Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

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 may transmit 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.

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 ~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.

Effect of long-term paired associative stimulation on the modulation of cortical sensorimotor oscillations after spinal cord injury.

STUDY DESIGN: A prospective interventional case series. OBJECTIVES: To explore changes in the modulation of cortical sensorimotor oscillations after long-term paired associative stimulation (PAS) in participants with spinal cord injury (SCI). SETTING: BioMag Laboratory, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. METHODS: Five patients with chronic incomplete SCI received unilateral spinal PAS to upper limb for 16-22 days. Changes in the modulation of sensorimotor oscillations in response to tactile stimulus and active and imaginary hand movements were assessed with magnetoencephalography recorded before and after the intervention. RESULTS: PAS restored the modulation of sensorimotor oscillations in response to active hand movement in four patients, whereas the modulation following tactile stimulation remained unaltered. The observed change was larger in the hemisphere that received PAS and preceded the clinical effect of the intervention. CONCLUSIONS: Long-term spinal PAS treatment, which enhances the motor functions of SCI patients, also restores the modulation of cortical sensorimotor oscillations.

Deep brain stimulation of subthalamic nucleus modulates cortical auditory processing in advanced Parkinson's Disease.

Deep brain stimulation (DBS) has proven its clinical efficacy in Parkinson's disease (PD), but its exact mechanisms and cortical effects continue to be unclear. Subthalamic (STN) DBS acutely modifies auditory evoked responses, but its long-term effect on auditory cortical processing remains ambiguous. We studied with magnetoencephalography the effect of long-term STN DBS on auditory processing in patients with advanced PD. DBS resulted in significantly increased contra-ipsilateral auditory response latency difference at ~100 ms after stimulus onset compared with preoperative state. The effect is likely due to normalization of neuronal asynchrony in the auditory pathways. The present results indicate that STN DBS in advanced PD patients has long-lasting effects on cortical areas outside those confined to motor processing. Whole-head magnetoencephalography provides a feasible tool to study motor and non-motor neural networks in PD, and to track possible changes related to cortical reorganization or plasticity induced by DBS.

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.

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.

Reduced evoked activity and cortical oscillations are correlated with anisometric amblyopia and impairment of visual acuity.

Amblyopia is a developmental disorder associated with abnormal visual experience during early childhood commonly arising from strabismus and/or anisometropia and leading to dysfunctions in visual cortex and to various visual deficits. The different forms of neuronal activity that are attenuated in amblyopia have been only partially characterized. In electrophysiological recordings of healthy human brain, the presentation of visual stimuli is associated with event-related activity and oscillatory responses. It has remained poorly understood whether these forms of activity are reduced in amblyopia and whether possible dysfunctions would arise from lower- or higher-order visual areas. We recorded neuronal activity with magnetoencephalography (MEG) from anisometropic amblyopic patients and control participants during two visual tasks presented separately for each eye and estimated neuronal activity from source-reconstructed MEG data. We investigated whether event-related and oscillatory responses would be reduced for amblyopia and localized their cortical sources. Oscillation amplitudes and evoked responses were reduced for stimuli presented to the amblyopic eye in higher-order visual areas and in parietal and prefrontal cortices. Importantly, the reduction of oscillation amplitudes but not that of evoked responses was correlated with decreased visual acuity in amblyopia. These results show that attenuated oscillatory responses are correlated with visual deficits in anisometric amblyopia.

A novel paired associative stimulation protocol with a high-frequency peripheral component: A review on results in spinal cord injury rehabilitation.

In recent decades, a multitude of therapeutic approaches has been developed for spinal cord injury (SCI), but few have progressed to regular clinical practice. Novel non-invasive, cost-effective, and feasible approaches to treat this challenging condition are needed. A novel variant of paired associative stimulation (PAS), high-PAS, consists of non-invasive high-intensity transcranial magnetic stimulation (TMS) and non-invasive high-frequency electrical peripheral nerve stimulation (PNS). We observed a therapeutic effect of high-PAS in 20 patients with incomplete SCI with wide range of injury severity, age, and time since injury. Tetraplegic and paraplegic, traumatic, and neurological SCI patients benefited from upper- or lower-limb high-PAS. We observed increases in manual motor scores (MMT) of upper and lower limbs, functional hand tests, walking tests, and measures of functional independence. We also optimized PAS settings in several studies in healthy subjects and began elucidating the mechanisms of therapeutic action. The scope of this review is to describe the clinical experience gained with this novel PAS approach. This review is focused on the summary of our results and observations and the methodological considerations for researchers and clinicians interested in adopting and further developing this new method.

Auditory Mapping With MEG: An Update on the Current State of Clinical Research and Practice With Considerations for Clinical Practice Guidelines.

