Cortical acetylcholine dynamics are predicted by cholinergic axon activity and behavior state.

Acetylcholine (ACh) is thought to play a role in driving the rapid, spontaneous brain-state transitions that occur during wakefulness; however, the spatiotemporal properties of cortical ACh activity during these state changes are still unclear. We perform simultaneous imaging of GRAB-ACh sensors, GCaMP-expressing basal forebrain axons, and behavior to address this question. We observed a high correlation between axon and GRAB-ACh activity around periods of locomotion and pupil dilation. GRAB-ACh fluorescence could be accurately predicted from axonal activity alone, and local ACh activity decreased at farther distances from an axon. Deconvolution of GRAB-ACh traces allowed us to account for sensor kinetics and emphasized rapid clearance of small ACh transients. We trained a model to predict ACh from pupil size and running speed, which generalized well to unseen data. These results contribute to a growing understanding of the precise timing and spatial characteristics of cortical ACh during fast brain-state transitions.

Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial.

Background: In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor µ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Objective: Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor µ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. Methods: We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months' follow-up. Results: Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. Conclusion: The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT05005780].

Variation in the distribution of large-scale spatiotemporal patterns of activity across brain states.

A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

Heartbeat-related spectral perturbation of electroencephalogram reflects dynamic interoceptive attention states in the trial-by-trial classification analysis.

Attending to heartbeats for interoceptive awareness initiates distinct electrophysiological responses synchronized with the R-peaks of an electrocardiogram (ECG), such as the heartbeat-evoked potential (HEP). Beyond HEP, this study proposes heartbeat-related spectral perturbation (HRSP), a time-frequency map of the R-peak locked electroencephalogram (EEG), and explores its characteristics in identifying interoceptive attention states using a classification approach. HRSPs of EEG brain components specified by independent component analysis (ICA) were used for the offline and online classification of interoceptive states. A convolutional neural network (CNN) designed specifically for HRSP was applied to publicly available data from a binary-state experiment (attending to self-heartbeats and white noise) and data from our four-state classification experiment (attending to self-heartbeats, white noise, time passage, and toe) with diverse input feature conditions of HRSP. From the dynamic state perspective, we evaluated the primary frequency bands of HRSP and the minimal number of averaging epochs required to reflect changing interoceptive attention states without compromising accuracy. We also assessed the utility of group ICA and models for classifying HRSP in new participants. The CNN for trial-by-trial HRSP with actual R-peaks demonstrated significantly higher classification accuracy than HRSP with sham, i.e., randomly positioned, R-peaks. Gradient-weighted class activation mapping highlighted the prominent role of theta and alpha bands between 200-600 ms post-R-peak-features absent in classifications using sham HRSPs. Online classification benefits from employing a group ICA and classification model, ensuring reliable accuracy without individual EEG precollection. These results suggest HRSP's potential to reflect interoceptive attention states, proposing transformative implications for clinical applications.

Sleep Deprivation Effects on Brain State Dynamics Are Associated With Dopamine D2 Receptor Availability Via Network Control Theory.

BACKGROUND: Sleep deprivation (SD) negatively affects brain function. Most brain imaging studies have investigated the effects of SD on static brain function. SD effects on functional brain dynamics and their relationship with molecular changes remain relatively unexplored. METHODS: We used functional magnetic resonance imaging to examine resting-brain state dynamics after one night of SD compared with rested wakefulness (N = 41) and assessed the association of brain state dynamics with striatal brain dopamine D2 receptor availability measured by positron emission tomography [11C]raclopride using network control theory. RESULTS: SD reduced dwell time and persistence probabilities, with the strongest effects in two brain states, one characterized by high default mode network and low dorsal attention network activity and the other by high frontoparietal network and low somatomotor network activity. Using network control theory, we showed that after SD, there was an overall increase in the control energy required for brain state transitions, with effects varying for different brain state transitions. Control energy requirement was negatively associated with transition probabilities under SD and restful wakefulness and accounted for SD-induced changes in transition probabilities. Alteration in the energy landscape was associated with SD-induced changes in striatal D2 receptor distribution. CONCLUSIONS: These findings demonstrate altered occurrence of internally and externally oriented brain states following acute SD and suggest an association with energy requirements for brain state transitions modulated by striatal D2 receptors.

Top-Down Task Goals Induce the Retrieval State.

