Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections

Abstract

Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)], but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (M1) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different M1 neuronal populations by applying transcranial magnetic stimulation over M1 with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti-Hebbian STDP in human long-range connections. The induction of bidirectional long-term potentiation or depression in M1 depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons.

Figure 1.

Schematic representation of the experimental procedure. A, The PAS protocol was applied over the left PPC and left M1. Mean normalized MNI coordinates of left PPC site were −48 ± 4, −65 ± 3, and 45 ± 3 mm (x, y, z, mean ± SD), and mean MNI coordinates of left M1 were −30 ± 3, −12 ± 3, and 71 ± 4 (x, y, z, mean ± SD). B, Across different experiments, we systematically varied the orientation of the stimulating coil over M1 [posterior–anterior (M1_PA) or anterior–posterior (M1_AP)] and the ISI for the PPC–M1 PAS. Positive paring indicate that the PPC input precedes the M1 pulse, whereas negative paring indicate that the PPC input is applied after the M1 pulse.

Figure 2.

PAS between the PPC and M1 with PA orientation. Aftereffects of PPC–M1_PA+5 ms, PPC–M1_PA−5 ms, and random PAS (A) and PPC–M1_PA+50 ms, PPC–M1_PA+20 ms, PPC–M1_PA−20 ms, and PPC–M1_PA−50 ms PAS (B) on MEP amplitude at baseline and different time points. C, Mean normalized data (percentage of change compared with baseline) obtained at the 11–15 min block after each PAS protocol. The emerging temporal profile follows the rules of anti-Hebbian STDP. D, Mean MEP amplitude during the paired PPC–M1 plasticity-inducing protocols at −5, −20, +5, and +20 ms. Error bars indicate SEM. *p < 0.05.

Figure 3.

PAS between the PPC and M1 with AP orientation. A, Mean MEP latencies obtained with different coil orientations. B, Aftereffects of PPC–M1_AP+5 ms and PPC–M1_AP−5 ms PAS on MEP amplitude. The induced STDP is opposite to that in Figure 2, compatible with a temporal profile that follows the rules of standard Hebbian STDP. C, Aftereffects of PPC–M1_AP+5 ms PAS on MEP amplitude tested with different coil orientations. D, Mean MEP amplitude during the paired PPC–M1_AP plasticity-inducing protocols at −5 and +5 ms. Error bars indicate SEM. *p < 0.05 compared with baseline. In B, * refers to MEP PA and ° refers to MEP AP.

Figure 4.

State dependency of PAS. Aftereffects of PPC–M1_PA+5 ms and PPC–M1_PA−5 ms PAS protocols on MEP amplitude when performed with subjects slightly contracting the FDI muscle during the entire protocol. Note that the effects are opposite to those induced by the same protocols when performed with subjects at rest (see Fig. 2). Error bars indicate SEM. *p < 0.05.

Figure 5.

Topographical specificity of PAS effects. Aftereffects of the PPC–M1_PA−5 ms PAS protocol on MEP recorded from the FDI and the ADM muscles. The PAS protocol was applied over the “hotspot” area for the FDI. Error bars indicate SEM. *p < 0.05.

Figure 6.

PAS effects on SICI/ICF intracortical circuits. Aftereffects of the PPC–M1_PA+5 ms (A) and PPC–M1_PA−5 ms (B) protocols assessed by standard SICI and ICF paired-pulse protocols. Error bars indicate SEM. *p < 0.05.

Figure 7.

PAS effects on SLAI and SICF intracortical circuits. A, B, Aftereffects of the PPC–M1_PA+5 ms (A) and PPC–M1_PA−5 ms (B) protocols assessed by SLAI. C, D, Aftereffects of the PPC–M1_PA+5 ms (C) and PPC–M1_PA−5 ms (D) protocols assessed by SICF protocols. Error bars indicate SEM.