Neuromodulation Using Primed Paired Associative Stimulation

Abstract

Purpose: Neuroplasticity governs mechanisms of cortical reorganization, adaptation and recovery following neural injury. Paired associative stimulation (PAS) alters neuroplasticity by pairing peripheral nerve and cortical stimuli which induces spike-timing-dependent-like plasticity. Preceding a principal bout of PAS that intends to weight plasticity in one direction (e.g. facilitatory) with a priming bout of PAS that intends to weight plasticity in the opposite direction (e.g. suppressive) may deploy homeostatic synaptic mechanisms resulting in a greater change from baseline corticospinal excitability. Exploring principles of homeostatic synaptic plasticity using all combinations of priming and principal suppressive PAS (PASLTD), facilitatory PAS (PASLTP) and sham PAS (PASSHAM), this study explores the efficacy of primed PAS as a method of neuromodulation and investigates a relationship between individual characteristics and response to PAS. Methods: Thirty-one healthy individuals were randomized into and completed one of two experiments. Experiment 1 (n=15, age 23.60 ± 2.33 years) investigated priming of PASLTD using a cross-over of the following four interventions separated by at least one-week washouts: 1. PASSHAM→PASLTD; 2. PASLTP→PASLTD; 3. PASLTD→PASLTD; 4. PASSHAM→PASSHAM. Experiment 2 (n=16, age 22.25 ± 2.28 years) investigated priming of PASLTP using a similar four-intervention cross-over of 1. PASSHAM→PASLTP; 2. PASLTD→PASLTP; 3. PASLTP→PASLTP; 4. PASSHAM→PASSHAM. The primary outcome for both experiments was the average peak-to-peak amplitude of 20 motor evoked potentials (MEPs) recorded at baseline and 0, 10, 20, 30, 40, 50 and 60 minutes following intervention. Secondary outcomes included presence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and the latency of MEPs collected using an anterior-posterior current flow across the central sulcus. Results: In Experiment 1, the PASLTP→PASLTD intervention produced a significant increase from baseline corticospinal excitability. Nonresponders had a significantly higher presence of the BDNF Val66Met polymorphism. In Experiment 2, no intervention produced a significant change from baseline excitability. Priming did not convert individual nonresponders to responders for any PAS intervention. Discussion: Our results highlight the complexity of synaptic plasticity and the difficulty in harnessing mechanisms of plasticity to augment neuromodulation strategies. Individual characteristics may influence response to PASLTD and optimal protocols may need to be established for stratified groups.