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Relatives of people with schizophrenia have a greater risk of developing the illness than others. The risk is progressively greater in relatives who are more genetically similar to the schizophrenic person. Studies of people adopted in infancy suggest that the increased risk of schizophrenia in the relatives of identified cases is attributed to inheritance rather than environment. The children of people with schizophrenia have a similar increased prevalence of the illness whether they are raised by their biological parents or by adoptive parents. Likewise, the family history of people with schizophrenia brought up by adoptive parents reveals an increased prevalence of the illness among their biological relatives but not among their relatives by adoption (Heston 1966; Kety et al. 1968; Kety et al. 1975; Tienari and Wynne 1994).

The neurodevelopmental hypothesis / Recently the view has emerged that schizophrenia is a neurodevelopmental disorder (Weinberger 1995a) "in which the primary cerebral insult or pathological process occurs during brain development long before the illness is clinically manifest" (Weinberger 1995b). According to this view, subjects with schizophrenia might have suffered from some form of cerebral maldevelopment during the gestational phase, in particular during the second trimester of gestation. For a variety of neurobiological reasons, the disorder would manifest itself only during early adult life, when some selected neuronal systems, maturing long after birth, become unable to cope with several types of psychosocial stress and life vicissitudes.
     Although this view is still circumstantial (Cannon 1997), several types of evidence tend to support it. In particular, it has been shown that complications of pregnancy and delivery increase the risk for developing schizophrenia two to three times, probably because of damage to the developing brain (McNeil 1988; Geddes and Lawrie 1995; Goodman 1988; Kendell et al. 1996). Perinatal hypoxia (deprivation of oxygen to the fetus), which occurs in some 20%-30% of people suffering from schizophrenia as compared to a base rate of 5%-10% in the general population, appears to be an important factor (McNeil, 1988; Cannon 1998). The risk of schizophrenia increases with the number of perinatal complications (McNeil 1988; Kendell et al. 1996; Eagles et al. 1990; O'Callaghan et al. 1992; Guenther-Genta et al. 1994).
     The risk of intrauterine brain damage is increased if a pregnant woman contracts a viral illness. It has been observed that more people with schizophrenia are born in the late winter or spring than at other times of year (Torrey et al. 1988) and that the proportion of people with schizophrenia born at this time increases after epidemics of viral illnesses such as influenza, measles, and chickenpox (Mednick et al. 1987; O'Callaghan et al. 1991; Barr et al. 1990; Sham et al. 1992). However, maternal viral infections probably account for only a small fraction of the increased risk for schizophrenia (Adams et al. 1993; Wilcox and Nasrallah 1987).

Physical abnormalities in the brain / Physical changes in the brain have been identified in some patients with schizophrenia. Such changes in the structure and function of the brain have been identified by the analysis of brain tissue after death, as well as by new brain imaging techniques that can be used to examine the brain while the person is alive. Computerized Tomography (CT-Scan) and Magnetic Resonance Imaging (MRI) provide images of the structure of the brain. Functional MRI and techniques that use isotopes, such as Single Photon Emission Tomography (SPECT) and Positron Emission Tomography (PET), are able to demonstrate cerebral regional blood flow (rCBF) changes and modifications of the chemistry of the brain.
     Early CT-Scan studies showed abnormalities in many patients with schizophrenia. These were mainly asymmetries of the brain and ventricular system, especially affecting the frontal lobes and the left hemisphere. This asymmetry is unrelated to the evolution or duration of illness or treatment and does not progress during the illness (Vita et al. 1997). It is therefore considered to reflect events that took place early during cerebral development. MRI studies have found similar results (Andreasen et al. 1986). The correlation with family history of the disease, season of birth, intrauterine viral exposure, obstetric complications (DeQuardo et al. 1996), and age of onset (Lim et al. 1996) remains unclear. Studies of sex differences (Cowell et al. 1996) have produced conflicting results. The abnormalities in the size of the brain and ventricular system, when present, are found during first episodes of the disease (Vita et al. 1997), reinforcing the interpretation that these abnormalities represent a long-standing vulnerability and are not a consequence of the evolution of the disease itself or of drug treatment.
     The correlation of structural abnormalities with symptoms or symptom clusters is less well supported, although the asymmetries seem to correlate with negative symptoms (Messimy et al. 1984). Negative symptoms also appear to be correlated with left temporal lobe atrophy (Turetsky et al. 1995). The greater the observed changes, the greater the severity of the person's thought disorder and auditory hallucinations (Suddath et al. 1990).
     In the baseline condition, SPECT shows a decrease in rCBF, especially in the frontal lobes, in more than 80% of patients (Steinberg et al. 1995). PET provides a similar picture of abnormalities. SPECT and PET regional cerebral blood flow (rCBF) studies have looked at the correlation of specific symptoms or symptom patterns with abnormalities in the blood flow of different regions. In general, positive symptoms are associated with hyperfunctioning of some areas and hypofunctioning of others, while negative symptoms are always correlated with hypoperfusion (Sabri et al. 1997).
     Electrophysiological brain recording using EEG tracings shows that most people with schizophrenia seem to be excessively responsive to repeated environmental stimuli (such as repeated clicking noises and flashing lights) and have a limited ability to blot out irrelevant material (Freedman et al. 1997).
     Postmortem examination of the brain tissue of individuals with schizophrenia has revealed problems in a certain type of brain cell--the inhibitor interneurons. Inhibitory interneurons damp down the action of the principal nerve cells, preventing them from responding to too many inputs. Thus, they prevent the brain from being overwhelmed by too much sensory information from the environment. These interneurons normally manufacture several neurotransmitters, including gamma-amino butyric acid (GABA), which gives them their inhibitory function. All these neurotransmitters are diminished in the interneurons of people with schizophrenia (Benes et al. 1991; Akbarian et al. 1993).
     Taken together, these findings suggest that in schizophrenia there is a deficit in the regulation of brain activity by interneurons, so that the brain over-responds to the many signals in the environment and lacks the ability to screen out unwanted stimuli. At the same time, there is a decrease in the size of the temporal lobes that process sensory inputs and make it possible for a person to develop new and appropriate behaviour. While the techniques discussed in this section provide clues concerning how brain function is affected in schizophrenia, they cannot be considered as essential for diagnosis or as part of the routine clinical evaluation of patients.
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