Engaging the retrieval state (Tulving, 1983) impacts processing and behavior (Long and Kuhl, 2019, 2021; Smith et al., 2022), but the extent to which top-down factors-explicit instructions and goals-versus bottom-up factors-stimulus properties such as repetition and similarity-jointly or independently induce the retrieval state is unclear. Identifying the impact of bottom-up and top-down factors on retrieval state engagement is critical for understanding how control of task-relevant versus task-irrelevant brain states influence cognition. We conducted between-subjects recognition memory tasks on male and female human participants in which we varied test phase goals. We recorded scalp electroencephalography and used an independently validated mnemonic state classifier (Long, 2023) to measure retrieval state engagement as a function of top-down task goals (recognize old vs detect new items) and bottom-up stimulus repetition (hits vs correct rejections (CRs)). We find that whereas the retrieval state is engaged for hits regardless of top-down goals, the retrieval state is only engaged during CRs when the top-down goal is to recognize old items. Furthermore, retrieval state engagement is greater for low compared to high confidence hits when the task goal is to recognize old items. Together, these results suggest that top-down demands to recognize old items induce the retrieval state independent from bottom-up factors, potentially reflecting the recruitment of internal attention to enable access of a stored representation.

On convergence properties of the brain-state-in-a-convex-domain.

Convergence in the presence of multiple equilibrium points is one of the most fundamental dynamical properties of a neural network (NN). Goal of the paper is to investigate convergence for the classic Brain-State-in-a-Box (BSB) NN model and some of its relevant generalizations named Brain-State-in-a-Convex-Body (BSCB). In particular, BSCB is a class of discrete-time NNs obtained by projecting a linear system onto a convex body of Rn. The main result in the paper is that the BSCB is convergent when the matrix of the linear system is symmetric and positive semidefinite or, otherwise, it is symmetric and the step size does not exceed a given bound depending only on the minimum eigenvalue of the matrix. This result generalizes previous results in the literature for BSB and BSCB and it gives a solid foundation for the use of BSCB as a content addressable memory (CAM). The result is proved via Lyapunov method and LaSalle's Invariance Principle for discrete-time systems and by using some fundamental inequalities enjoyed by the projection operator onto convex sets as Bourbaki-Cheney-Goldstein inequality.

Energy landscape analysis of brain network dynamics in Alzheimer's disease.

Background: Alzheimer's disease (AD) is a common neurodegenerative dementia, characterized by abnormal dynamic functional connectivity (DFC). Traditional DFC analysis, assuming linear brain dynamics, may neglect the complexity of the brain's nonlinear interactions. Energy landscape analysis offers a holistic, nonlinear perspective to investigate brain network attractor dynamics, which was applied to resting-state fMRI data for AD in this study. Methods: This study utilized resting-state fMRI data from 60 individuals, comparing 30 Alzheimer's patients with 30 controls, from the Alzheimer's Disease Neuroimaging Initiative. Energy landscape analysis was applied to the data to characterize the aberrant brain network dynamics of AD patients. Results: The AD group stayed in the co-activation state for less time than the healthy control (HC) group, and a positive correlation was identified between the transition frequency of the co-activation state and behavior performance. Furthermore, the AD group showed a higher occurrence frequency and transition frequency of the cognitive control state and sensory integration state than the HC group. The transition between the two states was positively correlated with behavior performance. Conclusion: The results suggest that the co-activation state could be important to cognitive processing and that the AD group possibly raised cognitive ability by increasing the occurrence and transition between the impaired cognitive control and sensory integration states.

Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focus on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the Motor Network (MN) and how the MN state affects responses to the transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to the left M1 in eight subjects at rest, with simultaneous EEG. Motor-evoked potentials (MEPs) were measured from the right hand. The source space functional connectivity of the left M1 to the whole brain was assessed using the imaginary part of the phase locking value at the frequency of the sensorimotor µ-rhythm in a 1 s window before the pulse. Group-level connectivity revealed functional links between the left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At the single-subject level, this relation is more highly expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity-based NIBS.

Brain states as wave-like motifs.

There is ample evidence of wave-like activity in the brain at multiple scales and levels. This emerging literature supports the broader adoption of a wave perspective of brain activity. Specifically, a brain state can be described as a set of recurring, sequential patterns of propagating brain activity, namely a wave. We examine a collective body of experimental work investigating wave-like properties. Based on these works, we consider brain states as waves using a scale-agnostic framework across time and space. Emphasis is placed on the sequentiality and periodicity associated with brain activity. We conclude by discussing the implications, prospects, and experimental opportunities of this framework.

The Thermodynamics of Mind.

