Belardinelli Lab

Abstract: The combination of transcranial magnetic stimulation and electroencephalography (TMS–EEG) is emerging as a valuable tool for investigating brain functions in health and disease. However, the detailed neural mechanisms underlying TMS–EEG responses, including TMS-evoked EEG potentials (TEPs) and TMS-induced EEG oscillations (TIOs), remain largely unknown. Combining TMS–EEG with pharmacological interventions provides a unique opportunity to elucidate the roles of specific receptor-mediated neurotransmissions in these responses. Here, we investigated the involvement of muscarinic acetylcholine receptor (mAChR)-mediated cholinergic neurotrans mission in TMS–EEG responses by evaluating the effects of mAChR antagonists on TEPs and TIOs in twenty-four healthy participants using a randomized, placebo-controlled crossover design. TEPs and TIOs were measured before and after administering a single oral dose of scopolamine (a non-selective mAChR antagonist), biperiden (an M1 mAChR antagonist), or placebo, with TMS targeting the left medial prefrontal cortex (mPFC), angular gyrus (AG), and supplementary motor area (SMA). The results indicated that mAChR-mediated cholinergic neurotransmission played a role in TEPs, but not TIOs, in a target-specific manner. Specifically, scopolamine significantly increased the amplitude of a local TEP component between approximately 40 and 63 ms post- stimulus when TMS was applied to the SMA, but not the mPFC or AG. Biperiden produced a similar but less pronounced effect. Importantly, the effects of these mAChR antagonists on TEPs were independent of those on sensory-evoked EEG potentials caused by TMS-associated sensory stimulation. These findings expand our un derstanding of TMS–EEG physiology, providing insights for its application in physiological and clinical research.

Authors: Yufei Song, Pedro C. Gordon, Paolo Belardinelli, Olivier Roy, Maryam Rostami, Johanna Metsomaa, Ulf Ziemann

Abstract: Objective: In healthy subjects, the trough vs. no-trough phases of the sensorimotor µ-rhythm correspond to high- vs. low-excitability states of the motor cortex (M1). We tested this excitability differentiation in the ipsilesional (iM1) and contralesional M1 (cM1) of chronic stroke patients. Methods: 19 chronic stroke patients received single-pulse transcranial magnetic stimulation (TMS), separately over the iM1 and cM1, during EEG recordings. High and low M1 excitability states were defined by binning a post-hoc estimate of the µ-phase at TMS delivery. TMS-evoked EEG potentials (TEPs) and time–frequency re sponses were characterized for excitability states and hemispheres. The motor function of the affected arm was tested by the Fugl-Meyer Assessment Upper Extremity (FMA-UE. Results: In cM1, TMS at the high- vs. low-excitability state resulted in larger TEP amplitudes and increased post- pulse power in the beta band. In iM1, these modulations were not significant except for post-pulse beta power. This retained excitability differentiation significantly correlated with FMA-UE. Conclusions: The degree of excitability differentiation in iM1 depending on phase of the sensorimotor µ-rhythm correlates with individual affected upper extremity motor function. Significance: The degree of excitability differentiation in iM1 might serve as a new independent marker of motor recovery.

Authors: Arianna Brancaccio, Wala Mahmoud, Davide Tabarelli, Ulf Ziemann, David Baur, Johanna Roesch, Paolo Belardinelli

Abstract:Background: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. Objective: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuro modulatory effects when targeting the DLPFC of patients with MDD. Methods: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. Results: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. Conclusions: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and effi cacy of brain oscillation-synchronized rTMS in MDD.

Authors:Brigitte Zrenner, Christoph Zrenner, Pedro Caldana Gordon, Paolo Belardinelli, Eric J. McDermott, Surjo R. Soekadar, Andreas J. Fallgatter, Ulf Ziemann, Florian Müller-Dahlhaus

Abstract: Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS EEG) is widely used for studying cortical reactivity and con nectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS EEG equipment and ap proaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS EEG covered all aspects that should be considered inTMS EEG experiments, providing methodological recommendations (when possible) for effective TMS EEG recordings and analysis. The panel identified and discussed the chal lenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

Authors: Julio C. Hernandez-Pavon, Domenica Veniero, Til Ole Bergmann, Paolo Belardinelli, Marta Bortoletto, Silvia Casarotto, Elias P. Casula, Faranak Farzan, Matteo Fecchio, Petro Julkunen, Elisa Kallioniemi, Pantelis Lioumis, Johanna Metsomaa, Carlo Miniussi, Tuomas P. Mutanen, Lorenzo Rocchi, Nigel C. Rogasch, Mouhsin M. Shafi, Hartwig R. Siebner, Gregor Thut, Christoph Zrenner, Ulf Ziemann, Risto J. Ilmoniemi

Abstract:Characterizing age-related alterations in brain networks is crucial for understanding aging trajectories and identifying deviations indicative of neurodegenerative disorders, such as Alzheimer’s disease. In this study, we developed a Fully Hyperbolic Neural Network (FHNN) to embed functional brain connectivity graphs derived from magnetoencephalography (MEG) data into low dimensions on a Lorentz model of hyperbolic space. Using this model, we computed hyperbolic embeddings of the MEG brain networks of 587 individuals from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Notably, we leveraged a unique metric—the radius of the node embeddings—which effectively captures the hierarchical organization of the brain, to characterize subtle hierarchi cal organizational changes in various brain subnetworks attributed to the aging process. Our findings revealed that a considerable number of subnetworks exhibited a reduc tion in hierarchy during aging, with some showing grad ual changes and others undergoing rapid transformations in the elderly. Moreover, we demonstrated that hyperbolic features outperform traditional graph-theoretic measures in capturing age-related information in brain networks. Over all, our study represents the first evaluation of hyperbolic embeddings in MEG brain networks for studying aging trajectories, shedding light on critical regions undergoing

Authors: Hugo Ramirez, Davide Tabarelli , Arianna Brancaccio , Paolo Belardinelli, Elisabeth B. Marsh, Michael Funke, John C. Mosher, Fernando Maestú , Mengjia Xu, Dimitrios Pantazis