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1.  Long Lasting Modulation of Cortical Oscillations after Continuous Theta Burst Transcranial Magnetic Stimulation 
PLoS ONE  2012;7(4):e35080.
Transcranial magnetic theta burst stimulation (TBS) differs from other high-frequency rTMS protocols because it induces plastic changes up to an hour despite lower stimulus intensity and shorter duration of stimulation. However, the effects of TBS on neuronal oscillations remain unclear. In this study, we used electroencephalography (EEG) to investigate changes of neuronal oscillations after continuous TBS (cTBS), the protocol that emulates long-term depression (LTD) form of synaptic plasticity. We randomly divided 26 healthy humans into two groups receiving either Active or Sham cTBS as control over the left primary motor cortex (M1). Post-cTBS aftereffects were assessed with behavioural measurements at rest using motor evoked potentials (MEPs) and at active state during the execution of a choice reaction time (RT) task in combination with continuous electrophysiological recordings. The cTBS-induced EEG oscillations were assessed using event-related power (ERPow), which reflected regional oscillatory activity of neural assemblies of θ (4–7.5 Hz), low α (8–9.5 Hz), µ (10–12.5 Hz), low β (13–19.5 Hz), and high β (20–30 Hz) brain rhythms. Results revealed 20-min suppression of MEPs and at least 30-min increase of ERPow modulation, suggesting that besides MEPs, EEG has the potential to provide an accurate cortical readout to assess cortical excitability and to investigate the interference of cortical oscillations in the human brain post-cTBS. We also observed a predominant modulation of β frequency band, supporting the hypothesis that cTBS acts more on cortical level. Theta oscillations were also modulated during rest implying the involvement of independent cortical theta generators over the motor network post cTBS. This work provided more insights into the underlying mechanisms of cTBS, providing a possible link between synchronised neural oscillations and LTD in humans.
PMCID: PMC3319628  PMID: 22496893
2.  Excitatory and inhibitory corticospinal responses to transcranial magnetic stimulation in patients with minor to moderate head injury 
OBJECTIVES—The changes in excitatory and inhibitory responses to transcranial magnetic stimulation (TMS), as attested by motor evoked potential (MEP) and silent period (SP) parameters, were compared in patients who sustained minor to moderate head injury.
METHODS—A total of 38 patients with brain concussion, and diffuse, focal, and combined brain injury and 20 healthy volunteers were examined. The MEPs and SPs were recorded from the abductor pollicis brevis muscle after single pulse TMS 2 weeks after head trauma. The parameters assessed were the MEP resting threshold, the MEP/M wave amplitude ratio, the central motor conduction time (CMCT), the SP threshold, the interthreshold difference (ITD), and the SP duration (SPD).
RESULTS—The main finding was an increase in the ITD in patients with mild and moderate head injury due to the relatively greater augmentation of the MEP threshold. This was associated with a reduction of the MEP/M wave amplitude ratio. The degree of MEP and SP changes depended on severity of head injury and was not related to the type of brain lesions. The SPD did not differ significantly in brain concussion, or diffuse, focal and combined brain injury groups compared with the control group. The CMCT was prolonged in patients with diffuse and combined brain lesions. Among subjective complaints only fatigue was significantly related to ITD, MEP, and SP threshold abnormalities.
CONCLUSIONS—The results suggest that mechanisms involved in MEP and SP generation are differently affected in head injury, the first being impaired more severely. The increase of the ITD accompanied by reduction of the MEP/M wave amplitude ratio may reflect a dissociated impairment of inhibitory and excitatory components of central motor control in head trauma.

PMCID: PMC1737339  PMID: 11309450
3.  Modulation of the Disturbed Motor Network in Dystonia by Multisession Suppression of Premotor Cortex 
PLoS ONE  2012;7(10):e47574.
Daily sessions of therapeutic transcranial brain stimulation are thought to prolong or amplify the effect of a single intervention. Here we show in patients with focal hand dystonia that additional, new effects build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. In a sham-controlled study, real or sham continuous theta burst stimulation (cTBS) was given once daily for five consecutive days to dorsolateral premotor cortex (PMd). Five days of real, but not sham, premotor cTBS improved intracortical inhibition in primary motor cortex (M1) to a similar extent on day 1 and day 5. However 5 days of cTBS were required to restore the abnormal PMd-M1 interactions observed on day 1. Similarly, excessive M1 plasticity seen at baseline was also significantly reduced by five days of real premotor cTBS. There was only a marginal benefit on writing. The results show that additional, new effects, at sites distant from the point of stimulation, build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. The results indicate that it may take many days of therapeutic intervention to rebalance activity in a complex network.
