Optimized Theta Burst Stimulation with Extended Intervals Enhances Excitatory-Inhibitory Balance
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Abstract
Summary Intermittent Theta Burst Stimulation (iTBS) is a patterned stimulation protocol FDA-cleared to treat depression, yet its outcomes are variable and mechanistically unclear. Here, using a combination of calcium imaging, histology, optogenetics and behavior, we show that one parameter of iTBS, the inter-train interval (ITI) between stimulation trains, plays a critical role in modulating GABAergic (and especially parvalbumin) neuronal activity, modulating subsequent neuronal plasticity and antidepressant effects. Shorter ITI stimulation protocols (4-10Ssinter-train intervals) activate GABA neurons, limiting resulting changes in cortical excitability and plasticity compared to extended interval TBS protocols (eTBS, with a 20s ITI). eTBS also drives the largest changes in synaptic / spine plasticity and leads to rapid and durable antidepressant-like effects after only a single stimulation session. Optogenetic activation of GABAergic neurons during eTBS blocks synaptic plasticity and rapid antidepressant effects. Together, these findings reveal a temporal control principle for TBS-induced cortical plasticity and provides a physiology-based strategy to improve TBS efficacy. Highlights Inter-train interval (ITI) controls excitatory-inhibitory balance during theta burst stimulation Short ITIs strongly activate PV interneurons limiting longer-term changes in glutamatergic excitatory plasticity Extended ITI (20s in particular) reduces inhibitory activity while maintaining sufficient activation of glutamatergic neurons to promote post-stimulation plasticity eTBS produces rapid and durable antidepressant-like effects that are blocked by GABAergic co-activation Graphical Abstract Inter-train interval (ITI) determines the balance between excitation and inhibition during theta burst stimulation (TBS), an FDA-cleared treatment for depression. (A) Short ITIs (4s) drive concurrent glutamatergic and GABAergic activation, with inhibitory dominance during stimulation and suppressed long-term modulation of excitability. Extending the ITI to 20s (eTBS) reduces GABAergic recruitment during stimulation, promoting sustained long-term glutamatergic modulation resulting cortical disinhibition, leading to rapid and durable antidepressant-like effects (B) . Optogenetic activation of GABAergic interneurons during eTBS abolishes synaptic and antidepressant effects, demonstrating that reduced inhibitory recruitment during eTBS is required for the rapid and durable behavioral effects observed with that protocol.
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Graphical Abstract
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.
Summary 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.
Highlights Systematic manipulation of inter-train intervals (ITIs) reveals an optimal 20s ITI for TBS-induced plasticity.
Extended ITIs enhance excitability in glutamatergic neurons while suppressing GABAergic activity.
PV interneurons are preferentially recruited during short-interval TBS, limiting sustained plasticity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This version includes additional data on non-stimulated sham animals, expanded analysis of GABAergic neurons across experimental groups, and new histological evidence characterizing excitatory and inhibitory cellular responses to acute stimulation. These additions strengthen the interpretation of stimulation-induced network dynamics.
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- last seen: 2026-05-20T01:45:00.602351+00:00