Modulating motor cortical oscillation with coordinated reset multifocal transcranial magnetic stimulation.

According to the theory of coordinated reset (CR) stimulation, multifocal bursts of stimuli delivered in a random order with a specific interval may reduce the resonance power of the oscillatory generator in the epicenter. We develop a noninvasive coordinated multifocal burst stimulation (COMBS) with three repetitive transcranial stimulation machines based on CR theory to modulate the target frequency in the primary motor cortex and to assess its effect on motor cortical excitability in separate experiments. Electroencephalography and electromyography were recorded in 16 healthy participants during a finger-tapping task, both before and after the intervention. The resting oscillatory power at the targeted frequency was not changed by COMBS. α-Band power was increased in both preparation and movement stages and the low ß-band power was increased in the movement stage of the finger tapping task. The extent of low ß-band event-related desynchronization was reduced by COMBS. There were no changes in reaction time, but there was a trend for a reduced error rate after COMBS. In another 14 healthy participants, there were no significant changes in cortical excitability before and after COMBS measured by rest motor threshold, short interval intracortical inhibition, short interval intracortical facilitation, and cortical silent period. The result indicates that COMBS may modify the cortical oscillatory power and its perturbation within specific movement stage.NEW & NOTEWORTHY This is the first study, to our knowledge, to apply coordinated reset (CR) neuromodulation to the motor cortex with three repetitive transcranial magnetic stimulation (rTMS) stimulators to assess its effect on cortical oscillation. The results revealed enhancement of α-band power specifically in preparation and movement stages and low ß-band power in the movement stage of a motor task. It postulated that CR stimulation may modify the motor cortical oscillation in the specific movement stages.

CART Peptides Differently Regulate Firing Rates and GABAergic Synaptic Inputs of DMV Neurons Innervating the Stomach Antrum and Cecum of Adult Male Rats.

BACKGROUND/AIM: Central administration of cocaine- and amphetamine-regulated transcript peptides (CARTp) alters gastrointestinal motility and reduces food intake in rats. Since neurons in the dorsal motor nucleus of the vagus (DMV) receive GABAergic and glutamatergic inputs and innervate the smooth muscle of gastrointestinal organs, we hypothesized that CARTp acts on the DMV or presynaptic neurons. METHODS: We used 3,3'-dioctadecyloxa-carbocyanine perchlorate (DiO) retrograde tracing with electrophysiological methods to record DMV neurons innervating the stomach antrum or cecum in brainstem slices from adult rats. RESULTS: DiO application did not change the electrophysiological properties of DMV neurons. CART55-102 had no effect on the basal firing rates of neurons in either the stomach antrum-labeled group (SLG) or cecum-labeled group (CLG). When presynaptic inputs were blocked, CART55-102 further increased the firing rates of the SLG, suggesting a direct excitatory effect. Spontaneous inhibitory postsynaptic currents (sIPSCs) occurred at a higher frequency in SLG neurons than in CLG neurons. CART55-102 reduced the amplitude and the frequency of sIPSCs in SLG neurons dose-dependently, with higher doses also reducing spontaneous excitatory postsynaptic currents (sEPSCs). Higher doses of CART55-102 reduced sIPSC and sEPSC amplitudes in CLG neurons, suggesting a postsynaptic effect. In response to incremental current injections, the SLG neurons exhibited less increases in firing activity. Simultaneous applications of current injections and CART55-102 decreased the firing activity of the CLG. Therefore, stomach antrum-projecting DMV neurons possess a higher gating ability to stabilize firing activity. CONCLUSION: The mechanism by which CARTp mediates anorectic actions may be through a direct reduction in cecum-projecting DMV neuron excitability and, to a lesser extent, that of antrum-projecting DMV neurons, by acting on receptors of these neurons.

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

Augmented efficacy of intermittent theta burst stimulation on the virtual reality-based cycling training for upper limb function in patients with stroke: a double-blinded, randomized controlled trial.