PMCID: PMC3468590  PMID: 23071824
4.  Brain-Derived Neurotrophic Factor – A Major Player in Stimulation-Induced Homeostatic Metaplasticity of Human Motor Cortex? 
PLoS ONE  2013;8(2):e57957.
Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val66met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val66met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val66met (n = 12) and val66val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val66met carriers and val66val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val66met polymorphism, our results do not support the notion that the BDNF val66met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.
PMCID: PMC3585283  PMID: 23469118
5.  Direct-current-dependent shift of theta-burst-induced plasticity in the human motor cortex 
Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200 s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex.
PMCID: PMC3279644  PMID: 22143872
Motor cortex plasticity; Long-term potentiation; Long-term depression; Plasticity regulation
6.  D2 Receptor Block Abolishes Theta Burst Stimulation-Induced Neuroplasticity in the Human Motor Cortex 
Neuropsychopharmacology  2011;36(10):2097-2102.
Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced.
PMCID: PMC3158306  PMID: 21697824
dopamine receptor; sulpiride; plasticity; motor cortex; transcranial magnetic stimulation; theta burst stimulation; dopamine; neuropharmacology; plasticity; clinical pharmacology/clinical trials; dopamine receptor; sulpiride; motor cortex; transcranial magnetic stimulation; theta burst stimulation
7.  Different effects of tetanic stimulation of facial nerve and ulnar nerve on transcranial electrical stimulation motor-evoked potentials 
Objective: Our objective was to examine whether prior tetanic stimulation of cranial nerves enhances the amplitudes of transcranial motor-evoked potentials (MEPs). Methods: Thirty patients undergoing elective craniotomy under propofol-fentanyl anesthesia with partial neuromuscular blockade were enrolled. Both control and posttetanic MEPs (c-MEPs and p-MEPs) monitoring were performed with a train of five pulses delivered to C3 or C4. c-MEPs were recorded from target muscles and p-MEPs were obtained 1 s after tetanic stimulation to the ulnar nerves and facial nerves. The amplitudes of paired MEPs were compared with Wilcoxon’s signed rank test. Results: When tetanic stimulation was separately applied to the facial nerves, amplitudes of p-MEPs from abductor pollicis brevis, orbicularis oculi or oris were similar with those of c-MEPs. When tetanic stimulations were separately applied to the ulnar nerves, the amplitudes of p-MEPs from the abductor pollicis brevis but not orbicularis oculi or oris were significantly enlarged compared with c-MEP. Conclusions: We found that only prior tetanic stimulation of ulnar nerve but not facial nerve could enlarge the amplitudes of trancranial hand MEPs. Augmentation of MEP amplitude via prior tetanic stimulation of peripheral nerve seems to originate from the subcortical level but not motor cortex.
PMCID: PMC3992401  PMID: 24753756
Motor-evoked potentials; tetanic stimulation; ulnar nerve; facial nerve; abductor pollicis brevis; orbicularis oculi; orbicularis oris
8.  Rapid and Scalable Plant-based Production of a Cholera Toxin B Subunit Variant to Aid in Mass Vaccination against Cholera Outbreaks 
Cholera toxin B subunit (CTB) is a component of an internationally licensed oral cholera vaccine. The protein induces neutralizing antibodies against the holotoxin, the virulence factor responsible for severe diarrhea. A field clinical trial has suggested that the addition of CTB to killed whole-cell bacteria provides superior short-term protection to whole-cell-only vaccines; however, challenges in CTB biomanufacturing (i.e., cost and scale) hamper its implementation to mass vaccination in developing countries. To provide a potential solution to this issue, we developed a rapid, robust, and scalable CTB production system in plants.
Methodology/Principal Findings
In a preliminary study of expressing original CTB in transgenic Nicotiana benthamiana, the protein was N-glycosylated with plant-specific glycans. Thus, an aglycosylated CTB variant (pCTB) was created and overexpressed via a plant virus vector. Upon additional transgene engineering for retention in the endoplasmic reticulum and optimization of a secretory signal, the yield of pCTB was dramatically improved, reaching >1 g per kg of fresh leaf material. The protein was efficiently purified by simple two-step chromatography. The GM1-ganglioside binding capacity and conformational stability of pCTB were virtually identical to the bacteria-derived original B subunit, as demonstrated in competitive enzyme-linked immunosorbent assay, surface plasmon resonance, and fluorescence-based thermal shift assay. Mammalian cell surface-binding was corroborated by immunofluorescence and flow cytometry. pCTB exhibited strong oral immunogenicity in mice, inducing significant levels of CTB-specific intestinal antibodies that persisted over 6 months. Moreover, these antibodies effectively neutralized the cholera holotoxin in vitro.
