Effects Of Continuous Theta-burst Stimulation Research Articles

Continuous theta-burst stimulation in patients with drug-resistant epilepsy: A single-blind placebo-controlled cross-over pilot study

ObjectivesTo evaluate the effect of continuous theta-burst stimulation (cTBS) in patients with drug-resistant epilepsy (DRE). MethodsTwelve patients with DRE (five with idiopathic generalized and seven with focal epilepsy) were included in this cross-over design study and randomized to either first sham or first active stimulation, each applied for 5 consecutive days. A round coil over the vertex was used in generalized epilepsy or a figure-of-8 coil over the “epileptogenic area” in focal epilepsy. Sham stimulation was given by placing the coil 90° perpendicular to the head. The number of seizures, electroencephalography findings, Quality of Life in Epilepsy Inventory (QOLIE-84), and Symptom Check List (SCL-90) scores evaluated during the 8–12 weeks before and after active and sham stimulations were compared statistically. ResultsEight patients could complete both active and sham stimulation periods of 5 days and two patients completed active stimulation sessions, without any significant adverse effects. The number of seizures significantly reduced after active cTBS, but not after sham stimulation, when compared with those recorded before the stimulation period. QOLIE scores were increased, but interictal epileptiform discharges and SCL-90 scores showed no difference after cTBS. Active stimulation was stopped in one patient after he experienced an aggravation of myoclonic seizures. ConclusionscTBS seemed to be relatively safe and gave promising results in reducing the frequency of seizures in patients with both generalized and focal DRE. This time-saving technique may ease the introduction of repetitive transcranial magnetic stimulation into the routine practice of busy epilepsy clinics.

Neural effects of continuous theta-burst stimulation in macaque parietal neurons.

Theta-burst transcranial magnetic stimulation (TBS) has become a standard non-invasive technique to induce offline changes in cortical excitability in human volunteers. Yet, TBS suffers from a high variability across subjects. A better knowledge about how TBS affects neural activity in vivo could uncover its mechanisms of action and ultimately allow its mainstream use in basic science and clinical applications. To address this issue, we applied continuous TBS (cTBS, 300 pulses) in awake behaving rhesus monkeys and quantified its after-effects on neuronal activity. Overall, we observed a pronounced, long-lasting, and highly reproducible reduction in neuronal excitability after cTBS in individual parietal neurons, with some neurons also exhibiting periods of hyperexcitability during the recovery phase. These results provide the first experimental evidence of the effects of cTBS on single neurons in awake behaving monkeys, shedding new light on the reasons underlying cTBS variability.

Continuous Theta-Burst Stimulation Promotes Paravascular CSF-Interstitial Fluid Exchange through Regulation of Aquaporin-4 Polarization in APP/PS1 Mice.

Amyloid-β (Aβ) deposition plays a crucial role in the occurrence and development of Alzheimer's disease (AD), and impaired Aβ clearance is the leading cause of Aβ deposition. Recently, studies have found that the glymphatic system performs similar functions to the peripheral lymphatic system. Glymphatic fluid transport mainly consists of cerebrospinal fluid (CSF) entering the brain from the paravascular space (PVS) by penetrating arteries and CSF and interstitial fluid exchanging mediated by aquaporin-4 (AQP4). This system promotes the drainage of interstitial fluid (ISF) in the parenchyma and removes metabolic waste, including Aβ, in the brain. Glymphatic system dysfunction plays an essential role in the occurrence and progression of AD. Regulation of glymphatic fluid transport may be a critical target for AD therapy. This study explored the regulatory effects of continuous theta-burst stimulation (CTBS) on the glymphatic system in APPswe/PS1dE9 (APP/PS1) mice with two-photon imaging. The results demonstrated that CTBS could increase glymphatic fluid transport, especially CSF and ISF exchange, mediated by improved AQP4 polarization. In addition, the accelerated glymphatic pathway reduced Aβ deposition and enhanced spatial memory cognition. It provided new insight into the clinical prevention and treatment of Aβ deposition-related diseases.

