Biology subjects

Tomasevic, L.

Publications and source records attributed to Tomasevic, L..

11 recordsLinked to original sources

bioRxiv2026

Opposing modulation of cortical and corticospinal excitability across movement-related beta stages

Discrete voluntary movement depends on rapid changes in neural excitability across cortical and corticospinal circuits, yet how intrinsic movement-related neural states shape multi-level excitability remains unclear. Here, we combined individualized, state-targeted transcranial magnetic stimulation (TMS) with electroencephalography and electromyography recordings during visually cued finger movements to probe excitability across movement-related beta-band dynamics during two complementary experiments. Immediate transsynaptic cortical excitability closely tracked intrinsic beta dynamics, with attenuation of the second immediate TMS-evoked potential during beta desynchronization and recovery during the post-movement beta rebound. In contrast, corticospinal excitability showed the opposite pattern, with larger motor-evoked potentials during beta desynchronization and reduced responses during beta rebound. Together, these findings identify endogenous beta-state dynamics as a key regulator of movement-related cortical excitability and reveal a fundamental dissociation between how intrinsic brain activity tunes local cortical excitability and corticospinal output in humans.

neuroscience↗

bioRxiv2026

1 Hz rTMS Is Not Inherently Inhibitory: Current Direction Determines Aftereffects and Reliability

ObjectiveAftereffects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) often differ within and between subjects and thus show low reliability. In this study we investigated the mean and individual aftereffects of 1 Hz rTMS using two opposing current directions, their reliability and potential influences of current direction, participants sex and state on cortical excitability modulations. MethodsThirteen healthy, right-handed participants underwent four experimental sessions separated by at least 7 days receiving 2000 pulses of suprathreshold 1 Hz rTMS over the primary motor cortex per session. Two sessions were conducted with an induced current direction of anterior-posterior - posterior-anterior (AP-PA) and two sessions with a PA-AP current direction. Before and after rTMS, 100 single TMS pulses were administered with the respective current direction and electromyography was recorded from the first dorsal interosseous. Questionnaires on demographic data and subjective ratings were completed during the experiment. ResultsLinear mixed effect model analysis revealed that 1 Hz rTMS induced an excitatory aftereffect when applied with the PA-AP current direction, and no aftereffect with AP-PA. There was a substantial interindividual variability with only three subjects showing an inhibition to 1 Hz rTMS overall. Also, current direction was the only predictor of rTMS aftereffect. Reliability values of these aftereffects were in the poor to moderate range. ConclusionsCurrent direction plays a crucial role in determining 1 Hz rTMS aftereffects. Reliability was found to be moderate at best. Additional to current direction, more factors need to be considered to tailor the 1 Hz rTMS aftereffects individually.

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bioRxiv2025

Not two sides of the same coin: Divergent effects of motor state on corticospinal and cortical responses to TMS of motor cortex

BackgroundTranscranial magnetic stimulation (TMS) of the motor cortex can elicit motor evoked potentials (MEPs) in target muscles, reflecting corticospinal excitability. MEP amplitudes increase with TMS intensity and can be facilitated by tonic muscle pre-activation. Since conventional transcranial evoked potentials (TEPs) also grow with increasing TMS intensity, cortical and corticospinal responses are often considered two facets of the same process. If this were true, changes in physiological motor state should modulate TEPs and MEPs in a similar manner. MethodsTo compare the state-dependency of cortical and corticospinal responses to single-pulse TMS, we simultaneously recorded TEPs and MEPs in 16 healthy young adults during relaxation and isometric contraction of the right first dorsal interosseous (FDI) muscle. For each condition, 100 biphasic TMS pulses were delivered to the left primary motor hand area at five different intensities centered around the resting motor threshold. ResultsTEP and MEP amplitudes increased with stimulation intensity. As predicted, tonic muscle contraction consistently facilitated MEP. On the contrary, muscle contraction attenuated two key peaks of the TEP (N15 and N100). The state-dependent effects of corticospinal and cortical responses were not correlated. DiscussionBoth TEPs and MEPs are reliably modulated by motor state, yet they differ in direction and their magnitudes do not scale with each other. These findings challenge the assumption that cortical and corticospinal responses are two aspects of the same process. MEP facilitation during contraction likely reflects increased spinal excitability, whereas TEP attenuation may reflect reduced responsiveness of cortico-cortical or cortico-subcortical networks.