BACKGROUND: Virtual reality and arm cycling have been reported as effective treatments for improving upper limb motor recovery in patients with stroke. Intermittent theta burst stimulation (iTBS) can increase ipsilesional cortical excitability, and has been increasingly used in patients with stroke. However, few studies examined the augmented effect of iTBS on neurorehabilitation program. In this study, we investigated the augmented effect of iTBS on virtual reality-based cycling training (VCT) for upper limb function in patients with stroke. METHODS: In this randomized controlled trial, 23 patients with stroke were recruited. Each patient received either 15 sessions of iTBS or sham stimulation in addition to VCT on the same day. Outcome measures were assessed before and after the intervention. Primary outcome measures for the improvement of upper limb motor function and spasticity were Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Modified Ashworth Scale Upper-Extremity (MAS-UE). Secondary outcome measures for activity and participation were Action Research Arm Test (ARAT), Nine Hole Peg Test (NHPT), Box and Block Test (BBT) and Motor Activity Log (MAL), and Stroke Impact Scale (SIS). Wilcoxon signed-rank tests were performed to evaluate the effectiveness after the intervention and Mann-Whitney U tests were conducted to compare the therapeutic effects between two groups. RESULTS: At post-treatment, both groups showed significant improvement in FMA-UE and ARAT, while only the iTBS + VCT group demonstrated significant improvement in MAS-UE, BBT, NHPT, MAL and SIS. The Mann-Whitney U tests revealed that the iTBS + VCT group has presented greater improvement than the sham group significantly in MAS-UE, MAL-AOU and SIS. However, there were no significant differences in the changes of the FMA-UE, ARAT, BBT, NHPT and MAL-QOM between groups. CONCLUSIONS: Intermittent TBS showed augmented efficacy on VCT for reducing spasticity, increasing actual use of the affected upper limb, and improving participation in daily life in stroke patients. This study provided an integrated innovative intervention, which may be a promising therapy to improve upper limb function recovery in stroke rehabilitation. However, this study has a small sample size, and thus a further larger-scale study is warranted to confirm the treatment efficacy. Trial registration This trial was registered under ClinicalTrials.gov ID No. NCT03350087, retrospectively registered, on November 22, 2017.

Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease.

Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell's laboratory in the early 2000s, which was named 'theta burst stimulation' (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, 'closed loop' stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John's contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.

Critical role of glutamatergic and GABAergic neurotransmission in the central mechanisms of theta-burst stimulation.

Theta-burst stimulation (TBS) is a varied form of repetitive transcranial magnetic stimulation (rTMS) and has more rapid and powerful effects than rTMS. Experiments on the human motor cortex have demonstrated that intermittent TBS has facilitatory effects, whereas continuous TBS has inhibitory effects. Huang's simplified model provides a solid basis for elucidating such after-effects. However, evidence increasingly indicates that not all after-effects of TBS are as expected, and high variability among individuals has been observed. Studies have suggested that the GABAergic and glutamatergic neurotransmission play a vital role in the aforementioned after-effects, which might explain the interindividual differences in these after-effects. Herein, we reviewed the latest findings on TBS from animal and human experiments on glutamatergic and GABAergic neurotransmissions in response to TBS. Furthermore, an updated theoretical model integrating glutamatergic and GABAergic neurotransmissions is proposed.

Intermittent theta burst stimulation enhances upper limb motor function in patients with chronic stroke: a pilot randomized controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial stimulation that has been used to enhance upper limb (UL) motor recovery. However, only limited studies have examined its efficacy in patients with chronic stroke and therefore it remains controversial. METHODS: This was a randomized controlled trial that enrolled patients from a rehabilitation department. Twenty-two patients with first-ever chronic and unilateral cerebral stroke, aged 30-70 years, were randomly assigned to the iTBS or control group. All patients received 1 session per day for 10 days of either iTBS or sham stimulation over the ipsilesional primary motor cortex in addition to conventional neurorehabilitation. Outcome measures were assessed before and immediately after the intervention period: Modified Ashworth Scale (MAS), Fugl-Meyer Assessment Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), Box and Block test (BBT), and Motor Activity Log (MAL). Analysis of covariance was adopted to compare the treatment effects between groups. RESULTS: The iTBS group had greater improvement in the MAS and FMA than the control group (η2 = 0.151-0.233; p < 0.05), as well as in the ARAT and BBT (η2 = 0.161-0.460; p < 0.05) with large effect size. Both groups showed an improvement in the BBT, and there were no significant between-group differences in MAL changes. CONCLUSIONS: The iTBS induced greater gains in spasticity decrease and UL function improvement, especially in fine motor function, than sham TBS. This is a promising finding because patients with chronic stroke have a relatively low potential for fine motor function recovery. Overall, iTBS may be a beneficial adjunct therapy to neurorehabilitation for enhancing UL function. Further larger-scale study is warranted to confirm the findings and its long-term effect. TRIAL REGISTRATION: This trial was registered under ClinicalTrials.gov ID No. NCT01947413 on September 20, 2013.

