The Effects of Waveform and Current Direction on the Efficacy and Test–Retest Reliability of Transcranial Magnetic Stimulation

•Different TMS pulse parameters (waveforms and current directions) interact with specific neural cortical components.•The influence of TMS pulse parameters on the efficacy and reliability of TMS measures has not been sufficiently studied.•The results show that waveform/current direction significantly influences the efficacy and reliability of TMS protocols.•Monophasic pulses induce greater and more reliable inhibition in LICI and SICI.•TMS pulses with an anterior–posterior component induce greater ICF, with biphasic pulses resulting in more reliable ICF. The pulse waveform and current direction of transcranial magnetic stimulation (TMS) influence its interactions with the neural substrate; however, their role in the efficacy and reliability of single- and paired-pulse TMS measures is not fully understood. We investigated how pulse waveform and current direction affect the efficacy and test–retest reliability of navigated, single- and paired-pulse TMS measures. 23 healthy adults (aged 18–35 years) completed two identical TMS sessions, assessing resting motor threshold (RMT), motor-evoked potentials (MEPs), cortical silent period (cSP), short- and long-interval intra-cortical inhibition (SICI and LICI), and intracortical facilitation (ICF) using either monophasic posterior–anterior (monoPA; n = 9), monophasic anterior–posterior (monoAP; n = 7), or biphasic (biAP-PA; n = 7) pulses. Averages of each TMS measure were compared across the three groups and intraclass correlation coefficients were calculated to assess test–retest reliability. RMT was the lowest and cSP was the longest with biAP-PA pulses, whereas MEP latency was the shortest with monoPA pulses. SICI and LICI had the largest effect with monoPA pulses, whereas only monoAP and biAP-PA pulses resulted in significant ICF. MEP amplitude was more reliable with either monoPA or monoAP than with biAP-PA pulses. LICI was the most reliable with monoAP pulses, whereas ICF was the most reliable with biAP-PA pulses. Waveform/current direction influenced RMT, MEP latency, cSP, SICI, LICI, and ICF, as well as the reliability of MEP amplitude, LICI, and ICF. These results show the importance of considering TMS pulse parameters for optimizing the efficacy and reliability of TMS neurophysiologic measures.