Quadripulse Stimulation Research Articles

Epidural magnetic stimulation of the motor cortex using an implantable coil

BackgroundMagnetic stimulation, represented by transcranial magnetic stimulation (TMS), is used to treat neurological diseases. Various strategies have been explored to improve the spatial resolution of magnetic stimulation. While reducing the coil size is the most impactful approach for increasing the spatial resolution, it decreases the stimulation intensity and increases heat generation. ObjectiveWe aim to demonstrate the feasibility of magnetic stimulation using an epidurally implanted millimeter-sized coil and that it does not damage the cortical tissue via heating even when a repetitive stimulation protocol is used. MethodsA coil with dimensions of 3.5 × 3.5 × 2.6 mm3 was epidurally implanted on the left motor cortex of rat, corresponding to the right hindlimb. Before and after epidural magnetic stimulation using a quadripulse stimulation (QPS) protocol, changes in the amplitude of motor evoked potentials (MEPs) elicited by a TMS coil were compared. ResultsThe experimental group showed an average increase of 88 % in MEP amplitude in the right hindlimb after QPS, whereas the MEP amplitude in the left hindlimb increased by 18 % on average. The control group showed no significant change in MEP amplitude after QPS in either hindlimb. The temperature changes at the coil surface remained <2 °C during repetitive stimulation, meeting the thermal safety limit for implantable medical devices. ConclusionThese results demonstrate the feasibility of epidural magnetic stimulation using an implantable coil to induce neuromodulation effects. This novel method is expected to be a promising alternative for focal magnetic stimulation with an improved spatial resolution and lowered stimulus current than previous magnetic stimulation methods.

Immediate effect of quadri-pulse stimulation on human brain microstructures and functions

Abstract It remains unclear whether repetitive stimulation of a single brain area immediately alters brain microstructure. Thus, we investigated the immediate changes in human brain microstructures following repetitive extrinsic excitation of the left primary motor cortex (M1) through quadri-pulse stimulation (QPS). Sixteen right-handed healthy adults underwent excitatory (QPS5) and inhibitory (QPS50) QPS. Diffusion magnetic resonance imaging (MRI) and resting-state functional MRI were conducted before and after QPS to detect microstructural and functional changes, respectively. No significant alterations in microstructural indices after QPS5 or QPS50 were observed in the cerebral cortex. The functional connectivity (FC) between the bilateral M1 was significantly decreased after QPS5, while it was not significantly modulated after QPS50. Microstructural changes exhibited no significant correlation with this FC change in any region after QPS5 or QPS50. Although no significant FC change was observed following QPS50, these results may suggest that repetitive stimulation of a single brain area can be insufficient to induce immediate microstructural alterations. This would be supported by demonstrating the lack of microstructural changes after QPS together with changes in cortical excitability of the stimulated region.

Age-related changes in responsiveness to non-invasive brain stimulation neuroplasticity paradigms: A systematic review with meta-analysis

ObjectivesWe aimed to summarise and critically appraise the available evidence for the effect of age on responsiveness to non-invasive brain stimulation (NBS) paradigms delivered to the primary motor cortex. MethodsFour databases (Medline, Embase, PsycINFO and Scopus) were searched from inception to February 7, 2023. Studies investigating age group comparisons and associations between age and neuroplasticity induction from NBS paradigms were included. Only studies delivering neuroplasticity paradigms to the primary motor cortex and responses measured via motor-evoked potentials (MEPs) in healthy adults were considered. Results39 studies, encompassing 40 experiments and eight NBS paradigms were included: paired associative stimulation (PAS; n = 12), repetitive transcranial magnetic stimulation (rTMS; n = 2), intermittent theta burst stimulation (iTBS; n = 8), continuous theta burst stimulation (cTBS; n = 7), transcranial direct and alternating current stimulation ((tDCS; n = 7; tACS; n = 2)), quadripulse stimulation (QPS; n = 1) and i-wave periodic transcranial magnetic stimulation (iTMS; n = 1). Pooled findings from PAS paradigms suggested older adults have reduced post-paradigm responses, although there was considerable heterogeneity. Mixed results were observed across all other NBS paradigms and post-paradigm timepoints. Conclusions/significanceWhilst age-dependent reduction in corticospinal excitability is possible, there is extensive inter- and intra-individual variability both within and between studies, making it difficult to draw meaningful conclusions from pooled analyses.

Long-term potentiation-like plasticity is retained during relapse in patients with Multiple Sclerosis

ObjectiveTo investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance. MethodsFacilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse. ResultsSynaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity. ConclusionsQPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies. SignificanceNew insights into synaptic plasticity during MS relapses are provided.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy

ObjectiveTo elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. MethodsParticipants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. ResultsLTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. ConclusionsLTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SignificanceThe degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

Quadripulse stimulation (qps): applications to neurological disorders

Quadripulse stimulation (qps): applications to neurological disorders

TMS and neocortical neurons: an integrative review on the micro-macro connection in neuroplasticity.

