VISN 22 Research
Current MIRECC Research Projects
Clinical Neuroscience and Genetics Unit (CNGU)
Co-Directors: David Braff, MD and Gregory Light, PhD
The Genetics of Endophenotypes and Schizophrenia (COGS) (PI: David Braff)
The Consortium on the Genetics of Schizophrenia (COGS-2) is an 6-site collaborative linked R01 study that aims to understand the genetic architecture of functionally important quantitative neurophysiological and neurocognitive endophenotypes and the qualitative phenotype of schizophrenia in 2,000 patients and 1,000 community comparison subjects (CCS). During the initial support period, the COGS-1 project developed a robust research platform for subject recruitment, careful clinical characterization, acquisition, quality assurance, and analysis of these endophenotypes in probands (N=305), clinically unaffected family members (N=1,014) and CCS (N=505). In addition, COGS-1 developed novel statistical genetics methods that take full advantage of the unique findings that have emerged to date. The COGS-2 renewal will extend the use of the original 3 neurophysiological and 3 neurocognitive endophenotypes, as well as additional heritable endophenotypes derived from COGS-1 using the Computerized Neurocognitive Battery (CNB). Given the increased importance of the relationship of these endophenotypes to functional outcome, COGS-2 will also add a functional status assessment battery, consisting of observer-based, surrogate and real-world functional status. COGS-2 will complete the originally proposed linkage analysis in the COGS-1 sample, as well as conduct a candidate gene study from the COGS-1 database using the custom COGS 1536 SNP Chip. COGS-2 will focus on ascertaining, testing and obtaining DNA from new samples of 2,000 schizophrenia patients and 1,000 CCS recruited via Specific Aim 1.
In Specific Aim 2, a genome wide association study (GWAS) using the current and most informative platform at the Center for Inherited Disease Research (CIDR) will be performed using the COGS-2 case-control data on the 9 COGS-2 quantitative endophenotypes and the qualitative diagnosis of schizophrenia. A complementary association study, using many strong-inference derived SNPs not included in the CIDR platform, will utilize the COGS SNP Chip array (94 candidate genes, 1536 SNPs) to assess SNP and copy-number variations (CNVs) associated with endophenotype deficits in schizophrenia as well as schizophrenia itself. In Specific Aim 3, SNPs and CNVs associated with these endophenotypes and schizophrenia will be compared with those in publicly available databases (e.g., GAIN, CATIE, BROAD). Furthermore, we will continue to develop the COGS platform and related innovative statistical genetics methods to identify and interrogate crucial genetic data in order to enhance the search for schizophrenia vulnerability genes, enhance the endophenotype strategy and ultimately identify molecular targets for the treatment and improved function of schizophrenia patients.
Gating and Inhibition in Schizophrenia (PI: David Braff)
This cross-species translational research program will use laboratory-based inhibitory biomarkers (IBs) to understand the genetic and neurobiological basis for the “group of schizophrenias.” The overarching goal of this project is to identify genetic variation associated with deficits in specific IBs in schizophrenia patients, and in parallel, to use animal model studies to clarify the neurobiological mechanisms linking these genes and IB deficits, i.e. the "gene-to-phene gap." In schizophrenia patients and normal comparison subjects, measures will assess 3 extensively studied primary IBs with known schizophrenia-linked deficits - prepulse inhibition of startle (PPI), startle habituation (HAB), and event related potentials (ERPs). IBs, their interrelationships, and associations with demographic, clinical, neurocognitive and functional outcomes will be examined. In mice and rats, PPI, HAB, and ERPs will be measured. In Aim 1, haplotype analyses will refine our preliminary IB-gene results. The genetic architecture of each IB in schizophrenia patients will be examined, focusing on 3 genes - NRG1; ERBB4; and COMT - together with other secondary genes of interest, based on preliminary association findings and/or the extant literature. Gene path analyses will more clearly define gene-gene interactions underlying biomarker-defined subgroups. Aim 2 will test 400 new schizophrenia patients and 400 new normal comparison subjects. These 800 new subjects will provide the power necessary to conduct the proposed behavioral and genetic analyses. Fine mapping will be performed to clarify the genetic substrates of biomarkers using the inclusive sample as well biomarker-defined subgroups based on the extreme deciles and quartiles of the distribution of IB measures. In Aim 3, pharmacological and molecular studies in rodents will explicate novel genetic mechanisms underlying IB deficits by: 1) assessing the impact of neuregulin-1 fragments on the IB deficits induced by dopamine agonists and NMDA antagonists in rats and mice; 2) assessing IB deficits in interneuron-specific ErbB4 “knock out” mice; and 3) characterizing “knock in” mice having Val/Val or Met/Met variants of the human COMT gene, complemented by regionally specific viral delivery of the COMT gene. Aim 4 will characterize changes in brain regional gene expression in rat models with construct validity for IB deficits in schizophrenia patients: neonatal ventral hippocampal lesions (NVHLs) and isolation rearing. RT-PCR studies in inbred rats will focus on genes found in preliminary cross-species studies to be associated with IB deficits (e.g. NRG1, ERBB4, COMT, GRID2, REELIN, and GRIN2B). Functional (neurochemical) consequences of differences in regional gene expression will also be confirmed in NVHL and isolation-reared rats. In aggregate, these 4 Aims will leverage powerful translational strategies to identify genes associated with IB deficits in schizophrenia patients, and to explicate the neurobiological mechanisms that mediate these associations.
