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.

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.

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.

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.

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.

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). Long-term 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.

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.

Two distinct auditory-motor circuits for monitoring speech production as revealed by content-specific suppression of auditory cortex.

Speech production, both overt and covert, down-regulates the activation of auditory cortex. This is thought to be due to forward prediction of the sensory consequences of speech, contributing to a feedback control mechanism for speech production. Critically, however, these regulatory effects should be specific to speech content to enable accurate speech monitoring. To determine the extent to which such forward prediction is content-specific, we recorded the brain's neuromagnetic responses to heard multisyllabic pseudowords during covert rehearsal in working memory, contrasted with a control task. The cortical auditory processing of target syllables was significantly suppressed during rehearsal compared with control, but only when they matched the rehearsed items. This critical specificity to speech content enables accurate speech monitoring by forward prediction, as proposed by current models of speech production. The one-to-one phonological motor-to-auditory mappings also appear to serve the maintenance of information in phonological working memory. Further findings of right-hemispheric suppression in the case of whole-item matches and left-hemispheric enhancement for last-syllable mismatches suggest that speech production is monitored by 2 auditory-motor circuits operating on different timescales: Finer grain in the left versus coarser grain in the right hemisphere. Taken together, our findings provide hemisphere-specific evidence of the interface between inner and heard speech.

Transcutaneous vagus nerve stimulation modulates tinnitus-related beta- and gamma-band activity.

OBJECTIVES: The ability of a treatment method to interfere with tinnitus-related neural activity patterns, such as cortical gamma rhythms, has been suggested to indicate its potential in relieving tinnitus. Therapeutic modulation of gamma-band oscillations with vagus nerve stimulation has been recently reported in epileptic patients. The aim of this study was to investigate the effects of transcutaneous vagus nerve stimulation (tVNS) on neural oscillatory patterns. DESIGN: We calculated the power spectral density and synchrony of magnetoencephalography recordings during auditory stimulation in seven tinnitus patients and eight normal-hearing control subjects. Comparisons between subject groups were performed to reveal electrophysiological markers of tinnitus. tVNS-specific effects within each group were studied by comparing recording blocks with and without tVNS. We also investigated the correlation of each measure with individual ratings of tinnitus distress, as measured by the tinnitus handicap inventory questionnaire. RESULTS: Tinnitus patients differed from controls in the baseline condition (no tVNS applied), measured by both cortical oscillatory power and synchronization, particularly at beta and gamma frequencies. Importantly, we found tVNS-induced changes in synchrony, correlating strongly with tinnitus handicap inventory scores, at whole-head beta-band (r = -0.857, p = 0.007), whole-head gamma-band (r = -0.952, p = 0.0003), and frontal gamma-band (r = -0.952, p = 0.0003). CONCLUSIONS: We conclude that tVNS was successful in modulating tinnitus-related beta- and gamma-band activity and thus could have potential as a treatment method for tinnitus.

Transcutaneous vagus nerve stimulation in tinnitus: a pilot study.

CONCLUSIONS: This pilot study shows that transcutaneous vagus nerve stimulation (tVNS), if combined with sound therapy (ST), reduces the severity of tinnitus and tinnitus-associated distress. Our magnetoencephalography (MEG) results show that auditory cortical activation can be modulated by the application of tVNS. Thus, tVNS might offer a new avenue to treat tinnitus and tinnitus-associated distress. OBJECTIVES: Recent studies suggest that tinnitus can be improved by tailored ST or by VNS plus ST. Our aims were to study whether tVNS has therapeutic effects on patients with tinnitus and, additionally, if tVNS has effects on acoustically evoked neuronal activity of the auditory cortex. METHODS: The clinical efficacy was studied by a short-term tVNS plus ST trial in 10 patients with tinnitus using disease-specific and general well-being questionnaires. tVNS was delivered to the left tragus. The acute effects of tVNS were evaluated in eight patients in the MEG study in which the N1m response was analyzed in terms of source level amplitude and latency in the presence or absence of tVNS. RESULTS: The treatment with tVNS plus ST produced improved mood and decreased tinnitus handicap scores, indicating reduced tinnitus severity. The application of tVNS decreased the amplitude of auditory N1m responses in both hemispheres.

Somatomotor mu rhythm amplitude correlates with rigidity during deep brain stimulation in Parkinsonian patients.

