Bayesian Dose-Finding for Theta Burst Stimulation Tolerability: A Randomized Study Comparing Intermittent and Continuous Protocols at Distinct Prefrontal Targets
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Background
Theta burst stimulation (TBS) is an efficient form of repetitive transcranial magnetic stimulation, but tolerability may depend on target and stimulation pattern, limiting translation to accelerated protocols.
Objective
To estimate tolerable intensities for intermittent TBS (iTBS) over F3, approximating left dorsolateral prefrontal cortex, and continuous TBS (cTBS) over Fp1, intended to engage more anterior ventral/frontopolar circuitry, in non-treatment-seeking adults with obesity or tobacco use disorder.
Methods
In an open-label randomized crossover titration study, 64 adults completed two TBS visits 7 days apart. Each visit included 3 sessions of 600 pulses, beginning at 80% resting motor threshold (RMT) with protocol-permitted escalation or de-escalation. The primary endpoint was participant-level maximum final maintained intensity. Bayesian grouped-binomial logistic regression estimated the intensity tolerated by 70% of participants (ED 70 ), and a prespecified rule selected the highest dose with at least 80% posterior probability of meeting 70% tolerability.
Results
Observed tolerability at 80% RMT was 86.4% for iTBS and 51.6% for cTBS. Primary-model ED 70 was 105.5% RMT (95% credible interval [CrI], 99.0%-113.9%) for iTBS and 69.2% RMT (95% CrI, 65.0%- 73.4%) for cTBS. The recommended intensity was 100% RMT for iTBS and 60% RMT for cTBS; no cTBS dose at or above 80% RMT met criterion. cTBS produced greater immediate symptom burden, whereas 24-hour symptoms were uncommon.
Conclusion
iTBS over F3 supported a future-trial design window of 90%-100% RMT, whereas cTBS over Fp1 showed a tolerability ceiling below 80% RMT. Future cTBS protocols targeting ventral prefrontal circuitry may need to move dorsally to improve tolerability.
