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Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs). Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: β = -0.25, p = 0.02; BVMT-R: β = -0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests. [ABSTRACT FROM AUTHOR]

BackgroundPrevious research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs).ObjectiveThis study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline.MethodsQPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale.ResultsOverall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: β = −0.25, p = 0.02; BVMT-R: β = −0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85).ConclusionOur study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests.

• The degree of LTP-like plasticity was correlated with amyloid and tau biomarkers. • The degree of LTP-like plasticity was correlated with cognitive function. • NBS techniques using QPS5 can be used as a neurophysiological biomarker for cognitive decline related to AD pathology. Amyloid-beta (Aβ) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer's disease (AD) diagnosis in subjects with cognitive decline. Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aβ42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with 11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aβ42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology. [ABSTRACT FROM AUTHOR]

Background: Cortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs). Objective: This study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS. Methods: QPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes. Results: There were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p < 0.001). Conclusion: Our study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease. [ABSTRACT FROM AUTHOR]

• QPS-induced plasticity is retained during acute relapses in Multiple Sclerosis. • Plasticity is higher in patients with motor disability than in patients without. • Metaplasticity may be important to prevent motor disability in Multiple Sclerosis. To 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. Facilitatory 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. Synaptic 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. QPS-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. New insights into synaptic plasticity during MS relapses are provided. [ABSTRACT FROM AUTHOR]

BackgroundCortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs).ObjectiveThis study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS.MethodsQPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes.ResultsThere were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p < 0.001).ConclusionOur study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease.

A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be established. Transcranial magnetic stimulation (TMS) is commonly used to aid in the diagnosis of dysphagia. Most diagnostic applications involve single-pulse TMS and motor evoked potential (MEP) recordings, the use of which is not clinically suitable in patients with severe dysphagia given the large variability in MEPs measured from the muscles involved in swallowing. Previously, we developed a TMS device that can deliver quadripulse theta-burst stimulation in 16 monophasic magnetic pulses through a single coil, enabling the measurement of MEPs related to hand function. We applied a system for MEP conditioning that relies on a 5 ms interval-monophasic quadripulse magnetic stimulation (QPS5) paradigm to produce 5 ms interval-four sets of four burst trains; quadri-burst stimulation (QBS5), which is expected to induce long-term potentiation (LTP) in the stroke patient motor cortex. Our analysis indicated that QBS5 conditioned left motor cortex induced robust facilitation in the bilateral mylohyoid MEPs. Swallowing dysfunction scores after intracerebral hemorrhage were significantly correlated with QBS5 conditioned-MEP parameters, including resting motor threshold and amplitude. The degree of bilateral mylohyoid MEP facilitation after left side motor cortical QBS5 conditioning and the grade of severity of swallowing dysfunction exhibited a significant linear correlation (r = -0.48/-0.46 and 0.83/0.83; R2 = 0.23/0.21 and 0.68/0.68, P < 0.001; Rt./Lt. side MEP-RMT and amplitudes, respectively). The present results indicate that RMT and amplitude of bilateral mylohyoid-MEPs after left motor cortical QBS5 conditioning as surrogate quantitative biomarkers for swallowing dysfunction after ICH. Thus, the safety and limitations of QBS5 conditioned-MEPs in this population should be further explored. [ABSTRACT FROM AUTHOR]

Background: Cortical 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. Objective: To investigate the association between the degree of cortical plasticity and cognitive performance and to compare plasticity between MS patients and healthy controls (HCs). Methods: The 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. Results: SDMT 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. Conclusions: We 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.

Transcranial magnetic stimulation (TMS) is commonly employed for diagnostic and therapeutic purposes to enhance recovery following brain injury, such as stroke or intracerebral hemorrhage (ICH). Single-pulse TMS, most commonly used for diagnostic purposes and with motor evoked potential (MEP) recordings, is not suitable for clinical use in patients with severe motor paresis. To overcome this problem, we developed a quadripulse theta burst transcranial magnetic stimulation (QTS) device that combines the output from 16 stimulators to deliver a train of 16 monophasic magnetic pulses through a single coil. High-frequency theta rhythm magnetic bursts (bursts of four monophasic pulses, at 500 Hz, i.e., with a 2-ms interpulse interval, repeated at 5 Hz) were generated via a set of 16 separate magnetic stimulators connected to a specially designed combination module. No adverse effects or electroencephalogram (EEGs) abnormalities were identified during or after the recordings. MEP amplification in the QTS during four-burst theta rhythm stimulations produced four independent MEPs 20 ms after each burst onset maximizing the final third or fourth burst, which exhibited significantly greater amplitude than those resulting from a single burst or pulse. Motor functional palsy grades after ICH and QTS-MEP parameters and resting motor threshold (RMT) and amplitudes were significantly correlated (r = −0.83/−0.81 and 0.89/0.87; R2 = 0.69/0.66 and 0.79/0.76, p < 0.001; anterior/posterior-stimulus polarity, respectively). In conclusion, QTS-MEPs enabled a linear functional evaluation in patients with various degrees of motor paresis. However, the benefits, safety, and limitations of this device should be further explored in future studies. [ABSTRACT FROM AUTHOR]