OBJECTIVE: Parkinsonian patients have abnormal oscillatory activity within the basal ganglia-thalamocortical circuitry. Particularly, excessive beta band oscillations are thought to be associated with akinesia. We studied whether cortical spontaneous activity is modified by deep brain stimulation (DBS) in advanced Parkinson's disease and if the modifications are related to the clinical symptoms. METHODS: We studied the effects of bilateral electrical stimulation of subthalamic nucleus (STN) on cortical spontaneous activity by magnetoencephalography (MEG) in 11 Parkinsonian patients. The artifacts produced by DBS were suppressed by tSSS algorithm. RESULTS: During DBS, UPDRS (Unified Parkinson's Disease Rating Scale) rigidity scores correlated with 6-10 Hz and 12-20 Hz somatomotor source strengths when eyes were open. When DBS was off UPDRS action tremor scores correlated with pericentral 6-10 Hz and 21-30 Hz and occipital alpha source strengths when eyes open. Occipital alpha strength decreased during DBS when eyes closed. The peak frequency of occipital alpha rhythm correlated negatively with total UPDRS motor scores and with rigidity subscores, when eyes closed. CONCLUSION: STN DBS modulates brain oscillations both in alpha and beta bands and these oscillations reflect the clinical condition during DBS. SIGNIFICANCE: MEG combined with an appropriate artifact rejection method enables studies of DBS effects in Parkinson's disease and presumably also in the other emerging DBS indications.

Effects of DBS on auditory and somatosensory processing in Parkinson's disease.

Motor symptoms of Parkinson's disease (PD) can be relieved by deep brain stimulation (DBS). The mechanism of action of DBS is largely unclear. Magnetoencephalography (MEG) studies on DBS patients have been unfeasible because of strong magnetic artifacts. An artifact suppression method known as spatiotemporal signal space separation (tSSS) has mainly overcome these difficulties. We wanted to clarify whether tSSS enables noninvasive measurement of the modulation of cortical activity caused by DBS. We have studied auditory and somatosensory-evoked fields (AEFs and SEFs) of advanced PD patients with bilateral subthalamic nucleus (STN) DBS using MEG. AEFs were elicited by 1-kHz tones and SEFs by electrical pulses to the median nerve with DBS on and off. Data could be successfully acquired and analyzed from 12 out of 16 measured patients. The motor symptoms were significantly relieved by DBS, which clearly enhanced the ipsilateral auditory N100m responses in the right hemisphere. Contralateral N100m responses and somatosensory P60m responses also had a tendency to increase when bilateral DBS was on. MEG with tSSS offers a novel and powerful tool to investigate DBS modulation of the evoked cortical activity in PD with high temporal and spatial resolution. The results suggest that STN-DBS modulates auditory processing in advanced PD. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc.

Sources of auditory brainstem responses revisited: contribution by magnetoencephalography.

Auditory brainstem responses provide diagnostic value in pathologies involving the early parts of the auditory pathway. Despite that, the neural generators underlying the various components of these responses have remained unclear. Direct electrical recordings in humans are possible only in limited time periods during surgery and from small regions of the diseased brains. The evidence of the generator sites is therefore fragmented and indirect, based strongly on lesion studies and animal models. Source modeling of EEG has been limited to grand averages across multiple subjects. Here, we employed magnetoencephalography (MEG) to shed more light on the neural origins of the auditory brainstem responses (ABR) and to test whether such deep brain structures are accessible by MEG. We show that the magnetic counterparts of the electric ABRs can be measured in 30 min and that they allow localization of some of the underlying neural sources in individual subjects. Many of the electric ABR components were present in our MEG data; however, the morphologies of the magnetic and electric responses were different, indicating that the MEG signals carry information complementary to the EEG data. The locations of the neural sources corresponding to the magnetic ABR deflections ranged from the auditory nerve to the inferior colliculus. The earliest cortical responses were detectable at the latency of 13 ms.

Human cortical representation of virtual auditory space: differences between sound azimuth and elevation.

Sounds convolved with individual head-related transfer functions and presented through headphones can give very natural percepts of the three-dimensional auditory space. We recorded whole-scalp neuromagnetic responses to such stimuli to compare reactivity of the human auditory cortex to sound azimuth and elevation. The results suggest that the human auditory cortex analyses sound azimuth, based on both binaural and monaural localization cues, mainly in the hemisphere contralateral to the sound, whereas elevation in the anterior space and in the lateral auditory space in general, both strongly relying on monaural spectral cues, are analyzed in more detail in the right auditory cortex. The binaural interaural time and interaural intensity difference cues were processed in the auditory cortex around 100-150 ms and the monaural spectral cues later around 200-250 ms.