Neuromodulatory Effects of Transcranial Direct Current Stimulation on Motor Excitability in Rats.

Transcranial direct current stimulation (tDCS) is a noninvasive technique for modulating neural plasticity and is considered to have therapeutic potential in neurological disorders. For the purpose of translational neuroscience research, a suitable animal model can be ideal for providing a stable condition for identifying mechanisms that can help to explore therapeutic strategies. Here, we developed a tDCS protocol for modulating motor excitability in anesthetized rats. To examine the responses of tDCS-elicited plasticity, the motor evoked potential (MEP) and MEP input-output (IO) curve elicited by epidural motor cortical electrical stimulus were evaluated at baseline and after 30 min of anodal tDCS or cathodal tDCS. Furthermore, a paired-pulse cortical electrical stimulus was applied to assess changes in the inhibitory network by measuring long-interval intracortical inhibition (LICI) before and after tDCS. In the results, analogous to those observed in humans, the present study demonstrates long-term potentiation- (LTP-) and long-term depression- (LTD-) like plasticity can be induced by tDCS protocol in anesthetized rats. We found that the MEPs were significantly enhanced immediately after anodal tDCS at 0.1 mA and 0.8 mA and remained enhanced for 30 min. Similarly, MEPs were suppressed immediately after cathodal tDCS at 0.8 mA and lasted for 30 min. No effect was noted on the MEP magnitude under sham tDCS stimulation. Furthermore, the IO curve slope was elevated following anodal tDCS and presented a trend toward diminished slope after cathodal tDCS. No significant differences in the LICI ratio of pre- to post-tDCS were observed. These results indicated that developed tDCS schemes can produce consistent, rapid, and controllable electrophysiological changes in corticomotor excitability in rats. This newly developed tDCS animal model could be useful to further explore mechanical insights and may serve as a translational platform bridging human and animal studies, establishing new therapeutic strategies for neurological disorders.

Inter-cortical modulation from premotor to motor plasticity.

KEY POINTS: Synaptic plasticity is involved in daily activities but abnormal plasticity may be deleterious. In this study, we found that motor plasticity could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Such changes in motor plasticity were associated with reduced learning of a simple motor task. We postulate that the premotor cortex adjusts the amount of motor plasticity to modulate motor learning through heterosynaptic metaplasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network, a concept that could be employed to intervene in diseases with abnormal plasticity. ABSTRACT: Primary motor cortex (M1) plasticity is known to be influenced by the excitability and prior activation history of M1 itself. However, little is known about how its plasticity is influenced by other areas of the brain. In the present study on humans of either sex who were known to respond to theta burst stimulation from previous studies, we found plasticity of M1 could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Motor plasticity was distorted and disappeared 30 min and 120 min, respectively, after premotor excitability was suppressed. Further evaluation revealed that such changes in motor plasticity were associated with impaired learning of a simple motor task. We postulate that the premotor cortex modulates the amount of plasticity within M1 through heterosynaptic metaplasticity, and that this may impact on learning of a simple motor task previously shown to be directly affected by M1 plasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network. Furthermore, such concepts could be translated into therapeutic approaches for diseases with aberrant plasticity.

Fatigue and Muscle Strength Involving Walking Speed in Parkinson's Disease: Insights for Developing Rehabilitation Strategy for PD.

Background. Problems with gait in Parkinson's disease (PD) are a challenge in neurorehabilitation, partly because the mechanisms causing the walking disability are unclear. Weakness and fatigue, which may significantly influence gait, are commonly reported by patients with PD. Hence, the aim of this study was to investigate the association between weakness and fatigue and walking ability in patients with PD. Methods. We recruited 25 patients with idiopathic PD and 25 age-matched healthy adults. The maximum voluntary contraction (MVC), twitch force, and voluntary activation levels were measured before and after a knee fatigue exercise. General fatigue, central fatigue, and peripheral fatigue were quantified by exercise-induced changes in MVC, twitch force, and activation level. In addition, subjective fatigue was measured using the Multidimensional Fatigue Inventory (MFI) and Fatigue Severity Scale (FSS). Results. The patients with PD had lower activation levels, more central fatigue, and more subjective fatigue than the healthy controls. There were no significant differences in twitch force or peripheral fatigue index between the two groups. The reduction in walking speed was related to the loss of peripheral strength and PD itself. Conclusion. Fatigue and weakness of central origin were related to PD, while peripheral strength was important for walking ability. The results suggest that rehabilitation programs for PD should focus on improving both central and peripheral components of force.

