Human Motor Cortex Excitability Research Articles

Excitatory-inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex.

Transcranial focus ultrasound stimulation (tFUS) is a promising non-invasive neuromodulation technology. This study aimed to evaluate the modulatory effects of tFUS on human motor cortex (M1) excitability and explore the mechanism of neurotransmitter-related intracortical circuitry and plasticity. Single pulse transcranial magnetic stimulation (TMS)-eliciting motor-evoked potentials (MEPs) were used to assessed M1 excitability in 10 subjects. Paired-pulse TMS was used to measure the effects of tFUS on GABA- and glutamate-related intracortical excitability and 1 H-MRS was used to assess the effects of repetitive tFUS on GABA and Glx (glutamine + glutamate) neurometabolic concentrations in the targeting region in nine subjects. The etFUS significantly increased M1 excitability, decreased short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). The itFUS significantly suppressed M1 excitability, increased SICI, LICI, and decreased intracortical facilitation (ICF). Seven times of etFUS decreased the GABA concentration (6.32%), increased the Glx concentration (12.40%), and decreased the GABA/Glx ratio measured by MRS, while itFUS increased the GABA concentration (18.59%), decreased Glx concentration (0.35%), and significantly increased GABA/Glx ratio. The findings support that tFUS with different parameters can exert excitatory and inhibitory neuromodulatory effects on the human motor cortex. We provide novel insights that tFUS change cortical excitability and plasticity by regulating excitatory-inhibition balance related to the GABAergic and glutamatergic receptor function and neurotransmitter metabolic level.

Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex

Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique that can modulate the excitability of cortical and deep brain structures with a high degree of focality. Previous human studies showed that TUS decreases motor cortex (M1) excitability measured by transcranial magnetic stimulation (TMS), but whether the effects appear beyond sonication and whether TUS affects the excitability of other interconnected cortical areas is not known. The time course of M1 TUS on ipsilateral and contralateral M1 excitability was investigated in 22 healthy human subjects via TMS-induced motor-evoked potentials. With sonication duration of 500 ms, we found suppression of M1 excitability from 10 ms before to 20 ms after the end of sonication, and the effects were stronger with blocked design compared to interleaved design. There was no significant effect on contralateral M1 excitability. Using ex-vivo measurements, we showed that the ultrasound transducer did not affect the magnitude or time course of the TMS-induced electromagnetic field. We conclude that the online-suppressive effects of TUS on ipsilateral M1 cortical excitability slightly outlast the sonication but did not produce long-lasting effects. The absence of contralateral effects may suggest that there are little tonic interhemispheric interactions in the resting state, or the intensity of TUS was too low to induce transcallosal inhibition.

Exploring parameters of gamma transcranial alternating current stimulation (tACS) and full-spectrum transcranial random noise stimulation (tRNS) on human pharyngeal cortical excitability.

Transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) have been shown to have physiological and functional effects on brain excitability and motor behavior. Yet, little is known about their effects in the swallowing system. To examine the effects and optimal stimulation parameters of tACS and tRNS for modulating excitability of human pharyngeal motor cortex. 10Hz (alpha), 20Hz (beta), 70Hz (gamma) tACS, 0.1-640Hz (full-spectrum) tRNS, and sham were applied over pharyngeal motor cortices at 1.5mA current intensity for 10min in 15 healthy participants. Pharyngeal motor-evoked and thenar motor-evoked potentials (PMEPs and TMEPs) were assessed before and up to 2h after stimulation with single-pulse transcranial magnetic stimulation. Averaged MEP amplitude and latency changes were analyzed using repeated measures ANOVA (rmANOVA). Two-way rmANOVA across all active interventions demonstrated a significant MEP interaction both in the stimulated pharyngeal cortex (F (4, 56)=1.731, p=0.038) and in the ipsilateral thenar cortex (F (4, 56)=1.506, p=0.048). Compared to sham, subsequent post hoc tests showed site-specific and sustained (60-120min) increases in PMEPs with gamma tACS and tRNS (p=0.005, p=0.027, respectively) and for TMEPs with beta tACS (p=0.006). Our findings suggest that the effects of tACS and tRNS are frequency-dependent and cortical (representation) site-specific with both gamma tACS and full-spectrum tRNS enhancing human pharyngeal cortical excitability. These techniques hold promise as potential treatments for neurological dysphagia.

