Preclinical experimental efforts in this project have thus far centered primarily on the cell biological and behavioral effects of TMS in our established rat model of neurocognitive aging. A key theme emerging from this work is that the response to TMS for both neurobiological and behavioral read-outs is critically dependent on age and cognitive status. In a current study, young and aged rats were initially characterized on a standard water maze task, followed weeks later by assessment on a second, implicit test of hippocampal memory, i.e., olfactory recognition. In the sample phase of this procedure, animals are presented with two identical odorants in an open field, and memory is tested 24 hours later, measured as the proportion of exploratory activity directed to the repeated presentation of the sample relative to exploration of a novel odorant. In the present experiment, roughly half the rats in each group received a bout of intermittent theta burst TMS shortly after the sample presentation, and the remainder were sham treated controls. Performance on the subsequent retention test was variable and between group comparisons generally were not statistically different. Nonetheless, the overall pattern of task performance differed substantially as a function of cognitive status. Specifically, for rats in the sham TMS condition, young and aged animals with normal spatial learning in the water maze also displayed significant 24-hour retention of odor memory, whereas aged rats with spatial memory impairment failed to exhibit reliable odor recognition. In contrast, the orthogonal pattern was observed in aged rats that received TMS in the immediate post sample period, i.e., aged rats with intact spatial memory displayed no odor recognition, whereas aged animals with water maze deficits exhibited odor recognition comparable to young subjects. Ongoing analysis in this project is aimed at identifying the neurobiological effects of TMS that might mediate the cognitive response to treatment. The significant implication of our interim findings for clinical translation, however, is that individual differences in neurocognitive status can critically dictate the response to non-invasive brain stimulation, and by extension, that protocols with documented efficacy in young adults might have unexpected outcomes in the context of Alzheimer pathogenesis or other neurodegenerative conditions.
