Paired Stimulation to Promote Lasting Augmentation of Corticospinal Circuits

Abstract

After injury, electrical stimulation of the nervous system can augment plasticity of spared or latent circuits through focal modulation. Pairing stimulation of two parts of a spared circuit can target modulation more specifically to the intended circuit. We discuss 3 kinds of paired stimulation in the context of the corticospinal system, because of its importance in clinical neurorehabilitation. The first uses principles of Hebbian plasticity: by altering the stimulation timing of presynaptic neurons and their postsynaptic targets, synapse function can be modulated up or down. The second form uses synchronized presynaptic inputs onto a common synaptic target. We dub this a "convergent" mechanism, because stimuli have to converge on a common target with coordinated timing. The third form induces focal modulation by tonic excitation of one region (e.g., the spinal cord) during phasic stimulation of another (e.g., motor cortex). Additionally, endogenous neural activity may be paired with exogenous electrical stimulation. This review addresses what is known about paired stimulation of the corticospinal system of both humans and animal models, emphasizes how it qualitatively differs from single-site stimulation, and discusses the gaps in knowledge that must be addressed to maximize its use and efficacy in neurorehabilitation.

Figure 1

Three paired stimulation models. The corticospinal tract (CST) connects motor cortex directly to the spinal cord. The termination of the CST is largely (>80%) onto interneurons in humans and exclusively so in rodents, but for simplicity it is depicted only as synapsing onto motoneurons. (a) Pre-post synapse model. Repetitive paired stimulation of a presynaptic neuron and its postsynaptic target modifies the strength of the synapse connecting them. The timing of pre-post synaptic neuron firing determines whether the synapse is made stronger or weaker. This is also termed Hebbian or spike-timing dependent plasticity. For corticospinal modulation, this strategy usually pairs motor cortex stimulation with back-propagating peripheral motor nerve stimulation [, –79]. (b) Convergent model. Two (or more) presynaptic neurons converge onto a common postsynaptic target. For corticospinal modulation, this strategy may pair motor cortex stimulation with afferent sensory nerve stimulation [87, 94]. (c) Phasic during tonic model. Adding tonic direct current stimulation concurrently with phasic stimulation at one or more sites can augment corticospinal circuit responses [95, 98, 99]. In this schematic, CST activation of motor cortex is modulated by direct current stimulation of the spinal cord.