State-Dependent Transcranial Magnetic Stimulation Synchronized with Electroencephalography: Mechanisms, Applications, and Future Directions
Abstract
1. Introduction
2. TMS and TMS-EEG
2.1. TMS
2.2. TMS-EEG
3. State-Dependent TMS-EEG Technology
3.1. Closed-Loop TMS-EEG and Task-Embedded TMS-EEG
- (1)
- Open-loop modulation applies predefined stimulation protocols without real-time feedback from brain states (Figure 1A). Traditional TMS protocols fall into this category.
- (2)
- Closed-loop modulation adjusts stimulation based on instantaneous neural activity, allowing brain “outputs” to influence inputs (Figure 1B) [61]. Closed-loop systems standardize initial states and investigate how specific brain states modulate stimulation effects. TMS protocols guided by real-time neural states are termed closed-loop TMS.
3.2. Fundamental Research on Closed-Loop TMS-EEG
- (1)
- Cortico-spinal responses (MEPs). Early closed-loop TMS studies primarily evaluate stimulation efficacy using MEPs or behavioral outcomes. Comparing MEP differences further validates connectivity variations in corticospinal synchronization across neural states. Iscan et al. demonstrated that pre-stimulus alpha oscillations correlate with inter-subject MEP variability during sTMS of the hand motor cortex: higher alpha amplitude dispersion corresponds to greater MEP variability [68]. Desideri et al. showed that phase-synchronized TMS with sensorimotor mu rhythms enhances motor-evoked responses in hand muscles [69]. Zrenner et al. proposed that mu rhythm phases reflect distinct corticospinal excitability states. By designing phase-locked rTMS protocols (peak vs. trough mu phases), they confirmed that real-time brain states modulate TMS-induced plasticity [70]. Building on this, Zrenner’s team applied mu-alpha phase-synchronized rTMS/TBS to the left dorsolateral prefrontal cortex (DLPFC) in treatment-resistant major depressive disorder (MDD), demonstrating specific neuromodulatory effects [71]. Beyond mu rhythms, Gordon et al. developed a closed-loop protocol triggering TMS at specific theta phases in the dorsomedial prefrontal cortex (DMPFC), validating its reliability [72]. Closed-loop principles also extend to spatial optimization: ervo et al. created an automated system adjusting figure-of-eight coil angles based on MEP feedback, rapidly identifying optimal angles for maximal MEP amplitudes—a novel application of closed-loop TMS [73].
- (2)
- Cortical responses (TMS-EEG). Despite TMS-EEG’s potential as a direct biomarker of TMS-evoked neural activity, hardware limitations and real-time processing challenges have hindered closed-loop TMS-EEG research. Early efforts, such as Fehér et al.’s alpha-rhythm-tACS-guided TMS-EEG, introduced artifacts from external stimulation, distorting recorded signals [74]. Quasi-closed-loop approaches (e.g., aligning TMS with task/external stimuli) simplify technical demands but risk confounding variables from additional neuromodulation. Recent advances in real-time EEG prediction are revitalizing closed-loop TMS-EEG. Momi et al. retrospectively analyzed whether TMS pulses occurred during the positive or negative phase of mu-frequency oscillations and examined the subsequent effects on interhemispheric connectivity [58]. In Table 1, we focused on recent closed-loop TMS-EEG studies over the past three years, revealing a prevalent use of strategies involving phase-controlled TMS output. The general practice of this strategy was to design a flexible TMS-EEG device and develop an effective phase prediction control algorithm to achieve closed-loop control functionality [75]. In the phase-locked loop TMS-EEG experiment, the EEG signals of the subjects were recorded, the phase information of the current neural activity rhythm was extracted, and based on the predetermined target phase value, the output timing of TMS real-time stimulation was guided to achieve phase-locked control. However, the physiological significance of EEG phase information remains unclear, and using alpha phase as a closed-loop control parameter makes it challenging to correlate TMS-EEG results with the physiological significance of the control parameter. More meaningful control strategies (such as microstates [76], Large-Scale Brain States [77,78]) were also gradually being discussed, and as closed-loop technologies were expected to play a significant role in addressing optimization timing issues in TMS-EEG and related mechanistic discussions, an increasing number of relevant studies will be reported in the future.
