limitations exist because practical and ethical considerations preclude using fMRI in conjunction with other powerful techniques that have been developed for use in studies of nonhuman species. Two of the most salient examples illustrate the point.
First, manipulation of the genome (i.e., creation of transgenic animals) and subsequent controlled expression of specific genes are becoming extremely valuable tools for assessing the functional contributions of specific cells, subcellular components and signaling pathways (see Picciotto, 1999, for a review). Methods of this type are now applied routinely using germ-line transgenic manipulations in mice, and their enormous relevance to research on the aging brain is only hinted at by recent highly publicized demonstrations that gene-induced alterations of neurotransmitter receptor concentrations has a marked influence on learning and memory (e.g., Mayford et al., 1996; Tang et al., 1999). To completely understand the underlying mechanisms and implications of such findings, brains that have been functionally altered will be probed using many standard anatomical and physiological techniques. To that list of techniques we can now add fMRI, which can be applied to rodents with very high spatial resolution, and which offers a view of global changes in brain organization and function that result from genetic manipulations.
In the near future it will also be possible to extend this genetic approach to other species, including nonhuman primates, by exploiting the capacity of genetically engineered viruses to introduce novel genes into the brains of adult animals. Moreover, this pairing of techniques from molecular biology and functional imaging will provide a powerful means to investigate both the contributions of specific cells or cellular components to age-related changes in brain function and to evaluate genetic intervention as a means to influence the course of such changes. None of this research can be performed using humans as subjects.
A second realm in which great potential exists for using fMRI in conjunction with other methods is single-and multiunit electrophysiology in nonhuman primates. The technology for this type of physiology, which is often profitably coupled with behavioral analysis, has evolved over the past 40 years to become a preeminent experimental approach in the field of cognitive neuroscience (e.g., Hubel, 1988). Its applications in the field of aging research are few to date, but when combined with fMRI in nonhuman primates, this approach promises to tie functional imaging data on age-related changes in the brain to a firm foundation of cellular physiology. The next section focuses specifically on this potential, considering the likely gains from it and how it can be realized.