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Funding Information: Source(s) of financial support: The study was supported by State funding for University‐level health research (TYH 2013311, Y122417012, and Y102218018), the Signe and Ane Gyllenberg Foundation, the Emil Aaltonen Foundation, and the Finnish Medical Foundation. Funding Information: Eija Kalso has received personal fees for participation in advisory board meetings of Pfizer and Orion Pharma, unrelated to this work. Dr. Juhani Ojala reports grants from Suomen Lääketieteen säätiö, outside the submitted work. Dr. Jukka Vanhanen reports grants from The Emil Aaltonen Foundation, grants from State funding for university‐level health research, during the conduct of the study. Part of Dr. Mari A. Kaunisto's salary is covered by a large Finnish biobank study FinnGen, funded by 12 international pharmaceutical companies (Abbvie, AstraZeneca, Biogen, Celgene, Genentech, a member of the Roche Group, GSK, Janssen, Maze Therapeutics, Merck/MSD, Novartis, Pfizer, and Sanofi) and Business Finland. Pantelis Lioumis has been consulting Nexstim Ltd. for issues not related to this study, such as motor and speech functional mapping until 2016. Dr. Jukka Putaala reports personal fees from Boehringer‐Ingelheim, personal fees and other from Bayer, grants and personal fees from BMS‐Pfizer, grants and personal fees from Abbott/St. Jude Medical, other from Vital Signum, other from Nokia Technologies, other from Bittium, other from BcB Medical, personal fees from Portola, personal fees from Terve Media, grants from Business Finland, grants from Amgen, personal fees from Herantis Pharma, other from Medixine, outside the submitted work; and he has participated in the European Stroke Organisation's guideline working groups on 1) poststroke hyperglycemia and 2) secondary prevention in patients with AF. He also has participated in the Finnish Duodecim Society's guideline working group on Ischemic stroke and TIA. The remaining authors have no potential conflicts to disclose. Conflict of Interest: Publisher Copyright: ©2021 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC on behalf of International Neuromodulation Society. Objectives: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. Materials and Methods: This prospective, randomized, double-blind, Sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations, and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which maytransmit TMS effects in pain control. Results: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17–20% pain relief), with no difference between M1, S2, or Sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. Conclusions: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

How does the brain process and control languages that are learned at a different age, when proficiency in all these languages is high? Early acquired strong languages are likely to have higher baseline activation levels than later learned less-dominant languages. However, it is still largely unknown how the activation levels of these different languages are controlled, and how interference from an irrelevant language is prevented. In this magnetoencephalography (MEG) study on language switching during auditory perception, early Finnish-Swedish bilinguals (N = 18) who mastered English with high proficiency after childhood were presented with spoken words in each of the three languages, while performing a simple semantic categorisation task. Switches from the later learned English to either of the native languages resulted in increased neural activation in the superior temporal gyrus (STG) 400–600 ms after word onset (N400m response), whereas such increase was not detected for switches from native languages to English or between the native languages. In an earlier time window of 350–450 ms, English non-switch trials showed higher activation levels in the inferior frontal gyrus (IFG), pointing to ongoing inhibition of the native languages during the use of English. Taken together, these asymmetric switch costs suggest that native languages are suppressed during the use of a non-native language, despite the receptive nature of the language task. This effect seems to be driven mostly by age of acquisition or language exposure, rather than proficiency. Our results indicate that mechanisms of control between two native languages differ from those of a later learned language, as upbringing in an early bilingual environment has likely promoted automatiation of language control specifically for the native languages.

