The Division of Translational Neuroscience of Schizophrenia focuses on developing, supporting, and administering programs of research, research training, and resource development aimed at understanding the pathophysiology of schizophrenia and related disorders, and hastening the translation of behavioral and neuroscience advances into innovations in clinical care.
The division supports a broad research portfolio, which includes studies of the phenotypic characterization and risk factors for schizophrenia and related disorders; clinical neuroscience to elucidate etiology and pathophysiology of these disorders; and psychopharmacologic and somatic treatment development.
One of the main focuses of our group is to investigate the nature and treatment of cognitive deficits commonly seen in schizophrenia and related disorders. It is now widely accepted that cognitive deficits are a core feature of schizophrenia and are highly implicated in the occupational and social deficits seen in this patient population. Another important focus of our research group is to conduct phenotyping to understand the genetic inheritance patterns of schizophrenia and related disorders. This research is being conducted by using molecular biological techniques in post-mortem brain tissue, as well as, a variety of physiological and genetic assessments in probands and their family members.
Our primary focus is to conduct research on the etiology and pathophysiology of schizophrenia and related disorders to:
- Define predictors and understand the mechanism of treatment response
- Create and refine biomarkers, behavioral assessments, and phenotypic characterizations of psychotic disorders
- Evaluate existing therapies for new indications, and, in collaboration, with academic, industry and regulatory agencies, hasten the development of more effective new treatments for psychotic disorders with an emphasis on schizophrenia
Our group supports an integrated research program to clarify psychopathology and neurocognitive deficits and understand the underlying pathophysiology. These efforts will help develop new treatments for enhancing neurocognition in schizophrenia and related disorders.
We propose to study:
- Human volunteers with schizophrenia and related disorders using in vivo brain imaging, novel pharmacological interventions, and post-mortem tissue analysis, and
- Laboratory mice with and without genetic manipulations using behavioral studies, electrophysiology, and pharmacology
Dallas Brain Collection (DBC)
The biologic basis of mental illnesses is largely unknown. In recent years, the development of newer and better technology has provided scientists greater opportunities to study the pathophysiology of these devastating illnesses. Human post-mortem brain tissue is an essential resource that facilitates translational research. It serves as a bridge allowing for discoveries in animals to feed forward into the clinical setting and vice versa. With the advent of modern neuroscience tools, human post-mortem research is becoming increasingly important in translation neuroscience. Recognizing this, the Neuropsychiatry Research Program was established in 2003 and is an integral part of the Division of Translational Neuroscience Research in Schizophrenia (DTNRS) at UT Southwestern.
Contact: Kelly Gleason, 214-645-2527
Human Post-Mortem Brain Collection
The Brain Tissue Program is designed to collect human post-mortem from cases of all major psychiatric disorders including schizophrenia, major depressive disorder, bipolar disorder, substance abuse, and healthy controls after obtaining consent from next of kin. Priority is placed on the collection of high quality tissue determined by assessing RNA and protein measures. Tissue is collected from recently deceased persons who come to the Dallas County Medical Examiner’s Office, UT Southwestern Transplant Service Center, or the UT Southwestern Willed Body Program. Once procured, the brain tissue is rapidly processed, frozen, and stored at -80°C for future use. Each brain provides tissue for hundreds of potential experiments and is an invaluable resource. Clinical history is obtained from interviews with caregivers and from medical records. Using structured and semi-structured interviews, we are able to create a rich clinical database. Panels of board certified psychiatrists review the clinical information and make independent diagnoses using DSM IV criteria. This is followed by establishing a consensus diagnosis for each case. In addition we determine the risk gene profiles on each case.
Quantitative Examination of the Limbic Cortex in Schizophrenia (Limbic)
This study seeks to identify and characterize the nature and localization of anatomic and chemical abnormalities in the limbic cortex of schizophrenic (hippocampus, entorhinal cortex, and anterior cingulated) contributing to the pathophysiology of the disease.
