Characterizing changes in the excitability of corticospinal projections to proximal muscles of the upper limb

Background: There has been an explosion of interest in methods of exogenous brain stimulation that induce changes in the excitability of human cerebral cortex. The expectation is that these methods may promote recovery of function following brain injury. To assess their effects on motor output, it is typical to assess the state of corticospinal projections from primary motor cortex to muscles of the hand, via electromyographic responses to transcranial magnetic stimulation. If a range of stimulation intensities is employed, the recruitment curves (RCs) obtained can, at least for intrinsic hand muscles, be fitted by a sigmoid function.

Objective/hypothesis: To establish whether sigmoid fits provide a reliable basis upon which to characterize the input–output properties of the corticospinal pathway for muscles proximal to the hand, and to assess as an alternative the area under the (recruitment) curve (AURC).

Methods: A comparison of the reliability of these measures, using RCs obtained for muscles that are frequently the targets of rehabilitation.

Results: The AURC is an extremely reliable measure of the state of corticospinal projections to hand and forearm muscles, which has both face and concurrent validity. Construct validity is demonstrated by detection of widely distributed (across muscles) changes in corticospinal excitability induced by paired associative stimulation (PAS).

Conclusion(s): The parameters derived from sigmoid fits are unlikely to provide an adequate means to assess the effectiveness of therapeutic regimes. The AURC can be employed to characterize corticospinal projections to a range of muscles, and gauge the efficacy of longitudinal interventions in clinical rehabilitation.

Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans

Many types of non-invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) has attracted particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval. We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (≥80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80, 140 and 250 Hz), current (1, 2 and 3 mA) and duration (500 and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation. When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a long term potentiation-type response. Their relative contributions will differ depending on the nature of the induction protocol that is used.

Modulation of human corticospinal excitability by paired associative stimulation

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation.

Mdx myotubes have normal excitability but show reduced contraction-relaxation dynamics.

The pathogenesis of Duchenne muscular dystrophy (DMD), characterised by lack of the cytoskeletal protein dystrophin, is not completely understood. An early event in the degenerative process of DMD muscle could be a rise in cytosolic calcium concentration. In order to investigate whether this leads to alterations of contractile behaviour, we studied the excitability and contractile properties of cultured myotubes from control (C57BL/10) and mdx mice, an animal model for DMD. The myotubes were stimulated electrically and their motion was recorded photometrically. No significant differences were found between control and mdx myotubes with respect to the following parameters: chronaxy and rheobase (0.33 +/- 0.03 ms and 23 +/- 4 V vs. 0.39 +/- 0.07 ms and 22 +/- 2 V for C57 and mdx myotubes, respectively), tetanisation frequency (a similar distribution pattern was found between 5 and 30 Hz), fatigue during tetanus (found in 35% of both types of myotubes) and post-tetanic contracture. In contrast, contraction and relaxation times were longer (P < 0.005) in mdx (36 +/- 2 and 142 +/- 13 ms, respectively) than in control myotubes (26 +/- 1 and 85 +/- 9 ms, respectively). Together with our earlier findings, these results suggest a decreased capacity for calcium removal in mdx cells leading, in particular, to alterations of muscle relaxation.