A Genome-Wide Methylation Scan for Epigenetic Contributions to Schizophrenia (PI: David Braff)
Schizophrenia is a common profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. This coordinated application builds on a strong foundation of an existing collaboration between six groups of investigators, with an already established and funded infrastructure, without which this research would not be possible. We have previously established a collaboration to investigate the epigenetics of SZ using a case-control approach with existing samples by collaborating with three large Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies on well-characterized patients, including quantitative neurocognitive phenotypes.
Here we approach the epigenetics of SZ in the family members of the probands currently under study, as well as the relationship of epigenetic variation to quantitative neurocognitive phenotypes such as executive function, memory, language and emotion processing. Our Specific Aims are: (2) To quantitatively assess methylation of >4 million CpG sites genome-wide, across 1000 SZ families, examining an average of 3 family members per proband with a total of 3000 family members; (2) To use these data to estimate the heritability of genome-wide methylation in SZ families, to perform family-based epigenetic association with SZ and to perform family-based integration of GWAS data with DNAm; and (3) to examine neurocognitive phenotypes available across families to estimate the relationship between methylation and cognitive efficiency within and across families. The proposed research offers a novel, timely, powerful, and comprehensive strategy for determining the familial epigenetic contribution to SZ, combining expertise in epigenetic technology of human disease with a network of collaborating consortia yielding large well-characterized samples of patients with SZ and their family members.
A Genomic Approach to Schizophrenia (PI: David Braff)
Our goal is to identify genes that are enriched for rare or de novo genomic deletions or duplications in persons with schizophrenia and to determine the functional consequences of these mutations. Structural genomic variants are important causes of human genetic variation and are increasingly implicated in human disease. We have shown that rare deletions and duplications that impact genes are significantly more frequent among individuals with shizophrenia than among controls. These mutations disproportionately affect genes involved with neural development. Other investigators have shown that de novo structural mutations are 8-fold more frequent among individuals with sporadic schizophrenia compared to controls.Using a gene-based design, we propose to identify genes that are disproportionately altered by structural mutations in persons with schizophrenia. We anticipate that a gene important to schizophrenia will harbor different disease-causing mutations in different affected individuals (Aim 1). We also will identify genes with de novo structural mutations in patients with sporadic schizophrenia (Aim 2). The consequences of structural mutations in the most significant candidate genes will be characterized experimentally to determine the impacts of mutations on gene function (Aim 3).
Cases have been assessed and sampled by four NIMH projects. These projects together have enrolled 1155 probands, 259 affected relatives, and 2965 unaffected relatives, including 431 proband-parent trios. Controls will be drawn from >3000 unrelated unaffected persons age >30 years from NIMH distribution 5. All cases and controls will be screened identically genome-wide with NimbleGen 2.1-million feature HD2 arrays, which can detect deletions and duplications as small as 3kb. Screening of the NIMH controls is supported by independent funds. If successful, our approach will identify multiple genes important for schizophrenia. Each of these genes should stimulate future efforts to develop more effective treatment and prevention strategies.
Pathway(s) from Genes to Functional Deficits of Schizophrenia Patients (PI: Gregory Light)
The overall aim of this research program is to identify the core predictors and determinants of functional disability in schizophrenia patients. This will be accomplished via the detailed demographic, clinical, neurophysiological, neurocognitive, genomic, and functional characterization of participants and the integration of data across multiple platforms. Once the genetic determinants and intermediate links in the pathways to outcome are identified, it will be possible to select strong-inference based molecular targets for developing new treatments aimed at ameliorating the most disabling features of schizophrenia. In addition, a unique product of this research will be the identification and integration of neurophysiological and genomic markers that are predictive of functional disability. These markers may be useful for the screening, early intervention, and tracking of individuals who are at risk for schizophrenia and/or functional disability.
Neurophysiological Determinants of Cognition and Everyday Functional Impairments of Schizophrenia Patients
In a series of studies, we continue to find that mismatch negativity (MMN), which is a very early electrophysiological response to an auditory stimulus and prepulse inhibition (PPI), may be useful for clinical characterization of schizophrenia patients and for drug development. Since MMN and PPI can be elicited in the absence of conscious and effortful attention, they probe a preattentive form of sensory memory not influenced by the subject’s motivation. These neurophysiological impairments in MMN are highly correlated with patients’ everyday functioning. MMN is also interesting because it is genetically transmitted and can be used to improve our understanding of the complex genetics of schizophrenia. Mismatch negativity and prepulse inhibition in patients with schizophrenia are related to functional outcome and may be a useful biomarker in clinical trials of innovative drugs.
Education and Dissemination Unit (EDU)
Co-Directors: Noosha Niv, PhD and Chris Reist, MD
Pilot Study of Couples-Based Resilience Enhancement Program for OIF/OEF Veterans (PI: Noosha Niv)
This project aims to adapt an existing family-based preventive intervention with a strong evidence base (Project FOCUS - Families Overcoming and Coping Under Stress) into a Couples-Based Resilience Enhancement Program for returning OEF/OIF veterans. The primary goal of this study is to determine whether the brief couple’s intervention is feasible at VA and acceptable to veterans and their partners. The secondary objective is to assess the impact of participation in reducing psychiatric symptoms and in improving family relationships and coping skills.