Cerebellar Continuous Theta Burst Stimulation for Aphasia Rehabilitation: Study Protocol for a Randomized Controlled Trial.

BackgroundLanguage recovery is limited in moderate to severe post-stroke aphasia patients. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool in improving language dysfunctions caused by post-stroke aphasia, but the treatment outcome is as yet mixed. Considerable evidence has demonstrated the essential involvement of the cerebellum in a variety of language functions, suggesting that it may be a potential stimulation target of TMS for the treatment of post-stroke aphasia. Theta burst stimulation (TBS) is a specific pattern of rTMS with shorter stimulation times and better therapeutic effects. The effect of continuous TBS (cTBS) on the cerebellum in patients with aphasia with chronic stroke needs further exploration.MethodsIn this randomized, sham-controlled clinical trial, patients (n = 40) with chronic post-stroke aphasia received 10 sessions of real cTBS (n = 20) or sham cTBS (n = 20) over the right cerebellar Crus I+ a 30-min speech-language therapy. The Western Aphasia Battery (WAB) serves as the primary measure of the treatment outcome. The secondary outcome measures include the Boston Diagnostic Aphasia Examination, Boston Naming Test and speech acoustic parameters. Resting-state fMRI data were also obtained to examine treatment-induced changes in functional connectivity of the cerebro-cerebellar network. These outcome measures are assessed before, immediately after, and 12 weeks after cerebellar cTBS intervention.DiscussionThis protocol holds promise that cerebellar cTBS is a potential strategy to improve language functions in chronic post-stroke aphasia. The resting-state fMRI may explore the neural mechanism underlying the aphasia rehabilitation with cerebellar cTBS.

Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model—experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A2AR/A1R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1β and NF- κB-ir and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.

Behavioral effects of continuous theta-burst stimulation in macaque parietal cortex

The neural mechanisms underlying the effects of continuous Theta-Burst Stimulation (cTBS) in humans are poorly understood. Animal studies can clarify the effects of cTBS on individual neurons, but behavioral evidence is necessary to demonstrate the validity of the animal model. We investigated the behavioral effect of cTBS applied over parietal cortex in rhesus monkeys performing a visually-guided grasping task with two differently sized objects, which required either a power grip or a pad-to-side grip. We used Fitts’ law, predicting shorter grasping times (GT) for large compared to small objects, to investigate cTBS effects on two different grip types. cTBS induced long-lasting object-specific and dose-dependent changes in GT that remained present for up to two hours. High-intensity cTBS increased GTs for a power grip, but shortened GTs for a pad-to-side grip. Thus, high-intensity stimulation strongly reduced the natural GT difference between objects (i.e. the Fitts’ law effect). In contrast, low-intensity cTBS induced the opposite effects on GT. Modifying the coil orientation from the standard 45-degree to a 30-degree angle induced opposite cTBS effects on GT. These findings represent behavioral evidence for the validity of the nonhuman primate model to study the neural underpinnings of non-invasive brain stimulation.

Continuous theta burst stimulation dilates meningeal lymphatic vessels by up-regulating VEGF-C in meninges

BackgroundLymphatic vessels (LVs) of meninges and lymphatic drainage in the brain have been investigated previously. Here, we examined the role of continuous theta burst stimulation (CTBS) in the modulation of meningeal LVs. MethodsTo explore the effects of CTBS on meningeal LVs, the diameters of LVs were measured between a real CTBS group and sham CTBS group of wild-type male mice. Vascular endothelial growth factor-C (VEGF-C) expression was subsequently calculated in both groups to account for lymphatic changes after CTBS. Sunitinib was administered by 3-day oral gavage to inhibit the VEGF receptor (VEGFR), and the effects of CTBS were further examined in the following groups: vehicle with real CTBS, vehicle with sham CTBS, sunitinib treatment with real CTBS, and sunitinib treatment with sham CTBS. ResultsThe lymphatic vessels were augmented, and the level of VEGF-C in meninges increased after CTBS. CTBS dilated meningeal lymphatic vessels were impaired after the VEGF-C/VEGFR3 pathway was blocked. ConclusionsCTBS can dilate meningeal lymphatic vessels by up-regulating VEGF-C in meninges.