Taken together, these results demonstrated that pCTB has robust producibility in Nicotiana plants and retains most, if not all, of major biological activities of the original protein. This rapid and easily scalable system may enable the implementation of pCTB to mass vaccination against outbreaks, thereby providing better protection of high-risk populations in developing countries.
Author Summary
Cholera sporadically causes outbreaks in regions where safe water supply and sanitation systems are not sufficient. As currently available vaccines are only effective for 2 to 3 years, reactive mass vaccination has been proposed to reduce mortality during outbreaks. Cholera toxin B subunit (CTB), when combined with killed whole-cell bacteria, has been shown to provide superior short-term protection, but manufacturing challenges of the protein limit its availability for mass vaccination programs in developing countries. Our work presented herein developed a rapid, robust, and scalable bioproduction system in plants for a CTB variant, pCTB. The system allowed for the accumulation of pCTB at >1 g per kg of fresh leaf of tobacco-related plants within 5 days, which accounts for over 1000 doses of original CTB included in the World Health Organization-prequalified vaccine Dukoral. We further analyzed in depth the integrity of pCTB using a series of biochemical, biophysical, and immunological experiments, demonstrating that the plant-made protein is feasible as a cholera vaccine antigen. Thus, pCTB plus killed bacteria may be ideal for reactive vaccination against cholera outbreaks.
PMCID: PMC3591335  PMID: 23505583
9.  Modulation of EEG Functional Connectivity Networks in Subjects Undergoing Repetitive Transcranial Magnetic Stimulation 
Brain topography  2013;27(1):172-191.
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that utilizes magnetic fluxes to alter cortical activity. Continuous theta-burst repetitive TMS (cTBS) results in long-lasting decreases in indices of cortical excitability, and alterations in performance of behavioral tasks. We investigated the effects of cTBS on cortical function via functional connectivity and graph theoretical analysis of EEG data. Thirty-one channel resting-state EEG recordings were obtained before and after 40 s of cTBS stimulation to the left primary motor cortex. Functional connectivity between nodes was assessed in multiple frequency bands using lagged max-covariance, and subsequently thresholded to construct undirected graphs. After cTBS, we find widespread decreases in functional connectivity in the alpha band. There are also simultaneous increases in functional connectivity in the high-beta bands, especially amongst anterior and interhemispheric connections. The analysis of the undirected graphs reveals that interhemispheric and interregional connections are more likely to be modulated after cTBS than local connections. There is also a shift in the topology of network connectivity, with an increase in the clustering coefficient after cTBS in the beta bands, and a decrease in clustering and increase in path length in the alpha band, with the alpha-band connectivity primarily decreased near the site of stimulation. cTBS produces widespread alterations in cortical functional connectivity, with resulting shifts in cortical network topology.
PMCID: PMC4026010  PMID: 23471637
TMS; EEG; Resting state; Networks; Functional connectivity; Graph theory
10.  Continuous theta-burst stimulation modulates tactile synchronization 
BMC Neuroscience  2013;14:89.
Temporal order judgement (TOJ) is the ability to detect the order of occurrence of two sequentially delivered stimuli. Previous research has shown that TOJ in the presence of synchronized periodic conditioning stimuli impairs TOJ performance, and this phenomenon is suggested to be mediated by GABAergic interneurons that cause perceptual binding across the two skin sites. Application of continuous theta-burst repetitive TMS (cTBS) over primary somatosensory cortex (SI) alters temporal and spatial tactile perception. The purpose of this study was to examine TOJ perception in the presence and absence of synchronized periodic conditioning stimuli before and after cTBS applied over left-hemisphere SI. A TOJ task was administered on the right index and middle finger (D2 and D3) in two separate sessions in the presence and absence of conditioning stimuli (a background low amplitude sinusoidal vibration).
CTBS reduced the impact of the conditioning stimuli on TOJ performance for up to 18 minutes following stimulation while sham cTBS did not affect TOJ performance. In contrast, the TOJ task performed in the absence of synchronized conditioning stimulation was unaltered following cTBS.