Pilot Study of Family Psychoeducation for Depression in Primary Care (PI: Noosha Niv)
This dual-site pilot study aims to explore a family psychoeducation adjunct to the TIDES model of coordinating depression treatment within primary care. There is reason to expect that an appropriate, efficient, and well-crafted family/caregiver intervention could augment TIDES’s effectiveness. The objective of this pilot study is to test the feasibility of a 4-session, psychoeducational, family/caregiver intervention designed to improve the effectiveness of TIDES in promoting treatment adherence and reducing symptoms in major depression.
Health Services Unit (HSU)
Co-Directors: Amy Cohen, PhD and Alex Young, MD
Impact on Practice and Culture in Public Clinics (PI: Joel Braslow)
Abstract not available.
Promoting Recovery Using Mental Health Providers (PEER) (PI: Amy Cohen)
Studies outside the VHA have shown that using “consumer providers” (CPs) can improve and augment care for those with serious mental illness (SMI). Similar to recovering addiction counselors, CPs are individuals with SMI who use their lived experiences to provide services to others with SMI. CPs can reach out to patients that are difficult to engage, assist patients with tasks of daily living, offer a variety of rehabilitation (vocational, social, residential) services, be role models and offer hope for recovery, and facilitate support groups. Research done outside the VHA has shown that CPs can provide services that yield at least equivalent patient outcomes with particular benefits noted on intensive case management teams. Based on these successes, the VA Mental Health Strategic Plan and Uniform Mental Health Services Package call for broader dissemination of CPs as way to make mental health services more recovery-oriented, a national priority. Employing mentally ill veterans has recently begun, although no effort has been made to evaluate their impact inside the VA mental health system. Its success outside the VHA and the recent emphasis on recovery-oriented care indicates a need to test this model in the VHA. The aim of this project is to conduct a randomized controlled trial assessing the impact of adding CPs to intensive case management teams (called MHICM in the VA). We compare 3 MHICM teams with CPs to 3 control MHICM teams (i.e., no CPs). Sites are the VAs at West Los Angeles, Sepulveda, Long Beach, San Diego, Loma Linda, and Las Vegas. The focus of the study is on documenting impacts on patient recovery outcomes (through longitudinal patient surveys) and the use of recovery-oriented care at the MHICM team level (through patient surveys; focus groups and interviews with VA stakeholders; and site visits). We will also measure patient level clinical outcomes.
Family Member Provider Outreach (FMPO) (PI: Amy Cohen)
The involvement of families in the mental health care of persons with severe mental illness (SMI) is widely acknowledged to be critical to the delivery of good clinical practice. The offering/delivery of Family Psychoeducation (FPE), a specific model of family involvement, is embedded in virtually every set of recommended evidence based practice recommendations or treatment guidelines. Despite these imperatives, efforts to implement FPE in the U.S. have reached a very limited numbers of families. Furthermore, empirical investigation of numerous systems of care in the U.S. suggests that families of these individuals have minimal contact with the mental health system. The failure to achieve optimal (e.g., FPE) or even minimally acceptable family involvement in care (e.g., contact with treatment team) has been discouraging. Drs. Dixon, Glynn, Cohen, and Murray-Swank have developed the Family Member Provider Outreach (FMPO) intervention, a manualized program that is consumer-centered and recovery-oriented. FMPO systematically engages the consumer in a discussion about family issues and concerns, permitting ambivalence, educating about options, and providing consumers with skills to talk with family members about being involved in their care and recovery. Results from the pilot suggest that this may be a promising approach to increase rates of family involvement in treatment.
Evaluation of New Directions North Dual Diagnosis Program (PI: Alison Hamilton)
There is a great need for dual diagnosis services, tailored to both substance abuse and psychiatric disorders, in the Los Angeles area, especially evidence-based recovery-oriented services such as supported employment. The New Directions North program, located on the West Los Angeles campus, is ideally suited to meet this need, providing dual diagnosis services to homeless male veterans in their 43-bed facility. Through a five year SAMHSA grant in 2006, New Directions North was funded to add supported employment services to their program. This project is an evaluation of this program. In order to examine the effectiveness of the New Directions North model, a series of structured interviews focusing on symptoms, medication compliance, substance use, quality of life, and functioning will be conducted with the New Directions patients. Employment outcomes will be tracked over time. The overall treatment context will be assessed through surveys administered to the patients and providers. Finally, focus groups of the patients and providers will be conducted to assess satisfaction.
Implementing Effective, Collaborative Care for Schizophrenia (EQUIP-2) (PI: Alexander Young)
Interventions are needed to improve the quality of routine care for schizophrenia. Clinical technologies such as supported employment, family psychoeducation, behavioral wellness education, and clozapine substantially improve patient outcomes, yet are typically not used. In the VA HSR&D EQUIP project, Young and colleagues developed methods for improving care for schizophrenia based on proven chronic illness management principles. These methods included information systems to support care improvement, protocols for managing the quality of care, and methods for implementing specific clinical technologies. EQUIP demonstrated that it is possible to improve care, while identifying successful strategies plus areas where new approaches will be needed. Young, Cohen and colleagues received a grant from VA HSR&D QUERI to conduct a controlled trial that builds on EQUIP, and evaluates an intervention for improving care for schizophrenia in four VISNs. The study is a clinic-level controlled trial. From the 4 participating VISNs, a total of 8 specialty mental health programs are matched into pairs. One program from each pair is chosen for the intervention and the other continues with care as usual. VISNs underwent a strategic planning process, and decided to focus on improving outcomes in work and weight domains. Patients with schizophrenia and clinic staff have been enrolled. The intervention is underway.