To not only survive, but also thrive, the brain must efficiently orchestrate distributed computation across space and time. This requires hierarchical organisation facilitating fast information transfer and processing at the lowest possible metabolic cost. Quantifying brain hierarchy is difficult but can be estimated from the asymmetry of information flow. Thermodynamics has successfully characterised hierarchy in many other complex systems. Here, we propose the 'Thermodynamics of Mind' framework as a natural way to quantify hierarchical brain orchestration and its underlying mechanisms. This has already provided novel insights into the orchestration of hierarchy in brain states including movie watching, where the hierarchy of the brain is flatter than during rest. Overall, this framework holds great promise for revealing the orchestration of cognition.

Simultaneous two-photon imaging and wireless EEG recording in mice.

Background: In vivo two-photon imaging is a reliable method with high spatial resolution that allows observation of individual neuron and dendritic activity longitudinally. Neurons in local brain regions can be influenced by global brain states such as levels of arousal and attention that change over relatively short time scales, such as minutes. As such, the scientific rigor of investigating regional neuronal activities could be enhanced by considering the global brain state. New method: In order to assess the global brain state during in vivo two-photon imaging, CBRAIN (collective brain research platform aided by illuminating neural activity), a wireless EEG collecting and labeling device, was controlled by the same computer of two-photon microscope. In an experiment to explore neuronal responses to isoflurane anesthesia through two-photon imaging, we investigated whether the response of individual cells correlated with concurrent EEG changes induced by anesthesia. Results: In two-photon imaging, calcium activities of the excitatory neurons in the primary somatosensory cortex disappeared in about 30s after to the initiation of isoflurane anesthesia. The simultaneously recorded EEG showed various transitional activity for about 7 min from the initiation of anesthesia and continued with burst and suppression alternating pattern thereafter. As such, there was a dissociation between excitatory neuron activity of the primary somatosensory cortex and the global brain activity under anesthesia. Comparison with existing methods: Existing methods to combine two-photon and EEG recording used wired EEG recording. In this study, wireless EEG was used in conjunction with two-photon imaging, facilitated by CBRAIN. More importantly, built-in algorithms of the CBRAIN can automatically detect brain state such as sleep. The codes used for EEG classification are easy to use, with no prior experience required. Conclusion: Simultaneous recording of wireless EEG and two-photon imaging provides a practical way to capture individual neuronal activities with respect to global brain state in an experimental set-up.

Dynamic reconfiguration of brain coactivation states that underlying working memory correlates with cognitive decline in clinically unimpaired older adults.

Impairments in working memory (WM) are evident in both clinically diagnosed patients with mild cognitive decline and older adults at risk, as indicated by lower scores on neuropsychological tests. Examining the WM-related neural signatures in at-risk older adults becomes essential for timely intervention. WM functioning relies on dynamic brain activities, particularly within the frontoparietal system. However, it remains unclear whether the cognitive decline would be reflected in the decreased dynamic reconfiguration of brain coactivation states during WM tasks. We enrolled 47 older adults and assessed their cognitive function using the Montreal Cognitive Assessment. The temporal dynamics of brain coactivations during a WM task were investigated through graph-based time-frame modularity analysis. Four primary recurring states emerged: two task-positive states with positive activity in the frontoparietal system (dorsal attention and central executive); two task-negative states with positive activity in the default mode network accompanied by negative activity in the frontoparietal networks. Heightened WM load was associated with increased flexibility of the frontoparietal networks, but the cognitive decline was correlated with reduced capacity for neuroplastic changes in response to increased task demands. These findings advance our understanding of aberrant brain reconfiguration linked to cognitive decline, potentially aiding early identification of at-risk individuals.

MEP and TEP features variability: is it just the brain-state?

