P124 Computational Prediction and Empirical Validation of Enhanced LTP Effects with Gentle iTBS Protocols
Kevin Kadak*1,2, Davide Momi1, Zheng Wang1, Sorenza P. Bastiaens1,2, Mohammad P. Oveisi1,3, Taha Morshedzadeh1,2, Minarose Ismail1,4, Jan Fousek5, and John D. Griffiths1,2,6 1Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto. 2Institute of Medical Sciences, University of Toronto 3Institute of Biomaterials and Biomedical Engineering, University of Toronto 4Department of Physiology, University of Toronto 5Central European Institute of Technology, Czech Republic 6Department of Psychiatry, University of Toronto *Email: kevin.kadak@mail.utoronto.ca Introduction
TMS is an established neuromodulatory technique for inducing and assessing cortical excitability changes. Intermittent theta-burst stimulation (iTBS), mimicking endogenous neural activity, yields clinical efficacy comparable to traditional protocols but with significantly shorter treatment durations [1,2]. Despite widespread use for depression treatments, iTBS suffers from high inter-subject response variability. We developed a computational model integrating calcium-dependent plasticity within corticothalamic circuitry to predict optimal iTBS parameters, subsequently validating these predictions through empirical testing of motor-evoked potentials (MEPs) across novel and canonical protocols.
Methods Our computational model simulated iTBS-induced plasticity effects following 600 pulses in corticothalamic circuitry by varying pulse-burst ratios and inter-burst frequency parameters. We then conducted a mixed-measure experimental paradigm testing standard (Protocol A) and four novel iTBS protocols (B-E; 2-5 pulse-burst, 3-7 Hz). MEPs were recorded pre-stimulation (PRE) and post-stimulation (POST1, POST2) to assess induced plasticity effects. Mixed-effects modelling was performed to analyze group-level effects and response rates. Results Our model predicted that gentler stimulation protocols characterized by lower pulse-burst ratios and targeted inter-burst frequencies would maximize long-term potentiation (LTP) effects while reducing response variance. Empirical results confirmed these predictions, with Protocol C (3 pulses/burst, 3 Hz) capturing the highest response rate (60% vs 47% for standard iTBS) and Protocol B (2 pulses/burst, 5 Hz) driving the strongest LTP effects among responders. Notably, protocols with frequencies aligned to participants' alpha subharmonics further modulated plasticity effects in Protocol B, while higher-frequency protocols (Protocol D, 7 Hz) initially induced LTD, which later inverted to LTP. Discussion Our findings demonstrate that gentler protocols outperform standard iTBS in driving consistent LTP effects, with efficacy further modulated by resonance between stimulation frequency and endogenous alpha subharmonics. This research highlights an important mechanistic basis for induced plasticity effects pertaining to protocol intensity whereby lower intensity protocols appear to better engage neuroplasticity mechanisms and mitigate metaplastic saturation. We provide a mechanistic framework and empirical validation for enhancing LTP protocols and improving clinical outcomes in TMS treatments for neuropsychiatric disorders.