Effects of D-Cycloserine on the Primary Motor Cortex Excitability in Healthy Human Subjects: A Paired-Pulse-Tms Protocol

Paired-pulse transcranial magnetic stimulation (ppTMS) can probe the human primary motor cortex excitability. Short interstimulus intervals (ISI<5ms) between a subthreshold and a suprathreshold pulse cause short-term intracortical inhibition (SICI), whereas longer ISI causes intracortical facilitation (ICF). NMDA-receptor antagonists decrease ICF, a proxy for glutamatergic transmission, and increase ICI and cortical silent period (CSP), for GABAergic transmission. The effect of NMDA-receptor agonists (e.g.

NON INVASIVE BRAIN STIMULATION TECHNIQUE – AN AREA NEEDS TO BE EXPLORED

Aspiration to enhance human capabilities by increasing cognitive functions and physical performance is a novel approach; however, mechanism to increase human performance to the highest level has been the topic of interest for the researchers since centuries. The activity of human brain can be altered through electrical stimulation that is purely noninvasive. Recently, Studies conducted by rehablitationists have emphasized the use of non-invasive electrical stimulation; one of the non-invasive brain stimulation (NIBS) techniques that induces excitability in human motor cortex is transcranial direct current stimulation (tDCS) that work by process of neuro modulation.

P81-T Homeostatic and metaplastic mechanisms of quadri-pulse theta burst stimulation using an inhibitory priming protocol

Homeostatic plasticity is considered to stabilize neural activity within a physiologically reasonable and dynamic range. Quadri-pulse-thetaburst stimulation (qTBS) is a patterned transcranial magnetic stimulation (TMS) protocol that induced lasting increase/decrease in neuronal excitability of human primary motor cortex (M1) probably corresponding to the model of LTP- and LTD-like plasticity. We investigated priming mechanisms of inhibitory qTBS on subsequent facilitating qTBS (experiment 1) and on subsequent inhibitory qTBS (experiment 2). Inhibitory qTBS consisted of 360 bursts given continuously to M1, with bursts of four biphasic TMS pulses, separated by inter-stimulus intervals (ISI) of 50 ms (20 Hz) and inter-burst intervals of 200 ms (5 Hz) (qTBS50/200). Facilitatory qTBS consisted of the same burst pattern but with ISI of 5 ms (200 Hz) (qTBS5/200). Resting motor threshold (RMT) and motor evoked potential (MEP) amplitudes were measured before priming (pre) and for 30 min (post1-post3) after priming. Following post 3, the second stimulation was applied and the RMT and MEP were measured for 60 min (post 4 – post7). In experiment 1 (qTBS50/200 – qTBS5/200), priming led to a decrease of MEP amplitudes (post 1–3), while MEP amplitudes increased following qTBS5/200 (post 4–7). In experiment 2 (qTBS50/200 – qTBS50/200), MEP amplitudes decreased following the priming protocol and returned to baseline after the qTBS50/200 protocol. Our results point towards homeostatic mechanisms of facilitatory qTBS5/200 following priming with qTBS50/200. In contrast, subsequent qTBS50/200 led to a de-depression like effect of MEP amplitudes suggesting metaplastic effects of two inhibitory qTBS protocols applied over M1.

