-on group and the brain activity of the SZ-off group was more similar to the NC group compared to the SZ-on group, which contradicts our prediction. The age range and the match between groups shall be considered more strictly in our future studies.Item [UT Southwestern Medical Center News](2006-01-18) McKenzie, Aline