Stochastic resonance at early visual cortex during figure orientation discrimination using transcranial magnetic stimulation

Visual noise usually reduces the visibility of stimuli. However, very low contrast or subliminal visual noise can sometimes enhance the visibility of low-contrast stimuli. It has been suggested that this enhancement occurs at the visual cortex. The aims of this study are to clarify the role of the early visual cortex (V1/V2) in the enhancement effect and to clarify the relationship of the SR characteristics among different experiments. Noise was added directly to the visual cortex by using transcranial magnetic stimulation (TMS) with randomly varying intensity. The location on the scalp and the timing (stimulus onset asynchrony, SOA) of TMS were specifically adjusted to target the early visual cortex. Contrast thresholds for figure orientation discrimination were measured as a function of TMS noise intensity. With increasing TMS noise intensity the contrast threshold for figure discrimination first decreased (enhancement) and then increased (impairment). These effects were clearly dependent both on scalp location and timing (SOA). The optimum SOA was around 60 ms, while the optimum location varied across participants. Outside the optimum location and SOA values, no TMS effects were found. The enhancement effect can be accounted for by the stochastic resonance (SR) theory based on a threshold device. In addition, we reveal similarity in characteristics of the SR phenomenon between different experiments.Peer reviewe

The role of neuronavigation in TMS-EEG studies : Current applications and future perspectives

Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) allows measuring noninvasively the electrical response of the human cerebral cortex to a direct perturbation. Complementing TMSEEG with a structural neuronavigation tool (nTMS-EEG) is key for accurately selecting cortical areas, targeting them, and adjusting the stimulation parameters based on some relevant anatomical priors. This step, together with the employment of visualization tools designed to perform a quality check of TMS-evoked potentials (TEPs) in real-time during TMS-EEG data acquisition, is pivotal for maximizing the impact of the TMS pulse on the cortex and in ensuring highly reproducible measurements within sessions and across subjects. Moreover, storing stimulation parameters in the neumnavigation system can help in replicating the stimulation parameters within and across experimental sessions and sharing them across research centers. Finally, the systematic employment of neumnavigation in TMS-EEG studies is also critical to standardize measurements in clinical populations in search for reliable diagnostic and prognostic TMS-EEG-based biomarkers for neurological and psychiatric disorders.Peer reviewe

Transcranial magnetic stimulation in assessment of cortical network properties

This Thesis demonstrates the way to combine navigated transcranial magnetic stimulation (nTMS) with electrophysiological techniques, such as electroencephalography (EEG) and magnetoencephalo­graphy (MEG). This technical and neurophysiological possibility allows the assessment of cortical excitability and functional connectivity with the advantage of high spatiotemporal resolution. Investigation of these cortical network properties can lead in deeper understanding of sensorimotor and speech networks and bridge the gap between basic research and clinical applications by means of TMS. First, we examined whether nTMS–EEG can be used as a marker of cortical excitability changes by investigating the reproducibility of EEG after TMS. We showed that reproducibility is a feature of TMS-evoked EEG responses if the parameters of the stimulation and coil orientation are kept the same. Utilization of navigation is crucial for such test–retest paradigms. The second part of the thesis elaborated the effect of neuronal state prior to TMS on cortico–cortical excitability. We demonstrated modulation of excitability not only of the contra- but also of the ipsilateral hemisphere during preparation and execution of unilateral movements. We also tested the methodology to measure the time onset of cortical activation by grading the levels of its modulation with TMS–EEG. Next, we utilized MEG to detect sensorimotor cortical sources. nTMS was used to target these sources and modulate their activity during a motor task after a sensory stimulation. We demonstrated that stimulation of the secondary somatosensory cortex can influence the primary one and amplify somatosensory processing. By this study, we set the methodological standards on how to use nTMS and MEG in mapping the sensorimotor cortex. Therefore, we applied our experience in presurgical mapping of epileptic patients before cortical resection. By combining the nTMS and MEG advantages, we created a noninvasive methodology to map the sensorimotor cortex. The results were as accurate as electrical cortical stimulation in most patients. Thus, it may be possible to replace costly invasive standard procedures, which pose a high risk for the patient, when the epileptic focus is near sensorimotor cortex and accessible to MEG. This motivated us to create another nTMS paradigm for mapping speech-related areas. We combined an object naming paradigm and repetitive TMS to find cortical sites sensitive to interference during the task. We recorded video of the experiment to evaluate the effect of TMS on the subjects’ performance. The results show that this method may map speech-related areas successfully. All in all, we show that recent advances in TMS set new standards in basic research and clinical applications, such as preoperative work- up and test–retest pharmacological studies. Cross-modal nTMS applications open new avenues in studying cortical network parameters