Test-Retest Reliability of the Effects of Continuous Theta-Burst Stimulation.

ObjectivesThe utility of continuous theta-burst stimulation (cTBS) as index of cortical plasticity is limited by inadequate characterization of its test–retest reliability. We thus evaluated the reliability of cTBS aftereffects, and explored the roles of age and common single-nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes.MethodsTwenty-eight healthy adults (age range 21–65) underwent two identical cTBS sessions (median interval = 9.5 days) targeting the motor cortex. Intraclass correlation coefficients (ICCs) of the log-transformed, baseline-corrected amplitude of motor evoked potentials (ΔMEP) at 5–60 min post-cTBS (T5–T60) were calculated. Adjusted effect sizes for cTBS aftereffects were then calculated by taking into account the reliability of each cTBS measure.ResultsΔMEP at T50 was the most-reliable cTBS measure in the whole sample (ICC = 0.53). Area under-the-curve (AUC) of ΔMEPs was most reliable when calculated over the full 60 min post-cTBS (ICC = 0.40). cTBS measures were substantially more reliable in younger participants (< 35 years) and in those with BDNF Val66Val and APOE ε4– genotypes.ConclusioncTBS aftereffects are most reliable when assessed 50 min post-cTBS, or when cumulative ΔMEP measures are calculated over 30–60 min post-cTBS. Reliability of cTBS aftereffects is influenced by age, and BDNF and APOE polymorphisms. Reliability coefficients are used to adjust effect-size calculations for interpretation and planning of cTBS studies.

The effect of continuous theta-burst stimulation on language interference in bilinguals

The effect of continuous theta-burst stimulation on language interference in bilinguals

Neural effects of continuous theta-burst stimulation on single neurons in macaque parietal cortex

Theta-burst transcranial magnetic stimulation (TBS) has recently received much interest because it can be used to up- or downregulate brain activity non-invasively. However, its behavioral effects are highly variable. A better understanding of TBS influence on different neuronal populations is currently needed to improve its reproducibility. We showed that single-pulse TMS (120% of resting motor threshold) induces a short-latency burst of action potentials lasting 80 ms (Romero et al., Soc Neurosci 2016). Here, we measured the after-effects of continuous TBS (cTBS, 300 pulses) on the TMS-induced burst and spontaneous neuronal activity in macaque parietal cortex during passive fixation. We first searched for well isolated single neurons, and recorded stable TMS-evoked bursts before cTBS. Next, we applied cTBS, and immediately resumed the single-pulse TMS protocol to assess changes in excitability up to 50 minutes post-cTBS. cTBS caused a reduction in spontaneous activity (31%, p < 0.001) and a robust reduction (29%, p

Effects of continuous theta-burst stimulation of the primary motor and secondary somatosensory areas on the central processing and the perception of trigeminal nociceptive input in healthy volunteers.

Noninvasive modulation of the activity of pain-related brain regions by means of transcranial magnetic stimulation promises an innovative approach at analgesic treatments. However, heterogeneous successes in pain modulation by setting reversible "virtual lesions" at different brain areas point at unresolved problems including the optimum stimulation site. The secondary somatosensory cortex (S2) has been previously identified to be involved in the perception of pain-intensity differences. Therefore, impeding its activity should impede the coding of the sensory component of pain intensity, resulting in a flattening of the relationship between pain intensity and physical stimulus strength. This was assessed using inactivating spaced continuous theta-burst stimulation (cTBS) in 18 healthy volunteers. In addition, cTBS was applied on the primary motor cortex (M1) shown previously to yield moderate and variable analgesic effects, whereas sham stimulation at both sites served as placebo condition. Continuous theta-burst stimulation flattened the relationship between brain activation and stimulus strength, mainly at S2, the insular cortex, and the postcentral gyrus (16 subjects analyzed). However, these effects were observed after inactivation of M1 while this effect was not observed after inactivation of S2. Nevertheless, both the M1 and the S2-spaced cTBS treatment were not reflected in the ratings of the nociceptive stimuli of different strengths (17 subjects analyzed), contrasting with the clear coding of stimulus strength by these data. Hence, while modulating the central processing of nociceptive input, cTBS failed to produce subjectively relevant changes in pain perception, indicating that the method in the present implementation is still unsuitable for clinical application.