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bioRxiv2025

Quantifying state-dependent control properties of brain dynamics from perturbation responses

The brain can be conceptualized as a control system facilitating transitions between states, such as from rest to motor activity. Applying network control theory to measurements of brain signals enables characterization of brain dynamics through control properties. However, most prior studies that have applied network control theory have evaluated brain dynamics under unperturbed conditions, neglecting the critical role of external perturbations in accurate system identification. In this study, we combine a perturbation input paradigm with a network control theory framework and propose a novel method for estimating the controllability Gramian matrix in a simple, theoretically grounded manner. This method provides insights into brain dynamics, including overall controllability (quantified by the Gramians eigenvalues) and specific controllable directions (represented by its eigenvectors). As a proof of concept, we applied our method to transcranial magnetic stimulationinduced electroencephalographic responses across four motor-related states and two resting states. We found that states such as open-eye rest, closed-eye rest, and motor-related states were more effectively differentiated using controllable directions than overall controllability. However, certain states, like motor execution and motor imagery, remained indistinguishable using these measures. These findings indicate that some brain states differ in their intrinsic control properties as dynamical systems, while others share similarities that make them less distinguishable. This study underscores the value of control theory-based analyses in quantitatively how intrinsic brain states shape the brains responses to stimulation, providing deeper insights into the dynamic properties of these states. This methodology holds promise for diverse applications, including characterizing individual response variability and identifying conditions for optimal stimulation efficacy. Significant statementThe brain can be viewed as a control system transitioning between states, such as from rest to motor activity. Previous studies using network control theory mostly evaluated brain dynamics without external perturbations, neglecting their role in accurate system identification. This study integrates perturbation inputs with network control theory to propose a method for estimating the controllability Gramian, thereby providing insights into brain dynamics. We applied this approach to TMS-induced EEG responses in motor-related and resting states. Our findings show that controllable directions (eigenvectors) allow better discrimination between states than overall controllability. Our method can quantitatively assess brain state differences, and has potential applications in characterizing individual response variability and optimizing stimulation efficacy.

neuroscience↗

bioRxiv2025

Rostro-caudal TMS mapping of immediate transcranial evoked potentials reveals a pericentral crescendo-decrescendo pattern

BackgroundWe recently demonstrated that single-pulse TMS of the primary sensorimotor hand area (SM1HAND) elicits an immediate transcranial evoked potential (iTEP). This iTEP response appears within 2-7 ms post-TMS, featuring high-frequency peaks superimposed on a slow positive wave. Here, we used a linear TMS-EEG mapping approach to characterize the rostro-caudal iTEP expression and compared it to that of motor-evoked potentials (MEPs). MethodsIn 15 healthy young volunteers (9 females), we identified the iTEP hotspot in left SM1HAND. We applied single biphasic TMS pulses at an intensity of 110% of resting motor threshold over six cortical sites along a rostro-caudal axis (2 cm rostral to 3 cm caudal to the SM1HAND hotspot). We analyzed site-specific iTEP and MEP responses. ResultsiTEP magnitude decreased rostrally and caudally from the SM1HAND hotspot. MEPs exhibited a similar rostro-caudal crescendo-decrescendo pattern. While iTEP and MEP response profiles were similar, normalized iTEP amplitudes decayed less rapidly at the first postcentral site. DiscussionThese findings support the idea that pericentral iTEPs reflect a direct response signature of the pericentral cortex, possibly involving a synchronized TMS-induced excitation of cortical pyramidal tract neurons. Similar but non-identical rostro-caudal patterns suggest that iTEPs and MEPs may arise from overlapping but distinct neuronal populations.

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bioRxiv2024

Methodological choices matter: A systematic comparison of TMS-EEG studies targeting the primary motor cortex

BackgroundTranscranial magnetic stimulation (TMS) triggers time-locked cortical activity that can be recorded with electroencephalography (EEG). Transcranial evoked potentials (TEPs) are widely used to probe brain responses to TMS. MethodsHere, we systematically reviewed 137 published experiments that studied TEPs elicited from TMS to the human primary motor cortex (M1) in healthy individuals to investigate the impact of methodological choices. We scrutinized prevalent methodological choices and assessed how consistently they were reported in published papers. We extracted amplitudes and latencies from reported TEPs and compared total cortical activation and specific TEP peaks and components. ResultsReporting of methodological details was overall sufficient, but some relevant information regarding the TMS settings and the recording and pre-processing of EEG data were missing in more than 25% of the included experiments. The published TEP latencies and amplitudes confirm the prototypical TEP waveform of M1, comprising distinct N15, P30, N45, P60, N100, and P180 peaks. However, variations in amplitude and latencies were evident across studies. Higher stimulation intensities were associated with overall larger TEP amplitudes. Active noise masking during TMS generally resulted in lower TEP amplitudes compared to no or passive masking but did not specifically impact those TEP peaks linked to long-latency sensory processing. Studies implementing independent component analysis (ICA) for artifact removal generally reported lower TEP amplitudes. ConclusionSome aspects of reporting practices could be improved in TEP studies to enable replication. Methodological choices, including TMS intensity and the use of noise masking or ICA, introduce systematic differences in reported TEP amplitudes. Further investigation into the significance of these and other methodological factors and their interactions is warranted.