A New Paired Associative Stimulation Protocol with High-Frequency Peripheral Component and High-Intensity 20 Hz Repetitive Transcranial Magnetic Stimulation-A Pilot Study

Paired associative stimulation (PAS) is a stimulation technique combining transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) that can induce plastic changes in the human motor system. A PAS protocol consisting of a high-intensity single TMS pulse given at 100% of stimulator output (SO) and high-frequency 100-Hz PNS train, or "the high-PAS " was designed to promote corticomotoneuronal synapses. Such PAS, applied as a long-term intervention, has demonstrated therapeutic efficacy in spinal cord injury (SCI) patients. Adding a second TMS pulse, however, rendered this protocol inhibitory. The current study sought for more effective PAS parameters. Here, we added a third TMS pulse, i.e., a 20-Hz rTMS (three pulses at 96% SO) combined with high-frequency PNS (six pulses at 100 Hz). We examined the ability of the proposed stimulation paradigm to induce the potentiation of motor-evoked potentials (MEPs) in five human subjects and described the safety and tolerability of the new protocol in these subjects. In this study, rTMS alone was used as a control. In addition, we compared the efficacy of the new protocol in five subjects with two PAS protocols consisting of PNS trains of six pulses at 100 Hz combined with (a) single 100% SO TMS pulses (high-PAS) and (b) a 20-Hz rTMS at a lower intensity (three pulses at 120% RMT). The MEPs were measured immediately after, and 30 and 60 min after the stimulation. Although at 0 and 30 min there was no significant difference in the induced MEP potentiation between the new PAS protocol and the rTMS control, the MEP potentiation remained significantly higher at 60 min after the new PAS than after rTMS alone. At 60 min, the new protocol was also more effective than the two other PAS protocols. The new protocol caused strong involuntary twitches in three subjects and, therefore, its further characterization is needed before introducing it for clinical research. Additionally, its mechanism plausibly differs from PAS with high-frequency PNS that has been used in SCI patients.Peer reviewe

The impact of TMS and PNS frequencies on MEP potentiation in PAS with high-frequency peripheral component

Paired associative stimulation (PAS) combines transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to induce plastic changes in the corticospinal tract. PAS employing single 0.2-Hz TMS pulses synchronized with the first pulse of 50–100 Hz PNS trains potentiates motor-evoked potentials (MEPs) in a stable manner in healthy participants and enhances voluntary motor output in spinal cord injury (SCI) patients. We further investigated the impact of settings of this PAS variant on MEP potentiation in healthy subjects. In experiment 1, we compared 0.2-Hz vs 0.4-Hz PAS. In experiment 2, PNS frequencies of 100 Hz, 200 Hz, and 400 Hz were compared. In experiment 3, we added a second TMS pulse. When compared with 0.4-Hz PAS, 0.2-Hz PAS was significantly more effective after 30 minutes (p = 0.05) and 60 minutes (p = 0.014). MEP potentiation by PAS with 100-Hz and 200-Hz PNS did not differ. PAS with 400-Hz PNS was less effective than 100-Hz (p = 0.023) and 200-Hz (p = 0.013) PNS. Adding an extra TMS pulse rendered PAS strongly inhibitory. These negative findings demonstrate that the 0.2-Hz PAS with 100-Hz PNS previously used in clinical studies is optimal and the modifications employed here do not enhance its efficacy.Peer reviewe

The use of F-response in defining interstimulus intervals appropriate for LTP-like plasticity induction in lower limb spinal paired associative stimulation