Neural effects of continuous Theta-Burst Stimulation on single neurons in macaque parietal cortex

Neural effects of continuous Theta-Burst Stimulation on single neurons in macaque parietal cortex

P088 Different modulation effects of TBS produced by different repetitive TMS machines

Introduction The Rapid2 from Magstim and MagPro X100 from MagVenture are 2 major TMS machines on the market. It is generally considered that both machines can produce similar stimulation and their effect are usually considered similar. However, a head-to-head comparison of the two machines has never been done. Thinking of the different inner designs of the 2 machines, it deserves a careful study to compare the effects of a single protocol produced by the two machines. Objectives To evaluate and compare the effects of theta burst stimulation (TBS) generated by Magstim Rapid2 and MagVenture MagPro X100 in the same subjects. Patients & Methods Healthy subjects have participated 2 sessions that were one week apart from each other in a randomized order. In each session, the effect of continuous TBS at 70% rest motor threshold followed by 1-min subtle voluntary contraction (cTBSc0) on the size of MEP was assessed. 30 baseline MEPs at approximately 1 mV were recorded. Then cTBSc0 was applied to the motor hot-spot. After contraction, 12 MEPs evoked by the stimulus intensity identical to that for baseline MEPs were recorded every minutes for 5 min then every 2 min until 21 min after cTBS. The only different between the two sessions is that cTBS was given by Magstim Rapid2 in one session and by MagVenture MagPro X100 in the other. Result Our data suggested that the effect of cTBSc0 generated by Magstim Rapid2 and by MagVenture MagPro X100 was different. The cTBSc0 by Magstim Rapid2 induced a significant excitatory effect as previously reported, while cTBSc0 by MagVenture Magpro X100 tended to generate an inhibitory effect. Conclusion Although the effects of all the TMS machines are generally considered the same, the present study suggests that such assumption may not be true. We suggest the further head-to-head comparison of different TMS machines in different protocols.

Continuous theta-burst stimulation may improve visuospatial neglect via modulating the attention network: a randomized controlled study

Background: Visuospatial neglect (VSN) is devastating and common after stroke, and is thought to involve functional disturbance of the attention network. Non-invasive theta-burst stimulation (TBS) may help restore the normal function of attention network, therefore facilitating recovery from VSN.Objective: This study investigated the effects of continuous TBS on resting-state functional connectivity (RSFC) in the attention network, and behavioral performances of patients with VSN after stroke.Methods: Twelve patients were randomly assigned to receive 10-day cTBS of the left posterior parietal cortex delivered at 80% (the cTBS group), or 40% (the active control group) of the resting motor threshold. Both groups received daily visual scanning training and motor function treatment. Resting-state functional MRI (fMRI) and behavioral tests including line bisection test and star cancelation test were conducted at baseline and after the treatment.Results: At baseline, the two groups showed comparable results in the resting-state fMRI experiments and behavioral tests. After treatment, the cTBS group showed lower functional connectivity between right temporoparietal junction (TPJ) and right anterior insula, and between right superior temporal sulcus and right anterior insula, as compared with the active control group; both groups showed improvement in the behavioral tests, with the cTBS group showing larger changes from baseline than the active control group.Conclusion: cTBS of the left posterior parietal cortex in patients with VSN may induce changes in inter-regional RSFC in the right ventral attention network. These changes may be associated with improved recovery of behavioral deficits after behavioral training. The TPJ and superior temporal sulcus may play crucial roles in recovery from VSN.

