Navigated transcranial magnetic stimulation in clinical practice and research

Navigated transcranial magnetic stimulation (nTMS) enables precise targeting of the induced electric field to selected cortical targets found by alignment of the head with a 3-D model of the subject’s brain. This is particularly important in studies of patients as some diseases, such as brain tumors, may modify the brain anatomy and function so that the external skull landmarks are not any more aligned with the brain structures. Comparison with the preoperative nTMS and intraoperative direct electrical cortical stimulation (DECS) localization of hand muscle cortical representations has given distances of 3-12 mm between the two methods. Preoperative nTMS mapping is associated with smaller craniotomies and more extensive resections of tumors. Mapping of speech areas with nTMS during videoed object naming is less specific but more sensitive than DECS and produces reliable “negative” maps: if speech nTMS does not find an active area from the area to be resected, DECS findings are highly improbable as well. The first study of clinical impact infers that speech nTMS is associated with smaller craniotomies and less postoperative speech dysfunctions. Good understanding of the relation of nTMS activation sites with those obtained by DECS adds attractivity of the use of nTMS also in the basic research of brain functions.Peer reviewe

Increasing the frequency of peripheral component in paired associative stimulation strengthens its efficacy

Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS), is emerging as a promising tool for alleviation of motor deficits in neurological disorders. The effectiveness and feasibility of PAS protocols are essential for their use in clinical practice. Plasticity induction by conventional PAS can be variable and unstable. Protocols effective in challenging clinical conditions are needed. We have shown previously that PAS employing 50 Hz PNS enhances motor performance in chronic spinal cord injury patients and induces robust motor-evoked potential (MEP) potentiation in healthy subjects. Here we investigated whether the effectiveness of PAS can be further enhanced. Potentiation of MEPs up to 60 minutes after PAS with PNS frequencies of 25, 50, and 100 Hz was tested in healthy subjects. PAS with 100 Hz PNS was more effective than 50 (P = 0.009) and 25 Hz (P = 0.016) protocols. Moreover, when administered for 3 days, PAS with 100 Hz led to significant MEP potentiation on the 3rd day (P = 0.043) even when the TMS target was selected suboptimally (modelling cases where finding an optimal site for TMS is problematic due to a neurological disease). PAS with 100 Hz PNS is thus effective and feasible for clinical applications.Peer reviewe

Neural mechanisms underlying word- and phrase-level morphological parsing

How is morphological and morphosyntactic information processed during sentence reading? Are the neural mechanisms underlying word- and phrase-level combinatorial processing overlapping or distinct? Here, electroencephalography (EEG) and magnetoencephalography (MEG) responses were recorded simultaneously during silent reading of Finnish sentences. The experimental conditions included 1) well-formed grammatical sentences (correct condition), 2) sentences containing morphosyntactic violations (adjective–noun number agreement violations), 3) morphological violations (incorrect stem allomorph and inflectional suffix combination), and 4) combined violations, containing both morphosyntactic and morphological violations. Signal space and source modeling results showed that morphosyntactic violations elicited a left anterior negativity effect, generated particularly in the left inferior frontal area. Morphological violations elicited a widespread negativity, resembling the N400. The neural sources of this negativity were localized most prominently to the right temporal cortical networks. Furthermore, all violations elicited P600 effects with similar widespread bilateral fronto-temporal neural generators that did not differ between morphosyntactic and morphological conditions. Our findings suggest at least partially distinct subnetworks in the fronto-temporal cortices for morphological and morphosyntactic parsing during the earlier stages of processes (∼400 ms post stimulus onset) and shared neural generators for the later processing stages.Peer reviewe

Modulation of sensory cortical activity by deep brain stimulation in advanced Parkinson's disease

Despite optimal oral drug treatment, about 90% of patients with Parkinson's disease develop motor fluctuation and dyskinesia within 5-10 years from the diagnosis. Moreover, the patients show non-motor symptoms in different sensory domains. Bilateral deep brain stimulation (DBS) applied to the subthalamic nucleus is considered the most effective treatment in advanced Parkinson's disease, and it has been suggested to affect sensorimotor modulation and relate to motor improvement in patients. However, observations on the relationship between sensorimotor activity and clinical improvement have remained sparse. Here, we studied the somatosensory evoked magnetic fields in 13 right-handed patients with advanced Parkinson's disease before and 7 months after stimulator implantation. Somatosensory processing was addressed with magnetoencephalography during alternated median nerve stimulation at both wrists. The strengths and the latencies of the similar to 60-ms responses at the contralateral primary somatosensory cortices were highly variable but detectable and reliably localized in all patients. The response strengths did not differ between preoperative and postoperative DBSON measurements. The change in the response strength between preoperative and postoperative condition in the dominant left hemisphere of our right-handed patients correlated with the alleviation of their motor symptoms (p = .04). However, the result did not survive correction for multiple comparisons. Magnetoencephalography appears an effective tool to explore non-motor effects in patients with Parkinson's disease, and it may help in understanding the neurophysiological basis of DBS. However, the high interindividual variability in the somatosensory responses and poor tolerability of DBSOFF condition warrants larger patient groups and measurements also in non-medicated patients.Peer reviewe

Effects of Long-Term Paired Associative Stimulation on Strength of Leg Muscles and Walking in Chronic Tetraplegia : A Proof-of-Concept Pilot Study

Recovery of lower-limb function after spinal cord injury (SCI) is dependent on the extent of remaining neural transmission in the corticospinal pathway. The aim of this proof-of-concept pilot study was to explore the effects of long-term paired associative stimulation (PAS) on leg muscle strength and walking in people with SCI. Five individuals with traumatic incomplete chronic tetraplegia (>34 months post-injury, motor incomplete, 3 females, mean age 60 years) with no contraindications to transcranial magnetic stimulation (TMS) received PAS to one or both legs for 2 months (28 sessions in total, 5 times a week for the first 2 weeks and 3 times a week thereafter). The participants were evaluated with the Manual Muscle Test (MMT), AIS motor and sensory examination, Modified Asworth Scale (MAS), and the Spinal Cord Independence Measure (SCIM) prior to the intervention, after 1 and 2 months of PAS, and after a 1-month follow-up. The study was registered at (NCT03459885). During the intervention, MMT scores and AIS motor scores increased significantly (p = 0.014 and p = 0.033, respectively). Improvements were stable in follow-up. AIS sensory scores, MAS, and SCIM were not modified significantly. MMT score prior to intervention was a good predictor of changes in walking speed (Radj2 = 0.962). The results of this proof-of-concept pilot study justify a larger trial on the effect of long-term PAS on leg muscle strength and walking in people with chronic incomplete SCI.Peer reviewe

Magnetoencephalographic Abnormalities in Creutzfeldt-Jakob Disease: A Case Report

Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease with no effective therapy available. We recorded spontaneous magnetoencephalography and auditory evoked fields (AEFs) from a male patient with a rapidly progressive memory disorder, ataxia and myoclonus. Post-mortem examination confirmed sporadic CJD. Sources of the abnormal slow wave activity were localized with a beamformer software. Sources of sharp transients and AEFs were modeled with equivalent current dipoles. The estimated sources of spontaneous activity abnormalities were more dominant in the left hemisphere, in line with left-dominant abnormalities in diffusion-weighted MRI. Sources of AEFs were found in both temporal lobes. Magnetoencephalography measurements on CJD patients are feasible, and provide efficient means for localizing abnormal cortical activity in CJD

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

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

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

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

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