P55. Probing homeostatic and metaplastic mechanisms of quadri-pulse theta burst stimulation using an inhibitory priming protocol

Question Changes in synaptic and neuronal efficacy such as long-term potentiation (LTP) and long-term depression (LTD) are thought to reflect synaptic processes underlying learning and memory. Homeostatic plasticity is considered to stabilize neural activity within a physiologically reasonable and dynamic range. Quadri-pulse-thetaburst stimulation (qTBS) is a recently introduced patterned transcranial magnetic stimulation (TMS) protocol that induced lasting increase or decrease in neuronal excitability of human primary motor cortex (M1) probably corresponding to the model of LTP- and LTD-like plasticity. Here, we aimed to probe homeostatic and metaplastic interactions of an inhibitory priming qTBS protocol on subsequent facilitating and inhibitory qTBS. Methods We investigated the priming mechanisms of inhibitory qTBS on subsequent facilitating qTBS (experiment 1) in 8 healthy volunteers and on subsequent inhibitory qTBS (experiment 2) in 9 healthy volunteers. Inhibitory qTBS consisted of 360 bursts given continuously to M1 (i.e. 1440 full-sine pulses) with bursts of four biphasic TMS pulses (duration 160 μ s) separated by inter-stimulus intervals (ISI) of 50 ms (20 Hz) and inter-burst intervals of 200 ms (5 Hz) (qTBS50/200). Facilitatory qTBS consisted of the same burst pattern but with ISI of 5 ms (200 Hz) (qTBS5/200). TMS was applied by a custom-made magnet stimulator (MSB, Munich). Resting motor threshold (RMT) and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1 mV were measured before priming qTBS50/200 (pre), directly after priming qTBS50/200 (post1), after 15 min (post2) and after 30 min (post3). Following post 3 measurements, the second stimulation (qTBS5/200 or qTBS50/200) was applied and the RMT and MEP were measured for 60 min (post4–post7). Results In experiment 1 (qTBS50/200–qTBS5/200), priming with qTBS50/200 led to a decrease of MEP amplitudes (post1–3), while MEP amplitudes increased following subsequent qTBS5/200 (post 4–7). Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. In experiment 2 (qTBS50/200–qTBS50/200), MEP amplitudes decreased following the priming protocol (post 1–3) and returned to baseline with a slight increase on post 6 after the subsequent qTBS50/200 protocol. Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. Conclusion Our preliminary results may point towards homeostatic mechanisms of facilitatory qTBS5/200 following priming with qTBS50/200. In contrast, subsequent qTBS50/200 led to a de-depression like effect of MEP amplitudes suggesting metaplastic effects of two inhibitory qTBS protocols applied over M1. Our findings may support the assumption that changes in cortico-spinal excitability following qTBS represent LTP- and LTD-like changes in synaptic transmission and corroborate metaplastic de-depression effects of high-frequency patterned rTMS protocols in human M1.

Recruitment of Additional Corticospinal Pathways in the Human Brain with State-Dependent Paired Associative Stimulation.

Standard brain stimulation protocols modify human motor cortex excitability by modulating the gain of the activated corticospinal pathways. However, the restoration of motor function following lesions of the corticospinal tract requires also the recruitment of additional neurons to increase the net corticospinal output. For this purpose, we investigated a novel protocol based on brain state-dependent paired associative stimulation.Motor imagery (MI)-related electroencephalography was recorded in healthy males and females for brain state-dependent control of both cortical and peripheral stimulation in a brain-machine interface environment. State-dependency was investigated with concurrent, delayed, and independent stimulation relative to the MI task. Specifically, sensorimotor event-related desynchronization (ERD) in the β-band (16-22 Hz) triggered peripheral stimulation through passive hand opening by a robotic orthosis and transcranial magnetic stimulation to the respective cortical motor representation, either synchronously or subsequently. These MI-related paradigms were compared with paired cortical and peripheral input applied independent of the brain state. Cortical stimulation resulted in a significant increase in corticospinal excitability only when applied brain state-dependently and synchronously to peripheral input. These gains were resistant to a depotentiation task, revealed a nonlinear evolution of plasticity, and were mediated via the recruitment of additional corticospinal neurons rather than via synchronization of neuronal firing. Recruitment of additional corticospinal pathways may be achieved when cortical and peripheral inputs are applied concurrently, and during β-ERD. These findings resemble a gating mechanism and are potentially important for developing closed-loop brain stimulation for the treatment of hand paralysis following lesions of the corticospinal tract.SIGNIFICANCE STATEMENT The activity state of the motor system influences the excitability of corticospinal pathways to external input. State-dependent interventions harness this property to increase the connectivity between motor cortex and muscles. These stimulation protocols modulate the gain of the activated pathways, but not the overall corticospinal recruitment. In this study, a brain-machine interface paired peripheral stimulation through passive hand opening with transcranial magnetic stimulation to the respective cortical motor representation during volitional β-band desynchronization. Cortical stimulation resulted in the recruitment of additional corticospinal pathways, but only when applied brain state-dependently and synchronously to peripheral input. These effects resemble a gating mechanism and may be important for the restoration of motor function following lesions of the corticospinal tract.

