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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.

SUBMITTER: Alder G

PROVIDER: S-EPMC6718871 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Alder Gemma G Signal Nada N Olsen Sharon S Taylor Denise D

Frontiers in neuroscience 20190827

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 prot ...[more]

PMID: 31507367

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Project description:Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo. Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 - 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.

Project description:ObjectiveTo determine whether neurophysiological mechanisms indicating cortical excitability, long-term potentiation (LTP)-like plasticity, GABAergic and glutamatergic function are altered in patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response.MethodsNeurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender-matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation-derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP-like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging.ResultsPAS-induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor-evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS-induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = -0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow-up assessments were available in six patients and demonstrated parallel improvement of PAS-induced plasticity and mRS.InterpretationAssessment of PAS-induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well-tolerated "electrophysiological biomarker" to monitor therapy response in the future.Clinical trial registrationClinicalTrials.gov: Identifier: NCT01865578.

Project description:Advances in our understanding of neural plasticity have prompted the emergence of neuromodulatory interventions, which modulate corticomotor excitability (CME) and hold potential for accelerating stroke recovery. Endogenous paired associative stimulation (ePAS) involves the repeated pairing of a single pulse of peripheral electrical stimulation (PES) with endogenous movement-related cortical potentials (MRCPs), which are derived from electroencephalography. However, little is known about the optimal parameters for its delivery. A factorial design with repeated measures delivered four different versions of ePAS, in which PES intensities and movement type were manipulated. Linear mixed models were employed to assess interaction effects between PES intensity (suprathreshold (Hi) and motor threshold (Lo)) and movement type (Voluntary and Imagined) on CME. ePAS interventions significantly increased CME compared to control interventions, except in the case of Lo-Voluntary ePAS. There was an overall main effect for the Hi-Voluntary ePAS intervention immediately post-intervention (p = 0.002), with a sub-additive interaction effect at 30 min' post-intervention (p = 0.042). Hi-Imagined and Lo-Imagined ePAS significantly increased CME for 30 min post-intervention (p = 0.038 and p = 0.043 respectively). The effects of the two PES intensities were not significantly different. CME was significantly greater after performing imagined movements, compared to voluntary movements, with motor threshold PES (Lo) 15 min post-intervention (p = 0.012). This study supports previous research investigating Lo-Imagined ePAS and extends those findings by illustrating that ePAS interventions that deliver suprathreshold intensities during voluntary or imagined movements (Hi-Voluntary and Hi-Imagined) also increase CME. Importantly, our findings indicate that stimulation intensity and movement type interact in ePAS interventions. Factorial designs are an efficient way to explore the effects of manipulating the parameters of neuromodulatory interventions. Further research is required to ensure that these parameters are appropriately refined to maximise intervention efficacy for people with stroke and to support translation into clinical practice.

Project description:Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cognition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China (approval No. TJ-A20151102) on July 11, 2015.

Dataset Information

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

Publications

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

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