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Functional Neuroanatomy of Working Memory as a Risk Factor for Schizophrenia

Date of Award

Summer 8-15-2009

Author's School

Graduate School of Arts and Sciences

Author's Department


Degree Name

Doctor of Philosophy (PhD)

Degree Type



Individuals with schizophrenia exhibit impaired working memory and associated deficits in functional brain activation within a network of brain regions including dorsolateral prefrontal cortex (DLPFC) (Barch et al., 2001; Carter et al., 1998; Meyer-Lindenberg et al., 2005; Perlstein, Carter, Noll & Cohen, 2001; Weinberger, 1988; Weinberger & Berman, 1996; Weinberger, Berman & Zec, 1986), thalamus, cerebellum, and hippocampus (Kubat-Silman, Dagenbach & Absher, 2002; Meyer-Lindenberg et al., 2005; Schlosser et al., 2003). First-degree relatives of individuals with schizophrenia, who do not yet demonstrate psychotic symptoms associated with the overt form of the disorder, exhibit similar (though less severe) impairments in working memory and brain activation to those seen in actively ill individuals. Such results suggest an abnormal neurodevelopmental process that may precede the onset of schizophrenia (Lencz, 2001). Behavioral measures of cognitive deficits alone, however, do not have sufficient predictive power to identify who will go on to develop schizophrenia (Davidson, 2000). Functional neuroimaging techniques that examine working memory related brain function may provide markers that more robustly detect those at higher risk for developing psychosis. The behavioral and neuroimaging literature suggests that working memory impairments in individuals with schizophrenia stem more from difficulties with executive demands (i.e., manipulation, updating of working memory contents) than with maintenance related functions (Fleming, Goldberg, Gold & Weinberger, 1995; Gold, Carpenter, Randolph, Goldberg & Weinberger, 1997; Kim, Glahn, Nuechterlein & Cannon, 2004; Perlstein, Dixit, Carter, Noll & Cohen, 2003). The literature also suggests that working memory impairments and associated brain function abnormalities are present in high-risk relatives of individuals with schizophrenia, although the nature of the deficit is less clear. For example, behavioral studies suggest that working memory impairments in high-risk individuals stem more from the executive function component of the working memory system; however, few studies have examined load sensitive activity in working memory to determine whether working memory impairments in highrisk individuals also stem more from difficulties with executive demands than maintenance related functions. The proposed study will be cross sectional and will provide critical information about the nature of working memory deficits and associated abnormalities in brain activation in individuals who are higher risk for developing schizophrenia, but who have not yet developed the disorder. The present investigation will address three aims: (1) to test the hypothesis that working memory performance in relatives of individuals with schizophrenia will be more impaired than that of low-risk relatives, but that the level of impairment will vary as a function of working memory load; (2) to test the hypothesis that individuals at risk for schizophrenia will show an altered relationship between working memory related brain activity and working memory load compared to low-risk relatives; and (3) to determine whether a relationship between brain function and behavioral problems exists in relatives of individuals with schizophrenia.


English (en)

Chair and Committee

Deanna M. Barch

Committee Members

Desirée A. White, Tamara Hershey, Todd Braver, Steven Petersen, Jose Mathews


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