Neuroimaging has revolutionized the diagnosis and treatment of brain disorders. It is difficult to imagine treating patients with brain tumors, cerebrovascular disorders or epilepsy without our current arsenal of imaging tools. The confirmation of structural abnormalities in the brains of people with schizophrenia in the 1980s led to excitement that neuroimaging would also lead to novel rational treatments for this syndrome.
Two subsequent decades of neuroimaging research have contributed enormously to our understanding of structural and functional differences between the brains of people with schizophrenia and healthy people. Imaging now offers insights into the mechanisms of action of drugs used to treat schizophrenia, and the genetic mechanisms that may be at the root of these disorders. Still, there is no "smoking gun" that marks pathophysiology, and imaging protocols to optimize treatment are not ready for clinical practice.
On the one hand, it is critical to recognize the current limitations of these methods for clinical practice. On the other hand, it is important for optimism to be sustained and solid research completed to advance these dramatic methods from the "bench" to the "bedside." We attempt to summarize both key challenges and promising leads from current research.
Phantom Syndrome
Schizophrenia's listing in the DSM-IV conveys a sense of authenticity that belies the lack of hard evidence for a unitary disease entity underlying this complex syndrome. It has long been acknowledged that the likely pathophysiological and etiological heterogeneity of schizophrenia pose major challenges to research and treatment. While it is clear that schizophrenia has a 10-fold increased risk among first-degree relatives of affected patients, concordance is only 50% in monozygotic twins. Furthermore, repeated replication failures in genetic linkage and association studies highlight the virtually certain polygenic substrates of the syndrome. Thus, it is illogical that neuroimaging should serve a diagnostic role or guide specific treatment regimens for the phenotype of schizophrenia per se. Instead, imaging tools will hopefully help dissect the contributions of multiple pathophysiological processes that increase vulnerability, and identify patterns of impaired and preserved neural system function.
This brief overview focuses only on selected structural and functional imaging modalities (the latter narrowly defined to encompass activation imaging and molecular imaging). Activation imaging examines brain metabolism, blood flow or blood oxygenation, either at rest or in response to specific cognitive or pharmacological challenges. Molecular imaging examines the uptake and clearance of specific tracers, generally by their binding to key molecules of interest--usually receptors, transporters or other cellular proteins.
We have not considered a diversity of other methods that may hold great promise. There is a unique and still largely untapped potential of magnetic resonance imaging (MRI) and spectroscopy (MRS). So far, MRI has focused largely on proton imaging. Even proton imaging has generally focused on a subset of possible contrast phenomena, leaving unexamined other biophysical properties of brain. Diffusion effects are now being examined, but magnetization transfer studies are rare. There are very few studies of other nuclear species (including sodium and carbon), and great opportunities to expand the use of MRS to study metabolic processes and drug effects (most studies have focused on a limited set of metabolites, often with low resolution, in the proton or phosphorus spectra). We also do not cover electrophysiological imaging approaches, including electroencephalography (EEG), event-related potentials (ERP) and magnetoencephalography (MEG). Event-related protocol studies have a very strong track record in schizophrenia research. Indeed one of the most consistent findings in people with schizophrenia is an abnormality in a specific ERP (the P300) that is normally generated in response to deviations in repetitive sensory stimulation (Ford, 1999).
