Clues from the Preterm Infant

Schizophrenia shows a typically remitting and relapsing course.5 If the neurodevelopmental hypothesis is correct, then why should a neurological injury sustained in utero lead to such variable symptoms in adulthood?

One possible link is that glia continue to be produced and myelination continues to develop well into middle age in key corticolimbic relay areas.159"161 Glia are not simply an important but passive matrix for the brain. In addition to their traditional roles in neuronal migration and inflammatory processes, glia are now known to provide trophic support to neurons, to regulate local neuronal metabolism and neurotransmission, and the formation of synapses (including pruning).162'163 The early appearance of ventriculomegaly suggests that there has been a profound loss of glia in prenatal life, as is seen on in utero imaging,1 such that there may be an inadequate number in adulthood to consistently support neuronal function. The loss of glia in patients suffering from schizophrenia and affective disorders is further evidence for pathological events in mid-gestation as this is the maximal time of increased glial proliferation and differentiation.165 The impact of prenatal loss of glia is perhaps best illustrated by the neurodevelopmental delay, behavioural abnormalities and increased rate of mental illness in children who are born prematurely,166"168 Pathologically, such infants demonstrate highly selective early white matter damage, which leads to long-term reductions in grey matter volume and complexity of neuronal structures.167'169,170 The neurological sequelae of preterm birth (including epilepsy, cerebral palsy and attention deficit) associated with these perinatal white matter lesions seem to be a consequence of the post-injury grey matter transformations.171,172 This sequence of events is strikingly similar to those in patients with schizophrenia. Disturbingly, there is now evidence to show that preterms are also at greater risk of developing mental illnesses such as schizophrenia in adulthood.173

Importandy, however, infants do not necessarily deliver even after a major insult in utero. There is now increasing evidence to show that neurodevelopmental delay in term babies is also associated with white matter loss and subsequendy impaired neuronal development which apparendy had its origins much earlier in fetal life.1

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