Spinal associative stimulation: a non-invasive stimulation paradigm to modulate spinal excitability

Abstract

Objective: Repetitive, paired peripheral and transcranial stimulation targeting the cerebral cortex can increase cortical excitability, outlasting the stimulation period. It is unknown whether paired stimulation specifically targeting the spinal cord can modulate spinal excitability. We tested whether the H-reflex facilitation from a sub-threshold conditioning TMS pulse could modulate spinal excitability if delivered repetitively.

Method: In 13 healthy subjects, we delivered single-pulse TMS (80% RMT) for the right soleus muscle, 20 ms prior to an electrical peripheral nerve stimulus delivered over the posterior tibial nerve on the same side at 0.1 Hz during 15 min.

Results: PNS alone evoked an H-reflex of 0.25 mV ± 0.06 SEM, while pairing of TMS and PNS facilitated the H-reflex to 0.7 ± 0.11 mV. TMS-PNS pairs delivered at 0.1 Hz for 15 min progressively increased in the evoked response to ∼130% (r(2) = 0.97) of the starting amplitude (normalized to 1st min). Post-intervention, H-reflex threshold decreased (pre = 12.9 ± 1.7 mA; post =11.6 ± 1.6 mA; p = 0.04), as did the stimulus intensity at maximum H-reflex amplitude (pre = 23.5 ± 02.8 mA; post = 21.6 ± 2.6 mA; p = 0.03), and recruitment curve width (pre = 11.6 ± 1.5 mA; post = 10.93 ± 1.4 mA; p = 0.03). No such changes were observed with intervention of PNS or TMS alone.

Conclusion: Paired stimulation targeting spinal facilitatory interactions, when applied repetitively, can increase spinal excitability during and after the intervention.

Significance: Spinal associative stimulation may have potential for neuromodulation in spinal cord injury patients.

Fig 1a

Schematic of the experimental set-up, a subthreshold, single pulse of TMS over the leg motor cortex, conditions segmentally the H-reflex, from a single supra-threshold PNS over the tibial nerve in the popliteal fossa. We proposed that this temporal association applied repetitively would leads to a Hebbian-like modulation of the spinal excitability.

Fig 1b

Experimental design and protocol. A within-subjects repeated-measures design was employed. An H-reflex recruitment curve (RC) was recorded at baseline then again following the intervention for each subject. The intervention involved a paired stimulation protocol, with sub-threshold TMS preceding PNS by 20ms (PNS intensity adjusted to elicit a conditioned H-reflex amplitude of 0.5-1.0mV) repeated at 0.1Hz for 15 minutes (90 stimulus pairs).

Fig 2a

Average rectified EMG traces from one subject illustrating that subthreshold TMS alone (80%RMT) resulted in no EMG response (top trace), suprathreshold PNS stimulation alone elicits a small H-reflex (middle trace), and when the same subthreshold TMS pulse precedes the PNS pulse by 20ms, the H-reflex amplitude grows substantially.

Fig 2b

Group mean data showing the effect of subthreshold TMS conditioning on the H-reflex. Relative to unconditioned H-reflex amplitude, a conditioning TMS pulse significantly increased the amplitude of the H-reflex.

Fig 3

Group mean data of conditioned H-reflex amplitude for each minute of the intervention showing a progressive increase in amplitude (~25%) across the intervention period. The regression equation is displayed.

Fig 4a

Pre-intervention H-reflex Recruitment Curve group data fit to a Gaussian curve, with overlaid group mean H-reflex recruitment curve data post intervention normalized to pre, illustrating the range of responses across subjects and the dominance of a left-hand shift, consistent across the group. A shift of the curve post intervention corresponds to decreased threshold, and larger evoked response relative to stimulus intensity.

Fig 4b

Group H-reflex recruitment curve data post-intervention normalized to pre-intervention, showing the shift to the left of the recruitment curve following the intervention.

Fig 5

(a) Example Gaussian curve, illustrating the reported parameters for the subsequent graphs reporting group mean data: Peak amplitude (calculated as the maximum H value in the curve), threshold (calculated as the corresponding stimulus intensity at 10% of the maximum H amplitude), and width (calculated as the full-width intensity half-maximum of the Gaussian); (b) group data showing that the PNS intensity at threshold is significantly reduced post intervention (mean±SEM); (c) the peak H reflex amplitude is significantly reduced post intervention; and (d) the H-reflex recruitment curve width is significantly reduced post intervention, indicating a smaller range of stimulus intensities required to produce a full recruitment curve.