Paired stimulation for spike-timing dependent plasticity quantified with single neuron responses in primate motor cortex

Spike-timing dependent plasticity (STDP) is an extensively studied topic. Previous studies have demonstrated stimulus induced targeted STDP both in vitro and in vivo, but a more consistent and robust method is required. We hypothesized there were two reasons contributing to the inconsistent results previously reported: 1. the measure of connectivity is poorly understood, and 2. the timing of stimulation is static or has low temporal specificity. To test our hypotheses, we applied paired stimulation to the primary motor cortex of awake primates. Single unit responses to stimulation were used as measures of connectivity, and we applied inter-stimulus intervals (ISIs) from {+/-}0.1 to {+/-}50 ms with sub-millisecond intervals. The excitatory single unit response resulted in very consistent changes after conditioning that was dependent on the ISI. Negative ISIs resulted in depression similar to classic STDP, but positive ISI also often resulted in depression. Normalizing the ISIs to the timing of the excitatory response revealed that potentiation only occurred if the second stimulus arrived before the response. Stimuli occurring around the time of the response often resulted in depression as strong as negative ISIs. We additionally tracked the changes in cortico-cortical evoked potentials (CCEPs), a commonly used measure of connectivity in plasticity experiments. CCEP changes showed a similar but more variable dependence to ISI. These results show that the classic STDP curve may be more difficult to induce due to interactions between excitatory and inhibitory circuitry, and that CCEPs may not be the ideal measure of changes in strength of connectivity.