Recently, brain imaging techniques have become available to study in vivo the biochemistry and the functional neuroanatomy of brain disorders. Earlier direct and indirect evidence has involved the hippocampus, the dorsolateral prefrontal cortex, and the dopamine system in the pathophysiology of schizophrenia. Different brain imaging techniques have further advanced our understanding of the role played by these neuroanatomical structures in schizophrenia. Positron Emission Tomography (PET) allows measurement of neurotransmitter receptors. As such, PET studies in shcizophrenia have suggested that steady -state dopamine may be reduced along with increased stimulus-induced release. Proton Magnetic Resonance Spectroscopy (1H-MRS) allows measurement of some aspects of brain biochemistry. N-acetylaspartate (NAA) is an amino-acid found almost exclusively in neurons and is thought to be a marker of functional neuronal integrity. Several 1H-MRS studies have reported NAA reductions in the hippocampus and in the dorsolateral prefrontal cortex of patients with schizophrenia suggesting neuronal pathology in these two brain areas. These reductions are not an epiphenomenon of chronicity of the illness or of treatment. Consistent with the physiology of dopamine release regulation, NAA reductions in dorsolateral prefrontal cortex seem to be associated with steady-state and stimulus-induced dysregulation of dopamine.

Functional Magnetic Resonance (fMRI) is an imaging technique with high spatial and temporal resolution that allows investigation of in vivo information about the functionality of discrete neuronal groups during their activity utilizing the magnetic properties of oxy- and deoxy-hemoglobin. fMRI permits the study of normal and pathological brain during performance of various neuropsychological functions. Several research groups have investigated prefrontal cognitive abilities (including working memory) in schizophrenia using functional imaging. Even if with some contradictions, large part of these studies have reported relative decrease of prefrontal cortex activity during working memory, defined as hypofrontality. However, hypofrontality is still one of the most debated aspects of the pathophysiology of schizophrenia because the results could be influenced by pharmacotherapy, performance and chronicity. The first fMRI studies in patients with schizophrenia seemed to confirm hypofrontality. However, more recent studies performed during a range of working memory loads showed that patients are hypofrontal at some segments of this range, while they are hyperfrontal at others. These studies seem to suggest that the alterations of prefrontal functionality are not only due to reduction of neuronal activity, but they probably are the result of complex interactions among various neuronal systems. One of these systems may be dopamine which is deeply involved in the physiological regulation of neuronal firing during working memory. In this regard, it has been shown that a functional polymorphism of the cathecol-O-methyl-transferase gene can affect working memory performance and neuronal activation.