3.3. Fundamental Research on Task-Embedded TMS-EEG
4. State Dependency of TMS-EEG: Conceptual Framework
4.1. Major Scientific Issues in State-Dependent TMS-EEG
- (1)
- Designing real-time closed-loop systems that integrate low-latency EEG preprocessing, predictive algorithms for neural state estimation, and appropriate control strategies to synchronize TMS pulses with target brain states. Traditional TMS-EEG techniques cannot precisely synchronize brain activity states at the moment of TMS stimulation, resulting in different initial states of induced TMS-EEG components. In contrast, closed-loop TMS delivers stimuli in sync with brain activity states, yielding closed-loop TMS-EEG data with a locked initial state. Closed-loop TMS-EEG technology comprises three fundamental components: selecting appropriate feedback signals to represent the current neural activity state, establishing precise and effective real-time closed-loop control strategies, and recording observational TMS-EEG signals. Due to the fact that EEG signals collected by the closed-loop TMS-EEG system are only available up to the present moment and there is a delay in signal acquisition and transmission, it is challenging to capture the current neural activity trends and predict future trends. Therefore, a time series forecasting approach is needed to extrapolate the EEG signals. Although EEG signals are non-stationary, the short-term brain information can be considered stationary, making brain signal prediction feasible. A commonly used method involves using an autoregressive model to forecast brain signal sequences, as shown in Formulas (1)–(5).
- (2)
- Achieving true closed-loop control requires developing novel modulation models and strategies. As the adaptive closed-loop brain stimulation proposed by Roesch et al., which dynamically adjusts controller parameters in real time based on the evolving relationship between stimulation inputs and system outputs [96]. However, this strategy still differs from strictly defined engineering closed-loop control, as TMS cannot actively drive EEG signals towards desired states in real time. In contrast, Humaidan et al. conducted a proof-of-concept experiment [97], pioneering the integration of closed-loop EEG-TMS with a reinforcement learning (RL) algorithm, specifically Deep-Q Learning. Targeting a two-node brain network (M1 and SMA) to enhance SMA-to-M1 facilitation, the algorithm autonomously optimized stimulation parameters (sensorimotor mu-rhythm phase) using observed facilitation levels as the reward signal. Different agents (simple Q-learning table and deep Q-learning) both successfully learned to identify the optimal stimulation phase, demonstrating RL’s feasibility for goal-directed real-time parameter optimization. The specific steps of the RL algorithm in the original text were as follows:
- (3)
- Investigating causal mechanisms by combining multiscale EEG analyses with pharmacological or computational approaches to dissect how brain states modulate TMS-evoked responses. Common physiological indicators of TMS-EEG can be categorized into three classes based on time domain, frequency domain, and spatial domain. The representative characteristics of these divisions are illustrated in Figure 3: the most typical features in the time domain include the temporal waveforms of TEP components and their whole-brain topographical distributions; in the frequency domain, typical features include neural oscillations (intrinsic frequencies); and in the spatial domain, it encompasses functional connectivity between different brain regions and network properties of brain functional networks. By mapping specific physiological features of TMS-EEG to actual functional states such as cognitive function, motor function, consciousness state, emotional state, and rehabilitation status, it is possible to construct a neural state-regulation strategy-cognitive function model based on state-dependent TMS.
- (4)
- Optimizing task-embedded protocols to align TMS pulses with distinct cognitive phases (e.g., perception, decision-making), enabling dynamic mapping of functional networks and their behavioral relevance through time-resolved connectivity tools (e.g., time-varying Granger causality [98]). By delivering TMS pulses at different time points during task processing, the originally static functional connectivity features are linked together at different stages of task processing. This dynamic presentation of TMS-EEG network connections over time forms a changing connectome [90]. This innovative technique extends TMS-EEG into the temporal dimension during tasks with the aim of enhancing the temporal resolution that may be compromised in task-related TMS-EEG studies due to the arbitrary timing of TMS pulses.
