The basic science initiatives of the VISN 3 MIRECC revolve around understanding the neuropsychological and neurobiological factors that contribute to serious mental illness (SMI) in veterans and in the population as a whole. Neuropsychological factors are studied with formal, systematic, and detailed assessments of veterans with SMI at regular intervals, while the centerpiece of the study of neurobiological factors is a well-established Brain Bank. Brain tissues donated to the Brain Bank are fully characterized neuropathologically and are distributed to dozens of VISN 3 MIRECC and external laboratories performing state-of-the-art neurobiological studies. T he combination of antemortem neuropsychological assessments and postmortem neurobiological studies provides the unprecedented opportunity to relate neuropsychological deficits to their potential neurobiological substrates.

• Mental health related peer-reviewed publications and abstracts since MIRECC award: 97
• Continued characterization of glutamine-glutamate-GABA pathway in schizophrenia
• Continued characterization of mRNA and protein expression of ionotropic glutamate receptors and associated transporters and intracellular trafficking molecules in schizophrenia
• Continued study of genome-wide gene expression by microarray to supplement the seventeen brain regions already studied with additional cases and in additional regions
• Continued study of glutamate- and myelin-related gene expression in anatomically defined nuclei within the thalamus and defined cortical and subcortical regions in schizophrenia
• Studies to characterize gene expression in laser assisted microdissections of identified cells in the cortex, hippocampus and thalamus in schizophrenia
• Continued exploration of myelin-associated gene expression in grey vs. white matter throughout the course of human development from less than one through 105 years of age (studies in collaboration with Joel Kleinman)
• Continued efforts to build on recent success to increase autopsy rates at the James J. Peters VA Medical Center
• Continued efforts to build on recent success to obtain brain tissue donations from Suffolk County ME
• Continued development of Brain Bank and associated neuropsychological data warehouse

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Brain Bank

The VISN 3 MIRECC Brain Bank is part of a larger Mental Illness and Alzheimer's Disease Brain Bank directed by V. Haroutunian, Ph.D., and is a joint initiative of the James J. Peters VA Medical Center Psychiatry Service and the Mount Sinai Department of Psychiatry. The MIRECC component of the Brain Bank accepts brain tissue donations from veterans receiving care at the NJ Veterans Health Care Network, VA Hudson Valley Health Care System, and the Northport VAMC. The Brain Bank is supported by multiple grants, including the VISN-3 MIRECC, an NIMH sponsored Mental Illness Clinical Research Center, the Mount Sinai School of Medicine Alzheimer's Disease Research Center, and a Program Project Grant to Study Early Dementia. It currently holds brain tissue specimens from over 1180 cases, many of which are generously donated by families of patients who have participated in neuropsychological assessment and treatment studies. After detailed neuropathological examination, brain tissue specimens are distributed to research laboratories within the James J. Peters VA Medical Center, the Mount Sinai School of Medicine, and over 20 different collaborating laboratories within the United States and abroad. This Brain Bank directly supports the Molecular biology, Neurochemistry and Neuroanatomy basic science projects of the VISN-3 MIRECC.

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Neuropsychological Assessments

Philip Harvey, PhD

The objective of the VISN3 Assessment Program is to perform state-of-the-art detailed clinical and neuropsychological assessments of SMI-veterans and to make these results available to health care professionals. The Assessment Battery consists of diagnostic reassessment, Assessment of Negative and Positive Symptoms (PANSS), Assessment of Cognition and Function (MMSE, CDR, CERAD Cognitive Battery, supplemented with additional assessments), the Social Adaptive Functioning Evaluation (SAFE) Scale or the Specific Levels of Functioning Scale (SLOF) depending on the residential status of the veteran. In addition to providing support for enhanced clinical care of veterans, this project directly supports the Neurochemistry and Neuroanatomy basic science projects of the VISN-3 MIRECC.

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Clinical Assessments in the Chronic Psychosis Project

Philip Harvey, PhD; Harry Haroutunian, PhD

This clinical initiative focuses on diagnostic re-evaluation, symptomatic assessment, cognitive evaluation, and functional appraisal. To date, over 900 assessments and 225 re-evaluations have been conducted at four VISN3 sites, and every VISN inpatient over age 55 has been seen. Recently, the project has received additional federal funding to expand the efforts into longitudinal assessment of functional skills in older community dwelling SMI patients. Expanding on the previous discharge monitoring studies, this five-year project will examine the course of cognitive and functional status, with the goal of identifying points of intervention.

The results of the joint MIRECC-Mt. Sinai study on aging in schizophrenia have been published in numerous refereed scientific journals and have been characterized by reviewers as essentially defining the field of cognitive and functional change in older patients with schizophrenia. These studies have both compared the characteristics of VA and public sector patients, as well as examining the course of functional status in large samples of patients including veterans.