Objective.The literature investigating the effects of alpha oscillations on corticospinal excitability is divergent. We believe inconsistency in the findings may arise, among others, from the electroencephalography (EEG) processing for brain-state determination. Here, we provide further insights in the effects of the brain-state on cortical and corticospinal excitability and quantify the impact of different EEG processing.Approach.Corticospinal excitability was measured using motor evoked potential (MEP) peak-to-peak amplitudes elicited with transcranial magnetic stimulation (TMS); cortical responses were studied through TMS-evoked potentials' TEPs features. A TMS-EEG-electromyography (EMG) dataset of 18 young healthy subjects who received 180 single-pulse (SP) and 180 paired pulses (PP) to determine short-intracortical inhibition (SICI) was investigated. To study the effect of different EEG processing, we compared the brain-state estimation deriving from three published methods. The influence of presence of neural oscillations was also investigated. To evaluate the effect of the brain-state on MEP and TEP features variability, we defined the brain-state based on specific EEG phase and power combinations, only in trials where neural oscillations were present. The relationship between TEPs and MEPs was further evaluated.Main results.The presence of neural oscillations resulted in more consistent results regardless of the EEG processing approach. Nonetheless, the latter still critically affected the outcomes, making conclusive claims complex. With our approach, the MEP amplitude was positively modulated by the alpha power and phase, with stronger responses during the trough phase and high power. Power and phase also affected TEP features. Importantly, similar effects were observed in both TMS conditions.Significance.These findings support the view that the brain state of alpha oscillations is associated with the variability observed in cortical and corticospinal responses to TMS, with a tight correlation between the two. The results further highlight the importance of closed-loop stimulation approaches while underlining that care is needed in designing experiments and choosing the analytical approaches, which should be based on knowledge from offline studies to control for the heterogeneity originating from different EEG processing strategies.

Laminar evoked responses in mouse somatosensory cortex suggest a special role for deep layers in cortical complexity.

It has been suggested that consciousness is closely related to the complexity of the brain. The perturbational complexity index (PCI) has been used in humans and rodents to distinguish conscious from unconscious states based on the global cortical responses (recorded by electroencephalography, EEG) to local cortical stimulation (CS). However, it is unclear how different cortical layers respond to CS and contribute to the resulting intra- and inter-areal cortical connectivity and PCI. A detailed investigation of the local dynamics is needed to understand the basis for PCI. We hypothesized that the complexity level of global cortical responses (PCI) correlates with layer-specific activity and connectivity. We tested this idea by measuring global cortical dynamics and layer-specific activity in the somatosensory cortex (S1) of mice, combining cortical electrical stimulation in deep motor cortex, global electrocorticography (ECoG) and local laminar recordings from layers 1-6 in S1, during wakefulness and general anaesthesia (sevoflurane). We found that the transition from wake to sevoflurane anaesthesia correlated with a drop in both the global and local PCI (PCIst ) values (complexity). This was accompanied by a local decrease in neural firing rate, spike-field coherence and long-range functional connectivity specific to deep layers (L5, L6). Our results suggest that deep cortical layers are mechanistically important for changes in PCI and thereby for changes in the state of consciousness.

Closed-Loop Brain Stimulation.

In the same way that beauty lies in the eye of the beholder, what a stimulus does to the brain is determined not simply by the nature of the stimulus but by the nature of the brain that is receiving the stimulus at that instant in time. Over the past decades, therapeutic brain stimulation has typically applied open-loop fixed protocols and has largely ignored this principle. Only recent neurotechnological advancements have enabled us to predict the nature of the brain (i.e., the electrophysiological brain state in the next instance in time) with sufficient temporal precision in the range of milliseconds using feedforward algorithms applied to electroencephalography time-series data. This allows stimulation exclusively whenever the targeted brain area is in a prespecified excitability or connectivity state. Preclinical studies have shown that repetitive stimulation during a particular brain state (e.g., high-excitability state), but not during other states, results in lasting modification (e.g., long-term potentiation) of the stimulated circuits. Here, we survey the evidence that this is also possible at the systems level of the human cortex using electroencephalography-informed transcranial magnetic stimulation. We critically discuss opportunities and difficulties in developing brain state-dependent stimulation for more effective long-term modification of pathological brain networks (e.g., in major depressive disorder) than is achievable with conventional fixed protocols. The same real-time electroencephalography-informed transcranial magnetic stimulation technology will allow closing of the loop by recording the effects of stimulation. This information may enable stimulation protocol adaptation that maximizes treatment response. This way, brain states control brain stimulation, thereby introducing a paradigm shift from open-loop to closed-loop stimulation.

Extraction of brain function pattern with visual-capture-task fMRI using dynamic time-window method in ADHD children.

