Extended-Interval Theta Burst Stimulation Enhances Glutamatergic Plasticity and Antidepressant Effects via Reduced GABAergic Recruitment

Abstract

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. HighlightsO_LIInter-train interval (ITI) controls excitatory-inhibitory balance during theta burst stimulation C_LIO_LIShort ITIs strongly activate PV interneurons limiting longer-term changes in glutamatergic excitatory plasticity C_LIO_LIExtended ITI (20s in particular) reduces inhibitory activity while maintaining sufficient activation of glutamatergic neurons to promote post-stimulation plasticity C_LIO_LIeTBS produces rapid and durable antidepressant-like effects that are blocked by GABAergic co-activation C_LI Graphical AbstractInter-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. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/608693v3_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15a7decorg.highwire.dtl.DTLVardef@1220forg.highwire.dtl.DTLVardef@63258forg.highwire.dtl.DTLVardef@13707e7_HPS_FORMAT_FIGEXP M_FIG C_FIG