1. Aging-related changes in cognitive functioning in treatment responsive and treatment refractory samples: Data from this study reveal that the experience of chronic psychotic symptoms may lead to cognitive decline.  Moreover, previous data have suggested that even ambulatory patients may experience decline in executive tasks and in information processing capacity.  The Boston Naming Test, the Animal Naming Test, Word List Learning, Letter-Number Sequencing, and the Constructional Praxis Test were used to assess differences between a normative sample of older healthy controls, a demographically similar sample of older healthy controls, ambulatory Schizophrenia patients aged 50 to 80, and an institutionalized and treatment refractory sample of Schizophrenic patients aged 50 to 80.
2. The impact of substance abuse: Substance abuse is very common in Schizophrenia, with approximately 50 percent of patients showing at least episodic abuse.  Though this is less of an issue for chronic populations, even treatment refractory patients often live in the community.  Data from this assessment suggest that dually diagnosed patients experience more overall cognitive decline with aging than do patients with Schizophrenia only, patients with Alcoholism only, and patient controls.  Global cognition was the only significant predictor of functional skills in the Schizophrenia/Schizoaffective Disorder plus Substance Abuse group. Symptoms, age, and education did not enter the equation.

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5-HT2CR and Suicide

Stella Dracheva, PhD

Results from a large number of studies have implied that a predisposition of people to suicidal behavior is strongly associated with both psychiatric disease and impaired serotonergic function.  The serotonergic involvement with suicide appears to be equally strong, regardless of the associated psychiatric disorder.  Therefore, brain serotonergic abnormalities may constitute a common basis for suicidal behavior irrespective of the underlying psychiatric illness.  The precise nature of serotonergic defects in suicide remains elusive, however.  The 5-HT2CR is a plausible candidate which might contribute to suicidal behavior because it has been shown to be widely distributed in the central nervous system and is thought to play an important role in regulating mood and affect.  We are currently investigating whether the editing of 5-HT2CR is altered in the victims of suicide compared to people who died by other causes.

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5-HT2CR and Drug Addiction

Stella Dracheva, PhD

A large body of evidence supports the hypothesis that 5HT2CRs that are expressed in the ventral tegmental area (VTA) modulate the basal activity of the dopamine (DA) midbrain neurons through the enhancement of the GABAergic inhibitory neurotransmission, and subsequently, control the rewarding effects of psychostimulants and other drugs of abuse (e.g. ethanol and nicotine).  Thus, it is plausible that differences in 5-HT2CR function in VTA influence individual differences in sensitivity to drugs of abuse.  In our future studies we are planning to investigate whether an individual’s repertoire of the 5-HT2CR isoforms may underlie phenotypic differences in responsivity to drugs of abuse and perhaps predisposition to addiction in rodents and humans.

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Clinical Genetics Research

Jeremy Silverman, PhD

Schizophrenia is strongly familial, but both genetic and non-genetic factors seem to be involved in its development.The specific genetic risk factors remain unknown. The first Molecular Genetics of Schizophrenia MGS-1 project, an affected sibling pair study, was completed in August 2003.  MGS-II, a genetic association study, began in September 2003 and will run through August 2007 in ten collaborating centers.  This NIMH-sponsored study is projected to employ 4,500 Schizophrenic patients and 4,500 controls in an effort to identify one or more Schizophrenia susceptibility genes.  A gene bank for Schizophrenia genetic association studies will also be established.

Research is underway to identify the link between certain characteristics called endophenotypes (such as eye movements and verbal memory) in families and the development of schizophrenia. Seven centers are collaborating to examine this relationship between genetic differences and potential endophenotypes. Six endophenotypes in patients with schizophrenia and in their family members were selected for measurement. Analyses will determine whether these endophenotypes reflect the influence of a single common gene or multiple genes.

Key measures of neurophysiological deficits include P50 event related suppression, prepulse inhibition of acoustic startle response, and the antisaccade task for eye movements. Neurocognitive deficits are revealed by poor performance on the Continuous Performance Test (CPT), the California Verbal Learning Test (CVLT) to assess verbal memory, and the Letter Number Sequencing subtest of the WAIS III to measure working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenic patients, which is evidence that these deficits may reflect part of the heritable risk for the illness. Goals of the study include the establishment of a neurocognitive/psychophysiological laboratory for genetic/family studies in Schizophrenia and other disorders; recruitment of fifteen Schizophrenic proband families a year for five years; establishment of a gene bank for 420 pedigrees; characterization of the complex relations among the major endophenotypes in the families; and implementation of a genome scan for Schizophrenia and endophenotypic traits.

