Jill Goldstein - US grants

The primary purpose of the request for this NIMH Scientist Development Award is to provide training and research experience in understanding brain-behavior relationships, in order to apply this knowledge to the development of models of schizophrenia. The focus is on the relationships between brain function and structure, as operationalized by tools in neuropsycology, behavioral neurology, and neuroanatomy. There are 4 elements to the proposal: 1) supervised training in neuropsychological assessment; 2) supervised training i neuroanatomy, including the measurement of brain structures using magnetic resonance imaging; 3) didactic seminars and course work in neuropsychology, neuroanatomy, behavioral neurology, and other basic neuroscience; and 4) supervised research experience that will apply knowledge and skills learned in training. Past research suggests that men and women may be at different risks for expressing particular forms of schizophrenia. This proposal presents a novel approach to elucidating some of the processes underlying gender differences in abnormal neurodevelopment in schizophrenia, by using dyslexia as a model. Dyslexia is a useful comparison group, since there are similarities between schizophrenia and dyslexia regarding pathological brain areas and sex effects. Thus, established findings in the literature on dyslexia may provide insights into the effect of sex on neuropsychological and cognitive deficits underlying schizophrenia. Hypotheses will be tested with 40 DSM-III-R schizophrenics and 40 normal controls, equally divided by sex, and proportionately matched on age, ethnicity and parental socioeconomic status. Patients will be randomly sampled from a large outpatient service and normal controls from the same catchment area. 40 DSM-III-R dyslexics will also be selected, matched on age, sex, ethnicity and parental SES, and sampled from 2 learning disorder outpatient clinics in the same catchment area. Variables assessed include neurodevelopmental and perinatal history, symptomatology, neurospsychological and cognitive tests, family history of psychiatric and autoimmune disorders, and structural brain imaging. Hypotheses regarding gender differences in brain structure and function focus on prefrontal and temporal lobe regions and laterality effects, which have been found to be important for understanding brain dysfunction in schizophrenia. The proposed training would extend the epidemiologic skills of the investigator into the area of neuroscience and provide a basis for a more informed perspective from which to develop models of schizophrenia.

DESCRIPTION (Adapted from applicant's abstract): Numerous studies suggest that a network of interrelated brain areas are involved in attentional processes and working memory. Areas of the brain implicated in attention and working memory are key regions in which structural abnormalities and functional deficits have been identified in schizophrenia and been found to be sexually dimorphic in normals. However, few studies have specifically focused on elucidating sex differences in attention/working memory in schizophrenia. Further, there is some evidence that sex differences in cognitive processing differ by sensory modality, i.e., auditory versus visual cognitive stimuli. The investigator's and others' work have shown that schizophrenic men and women may be at differential risks for expressing different forms of the illness. Thus, an understanding of sex differences in attention and working memory may be important for understanding the heterogeneity of cognitive deficits in schizophrenia. This Small Grant proposes a two-year pilot study to use fMRl to identity sex differences in the neural processing of verbal and nonverbal sustained attention and working memory in two sensory modalities, i.e., auditory versus visual. The investigator will develop cognitive paradigms for use in the fMRI environment to specifically test hypotheses focused on sex differences. Nonverbal auditory and verbal and nonverbal visual sustained attention/working memory paradigms will be developed, matched for degree of difficulty, with the investigator's already-developed and tested verbal auditory sustained attention paradigm. The sample will consist of 20 DSM-IV schizophrenics, half men/half women, and 20 normal controls individually matched, within sex, on age, ethnicity, parental socioeconomic status (SES), Wide Range Achievement Test (WRAT) reading, and right-handedness. Subjects will be randomly selected from the investigator's larger sample of well characterized outpatient chronic schizophrenics and matched normal controls, who have already received a battery of clinical and cognitive tests, and some of whom have received structural imaging. Based on the investigator's and others' previous studies, the investigator predicts significant sex differences in: activations of the inferior and dorsolateral prefrontal cortex, posterior parietal cortex, and in the anterior cingulate gyrus; in lateralization of hemispheric activations from verbal versus nonverbal cognitive stimuli; and in visual versus auditory stimuli. Findings will contribute to an understanding of sex differences in the nature of schizophrenia, and how, or whether, they deviate from sex differences in the normal brain.