Motor cortical plasticity and corticospinal tract diffusion tensor image in patients with Parkinson’s disease and essential tremor

s / Brain Stimulation 8 (2015) 326e342 342 Background: Non-invasive brain stimulation (NIBS) protocols can interfere with or even facilitate motor learning. However, it is still unclear whether the response to NIBS protocols, such as theta-burst stimulation (TBS), can predict its ability to interfere with or enhance learning of a motor task. We aim to investigate this question using TBS and a ballistic finger movement task. Methods: Eight right handed healthy human volunteers participated in the study. Experiment 1: We investigated the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) on cortical excitability. Thirty motor evoked potentials (MEP) were measured before and after intervention (cTBS or iTBS) for 30 min. Experiment 2: In separate sessions, we tested the effects of cTBS or iTBS on a ballistic finger movement task. Subjects were required to make rapid index finger abduction movements of the right hand paced at a rate of 0.5 Hz. One block consists of 75 movements for 2.5 min and 4 blocks were tested in total. Between blocks 2 and 3, either cTBS or iTBS was applied over left M1. We quantified the learning effect by measuring the increase the mean peak acceleration (ACC) for each set of 30 consecutive movements. Results: In experiment 1, there was a non-significant trend for MEPs to get smaller after cTBS and larger after iTBS. In experiment 2, cTBS or iTBS did not change ACC immediately after application of TBS. However, ACC increased significantly more in the final block of trials after cTBS than it did after iTBS. The normalized ACC in the last block was negatively correlated with excitability changes induced by cTBS in experiment 1 (Spearman’s r 1⁄4 0.881, p 1⁄4 0.002). Conclusions: This preliminary result suggest that cTBS did not affect early consolidation in M1, but facilitated further performance gains in model-free learning. The effect on performance was correlated with the effect of cTBS on MEPs.

Long-term effects of continuous theta-burst stimulation in visuospatial neglect.

To investigate whether the efficacy of continuous theta-burst stimulation (cTBS) for improving visuospatial neglect can be enhanced by providing more days of stimulation and more stimulation trains per day. In a prospective study, right-handed patients with right hemisphere stroke and visuospatial neglect were randomized to cTBS or sham cTBS treatment for 2 weeks and were followed up for 4 weeks. The cTBS group received active cTBS over the posterior parietal cortex of the unaffected hemisphere, combined with conventional rehabilitation therapy. Changes in scores for two paper-pencil tests for visuospatial neglect (star cancellation and line bisection) were evaluated. In each group, 10 patients completed follow up. Compared with the sham group, star cancellation test scores in the cTBS group were improved by 37.03% at the end of treatment and by 47.21% after 4 weeks' follow up, and the line bisection score improved by 21.37% at the end of treatment and by 35.99% after 4 weeks' follow up. These results suggest that the efficacy of cTBS in visuospatial neglect can be enhanced and prolonged by increasing the days of stimulation and the number of stimulation trains per day over the left posterior parietal cortex.

Continuous theta-burst stimulation over primary somatosensory cortex modulates short-latency afferent inhibition

ObjectiveThe present study investigated the effects of continuous theta-burst stimulation (cTBS) over primary somatosensory (SI) and motor (M1) cortices on motor-evoked potentials (MEPs) and short-latency afferent inhibition (SAI). MethodsMEPs and SAI were recorded from the first dorsal interosseous (FDI) muscle of the right hand following 30Hz cTBS over left-hemisphere SI and M1 delivered to the same participants in separate sessions. Measurements were taken before and up to 60min following cTBS. ResultsCTBS over M1 suppressed MEPs and did not alter SAI. In contrast cTBS over SI facilitated MEPs and decreased median and digital nerve evoked SAI. ConclusionsThese findings indicate that SAI amplitude is influenced by cTBS over SI but not M1, suggesting an important role for SI in the modulation of this circuit. These data provide further evidence that cTBS over SI versus M1 has opposite effects on corticospinal excitability. SignificanceTo date, plasticity-inducing TMS protocols delivered over M1 have failed to modulate SAI, and the present research continues to support these findings. However, in young adults, cTBS over SI acts to reduce SAI and simultaneously increase corticospinal excitability. Future studies may investigate the potential to modulate SAI via targeting neural activity within SI.