A Data-Driven Approach to Responder Subgroup Identification after Paired Continuous Theta Burst Stimulation.

Background: Modulation of cortical excitability by transcranial magnetic stimulation (TMS) is used for investigating human brain functions. A common observation is the high variability of long-term depression (LTD)-like changes in human (motor) cortex excitability. This study aimed at analyzing the response subgroup distribution after paired continuous theta burst stimulation (cTBS) as a basis for subject selection.Methods: The effects of paired cTBS using 80% active motor threshold (AMT) in 31 healthy volunteers were assessed at the primary motor cortex (M1) corresponding to the representation of the first dorsal interosseous (FDI) muscle of the left hand, before and up to 50 min after plasticity induction. The changes in motor evoked potentials (MEPs) were analyzed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM) and computed ABC analysis.Results: The probability density distribution of the MEP changes from baseline was tri-modal, showing a clear separation at 80.9%. Subjects displaying at least this degree of LTD-like changes were n = 6 responders. By contrast, n = 7 subjects displayed a paradox response with increase in MEP. Reassessment using ABC analysis as alternative approach led to the same n = 6 subjects as a distinct category.Conclusion: Depressive effects of paired cTBS using 80% AMT endure at least 50 min, however, only in a small subgroup of healthy subjects. Hence, plasticity induction by paired cTBS might not reflect a general mechanism in human motor cortex excitability. A mathematically supported criterion is proposed to select responders for enrolment in assessments of human brain functional networks using virtual brain lesions.

Modulation of sensorimotor circuits during retrieval of negative Autobiographical Memories: Exploring the impact of personality dimensions

Autobiographical Memory (AM) retrieval refers to recollection of experienced past events. Previous Transcranial Magnetic Stimulation (TMS) studies have shown that presentation of emotional negative stimuli affects human motor cortex excitability resulting in larger motor evoked potentials (MEPs). Up to date no TMS studies have been carried out in order to investigate the effect of personal memories with negative emotional value on corticospinal excitability. In this study we hypothesized that negative AM retrieval will modulate corticomotor excitability and sensorimotor integration as determined by TMS neurophysiological parameters. Furthermore, we investigated whether TMS responses during retrieval of negative AM are associated with specific personality traits.Twelve healthy subjects were asked to recall either a negative or a neutral AM across two different days in a randomized order. During this memory retrieval, the following TMS parameters were recorded: MEPs; Short- interval intracortical inhibition (SICI) and Intracortical facilitation (ICF); Short-latency afferent inhibition (SAI) and Long- latency afferent inhibition (LAI). Personality traits were assessed by using the Big Five scale. Statistical analysis was performed using factorial ANOVAs and multiple linear regression models. When compared to retrieval of neutral AM, recollection of negative AM induced a larger increase in MEP amplitude, an increase in ICF, and a decrease in SAI. The neuroticism personality trait was a significant predictor of the MEP amplitude increase during retrieval of negative AM. Altogether these results indicate that cortical excitability and sensorimotor integration are selectively modulated by the valence of AM. These results provide the first TMS evidence that the modulatory effect of the AM retrieval is associated with specific personality traits.