We conclude that cTBS suppresses inhibitory networks in SI that mediate perceptual binding during TOJ synchronization. CTBS offers one method to suppress cortical excitability in the cortex and potentially benefit clinical populations with altered inhibitory cortical circuits. Additionally, TOJ measures with conditioning stimuli may provide an avenue to assess sensory processing in neurologically impaired patient populations.
PMCID: PMC3844444  PMID: 23968301
Temporal order judgment; Continuous theta-burst TMS; Synchronization effect; Cortical Metrics device; Primary somatosensory cortex; Tactile perception
11.  Theta Burst Stimulation Applied over Primary Motor and Somatosensory Cortices Produces Analgesia Unrelated to the Changes in Nociceptive Event-Related Potentials 
PLoS ONE  2013;8(8):e73263.
Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO2 laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.
PMCID: PMC3748010  PMID: 23977382
12.  Cerebellar theta burst stimulation modulates short latency afferent inhibition in Alzheimer's disease patients 
The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). Previous findings demonstrated that high density of cholinergic receptors is found in the thalamus and the cerebellum compared with the cerebral cortex and the hippocampus. We aimed at investigating whether activation of the cerebello-thalamo-cortical pathway by means of cerebellar theta burst stimulation (TBS) could modulate central cholinergic functions evaluated in vivo by using the neurophysiological determination of Short-Latency Afferent Inhibition (SLAI). We tested the SLAI circuit before and after administration of cerebellar continuous TBS (cTBS) in 12 AD patients and in 12 healthy age-matched control subjects (HS). We also investigated potential changes of intracortical circuits of the contralateral primary motor cortex (M1) by assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF). SLAI was decreased in AD patients compared to HS. Cerebellar cTBS partially restored SLAI in AD patients at later inter-stimulus intervals (ISIs), but did not modify SLAI in HS. SICI and ICF did not differ in the two groups and were not modulated by cerebellar cTBS. These results demonstrate that cerebellar magnetic stimulation is likely to affect mechanisms of cortical cholinergic activity, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD.
PMCID: PMC3575596  PMID: 23423358
transcranial magnetic stimulation; cortical plasticity; cholinergic; cerebellum; Alzheimer's disease
13.  Evaluation of corticospinal excitability in cervical myelopathy, before and after surgery, with transcranial magnetic stimulation: a pilot study 
European Spine Journal  2012;22(1):189-196.
A pilot study to examine the impact of cervical myelopathy on corticospinal excitability, using transcranial magnetic stimulation, and to investigate whether motor evoked potential (MEP) and silent period (SP) recruitment curve (RC) parameters can detect changes in corticospinal function pre- and post-surgery.
We studied six cervical myelopathy patients undergoing surgery and six healthy controls. Clinical and functional scores and neurophysiological parameters were examined prior to and 3 months following the surgery.
MEP latencies for abductor pollicis brevis (APB) and tibialis anterior (TA) muscles and central motor conduction time were prolonged pre- and post-surgery; SP durations were differentially altered. There were significant differences in parameters of RCs for (1) MEP area in APB (max values, S50) and TA (slope) between controls and patients pre- and post-surgery and (2) SP duration in APB (max values) between patients pre-surgery and controls.
The findings of this pilot study suggest an uncoupling of excitatory and inhibitory pathways, which persists at 3 months following cord decompression. RCs for MEP and SP at 3 months provide more information on the functional status of the cord and prompts for a longer term follow-up.
PMCID: PMC3540307  PMID: 23132280
Myelopathy; Transcranial magnetic stimulation; Motor evoked potential; Cortical silent period; Recruitment curves
14.  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.
PMCID: PMC3665911  PMID: 23637183
15.  The Supplementary Motor Area Exerts a Tonic Excitatory Influence on Corticospinal Projections to Phrenic Motoneurons in Awake Humans 
PLoS ONE  2013;8(4):e62258.
In humans, cortical mechanisms can interfere with autonomic breathing. Respiratory-related activation of the supplementary motor area (SMA) has been documented during voluntary breathing and in response to inspiratory constraints. The SMA could therefore participate in the increased resting state of the respiratory motor system during wake (i.e. "wakefulness drive to breathe").
