Driving theta-gamma oscillations modulates extrasynaptic GABAergic tone: a tACS-TMS study

Abstract BACKGROUND Theta-gamma phase-amplitude coupled (θγ-PAC) oscillations in primary motor cortex (M1) have been shown to support motor skill acquisition. Past research has shown that driving gamma activity at the theta peak (TGP), but not the theta trough (TGT) using transcranial alternating current stimulation (tACS) enhances motor learning (Akkad et al., 2021). However, the neurophysiological mechanisms underlying this phase-specific effect remain unclear. METHODS In a double-blind, sham-controlled, cross-over study, twenty-two healthy participants received 20 minutes of 75Hz/6Hz TGP-tACS, TGT-tACS, or sham stimulation over M1. We used paired-pulse transcranial magnetic stimulation (TMS) to assess GABAergic and NMDAR-mediated activity before, during, and after tACS. Outcome measures included short-interval intracortical inhibition at 1ms (SICI1ms; extrasynaptic GABAergic tone) and 2.5ms (SICI2.5ms; synaptic GABAA activity), intracortical facilitation at 12ms (ICF12ms; NMDAR activity), and motor evoked potential (MEP) amplitude (corticospinal excitability). RESULTS TGP-tACS selectively decreased SICI1ms, a putative marker of extrasynaptic GABAergic tone (main effect of Stimulation: p=.021), with significant differences between TGP and TGT during late stimulation (p=.047). No significant effects were observed on corticospinal excitability, synaptic GABAergic activity (SICI2.5ms), or NMDAR signalling (ICF12ms). CONCLUSIONS Driving theta-gamma oscillations at the theta peak using tACS specifically modulates extrasynaptic GABAergic tone in M1 without affecting corticospinal excitability or synaptic inhibition. Given that reductions in GABAergic signalling supports motor learning, these findings provide a neurophysiological mechanism for the phase-specific behavioural effects of θγ-PAC tACS and suggest a potential therapeutic approach for facilitating motor recovery after stroke. Highlights Theta-gamma peak tACS selectively reduces extrasynaptic GABA in human motor cortex Only gamma at the peak, not trough, of theta stimulation modulates GABA No effects on corticospinal excitability, synaptic GABA, or NMDAR signalling tACS-TMS reveals mechanism for phase-dependent motor learning effects