High-frequency focal repetitive cerebellar stimulation induces prolonged increases in human pharyngeal motor cortex excitability.

Neurostimulation is a rapidly emerging approach to swallowing rehabilitation, but cerebellar stimulation has not been explored as a treatment. Such proposed therapies for post-stroke dysphagia have required confirmation of physiological effects and optimisation of parameters in healthy humans prior to translational progression into patient groups. There is strong evidence for a role of the cerebellum in swallowing physiology, but this relationship has been under-explored. Recently, single pulses of cerebellar magnetic stimulation have been shown to directly evoke responses from pharyngeal musculature and produce short-term enhancement of cortico-pharyngeal motor evoked potentials, suggesting the feasibility of a cerebellar approach to neurostimulation in the swallowing system. We therefore examined multiple parameters of repetitive cerebellar magnetic stimulation and have described the optimal settings to provoke longer-lasting changes in swallowing neurophysiology. Based on evidence from the post-stroke dysphagia neurostimulation literature, these changes may have a therapeutic potential for swallowing rehabilitation. Brain neurostimulation has been shown to modulate cortical swallowing neurophysiology in post-stroke dysphagia with therapeutic effects which are critically dependent on the stimulation parameters. Cerebellar neurostimulation is, however, a novel, unexplored approach to modulation of swallowing pathways as a prelude to therapy for dysphagia. Here, we randomised healthy human subjects (n=17) to receive one of five cerebellar repetitive TMS (rTMS) interventions (Sham, 1Hz, 5Hz, 10Hz and 20Hz) on separate visits to our laboratory. Additionally, a subset of subjects randomly received each of three different durations (50, 250, 500 pulses) of optimal frequency versus sham cerebellar rTMS. Prior to interventions subjects underwent MRI-guided single-pulse transcranial magnetic stimulation (TMS) to co-localise pharyngeal and thenar representation in the cortex and cerebellum (midline and hemispheric) before acquisition of baseline motor evoked potential (MEP) recordings from each site as a measure of excitability. Post-interventional MEPs were recorded for an hour and compared to sham using repeated measures ANOVA. Only 10Hz cerebellar rTMS increased cortico-pharyngeal MEP amplitudes (mean bilateral increase 52%, P=0.007) with effects lasting 30min post-intervention with an optimal train length of 250 pulses (P=0.019). These optimised parameters of cerebellar rTMS can produce sustained increases in corticobulbar excitability and may have clinical translation in future studies of neurogenic dysphagia.

An unavoidable modulation? Sensory attention and human primary motor cortex excitability.

The link between basic physiology and its modulation by cognitive states, such as attention, is poorly understood. A significant association becomes apparent when patients with movement disorders describe experiences with changing their attention focus and the fundamental effect that this has on their motor symptoms. Moreover, frequently used mental strategies for treating such patients, e.g. with task-specific dystonia, widely lack laboratory-based knowledge about physiological mechanisms. In this largely unexplored field, we looked at how the locus of attention, when it changed between internal (locus hand) and external (visual target), influenced excitability in the primary motor cortex (M1) in healthy humans. Intriguingly, both internal and external attention had the capacity to change M1 excitability. Both led to a reduced stimulation-induced GABA-related inhibition and a change in motor evoked potential size, i.e. an overall increased M1 excitability. These previously unreported findings indicated: (i) that cognitive state differentially interacted with M1 physiology, (ii) that our view of distraction (attention locus shifted towards external or distant location), which is used as a prevention or management strategy for use-dependent motor disorders, is too simple and currently unsupported for clinical application, and (iii) the physiological state reached through attention modulation represents an alternative explanation for frequently reported electrophysiology findings in neuropsychiatric disorders, such as an aberrant inhibition.