The SMA was conditioned by continuous theta burst magnetic stimulation (cTBS, inhibitory) and 5 Hz conventional rTMS (5 Hz, excitatory). The ensuing effects were described in terms of the diaphragm motor evoked response (DiMEPs) to single-pulse transcranial magnetic stimulation over the motor cortex. DiMEPs were recorded at baseline, and at 3 time-points ("post1", "post2", "post3") up to 15 minutes following conditioning of the SMA.
cTBS reduced the amplitude of DiMEPs from 327.5±159.8 µV at baseline to 243.3±118.7 µV, 217.8±102.9 µV and 240.6±123.9 µV at post 1, post 2 and post 3, respectively (F = 6.341, p = 0.002). 5 Hz conditioning increased the amplitude of DiMEPs from 184.7±96.5 µV at baseline to 270.7±135.4 µV at post 3 (F = 4.844, p = 0.009).
The corticospinal pathway to the diaphragm can be modulated in both directions by conditioning the SMA. This suggests that the baseline respiratory activity of the SMA represents an equipoise from which it is possible to move in either direction. The resting corticofugal outflow from the SMA to phrenic motoneurones that this study evidences could putatively contribute to the wakefulness drive to breathe.
PMCID: PMC3628339  PMID: 23614046
16.  Cerebellum to motor cortex paired associative stimulation induces bidirectional STDP-like plasticity in human motor cortex 
The cerebellum is crucially important for motor control and adaptation. Recent non-invasive brain stimulation studies have indicated the possibility to alter the excitability of the cerebellum and its projections to the contralateral motor cortex, with behavioral consequences on motor control and adaptation. Here we sought to induce bidirectional spike-timing dependent plasticity (STDP)-like modifications of motor cortex (M1) excitability by application of paired associative stimulation (PAS) in healthy subjects. Conditioning stimulation over the right lateral cerebellum (CB) preceded focal transcranial magnetic stimulation (TMS) of the left M1 hand area at an interstimulus interval of 2 ms (CB→M1 PAS2 ms), 6 ms (CB→M1 PAS6 ms) or 10 ms (CB→M1 PAS10 ms) or randomly alternating intervals of 2 and 10 ms (CB→M1 PASControl). Effects of PAS on M1 excitability were assessed by the motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar-motor cortex inhibition (CBI) in the first dorsal interosseous muscle of the right hand. CB→M1 PAS2 ms resulted in MEP potentiation, CB→M1 PAS6 ms and CB→M1 PAS10 ms in MEP depression, and CB→M1 PASControl in no change. The MEP changes lasted for 30–60 min after PAS. SICI and CBI decreased non-specifically after all PAS protocols, while ICF remained unaltered. The physiological mechanisms underlying these MEP changes are carefully discussed. Findings support the notion of bidirectional STDP-like plasticity in M1 mediated by associative stimulation of the cerebello-dentato-thalamo-cortical pathway and M1. Future studies may investigate the behavioral significance of this plasticity.
PMCID: PMC3446544  PMID: 23049508
cerebello-dentato-thalamo-cortical pathway; spike-timing dependent-like plasticity; cerebellum; motor cortex; transcranial magnetic stimulation; paired associative stimulation; human
17.  Effect of Stimulation Polarity of Transcranial Direct Current Stimulation on Non-dominant Hand Function 
To evaluate motor excitability and hand function on the non-dominant side according to the polarity of transcranial direct current stimulation (tDCS) on the motor cortex in a healthy person.
tDCS was applied to the hand motor cortex for 15 minutes at an intensity of 1 mA in 28 healthy right-handed adults. Subjects were divided randomly into four groups: an anodal tDCS of the non-dominant hemisphere group, a cathodal tDCS of the non-dominant hemisphere group, an anodal tDCS of the dominant hemisphere group, and a sham group. We measured the motor evoked potential (MEP) in the abductor pollicis brevis and Jabsen-Taylor hand function test (JTT) in the non-dominant hand prior to and following tDCS. All study procedures were done under double-blind design.
There was a significant increase in the MEP amplitude and a significant improvement in the JTT in the non-dominant hand following anodal tDCS of the non-dominant hemisphere (p<0.05). But there was no change in JTT and a significant decrease in the MEP amplitude in the non-dominant hand following cathodal tDCS on the non-dominant hemisphere and anodal tDCS of the dominant hemisphere.
Non-dominant hand function is improved by increased excitability of the motor cortex. Although motor cortex excitability is decreased in a healthy person, non-dominant hand function is maintained. A homeostatic mechanism in the brain might therefore be involved in preserving this function. Further studies are warranted to examine brain functions to clarify this mechanism.
