48 NEUROCOGNITIVE FUNCTIONING IN PATIENTS WITH SCHIZOPHRENIA: AN OVERVIEW TERRY E. GOLDBERG MICHAEL F. GREEN Increasingly, neurocognitive paradigms are used to study patients with schizophrenia. With such paradigms, the cog- nitive abnormalities in schizophrenia are characterized by means of experimental and clinical tests. These techniques have indicated that some types of cognitive impairment are not only reliably present in schizophrenia, but are also cen- tral and enduring features of the disease. This chapter, a revision of the one published in 1995, focuses on certain recentadvancesincharacterizingtheprecisenatureofcogni- tive impairments in schizophrenia, on understanding the implications of these for treatment given the course and relationship to outcome of these variables, and on novel applications of neurocognitive approaches to the genetics of schizophrenia. Cognitive abnormalities were noted by early investigators of schizophrenia. In the original clinical descriptions of schizophrenia made by Kraepelin (64), he commented, ‘‘Mental efficiency is always diminished to a considerable degree. The patients are distracted, inattentive . . . they can- not keep the thought in mind.’’ Some years later, Shakow (95) began a series of studies in which he examined abnor- malities in patients’ reaction time in response to different types of readiness information and imperative stimuli. Hunt and Cofer (54) noted the intellectual quotient (IQ) of schizophrenic patients to be lower than that of normal con- trols. However, the increasing influence of psychodynamic theory tended to minimize the significance of the cognitive deficits of schizophrenia. It was thought that the deficits displayed on formal psychologic testing were secondary to impaired motivation or cooperation, gross breakdowns in reality testing, or disordered thought processes. Terry E. Goldberg: Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. Michael F. Green: Department of Psychiatry and Biobehavioral Sciences, University of California School of Medicine, Los Angeles, California. This view changed rapidly with the advent of in vivo techniques of brain imaging. First, it became evident that the lateral cerebral ventricles of patients with schizophrenia are larger than those of controls on computed tomography (96). Second, functional brain imaging suggested that the frontal lobe blood flow or metabolism of schizophrenic pa- tients is decreased. Moreover, it was shown that one type of cognitive impairment, poor performance on the Wisconsin Card Sorting Test (WCST), is directly linked to impaired activation of the prefrontal cortex in regional cerebral blood flow (106). It was within this context that a series of studies in which broad neuropsychological test batteries were used demonstrated that patients with chronic schizophrenia could not be reliably discriminated from heterogeneous brain-damaged populations (69). These findings led to a reinterpretation of the original neuropsychological studies; it was increasingly realized that patients with schizophrenia perform in the range typically found in brain-damaged pop- ulations because schizophrenia involves structural and func- tional abnormalities of the brain that are, in some sense, primary, and compromise to a differential degree frontal lobe and temporal lobe function. From this perspective, schizophrenia is viewed as a disease of cortex in which infor- mation processing dysfunction is an obligatory concomi- tant. We examine certain crucial, conceptually driven issues that derive from this view: What is the course of global cognitive impairment in schizophrenia? What is the charac- ter of neurocognitive impairments in schizophrenia? What is the relevance of traits like neurocognitive impairment to linkage or association studies in which the goal is to discover susceptibility genes relevant to the etiology of schizophre- nia? We conclude this chapter by noting that neurocognitive impairments may be of prognostic significance in schizo- phrenia because of the importance of such functions in pro- viding orientation to and encoding relevant environmental information, remembering new information, propitiously