Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits

Abstract

Anatomical, physiological, and functional connectivity exists between the neurons of the primary motor cortex (M1) and spinal cord. Paired associative stimulation (PAS) produces enduring changes in M1, based on the Hebbian principle of associative plasticity. The present study aimed to establish neurophysiological changes in human cortical and spinal neuronal circuits by pairing noninvasive transspinal stimulation with transcortical stimulation via transcranial magnetic stimulation (TMS). We delivered paired transspinal and transcortical stimulation for 40 min at precise interstimulus intervals, with TMS being delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Transspinal-transcortical PAS markedly decreased intracortical inhibition, increased intracortical facilitation and M1 excitability with concomitant decreases of motor threshold, and reduced the soleus Hoffmann's reflex (H-reflex) low frequency-mediated homosynaptic depression. Transcortical-transspinal PAS did not affect intracortical circuits, decreased M1 excitability, and reduced the soleus H-reflex-paired stimulation pulses' mediated postactivation depression. Both protocols affected the excitation threshold of group Ia afferents and motor axons. These findings clearly indicate that the pairing of transspinal with transcortical stimulation produces cortical and spinal excitability changes based on the timing interval and functional network interactions between the two associated inputs. This new PAS paradigm may constitute a significant neuromodulation method with physiological impact, because it can be used to alter concomitantly excitability of intracortical circuits, corticospinal neurons, and spinal inhibition in humans.

Keywords: H-reflex; PAS; TMS; motor cortex; spinal cord; transspinal stimulation.

Copyright © 2016 the American Physiological Society.

Figures

Fig. 1.

Paired associative stimulation (PAS) protocol. A: simplified illustration of transcranial magnetic stimulation (TMS volley) and transspinal stimulation-mediated volleys upon paired pulses. Note that TMS volleys are descending, whereas transspinal stimulation-mediated volleys are orthodromic and antidromic and can reach both brain hemispheres as transspinal stimulation alone evokes transspinal-evoked potentials in nearly all leg muscles bilaterally. PAS was delivered at timings during which corticospinal neurons, activated via TMS, arrived at the corticospinal neuron before spinal motoneurons were activated transynaptically by the transspinal stimulation (transcortical-transspinal PAS) and during which transspinal-mediated, ascending volleys arrived at the cortex before TMS was delivered over M1 (transspinal-transcortical PAS). B: electromyography (EMG) recordings from the right tibialis anterior (TA) muscle upon transspinal stimulation alone, TMS alone, and during transspinal-transcortical PAS and transcortical-transspinal PAS. During transspinal-transcortical PAS, a clear separation of motor- and transspinal-evoked potentials (MEPs and TEPs, respectively) is possible based on their associated latencies and durations, whereas summation of TA MEPs and TEPs in the surface EMG is evident at the interstimulus used to deliver transcortical-transspinal PAS. S20B and S22A, subjects 20B and 22A, respectively.

Fig. 2.

Intracortical measures before and after transspinal-transcortical PAS. A: nonrectified waveform averages of conditioned tibialis anterior motor-evoked potentials (TA MEPs) by subthreshold transcranial magnetic stimulation (TMS) from 2 subjects, before (gray lines) and after (red lines) transspinal-transcortical PAS. B: overall amplitude of TA MEPs conditioned by subthreshold TMS from all subjects. C: mean raw amplitude of control TA MEPs recorded before and after PAS. auc, area under curve. Error bars indicate SE; *P < 0.05.

Fig. 3.

Intracortical measures before and after transcortical-transspinal PAS. A: nonrectified waveform averages of conditioned tibialis anterior motor-evoked potentials (TA MEPs) by subthreshold transcranial magnetic stimulation (TMS) from 2 subjects before (gray lines) and after (red lines) transcortical-transspinal PAS. B: overall amplitude of TA MEPs conditioned by subthreshold TMS from all subjects. C: mean raw amplitude of control TA MEPs recorded before and after PAS. Error bars indicate SE.

Fig. 4.

Corticospinal excitability before and after PAS. A and B: tibialis anterior motor-evoked potential (TA MEP) recruitment curves from all subjects before (open circles) and after (solid circles) transspinal-transcortical and transcortical-transspinal PAS, respectively. The pool data are normalized to the maximal MEP (MEPmax) size and plotted in multiples of stimulation intensities corresponding to 50% MEPmax; a sigmoid fit to the data is also shown. Analysis showed a significant effect of time for the transspinal-transcortical PAS with increased MEP sizes from 0.9 to 1.2 50% MEPmax and decreased MEP sizes at 1.3 50% MEPmax for the transcortical-transspinal PAS. *P < 0.05 is indicated as arrows.

Fig. 5.

Spinal excitability before and after PAS. A–D: soleus M-wave and H-reflex recruitment curves from all subjects before (open circles) and after (solid circles) transspinal-transcortical and transcortical-transspinal PAS. The pool data illustrated in A–D are normalized to the homonymous maximal M-wave (Mmax) and are plotted in multiples of stimulation intensities corresponding to 50% of the Mmax. E and F: the soleus H-reflex recruitment curves were assembled from stimulation intensities in which H-reflexes were absent until they reached maximal amplitudes, with the sigmoid function fitted before (open circles) and after (solid circles) transspinal-transcortical and transcortical-transspinal PAS, indicated with H-reflexes plotted against stimulation intensities and grouped based on motor threshold (MT) observed both before and after PAS.

Fig. 6.

Spinal inhibitory measures before and after PAS. A and B: soleus H-reflex sizes as a percentage of the homonymous Mmax from all subjects before (open circles) and after (solid circles) transcortical-transspinal and transspinal-transcortical PAS, recorded at different stimulation frequencies and in response to paired stimulation pulses at interstimulus intervals of 100 and 50 ms at 0.2 Hz. Soleus H-reflexes, recorded at 0.2 Hz before and after PAS at exactly the same stimulation intensities (insets 1 and 2), illustrate that a clear shift in the recruitment order of Ia afferents (inset 3) occurred after both PAS protocols. Error bars represent SE; *P < 0.05.