The Developmental Neurobiology of Working Memory Deficits as a Risk Factor for Schizophrenia

Developmental Disturbances in the Neural Systems Supporting Working Memory As Endophenotypic Markers of Risk for Schizophrenia (Barch, DM)

Many theorists have hypothesized that schizophrenia is a neurodevelopmental disorder in which critical maturational events may fail to occur prior to or during puberty, which in turn leads to development of the manifest disorder during or following puberty. However, few studies have directly examined this hypothesis in the context of functional brain activation disturbances associated with cognitive markers of risk for schizophrenia. One such promising marker is a disturbance in working memory function (the ability to temporarily maintain and manipulate information). A variety of lines of research have demonstrated that individuals at risk for schizophrenia demonstrate alterations in working memory. Further, siblings at risk for schizophrenia who go on to develop the manifest illness demonstrate worse working memory in childhood as compared to their siblings who do not go on to develop schizophrenia. Unfortunately, purely behavioral measures of working memory do not have sufficient positive predictive power to be clinically useful indicators of heightened risk for the development of schizophrenia. However, the use of functional imaging measures to examine brain activation during working memory performance may provide markers that are effective in detecting specific risk for the development of psychosis. Several published studies have now demonstrated that the first degree relatives of individuals with schizophrenia show alternations in working memory-related functional brain activity, particularly in dorsolateral prefrontal cortex (DLPFC). Our hypotheses are that: 1) developmental abnormalities in working memory-related brain activation among children at risk for schizophrenia reflect an arrested development of cognitive control processes, such that normal maturational changes in working memory that occur around puberty are either developmentally delayed or never occur; and 2) children at risk for schizophrenia will show either intact or even enhanced activation associated with the maintenance of information in working memory, but reduced activation associated with the central executive components of working memory. To test these hypotheses, we will use functional magnitude resonance imaging to assess brain activation in the young (ages 7-10) and peri-pubertal (ages 11-14) siblings of individuals with schizophrenia, as well as age and socioeconomic status matched controls. We will use a continuous working memory task called the NBACK that will allow to examine different levels of load. In addition, we will use a novel state-item design that will allow us to examine functional brain activation associated with processes that are sustained throughout the course of a working memory task (e.g., maintenance of information), versus those that may occur time locked to specific trials (e.g., the manipulation of the contents of working memory). We predict that the peri-pubertal high-risk siblings will show greater evidence of altered working memory-related functional brain activation than the young high-risk siblings, and that the brain activation patterns of the peri-pubertal children will resemble those of young low-risk siblings, consistent with the hypothesis of maturational delays or arrest in neural development.