A Systematic Review of Paired Associative Stimulation (PAS) to Modulate Lower Limb Corticomotor Excitability: Implications for Stimulation Parameter Selection and Experimental Design

Abstract

Non-invasive neuromodulatory interventions have the potential to influence neural plasticity and augment motor rehabilitation in people with stroke. Paired associative stimulation (PAS) involves the repeated pairing of single pulses of electrical stimulation to a peripheral nerve and single pulses of transcranial magnetic stimulation over the contralateral primary motor cortex. Efficacy of PAS in the lower limb of healthy and stroke populations has not been systematically appraised. Optimal protocols including stimulation parameter settings have yet to be determined. This systematic review (a) examines the efficacy of PAS on lower limb corticomotor excitability in healthy and stroke populations and (b) evaluates the stimulation parameters employed. Five databases were searched for randomized, non-randomized, and pre-post experimental studies evaluating lower limb PAS in healthy and stroke populations. Two independent reviewers identified eligible studies and assessed methodological quality using a modified Downs and Blacks Tool and the TMS Checklist. Intervention stimulation parameters and TMS measurement details were also extracted and compared. Twelve articles, comprising 24 experiments, met the inclusion criteria. Four articles evaluated PAS in people with stroke. Following a single session of PAS, 21 experiments reported modulation of corticomotor excitability, lasting up to 60 min; however, the research lacked methodological rigor. Intervention stimulation parameters were highly variable across experiments, and whilst these appeared to influence efficacy, variations in the intervention and outcome assessment methods hindered the ability to draw conclusions about optimal parameters. Lower limb PAS research requires further investigation before considering its translation into clinical practice. Eight key recommendations serve as guide for enhancing future research in the field.

Induction of Neural Plasticity Using a Low-Cost Open Source Brain-Computer Interface and a 3D-Printed Wrist Exoskeleton

“…The variability in the MEP size is affected by multiple factors, such as attention and time of day (reviewed in Refs. [ 33 , 34 ]), but it may also be due to the variable response of neuromodulation interventions [ 35 , 36 , 37 , 38 ]. It should also be noted that there exist other types of techniques that have been used for the induction of neural plasticity and proposed for stroke rehabilitation, and that activate the cortical brain areas [ 39 ].…”

“…TMS has also been paired with afferent inflow from the electrical stimulation of a peripheral nerve (paired associative stimulation). This protocol has been used to consistently induce neural plasticity when the correct interstimulus interval between the magnetic and electrical stimulation has been selected [ 33 ]. However, the use of TMS may not be tolerated well by some stroke patients [ 41 ], and there would be safety precautions to consider [ 29 ].…”

Investigating the Intervention Parameters of Endogenous Paired Associative Stimulation (ePAS)

“…The decision to investigate MEP area was based on literature that suggests it may be more sensitive to changes due to the polyphasic nature of MEPs in the lower limb [67,68]. The decision to investigate both absolute and relative MEP data was consistent with a number of previous neuromodulation studies [9,27]. Absolute MEP amplitude values were established by extracting the peak-to-peak amplitude of each individual MEP observation.…”

Paired Associative Stimulation Fails to Induce Plasticity in Freely Behaving Intact Rats

“…Studies have also employed modified PAS protocols with mixed success in improving functional recovery after neurovascular insult, both in animals (Shin et al, 2008) and in humans (Castel-Lacanal et al, 2007;Castel-Lacanal et al, 2009;Rogers et al, 2011;Cho et al, 2016;Ferris et al, 2018;Palmer et al, 2018;Tarri et al, 2018a). PAS initially showed great promise for rehabilitation, however enthusiasm for this approach has been tempered by lack of experimental rigor and inconsistent results (Alder et al, 2019). PAS has shown to have a very high inter-subject variability (Sale et al, 2007;McGie et al, 2014;Tarri et al, 2018b), its effects are strongly dependent on mindful, persistent attention on the target limb (Stefan et al, 2004) or even failed to induce any consistent plastic effects (McGie et al, 2014).…”