Less might be more: Conduction failure as a factor possibly limiting the efficacy of higher frequencies in rTMS protocols

Introduction: rTMS has been proven effective in the treatment of neuropsychiatric conditions, with class A (definite efficacy) evidence for treatment of depression and pain (Lefaucheur et al., 2014). The efficacy in stimulation protocols is, however, quite heterogeneous. Saturation of neuronal firing by HFrTMS without allowing time for recovery may lead to neuronal response failures (NRFs) that compromise the efficacy of stimulation with higher frequencies. Objectives: To examine the efficacy of different rTMS temporal stimulation patterns focusing on a possible upper stimulation limit related to response failures. Protocol patterns were derived from published clinical studies on therapeutic rTMS for depression and pain. They were compared with conduction failures in cell cultures. Methodology: From 57 papers using protocols rated class A for depression and pain (Lefaucheur et al., 2014) we extracted Inter-train interval (ITI), average frequency, total duration and total number of pulses and plotted them against the percent improvement on the outcome scale. Specifically, we compared 10 Hz trains with ITIs of 8 s (protocol A) and 26 s (protocol B) in vitro on cultured cortical neurons. Results: In the in vitro experiments, protocol A with 8-s ITIs resulted in more frequent response failures, while practically no response failures occurred with protocol B (26-s intervals). The HFrTMS protocol analysis exhibited no significant effect of ITIs on protocol efficiency. Discussion: In the neuronal culture, longer ITIs appeared to allow the neuronal response to recover. In the available human dataset on both depression and chronic pain, data concerning shorter ITIs is does not allow a significant conclusion. Significance: NRF may interfere with the efficacy of rTMS stimulation protocols when the average stimulation frequency is too high, proposing ITIs as a variable in rTMS protocol efficacy. Clinical trials are necessary to examine effect of shorter ITIs on the clinical outcome in a controlled setting.