Functional brain imaging: twenty-first century phrenology or psychobiological advance for the millennium?

For those of us interested in neurochemical pathology of the major neuropsychiat-ric disorders—including schizophrenia, affective disorders, Alzheimer's disease and other dementias, and the addictions—the last several years have witnessed a marked paradigm shift. From reliance on animal models of psychopathology with all of their shortcomings (1) to the neuroendocrine window strategy with its pitfalls (2) to post-mortem studies with their inherent difficulties (3), the field has evolved to the use of multidisciplinary techniques, of which functional brain imaging represents one of the most promising yet least understood. This issue of the Journal contains three reports of research that used two functional brain imaging techniques, positron emission to-mography (PET) and magnetic resonance spectroscopy (MRS). These two techniques, together with functional magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT), constitute the " big four " of functional brain imaging modalities most commonly used today. Below we briefly review the strengths and weaknesses of each of these techniques, their great promise for research in psychiatry , and how the reports contained in this issue advance their respective fields. PET and the related SPECT represent planar radiometric functional imaging techniques. Both use the intravenous or inhalational administration of radiopharmaceuti-cals and detectors specialized for localizing photons (gamma rays) emitted by positron annihilation to support neurophysiologic, neuroreceptor, and neurochemical imaging. Neurophysiologic imaging refers to the use of cerebral blood flow radiotracers (15 OH 2 , [ 15 O]butanol, C 15 O 2 , 133 Xe, [ 99m Tc]HMPAO) or metabolic radiotracers ([ 18 F]fluorodeoxyglucose) to spatially resolve the hemodynamic and metabolic correlates of neural circuit activity. The metabolic costs of synaptic transmission are high and relate largely to adenosine triphosphate (ATP) consumption in support of the ion pump activity that drives sodium and potassium gradients across neuronal membranes. Functional imaging of brain activity using PET or SPECT actually involves the localization of changes in oxygen and glucose utilization for ATP synthesis by oxida-tive glycolysis, which is correlated very highly with neuronal activity. Neuroreceptor imaging refers to the use of PET or SPECT radionuclides bound to ligands possessing a high and selective affinity for neurotransmitter receptors or transporters. Tracer kinetic models are used to convert local positron annihilations into estimates of receptor or transporter density, distribution, or occupancy. Neurochemical imaging refers to the use of PET or SPECT radionuclides bound to precursors (e.g., DOPA) of enzymatic reactions that support neurotransmitter synthesis. Functional MRI refers …