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.