Endophenotypic markers of schizophrenia and schizotypal personality


Clinical symptoms of schizophrenia fluctuate over time but some of the cognitive and perceptual deficits are permanent and stable(e.g., WM deficit, smooth pursuit eye tracking deficit). These cognitive deficits are also observed in about half of the unaffected first-degree relatives. In the past 15 years, we have examined healthy first-degree relatives of schizophrenic patients and psychometrically-ascertained schizotypal individuals to further identify core cognitive deficits that may be true endophenotypic markers. We now know that by mid-adolescence, those at high-risk for schizophrenia show WM and smooth pursuit eye tracking deficits (both mediated by the prefrontal cortex) even though they are not symptomatic. In addition to WM and smooth pursuit eye tracking deficit, there are subtle deficits in attentional inhibition and thought disorder and reduced laterality to be potential markers for schizophrenia. 


A very important task that lies ahead is specifying cognitive and neuroanatomical markers for ultra high-risk individual and to determine the earliest time point at which we may detect these signs. The first episode of schizophrenia typically presents itself during late adolescence to early adulthood but a long prodromal period precedes it. Indeed some non-clinical signs may be detected in childhood (e.g. neuromotor abnormalities in infancy, language delay, reduced laterality). Past research suggests that cognitive data in children may be useful in predicting future psychosis, especially performance on tasks that involve WM, attention and language.


To identify key events that precede psychosis, we need to examine neuroanatomical and behavioral changes in high-risk children, especially from pre-puberty to late adolescence. The associative neocortex continues to mature during adolescence; these anatomical changes should be reflected in cognitive and affective functions. Interacting with the cortical changes and maturation is gender; there are sex differences in the timing of the onset of schizophrenia and in the rate of brain maturation (e.g. De Belliset al, 2001; Benes et al, 1994). Here are the two key maturational changes that are central to our purpose. During adolescence, there is a two-fold increase in myelination of key corticolimbic relay areas (e.g. Benes et al, 1994). The onset of puberty and maturation rate are also associated with the extent of pruning of the excitatory connections (Huttenlocher, 1979). Abnormal pruning has been linked to the genesis of auditory hallucinations, semantic abnormalities and WM deficit (Hoffman & McGlashan, 1997), three key behavioral signs of schizophrenia.


Brain changes can be tracked in-vivo with structural and functional imaging and correlated with cognitive and affective behaviors in healthy and high-risk children. Although we are very far from specifying the phenotype of schizophrenia, we are beginning to see an emerging pattern in cognitive profiles. Future studies should focus more on the individuals at risk. Identifying the cognitive signs in children at ultra high risk for psychosis is one of the most important tasks ahead. If we know what signs to look for, direct intervention should be possible before full-blown psychosis emerges. Here, knowing the behavioral markers will be practically very useful.


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