Although there has been an increase in the clinical use of TMS for a variety of conditions, the neurobiological mechanisms responsible for the effects of rTMS remain poorly understood. As a starting point aimed at informing intervention studies on neurocognitive aging, we conducted a genome-wide microarray analysis examining the effects of rTMS on cortical gene expression in young and aged rats. Microdissected parietal cortex and hippocampal samples from young mature (6 mos.) and aged (24 mos.) male Long-Evan rats were analyzed using Agilent whole rat genome microarrays, 48 hours after rTMS. A total of 16 animals were examined: 4 young/stimulated, 4 young/sham, 4 aged/stimulated, 4 aged/sham. rTMS was implemented using a MagStim rapid stimulator and a 70mm figure-of-eight coil centered over the dorsal hippocampus and overlying neocortex. Rats were anesthetized (dexmedetomidine, 0.03 and 0.035 mg.kg-1 aged and young animals, respectively) and received intermittent theta burst stimulation (iTBS); 600 pulses applied as bursts of 3 pulses (50Hz) repeated at 5Hz as 20 trains of 2s repeated at intervals of 10s. This pattern was repeated 5 times at 15 min intervals. Stimulus strength was individually adjusted, just below the threshold for evoking visible neck muscle activity (11-20% machine power). Initial results indicate that iTBS potently affects cortical gene expression, and that the specific pattern of effects differs substantially in young and aged rats, with limited overlap between the two groups. We identified over 300 genes differentially expressed after rTMS relative to sham, including many implicated in disorders for which TMS is being tested clinically, including: Alzheimers disease (SORL1, ADAM17, KLK6), Parkinsons (NR4A2, TFEB, ATP1A3), epilepsy (GRIN2D, ATP1A3, MEF2C, FLNA, HCN2), depression (ATP1A3, NR4A2, HTR2C), drug abuse (FMO1, BMP7, GABRG1, NR4A3), and schizophrenia (HTRC2, GRIN2D, NR4A2). The results also indicate that high frequency stimulation induces complex changes in gene expression differentially in young and aged rats, including changes related to synaptic plasticity, neuronal activity, and neurogenesis, among others. These findings will be reported at this year's annual Society for Neuroscience meeting. Defining the effects of aging on the gene expression response to TMS represents an important step toward informed clinical translation.
