Involvement of N-methyl-d-aspartate receptors in plasticity induced by paired corticospinal-motoneuronal stimulation in humans

Plasticity can be induced at human corticospinal-motoneuronal synapses by delivery of repeated, paired stimuli to corticospinal axons and motoneurons in a technique called paired corticospinal-motoneuronal stimulation (PCMS). To date, the mechanisms of the induced plasticity are unknown. To determine whether PCMS-induced plasticity is dependent on N-methyl-d-aspartate receptors (NMDARs), the effect of the noncompetitive NMDAR antagonist dextromethorphan on PCMS-induced facilitation was assessed in a 2-day, double-blind, placebo-controlled experiment. PCMS consisted of 100 pairs of stimuli, delivered at an interstimulus interval that produces facilitation at corticospinal-motoneuronal synapses that excite biceps brachii motoneurons. Transcranial magnetic stimulation elicited corticospinal volleys, which were timed to arrive at corticospinal-motoneuronal synapses just before antidromic potentials elicited in motoneurons with electrical brachial plexus stimulation. To measure changes in the corticospinal pathway at a spinal level, biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were measured before and for 30 min after PCMS. Individuals who displayed a ≥10% increase in CMEP size after PCMS on screening were eligible to take part in the 2-day experiment. After PCMS, there was a significant difference in CMEP area between placebo and dextromethorphan days ( P = 0.014). On the placebo day PCMS increased average CMEP areas to 127 ± 46% of baseline, whereas on the dextromethorphan day CMEP area was decreased to 86 ± 33% of baseline (mean ± SD; placebo: n = 11, dextromethorphan: n = 10). Therefore, dextromethorphan suppressed the facilitation of CMEPs after PCMS. This indicates that plasticity induced at synapses in the human spinal cord by PCMS may be dependent on NMDARs. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation can strengthen the synaptic connections between corticospinal axons and motoneurons at a spinal level in humans. The mechanism of the induced plasticity is unknown. In our 2-day, double-blind, placebo-controlled study we show that the N-methyl-d-aspartate receptor (NMDAR) antagonist dextromethorphan suppressed plasticity induced by paired corticospinal-motoneuronal stimulation, suggesting that an NMDAR-dependent mechanism is involved.

Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS−) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS−, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI. NEW & NOTEWORTHY Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract.

Ventrolateral medullary neurons relay cardiovascular inputs to the paraventricular nucleus

Horseradish peroxidase (HRP) and single-unit recording experiments were done in cats to identify neurons in ventrolateral medulla (VLM) that project directly to the paraventricular nucleus (PVH) and relay cardiovascular information from carotid sinus (CSN) and aortic depressor (ADN) nerves. After diffusion of HRP into the PVH, retrogradely labeled neurons were observed in the VLM. The region of the VLM containing HRP-labeled neurons was then explored for single units antidromically activated by stimulation of the PVH in chloralosed, paralyzed, and artificially ventilated cats. These units were then tested for their responses to stimulation of the CSN and ADN. Antidromic potentials were recorded from 100 units in the VLM. Of these units, 65% were orthodromically excited by stimulation of buffer nerves; 28 by only CSN, 19 by only ADN, and 18 by both CSN and ADN. The axons of antidromically activated units responding to buffer nerves conducted at slower velocities than those of nonresponsive units. These data demonstrate that VLM neurons projecting directly to PVH integrate cardiovascular afferent information and suggest that these VLM neurons may be involved in the control of the activity of magnocellular neurosecretory neurons in the PVH during activation of baroreceptor and chemoreceptor afferent fibers.

Axotomy increases excitability in crayfish fast flexor motoneuron somata

Somata of crayfish fast flexor motoneurons whose axons had been cut several days previously were found to display much greater electrical excitability than intact contralateral controls. This increased excitability was evidenced by the consistent appearance in intracellular (soma) recordings of overshooting action potentials during antidromic stimulation, in contrast to the decremented passive antidromic potentials usually seen in control cells. The excitability increase was apparently shared by all fast flexor motoneurons whose axons pass out through the severed (main third) root (arising from three major clusters of somata in two ganglia); it also occurred when only one of the first two major branches of the root was cut. These findings corroborate and extend similar results from crayfish and other arthropods, and may find application in the study of central motoneuron circuitry.