Induction of LTD-like corticospinal plasticity by low-frequency rTMS depends on pre-stimulus phase of sensorimotor μ-rhythm

Abstract

Background: Neural oscillations reflect rapidly changing brain excitability states. We have demonstrated previously with EEG-triggered transcranial magnetic stimulation (TMS) of human motor cortex that the positive vs. negative peak of the sensorimotor m-oscillation reflect corticospinal low-vs. high-excitability states. In vitro experiments showed that induction of long-term depression (LTD) by low-frequency stimulation depends on the postsynaptic excitability state. Objective/Hypothesis: We tested the hypothesis that induction of LTD-like corticospinal plasticity in humans by 1 Hz repetitive TMS (rTMS) is enhanced when rTMS is synchronized with the low-excitability state, but decreased or even shifted towards long-term (LTP)-like plasticity when synchronized with the high-excitability state. Methods: We applied real-time EEG-triggered 1-Hz-rTMS (900 pulses) to the hand area of motor cortex in healthy subjects. In a randomized double-blind three-condition crossover design, pulses were synchronized to either the positive or negative peak of the sensorimotor m-oscillation, or were applied at random phase (control). The amplitude of motor evoked potentials was recorded as an index of corticospinal excitability before and after 1-Hz-rTMS. Results: 1-Hz-rTMS at random phase resulted in a trend towards LTD-like corticospinal plasticity. RTMS in the positive peak condition (i.e., the low-excitability state) induced significant LTD-like plasticity. RTMS in the negative peak condition (i.e., the high-excitability state) showed a trend towards LTP-like plasticity, which was significantly different from the other two conditions. Conclusion: The level of corticospinal depolarization reflected by phase of the m-oscillation determines the degree of corticospinal plasticity induced by low-frequency rTMS, a finding that may guide future personalized therapeutic stimulation.

Phase-dependent offline enhancement of human motor memory

“…This LTP-like plasticity could have then strengthened the skill memory trace, leading to either stronger rapid [8,9] or overnight offline performance gains [1,36,59]. This scenario is consistent with recent work showing that neuromodulatory TMS protocols applied at mu trough phases preferentially induce LTP-like plasticity [13,18]. However, the absence of differential changes in mu power and broadband responses to individual TMS pulses throughout the entire duration of phase-dependent TMS between the peak and trough groups do not support this possibility.…”

“…Further, declarative memories are thought to be formed during one hippocampal oscillatory phase and retrieved during another [23,29]. These phase-dependent memory dynamics may be caused by an endogenous bias towards LTP during some phases and LTD during others [30e32], similar to that reported recently in human M1 [13,18]. Consistent with proposals of phasedependent brain function, single neuron spikes encode significantly more information [19,33,34] and can integrate this information more effectively [35] during restricted oscillatory phase ranges.…”

“…What could explain this result? It is possible that phasedependent TMS applied at mu trough but not peak phases preferentially induced LTP-like plasticity within a network of motorrelated brain regions [13,18], including those showing the strongest broadband responses to phase-dependent TMS (see Fig. 4).…”

“…In addition, both the direction and magnitude of neuroplasticity induction within human M1 depends on sensorimotor mu phase, with LTP-like plasticity occurring preferentially during mu trough phases [13,18] and weak LTD-like plasticity occurring during mu peak phases [18]. It is therefore possible that, in addition to determining the direction and extent of M1 neuroplasticity induction as assessed using electrophysiological measures [13,18], sensorimotor mu peak and trough phases differently contribute to motor skill learning.…”

The Expanding Horizon of Neural Stimulation for Hyperkinetic Movement Disorders

“…Targeting differential brain states by means of phase estimation has also been associated to increased effectiveness in inducing synaptic plasticity: Baur and colleagues suggested that 1 Hz rTMS induces stronger long-term depression-like plasticity in M1 if pulses are delivered at the positive peak of the mu rhythm, when compared to 1 Hz rTMS given at a random phase. By contrast, when stimuli correspond to the negative peak of mu rhythm, a trend toward long-term potentiation-like plasticity occurs (19). Whether this greater effects in modulation of brain activity can translate into more effective therapies is yet to be established.…”