Strucutural brain imaging at the onset of schizophrenia:What have we learned and what have we missed.

Over the past 50 years, the application of structural neuroimaging techniques to schizophrenia research has added relevant information about the pathophysiology of the disorder. Several lines of investigation gave strong evidence that schizophrenia is associated with multiple subtle brain abnormalities that involve both cerebral grey and white matter volumes and structure. The time of onset and longitudinal course of brain morphological abnormalities support the notion that brain pathology of schizophrenia has a neurodevelopmental component and a progressive course, although several confounders of brain changes should be carefully taken into account. Brain anomalies detected before and close to the onset of schizophrenia are likely to be unrelated to confounders of brain changes such as antipsychotic drug treatment, duration of illness or illicit substance abuse, i.e. they related to the pathological process of the disorder per se. Nonetheless, clinically useful diagnostic or prognostic biomarkers have not derived from neuroimaging studies and this is likely related to the neurobiological heterogeneity of the disorder. Thus, there is the compelling need to set new methodological standards for developing innovative hypothesis-driven studies to overcome what we have missed to date in neuroimaging research in schizophrenia.