Although there are no immediate clinical implications of these findings, their usefulness for the understanding of normal brain development and disease pathophysiology is great. Longitudinally acquired scans during the critical period of brain development provide clues to the underlying disease mechanism. For instance, we now know that regional structural modulations probably reflective of synaptic and dendritic remodeling are ongoing in the brain throughout adolescence.13 The shape of the developmental curves seen in children with ADHD almost parallels normal brain development (Figure 1), indicating a fixed and probably early developmental abnormality. The anatomical MRI studies and symptom and neuropsychological test profiles support the postulated dysfunction of cerebellar-striatal-prefrontal circuitry in ADHD.14 On the other hand, the progressive and region-specific nature of gray matter loss in COS shows this to be, in part, a late neurodevelopmental disorder. We speculate that the earlier tissue loss seen might trigger the onset of psychosis. Thus, these 2 illnesses of childhood appear to involve different developmental trajectories. With the advent of sophisticated brain-mapping techniques, it is now possible to map the progressive tissue loss in a region-specific manner. This development could allow correlation of the clinical symptoms, and pathophysiology of the illness with localized structural alterations. Thus, early parietotemporal gray matter loss in COS could partially explain the premorbid speech and language deficits seen in these children. Similarly, regional tissue loss in COS can be examined in relation to heritability patterns.15 For example, young unaffected siblings of COS probands appear to share the parietal gray matter volume reduction. This finding strongly suggests a genetic vulnerability to this complex illness (N.G., unpublished data, May 2002). Postmortem studies show regional heterochronicity in synaptic pruning during childhood and adolescence,13 and schizophrenia is postulated to be a disorder of "overpruning," in which loss of neuropil is seen without any neuronal loss.16 This hypothesis is supported by the imaging findings of regional and progressive loss of gray matter seen in schizophrenia without any white matter changes. The finding is compatible with the results of molecular studies of schizophrenia in adults. For example, a recent study using postmortem tissue and gene microarrays found reduced expression of transcripts associated with the regulation of presynaptic function in the prefrontal cortex in schizophrenia. Alterations in 2 of the most consistently abnormal transcripts in this gene group, N-ethylmaleimide–sensitive factor and synapsin II, could lead to altered synapse formation, pruning, or both and may ultimately lead to loss of neuropil and gray matter volume.17 Thus, the MRI abnormalities may provide clues to candidate mechanisms of this illness.