Abstract
Paired Associative Stimulation (PAS) has been explored in humans as a non-invasive tool to drive plasticity and promote recovery after neurological insult. A more thorough understanding of PAS-induced plasticity is needed to fully harness it as a clinical tool. Here, we tested the efficacy of PAS with multiple inter-stimuli intervals in an awake rat model in order to study the principles of associative plasticity. Using chronically implanted electrodes in motor cortex and forelimb, we explored PAS parameters to effectively drive plasticity. We assessed changes in corticomotor excitability using a closed loop, EMG-controlled cortical stimulation paradigm. We tested eleven PAS intervals, chosen to force the coincidence of neuronal activity in the rats’ motor cortex and spinal cord with timings relevant to the principles of Hebbian spike-timing-dependent plasticity. However, despite a relatively large number of stimulus pairings (300), none of the tested intervals reliably changed corticospinal excitability relative to control conditions. Our results question PAS effectiveness under these conditions.
Significance Statement Paired Associative Stimulation (PAS) can be applied non-invasively to modulate corticomotor plasticity in humans. However, our understanding of how we can use paired stimuli to produce the greatest beneficial reshaping of corticomotor connections in vivo is still rudimentary. We completed a systematic study varying inter-stimulus intervals between cortical and muscle stimulation in a freely-behaving rat PAS model, following the principles of spike-timing dependent plasticity (STDP). Crucially, our experiments have not demonstrated that the STDP model is effective in vivo using our PAS protocol. We discuss several other factors in addition to the inter-stimulus interval which may play a larger role in driving plasticity, and potential ways that the field can approach future work.
- Hebbian Plasticity
- Motor Cortex
- Paired Associative Stimulation
- Rodent Models
- Spike-Timing-Dependent Plasticity
- Spinal Cord
Footnotes
The authors report no conflicts of interest.
The authors declare no competing financial interests.
WT was supported by the FRQS Doctoral Training Fellowship, the Centre de Recherche en Neurosciences (CTRN) Excellence Award and the 2019 Society for Neuroscience (SFN) Trainee Professional Development Award (TPDA). MHL was supported by the Canada Graduate Scholarships-Master’s Program and Master’s Fellowship Program of the FRQS, as well as the Fonds Wilbrod-Bhérer from the Faculty of Medicine of Université Laval. He is now at the Centre de recherche de l'Hôtel-Dieu de Lévis, CISSS Chaudière-Appalaches, Lévis, QC, Canada. CE was supported by FRQS 35012 Junior 1 salary grant, NSERC RGPIN-2017-06120, and FRQNT 2018-PR-207644 operating grants.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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