Neuroimaging Unit (NIU)
Director: Gregory Brown, PhD
Effects of a Cognitive Enhancer on Brain Function in Schizophrenia: A Double-Blind Placebo Controlled Pharmaco-fMRI Trial (PI: Lisa Eyler)
Current treatments for schizophrenia primarily target psychotic symptoms and provide only minimal cognitive benefits. The cholinergic system has been linked to cognitive function, particularly in degenerative diseases like Alzheimer’s, and pro-cholinergic agents appear to delay progression of cognitive deficits and may slow functional brain changes in that disorder. We tested whether augmenting standard atypical antipsychotic treatment with donepezil, an acetylcholinesterase inhibitor, would improve cognitive performance, clinical symptoms, performance-based measures of functional abilities, or brain response during attention and learning tasks among schizophrenia patients. Clinically-stable outpatients with schizophrenia or schizoaffective disorder were enrolled in a double-blind, placebo-controlled augmentation trial. Participants received 5 mg of donepezil or identical-looking placebo for 4 weeks, then 10mg for 8 weeks, followed by 2 weeks at 5mg, in addition to their stable dose of atypical antipsychotic medication. Neuropsychological and clinical assessments were performed at baseline and 12 weeks. A subset of participants received functional magnetic resonance imaging at these timepoints as well, and a healthy comparison group that did not participate in the trial was also scanned on two occasions.
Structural and Functional Brain Aging in Bipolar Disorder (PI: Lisa Eyler)
The number of elderly mentally ill individuals with bipolar disorder will increase rapidly in the coming decades, yet there has been little research focused on geriatric bipolar patients. In particular, little is known about changes in brain structure and function due to aging that may underlie worsening cognition. The project aims to (1) investigate age-related differences in the structure, function, and connectivity of the prefrontal cortex (PFC) in bipolar disorder, whether these differences are greater than would be expected due to normal age-related changes, and, if so, whether these more pronounced structure and function changes appear to be linked to longer duration of illness and worse course of illness, (2) examine whether gray and white matter structural integrity serve as possible mediators of the relationship between age and chronicity of bipolar illness, on the one hand, and PFC function and functional connectivity, on the other, and (3) examine whether PFC function and functional connectivity serve as possible mediators of the relationship between age and chronicity of bipolar illness, on the one hand, and cognitive performance, on the other. We will use a cross-sectional design to study a large group of patients with Bipolar I disorder and healthy individuals ranging in age from 30 to 79 years. Patients will be stably medicated, will not be experiencing a manic or depressive episode, and will be free of other Axis I disorders or current substance abuse or dependence. Assessment will include measures of cognitive performance, clinical symptom levels, and magnetic resonance imaging scans. PFC gray matter thickness, white matter organization in tracts that connect with the PFC, resting perfusion and functional response of the prefrontal cortex and connected regions during a working memory task will be measured. Results of this study will help characterize the course of brain pathology in bipolar disorder and enable future longitudinal investigations using the most powerful measures and focusing on the most likely time period for change.
Voxel-based morphometry of patients with bipolar I disorder and schizophrenia
The issue of similarities and differences in neuroanatomical structure between schizophrenia (SZ) and bipolar I disorder (BP), and how each group differs from healthy individuals is a long-standing question in psychiatry. Recently, voxel-based morphometry (VBM) has been increasingly applied in elucidating structural brain changes associated with these functional psychotic disorders. However, VBM studies in SZ and BP have reported inconsistent results. Potential causes of these inconsistencies include differences in the samples studied, especially differences in age, gender, duration of illness, or subtypes of BP. The aim of the study was to compare gray matter volumes in a cross-sectional VBM design including subjects with chronic SZ, chronic BP and healthy control (HC) subjects matched for age, gender and duration of illness. Seventeen subjects with SZ, 15 subjects with BP, and 21 HC subjects without psychiatric illness were studied. Study inclusion criteria were 1) age: 25-70; 2) duration of illness: over 3 years; and 3) DSM-IV bipolar I disorder or schizophrenia. Groups were well matched on age, gender, and illness duration. Scans were performed with a 1.5-Tesla Siemens Magnetom Vision scanner and images were analyzed using optimized VBM implemented in SPM5. Compared with HC group, both SZ and BP groups showed evidence of reduced cortical volume in right middle frontal region and right superior and middle temporal regions. However, volume reductions in bilateral thalamic regions and bilateral hippocampus, right amygdala and right putamen were specific to SZ group. The results suggest that patients with SZ and BP show similar loss of brain volume in the neocortex, whereas only schizophrenia patients show loss in archicortex and basal ganglia. These similarities and differences of structural abnormalities may be important factors in the common and differential manifestations of these two functional psychotic disorders.