Cortical 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. To investigate the association between the degree of cortical plasticity and cognitive performance and to compare plasticity between MS patients and healthy controls (HCs). The 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. SDMT 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. We 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. • QPS-induced plasticity correlates with cognitive performance in RRMS patients. • Cognitively impaired RRMS patients are characterized by reduced plasticity. • QPS may be apt to investigate the prognostic value of cortical plasticity in MS. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is commonly employed for diagnostic and therapeutic purposes to enhance recovery following brain injury, such as stroke or intracerebral hemorrhage (ICH). Single-pulse TMS, most commonly used for diagnostic purposes and with motor evoked potential (MEP) recordings, is not suitable for clinical use in patients with severe motor paresis. To overcome this problem, we developed a quadripulse theta burst transcranial magnetic stimulation (QTS) device that combines the output from 16 stimulators to deliver a train of 16 monophasic magnetic pulses through a single coil. High-frequency theta rhythm magnetic bursts (bursts of four monophasic pulses, at 500 Hz, i.e., with a 2-ms interpulse interval, repeated at 5 Hz) were generated via a set of 16 separate magnetic stimulators connected to a specially designed combination module. No adverse effects or electroencephalogram (EEGs) abnormalities were identified during or after the recordings. MEP amplification in the QTS during four-burst theta rhythm stimulations produced four independent MEPs 20 ms after each burst onset maximizing the final third or fourth burst, which exhibited significantly greater amplitude than those resulting from a single burst or pulse. Motor functional palsy grades after ICH and QTS-MEP parameters and resting motor threshold (RMT) and amplitudes were significantly correlated (r = −0.83/−0.81 and 0.89/0.87; R2 = 0.69/0.66 and 0.79/0.76, p < 0.001; anterior/posterior-stimulus polarity, respectively). In conclusion, QTS-MEPs enabled a linear functional evaluation in patients with various degrees of motor paresis. However, the benefits, safety, and limitations of this device should be further explored in future studies.

Background: Theta 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. Objective: To 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. Methods: Forty-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. Results: The 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. Conclusion: QPS is more effective and stable for synaptic plasticity induction than TBS.

Theta 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. To 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. Forty-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. The 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. QPS is more effective and stable for synaptic plasticity induction than TBS. • Direct, head-to-head comparison of the effects and variability between TBS and QPS. • QPS induced stronger motor cortical plasticity than TBS. • QPS showed less interindividual variability than TBS. [ABSTRACT FROM AUTHOR]

A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be established. Transcranial magnetic stimulation (TMS) is commonly used to aid in the diagnosis of dysphagia. Most diagnostic applications involve single-pulse TMS and motor evoked potential (MEP) recordings, the use of which is not clinically suitable in patients with severe dysphagia given the large variability in MEPs measured from the muscles involved in swallowing. Previously, we developed a TMS device that can deliver quadripulse theta-burst stimulation in 16 monophasic magnetic pulses through a single coil, enabling the measurement of MEPs related to hand function. We applied a system for MEP conditioning that relies on a 5 ms interval-monophasic quadripulse magnetic stimulation (QPS5) paradigm to produce 5 ms interval-four sets of four burst trains; quadri-burst stimulation (QBS5), which is expected to induce long-term potentiation (LTP) in the stroke patient motor cortex. Our analysis indicated that QBS5 conditioned left motor cortex induced robust facilitation in the bilateral mylohyoid MEPs. Swallowing dysfunction scores after intracerebral hemorrhage were significantly correlated with QBS5 conditioned-MEP parameters, including resting motor threshold and amplitude. The degree of bilateral mylohyoid MEP facilitation after left side motor cortical QBS5 conditioning and the grade of severity of swallowing dysfunction exhibited a significant linear correlation ( r = -0.48/-0.46 and 0.83/0.83; R 2 = 0.23/0.21 and 0.68/0.68, P < 0.001; Rt./Lt. side MEP-RMT and amplitudes, respectively). The present results indicate that RMT and amplitude of bilateral mylohyoid-MEPs after left motor cortical QBS5 conditioning as surrogate quantitative biomarkers for swallowing dysfunction after ICH. Thus, the safety and limitations of QBS5 conditioned-MEPs in this population should be further explored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fujiki, Hata, Anan, Matsushita, Kawasaki and Fudaba.)

A variety of noninvasive brain stimulation techniques have been used to study neuronal plasticity. Mostly, noninvasive techniques have been employed, and the bulk of studies have focused on the motor system, because its physiology is more readily accessible and physiological properties can be studied with greater detail than in other systems. In many of the protocols, general conclusions have been drawn from the motor potentials evoked by transcranial magnetic stimulation of the primary motor cortex. Several of the phenomena induced by noninvasive brain stimulation have been mapped on to cellular physiological mechanisms such as synaptic long-term potentiation or long-term depression. Although some parallelisms are intriguing, this approach has also its limitations, and more direct verification of physiological phenomena by animal studies is needed., (© 2013 Elsevier B.V. All rights reserved.)