T116. Where less is more: Conduction failures may limit the upper frequency in rTMS induced plasticity and in cell culture data

Introduction: Repetitive transcranial magnetic stimulation (rTMS) has been found to be a promising noninvasive therapeutic tool for a variety of neuropsychiatric conditions. Therapeutic utility of rTMS was classified to have class A evidence for treatment of depression and chronic pain. In different stimulation protocols intervals have been introduced between high frequency (HF) trains for safety concerns and other practical reasons, which might affect efficacy of rTMS therapy. Method(s): To examine effects of temporal patterns of rTMS beyond stimulation frequency in its classical sense on efficacy of rTMS. Invitro neuronal cultures were used to compare between protocols used by Herwig et al. (2007) (Protocol A) and O'Reardon et al. (Protocol B). Both used 10 Hz but with different parameters such as inter-train interval (ITI) and average stimulation frequency per minute resulting in different outcome. To test the hypothesis that intervals between rTMS trains can affect their therapeutic efficacy, we extracted the data from 57 papers on clinical trials about depression and chronic pain discussed in Lefaucheur et al. (2014). The inter-train interval (ItI) and average frequency, defined as a ratio of total pulse number to the entire duration of a single rTMS session, were plotted against the percentage improvement of the outcome scale, which was the Hamilton Depression Scale for depression and Visual analog scale for the chronic pain. To augment the analysis, in vitro experiments were conducted on cultured cortical neurons that were functionally isolated from their network using a cocktail of synaptic blockers. 10 Hz Trains were applied with ITI of 8 s: protocol (A) and 26 s: protocol (B). Result(s): HFrTMS protocols using ITI < 20 s were less effective in comparison to longer ITI in depression and pain as well as accordingly average frequencies < 1.3 Hz showing better results. The in vitro experiments comparing protocol (A) lead to a substantial fraction of response failures, while in protocol (B) practically no response failures occur. This difference is attributed to the longer ITI, 26 s, in protocol (B). Conclusion(s): Saturation of neuronal firing by HFrTMS without allowing some time for recovery may lead to neuronal response failures (NRFs) compromising the efficacy of higher frequency stimulation. Longer ITIs would allow the neurons to recover from the NRF. Significance: The efficacy of rTMS stimulation protocols may be impaired under too high average stimulation frequency because of conduction failures.