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Neuroimaging Studies

[No PI]

Conte Center affiliated studies on DTI, MTI, and Proton MRS are underway to assess cognitive components and functional outcomes of Chronic Schizophrenics.  The studies involve complete cognitive batteries, symptomological assessments, and investigation of brain white matter structures and neurochemicals.

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fMRI of VisuoSpatial Working Memory in Schizotypal Personality Disorder

Harold Koenigsberg, MD, et al

As with Schizophrenic patients, the visuo-spatial working memory of individuals with Schizotypal Personality Disorder (SPD) is impaired. Visuo-spatial working memory (VSWM) affects a wider range of Schizophrenic patients than does impairment in verbal working memory, and connects to extensive non-human primate work including single-cell recordings. This study was developed with the hypothesis that SPD patients will activate regions in the frontal part of the brain normally used in working memory (called regions BA9/46) less strongly than will healthy volunteers, and that SPD individuals will activate a different region at the very front of the brain (the frontal pole; called region BA10) more strongly than will healthy volunteers, while performing the VSWM task. Preliminary data reveal that SPD patients and healthy controls (HC) show increased activation during the memory maintenance period compared to the control condition. However, HC’s exhibit greater activation in right BA9/46 than do SPD patients, while SPD patients show greater activation in right BA10 than do HC’s. In addition, our findings on ventral prefrontal cortex activation, activation in premotor areas, and parietal cortex activation replicate findings from published literature on spatial memory. Future directions include a comparison of Schizophrenic, SPD, and HC subjects in the same study, employment of a larger sample size, and examination of the effect of working memory load.

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A Thalamocentric Approach to the Neuroanatomy of Schizophrenia: A Quantitative Study in Immunocytochemically Identified Thalamocortical Projection Neurons

William Byne, MD, PhD

Schizophrenia is a psychiatric disorder characterized by functional and structural abnormalities in multiple brain regions, all of which communicate with the part of the brain called the thalamus. The thalamus can, therefore, be considered as a communication hub of the brain. Pathology in a given brain region may induce pathology in other regions of the brain with which it communicates. Thus the abnormalities in multiple brain regions in schizophrenia may be causally related by virtue of their communication with the thalamus.

We have, therefore, investigated the thalamus for pathology associated with schizophrenia. Our overarching hypothesis is that pathology will be found in those regions of the thalamus that communicate with other brain regions which are known to be abnormal in schizophrenia. We have identified two large regions (nuclei) of the thalamus that are characterized by decreased volume and cell number in schizophrenia. These nuclei are the mediodorsal nucleus and pulvinar. The present application focuses on the pulvinar, which comprises five separate divisions, each of which has a different pattern of communication (connections) with other brain regions. Identifying exactly which of these divisions are affected in schizophrenia is therefore essential to understanding how the disorder alters brain circuitry. The study employs autopsied human thalami obtained from the Brain Bank, and aims to examine approximately thirty-six specimens (eighteen from schizophrenics and eighteen from nonschizophrenic comparisons).

To date there has been no satisfactory unifying hypothesis to explain the multiple functional and neuroanatomical abnormalities associated with schizophrenia. We have adopted an approach to neuroanatomical schizophrenia research which is premised on the unifying hypothesis that some of the multiple brain abnormalities associated with this disorder are etiologically related by virtue of the communication of the affected brain regions with the thalamus. Rather than resulting from multiple lesions independently affecting various functional circuits, multiple functional deficits might be better explained by a lesion in the thalamus where the relevant circuits converge. Because pathology in one brain region may induce pathology in other brain regions with which it communicates, thalamic pathology may also hold a key to understanding why multiple brain regions exhibit schizophrenia-associated structural, cellular, and neuromolecular anomalies.

We have demonstrated a schizophrenia-associated loss of volume in the mediodorsal nucleus and in the pulvinar of the thalamus in both postmortem histological and in vivo neuroimaging studies. Our large scale (N=101) MRI study included neuroleptic naive subjects ranging in age from 18-73 and suggested that the volume loss is independent of neuroleptic exposure and does not progress with age. Our postmortem studies have demonstrated neuronal loss in both of these thalamic nuclei and a loss of dendritic material in two of their prefrontal cortical fields. Both of these thalamic nuclei are comprised of multiple subdivisions which have unique sets of efferent and afferent projections. Understanding which subdivions are affected is, therefore, crucial to understanding how schizophrenia may impair neural circuitry. Current work employs well-characterized material from the Mount Sinai/James J. Peters VA Medical Center Schizophrenia Brain Bank and is aimed at determining precisely which cell types (e.g., glia, projection neurons, interneurons) and which subdivisions of the mediodorsal nucleus and pulvinar are affected in schizophrenia. We are also beginning to examine the thalamus for abnormalities associated with major depression and bipolar disorder.

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