PMCID: PMC3309318  PMID: 22506229
tDCS; Transcranial direct current stimulation; Jabsen-Taylor hand function test; Cortical excitability
18.  Factors Affecting the Motor Evoked Potential Responsiveness and Parameters in Patients With Supratentorial Stroke 
To investigate the factors which affect the motor evoked potential (MEP) responsiveness and parameters and to find the correlation between the function of the upper extremities and the combined study of MEP with a diffusion tensor tractography (DTT) in patients with stroke.
A retrospective study design was used by analyzing medical records and neuroimaging data of 70 stroke patients who underwent a MEP test between June 2011 and March 2013. MEP parameters which were recorded from the abductor pollicis brevis muscle were the resting motor threshold, latency, amplitude, and their ratios. Functional variables, Brunnstrom stage of hand, upper extremity subscore of Fugl-Meyer assessment, Manual Function Test, and the Korean version of Modified Barthel Index (K-MBI) were collected together with the biographical and neurological data. The DTT parameters were fiber number, fractional anisotropy value and their ratios of affected corticospinal tract. The data were compared between two groups, built up according to the presence (MEP-P) or absence (MEP-N) of MEP on the affected hand.
Functional and DTT variables were significantly different between MEP-P and MEP-N groups (p<0.001). Among the MEP-P group, the amplitude ratio (unaffected/affected) was significantly correlated with the Brunnstrom stage of hand (r=-0.427, p=0.013), K-MBI (r=-0.380, p=0.029) and the time post-onset (r=-0.401, p=0.021). The functional scores were significantly better when both MEP response and DTT were present and decreased if one or both of the two studies were absent.
This study indicates MEP responsiveness and amplitude ratio are significantly associated with the upper extremity function and the activities of daily living performance, and the combined study of MEP and DTT provides useful information.
PMCID: PMC3953359  PMID: 24639922
Motor evoked potential; Diffusion tensor imaging; Stroke; Motor function; Activities of daily living
19.  Recombinant fusion protein of cholera toxin B subunit with YVAD secreted by Lactobacillus casei inhibits lipopolysaccharide-induced caspase-1 activation and subsequent IL-1 beta secretion in Caco-2 cells 
BMC Biotechnology  2014;14:38.
Lactobacillus species are used as bacterial vectors to deliver functional peptides to the intestine because they are delivered live to the intestine, colonize the mucosal surface, and continue to produce the desired protein. Previously, we generated a recombinant Lactobacillus casei secreting the cholera toxin B subunit (CTB), which can translocate into intestinal epithelial cells (IECs) through GM1 ganglioside. Recombinant fusion proteins of CTB with functional peptides have been used as carriers for the delivery of these peptides to IECs because of the high cell permeation capacity of recombinant CTB (rCTB). However, there have been no reports of rCTB fused with peptides expressed or secreted by Lactobacillus species. In this study, we constructed L. casei secreting a recombinant fusion protein of CTB with YVAD (rCTB–YVAD). YVAD is a tetrapeptide (tyrosine–valine–alanine–aspartic acid) that specifically inhibits caspase-1, which catalyzes the production of interleukin (IL)-1β, an inflammatory cytokine, from its inactive precursor. Here, we examined whether rCTB–YVAD secreted by L. casei binds to GM1 ganglioside and inhibits caspase-1 activation in Caco-2 cells used as a model of IECs.
We constructed the rCTB–YVAD secretion vector pSCTB–YVAD by modifying the rCTB secretion vector pSCTB. L. casei secreting rCTB–YVAD was generated by transformation with pSCTB–YVAD. Both the culture supernatant of pSCTB–YVAD-transformed L. casei and purified rCTB–YVAD bound to GM1 ganglioside, as did the culture supernatant of pSCTB-transformed L. casei and purified rCTB. Interestingly, although both purified rCTB–YVAD and rCTB translocated into Caco-2 cells, regardless of lipopolysaccharide (LPS), only purified rCTB–YVAD but not rCTB inhibited LPS-induced caspase-1 activation and subsequent IL-1β secretion in Caco-2 cells, without affecting cell viability.
The rCTB protein fused to a functional peptide secreted by L. casei can bind to GM1 ganglioside, like rCTB, and recombinant YVAD secreted by L. casei may exert anti-inflammatory effects in the intestine. Therefore, rCTB secreted by L. casei has potential utility as a vector for the delivery of YVAD to IECs.
PMCID: PMC4031163  PMID: 24884459
Caspase-1; Cholera toxin B subunit; GM1 ganglioside; Interleukin-1β; Lactobacillus casei; YVAD
20.  Effects of 30 Hz Theta Burst Transcranial Magnetic Stimulation on the Primary Motor Cortex 
Journal of Neuroscience Methods  2012;208(2):161-164.