Objective Cortico-muscular coherence (CMC) is thought to reflect the interplay between cortex and muscle in motor coordination. In Parkinson's disease (PD) patients, levodopa has been shown to enhance CMC. This study examined whether subthalamic nucleus (STN) deep brain stimulation (DBS) affects the CMC in advanced PD. Methods Magnetoencephalography (MEG) and electromyography (EMG) measurements were done simultaneously both with DBS on and off to determine the CMC during wrist extension. The spatiotemporal signal space separation (tSSS) was used for artifact suppression. Results CMC peaks between 13 and 25Hz were found in 15 out of 19 patients. The effect of DBS on CMC was variable. Moreover, the correlation between CMC and motor performance was inconsistent; stronger CMC did not necessarily indicate better function albeit tremor and rigidity may diminish the CMC. Patients having CMC between 13 and 25Hz had the best motor scores at the group level. Conclusions DBS modifies the CMC in advanced PD with large interindividual variability. Significance DBS does not systematically modify CMC amplitude in advanced PD. The results suggest that some components of the CMC may be related to the therapeutic effects of DBS.

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-response

Objective This article explores the feasibility of a novel repetitive navigated transcranial magnetic stimulation (rnTMS) system and compares language mapping results obtained by rnTMS in healthy volunteers and brain tumor patients. Methods Fifteen right-handed healthy volunteers and 50 right-handed consecutive patients with left-sided gliomas were examined with a picture-naming task combined with time-locked rnTMS (5–10 Hz and 80–120% resting motor threshold) applied over both hemispheres. Induced errors were classified into four psycholinguistic types and assigned to their respective cortical areas according to the coil position during stimulation. Results In healthy volunteers, language disturbances were almost exclusively induced in the left hemisphere. In patients errors were more frequent and induced at a comparative rate over both hemispheres. Predominantly dysarthric errors were induced in volunteers, whereas semantic errors were most frequent in the patient group. Conclusion The right hemisphere’s increased sensitivity to rnTMS suggests reorganization in language representation in brain tumor patients. Significance rnTMS is a novel technology for exploring cortical language representation. This study proves the feasibility and safety of rnTMS in patients with brain tumor.

Background Recently, navigated transcranial magnetic stimulation (nTMS) has been suggested to be useful in preoperative functional localization of motor cortex in patients having tumors close to the somatomotor cortex. Resection of tumors in anatomically predicted eloquent areas without adverse effects have emphasized functional plasticity elicited by intracranial pathology. Objective To describe functional plasticity of motor cortex indicated by nTMS in two patients with epilepsy. Methods nTMS, functional MRI (fMRI), diffusion-tensor (DT)-tractography and magnetoencephalography (MEG) were utilized to preoperatively localize motor cortical areas in the workup for epilepsy surgery. The localizations were compared with each other, with the cortical anatomical landmarks, and in one patient with invasive electrical cortical stimulation (ECS). Results In two out of 19 studied patients, nTMS identified motor cortical sites that differed from those indicated by anatomical landmarks. In one patient, nTMS activated preferentially premotor cortex rather than pathways originating from the precentral gyrus. MEG and fMRI localizations conformed with nTMS whereas ECS localized finger motor function into the precentral gyrus. Resection of the area producing motor responses in biphasic nTMS did not produce a motor deficit. In the other patient, nTMS indicated abnormal ipsilateral hand motor cortex localization and confirmed the functionality of aberrant motor cortical representations of the left foot also indicated by fMRI and DT-tractography. Conclusion nTMS may reveal the functional plasticity and shifts of motor cortical function. Epileptic foci may modify cortical inhibition and the nTMS results. Therefore, in some patients with epilepsy, the nTMS results need to be interpreted with caution with regard to surgical planning.