Auditory evoked fields (AEFs) are well suited for studies of auditory processing in patients. Their sources have been localized to Heschl's gyri and to the supratemporal auditory cortices. Auditory evoked fields are known to be modulated by peripheral and central lesions of auditory pathways and to reflect group-level pathophysiology of neurodevelopmental and psychiatric disorders. They are useful in lateralization of language processes for planning neurosurgery and for localization of language-related cortex. The recently developed artifact rejection and movement compensation methods will enhance and extend the use of AEFs in studies of clinical patients and pediatric groups. New pediatric magnetoencephalography systems will facilitate clinical AEF studies of developmental disorders. In addition to their established use in planning neurosurgery, AEF findings in several new clinical patient groups suffering, e.g., from developmental, neurodegenerative, or psychiatric disorders have been reported. Several recent investigations report the correlations with clinical symptoms and sensitivity and specificity profiles of AEFs in studies of these disorders; this development is mandatory in gaining wider clinical approval for the use of AEFs in clinical practice dealing with individual patients. Most promising future research lines of clinical applicability of AEFs focus on developmental and psychiatric disorders.

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 clinicaltrials.gov (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 ( R adj 2 = 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.

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.

Paired associative stimulation improves hand function after non-traumatic spinal cord injury: A case series.

OBJECTIVES: Long-term paired associative stimulation (PAS) is a non-invasive combination of transcranial magnetic stimulation and peripheral nerve stimulation and leads to improved hand motor function in individuals with incomplete traumatic tetraplegia. Spinal cord injuries (SCIs) can also be induced by neurological diseases. We tested a similar long-term PAS approach in patients with non-traumatic neurological SCI. METHODS: In this case series, five patients with non-traumatic tetraplegia received PAS to the weaker upper limb 3 to 5 times per week for 6 weeks. Patients were evaluated by manual muscle testing (MMT) before and immediately after the therapy and at the 1- and 6-month follow-ups. Patients were also evaluated for spasticity, hand mechanical and digital dynamometry, pinch test and Box and Block test. RESULTS: MMT values of all patients improved at all post-PAS evaluations. The mean ±â€¯standard error MMT increase was 1.44 ±â€¯0.37 points (p = 0.043) immediately after PAS, 1.57 ±â€¯0.4 points (p = 0.043) at the 1-month follow-up and 1.71 ±â€¯0.47 points (p = 0.043) at the 6-month follow-up. The pinch test, digital dynamometry and Box and Block test results also improved in all patients. CONCLUSIONS: Long-term PAS may be a safe and effective treatment for improving hand function in patients with non-traumatic tetraplegia. SIGNIFICANCE: This is the first report demonstrating the therapeutic potential of PAS for neurological SCI.

The use of electronic coil location control for focal magnetic stimulation at the cervical level.

BACKGROUND: Accurate re-positioning of the coil is challenging in magnetic stimulation at the cervical spinal level. The applicability of coil location control for this type of stimulation is unexplored. NEW METHOD: Utilizing a figure-of-eight coil and anatomy-specific models of the magnetic stimulation system, we developed a novel technique that enables probing corticospinal excitability at the cervical spinal level. Magnetic stimulation was performed in 9 healthy subjects at C2-C6 spinal levels using a figure-of-eight coil and a coil tracking system. MEPs were recorded from the abductor digiti minimi muscle. The functioning of the coil tracking system was tested with an estimated electric field maximum (eEFM) above the C1 cervical level (group 1) and below (group 2). Motor-evoked potential (MEP) reproducibility was assessed with intra-class correlation coefficient (ICC). RESULTS: The use of coil location control in cervical level focal magnetic stimulation enabled the recording of highly reproducible MEPs. Within one co-registration, the ICC 95% confidence interval (CI) in group 1 was 0.89-0.99 and in group 2 was 0.24-0.85. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: This method can be used for accurate maintenance and retrieval of the focal coil position at the cervical level with low spatial variability during stimulation. Existing methodologies employ determination of the coil location based on external landmarks, which makes the procedure cumbersome. This technique can optimize existing stimulation protocols and facilitate development of navigated spinal stimulation.

Localization of Sensorimotor Cortex Using Navigated Transcranial Magnetic Stimulation and Magnetoencephalography.

The mapping of the sensorimotor cortex gives information about the cortical motor and sensory functions. Typical mapping methods are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG). The differences between these mapping methods are, however, not fully known. TMS center of gravities (CoGs), MEG somatosensory evoked fields (SEFs), corticomuscular coherence (CMC), and corticokinematic coherence (CKC) were mapped in ten healthy adults. TMS mapping was performed for first dorsal interosseous (FDI) and extensor carpi radialis (ECR) muscles. SEFs were induced by tactile stimulation of the index finger. CMC and CKC were determined as the coherence between MEG signals and the electromyography or accelerometer signals, respectively, during voluntary muscle activity. CMC was mapped during the activation of FDI and ECR muscles separately, whereas CKC was measured during the waving of the index finger at a rate of 3-4 Hz. The maximum CMC was found at beta frequency range, whereas maximum CKC was found at the movement frequency. The mean Euclidean distances between different localizations were within 20 mm. The smallest distance was found between TMS FDI and TMS ECR CoGs and longest between CMC FDI and CMC ECR sites. TMS-inferred localizations (CoGs) were less variable across participants than MEG-inferred localizations (CMC, CKC). On average, SEF locations were 8 mm lateral to the TMS CoGs (p < 0.01). No differences between hemispheres were found. Based on the results, TMS appears to be more viable than MEG in locating motor cortical areas.