Effects of Word Length and Stimulus Degradation on the Working Memory Performance of Schizophrenia Patients
This new study will examine two component processes of working memory that have been hypothesized to contribute to the working memory deficit observed among individuals with schizophrenia. In a parametric factorial design, three levels of stimulus degradation will be crossed with three levels of word length to manipulate perceptual and working memory span loads in a delayed response task. Twenty-six veterans with chronic schizophrenia stable on their medications will be compared with age and gender matched healthy participants. Electroencephalography will be performed during the task. The P1-N1-P2 complex will be monitored for effects of perceptual load and a negative wave starting 200 msec following the presentation of the memory stimuli will be examined for changes related to working memory span load.
Brain Imaging of Mouse Models of Psychosis
This program of research aims to characterize the structural and functional brain changes in mouse models of severe metal illness. The initial study will measure hippocampal volume, shape, and cortical thickness in mice with reduced expression of the SP4 allele. Previous research with SP4 deficient mice have revealed robust deficits in sensorimotor gating, a common finding among patients with schizophrenia, vacuolization of the hippocampus and decreased expression of neurotrophin-3 expression in the dentate gyrus. Brain measures in SP4 deficient mice will be compared with wild type mice. A thorough understanding of the neurobiology of severe psychiatric disorders requires the integration of molecular and cellular information with information about distributed brain systems. The tools of molecular genetics permits the investigation of specific molecular and genetic pathways involved in the cellular neurobiology of brain functions. Brain imaging methods provide data about the structural and functional neuroanatomy of brain systems. By integrating molecular and anatomical information, this study seeks to provide a more complete theory of one neurobiological pathway involved in hippocampal development. By relating changes in hippocampal volume and shape observed in SP4 deficient mice to hippocampal changes observed in schizophrenia and other severe mental illnesses, the animal research will improve the field’s understanding of human disease. Ultimately, improved understanding of the neurobiology of neuropsychiatric disorders will stimulate the development of new treatments.
Brain-Performance Correlates of Working Memory Retrieval in Schizophrenia: A Cognitive Modeling Approach
Correlations of cognitive functioning with brain activation during a Sternberg item recognition paradigm (SIRP) were investigated in 89 patients with schizophrenia and in 93 healthy controls studied at 8 sites. Patients were matched group-wise with comparison subjects on age, gender, handedness, and parental education. To measure memory scanning times, 4 response time models were fit to SIRP data. The best fitting model assumed exhaustive serial memory scanning followed by self-terminating memory search and involved one intercept parameter to represent SIRP processes not contributing directly to memory scanning. Patients displayed significantly longer response times with increasing memory load and differed on the memory scanning, memory search, and intercept parameters of the best fitting probability model. Groups differed in the correlation between the memory scanning parameter and linear brain response to increasing memory load within left inferior and left middle frontal gyrus, bilateral caudate, and right precuneus. The pattern of findings in these regions indicated that high scanning capacity was associated with high neural capacity among healthy subjects but that scanning speed was uncoupled from brain response to increasing memory load among schizophrenia patients. Group differences in correlation of the best fitting model’s scanning parameter with a quadratic trend in brain response to increasing memory load suggested inefficient or disordered patterns of neural inhibition among individuals with schizophrenia. The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among schizophrenia patients.
Neuropsychopharmacology Unit (NPP)
Director: Mark Geyer, PhD
Attention and Inhibition in Bipolar Disorder: A Translational Paradigm (PI: Gregory Asgaard)
This project aims to better understand deficits in attention and inhibition in bipolar disorder by developing a functional brain imaging paradigm to sensitively assess these domains. In order to promote translation between model systems, such as the rodent, and human neurophysiological studies, the human task is being developed to exactly mirror the structure and demands of a rodent version of the continuous performance task developed in the Geyer lab within this MIRECC. The Pala Pilot funded project will develop and test the attention task and gather initial validation data on healthy volunteers using functional magnetic resonance imaging. Once validated, the task will be available to MIRECC researchers to use in future studies focusing on understanding cognitive and brain functioning deficits in serious mental illness. The similarity of the human task to the paradigm used in rodents will facilitate translational studies to understand the mechanism of attentional impairment in bipolar disorder.
Sp4 Pathway in Hippocampus Modulated Sensorimotor Gating (PI: Mark Geyer)
Hippocampal abnormalities are important susceptibility factors for several human psychiatric disorders. Sensorimotor gating, assessed by prepulse inhibition of startle, is reduced in and provides a cross-species endophenotype for a group of psychiatric gating disorders, including schizophrenia, bipolar disorder, autism, and ADHD. In preliminary work, hypomorphic Sp4 mutant mice displayed vacuolization in the hippocampal dentate gyrus, reduced expression of the Grk4 gene in the hippocampus and cortex, robust deficits in sensorimotor gating and contextual memory, and decreased exploration of novel environments. The molecular, hippocampal, and behavioral abnormalities of the Sp4 mutant mice mimic several phenotypes for neuropsychiatric gating disorders. Specific Aim 1 will assess the cell autonomous roles of the Sp4 gene in the vacuolization of dentate gyrus, and the associated deficits in sensorimotor gating and contextual memory. A mouse line will be created with an inducible cre-ERT2 gene fused within the 3’ UTR of the endogenous Desmoplakin (Dsp) gene by internal ribosome entry site without knocking-out Dsp expression. Tamoxifen will be used to activate the cre that in turn will reactivate or ablate the Sp4 expression in dentate granule cells. Hippocampal structural and functional abnormalities will be assessed in these rescue or conditional knockout mice. Specific Aim 2 will identify Sp4-mediated genetic pathways in the hippocampus that subserve novel object exploration. Studies will (a) further analyze the defective novelty exploration of the hypomorphic Sp4 mice in established paradigms; (b) examine whether the restoration or ablation of Sp4 expression in the dentate granule cells (Aim 1) can rescue or cause the defective novelty response. Specific Aim 3 will examine the role of the Grk4-mediated signaling pathway in the modulation of sensorimotor gating in Sp4 hypomorphic mice, using both pharmacological and genetic approaches. Cell culture experiments will examine Grk4-mediated desensitization of both dopamine D1 and mGluR1 receptors in the Sp4 mutant hippocampal cells. Antagonists of dopamine D1 and mGluR1 receptors will be administered to the hypomorphic Sp4 mutant mice to test for reversal of the prepulse inhibition deficit. To evaluate the disruption of Grk4-mediated GPCR signaling pathway in the modulation of sensorimotor gating and hippocampal vacuolization, double knockout mice combining the Sp4 deletion with either dopamine D1 or mGluR1 receptor genes will be generated. These experiments will yield novel insights into genetic pathways within the hippocampus that underlie behavioral abnormalities relevant to several psychiatric disorders.