Adequate sleep is important for the health and well being of animals but we lack non-invasive methods to record sleep states from group-housed, freely-moving farm animals. We used electrophysiological data (electroencephalography; EEG, electromyography; EMG, and electro-oculography; EOG) to characterize sleep states in calves and examined how well observations of resting behaviour were correlated with the electrophysiological data. We obtained 20 h of EEG, EMG and EOG recordings from each of six pair-housed dairy calves using an ambulatory EEG recording device, while recording their resting posture via direct observation. Visual scoring of the electrophysiological data was used to distinguish between awake, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep during 30 s epochs. Calves were asleep for a mean (±S.D.) 25% (±2.0) of all observations in 50 (±22) bouts of 5 (±2) min per day. NREM sleep composed 55% (±7) and REM sleep 45% (±7) of the calves’ total sleep time. Both types of sleep occurred in short bouts of 2–3 min. According to electrophysiological data, calves were awake during 81% (±9) of the 30 s-epochs when the calf was standing or resting with its head lifted up and moving. Observations of “the calf resting head lifted up still” predicted 55% (±9) of the epochs of NREM sleep. The best behavioural predictor of REM sleep was “the calf resting with neck relaxed”, which predicted 61% (±9) of the epochs of REMS. The calves’ resting body postures can successfully be used to estimate calves’ total duration of time asleep and duration of time spent in REM and NREM sleep states. However, there was less success in estimating the time spent in the different phases of sleep during each 30 s epoch. Electrophysiological data can be recorded non-invasively from freely-moving, group-housed calves and observations of resting behaviour can identify when calves are asleep, although further work is needed to use behaviour to identify the phases of sleep.

Abnormal low-frequency entrainment in sensorimotor cortical areas of Parkinson's disease (PD) patients has been observed in MEG recordings. Efficacy of high-frequency stimulation of subthalamic nucleus (STN) in treating PD may result from blocking such abnormal oscillations. Artifacts elicited by stimulation have precluded MEG study of such patients. We recorded spontaneous MEG activity with a 306-channel Elekta Neuromag® instrument from a Parkinsonian patient with an implanted neurostimulator, with electrodes in both subthalamic nuclei when 130-Hz STN stimulation was on and off. Auditory evoked fields (AEFs) were recorded as well. Brain activity was revealed by applying temporally extended signal space separation on the signals strongly contaminated by stimulation-related artifacts. Bipolar STN stimulation decreased spontaneous activity in the 3–20 Hz range over the right sensorimotor cortex both when eyes were open and closed. Less systematic changes were observed over the left hemisphere where monopolar stimulation was associated with an increase of the low-frequency activity. Suppression of occipital alpha activity in eyes open condition as well as AEF source locations corresponded with those in normal subjects. The results suggest that STN stimulation modifies spontaneous activity over the sensorimotor cortices.

Therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are extensively studied in patients with Parkinson's disease (PD). rTMS to primary motor cortex (M1) induces dopamine release in the putamen: consequently M1 is an interesting target for rTMS in PD. The rTMS over M1 in PD patients reduces the reaction time, improves the Unified Parkinson's Disease Rating Scale (UPDRS) scores and alleviates bradykinesia and hypokinesia. However, the effects of rTMS on spontaneous brain activity are not known. We investigated whether subthreshold rTMS to M1 modulated spontaneous oscillations recorded with magnetoencephalography (MEG). MEG from nine medicated, non-demented PD patients displayed a significant increase in beta oscillations after rTMS in the stimulated hemisphere. Minimum current estimate calculations revealed an increase of beta oscillatory activity after the rTMS treatment over the Rolandic regions. The rTMS in PD patients alters spontaneous brain activity as seen with MEG, probably by modulating cortico-thalamo-basal ganglia networks.

Somatosenosor evoked magnetic fields (SEFs) to contralateral medium and ulnnar nerve stimulation were analyzed in 10 patients with multiple sclerosis and in 8 healthy controls. SEFs were recorded with a 24-channel SQUID gradiometer over both hemispheres. Seven patients' showed abnormally large-amplitude SEF deflections at 60–80 msec; 5 of them had multiple lesions around lateral ventricles in magnetic resonance imaging. In 2 patients with plaques at the level of 3rd and 4th ventricles and medulla, the 30 msce response were enlarged. The equivalent sources of 20 msec and 30–80 msec responses were in the primary hand sensorimotor cortex both in patients and in control subjects. The results suggest that early and middle-latency SEFs reflect parallel processing of somatosensory input. Recording of middle-latency evoekd responses, electric or magnetic, may give additional information about the somatosensory function in multiple sclerosis.