DESCRIPTION: (Adapted from applicant's abstract): The investigators are proposing a 5-year competing continuation study to test the hypothesis that one's sex modifies brain volume abnormalities in schizophrenia (SCZ) in areas that are normally sexually dimorphic and places males at higher risk for more severe cognitive consequences than females with SCZ. Based on preliminary findings in MH56956 and others' work, they predict that males and females will differ in volumetric reductions in specific cortical regions and their associated areas in the corpus callosum, differences will contribute to explaining more severe verbal learning/memory deficits in males. Further predictions that these "sex-specific " cortical reductions in SCZ will more likely be associated with prenatal insults than with peri/postnatal insults. Finally, we will test whether prenatal insults result in similar sex-specific cortical volumetric reductions in subjects with SCZ compared with affective psychoses. A unique opportunity to test the hypotheses using subjects who were originally ascertained from a community sample of pregnancies from the Providence and Boston cohorts of the National Collaborative Perinatal Project (NCPP). Pregnancies were followed prospectively, bloods were drawn from mothers, and the children were regularly evaluated up to age 7. Serologic assays of exposures are currently being conducted at no cost to this proposal. From the NCPP sample, the investigators have been conducting a case-control study, in which they will have systematically located, recruited and diagnosed 123 DSM-IV psychotic cases, approximately 60 percent with SCZ and 40 percent with affective psychoses, who are now 3340 years of age. Subjects and their parents are evaluated clinically, and family history information (i.e. potential genetic vulnerability) is obtained. Cases are individually matched to normal controls based on age, sex, ethnicity, study site, and history of obstetric insults. In the proposed study, expectations to successfully reascertain 105 of these cases and 105 matched controls to conduct structural magnetic resonance imaging (MRI) and a cognitive battery focused on the components of verbal learning/memory. The investigators are using a sophisticated parcellation technique of MR scans that reliably identifies gray and white matter in cortical and subcortical regions. The tests of the hypotheses will provide us with knowledge about the relationships between brain morphology and cognition in SCZ, how one's sex may modify these relationships, the potential role of the timing of insults in producing these abnormalities, and whether the impact of sex is disease-specific or shared by another illness, suggesting some robust properties of the normal female and male brain in the face of disease.

This is a proposed Phase III of our Neurodevelopmental Study of Schizophrenia, in which we intend to assess the consequences of genetic and/or pre- and perinatal complications (PPCs) using high resolution structured magnetic resonance imaging (MRI). Studies of schizophrenia have implicated gray and white matter abnormalities in limbic-diencephalic, paralimbic, and prefrontal brain regions. These brain abnormalities result from genetic and/or environmental (i.e., obstetric) factors. Further, some nonpsychotic relatives of patients with schizophrenia suffer from similar, milder, ("subsyndromal") dysfunctions. We are proposing a 5-year study to continue a 40-year prospective high risk study to directly test the consequences of genetic vulnerability (assessed by psychosis in the parent) and specific PPCs (i.e., chronic fetal hypoxia and infections in the second trimester), on cortical and subcortical brain volumes in adult offspring of parents with schizophrenia or affective psychoses. We have a unique opportunity to re-evaluate subjects that we have carefully studied by clinical and neuropsychological evaluations in Phase II of the study. The sample was originally ascertained from a community cohort of pregnancies drawn from the Providence and Boston cohorts of the National Collaborative Perinatal Project. At these sites, 17,741 pregnancies were followed prospectively and systematically recorded, and the offspring's mental and physical development were assessed at 4 and 8 months, and 1,4, and 7 years of age. We have systematically located, recruited, and diagnosed 200 parents with psychotic disorders, and 200 normal comparison parents, individually-matched on specific parent and offspring characteristics. 403 of their adult offspring, ages 31-37, have been identified in Phase II. We estimate that we will ascertain 85 percent of these 403 offspring for MRI. This study is unique in that we can specify developmental predictors of structural brain abnormalities and their functional consequences due to risk and obstetric status, for offspring who become psychotic, or exhibit subsyndromal expressions of the genetic diathesis. Further, we will identify the contribution of PPCs and/or genetic vulnerability to neural circuit abnormalities and demonstrate the specificity for schizophrenia versus affective psychosis. We will use a high resolution MRI and highly detailed, reliable image analysis techniques programs to link etiological predisposition to adult brain volumes (i.e., in limbic-diencephalic, paralimbic and cortical regions, and white matter tracts). This study has important implications for understand2ing the etiology and development of schizophrenia.