many other phenomena of tissue remodeling. In other words, because of such changes, the correlation between MR signal and neuronal activity may change as a function of age. A potential consequence of this confound is the possibility that an MR signal seen in a 20-year-old human may have an altogether different neuronal origin than the same signal in a 60-year-old, which—if unrecognized—could have profound implications for research and clinical diagnosis. fMRI in nonhuman primates offers a means to eliminate this confound. Specifically, by evaluating the correlation between the MR signal and neuronal response (outlined above) as a function of age, it should be possible to establish ''normalization factors" that can be used to appropriately compare MR signals across different age groups.

In addition to their use for data normalization, any observed age-related changes in the MR-neuronal response correlation may be of interest in their own right. Such changes may be indicative of a decline in the metabolic requirements of specific cell groups and could perhaps be diagnostic of early age-related loss of function. Data informative of the correlation between MR signal and the activity of specific cell populations can be obtained only in nonhuman species.

Use of fMRI Signals to Guide and Evaluate Manipulation/Intervention Studies

Because fMRI reflects neuronal activity with good spatial and temporal precision, it promises to be a valuable tool for the identification and characterization of age-related loss of function and specific brain pathologies. Once age-related neuronal changes are detected, experiments can be designed to address hypotheses about their origins or to evaluate intervention intended to promote recovery—in each case using the characterized MR signal as a dependent measure. For example, one might use the MR signal as a means to evaluate the effects of estrogen administration on the activity of specific cell groups as a function of age. Perhaps the most exciting and promising prospect in this domain is the use of genetic manipulations (i.e., creation of transgenic animals and selective expression of novel genes in targeted cell populations) to alter cell signaling, metabolism, or firing rate in a precisely targeted manner, with the goal of promoting recovery from selective age-related loss of function. As indicated above, genetic manipulations of this type will soon be possible in nonhuman primates using genetically engineered viruses for introduction of novel genes. As a dependent measure, the MR signal can provide a repeated and highly localized assessment of the effects of such manipulations on brain function. Perhaps one day successful interventions can be employed in humans. At the present time, nonhuman primates provide an ideal model for studies of this type.

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