Attention deficit/Hyperactivity disorder (ADHD) has a great impact on children's development. This paper uses a novel adaptive brain state extraction algorithm to construct a dynamic time-window brain network, which captures the brain function pattern characteristics of ADHD children with higher temporal resolution. The test data were acquired by functional magnetic resonance imaging (fMRI) obtained from 23 children with ADHD during the visual-capture-task [age: (8.27 ± 2.77)]. A spatial standard deviation method is used after the initial data processing, to extract the brain activity pattern state; An improved clustering algorithm is constructed to verify the changes made to the dynamic time-window brain network model. There can be seen clear differences between each state within 0.05 s after the test. The results show that our improved new framework can effectively obtain the characteristics of dynamic brain functional connection strength changes during the task. In addition, the new algorithm is able to capture the dynamic changes of the brain network, with an 80 % improvement compared to traditional methods for the average modularity value Q. This work demonstrates a novel approach to find out the pattern changes between dynamic brain function connections, which can be of great significance for the adjuvant treatment of children with ADHD.

Human brain state dynamics reflect individual neuro-phenotypes.

Neural activity and behavior manifest state and trait dynamics, as well as variation within and between individuals. However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatio-temporal features of co-activation patterns at the single subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of occupying a particular co-activation pattern is reproducible and associated with neural and behavioral features. This combined analysis of state-trait variations holds promise for developing reproducible neuroimaging markers of individual life functional outcome.

Improved dynamic functional connectivity estimation with an alternating hidden Markov model.

Dynamic functional connectivity (DFC) analysis has been widely applied to functional magnetic resonance imaging (fMRI) data to reveal the time-varying functional interactions between brain regions. Although the sliding window (SW) method is popular for DFC analysis, the selection of window length is hard, and the temporal resolution is limited by the window length. The hidden Markov model (HMM) without the limitation of window length has been proven to be able to estimate time-varying brain states from fMRI data. However, HMM tends to be overfitted in DFC analysis of fMRI data because of the high spatial dimension and the limited sample size of fMRI data. In this study, we proposed an alternating HMM (aHMM) method that used the functional connectivity estimation of SW to initialize the covariance matrix of HMM and adopted an alternating HMM procedure to reduce the number of parameters during each optimization. The simulated and real fMRI resting data from the Human Connectome Projects showed that aHMM produced better robustness to noise, parameter number and sample size in DFC estimation than SW and HMM. For the real fMRI resting data of cerebral small vessel disease (CSVD), results of aHMM revealed that amnesia and mild cognitive impairment (aMCI) caused the CSVD with aMCI (CSVD-aMCI) group tended to spend more time on the brain state with overall weak connections and less time on the state with overall strong connections than the CSVD-controls. Moreover, CSVD-aMCI showed significantly lower connectivity amplitude and higher connectivity fluctuation than CSVD-control. In contrast, HMM did not detect intergroup differences of the connectivity amplitude and fluctuations and SW did not detect intergroup differences of connectivity fluctuations and fraction of time. The results further indicated that aHMM outperformed HMM and SW in detecting inter-group differences of temporal properties of DFC and connectivity fluctuations. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09874-3.

TMS of parietal and occipital cortex locked to spontaneous transient large-scale brain states enhances natural oscillations in EEG.

BACKGROUND: Fluctuating neuronal network states influence brain responses to transcranial magnetic stimulation (TMS). Our previous studies revealed that transient spontaneous bihemispheric brain states in the EEG, driven by oscillatory power, information flow and regional domination, modify cortical EEG responses to TMS. However, the impact of ongoing fluctuations of large-scale brain network states on TMS-EEG responses has not been explored. OBJECTIVES: To determine the effects of large-scale brain network states on TMS-EEG responses. METHODS: Resting-state EEG and structural MRI from 24 healthy subjects were recorded to infer large-scale brain states. TMS-EEG was acquired with TMS at state-related targets, identified by the spatial distribution of state activation power from resting-state EEG. TMS-induced oscillations were measured by event-related spectral perturbations (ERSPs), and classified with respect to the brain states preceding the TMS pulses. State-locked ERSPs with TMS at specific state-related targets and during state activation were compared with state-unlocked ERSPs. RESULTS: Intra-individual comparison of ERSPs by threshold free cluster enhancement (TFCE) revealed that posterior and visual state-locked TMS, respectively, increased beta and alpha responses to TMS of parietal and occipital cortex compared to state-unlocked TMS. Also, the peak frequencies of ERSPs were increased with state-locked TMS. In addition, inter-individual correlation analyses revealed that posterior and visual state-locked TMS-induced oscillation power (ERSP clusters identified by TFCE) positively correlated with state-dependent oscillation power preceding TMS. CONCLUSIONS: Spontaneous transient large-scale brain network states modify TMS-induced natural oscillations in specific brain regions. This significantly extends our knowledge on the critical importance of instantaneous state on explaining the brain's varying responsiveness to external perturbation.