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bioRxiv2023

Transcranial magnetic stimulation of primary motor cortex elicits a site-specific immediate transcranial evoked potential

BackgroundTranscranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation (TMS). Immediate transcranial evoked potentials (i-TEPs) have been obscured by pulse and muscular artifacts. Thus, the TEP peaks that are commonly reported have latencies that are too long to be caused by direct excitation of cortical neurons. MethodsIn 14 healthy individuals, we recorded i-TEPs evoked by a single biphasic TMS pulse targeting the primary motor hand area (M1HAND) or parietal or midline control sites. Sampling EEG at 50 kHz enabled us to reduce the duration of the TMS pulse artifact to a few milliseconds, while minor adjustments of the TMS coil tilt or position enabled us to avoid cranial muscular twitches during the experiment. ResultsWe observed an early positive EEG deflection starting after approx. 2 ms combined with a series of peaks with an inter-peak interval of [~]1.1-1.4 ms in electrodes overlying the stimulated sensorimotor region. This multi-peak i-TEP response was only evoked by TMS of the M1HAND region and was modified by changes in stimulation intensity and current direction. DiscussionSingle-pulse TMS of the M1HAND evokes an immediate local multi-peak response at the cortical site of stimulation. Our results suggest that the observed i-TEP patterns are genuine cortical responses evoked by TMS caused by synchronized excitation of pyramidal neurons in the targeted precentral cortex. This notion needs to be corroborated in future studies, including further investigations into the potential contribution of instrumental or physiological artifacts.

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bioRxiv2021

Relationship between high-frequency activity in the sensory and the motor hand areas, and regional myelin content

BackgroundThe human primary sensory (S1) and primary motor (M1) hand areas feature high-frequency neuronal responses. Electrical nerve stimulation evokes high-frequency oscillations (HFO) at around 650 Hz in the contralateral S1. Likewise, transcranial magnetic stimulation (TMS) of M1 can evoke a series of descending volleys in the corticospinal pathway that can be detected non-invasively with a paired-pulse TMS protocol, called short interval intracortical facilitation (SICF). SICF features several peaks of facilitation of motor evoked potentials in contralateral hand muscles, which are separated by inter-peak intervals resembling HFO rhythmicity. HypothesisIn this study, we tested the hypothesis that the individual expressions of HFO and SICF are tightly related to each other and to the regional myelin content in the sensorimotor cortex. MethodsIn 24 healthy volunteers, we recorded HFO and SICF, and, in a subgroup of 20 participants, we mapped the cortical myelin content using the ratio between the T1- and T2-weighted MRI signal as read-out. ResultsThe individual frequencies and magnitudes of HFO and SICF curves were tightly correlated: the intervals between the first and second peak of cortical HFO and SICF showed a positive linear relationship (r= 0.703, p< 0.001), while their amplitudes were inversely related (r= -0.613, p= 0.001). The rhythmicity, but not the magnitude of the high-frequency responses, was related to the cortical myelin content: the higher the cortical myelin content, the shorter the inter-peak intervals of HFO and SICF. ConclusionThe results confirm a tight functional relationship between high-frequency responses in S1 (i.e., HFO) and M1 (i.e., as measured with SICF). They also establish a link between the degree of regional cortical myelination and the expression of high-frequency responses in the human sensorimotor cortex, giving further the opportunity to infer their generators.

