Targeted Modulation of Human Brain Interregional Effective Connectivity With Spike-Timing Dependent Plasticity

Abstract

Objective: The ability to selectively up- or downregulate interregional brain connectivity would be useful for research and clinical purposes. Toward this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been developed in which two areas are repeatedly stimulated with a millisecond-level asynchrony. However, ccPAS results in humans using bifocal transcranial magnetic stimulation (TMS) have been variable, and the mechanisms remain unproven. In this study, our goal was to test whether ccPAS mechanism is spike-timing-dependent plasticity (STDP).

Materials and methods: Eleven healthy participants received ccPAS to the left primary motor cortex (M1) → right M1 with three different asynchronies (5 milliseconds shorter, equal to, or 5 milliseconds longer than the 9-millisecond transcallosal conduction delay) in separate sessions. To observe the neurophysiological effects, single-pulse TMS was delivered to the left M1 before and after ccPAS while cortico-cortical evoked responses were extracted from the contralateral M1 using source-resolved electroencephalography.

Results: Consistent with STDP mechanisms, the effects on synaptic strengths flipped depending on the asynchrony. Further implicating STDP, control experiments suggested that the effects were unidirectional and selective to the targeted connection.

Conclusion: The results support the idea that ccPAS induces STDP and may selectively up- or downregulate effective connectivity between targeted regions in the human brain.

Keywords: Cortico-cortical paired associative stimulation; diffusion MRI tractography; effective connectivity; electroencephalography; spike-timing dependent plasticity.

Figure 1.

Model of ccPAS and STDP. (Left) ccPAS can be delivered by stimulating two cortical areas, A and B, that are axonally connected (here, left and right M1, coronal slice with MRI tractography) with bifocal TMS. To induce STDP in area B, areas A and B are stimulated at slightly different times (“asynchrony”). Note that the axons are long-range, which results in an axonal conduction delay from area A to B (here, 9 milliseconds) that must be considered when selecting the asynchrony. (Right) During ccPAS, to induce STDP in the target synapse in area B, TMS pulses are delivered at three different asynchronies on separate days. The target synapse is shown with the presynaptic component (axon terminal) for a neuron originating in area A and the postsynaptic component (dendrite) for a neuron in area B; the black arrowheads indicate the direction of effective connectivity being considered in the main experiment analysis, and the red color indicates which side of the synapse is activated first. When the asynchrony is slightly longer than the conduction delay (top), presynaptic activations occur before presynaptic, leading to strengthening of the target synapse, which results in increased effective connectivity A → B. If the asynchrony equals the conduction delay (middle), both sides of the synapse are activated simultaneously, and there is no STDP. When the asynchrony is shorter than the conduction delay (bottom), synaptic efficacy at the target synapse decreases, which results in weaker effective connectivity A → B. Note that the transcallosal connections between A and B are reciprocal; here, we only illustrate the direction from A → B. Supplementary Data Figure S1 shows the pre- to postsynaptic timings in area A for the opposite B → A direction for the same ccPAS protocol (control experiment for directionality). LTD, long-term depression; LTP, long-term potentiation. [Color figure can be viewed at www.neuromodulationjournal.org]

Figure 2.

Experimental design. To assess strengths of the target synapses before (Before) in addition to 10 minutes (After[1]) and 60 minutes (After [2]) after ccPAS, spTMS was delivered to the left M1 while extracting ccEPs from the right M1 (main experiment). In additional runs (not shown), spTMS was delivered to the right M1 while extracting ccEPs from the left M1 at the Before/After[1] / After[2] time points (control experiment for directionality). The ccPAS modulation consisted of delivering 180 TMS pulse pairs at a rate of 0.2 Hz, when the first pulse was delivered to the left M1 and the second pulse to the right M1, with asynchronies of 14 milliseconds, 9 milliseconds, or 4 milliseconds, on separate visits. Spatial extent of the TMS activations was estimated from the TMS-induced E-fields (red) that were also used for extracting the ccEPs from the right M1 (main experiment) and left M1 (control experiment for directionality). [Color figure can be viewed at www.neuromodulationjournal.org]

Figure 3.

MRI tractography results. These group-level results (N = 7) were recorded on a Siemens Prisma and a 64-channel receiver array using a simultaneous multislice sequence with 257 directions and a grid-sampling scheme with 22 different nonzero b values ranging between 150 and 4000. The left and right M1 (red), extracted from the TMS E-fields, were here used as seeds for probabilistic tractography (left M1 as seed, right M1 as waypoint mask). The tractography result (yellow) is consistent with a major transcallosal axonal bundle connecting the left and right M1. Coronal slice at the M1 level, posterior view (anatomical left on left). [Color figure can be viewed at www.neuromodulationjournal.org]

Figure 4.

Main experiment: ccEP time courses extracted from right M1. These group-level responses were recorded in the runs in which spTMS was delivered to the left M1. (Left) The group-level nonnormalized time courses for the 14-millisecond, 9-millisecond, and 4-millisecond ccPAS asynchronies. After an initial TMS pulse artifact at approximately 0 to 4 milliseconds, there were well-defined evoked response components at approximately 5 to 10 milliseconds and longer-lasting deflections up to approximately 20 milliseconds, here most clearly seen in the 14-millisecond asynchrony data. Therefore, for statistical analysis, AUC values were extracted from the 5-to 20-millisecond time window for all conditions. (Right) The corresponding results for 5-to 20-millisecond AUC values (mean with SEM error bars). Consistent with STDP mechanisms, there were significant (≤ 0.05) differences between the Asynchrony conditions (black vertical bars with stars) in addition to changes from Before PAS to the After[1]/After[2] PAS time points for the 14- and 4-millisecond asynchronies (colored horizontal bars with stars), and the changes occurred in the predicted directions. When comparing the time courses (three leftmost panels) with the AUC results (rightmost panel), note that the group-level time courses were averaged across subjects without normalization, whereas in the AUC analysis, the individual values were normalized relative to each subject’s Before values. [Color figure can be viewed at www.neuromodulationjournal.org]

Figure 5.

Control experiment for directionality: ccEPs extracted from left M1. These group-level responses were recorded in the runs in which spTMS was delivered to the right M1. (Left) The nonnormalized group-level time courses between the 14-millisecond, 9-millisecond, and 4-millisecond ccPAS asynchronies. (Right) The corresponding AUC results for 5-to 20-millisecond amplitude values (mean with SEM error bars, normalized relative to the Before values). Although the response amplitudes increased from Before to After[1]/After[2], they did so regardless of Asynchrony, which is not consistent with STDP mechanisms, suggesting that, as predicted, the STDP effects were unidirectional. [Color figure can be viewed at www.neuromodulationjournal.org]