Monoamine and Hallucinogen Effects on Rodent Behavior (PI: Mark Geyer)
The goal of this project is to use rodent models to elucidate the mechanisms underlying the behavioral effects of hallucinogenic drugs of abuse, including MDMA (”Ecstasy”), LSD, phencyclidine (PCP), and ketamine (“Special K”), as well as natural products used in recreational, ritual, or religious contexts, including psilocybin mushrooms (psilocin) and Ayahuasca tea (DMT, 5MeODMT, harmaline). Based on the profound effects of hallucinogens on responses to sensory and emotional stimuli, the two complementary behavioral paradigms used to assess drug effects in both rats and mice include prepulse inhibition of the startle response, an operational measure of sensorimotor gating, and a multivariate profile of exploratory and locomotor responses provided by both rat and mouse Behavioral Pattern Monitor systems. These computerized systems assess activity, exploration, and behavioral organization – three major aspects of rodent behavior in an open field. The project has five specific aims. Aim 1 is to further characterize the contributions of specific serotonin (5HT) and dopamine receptors to the behavioral effects of the 5HT releaser MDMA in genetically engineered mice lacking specific subtypes of 5HT or dopamine receptors. Aim 2 is to characterize and identify the respective contributions of the 5HT1A and 5HT2A receptors to the behavioral effects of the synthetic equivalent of Ayahuasca (“Pharmahuasca”) in rodents, using pharmacological and genetic manipulations. Aim 3 is to assess the respective contributions of 5HT1A and 5HT2A receptors to the behavioral effects of glutamatergic hallucinogens, and thereby evaluate the new hypothesis that the effects of both serotonergic and glutamatergic hallucinogens are mediated by some common mechanisms. Aim 4 is to use similar approaches to test for common contributions of metabotropic glutamate receptors, particularly mGluR5, to the behavioral effects of glutamatergic and serotonergic hallucinogens. Aim 5 will initiate a new line of research examining the contributions of the major stress-related hormone, corticotropin releasing factor (CRF), to the behavioral effects of hallucinogens. Studies will explore the exaggerated responses to threatening or stressful aspects of novel environments produced by serotonergic hallucinogens in rodents, which are similar to the fear and stress responses produced by LSD in humans. This research is designed to elucidate the neurobiological mechanisms responsible for the acute effects of hallucinogens, which presumably lead to the recreational use of these drugs of abuse.
Developmental Models of Gating Deficits in Schizophrenia (PI: Mark Geyer)
Prepulse inhibition (PPI) of the acoustic startle reflex refers to the ability of a weak stimulus preceeding a startling stimulus to inhibit the response to that stimulus. PPI is an operational measure of sensorimotor gating that is amenable to cross-species comparisons. Deficits in PPI have been reported repeatedly in patients with schizophrenia and other psychiatric disorders characterized by abnormalities in sensory, cognitive, or motor gating. Because some forms of schizophrenia appear to be attributable to early developmental insults such as prenatal infection or birth complications, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Isolation rearing of rats and mice from weaning is a non-pharmacological manipulation that leads to deficits in prepulse inhibition of startle. Similar deficits in PPI are produced in rats exposed to a prenatal immune challenge. The current proposal will extend and integrate studies of isolation rearing into the broader framework of neurodevelopmental insults, based on the conceptual and empirical connections between social isolation, chronic stress, and immune/inflammatory activation. To clarify the biological underpinnings of this integrated model, the aims of this grant are to examine the mechanistic role of alterations in the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and the stress-related neuropeptide, corticotropin releasing factor (CRF) in isolation- and immune-mediated developmental models of sensorimotor gating deficits. Recently the endogenous NMDA receptor antagonist kynurenic acid has been shown to disrupt PPI in rats. Hence, Aim 1 studies will assess the contribution of KYNA and its metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) to isolation rearing-induced PPI deficits in rats. Based on the observation that schizophrenia may be associated with a prenatal immune insult (e.g. exposure to a virus), Aim 2 studies will further characterize the effects of prenatal immune challenge on PPI and examine the contribution of KYNA to these immune-related effects on PPI. The anxiety-like phenotype and exaggerated stress responses in isolation-reared rats are consistent with alterations in the brain’s CRF system. Hence, Aim 3 studies will test the hypothesized differential roles of specific CRF receptors in mediating isolation rearing-induced deficits in PPI in mice, using CRF-R1 and CRF-R2 null mutant mice.