Functional Dopaminergic Neurons in Substantia Nigra are Required for Transcranial Magnetic Stimulation-Induced Motor Plasticity.

Repetitive magnetic stimulation (rTMS), including theta burst stimulation (TBS), is capable of modulating motor cortical excitability through plasticity-like mechanisms and might have therapeutic potential for Parkinson's disease (PD). An animal model would be helpful for elucidating the mechanism of rTMS that remain unclear and controversial. Here, we have established a TMS model in rat and applied this model to study the impact of substantia nigra dopamine neuron on TBS-induced motor plasticity in PD rats. In parallel with human results, continuous TBS (cTBS) successfully suppressed motor evoked potentials (MEPs), while MEPs increased after intermittent TBS (iTBS) in healthy rats. We then tested the effect of iTBS in early and advanced 6-hydroxydopamine (6-OHDA)-lesioned PD. Moreover, dopaminergic neurons in substantia nigra and rotation behavior were assessed to correlate with the amount of iTBS-induced plasticity. In results, iTBS-induced potentiation was reduced in early PD rats and was absent in advanced PD rats. Such reduction in plasticity strongly correlated with the dopaminergic cell loss and the count of rotation in PD rats. In conclusion, we have established a TMS PD rat model. With the help of this model, we confirmed the loss of domaninergic neurons in substantia nigra resulting in reduced rTMS-induced motor plasticity in PD.

Using surface electromyography to guide the activation during motor-evoked potential measurement: An activation control method for follow-up studies.

OBJECTIVE: This study evaluated the reliability and validity of a convenient method that uses the real-time feedback surface electromyography (sEMG) to control muscle activation while measuring the MEP recorded from the quadriceps muscle in patients with stroke. METHODS: It measured the MEP parameters as well as the clinical assessment at initial test. Participants were directed to adjust their quadriceps contraction to extend the knee isometrically and maintain the EMG amplitude at 0.2 mV. MEPs were measured 2 weeks after the initial test again to assess the reliability of this measurement. RESULTS: A good test-re-test reliability was demonstrated with an intra-class correlation coefficient (ICC) > 0.8 for the motor threshold and a moderate reliability (ICC > 0.6) for the MEP latency and MEP amplitude, for both paretic and non-paretic legs. Patients with present MEPs had significantly higher scores in muscle power, the Fugl-Meyer assessment, the balance sub-scale of performance-oriented mobility assessment and the Barthel index; and lower NIHSS scores than those of patients with absent MEPs (all p < 0.05). CONCLUSION: The sEMG-guided low level muscle activation is suitable for MEP assessment in patients with leg weakness after a stroke and may be used for long-term follow-up studies.

Intensity sensitive modulation effect of theta burst form of median nerve stimulation on the monosynaptic spinal reflex.

The effects of electrical stimulation of median nerve with a continuous theta burst pattern (EcTBS) on the spinal H-reflex were studied. Different intensities and durations of EcTBS were given to the median nerve to 11 healthy individuals. The amplitude ratio of the H-reflex to maximum M wave (H/M ratio), corticospinal excitability and inhibition measured using motor evoked potentials (MEPs), short-interval intracortical inhibition and facilitation (SICI/ICF), spinal reciprocal inhibition (RI), and postactivation depression (PAD) were measured before and after EcTBS. In result, the H/M ratio was reduced followed by EcTBS at 90% H-reflex threshold, and the effect lasted longer after 1200 pulses than after 600 pulses of EcTBS. In contrast, EcTBS at 110% threshold facilitated the H/M ratio, while at 80% threshold it had no effect. Maximum M wave, MEPs, SICI/ICF, RI, and PAD all remained unchanged after EcTBS. In conclusion, EcTBS produced lasting effects purely on the H-reflex, probably, through effects on postsynaptic plasticity. The effect of EcTBS depends on the intensity and duration of stimulation. EcTBS is beneficial to research on mechanisms of human plasticity. Moreover, its ability to modulate spinal excitability is expected to have therapeutic benefits on neurological disorders involving spinal cord dysfunction.