Tian D, Izumi S. TMS and neocortical neurons: an integrative review on the micro-macro connection in neuroplasticity. Jpn J Compr Rehabil Sci 2023; 14: 1-9. Neuroplasticity plays a pivotal role in neuroscience and neurorehabilitation as it bridges the organization and reorganization properties of the brain. Among the numerous neuroplastic protocols, transcranial magnetic stimulation (TMS) is a well-established non-invasive protocol to induce plastic changes in the brain. Here, we review the findings of four plasticity-inducing TMS protocols in the human motor cortex with relatively evident mechanisms: conventional repetitive TMS (rTMS), theta-burst stimulation (TBS), quadripulse stimulation (QPS) and paired associative stimulation (PAS). Based on the reviewed evidence and a preliminary TMS neurocytological model proposed in our previous report, we further integrate the neurophysiological evidence and plasticity rules of these protocols to present an updated micro-macro connection model between neocortical neurons and the neurophysiological evidence in TMS. This prototypical model will guide further efforts to understand the neural circuit of the motor cortex, the mechanisms of TMS, and the advance of neuroplasticity technologies and their outcomes.

Clinical Practice Guidelines for the Therapeutic Use of Repetitive Transcranial Magnetic Stimulation in Neuropsychiatric Disorders.

Clinical Practice Guidelines for the Therapeutic Use of Repetitive Transcranial Magnetic Stimulation in Neuropsychiatric Disorders.

The degree of cortical plasticity correlates with cognitive performance in patients with Multiple Sclerosis

BackgroundCortical reorganization and plasticity may compensate for structural damage in Multiple Sclerosis (MS). It is important to establish sensitive methods to measure these compensatory mechanisms, as they may be of prognostic value. ObjectiveTo investigate the association between the degree of cortical plasticity and cognitive performance and to compare plasticity between MS patients and healthy controls (HCs). MethodsThe amplitudes of the motor evoked potential (MEP) pre and post quadripulse stimulation (QPS) applied over the contralateral motor cortex served as measure of the degree of cortical plasticity in 63 patients with relapsing-remitting MS (RRMS) and 55 matched HCs. The main outcomes were the correlation coefficients between the difference of MEP amplitudes post and pre QPS and the Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R), and the QPSxgroup interaction in a mixed model predicting the MEP amplitude. ResultsSDMT and BVMT-R correlated significantly with QPS-induced cortical plasticity in RRMS patients. Plasticity was significantly reduced in patients with cognitive impairment compared to patients with preserved cognitive function and the degree of plasticity differentiated between both patient groups. Interestingly, the overall RRMS patient cohort did not show reduced plasticity compared to HCs. ConclusionsWe provide first evidence that QPS-induced plasticity may inform about the global synaptic plasticity in RRMS which correlates with cognitive performance as well as clinical disability. Larger longitudinal studies on patients with MS are needed to investigate the relevance and prognostic value of this measure for disease progression and recovery.

Epilepsy and TMS

NBS has been used for epilepsy in three aspects: pathophysiology, antiepileptic drugs, and treatment. Pathophysiological analysis by TMS Several parameters of transcranial magnetic stimulation (TMS) studies are considered to reflect a specific electrophysiological function at the motor cortex. The motor threshold may represent sodium channel function; the short interval intracortical inhibition (SICI), GABAA function; intracortical facilitation (ICF), glutamate function. These functional abnormalities have been shown in several epileptic disorders. I will show GABAA dysfunction in patients with myoclonus epilepsy. Antiepileptic drugs and TMS The above methods TMS were used for studying the mechanism of action of most anti-epileptic drugs. The above functions were compared between real drug intake and placebo intake in normal subjects. Some drugs are compatible with sodium channel blocker, some others are enhancer of BAGAergic function, and some of them show glutamate blocker (AMPA blocker). These physiological speculations from human experiments are all compatible with their proposed mechanism action speculated from animal experiments. I will show the results of perampanel. Treatment by NBS Several NBS methods have been applied to patients with epilepsy. Repetitive TMS and transcranial magnetic stimulation (tDCS) were used for this purpose. I will describe quadripulse stimulation (QPS) and show an aggravation of epilepsy by LTD induction by QPS. We have no consensus about the effectiveness of rTMSs for epilepsy. Critical review of tDCS treatment of epilepsy concluded that no recommendation can be made about the potential efficacy of tDCS in the treatment of any type of epilepsy.

