Transcranial magnetic stimulation (TMS) has proven to be an effective method for examining cortical excitability. One widely used application of TMS involves delivering a large number of TMS pulses over a fixed duration at either a fixed frequency, such as 1Hz or 10Hz (Chen et al., 1997), or using patterned bursts of pulses, like theta burst stimulation (Huang et al., 2005) or Quadripulse stimulation (Hamada et al., 2008). These approaches have demonstrated alterations in cortical excitability lasting up to one hour after the stimulation (Chen et al., 1997; Huang et al., 2005; Hamada et al., 2008). Typically, changes in cortical excitability are assessed by applying repetitive TMS (rTMS) to the motor cortex and subsequently delivering single TMS pulses to evoke motor evoked potentials (MEPs) at specific intervals following the cessation of rTMS. The changes in MEP amplitude relative to a baseline measurement are then analysed to determine the effectiveness of rTMS in modulating cortical excitability.
The effects of rTMS on cortical excitability exhibit considerable variability, with some individuals showing predictable effects, while others display no effect or effects contrary to expectations. For instance, Hamada et al. (2013) demonstrated that the variability in response to continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) is substantial, to the extent that no group-level effect is observed. Various potential explanations exist to account for this variability. One possible factor is the utilisation of a sinusoidal biphasic pulse, which is predominantly employed in these experiments (Goetz et al., 2016). Recently, the Elevate TMS device has allowed researchers to explore the impact of novel pulse shapes within rTMS protocols (Goetz et al., 2016; Halawa et al., 2019). In such investigations, the frequency of rTMS remains constant across protocols, but the pulse shape or width varies, enabling the identification of optimal parameters for inducing changes in cortical excitability.
Adjustable Pulse Shape and Width
Goetz et al. (2016) used the above rTMS protocol to assess their cTMS device. The structure of the session involved an initial excitability probing train that lasted approximately 13 minutes. The train consisted of 80 pulses, comprising equal number of 4 different proving pulse conditions, to establish a baseline. The rTMS intervention was performed, utilising 1 of 4 pulse shapes in a 1 Hz, 1000 pulse train at 97.5% of the rMT. Finally, a corresponding probing train of 180 pulses was applied immediately after the rTMS intervention to quantify excitability changes.
The Elevate transcranial magnetic stimulation (TMS) devices offer the flexibility to modify rectangular pulse shapes, including monophasic or biphasic pulses, with adjustable pulse width. In one study, rTMS was applied at a frequency of 10Hz for 16 minutes, using four different pulse shapes targeted at the motor cortex (Goetz et al., 2016). The results indicated that while all monophasic pulse shapes had lasting inhibitory effects on motor evoked potential (MEP) amplitude, the biphasic pulse shape did not produce a similar effect. Among the monophasic pulses, the most effective in producing offline effects was the semi-monophasic pulse with a posterior-anterior (PA) current flow. These findings suggest that a biphasic pulse may not be optimal for inducing long-lasting changes in cortical excitability.
Another experiment investigated the impact of varying pulse width, while keeping pulse frequency constant, on the offline effect of rTMS on cortical excitability (Halawa et al., 2019). In this study, a monophasic pulse with pulse widths of 40μs, 80μs, or 120μs was used, with 900 pulses delivered at a frequency of 1Hz. The results revealed that pulse width influenced both the direction and magnitude of the offline effect on MEP amplitude. A longer pulse width (120μs) led to an increase in MEP amplitude, while shorter pulse widths (40μs or 80μs) induced an inhibitory effect. Overall, these findings suggest that the presence of an inhibitory or excitatory effect depends on pulse width, while the magnitude of the overall effect is determined by pulse shape, with monophasic pulses inducing a current flow in the anterior-posterior (AP) direction appearing to be the optimal choice.
Furthermore, the effect of pulse shape and pulse width extends to the latency and amplitude of the motor threshold, indicating that different neural populations may be influenced depending on the magnetic pulse shape. Increasing the pulse width has been found to decrease MEP latency with AP currents (D’Ostilio et al., 2016; Halawa et al., 2019), while reducing the amplitude of the second phase of a biphasic pulse (making it more monophasic) reduces the motor threshold (Sommer et al., 2018). Similarly, decreasing the amplitude of the first phase of a biphasic pulse alters the MEP latency (Halawa et al., 2019; Sommer et al., 2018). These changes in MEP amplitude suggest that TMS pulse parameters can selectively target different populations of neurons, offering an opportunity to refine rTMS and single pulse protocols beyond the conventional biphasic sinusoidal waveform typically used in TMS research (Halawa et al., 2019; Sommer et al., 2018).
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.
- Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Chen, R., Classen J. and Gerloff, C., et al. Neurology 48(5): 1398-1403. (1997)
- Effect of coil orientation on strength-duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation. D’Ostilio, K. et al. Clin Neurophysiol 127(1): 675-683. (2016)
- Enhancement of neuromodulation with novel pulse shapes generated by controllable pulse parameter transcranial magnetic stimulation. Goetz, S.M. et al. Brain Stimulation 9(1): 39-47. (2016)
- Neuronal tuning: selective targeting of neuronal populations via manipulation of pulse width and directionality. Halawa, I., Shirota, Y. and Neef, A., et al. Brain Stimulation 12(5): 1244-1252. (2019)
- Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. Hamada, M. et al. J Physiol 586(16): 3927-3947. (2008)
- The role of interneuron networks in driving human motor cortical plasticity. Hamada, M., Murase, N. and Hasan, A., et al. Cereb Cortex 23(7): 1593-1605. (2013)
- Theta burst stimulation of the human motor cortex. Huang, Y., Edwards, M.J. and Rounis, E., et al. Neuron 45(2): 201-206. (2005)
- TMS of primary motor cortex with a biphasic pulse activated two independent sets of excitable neurons. Sommer, M. et al. Brain Stimulation 11(3): 558-565. (2018)
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