4.2. Challenges
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Authors | N | Strategy | Main Result(s) |
---|---|---|---|
Ding et al. [79] | 30 | Alpha-phase-locked TMS with O1 electrode | 1. Closed-loop TMS can improve the stability between trials, thereby reducing the variability of TMS-EEG data results. 2. Multiple time features, frequency features and spatial features of TMS-EEG were influenced by the alpha phase at the time of stimulation. |
Perera et al. [80] | 18 | Alpha-phase-locked TMS with Hjort-Laplacian C3 electrode | 1. MEP amplitude was positively influenced by alpha power and phase, exhibiting more robust responses during the trough phase and high power levels. 2. Alpha power and phase had an impact on TEP characteristics. |
Bigoni et al. [81] | 20 | Mu/Beta-phase-locked TMS with Hjort-Laplacian C3 electrode | 1. Pre-TMS mu oscillatory power and phase significantly predicted both early and late cortical EEG responses. 2. Pre-TMS beta power significantly predicted early and late TEP components. |
Erickson et al. [82] | 19 | Alpha-phase-locked TMS with C3 electrode | 1. Alpha-phase resetting and N100 amplitude depended on TMS intensity and were significant versus peripheral auditory sham stimulation. 2. Alpha-phase inversion after stimulations near peaks but not troughs in the endogenous rhythm. |
Ding et al. [76] | 21 | Microstate | The N100 component of microstate C group was significantly higher than of microstate D group, and the P180 component of microstate D group was significantly higher than of microstate B groupand slightly higher than of microstate C. |
Marzetti et al. [77] | - | Fast-Dynamic Large-Scale Brain States identified by Hidden Markov Model (HMM) | Introduced the Endpoint-Related Fast-Dynamic Large-Scale Brain State (ER-FLBS) concept–a dynamic whole-brain network state that serves as a spatiotemporal reference for optimizing TMS efficacy. |
Makkinayeri et al. [78] | 20 | Fast-Dynamic Large-Scale Brain States identified by HMM | 1. A significant link between rapid transient large-scale brain networks and corticospinal excitability. 2. MEPs were enhanced when the motor network was more active pre-stimulation. |
Authors | N | Strategy | Main Result(s) |
---|---|---|---|
Fernandez-Linsenbarth et al. [89] | 27 healthy controls and 22 patients | Auditory oddball task | The task-related cortical activity modulation deficit in schizophrenia patients: Schizophrenia patients showed higher cortical reactivity following transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex compared to healthy controls. |
Ding et al. [90] | 30 | Visually guided gap saccade task | Significant differences in information flow in the gamma bands TMS-EEG data at different task stages. |
Casula et al. [91] | 22 | Go/NoGo task | 1. A task-specific bidirectional alteration in theta/gamma connectivity between the supplementary motor cortex (SMA) and M1 was observed. 2. When participants were instructed to suppress their responses, distinct N100 complements emerged. |
Fong et al. [92] | 32 | Cerebellar TMS during visuomotor adaptation | The P80 and N110 peaks were consistently observed in the cerebellar motor learning experiment, exhibiting varying amplitudes across different stages of learning. |
Bianco et al. [93] | 14 | Go/No-Go task | When TMS was applied over the SMA during the late Bereitschaftspotential phase, increased cortical activity was observed based on source reconstruction within the stimulated region. |
Guidali et al. [94] | 25 | Action observation task | Under normal conditions, the M1 alpha network recruited during left-hand movement observation is significantly stronger than during static hand observation. Beta connectivity during left-hand movement observation is suppressed compared to all other conditions. |
Zazio et al. [95] | 20 healthy controls and 20 patients | Visuo-tactile spatial congruency (VTSC) | Subjects presented altered TEP connectivity patterns during both touch perception and touch observation, with no differential modulation between human-directed and object-directed touches in the observation condition. |
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Chen, H.; Liu, T.; Song, Y.; Ding, Z.; Li, X. State-Dependent Transcranial Magnetic Stimulation Synchronized with Electroencephalography: Mechanisms, Applications, and Future Directions. Brain Sci. 2025, 15, 731. https://doi.org/10.3390/brainsci15070731
Chen H, Liu T, Song Y, Ding Z, Li X. State-Dependent Transcranial Magnetic Stimulation Synchronized with Electroencephalography: Mechanisms, Applications, and Future Directions. Brain Sciences. 2025; 15(7):731. https://doi.org/10.3390/brainsci15070731
Chicago/Turabian StyleChen, He, Tao Liu, Yinglu Song, Zhaohuan Ding, and Xiaoli Li. 2025. "State-Dependent Transcranial Magnetic Stimulation Synchronized with Electroencephalography: Mechanisms, Applications, and Future Directions" Brain Sciences 15, no. 7: 731. https://doi.org/10.3390/brainsci15070731
APA StyleChen, H., Liu, T., Song, Y., Ding, Z., & Li, X. (2025). State-Dependent Transcranial Magnetic Stimulation Synchronized with Electroencephalography: Mechanisms, Applications, and Future Directions. Brain Sciences, 15(7), 731. https://doi.org/10.3390/brainsci15070731