Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation

Abstract

Associative stimulation has been shown to enhance excitability in the human motor cortex (Stefan et al. 2000); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single‐pulse TMS‐evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N‐methyl‐d‐aspartate (NMDA) receptor antagonist known to block long‐term potentiation (LTP). Further experiments employing the double‐shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP‐like mechanisms may underlie the cortical plasticity induced by IPAS.

Plasticity in the developing brain: Implications for rehabilitation

“…It has been hypothesized that excessive inhibition following stroke may be related to a combination of dysregulation of intrinsic GABAergic interneurons and interhemispheric inhibition transmitted through crossed callosal fibers . Other research showed that repetitive stimulation to somatosensory cortex through the median nerve paired with TMS pulses delivered to motor cortex synergistically enhances the excitability of motor cortex [Stefan et al, 2002]. These results are consistent with a model of synaptic plasticity associated with LTP mediated by NMDA type glutamate receptors as studied in laboratory models.…”

Imaging human brain networks to improve the clinical efficacy of non-invasive brain stimulation

“…Stimulation can either enhance or inhibit local neural activity (Stefan et al, 2000;Huang et al, 2005). The changes induced with these stimulation paradigms are thought to reflect long-term potentiation (LTP)-like or longterm depression (LTD)-like changes in synaptic efficacy (Stefan et al, 2002). rTMS can either be applied during a task (i.e., online), or before or after the task (i.e., offline).…”

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

“…In a prior study, we compared two stimulation protocols for which robust effects have been described-paired associative stimulation (PAS) and theta burst stimulation (TBS)-and found that more consistent changes in motor cortical excitability were induced by PAS (Player et al, 2012). PAS-induced increases in cortical excitability are considered to be at least partially dependent on associative long-term potentiation (LTP) (Stefan et al, 2002), which is modulated by BDNF through both pre-and postsynaptic mechanisms (Yoshii and Constantine-Paton, 2010), known to be crucial for neuroplasticity. These mechanisms are believed to underlie motor learning and memory formation (Letzkus et al, 2007), hence providing an appropriate model for testing neuroplasticity.…”