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.

Spontaneous sensorimotor cortical activity is suppressed by deep brain stimulation in patients with advanced Parkinson's disease.

Advanced Parkinson's disease (PD) is characterized by an excessive oscillatory beta band activity in the subthalamic nucleus (STN). Deep brain stimulation (DBS) of STN alleviates motor symptoms in PD and suppresses the STN beta band activity. The effect of DBS on cortical sensorimotor activity is more ambiguous; both increases and decreases of beta band activity have been reported. Non-invasive studies with simultaneous DBS are problematic due to DBS-induced artifacts. We recorded magnetoencephalography (MEG) from 16 advanced PD patients with and without STN DBS during rest and wrist extension. The strong magnetic artifacts related to stimulation were removed by temporal signal space separation. MEG oscillatory activity at 5-25 Hz was suppressed during DBS in a widespread frontoparietal region, including the sensorimotor cortex identified by the cortico-muscular coherence. The strength of suppression did not correlate with clinical improvement. Our results indicate that alpha and beta band oscillations are suppressed at the frontoparietal cortex by STN DBS in PD.

Language mapping with navigated transcranial magnetic stimulation in pediatric and adult patients undergoing epilepsy surgery: Comparison with extraoperative direct cortical stimulation.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) is becoming increasingly popular in noninvasive preoperative language mapping, as its results correlate well enough with those obtained by direct cortical stimulation (DCS) during awake surgery in adult patients with tumor. Reports in the context of epilepsy surgery or extraoperative DCS in adults are, however, sparse, and validation of nTMS with DCS in children is lacking. Furthermore, little is known about the risk of inducing epileptic seizures with nTMS in pediatric epilepsy patients. We provide the largest validation study to date in an epilepsy surgery population. METHODS: We compared language mapping with nTMS and extraoperative DCS in 20 epilepsy surgery patients (age range 9-32 years; 14 children and adolescents). RESULTS: In comparison with DCS, sensitivity of nTMS was 68%, specificity 76%, positive predictive value 27%, and negative predictive value 95%. Age, location of ictal-onset zone near or within DCS-mapped language areas or severity of cognitive deficits had no significant effect on these values. None of our patients had seizures during nTMS. SIGNIFICANCE: Our study suggests that nTMS language mapping is clinically useful and safe in epilepsy surgery patients, including school-aged children and patients with extensive cognitive dysfunction. Similar to in tumor surgery, mapping results in the frontal region are most reliable. False negative findings may be slightly more likely in epilepsy than in tumor surgery patients. Mapping results should always be verified by other methods in individual patients.

Combining rTMS With Intensive Language-Action Therapy in Chronic Aphasia: A Randomized Controlled Trial.

Neuromodulation technologies, such as transcranial magnetic stimulation (TMS), are promising tools for neurorehabilitation, aphasia therapy included, but not yet in common clinical use. Combined with behavioral techniques, in particular treatment-efficient Intensive Language-Action Therapy (ILAT, previously CIAT or CILT), TMS could substantially amplify the beneficial effect of such behavioral therapy alone (Thiel et al., 2013; Martin et al., 2014; Mendoza et al., 2016; Kapoor, 2017). In this randomized study of 17 subjects with post-stroke aphasia in the chronic stage, we studied the combined effect of ILAT and 1-Hz placebo-controlled navigated repetitive TMS (rTMS) to the right-hemispheric inferior frontal cortex-that is, to the anterior part of the non-dominant hemisphere's homolog Broca's area (pars triangularis). Patients were randomized to groups A and B. Patients in group A received a 2-week period of rTMS during naming training where they named pictures displayed on the screen once every 10 s, followed by 2 weeks of rTMS and naming combined with ILAT. Patients in group B received the same behavioral therapy but TMS was replaced by sham stimulation. The primary outcome measures for changes in language performance were the Western Aphasia Battery's aphasia quotient AQ; the secondary outcome measures were the Boston naming test (BNT) and the Action naming test (Action BNT, ANT). All subjects completed the study. At baseline, no statistically significant group differences were discovered for age, post-stroke time or diagnosis. ILAT was associated with significant improvement across groups, as documented by both primary and secondary outcome measures. No significant effect of rTMS could be documented. Our results agree with previous results proving ILAT's ability to improve language in patients with chronic aphasia. In contrast with earlier claims, however, a beneficial effect of rTMS in chronic post-stroke aphasia rehabilitation was not detected in this study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03629665.

Language control mechanisms differ for native languages: Neuromagnetic evidence from trilingual language switching.

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) 400-600ms 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 350-450ms, 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.