Title : State-dependent cortical responses to one-day accelerated i-TBS with NMDA receptor priming: A TMS-EEG study
Abstract:
In Major Depressive Disorder (MDD), intermittent theta-burst stimulation (iTBS) is used to induce LTP-like plasticity that is at least partly dependent on NMDA receptor–mediated synaptic mechanisms, but the temporal dynamics of these effects and their dependence on ongoing brain state remain incompletely understood. It is also unclear how pharmacological modulation alters cortical excitability and network-level processes underlying the temporal expression of iTBS-induced plasticity. While motor-evoked potentials (MEPs) index corticospinal excitability, TMS-evoked potentials (TEPs) provide a complementary measure of cortical reactivity and excitatory–inhibitory balance that may capture distributed cortical responses to stimulation. We examined how augmentation of accelerated iTBS (a-iTBS) with D-cycloserine (DCS), a partial NMDA receptor agonist, modifies temporal and state-dependent cortical responses in MDD.
In a randomized, placebo-controlled study (n=30), participants received ten a-iTBS sessions (1,800 pulses each) within a single day, spaced 50 minutes apart. The DCS group received 250 mg of DCS, and the placebo group received inert capsules. Corticospinal excitability was assessed using MEPs (120% rMT) recorded from the abductor pollicis brevis before and after each iTBS session, and cortical reactivity was assessed using TEPs (140% rMT) over the left dorsolateral prefrontal cortex before and after the 1st, 2nd, and 10th sessions. Pre-stimulus EEG was analysed using Hidden Markov Models (HMM) to identify recurring brain states and their association with evoked responses and clinical outcomes measured with the Patient Health Questionnaire-9 (PHQ-9).
Placebo a-iTBS produced a progressive increase in MEP amplitude across sessions, consistent with cumulative facilitation across repeated stimulation, along with reduced immediate post-stimulation facilitation. In contrast, the DCS group showed elevated baseline corticospinal excitability and no progressive increase in MEP amplitude across sessions.
TMS-EEG measures indicated higher cortical responsivity in the DCS group compared to placebo. DCS-related effects were most pronounced in the N100 and later TEP components, whereas placebo-related effects emerged earlier (>60 ms post-stimulation). Repeated iTBS sessions produced cumulative modulation of later (>100 ms) TEP components, indicating that stimulation history influenced the temporal profile of cortical responses.
HMM analysis identified four recurring brain states shared across participants with MDD. State 3 showed stronger DMN–VAN connectivity, shorter mean lifetime, and increased switching frequency. Occupancy of this state was associated with N40 amplitude in the DCS group, whereas global connectivity measures were associated with N100 amplitude, indicating component-specific relationships between brain-state dynamics and TMS-evoked responses.
Exploratory clinical analyses showed PHQ-9 (pre–post one-day a-iTBS) improvement in 66.7% of participants receiving DCS (4/6) and 71.4% receiving placebo (5/7). Symptom trajectories indicated substantial inter-individual variability in both groups. Stratification by pharmacological history, age, and sex identified specific predictors associated with the 33.3% worsening rate observed in the DCS group. These findings should be interpreted cautiously given the small sample size.
Our results indicates that stimulation-induced plasticity in MDD appears to depend on both stimulation history and prestimulus brain state, which jointly influence the temporal profile of cortical responses without corresponding differences in clinical outcome in this sample.
