Both MRI and MRS offer evidence, which is consistent with a neurodegenerative pathologic process in schizophrenia that occurs primarily but not exclusively in the early stage of the illness. Recent MRI studies of first-episode and childhood-onset schizophrenia samples using more rigorous and standardized methods have found cortical gray matter and ventricular system volume changes. The findings of volume reductions in cortical gray matter and increases in ventricular system volume can be described as consistent with a process causing pathomorphologic progression and neurodegeneration Investigators have considered the role of molecular mechanisms in the neuropathology of schizophrenia. In this context, proponents of neurodegenerative theories have suggested that the absence of gliosis and evidence of cell degeneration could be due to the fact that the pathophysiology involves a graded apoptosis rather than a fulminant necrotic process. Apoptosis is evanescent and difficult to detect histopathologically before or after the process unfolds. Studies have shown that various neurochemical events at the synapse can induce apoptosis. Such triggering actions include excessive glutamate stimulation, calcium influx reactive oxygen species all of that can induce caspase activation in dendrites. Local activation of caspases that initiate the apoptotic cascade can spread to the cell body or remain localized producing neurodegenerative synapse loss and synaptic remodeling. The reduced size and increased density of neurons, in the absence of decreased numbers of neurons or glia and decreased cortical thickness, indicate that cell processes and synaptic connections are reduced in schizophrenia. This is consistent with reports of decreased concentrations of synaptic proteins (e.g., synaptophysin). These cell processes and synapses could be lost as a consequence of a neurochemically mediated (through dopamine and/or glutamate) synaptic apoptosis that would compromise cell function and alter brain morphology without, however, producing serious cell injury (and thus inducing glial reactions).