Inhibitory Deficits in Mania and Hyperdopaminergic Mice
The primary focus of this translational research project is to characterize inhibitory deficits in patients with bipolar mania and to further develop and evaluate potential animal models of these deficits using drug-treated and genetically engineered mice. There is currently little information regarding the neural substrate abnormalities underlying the mania of BD, but it has been suggested that the manic state may involve a dysregulation of dopaminergic systems that control inhibitory functions and that mood stabilizers may serve to “normalize” cortical and subcortical hyperactivity. There is a striking paucity of preclinical models related to BD, which has hindered examination of neural circuit abnormalities contributing to BD. Therefore, we propose to use a translational research strategy and cross-species measures that reflect abnormalities in dopaminergic systems to further our understanding of BD. Specifically, we propose parallel studies of inhibitory deficits in manic BD patients and in mice in which the dopamine (DA) transporter (DAT) has been manipulated either pharmacologically (i.e. amphetamine) or genetically (i.e. DAT knockdown and knockout mice). Because inhibition cannot be characterized adequately by any one operational measure, we will assess inhibitory deficits in multiple domains: 1) sensorimotor gating; 2) motor activity levels; and 3) sequential patterns in decision-making (humans) or exploratory (mice) behavior. BD patients with mania will be studied during highly symptomatic and remitted states and after treatment with mood stabilizers and/or atypical antipsychotic drugs. We will examine whether inhibitory deficits are present in acute manic states and whether they are ameliorated as the mania resolves and will study associations between our measures of inhibition and treatment. We will test the hypothesis that mutant mice lacking the normal complement of dopamine transporters might serve as a model of the inhibitory deficits in BD and that DAT-deficient mice might provide an animal model with predictive validity for the identification of mood stabilizers and/or antimanic agents.
Treatment Unit (TU)
Director: Michael Green, PhD
Cognitive-Behavioral Therapy in Veterans with Schizophrenia (PI: Shirley Glynn)
This is a randomized trial comparing the benefits of participating in 6 months of cognitive-behavioral therapy (CBT) for psychosis to those accruing from 6 months of supportive therapy in stable outpatients with schizophrenia and schizoaffective disorder. We hypothesize that participation in the CBT will yield significantly greater symptom reductions, more lessening of distress, and greater increases in functional outcomes at the end of treatment compared to the supportive therapy. Secondarily, we are also examining the role of neurocognition, as assessed with the MATRICS battery, as a predictor of CBT outcome. The study is being conducted at the VA Greater Los Angeles Healthcare System at West Los Angeles and is currently recruiting veteran participants. For more information, please call the project office at 310-268-3163.
Caregiver Psychoeducation and Support: Improving Outcomes in AD/ADRD (PI: Shirley Glynn)
This is a randomized trial comparing the benefits of participating in 6 months of online caregiver education and support to those accruing from 6 months of telephone support for persons with Alzheimer’s and other aging related memory disorders. We hypothesize that participation in the online intervention will yield significantly slower decline in the patient and reduced burden and improved self-care in caregivers compared to the telephone support. The online program is a private password protected website which includes online streaming video lectures for relatives, educational materials, a private chat room with real-time facilitated chat with other caregivers, a discussion board, and resource links. The study is being conducted at the VA Greater Los Angeles Healthcare System at West Los Angeles and is currently recruiting veteran and community participants from throughout Los Angles, Ventura, and Santa Barbara counties. Both the patient and caregiver must consent to be part of the study. For more information, please call the project office at 310-268-3163.
Improving Basic and Social Cognition for Veterans with Schizophrenia (PI: Michael Green)
In this study, subjects with schizophrenia or schizoaffective disorder are randomly assigned to one of 4 training groups: 1) social cognitive training, 2) cognitive remediation, 3) a combined social cognitive and basic cognitive intervention, or 4) a control condition of discussing current events. All groups meet in one-hour sessions held twice a week over the course of 12 weeks in small groups of 4-6.The Social Cognition Intervention is a 24-session, manualized intervention program that was recently developed by MIRECC investigators. It is specifically designed to improve emotion perception, social context processing, and theory of mind / attributional bias in veterans with schizophrenia and schizoaffective disorder. The goals of this 2-year pilot study are to validate a novel intervention for social cognition as a necessary initial step toward the eventual goal of reducing disability for patients.
Early Visual Processing in Schizophrenia (PI: Michael Green)
This project continues a bi-directional research program that starts with careful characterization of visual processing deficits in schizophrenia and moves systematically into exploration of neural substrates on the one hand, and functional outcome on the other. Considerable information about schizophrenia can be obtained by a close examination of a well-characterized neurocognitive deficit, in the case of this research program, it is early visual processing. This research program is gathering information on the underlying neural substrates of visual processing in schizophrenia (using electrophysiology and fMRI). Knowledge of the relationships between perceptual deficits and daily activities and the mechanisms for these relationships will help us to understand limitations on functional outcome in schizophrenia, help make predictions about outcome, and lead to design of targeted interventions.
