Longitudinal investigations of children who are statistically more likely to develop schizophrenia became popular during the 1950s and continue to offer rich clinical data today. In 1952, Barbara Fish launched the New York Infant High-risk Study, the first formal investigation of children born to schizophrenic mothers . Based on her work, Fish theorized that the vulnerability seen in children of schizophrenic mothers was related to defective neural integration, which could be detected in infancy . Fish described pandysmaturation (PDM), which was thought to be a marker for this neurointegrative defect . PDM is characterized by slowed skeletal growth, ''transient lags'' in development during the first two years of life, and an abnormal profile where more complex developmental tasks are achieved while relatively simple tasks are failed . Since Fish launched her study, many other high-risk studies have been initiated, such as the Copenhagen High-risk Project , the National Institute of Mental Health (NIMH) Israeli High-risk Study , the New York High-risk Project  and the Jerusalem Infant Development Study , among others. A brief overview of these first-generation high-risk studies follows; other sources provide more exhaustive reviews [23-31].
In 1962, Mednick and Schulsinger launched the Copenhagen High-risk Project . They based their investigation on the hypothesis that preschizophrenic children inherit an overly sensitive autonomic nervous system, which leads to an avoidance of excessively stressful environments . Participants in this study were between the ages of 9 and 20 at the start of the investigation and were identified through central social and medical registers as having severely schizophrenic mothers. A control group of low-risk children matched for age and socioeconomic status was also included. From their sample, Mednick et al.  found that children of schizophrenic mothers were predisposed to schizophrenia spectrum disorders, not just to schizophrenia. This predisposition was more likely to be transmitted by mothers whose schizophrenia began at an earlier age and by mothers who had multiple relatives with schizophrenia, making for a larger genetic load . Follow-up investigations shed light on personality variables that appear to predict future schizophrenia in high-risk individuals . Although prior research with the Copenhagen subjects did not identify any premorbid differences in personality variables, a 25-year follow-up suggested that personality variables could distinguish paranoid preschizo-phrenic subjects from high-risk individuals who did not become ill . Specifically, on a modified version of the Minnesota Multiphasic Personality Inventory (MMPI), paranoid preschizophrenics had deviant scores on the psychoticism scale, the paranoid schizophrenia scale, and a scale measuring unusual thoughts and experiences . They also endorsed items that were indicative of psychotic processes, withdrawal and social aversion . Earlier results from the Copenhagen study suggest that 5% of children of paranoid schizophrenic mothers were schizophrenic at age 24, whereas 29% of the offspring of non-paranoid schizophrenics had the disorder .
Another investigation, the NIMH Israeli High-risk Study, overseen by Rosenthal and colleagues, was initiated in 1965 . This study provided a unique opportunity to evaluate the stress-diathesis model of schizophrenia. As mentioned previously, this model proposes that the development of schizophrenia includes genetic vulnerability (diathesis) and environmental contributors (stress). In the Israeli study, school-age children with a schizophrenic parent (high-risk children), who were being raised either by professional child-care workers on a kibbutz or in a traditional family setting, were included. Control groups included non-high-risk children being reared on a kibbutz or by their own parents in a nuclear family. One goal of this investigation was to assess whether reduced exposure to a schizophrenic parent would yield better outcome . Results indicated that children with clear neurobehavioural deficits and poor social competence were at greatest risk for later development of schizophrenia spectrum illness , and that children reared on the kibbutz developed psychiatric disorders at more than double the rate of high-risk children raised in traditional families . In a follow-up study at age 30, high-risk kibbutz cases were significantly more likely to have an Axis I diagnosis as compared to children reared by a schizophrenic parent . Several possible environmental factors unique to the kibbutz environment were implicated in this finding, including the stressful and demanding nature of this setting .
The New York High-risk Project, initiated by Erlenmeyer-Kimling and colleagues in 1971, included children between 7 and 12 years of age who were the offspring of at least one schizophrenic parent . Comparison groups included offspring of parents with affective disorder and children of psychiatrically healthy parents. A follow-up conducted when the offspring were approximately age 27 showed that the best predictor of adult psychosis, hospitalization and dysfunction was having a schizophrenic parent .
Attentional difficulties have been of interest to high-risk researchers and consistently emerge as a possible neurobehavioural marker in such studies. In the New York High-risk Project, more than a quarter of high-risk children showed problems with attention by age 7 and these difficulties persisted into adolescence and adulthood . Attention deficits measured at the onset of adolescence yielded approximately 78% correct classification of future schizophrenia spectrum disorders, with a sensitivity of 67% and a specificity of 79% . This is considerably better than the prediction afforded by looking at genetic vulnerability alone. While attentional deficits appear to be a promising indicator, Cornblatt et al.  urge caution and note that the specificity of this predictor has not yet been demonstrated in studies comparing adolescents with attention deficit disorder versus those with a schizophrenic parent.
The sensitivity and specificity of other neurobehavioural markers has also been investigated in the New York High-risk Project. Sensitivity for predicting schizophrenia spectrum disorders was 83% for verbal memory deficits and 75% for gross motor skills . According to the authors, attention deviance appears to be a less sensitive predictor than the aforementioned ones, although it is associated with fewer false positives. A combination approach using an assessment of verbal memory, gross motor skills, and attention deviance offered the best predictive possibility . This combination yielded a 10% false positive rate, 46% positive predictive validity and 83% overall accuracy . One specific type of attention, the ability to shift attention from one aspect of a stimulus to another, has also been assessed in high-risk individuals. The Wisconsin Card Sorting Test (WCST) , a measure of mental flexibility or shifting attention, did not distinguish young adult offspring of schizophrenic parents from controls in the Israeli High-risk study . However, in the New York High-risk Project, young adults with a schizophrenic parent had a profile similar to that seen in schizophrenic patients, albeit in milder form . Future investigations designed to assess performance on varied attentional tasks might allow for further refinement of this predictor and might also help to distinguish children and adolescents with attention deficit from those who are at high risk for developing schizophrenia.
In 1973 another longitudinal study was launched by Marcus and colleagues, the Jerusalem Infant Development Study . This investigation offered further evidence in support of Barbara Fish's neurointegrative deficit theory . Between 1973 and 1976, pregnant women in Jerusalem who either had schizophrenia or were married to a man with the disorder were recruited for the study . Control subjects included pregnant women with a history of affective disorders, personality disorders, neuroses or no psychiatric history. The researchers found that a subgroup of high-risk children had poor motor and sensorimotor performance during their first year, and although prenatal, perinatal and postnatal complications could not fully account for these differences, such insults had a more significant effect on these children . High-risk children also exhibited perceptual and attentional difficulties in childhood . Although motoric signs were evident, perceptual-cognitive functioning was more closely associated with parental diagnosis of schizophrenia . Follow-up in adolescence suggested that a significant number of these children continued to show poor neurobehavioural functioning and poor psychiatric adjustment . As adolescents, they also showed evidence of poor peer relationships, immaturity and unpopularity . Such difficulties were especially evident in opposite-sex interactions . The findings from the Jerusalem High-risk Study provide support for a neurodevelopmental model of schizophrenia spectrum disorders and suggest that neurobehavioural signs are measurable across development.
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