Background In spinal paired associative stimulation (PAS), orthodromic volleys are induced by transcranial magnetic stimulation (TMS) in upper motor neurons, and antidromic volleys by peripheral nerve stimulation (PNS) in lower motor neurons of human corticospinal tract. The volleys arriving synchronously to the corticomotoneuronal synapses induce spike time-dependent plasticity in the spinal cord. For clinical use of spinal PAS, it is important to develop protocols that reliably induce facilitation of corticospinal transmission. Due to variability in conductivity of neuronal tracts in neurological patients, it is beneficial to estimate interstimulus interval (ISI) between TMS and PNS on individual basis. Spinal root magnetic stimulation has previously been used for this purpose in spinal PAS targeting upper limbs. However, at lumbar level this method does not take into account the conduction time of spinal nerves of the cauda equina in the spinal canal. New method For lower limbs spinal PAS, we propose estimating appropriate ISIs on the basis of F-response and motor-evoked potential (MEP) latencies. The use of navigation in TMS and ensuring correct PNS electrode placement with F-response recording enhances the precision of the method. Results Our protocol induced 186 ± 17% (mean ± STE) MEP amplitude facilitation in healthy subjects, being effective in all subjects and nerves tested. Comparison with existing method We report for the first time the individual estimation of ISIs in spinal PAS for lower limbs. Conclusions Estimation of ISI on the basis of F and MEP latencies is sufficient to effectively enhance corticospinal transmission by lower limb spinal PAS in healthy subjects. Keywords Paired associative stimulation; Neuronal plasticity; Transcranial magnetic stimulation; Electrical stimulation therapy; F-responsePeer reviewe

State-dependent TMS effects in the visual cortex after visual adaptation : A combined TMS-EEG study

Objective: The impact of transcranial magnetic stimulation (TMS) has been shown to depend on the initial brain state of the stimulated cortical region. This observation has led to the development of paradigms that aim to enhance the specificity of TMS effects by using visual/luminance adaptation to modulate brain state prior to the application of TMS. However, the neural basis of interactions between TMS and adaptation is unknown. Here, we examined these interactions by using electroencephalography (EEG) to measure the impact of TMS over the visual cortex after luminance adaptation. Methods: Single-pulses of neuronavigated TMS (nTMS) were applied at two different intensities over the left visual cortex after adaptation to either high or low luminance. We then analyzed the effects of adaptation on the global and local cortical excitability. Results: The analysis revealed a significant interaction between the TMS-evoked responses and the adaptation condition. In particular, when nTMS was applied with high intensity, the evoked responses were larger after adaptation to high than low luminance.Conclusion: This result provides the first neural evidence on the interaction between TMS with visual adaptation. Significance: TMS can activate neurons differentially as a function of their adaptation state.(c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Cortical Excitability Measured with nTMS and MEG during Stroke Recovery

Objective. Stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere. Stroke recovery has been studied using transcranial magnetic stimulation (TMS). Spontaneous brain oscillations and somatosensory evoked fields (SEFs) measured by magnetoencephalography (MEG) are modified in stroke patients during recovery. Methods. We recorded SEFs and spontaneous MEG activity and motor threshold (MT) short intracortical inhibition (SICI) and intracortical facilitation (ICF) with navigated TMS (nTMS) at one and three months after first-ever hemispheric ischemic strokes. Changes of MEG and nTMS parameters attributed to gamma-aminobutyrate and glutamate transmission were compared. Results. ICF correlated with the strength and extent of SEF source areas depicted by MEG at three months. The nTMS MT and event-related desynchronization (ERD) of beta-band MEG activity and SICI and the beta-band MEG event-related synchronization (ERS) were correlated, but less strongly. Conclusions. This first report using sequential nTMS and MEG in stroke recovery found intra-and interhemispheric correlations of nTMS and MEG estimates of cortical excitability. ICF and SEF parameters, MT and the ERD of the lesioned hemisphere, and SICI and ERS of the nonlesioned hemisphere were correlated. Covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system.Peer reviewe

Paired Associative Stimulation with High-Frequency Peripheral Component Leads to Enhancement of Corticospinal Transmission at Wide Range of Interstimulus Intervals

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Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand

A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38-68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0-5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 +/- 0.17 points (p <0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 +/- 29%, p = 0.046, n = 5 patients). Longterm PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.Peer reviewe