Transcranial magnetic stimulation (TMS) has been a successful means of probing cortical excitability. One of the most popular uses of TMS is to apply a large number of TMS pulses for a fixed time period at either a fixed frequency (e.g. 1 Hz, 10 Hz) (Chen et al., 1997) or to apply patterned bursts of pulses such as theta burst stimulation (Huang et al., 2005) or Quadro-pulse stimulation (Hamada et al., 2008). Such approaches have revealed changes in cortical excitability for up to one hour after stimulation (Chen et al., 1997; Huang et al., 2005; Hamada et al., 2008). Usually, a change in cortical excitability is revealed by applying rTMS to the motor cortex and then applying single TMS pulses to the motor cortex to evoke MEPs at certain intervals after the termination of rTMS. The change in MEP amplitude over time relative to baseline is then used to establish whether rTMS has successfully produced changes in cortical excitability.
There is considerable variability in the effects of rTMS on cortical excitability with some subjects showing an effect in a predictable direction but others show either no effect or an effect opposite to what is predicted. For example, Hamada et al. (2013) revealed that the variability in the response to continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) is of such magnitude that no effect is present at the group level. A number of potential explanations exist for why such variability exists. One potential reason is the type of pulse shape that is employed - a sinusoidal biphasic pulse - is almost exclusively used in these experiments (Goetz et al., 2016). Recently, the Elevate TMS device has enabled the effect of novel pulse shapes within rTMS protocols to be investigated (Goetz et al., 2016; Halawa et al., 2019). In such investigations, the frequency of rTMS in each protocol is kept constant but the pulse shape or pulse width within each protocol differs, enabling the optimal parameters for changing cortical excitability to be discovered.
Adjustable Pulse Shape and Width
The Elevate TMS devices enable rectangular pulse shapes, which can be monophasic or biphasic with a variable pulse width to be altered. One experiment applied rTMS at 10 Hz for 16 minutes with four different pulse shapes to the motor cortex (Goetz et al., 2016). Here, all monophasic pulse shapes but not a biphasic pulse shape produced lasting inhibitory effects on MEP amplitude (Goetz et al., 2016). The most successful pulse at producing offline effects was a semi-monophasic pulse with an induced current travelling in the posterior-anterior (PA) direction (Goetz et al., 2016). This evidence suggests that a biphasic pulse may not be optimal for producing a lasting effect on cortical excitability. A different experiment looked at how changing the pulse width whilst keeping pulse frequency constant influenced the offline effect of rTMS on cortical excitability (Halawa et al., 2019). Here, the pulse was monophasic but the pulse width was either 40 μs, 80 μs or 120 μs whilst 900 pulses were delivered at 1 Hz. Here, the pulse width was found to impact the direction and the magnitude of the offline effect on MEP amplitude. When a longer pulse width (120 μs) was used, MEP amplitude increased. However, when shorter pulse widths (40 μs or 80 μs) were used an inhibitory effect was present. Taken together, it appears that the presence of an inhibitory or excitatory effect depends on the pulse width but the magnitude of the overall effect is determined by pulse, with monophasic pulses with induced current travelling in the AP direction appearing to be optimal.
The effect of pulse shape and pulse width also affects the latency and amplitude of the motor threshold, suggesting that different neural populations might be affected depending on the shape of the magnetic pulse. Increasing the pulse width appears to reduce MEP latency with AP currents (D’Ostilio et al., 2016; Halawa et al., 2019) whereas reducing the amplitude of the second phase of the biphasic pulse (making it ‘more monophasic’) reduces the motor threshold (Sommer et al., 2018). Reducing the amplitude of the first phase of a biphasic pulse also appears to change the latency of the MEP (Halawa et al., 2019; Sommer et al., 2018). Such changes in MEP amplitude suggest that different populations of neurons could be selectively targeted by changing TMS pulse parameters (Halawa et al., 2019; Sommer et al., 2018), which can refine rTMS and single pulse protocols by going beyond the conventional biphasic sinusoidal waveform in TMS research.
- Neuronal tuning: Selective targeting of neuronal populations via manipulation of pulse width and directionality. I. Halawa, Y. Shirota, A. Neef, M. Sommer, W. Paulus. Brain Stimulation. October 2019
- TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones. Martin Sommer, Matteo Ciocca, Raffaella Chieffo, Paul Hammond, Andreas Neef, Walter Paulus, John C.Rothwell, Ricci Hannah. Brain Stimulation. June 2018
- Enhancement of Neuromodulation with Novel Pulse Shapes Generated by Controllable Pulse Parameter Transcranial Magnetic Stimulation. Stefan M Goetz, Bruce Luber, Sarah H Lisanby, David L K Murphy, I Cassie Kozyrkov, Warren M Grill, Angel V Peterchev. Brain Stimulation. February 2016
- Effect of coil orientation on strength-duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation. Kevin D'Ostilio, Stefan M Goetz, Ricci Hannah, Matteo Ciocca, Raffaella Chieffo, Jui-Cheng A Chen, Angel V Peterchev, John C Rothwell. Clinical Neurophysiology. January 2016
- The role of interneuron networks in driving human motor cortical plasticity. Masashi Hamada, Nagako Murase, Alkomiet Hasan, Michelle Balaratnam, John C Rothwell. Cerebral Cortex. July 2013
- Theta burst stimulation of the human motor cortex. Ying-Zu Huang, Mark J Edwards, Elisabeth Rounis, Kailash P Bhatia, John C Rothwell
. Neuron. January 2005
- Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. R Chen, J Classen, C Gerloff, P Celnik, E M Wassermann, M Hallett, L G Cohen. Neurology. May 1997
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