Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground

Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and malfunction of brain dopamine systems-have often seemed difficult to reconcile. This article reviews recent research that suggests a heuristically useful reconciliation centered on the functional neuroanatomical concept of prefrontal-temporolimbic cortical connectivity. Anatomical findings from postmortem studies and neuropsychological and neuroimaging studies of brain function in patients with schizophrenia have implicated a developmental 'dysconnection' of temporolimbic-prefrontal cortices. The possibility that such dysconnection can account for the principal phenomenology of the illness, including its delayed onset and its treatment, is suggested by neurologic disease analogies such as metachromatic leukodystrophy and by recent studies in animals with developmental cortical lesions. Studies mapping neuronal gene expression indicate that all antipsychotic drugs modulate DNA transcription in a region of the nucleus accumbens that receives converging inputs from prefrontal and temporolimbic cortices, suggesting that indirect compensation for dysfunctional communication between prefrontal and temporolimbic cortices is a therapeutic mechanism of these drugs. Treatments aimed at direct cortical compensation may be more effective.