Theta Burst Stimulation (TBS) is a relatively new form of repetitive Transcranial Magnetic Stimulation (TMS) used to probe neuroplasticity in the human cortex. Thirty-Hz TBS, a variation of the originally described 50 Hz TBS, has been shown to induce cortical changes in several nonmotor regions. However, its effects over the primary motor cortex have not been examined. Due to TMS device mechanical properties, 30 Hz TBS is advantageous over 50 Hz TBS in that it can be delivered at higher stimulation intensities. The goal of this pilot study is to examine the neurophysiologic effects of 30 Hz TBS on the primary motor cortex (M1) of healthy adults. Eighteen right-handed adults (33 ± 9.0 years; M:F = 8:10) completed intermittent TBS (iTBS) or continuous TBS (cTBS) over left M1. TBS was performed with Magstim® SuperRapid2 with stimulation bursts (3 pulses at 30 Hz) repeating every 200 milliseconds. For iTBS, each 2-second stimulation train was separated by 8 seconds but there was no pause between trains for cTBS. Each TBS consisted of a total of 600 pulses delivered at an intensity of 90%*Resting Motor Threshold. Motor-Evoked Potentials (MEP) in the right first dorsal interosseous muscle were measured before, and one and ten minutes after TBS. Pre/post-TBS MEP amplitudes were compared using repeated-measures ANOVA. MEP amplitudes increased after 30 Hz iTBS and decreased after 30 Hz cTBS (TBS-Type*Time effect p=0.009). In conclusion, 30 Hz TBS induced similar neurophysiologic effects over M1 as conventional 50 Hz TBS.
PMCID: PMC3398243  PMID: 22627376
Repetitive Transcranial Magnetic Stimulation; Theta Burst Stimulation; Neuroplasticity; Motor Cortex
21.  Theta burst repetitive transcranial magnetic stimulation attenuates somatosensory evoked potentials from the lower limb 
BMC Neuroscience  2012;13:133.
Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation which has been shown to alter cortical excitability in the upper limb representation of primary somatosensory cortex (SI). However, it is unknown whether cTBS modulates cortical excitability within the lower limb representation in SI. The present study investigates the effects of cTBS over the SI lower limb representation on cortical somatosensory evoked potentials (SEPs) and Hoffmann reflex (H-reflex) following tibial nerve stimulation at the knee. SEPs and H-reflex were recorded before and in four time blocks up to 30 minutes following cTBS targeting the lower limb representation within SI.
Following cTBS, the P1-N1 first cortical potential was significantly decreased at 12–16 minutes. CTBS also suppressed the P2-N2 second cortical potential for up to 30 minutes following stimulation. The H-reflex remained statistically unchanged following cTBS although there was a modest suppression observed.
We conclude that cTBS decreases cortical excitability of the lower limb representation of SI as evidenced by suppressed SEP amplitude. The duration and magnitude of the cTBS after effects are similar to those observed in upper limb studies.
PMCID: PMC3504565  PMID: 23113936
Continuous theta burst stimulation; Somatosensory evoked potentials; Hoffmann reflex; Lower limb
22.  Isolating a cerebellar contribution to rapid visual attention using transcranial magnetic stimulation 
Patient and neuroimaging research have provided increasing support for a role of the posterior-lateral cerebellum in cognition, particularly attention. During rapid serial visual presentation, when two targets are presented in close temporal proximity (<500 ms), accuracy at detecting the second target (T2) suffers. This phenomenon is known as the attentional blink (AB), and in cerebellar lesion patients this effect is exaggerated. Damage to the cerebellum may thus disrupt the use of attentional resources during stimulus processing conditions that are temporally demanding. There are reciprocal connections between the cerebral cortex and the contralateral cerebellum, these connections allow for the possibility that lateralized functions in the cerebral cortex (such as language) remain lateralized in the cerebellum. The purpose of this study was to investigate the temporal characteristics of the cerebellar contribution to the AB and to functionally localize the contribution of the cerebellum to the AB using transcranial magnetic stimulation (TMS). We hypothesized that T2 accuracy would decrease after right cerebellar stimulation when the delay between the first target (T1) and T2 was short (120–400 ms) compared to long (720–960 ms). We used continuous theta burst stimulation (cTBS), a form of TMS, to transiently inhibit a focal population of neurons in the left and right posterior-lateral cerebellum of healthy participants (n = 45). Three groups of participants (n = 15) performed the AB before and after either sham, left, or right cerebellar stimulation. The results of this cTBS study support our hypothesis. During the short delay, participants in the right cTBS group showed a greater AB magnitude compared to both the left and sham cTBS groups (p < 0.05). No difference in T2 detection was found over long delays. The results provide further support for a cerebellar contribution to an integrated neural network recruited during temporally demanding attention-based tasks.
