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Schizophrenia Arises From An Early Neurodevelopmental Insult, Interacts With Postpubertal Brain Maturation

Schizophrenia arises when an early neurodevelopmental insult interacts with either normal or abnormal dynamic changes that occur as the brain develops into adolescence, according to an Australian review of the scientific literature.

The authors suggest that there is potential for intervention to "prevent, ameliorate or delay" the structural changes that occur before the first episode.

Research conducted by the article's lead author, Dr Christos Pantelis, associate professor at the neuropsychiatry research and academic unit of the Sunshine Hospital, St Albans, Victoria, Australia, showed that patients with schizophrenia had reduced folding in the anterior cingulate cortex (ACC) and therefore lacked the leftward sulcal asymmetry seen in patients without the disease. Folding in this area is almost complete by the third trimester of pregnancy and is stable thereafter, indicating that anomalies are prenatal in origin. Other evidence for prenatal neurodevelopmental abnormalities in schizophrenia included tissue loss and structural changes such as ventricular enlargement.

The authors said that this evidence was consistent with early neurodevelopmental insult. However, the argument that the onset of schizophrenic symptoms was delayed because it arose only when the affected brain circuitry was "placed under functional demand", was not convincing.

"Given that neurodevelopment does not end with birth, a model that incorporates possible anomalies of later developmental processes such as myelination or synaptic pruning is required," they said. Functional imaging studies, including the group's own work, suggest disconnectivity between the cingulate-hippocampal and prefrontal-medial temporal networks. Increased myelination of these areas occurs during adolescence and early adulthood, which provides a possible explanation for the onset of symptoms at this time.

There is also evidence that structural brain changes occur as psychosis is developing and after illness onset. In a prospective longitudinal study of patients at ultra high risk of developing psychoses, in those who went on to develop psychosis, three regions of the left hemisphere were reduced - a left inferior frontal region, a left medial temporal region that included the hippocampus, surrounding parahippocampal gyrus and the fusiform gyrus, and the cingulate bilaterally. Two other studies showed that whole brain volume declined at about 1 to 2% per year as the disease progressed.

The article also highlighted evidence for a modular disease trajectory based on the literature on normal brain development, which suggests that different circuits within the brain are activated at various points in the life course. Thus, in schizophrenics, neuromotor dysfunction, for example, is most pronounced in early childhood and late in life, whereas psychosis is most pronounced in late adolescence and early adulthood.

The authors proposed that functions activated earlier on in life (such as motor function) when the brain is more adaptable are affected less severely at onset of disease than those that "come online" later on in development (such as executive functions). This, they said, was because early on in development, the brain was more able to moderate the behavioural expression of the early lesion. For functions that were activated later on, more severe symptoms arose at onset as a result of a "reduced capacity to provide the appropriate central nervous system environment for the maturation of complex and multifaceted brain functions that require multiple circuits."
Aust N Z J Psychiatry 2003 Aug;37:4:399-406. "Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences"

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