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bioRxiv2021

Profiling the transcallosal response of rat motor cortex evoked by contralateral optogenetic stimulation of glutamatergic cortical neurons

BackgroundEfficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control. ObjectiveWe employed optogenetic stimulation to establish a framework for probing transcallosal M1-M1 interactions in rats. MethodsIn male rats, we optogenetically stimulated glutamatergic neurons in right M1 and recorded the transcallosally evoked potential with chronically implanted electrodes in contralateral left M1 during dexmedetomidine anesthesia. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1. ResultsOptogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. Median N1 latencies remained stable, once stimulation elicited a reliable N1 peak and did not display a systematic shortening with increasing stimulation intensity or duration. ConclusionsOptogenetically stimulated glutamatergic neurons in M1 can reliably evoke a transcallosal response in anesthetized rats and can be used to characterize the relationship between "stimulation dose" and "response magnitude" (i.e., the gain function) of transcallosal M1-to-M1 glutamatergic connections. Detailed knowledge of the stimulus-response relationship is needed to optimize the efficacy of optogenetic stimulation. Since transcallosal M1-M1 interactions can also be probed non-invasively with transcranial magnetic stimulation in humans, our optogenetic stimulation approach bears translational potential for studying how unilateral M1 stimulation can induce interhemispheric plasticity.

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bioRxiv2019

No trace of phase: Corticomotor excitability is not tuned by phase of pericentral mu-rhythm

BackgroundThe motor potentials evoked by transcranial magnetic stimulation (TMS) over the motor hand area (M1-HAND) show substantial inter-trial variability. Pericentral mu-rhythm oscillations, might contribute to inter-trial variability. Recent studies targeting mu-activity based on real-time electroencephalography (EEG) reported an influence of mu-power and mu-phase on the amplitude of motor evoked potentials (MEPs) in a preselected group with strong pericentral mu-activity. Other studies that determined mu-power or mu-phase based on post-hoc trial sorting according in non-preselected individuals were largely negative.\n\nObjectivesTo reassess if cortico-spinal activity is modulated by the mu-rhythm, we applied single-pulse TMS to the M1-HAND conditional on the phase of the intrinsically expressed pericentral mu-rhythm in 14 non-preselected healthy young participants.\n\nMethodsTMS was given at 0, 90, 180, and 270 degrees of the mu-phase. Based on the absence of effects of mu-phase or mu-power when analyzing the mean MEP amplitudes, we also computed a linear mixed effects model, which included mu-phase, mu-power, inter-stimulus interval (ISIs) as fixed effects, treating the subject factor as a random effect.\n\nResultsMixed model analysis revealed a significant effect of mu-power and ISI, but no effect of mu-phase and no interactions. MEP amplitude scaled linearly with lower mu-power or longer ISIs, but these modulatory effects were very small relative to inter-trial MEP variability.\n\nConclusionOur largely negative results are in agreement with previous offline TMS-EEG studies and point to a possible influence of ISI. Future research needs to clarify under which circumstances the responsiveness of human the M1-HAND to TMS depends on the synchronicity with mu-power and mu-phase.\n\nHighlightsO_LIPhase-triggered TMS at four distinct phases of the ongoing mu-oscillations is technically feasible in non-preselected young volunteers\nC_LIO_LITargeting the ongoing mu-activity did not reveal consistent modulatory effect of mu-phase on corticospinal excitability in a non-preselected group\nC_LIO_LIMixed-effects analysis revealed a weak but significant effect of pre-stimulus mu-power and ISI on corticospinal excitability\nC_LI

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bioRxiv2018

The non-transcranial TMS-evoked potential is an inherent source of ambiguity in TMS-EEG studies

Transcranial Magnetic Stimulation (TMS) excites populations of neurons in the stimulated cortex, and the resulting activation may spread to connected brain regions. The distributed cortical response can be recorded with electroencephalography (EEG). Since TMS also stimulates peripheral sensory and motor axons and generates a loud \"click\" sound, the TMS-evoked EEG potential (TEP) not only reflects neural activity induced by transcranial neuronal excitation but also neural activity reflecting somatosensory and auditory processing. In 17 healthy young individuals, we systematically assessed the contribution of multisensory peripheral stimulation to TEPs using a TMS-compatible EEG system. Real TMS was delivered with a figure-of-eight coil over the left para-median posterior parietal cortex or superior frontal gyrus with the coil being oriented perpendicularly or in parallel to the target gyrus. We also recorded the EEG responses evoked by sham stimulation over the posterior parietal and superior frontal cortex, mimicking the auditory and somatosensory sensations evoked by real TMS. We applied state-of-the-art procedures to attenuate somatosensory and auditory confounds during real TMS, including the placement of a foam layer underneath the coil and auditory noise masking. Despite these precautions, the temporal and spatial features of the cortical potentials evoked by real TMS at the prefrontal and parietal site closely resembled the cortical potentials evoked by realistic sham TMS, both for early and late TEP components. Our findings stress the need to include a peripheral multisensory control stimulation in the study design to enable a dissociation between truly transcranial and non-transcranial components of TEPs.

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