Kavli Affiliate: Dhakshin Ramanathan and Jyoti Mishra
| Authors: Morteza Salimi, Milad Nazari, Jonathan Mishler, Jennifer Rodger, Sahar Jomehpour, Jyoti Mishra and Dhakshin Ramanathan
| Summary:
Varying inter-train intervals (ITIs) during theta burst stimulation (TBS) differentially modulates neuronal activity in the medial prefrontal cortex. Short ITIs (e.g., ITI 4 s) induce strong glutamatergic excitation but fail to induce long-term changes post-stimulation. By contrast, an extended ITI of 20 seconds (eTBS, green star) optimally enhances long-term excitability in glutamatergic neurons while suppressing GABAergic interneurons, indicating a shift in excitation-inhibition balance that promotes cortical plasticity. Electrical theta burst stimulation (TBS) with different inter-train intervals (ITIs) was first used to characterize bidirectional synaptic plasticity in brain slices. Despite a lack of understanding of mechanism, TBS has been adopted by rTMS research and clinical protocols to drive plasticity in the human brain, with variable results. To uncover how TBS modulates excitability in vivo, we systematically screen the impact of electrical TBS with different ITIs on rodent cortical neurons. Short inter-train intervals (4-10s) increased calcium activity in both glutamatergic and GABAergic neurons during stimulation, whereas extended ITIs (20s) yielded modest but significant activation of glutamatergic cells and minimal activation of GABAergic cells. TBS with an ITI of 20s emerged as a plasticity “sweet spot” that maximized long-term activation of glutamatergic neurons, potentially through suppression of GABAergic neurons(1–3). Translating our novel iTBS electrical stimulation protocol to rTMS interventions has the potential to deliver heightened plasticity and improved therapeutic outcomes.