Restoration of Central Programmed Movement Pattern by Temporal Electrical Stimulation-Assisted Training in Patients with Spinal Cerebellar Atrophy.

Disrupted triphasic electromyography (EMG) patterns of agonist and antagonist muscle pairs during fast goal-directed movements have been found in patients with hypermetria. Since peripheral electrical stimulation (ES) and motor training may modulate motor cortical excitability through plasticity mechanisms, we aimed to investigate whether temporal ES-assisted movement training could influence premovement cortical excitability and alleviate hypermetria in patients with spinal cerebellar ataxia (SCA). The EMG of the agonist extensor carpi radialis muscle and antagonist flexor carpi radialis muscle, premovement motor evoked potentials (MEPs) of the flexor carpi radialis muscle, and the constant and variable errors of movements were assessed before and after 4 weeks of ES-assisted fast goal-directed wrist extension training in the training group and of general health education in the control group. After training, the premovement MEPs of the antagonist muscle were facilitated at 50 ms before the onset of movement. In addition, the EMG onset latency of the antagonist muscle shifted earlier and the constant error decreased significantly. In summary, temporal ES-assisted training alleviated hypermetria by restoring antagonist premovement and temporal triphasic EMG patterns in SCA patients. This technique may be applied to treat hypermetria in cerebellar disorders. (This trial is registered with NCT01983670.).

Selective modulation of motor cortical plasticity during voluntary contraction of the antagonist muscle.

A fundamental approach for resolving motor deficits in patients suffering from various neurological diseases is to improve the impaired cortical function through the modulation of plasticity. In order to advance clinical practice in this regard, it is necessary to better understand the interactions that occur between functional neuromuscular activity and the resulting cortical plasticity. This study tested whether the voluntary contraction of an antagonist muscle modulates the plasticity-like effect of continuous theta burst stimulation (cTBS) recorded from the agonist. The effects of various opposing torques produced by the antagonist were also measured. As a result, the suppressing effect of cTBS was enhanced by mild antagonist contraction, whereas effortful antagonist contraction suspended the plasticity caused by cTBS. In contrast, the antagonist contractions right after cTBS did not significantly influence the effect of cTBS. The results indicate that the antagonist activity alters the effect of cTBS, especially in protocols with synchronous magnetic stimulation and antagonist contraction. Such modulation on cTBS may be through a reciprocal mechanism within the motor cortex, although the spinal regulation of the motoneuronal pool cannot be fully excluded. The present findings are beneficial for elucidating the mechanism of neuromuscular control and for resolving related neurological disorders.

Reduced cortical plasticity and GABAergic modulation in essential tremor.

Essential tremor (ET) is the most common movement disorder among adults. Cerebellar dysfunction is thought to be involved in the pathogenesis of ET; however, imaging, electrophysiological studies, and clinical observations have suggested that the cerebral cortex also may participate. We sought to investigate the possible motor cortical contribution to ET by assessing response to continuous theta-burst stimulation (cTBS), a recognized tool that can produce transient plastic changes, in the primary motor and premotor cortex of patients with ET. We compared parameters, including motor-evoked potential amplitude, cortical silent period, and short-interval intracortical inhibition, before and after applying cTBS in healthy controls and patients with ET. We found that, although cTBS applied to either the motor or premotor cortex was capable of producing a suppressive effect on motor cortical excitability in ET patients, the effects lasted for a significantly shorter time compared with the effect produced in healthy individuals. The change seen in measures of intracortical inhibition after motor cortical or premotor cTBS in healthy controls was reduced or absent in the ET patients. Tremor amplitude was decreased significantly after applying cTBS over either the motor or premotor cortex, but the tremor frequency remained unchanged. These findings suggest that inhibitory circuits within the motor cortex are aberrant and less modifiable in ET patients. The reduced plasticity in response to motor and premotor TBS supports the theory of abnormal gamma-aminobutyric acid (GABA) modulation in ET.

Microelectrodes with gold nanoparticles and self-assembled monolayers for in vivo recording of striatal dopamine.