Alpha Oscillatory Activity Causally Linked to Working Memory Retention: Insights From Online Phase-Locking Closed-Loop Transcranial Alternating Current Stimulation

Responses to plasticity-inducing brain stimulation protocols are highly variable. However, no data are available concerning the variability of responses to quadripulse stimulation (QPS).We assessed the QPS parameters of motor cortical plasticity induction in a systematic manner, and later investigated the variability of QPS using optimal parameters.First, two different interburst intervals (IBI) with the same total number of pulses were compared. Next we investigated three different IBIs with a different total number of pulses but with same duration of intervention. We also compared the after-effects of monophasic and biphasic QPS. Finally, variability of QPS was tested in 35 healthy subjects. Twenty motor evoked potentials (MEPs) were measured every 5–10 min for up to one hour after intervention.QPS at an IBI of 5 s produced MEPs changes that are dependent on the interstimulus interval of the four magnetic pulses, consistent with previous reports. Unexpectedly, QPS at an IBI of 2.5 s did not induce any plasticity, even with the same total number of pulses, that is, 1440. QPS at an IBI of 7.5 s produced a variable response but was likely to be comparable to conventional QPS. Biphasic QPS had shorter lasting after-effects compared with monophasic QPS. Finally, the after-effects of QPS were relatively consistent across subjects: more than 80% of subjects responded as expected in the excitatory QPS at an IBI of 5 s.The IBI, total duration of the procedure and pulse waveform strongly affected the magnitude or duration of the plasticity induced by QPS. In this cohort, 80% of subjects responded to excitatory QPS as expected.

Transcranial stimulation (TCS) O-TS002. Combining SICF and ICF with QPS boosts excitability increase in the primary motor cortex

Introduction . After-effects induced by repetitive transcranial magnetic stimulation (rTMS) at the primary motor cortex (M1) are usually indexed by the amplitude of the motor evoked potential (MEP). They depend on various parameters, in particular on the temporal pattern. Quadripulse stimulation (QPS; high-frequency train of four pulses delivered every-five seconds for 30 min) was originally invented based on a repetitive paired-pulse TMS (ppTMS) protocol, which utilized short-interval intracortical facilitation (SICF) as a building block. Here, we tried to test whether after-effects of QPS can be increased by integrating either SICF, intracortical facilitation (ICF) or long-interval intracortical inhibition (LICI). Methods . Three conditions were compared using a cross-over design in 23 healthy volunteers. The three conditions were SICF + ICF, SICF + LICI, and QPS-like. In SICF + ICF, two pulses with a 1.5 ms inter-stimulus interval (ISI) were repeated twice, separated by 10 ms (ICF). Likewise, in SICF + LICI two pulses with a 1.5 ms interval were repeated at 100-ms interval (LICI). In the QPS-like condition, the four pulses were evenly delivered at 5-ms intervals. In all three conditions the four pulses were repeated every-five seconds for 10 minutes. Amplitude of MEP elicited by single pulse TMS was measured before the intervention, and up to 60 minutes after it. The MEP amplitudes were normalized to the baseline and served as the main outcome. Results . The combination of two facilitatory ppTMS, SICF + ICF, resulted in significantly increased MEP amplitudes over time whereas combining the facilitatory SICF with the inhibitory LICI tended to decrease the MEP amplitude. QPS with 10-minute intervention time had no effect in contrast to the 3-times longer original QPS paradigm. Conclusion . The efficacy of the original QPS can be maintained with one third of stimulation time when differently organized in time along with optimal values for SICF + ICF.

Numerical Modeling of Plasticity Induced by Quadri-Pulse Stimulation

Quadri-pulse stimulation (QPS), a type of repetitive transcranial magnetic stimulation (rTMS), can induce a considerable aftereffect on cortical synapses. Human experiments have shown that the type of effect on synaptic efficiency (in terms of potentiation or depression) depends on the time interval between pulses. The maturation of biophysically-based models, which describe the physiological properties of plasticity mathematically, offers a beneficial framework to explore induced plasticity for new stimulation protocols. To model the QPS paradigm, a phenomenological model based on the knowledge of spike timing-dependent plasticity (STDP) mechanisms of synaptic plasticity was utilized where the cortex builds upon the platform of neuronal population modeling. Induced cortical plasticity was modeled for both conventional monophasic pulses and unidirectional pulses generated by the cTMS device, in a total of 117 different scenarios. For the conventional monophasic stimuli, the results of the predictive model broadly follow what is typically seen in human experiments. Unidirectional pulses can produce a similar range of plasticity. Additionally, changing the pulse width had a considerable effect on the plasticity (approximately 20% increase). As the width of the positive phase increases, the size of the potentiation will also increase. The proposed model can generate predictions to guide future plasticity experiments. Estimating the plasticity and optimizing the rTMS protocols might effectively improve the safety implications of TMS experiments by reducing the number of delivered pulses to participants. Finding the optimal stimulation protocol with the maximum potentiation/depression can lead to the design of a new TMS pulse generator device with targeted hardware and control algorithms.

Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS

BackgroundTheta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS. ObjectiveTo compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS. MethodsForty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed. ResultsThe facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS. ConclusionQPS is more effective and stable for synaptic plasticity induction than TBS.

TMS Intervention of Human Neuronal Network

I describe quadripulse stimulation (QPS) briefly, and show several examples of its applications, such as rTMS treatment of Parkinson's disease, gait induction by lumbar rTMS, and roles of presupplementary motor area (pre-SMA) and SMA in visuo-motor sequence learning, role of SMA in negative compatibility effect, and role of dendritic back propagation potential in I-wave generation.

Quadripulse stimulation (QPS).

Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5s for 30min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex. In this mini-review, we briefly introduce QPS: (i) principle and cortical plasticity (stimulators and protocols, synaptic plasticity, underlying mechanisms, meta-plasticity, axonal plasticity, and drug effects), (ii) robust and strong neural plasticity induction (variability, influence of phasic muscle contraction, independency of BDNF polymorphism, sensory cortical plasticity, neural plasticity in the contralateral hemisphere, on-line effects on the brain networks, studies of normal brain physiology, and visuomotor sequence learning), (iii) therapeutic applications to neurological and psychiatric disorders (Parkinson's disease, epilepsy, cerebrovascular disease, and major depression), (iv) safety, and (v) future issues. Based on this evidence, we propose that QPS is currently the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans.

Exploring the form- And time-dependent effect of low-frequency electromagnetic fields on maintenance of hippocampal long-term potentiation.

Low-frequency electromagnetic field (LF-EMF) stimulation is an emerging neuromodulation tool that is attracting more attention because of its non-invasive and well-controlled characteristics. However, the effect of different LF-EMF features including the forms and the time of addition on neuronal activity has not been completely understood. In this study, we used multi-electrode array (MEA) systems to develop a flexible in vitro magnetic stimulation device with plug-and-play features that allows for real-time delivery of LF-EMFs to biological tissues. Crucially, the method enables different forms of LF-EMF to be added at any time to a long-term potentiation (LTP) experiment without interrupting the process of LTP induction. We demonstrated that the slope of field excitatory postsynaptic potentials (fEPSPs) decreased significantly under post or priming uninterrupted sine LF-EMFs. The fEPSPs slope would continue to decline significantly when LF-EMFs were added two times with a 20-min interval. Paired-pulse ratio (PPR) was analyzed and the results reflected that LF-EMFs induced LTP was expressed postsynaptically. The results of pharmacological experiments indicated that AMPA receptor activity was involved in the process of LTP loss caused by post-LF-EMFs. Moreover, the effect of priming sine or Quadripulse stimulation (QPS)-patterned LF-EMFs depended on the time interval between the end of LF-EMF and the beginning of baseline recording. Interestingly, the effect of sine LF-EMFs on LTP would not disappear within 120min, while the impact of QPS-patterned LF-EMFs on LTP might disappear after 90min. These results indicated that LF-EMF might have a form- and time-dependent effect on LTP.

MRI-based visualization of rTMS-induced cortical plasticity in the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability for minutes to hours after the end of intervention. However, it has not been precisely determined to what extent cortical plasticity prevails spatially in the cortex. Recent studies have shown that rTMS induces changes in “interhemispheric” functional connectivity, the resting-state functional connectivity between the stimulated region and the symmetrically corresponding region in the contralateral hemisphere. In the present study, quadripulse stimulation (QPS) was applied to the index finger representation in the left primary motor cortex (M1), while the position of the stimulation coil was constantly monitored by an online navigator. After QPS application, resting-state functional magnetic resonance imaging was performed, and the interhemispheric functional connectivity was compared with that before QPS. A cluster of connectivity changes was observed in the stimulated region in the central sulcus. The cluster was spatially extended approximately 10 mm from the center [half width at half maximum (HWHM): approximately 3 mm] and was extended approximately 20 mm long in depth (HWHM: approximately 7 mm). A localizer scan of the index finger motion confirmed that the cluster of interhemispheric connectivity changes overlapped spatially with the activation related to the index finger motion. These results indicate that cortical plasticity in M1 induced by rTMS was relatively restricted in space and suggest that rTMS can reveal functional dissociation associated with adjacent small areas by inducing neural plasticity in restricted cortical regions.

S5-2. Paired-associative quadripulse stimulation: New plasticity induction method

S5-2. Paired-associative quadripulse stimulation: New plasticity induction method

FV 2 Metaplastic interactions following a facilitating quadri-pulse theta burst stimulation protocol

FV 2 Metaplastic interactions following a facilitating quadri-pulse theta burst stimulation protocol