Acute effects of lithium on excitability of human motor cortex

ObjectiveLithium has been widely used to treat bipolar affective disorder for over 60years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS). MethodsTen healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450mg, 900mg, or 1350mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration. ResultsTwo hours post drug administration, 450mg of lithium carbonate increased the slope of the MEP IO-curve while 1350mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation. ConclusionsThe acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship. SignificanceFindings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.

Resistant Against De-depression: LTD-Like Plasticity in the Human Motor Cortex Induced by Spaced cTBS

The long-term depression (LTD)-like changes in human primary motor cortex (M1) excitability induced by continuous theta burst stimulation (cTBS) are subject to reversal (i.e., de-depression) following behavioral engagement of M1, limiting its therapeutic potential under behaviorally relevant conditions. Experiments in animals suggest that the repeated, spaced application of stimulation trains may consolidate synaptic plasticity, making it resistant to reversal by physiological activity. Although there is evidence that repeated cTBS prolongs LTD-like M1 neuroplasticity in humans, whether these effects are resistant to de-depression has not been tested. We investigated whether the neuroplastic effects of paired cTBS trains were resistant to de-depression by a sustained, submaximal voluntary contraction of the hand muscles. In the absence of cTBS, voluntary contraction had no effect on motor evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. While the LTD-like MEP depression induced by a single cTBS was abolished by subsequent voluntary contraction, paired cTBS induced MEP depression that was resistant to reversal. This MEP depression was also resistant to reversal when an experimental de-depression protocol was used instead of a voluntary contraction. Our findings suggest that repeated cTBS applications consolidate LTD-like M1 neuroplasticity, which may have important implications for the clinical application of cTBS.

Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation

Transcranial random noise stimulation (tRNS) can increase the excitability of hand area of the primary motor cortex (M1). The aim of this study was to compare the efficacy of tRNS and transcranial direct current stimulation (tDCS) on the leg motor cortex. Ten healthy subjects received anodal, cathodal tDCS, tRNS and sham stimulation for 10 min using 2 mA intensity during separate experimental sessions. Single pulse transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) measurements were used to assess motor cortical excitability changes after the stimulation. Similar to the hand area, we found that both tRNS and anodal tDCS induced an increase of the amplitude of the MEPs. Anodal tDCS induced a constant gradual increase of corticospinal excitability until 60 min post-stimulation, whereas the effect of tRNS was immediate with a duration of 40 min following stimulation. The cathodal tDCS induced decrease in MEP amplitude did not reach statistical significance. Our results suggest that although the leg area has a deeper position in the cortex compared to the hand area, it can be reached by weak transcranial currents. Both anodal tDCS and tRNS had comparable effect on cortical excitability.

Minocycline exerts acute inhibitory effects on cerebral cortex excitability in humans

Minocycline has efficacy to alleviate seizure activity in animal models of epilepsy. Among other mechanisms it has been postulated that minocycline can inhibit microglial activation and develop beneficial effects by decreasing glutamate excitotoxicity. To explore acute effects of minocycline on human motor cortex excitability we used single- and paired-pulse transcranial magnetic stimulation in 12 healthy subjects 4h after a single oral dose of 200mg minocycline or placebo was administered in a randomised, double-blind, placebo-controlled crossover design. Mean cortical silent period, an inhibitory parameter of predominantly intracortical origin, was prolonged after minocycline compared to placebo, while other TMS parameters of cortical excitability remained unchanged. The results demonstrate that a particular parameter of cortical inhibition is rapidly increased after a single oral dose of minocycline in humans.

P 84. High-frequency neuronavigated cerebellar repetitive Transcranial Magnetic stimulation (rTMS) increases human pharyngeal motor cortex excitability

Animal studies, human brain imaging and more recently Transcranial Magnetic Stimulation (TMS) suggest a role for the cerebellum in human swallowing. Moreover, paired-pulse cerebellar-cortical TMS delivered in rapid succession (50–200 ms intervals) facilitates pharyngeal motor cortex excitability ( Jayasekeran et al., 2011 ). The aim of this study was to determine if longer trains of rTMS can induce long-lasting changes in pharyngeal cortical excitability that may prove to be therapeutically useful for dysphagia after stroke. In 17 healthy adults (6 female, age range 18–61 yrs), anatomical MR brain scans were acquired. Thereafter participants were intubated with an intraluminal catheter to record pharyngeal electromyography and underwent TMS cortical mapping with neuronavigation to co-localise pharyngeal motor representation bilaterally, hand motor cortex and the cerebellar site which evoked the largest pharyngeal motor response. Subjects were then randomised to receive one of 5 neuronavigated cerebellar rTMS interventions (Sham, 1 Hz, 5 Hz, 10 Hz and 20 Hz, at least 1 week apart) to the cerebellar site evoking the largest baseline pharyngeal responses to single-pulse cerebellar TMS. Bihemispheric pharyngeal cortical excitability (ipsilateral and contralateral cortex to cerebellum site) was measured at baseline and for up to 1 h post cerebellar rTMS intervention. Abductor pollicis brevis (APB) recordings were used as control. Interventional data were compared to sham using repeated measures ANOVA. Cerebellar rTMS was tolerated well and delivered at an average intensity of 55% of stimulator output. Compared to Sham, 10 Hz cerebellar rTMS increased pharyngeal cortical excitability ( F (1,16) = 8.3, ∗ p = 0.01), with maximal size and durational effects seen primarily in the contralateral pharyngeal cortex (+72%, ∗∗ p = 0.02, Fig. 1 ). By contrast, 1 Hz ( F (1,16) = 0.3, p = 0.60), 5 Hz ( F (1,16) = 0.5, p = 0.48), and 20 Hz rTMS ( F (1,16) = 1.3, p = 0.27) cerebellar conditioning did not significantly alter pharyngeal excitability compared to Sham. APB responses were not significantly different to sham after any intervention. Our data show for the first time that high-frequency (10 Hz) cerebellar stimulation can produce long-lasting increases in human pharyngeal motor cortex excitability, with larger and longer-lasting effects of the intervention primarily seen in the contralateral projection. Hence 10 Hz cerebellar rTMS may play a therapeutic role in the treatment of dysphagia after hemispheric stroke.

Effects of lacosamide and carbamazepine on human motor cortex excitability: A double-blind, placebo-controlled transcranial magnetic stimulation study

PurposeLacosamide (LCM) and carbamazepine (CBZ) are antiepileptic drugs both acting on neuronal voltage-gated sodium channels. Patch-clamp studies demonstrated significant differences in how LCM and CBZ affect neuronal membrane excitability. Despite valuable information patch-clamp studies provide, they also comprise some constraints. For example, little is known about effects of LCM on intracortical synaptic excitability. In contrast, transcranial magnetic stimulation (TMS) can describe drug-induced changes at the system level of the human cerebral cortex. MethodsThe present study was designed to explore dose-depended effects of LCM and effects of CBZ on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in healthy human subjects. Subjects received 600mg CBZ, 200mg LCM, 400mg LCM or placebo preceding TMS measurements. ResultsCompared to placebo, TMS motor thresholds were significantly increased after carbamazepine and lacosamide, with a trend for a dose dependent effect of lacosamide. Both, carbamazepine and lacosamide did not affect TMS parameters of intracortical synaptic excitability. ConclusionsTMS measurements suggest that lacosamide and carbamazepine predominantly act on neuronal membrane excitability.

OC-036 Neuronavigated Repetitive Cerebellar Stimulation Produces Long-Lasting Activation of Human Cortical Swallowing Projections

Introduction Animal studies, human brain imaging and more recently Transcranial Magnetic Stimulation (TMS) suggest a role for the cerebellum in human swallowing. Moreover, paired-pulse cerebellar-cortical TMS delivered in rapid succession (50–200 ms intervals) facilitates pharyngeal motor cortex excitability. We therefore hypothesised that high-frequency (5–20 Hz) repetitive TMS (rTMS) of the cerebellum could modulate pharyngeal motor cortex excitability producing long-lasting changes that may prove to be therapeutically useful for dysphagia after stroke. Methods In 17 healthy adults (6 female, age range 18–61 yrs), anatomical MR brain scans were acquired. Thereafter participants were intubated with an intraluminal catheter to record pharyngeal electromyography and underwent TMS cortical mapping with neuronavigation to co-localise pharyngeal motor representation bilaterally, hand motor cortex and the cerebellar site which evoked the largest pharyngeal motor response. Subjects were then randomised to receive one of 5 neuronavigated cerebellar rTMS interventions (Sham, 1 Hz, 5 Hz, 10 Hz and 20 Hz, at least 1 week apart) to the cerebellar site evoking the largest baseline pharyngeal responses to single-pulse cerebellar TMS. Bihemispheric pharyngeal cortical excitability (ipsilateral and contralateral cortex to cerebellum site) was measured at baseline and for up to one hour post cerebellar rTMS intervention. Abductor pollicis brevis (APB) recordings were used as control. Interventional data were compared to sham using repeated measures ANOVA. Results Cerebellar rTMS was tolerated well and delivered at an average intensity of 55% of stimulator output. Compared to Sham, 10Hz cerebellar rTMS increased pharyngeal cortical excitability (F (1.16) = 8.3, * p = 0.01), with maximal size and durational effects seen primarily in the contralateral pharyngeal cortex (+72%, ** p = 0.02, Figure 1 ). By contrast, 1Hz (F (1.16) = 0.3, p = 0.60), 5Hz (F (1.16) = 0.5, p = 0.48), and 20Hz rTMS (F (1.16) = 1.3, p = 0.27) cerebellar conditioning did not significantly alter pharyngeal excitability compared to Sham. APB responses were not significantly different to sham after any intervention. Conclusion Our data show for the first time that high-frequency (10Hz) cerebellar stimulation can produce long-lasting increases in human pharyngeal motor cortex excitability, with larger and longer-lasting effects of the intervention primarily seen in the contralateral projection. Hence 10 Hz cerebellar rTMS may play a therapeutic role in the treatment of dysphagia after hemispheric stroke. Disclosure of Interest None Declared

Oscillatory Beta Activity Mediates Neuroplastic Effects of Motor Cortex Stimulation in Humans

Continuous theta burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation protocol that can inhibit human motor cortex (M1) excitability and impair movement for ≤ 1 h. While offering valuable insights into brain function and potential therapeutic benefits, these neuroplastic effects are highly variable between individuals. The source of this variability, and the electrophysiological mechanisms underlying the inhibitory after-effects, are largely unknown. In this regard, oscillatory activity at beta frequency (15-35 Hz) is of particular interest as it is elevated in motor disorders such as Parkinson's disease and modulated during the generation of movements. Here, we used a source-level magnetoencephalography approach to investigate the hypothesis that the presence of neuroplastic effects following cTBS is associated with concurrent changes in oscillatory M1 beta activity. M1 cortices were localized with a synthetic aperture magnetometry beamforming analysis of visually cued index finger movements. Virtual electrode analysis was used to reconstruct the spontaneous and movement-related oscillatory activity in bilateral M1 cortices, before and from 10 to 45 min after cTBS. We demonstrate that 40 s of cTBS applied over left M1 reduced corticospinal excitability in the right index finger of 8/16 participants. In these responder participants only, cTBS increased the power of the spontaneous beta oscillations in stimulated M1 and delayed reaction times in the contralateral index finger. No further changes were observed in the latency or power of movement-related beta oscillations. These data provide insights into the electrophysiological mechanisms underlying cTBS-mediated impairment of motor function and demonstrate the association between spontaneous oscillatory beta activity in M1 and the inhibition of motor function.