Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain?

In an era of dramatic discoveries in neuroscience and genetics, it is likely that many popular theories and formulations about mental illness will need to be revised, if not discarded. The “neurodevelopmental hypothesis” is one of the popular theories about the origins of schizophrenia, which posits that abnormalities of early brain development increase risk for the subsequent emergence of the clinical syndrome. 1-3 An early piece of evidence in support of this hypothesis was the apparent lack of progression of cerebral ventricular enlargement observed with computed tomography during illness. 4-9 An important assumption of the neurodevelopmental hypothesis is that the putative primary pathologic condition of the brain is a reflection of abnormalities of early development. The neurodevelopmental hypothesis thus assumes that developmental neuropathologic conditions should arrest early in life and not continue to progress. The computed tomography results showing no apparent progression seemed consistent with this assumption. However, a recent series of magnetic resonance imaging (MRI) studies has called into question this assumption, by revealing changes in measurements of brain structures over short periods in patients who have been ill for varying durations and at various stages of life. These recent studies 10-14 have generated enthusiasm for a “neurodegenerative hypothesis,” harkening back to proposals of Kraepelin and other neuropathologists during the first quarter of the 20th century that there is destruction of neural tissue associated with psychosis. In fact, results of MRI measurements have been cited as support for a much broader conceptual revolution in psychiatry, a “neurotoxicity hypothesis” for many psychiatric illnesses, including affective disorders 15,16 and anxiety and stress disorders 17-19 and even jet lag. 20 This recent trend has been bolstered by basic discoveries about the adaptability of neuronal connections 21 and the viability and reproducibility of neurons in the adult brain (eg, apoptosis and neurogenesis). 22,23 These developments have led some to opine that the neurodegenerative hypothesis of schizophrenia may have been unjustly overshadowed by the ascendancy of the neurodevelopmental hypothesis. 24