Several laboratories have generated data suggesting limbic pathology in schizophrenia; our own in vivo imaging and post-mortem studies suggest a limbic focus as well. Recently, data from Csernansky et al. have suggested that pathology in the hippocampus and the medial aspect of the body (subiculum); this might explain the variability of outcomes reported across studies in post-mortem analyses, because few studies control for hippocampal axis. To answer this question, we have paired anatomic and neurochemical measures within the hippocampus, entorhinal cortex, and anterior cingulated from anterior to posterior extent, quantifying markers of neuronal structure and transmission which may be abnormal in schizophrenic limbic cortex.
The hypothesis driving this work is based on our in vivo imaging data from patient studies and our animal model work, which are extensively in agreement with the published literature. We have raised the speculative hypothesis that positive symptoms in schizophrenia are associated with reduced glutamatergic hippocampal efferent signal to its projection fields, including entorhinal cortex, anterior thalamus, and anterior cingulated may underlie the generation of psychotic symptoms in schizophrenia.
Twenty-four post-mortem schizophrenia brains with paired EC, hippocampi, and cingulates will be compared to the same structures in 24 matched healthy and 12 matched psychotic control brains. We will study neuronal number, sympatic and dendritic density, along with neurochemical measures of the glutamate and GABA, systems along with the A-P-extent of these structures. We postulate that only certain regions of hippocampus will be affected (lateral head and medial body), and that the neurochemical abnormalities in these regions will colocalize with neuronal number and/or sympatic and dendritic changes, and that related regions of hippo, EC, and ACC will be affected. These data will have implications for understanding the mechanisms of the illness and for directing future new discovery for schizophrenia therapeutics.
Neural Substrates of Appetitive Behavior in Mood and Motivation (CONTE)
The timely translation of molecular hypotheses based on animal models to the human syndrome of depression is one of the primary goals of our Conte Center. Based on the tight focus of our Center on the brain's reward circuitry, the task of translation is advantaged in two main ways. First, the anatomy of this circuit, which has been well described in animals as discussed elsewhere in this application, has direct analogues in humans, which have been validated increasingly by brain imaging.
Second, much is already known about the anatomy of these circuits in humans and, to a lesser degree, their neurochemistry. Nevertheless, brain reward circuits in humans remain largely uncharacterized in human depression, which is similar to the relative lack of attention to these circuits in animal models. Indeed, the raison d'etre of this Conte Center is to correct this relative inattention. The most direct and feasible methodology with which to query reward circuits in human brain for molecular changes in depression is the analysis of post-mortem brain. This is because virtually all of the proteins implicated in reward circuits in animal models cannot yet be investigated by brain imaging, given the lack of suitable radioligands.
In contrast, analysis of these proteins and their encoding genes and mRNAs is straightforward in human post-mortem brain – assuming high quality tissue, detailed clinical information, and customized, accurate brain dissections. As described in General Description of Overall Center, the major reward circuit in the brain arises in dopaminergic neurons of the VTA (ventral tegmental area) and the regions in limbic forebrain to which these neurons project, in particular, the NAc (nucleus accumbens). This Project, like Projects 1-4, therefore, focuses on these two regions in human brain. In addition, we will analyze particular hypothalamic nuclei, given the important role played by these nuclei in appetitive behavior, and their strong projections to the VTA-NAc.
Treating Cognition in Schizophrenia: Atomoxetine and Cognitive Remediation
Persons with schizophrenia, despite receiving optimal doses of antipsychotic medications that reduce or entirely obliterate psychotic symptoms, still fail to fully recover function. Research has shown that it is the cognitive dysfunction along with the negative symptoms that account for persistent psychosocial dysfunction.
The field has recently taken on the task of identifying, testing, and developing new treatments for cognitive dysfunction in schizophrenia through the NIMH-sponsored MATRICS and TURNS projects. The work of these groups is partially completed and they have defined for us (1) the nature of the cognitive dysfunction, (2) a battery of recommended neuropsychological tests to assess these cognitive features, and (3) likely molecular targets for cognitive enhancement (Psychopharmacology, June, 2004).
