Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke.

Joshua Silverstein,Allan Wu,Linda M Gerber,Mar Cortes,Rajiv R Ratan,Alejandra Climent,Marco Iacoboni,Clara Oromendia,Bruce Dobkin,Dylan J Edwards,Tomoko Kitago,Pasquale Fonzetti,Katherine Zoe Tsagaris

doi:10.3389/fnins.2019.00792

Abstract

Background and PurposeThe potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke.MethodsWe examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period.ResultsWe found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study.ConclusionPaired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement.

Highlights

The capacity of the brain to make structural, physiological, and genetic adaptations following stroke, otherwise known as plasticity, is likely to be critical for improving sensorimotor impairments and functional activities
The predictive value of paired associative stimulation (PAS) for drug-induced functional recovery post-stroke has yet to be established, our data suggest that, while clinical doses of memantine can penetrate into the central nervous system (CNS) to affect function, we found no evidence that it enhances amplitude increase post-intervention may suggest an alternative methodological approach for PAS application in post-stroke drug dosing studies
The weekly dexterity and strength measures did not significantly vary. These findings indicate that while PAS plasticity is not observed in the presence of memantine, there was no appreciable disruption to functional performance in either the PAS-targeted hand or the affected hand of chronic stroke patients, associated with weekly escalating dose of memantine, and repeated exposure to PAS

Summary

Introduction

The capacity of the brain to make structural, physiological, and genetic adaptations following stroke, otherwise known as plasticity, is likely to be critical for improving sensorimotor impairments and functional activities. There is currently no accepted method in stroke patients for evaluating the potential effectiveness or individual responsiveness to putative “plasticity enhancing” drugs in an efficient, low-cost, crosssectional manner, in order to establish target engagement in humans and to avoid the extensive time and cost of protracted clinical trials. The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke

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