guided by quite different conditions than those for mature adults. Finally, the “work” of an adolescent is quite generally to do well in school, whereas the “work” of an adult is normally to find a paying job. Again, assessment tools have simply not been defined for assessing these aspects of psychosocial functioning in adolescents.

Through the use of neuroimaging, neuropathology, and neurogenetics, substantial progress in understanding the neural underpinnings of schizophrenia is being made. Excellent work has been done recently that examines the relationship between brain development and the occurrence of schizophrenia in children and adoles cents, as described in other chapters (DeLisi, 1997; Giedd et al., 1999; Gur, Maany, et al., 1998; 1999; Ho et al., 2003; Jacobsen et al., 1998; Kumra et al., 2000; Lieberman, Chakos, et al., 2001; Rapoport et al., 1997; Thompson, Vidal, et al., 2001). As this work continues to mature, however, more work needs to be done to examine precisely how the specific symptoms of schizophrenia arise in the human brain, and whether imaging and other tools can be used to assist in diagnosis, treatment planning, and ultimately prevention.

This work must also address several questions in the realm of phenomenology. Specifically, how should we proceed as we attempt to link phenomenology to neural mechanisms? As discussed above, the phenomenology has multiple levels and aspects—symptoms, outcome, cognitive function, and psychosocial function. Which of these should be linked to imaging and other “biological” measures?

Most work to date has taken several different approaches. At the simplest level, investigators have conducted studies linking specific symptoms to neural measures. For example, studies have used positron emission tomography (PET) to identify brain regions active during auditory hallucinations (e.g., Silbersweig et al., 1995). Other investigators have examined symptoms such as thought disorder in relation to brain measures (e.g., Shenton et al., 1992). One of the critical conceptual issues, however, is the fact that the phenomenology of schizophrenia is

complex. That is, the illness cannot be characterized on the basis of a single symptom. Although auditory hallucinations are common in schizophrenia, they are not omnipresent. Therefore, other investigators have proceeded by examining groups of symptoms that are correlated with one another, or “dimensions.” Many factor analytic studies have examined the factor structure of the symptoms of schizophrenia; nearly all find that the symptoms group naturally into three dimensions: psychoticism, disorganization, and negative symptoms (Andreasen, 1986; Andreasen, O'Leary, et al., 1995; Andreasen, Olsen, & Dennert, 1982; Arndt, Alliger, & Andreasen, 1991; Arndt, Andreasen, Flaum, Miller, & Nopoulos, 1995; Bilder, Mukherjee, Rieder, & Pandurangi, 1985; Gur et al., 1991; Kulhara, Kota, & Joseph, 1986; Lenzenweger, Dworkin, & Wethington, 1989; Liddle, 1987). Some studies have used the dimensional approach to examine brain–behavior relationships. Several studies also suggest that these three dimensions may have different functional neural substrates as seen with PET, or different structural brain correlates as evaluated with magnetic resonance imaging (MRI), and may also have different and independent longitudinal courses (Andreasen, Arndt, Alliger, Miller, & Flaum, 1995; Andreasen et al., 1996, 1997; Arndt et al., 1995; Flaum et al., 1995, 1997; Gur et al., 1991; Miller, Arndt, & Andreasen, 1993; O'Leary et al., 2000).

In concert with this work examining the symptoms of schizophrenia, other investigators have pursued the study of relationships between cognition and brain measures. Some have argued that some form of cognitive dysfunction may ultimately provide the best definition of the phenotype of schizophrenia, and that ultimately cognitive measures may replace symptom measures in defining the phenomenology of schizophrenia (Andreasen, 1999). Again, however, a consensus has not been achieved.

Contemporary geneticists applying the tools of modern genetics have become very much aware of how important it is to have good definitions of complex disorders such as schizophrenia. In fact, reflecting this awareness, they are beginning to speak about a new (but actually old) field, referred to as “phenomics,” the genetic underpinnings of phenomenology. The emergence of this term reflects the fact that the definition of the phenotype of illnesses like schizophrenia may be the single most important component of modern genetic studies.

Here the issues are very similar to those discussed above, involving the relationship between clinical presentation and neural mechanisms. At what level should the phenotype be defined? The symptom level? Dimension level? Diagnosis level? Cognitive level? Or should we abandon these more superficial clinical measurements and attempt to find more basic definitions, often referred to as “endophenotypes,” or “measurable components unseen by the unaided eye along the pathway between disease and distal genotype” (Gottesman & Gould, 2003)?

In this instance, there may be some consensus. Many investigators believe that endophenotypic definitions may provide a better index of the presence of this disorder than classic symptom-based definitions, such as those created by the DSM or ICD. There is as of yet, however, no strong consensus on what the “best” endophenotypes may be. Some candidates that have been proposed include problems with working memory, eye tracking, or prepulse inhibition. To date, most of this work has been conducted with adults. The application of this approach to defining and identifying the schizophrenia endophenotype in children and adolescents is another important future direction, as is the search for additional new candidate endophenotypes.

Cognitive deficits have been recognized since early descriptions of schizophrenia, when it was called “dementia praecox.” More recent evidence confirms that cognitive deficits are evident in vulnerable individuals, are present at the onset of illness, and predict outcome. Furthermore, as summarized in Chapters 6 and 7, early detection and efforts at intervention may hold a key for ameliorating the ravages of schizophrenia later in life. Here we will describe evidence for deficits in neuromotor and neurocognitive functioning, with special emphasis on early presentation.