PMCID: PMC3426766  PMID: 22936903
cerebellum; cognition; visual attention; theta burst stimulation; attentional blink
23.  Theta-Burst Stimulation-Induced Plasticity over Primary Somatosensory Cortex Changes Somatosensory Temporal Discrimination in Healthy Humans 
PLoS ONE  2012;7(3):e32979.
The somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols.
Methodology/Principal Findings
To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli.
Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson's disease.
PMCID: PMC3296748  PMID: 22412964
24.  Abnormal bihemispheric responses in schizophrenia patients following cathodal transcranial direct stimulation 
Post-mortem and in vivo studies provide evidence for a link between reduced plasticity and dysconnectivity in schizophrenia patients. It has been suggested that the association between plasticity and connectivity contributes to the pathophysiology and symptomatology of schizophrenia. However, little is known about the impact of glutamate-dependent long-term depression (LTD)-like cortical plasticity on inter-hemispheric connectivity in schizophrenia patients. The aim of the present study was to investigate LTD-like cortical plasticity following excitability-diminishing cathodal transcranial direct current stimulation (tDCS) of the left primary motor cortex (M1) and its effects on the non-stimulated right M1. Eighteen schizophrenia patients and 18 matched (age, gender, handedness, and smoking status) control subjects were investigated in this study. Corticospinal excitability changes following tDCS and intra-cortical inhibitory circuits were monitored with transcranial magnetic stimulation. On the stimulated hemisphere, cathodal tDCS increased resting motor thresholds (RMT) in both groups and decreased motor-evoked potential (MEP) sizes in healthy controls to a greater extent compared to schizophrenia patients. On the non-stimulated hemisphere, RMTs were increased and MEPs were decreased only in the healthy control group. Our results confirm previous findings of reduced LTD-like plasticity in schizophrenia patients and offer hypothetical and indirect in vivo evidence for an association between LTD-like cortical plasticity and inter-hemispheric connectivity in schizophrenia patients. Moreover, our findings highlight the impact of plasticity on connectivity. Dysfunctional N-methyl d-aspartate receptors or modulation of dopaminergic transmission can explain these findings. Nevertheless, the effects of antipsychotic medication still need to be considered.
PMCID: PMC3412954  PMID: 22318337
Schizophrenia; Cortical plasticity; Cortical connectivity; Glutamate; Transcranial direct current stimulation
25.  Dissociating the Role of the pre-SMA in Response Inhibition and Switching: A Combined Online and Offline TMS Approach 
The pre-supplementary motor area (pre-SMA) is considered to be a key node in the cognitive control of actions that require rapid updating, inhibition, or switching, as well as working memory. It is now recognized that the pre-SMA is part of a “cognitive control” network involving the inferior frontal gyrus (IFG) and subcortical regions, such as the striatum and subthalamic nucleus. However, two important questions remain to be addressed. First, it is not clear if the main role of the pre-SMA in cognitive control lies in inhibition or switching of actions. From imaging evidence, the right pre-SMA is consistently recruited during inhibition and switching, but the extent to which it participates specifically in either of these processes is unknown. Secondly, the pre-SMA may perform inhibition and switching alone or as part of a larger brain network. The present study used online and offline transcranial magnetic stimulation (TMS) to dissociate the roles of pre-SMA in cognitive control, but also to investigate the potential contribution of connectivity between the pre-SMA and IFG. We applied continuous theta burst stimulation (cTBS) over the right IFG before participants performed a stop switching task while receiving single TMS pulses over the right pre-SMA. The results were compared to a sham cTBS session and pulses applied over the vertex region. Significant worsening of inhibition as well as response adaptation during inhibition was found when applying pulses over the pre-SMA. However, no such worsening was observed in switch trials. Additionally, after cTBS over the IFG, inhibition was also delayed, suggesting its critical necessity in stopping of actions. The results reveal a key contribution of the pre-SMA in inhibition and could suggest a dissociative role in the switching of actions. These findings indicate there is an essential union between IFG and pre-SMA during inhibition.
PMCID: PMC3629293  PMID: 23616761
response inhibition; switching; working memory; cognitive control; TMS; pre-SMA

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