Electrochemical determination of in vivo dopamine (DA) using implantable microelectrodes is essential for monitoring the DA depletion of an animal model of Parkinson's disease (PD), but faces substantial interference from ascorbic acid (AA) in the brain area due to similar electroactive characteristics. This study utilizes gold nanoparticles (Au-NPs) and self-assembled monolayers (SAMs) to modify platinum microelectrodes for improving sensitivity and specificity to DA and alleviating AA interference. With appropriate choice of ω-mercaptoalkane carboxylic acid chain length, our results show that a platinum microelectrode coated with Au-NPs and 3-mercaptopropionic acid (MPA) has approximately an 881-fold specificity to AA. During amperometric measurements, Au-NP/MPA reveals that the responsive current is linearly dependent on DA over the range of 0.01-5 µM with a correlation coefficient of 0.99 and the sensitivity is 2.7-fold that of a conventional Nafion-coated electrode. Other important features observed include fast response time (below 2 s), resistance to albumin adhesion and low detection limit (7 nM) at a signal to noise ratio of 3. Feasibility of in vivo DA recording with the modified microelectrodes is verified by real-time monitoring of electrically stimulated DA release in the striatum of anesthetized rats with various stimulation parameters and administration of a DA uptake inhibitor. The developed microelectrodes present an attractive alternative to the traditional options for continuous electrochemical in vivo DA monitoring.

Abnormal bidirectional plasticity-like effects in Parkinson's disease.

Levodopa-induced dyskinesia is a major complication of long-term dopamine replacement therapy for Parkinson's disease that becomes increasingly problematic in advanced Parkinson's disease. Although the cause of levodopa-induced dyskinesias is still unclear, recent work in animal models of the corticostriatal system has suggested that levodopa-induced dyskinesias might result from abnormal control of synaptic plasticity. In the present study, we aimed to explore control of plasticity in patients with Parkinson's disease with and without levodopa-induced dyskinesias by taking advantage of a newly developed protocol that tests depotentiation of pre-existing long-term potentiation-like synaptic facilitation. Long-term potentiation-like plasticity and its reversibility were studied in the motor cortex of 10 healthy subjects, 10 patients with Parkinson's disease and levodopa-induced dyskinesias, who took half of the regular dose of levodopa and 10 patients with Parkinson's disease without levodopa-induced dyskinesias, who took either half or the full dose of levodopa. Patients with Parkinson's disease without levodopa-induced dyskinesias had normal long-term potentiation- and depotentiation-like effects when they took their full dose of levodopa, but there was no long-term potentiation-like effect when they were on half dose of levodopa. In contrast, patients with levodopa-induced dyskinesias could be successfully potentiated when they were on half their usual dose of levodopa; however, they were unresponsive to the depotentiation protocol. The results suggest that depotentiation is abnormal in the motor cortex of patients with Parkinson's disease with levodopa-induced dyskinesias and that their long-term potentiation-like plasticity is more readily affected by administration of levodopa than their clinical symptoms.

Impact of operator experience on transcranial magnetic stimulation.

OBJECTIVE: To determine the impact of an operator's experience on transcranial magnetic stimulation (TMS) measurement. METHODS: Operator B (beginner), operator E (expert), and 30 healthy participants joined the study consisting of two experiments. In each experiment, each operator performed a TMS protocol on each participant in a random order. RESULTS: Compared with operator E, operator B exhibited higher resting motor threshold (RMT) in experiment I (60.1 ±â€¯13.0 vs. 57.4 ±â€¯10.9% maximal stimulation output, p = 0.017) and the difference disappeared in experiment II (p = 0.816). In 1-mV motor evoked potential (MEP) measurement, operator B exhibited higher standard deviation indicating lower consistency in experiment I compared with experiment II (1.05 ±â€¯0.40 vs. 1.05 ±â€¯0.16 mV with unequal variances, p = 0.001) and had poor intrarater reliability between the experiments (intraclass correlation coefficient = -0.130). There was no difference in the results of active motor threshold, silent period, paired-pulse stimulation, or continuous theta burst stimulation between the operators. CONCLUSIONS: An operator's experience in TMS may affect the results of RMT measurement. With practice, a beginner may choose a more precise stimulation location and have higher consistency in 1-mV MEP measurement. SIGNIFICANCE: We recommend that a beginner needs to practice for precise stimulation locations before conducting a trial or clinical practice.

Strengthening the GABAergic System Through Neurofeedback Training Suppresses Implicit Motor Learning.

Gamma-aminobutyric acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning.