Increasing the frequency of peripheral component in paired associative stimulation strengthens its efficacy

Aleksandra Tolmacheva, Jyrki P Mäkelä, Anastasia Shulga, Aleksandra Tolmacheva, Jyrki P Mäkelä, Anastasia Shulga

Abstract

Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS), is emerging as a promising tool for alleviation of motor deficits in neurological disorders. The effectiveness and feasibility of PAS protocols are essential for their use in clinical practice. Plasticity induction by conventional PAS can be variable and unstable. Protocols effective in challenging clinical conditions are needed. We have shown previously that PAS employing 50 Hz PNS enhances motor performance in chronic spinal cord injury patients and induces robust motor-evoked potential (MEP) potentiation in healthy subjects. Here we investigated whether the effectiveness of PAS can be further enhanced. Potentiation of MEPs up to 60 minutes after PAS with PNS frequencies of 25, 50, and 100 Hz was tested in healthy subjects. PAS with 100 Hz PNS was more effective than 50 (P = 0.009) and 25 Hz (P = 0.016) protocols. Moreover, when administered for 3 days, PAS with 100 Hz led to significant MEP potentiation on the 3rd day (P = 0.043) even when the TMS target was selected suboptimally (modelling cases where finding an optimal site for TMS is problematic due to a neurological disease). PAS with 100 Hz PNS is thus effective and feasible for clinical applications.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Paired associative stimulation protocol. (A) The single TMS pulse, delivered once every 5 s, is synchronized at the spinal level with the first pulse of the PNS train, which consists of 6 pulses delivered at 25, 50, or 100 Hz. (B) Five selected sites in the M1 in Experiment 2 in a representative subject. The hotspot of the target muscle (AH) is in the center; four surrounding sites placed equidistant from the central site form a square and represent suboptimal sites of the target muscle. (C) PAS setup.
Figure 2
Figure 2
PAS/100 Hz is the most effective in potentiating MEPs. (A) MEP potentiation (post-PAS normalized to pre-PAS minus 100%) induced by protocols utilizing PNS of 25, 50, and 100 Hz and control PNS of 100 Hz measured immediately after, 30 min, and 60 min after the stimulation. Data are presented as mean ± s.e.m. (n = 10 subjects). (B) MEP potentiation induced by PAS/100 Hz in individual subjects in Experiment 1. MEPs were measured before and after PAS. MEP potentiation was induced in all 10 subjects. (C) The average of 30 MEPs in a representative subject before and after PAS/100.
Figure 3
Figure 3
PAS/100 Hz induces MEP potentiation in the upper limb. MEP potentiation (post-PAS normalized to pre-PAS minus 100%) induced by PAS/100 Hz to right abductor pollicis brevis (Experiment 1) measured immediately after, 30 min, and 60 min after the stimulation. Data are presented as box plots showing median and 1st and 3rd quartiles (n = 5 subjects).
Figure 4
Figure 4
PAS/100 Hz administered for 3 consecutive days induces MEP potentiation even if a suboptimal cortical stimulation site is selected. MEP potentiation (post-PAS vs pre-PAS) is induced by PAS/100 Hz measured from the suboptimal area and adjacent sites in the M1 in all 5 subjects at the 3rd day of stimulation. Individual MEP potentiation data of the 5 subjects (different line colors) is shown.

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