Facilitatory motor cortex plasticity induced by paired associative stimulation in the awake rhesus monkey

Externally induced neuroplastic changes of cortical excitability may be of therapeutic value in several neuro-psychiatric disorders. However, potent stimulation paradigms leading to therapeutically relevant after-effects are required. In order to enable the shaping of advanced stimulation protocols we developed a primate model of transcranial magnetic stimulation (TMS). To evaluate the model, we measured the after-effects of paired associative stimulation on motor-cortical excitability using focal TMS.

Two male rhesus monkeys were trained to tolerate the fixation of the forearm and to relax the hand muscles. Surface EMG was recorded from the first dorsal interosseous Motor evoked potentials (MEPs) elicited by TMS with a Magstim double small coil 25mm, were recorded. The animals were trained to maintain a relaxed EMG-monitored muscle activity during the stimulation procedure. Single electrical stimuli were delivered to the right median nerve at the level of the wrist (intensity 10 mA, pulse duration 200ms) and followed by TMS applied at the contralateral hot-spot of FDI with a time interval of 5ms and 15ms. TMS intensity was adjusted to obtain a MEP amplitude of 1mV. 200 trials were performed at 0,25Hz. To measure the motor cortex excitability before the PAS, single pulse TMS was applied. The after effects of the PAS were measured applying single pulse TMS (baseline intensity, 100 stimuli at 0,25Hz). This was performed immediately and every hour for 4 hours.

When applied at ISI 15ms, PAS led to a significant increase of MEP amplitude during the first 2 hours post intervention. As compared to baseline, MEPs reached a maximum value of 298% when measured 2 hours after PAS, returning to baseline after that. At ISI 5ms no significant changes of MEP amplitude were found compared to baseline during the 4 hours of recording.

Our results demonstrate that cortical neuroplasticity cortex can be induced and monitored in the wake rhesus monkey entirely by external means. The facilitatory associative plasticity induced by PAS in our model has a similar temporal profile as previously observed in humans, but the intensity of the enhanced excitability is twice larger. We conclude that the rhesus monkey represents a valuable model for studying motor cortical neuroplasticity at a systemic level, permitting the development and evaluation of intensified stimulation protocols, i.e. of rTMS, transcranial direct current stimulation or PAS, without taking human subject at risk.