Based on a considerable basic literature, we have been impressed that it may not only be a drug treatment (e.g., atomoxetine in this application) but also psychological approaches (e.g., cognitive remediation, in this application) that are needed to work together to optimally improve cognition in schizophrenia. Therefore, we have developed the hypothesis that the use of cognitive remediation in the context of a cognitive enhancing medication will be necessary for optimal cognitive improvement in schizophrenia.
But, little direct preliminary data exist to suggest which drug and which cognitive approach may be effective, nor what the parameters of response to expect (e.g., effect size; response rate; attrition). Therefore, we are piloting the medication atomoxetine (to target one of MATRICS’s highest-scored molecular targets: the D1 dopamine receptor in prefrontal cortex) along with a cognitive remediation routine (one that is already developed and has shown promise by itself in preliminary studies) for the treatment of cognitive dysfunction in schizophrenia. We apply each putative treatment alone and combined, in a standard four cell design, and evaluate neuropsychological function as the primary outcome measure, and we collect preliminary data on psychosocial improvements occurring with treatment, to determine its time course.
A Randomized Double-Blind, Placebo-Controlled Study
The purpose of the study was to demonstrate the cognitive enhancing effects of BF2.649 in Schizophrenia and Schizoaffective Patients
BF2.649 is an antagonist at the histamine H3 receptor, and an indirect acting agonist of the histamine system by way of its H3 autoreceptor affinity. This protocol will test BF2.649 for its effect on improving cognitive function in schizophrenia.
We will recruit persons with schizophrenia or schizoaffective disease who are currently in a stable phase of their illness, but still display cognitive symptoms and have consequent psychosocial dysfunction. Each qualifying recruit will either be taking a second generation antipsychotic drug (APD) (the specific allowed drugs, to be discussed) or be willing to change to such a drug. We will select an antipsychotic drug(s) with low histamine affinity; aripiprazole is a qualifying antipsychotic. Each study subject will spend 4 weeks on a fixed dose of APD with stable symptoms, during which time the baseline workup will be completed. At the beginning of the double-blind phase of the protocol (study week 5), each study subject will have a full symptom assessment, side effects, and neuropsychological battery along with the full chemistry and baseline safety study workup. Then, each subject (while remaining on their APD) will be randomized to BF2.649 or placebo. The dose of BF2.649 will be 40 mg/day.
Assessment of safety parameters and side effects will occur once weekly for the first 4 weeks (through study week 8) and then every other week for the next 8 weeks (to study week16). Symptomatic outcome measures will be measured during the double blind phase weekly for the first 4 weeks (through study week 8) and monthly thereafter. The neuropsychological battery will be done first at medication start (study week 4) and repeated at the end of the 12 week double blind phase (study week16). At the end of 12 weeks (study week16), the double blinded drug will be stopped and the patient followed weekly for the next 4 weeks with clinical, safety, and side effect measures( study week 20). Each study participant will be seen weekly throughout the protocol for clinical assessment.
A Randomized Double-Blind, Placebo-Controlled Study to Demonstrate the Effects of Pramlintide
The study focuses on the effects of Pramlintide on weight reduction in clozapine- and olanzapine-induced weight gain in obese people diagnosed with schizophrenia.
The majority of people with schizophrenia are treated with second generation antipsychotic drugs, the best of which are clozapine and olanzapine. Each of these drugs cause significant weight gain at an average of 2 kg/month and often greater in individual people. Over the course of 1 year of treatment, reports of 60 pounds of weight gain are not uncommon.
In addition, associated with the weight gain but often expressed independently, these drugs can produce aspects of the metabolic syndrome, including increases in cholesterol, triglycerides, and frank diabetes with insulin insensitivity. Olanzapine is an antipsychotic drug with demonstrated effectiveness in the treatment of schizophrenia; there are some indications that it has some superior action; therefore, a mechanism to treat olanzapine-induced weight gain and the associated metabolic symptoms would be a great asset to patients using this drug.
Drug treatments that could reduce or treat the weight gain and metabolic symptoms would permit many people with schizophrenia to continue to receive the benefits of olanzapine and clozapine with reduced side effect burden. Providing effective treatments for the drug-induced weight gain and metabolic symptoms could also influence the choice of these drugs prescribed for this indication.
Pramlintide is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Amylin is a 37-amino peptide; it is colocalized with insulin in secretory granules in the pancreas and co-secreted with insulin by pancreatic beta cells in response to food intake. Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms. Amylin slows gastric emptying, without altering the overall absorption of nutrients.
In addition, amylin suppresses glucagon secretion, which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally mediated modulation of appetite. Pramlintide demonstrates these actions of amylin in the animal and human. It augments the effects of insulin on glucose control in diabetes and it reduces appetite, suggesting its independent application in treating obesity. Moreover, pramlintide has been shown to reduce weight gain in olanzapine-treated laboratory animals (Amylin data), suggesting its application in olanzapine-induced weight gain in humans.
Hippocampal Learning and Memory Mechanisms in Schizophrenia
Neuroimaging of the Medial Temporal Lobe
Antipsychotic Influence on Altered MTL Neuronal Activity in Schizophrenia (Altered MTL)
Alterations in the function of the medial temporal lobe (MTL) have been described in schizophrenia (SZ). The MTL shows elevated basal perfusion and decreases in task-stimulated activations in SZ, especially in the anterior MTL. The examination of these MTL changes in SZ will be challenging because antipsychotic drugs (APD) – used to treat almost all people with the illness – attenuate these behavioral and functional alterations; therefore, the studies proposed here will necessarily involve untreated (SZ-off) as well as treated (SZ-on) volunteers with schizophrenia.
Now is an optimal time to characterize these MTL functions in schizophrenia because of the sophisticated research tools available to determine regional neuronal activity in brain, the rich advances in cognitive neuroscience, and the focus of SZ research on cognition. It is a propitious time to examine mechanisms associated with hippocampal dysfunction in schizophrenia given the multiple efforts to develop treatments for cognition, treatments that may affect the MTL. Examination of the MTL abnormalities in SZ as described in this proposal will require assessment of both perfusion and task-stimulated activity, since both appear altered, may interact with each other and may be differentially reflected in two of the SZ symptom domains, psychosis and cognition.
Current imaging methods allow for a standard- and a high-resolution examination of MTL, so we will pursue both the standard-resolution whole brain approach to test which CNS areas overall are altered during declarative memory tasks in SZ along with the MTL, as well as the high-resolution (high-res), focused method to test which subfields of hippocampus are altered in SZ and to associate these changes with symptoms of the illness. Under both conditions, we will examine the effect of APD treatment on perfusion and activation.
One of the ultimate goals in exploring the effects of APD on MTL memory function in schizophrenia is the promise of discovering a more direct, possibly more efficient, pharmacological approach for correcting altered MTL-associated symptoms in the illness. This proposal suggests, not that the MTL is the only region associated with pathology in SZ, but rather that it is a critical player in the overall expression of psychopathology and a good model region in which to examine a new formulation for symptoms.
What we propose in this application is to examine memory performance and MTL function in SZ to determine the nature, extent, and circumstances of the changes in MTL neuronal activity in schizophrenia. This project represents a close collaboration between two laboratories, one focused on schizophrenia studies (Tamminga at UTSW) and the other on human memory mechanisms (Wagner at Stanford), together attempting to translate basic cognitive neuroscience to the understanding of symptom domains in SZ. Although this proposal includes only the experiments in SZ, it is based on extensive collaboration between the two sites, involving interactions around concepts and paradigms, shared methodology, and analytic approaches.
Volunteers with schizophrenia as well as healthy individuals are recruited from the Dallas-Fort Worth metropolitan area. Once volunteers are recruited into the UTSW Schizophrenic Research Clinic patient registry, they will go through the structured clinical interview and receive a consensus diagnosis by at least two experienced clinicians. Those volunteers who fit within the inclusion and exclusion criteria are then recruited into various studies.
All volunteers must abstain from recreational drugs during the course of the research, and be available to attend various appointments during the program they sign up for.
If you would like to be contacted regarding our studies and your possible involvement, please contact us via the email or phone number listed. A recruiter will be in contact with you to begin the process.
All information gathered is kept strictly confidential.