MATRICS-CT - Validation of Intermediate Measures (VIM) Study for Clinical Trials of Cognition in Schizophrenia (PI: Michael Green)
MATRICS-CT (for co-primary and translation) is an NIMH initiative - supported by a partnership of pharmaceutical companies. It addresses two potential obstacles that were identified during the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia). The first obstacle identified was the lack of a consensus regarding instruments for measuring functioning that can be used in relatively brief clinical trials. In an early MATRICS meeting, the Food and Drug Administration stated that improvement on neuropsychological tests would be insufficient for approval of a drug for CIAS. Improvement on the tests should be accompanied by improvement on a measure of functioning or the patient's perception of improved cognition. (The agency did not require actual improvement in community functioning but improvement in a measure that had greater face validity than a neuropsychological task.) MATRICS-CT will develop a consensus regarding the best instrument or instruments for measuring functioning in these trials. The second obstacle was the need for versions of the MATRICS Consensus Clinical Battery (MCCB) that could be administered in languages other than English. MATRICS-CT will translate the MCCB into languages that are commonly used for large international trials.
Affective Decision Making in Schizophrenia: An Electrophysiological Examination (PI: William Horan)
This project uses affective neuroscience methods to follow up on our earlier finding that individuals with schizophrenia do not effectively incorporate information about rewards and punishments to guide decision-making. ERP paradigms will be administered to 40 schizophrenia outpatients and 40 healthy controls to assess two key components of decision making: 1) Evaluative Categorization: the initial evaluation of and attentional allocation to negative vs. positive stimuli, and 2) Affective Feedback Monitoring: monitoring feedback about expected versus actual response outcomes. Results will help clarify the scope and neural correlates of decision making impairments in schizophrenia.
Social Neuroscience of Schizophrenia (PI: William Horan)
The project investigates neural mechanisms that contribute to poor social cognitive functioning in people with schizophrenia. This work is guided by a social neuroscience model of empathy, which is defined as the capacity to understand and respond to the unique affective experiences of another person. 33 schizophrenia outpatients and 33 healthy controls will complete complementary electrophysiological and functional Magnetic Resonance Imaging paradigms designed to assess empathy's three component processes: shared representations (mirror neuron system activity), perspective taking, and emotion regulation. This research can help identify neural circuits that can be treated through pharmacological interventions and biomarkers of empathic disturbances in schizophrenia.
Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS) (PI: William Horan)
In this multi-site study, investigators from VAGLAHS/UCLA, UC-Berkeley, U. Pennsylvania, and U. Maryland will refine and validate a new assessment instrument, the Negative Symptoms Rating Scale (NSRS), for use in clinical trials and other types of research. The beta version of this scale was developed through a consensus-based process that was initiated at the NIMH-MATRICS Consensus Development Conference on Negative Symptoms. State-of-the-art statistical procedures will be used to validate this scale in sample of 500 people with schizophrenia.
Cognitive Rehabilitation and Work Outcome in Schizophrenia (PI: Robert Kern)
In this community-based study, a psychosocial training intervention called errorless learning is being examined for its efficacy at improving work outcome in persons with schizophrenia. Errorless learning is a training intervention that is designed to compensate for cognitive impairments that may impede or restrict skill acquisition. This approach is borne out of the experimental psychology literature and is based on the notion that learning is stronger and more durable if it occurs in the absence of errors. Study participants at the San Fernando Mental Health Center (SFMHC) who are enrolled in their Wellness program and express interest in gaining competitive employment will be randomized to errorless learning or conventional instruction. These training methods will be used to help study participants address work-related problems after job placement. Training will be conducted by the employment specialists at SFMHC. The study will also examine predictors of work outcome such as neurocognition, motivation, alcohol/substance abuse, medication adherence, symptom changes, and demographic variables.
Errorless Learning for Improving Work Outcome in Schizophrenia (PI: Robert Kern)
In this VA-based study, veterans with schizophrenia who are enrolled in the VA supported employment program, using the evidence-based Individual Placement and Support model, are randomized to errorless learning vs. treatment-as- usual after job placement. Once placed, a baseline assessment of work performance is conducted within the first four weeks on the job to identify two work-related problems that are the targets of intervention. One of the problems is identified as a difficulty in performing some aspect of the veterans’ assigned job duties. The other target includes some other work-related problem such as social communication or adherence to work rules/regulations. Training is conducted by VA employment specialists under the direction of the PI. Veterans are followed for one year after job placement.
Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) (PI: Stephen Marder)
The TURNS program is a National Institute of Mental Health (NIMH) supported network that provided an infrastructure for clinical studies of pharmacological agents for enhancing neurocognition in patients with schizophrenia.
Converging Approaches to Gamma Band Abnormalities in Schizophrenia (PI: Jonathan Wynn)
This project investigates the neural sources that contribute to poor visual perception and poor cognition in schizophrenia patients. Using two basic paradigms to assess visual perception and cognition, 50 schizophrenia patients and 50 healthy controls will have their EEG recorded as well as a separate fMRI scan using the same procedures. It is thought that failures to synchronize neural activity within the gamma-band range (30-70 Hz) in the EEG contribute to poor visual perception and cognition in schizophrenia. Moreover, it is thought that gamma-band activity is more closely tied to fMRI neural activity than traditional ERP measurements. Using two different neuroimaging techniques, this study is taking a converging approach to explore where and when visual and cognitive deficits are seen in schizophrenia patients.