Reliability of a new measure of motoneuron excitability

Objectlve:--This study examined the intraclass reliability· of different measures of the excitability of the Hoffmann reflex, derived from stimulus-response curves. The slope of the regression line of the H-reflex stimulus-response curve advocated by Funase et al. (1994) was also compared to the peak of the first derivative of the H-reflex stimulus-response curve (dHIdVmax), a new measure introduced in this investigation. A secondary purpose was to explore the possibility of mood as a covariate when measuring excitability of the H-reflex arc. Methods: The H-reflex amplitude at a stimulus intensity corresponding to 5% of the maximum M-wave (Mmax) is an established measure that was used as an additional basis of comparison. The H-reflex was elicited in the soleus for 24 subjects (12 males and 12 females) on five separate days. Vibration was applied to the Achilles tendon prior to stimulation to test the sensitivity of the measures on test day four. The means of five evoked potentials at each gradually increasing intensity, from below H-reflex threshold to above Mmax, were used to create both the H-reflex and M-wave stimulus response curves for each subject across test days. The mood of the subjects was assessed using the Subjective Exercise Experience Scale (SEES) prior to the stimulation protocol each day. Results: There was a modest decrease in all H-reflex measures from the first to third test day, but it was non-significant (P's>0.05). All measures of the H-reflex exhibited a profound reduction following vibration on test day four, and then returned to baseline levels on test day five (P's<0.05). The intraclass correlation coefficient (ICC) for H-reflex amplitude at 5% of Mmax was 0.85. The ICC for the slope of the regression line was 0.79 while it was 0.89 for dH/dVmax. Maximum M-wave amplitude had an ICC of 0.96 attesting to careful methodological controls. The SEES subscales of fatigue and psychological well-being remained unchanged IV across the five days. The psychological distress subscale (PO.05). Conclusions: The peak of the first derivative of the H-reflex stimulus-response curve (dH/dVmax) was shown to have comparable reliability and sensitivity to other more established measures of excitability. Psychological distress and the amplitude of the H-reflex at 5% Mmax follow similar trends across days, however there was no significant correlation between the two measures. Significance: The proposed method appears to be a more robust measure ofH-reflex excitability than the other methods tested. As such it would be an advantageous method to apply in clinical and investigative settings. Additionally, the results suggest that the relationship between psychological distress and H-reflex amplitude should be investigated further.

Corticospinal excitability not affected by negative motor imagery or intention

Bien que l’imagerie motrice positive ait été bien étudiée et est utilisée en réhabilitation, l’effet de l’imagerie motrice négative est beaucoup moins connu. Le but de cette recherche était de définir si l’intention et/ou l’imagerie motrice négative serait en mesure de réduire l’effet d’une stimulation magnétique transcrânienne (SMT) sur le cortex moteur. Vingt participants ont reçu trente stimulations de SMT dans trois situations différentes : En restant passif, en portant une attention particulière aux sensations dans leur main ou en tentant de réduire l’effet de la SMT. La moitié des participants ont utilisé une stratégie d’imagerie motrice, l’autre moitié leur intention. Dans les deux cas, l’amplitude dans la condition de modulation n’a pas été réduite de façon significative.

Contributions des voies vestibulospinale et corticospinale au contrôle des mouvements du bras

Le contrôle des mouvements du bras fait intervenir plusieurs voies provenant du cerveau. Cette thèse, composée principalement de deux études, tente d’éclaircir les contributions des voies tirant leur origine du système vestibulaire et du cortex moteur. Dans la première étude (Raptis et al 2007), impliquant des mouvements d’atteinte, nous avons cerné l’importance des voies descendantes partant du système vestibulaire pour l’équivalence motrice, i.e. la capacité du système moteur à atteindre un but moteur donné lorsque le nombre de degrés de liberté articulaires varie. L’hypothèse émise était que le système vestibulaire joue un rôle essentiel dans l’équivalence motrice. Nous avons comparé la capacité d’équivalence motrice de sujets sains et de patients vestibulodéficients chroniques lors de mouvements nécessitant un contrôle des positions du bras et du tronc. Pendant que leur vision était temporairement bloquée, les sujets devaient soit maintenir une position de l’index pendant une flexion du tronc, soit atteindre une cible dans l’espace péri-personnel en combinant le mouvement du bras avec une flexion du tronc. Lors d’essais déterminés aléatoirement et imprévus par les participants, leur tronc était retenu par un mécanisme électromagnétique s’activant en même temps que le signal de départ. Les sujets sains ont pu préserver la position ou la trajectoire de l’index dans les deux conditions du tronc (libre, bloqué) en adaptant avec une courte latence (60-180 ms) les mouvements articulaires au niveau du coude et de l’épaule. En comparaison, six des sept patients vestibulodéficients chroniques ont présenté des déficits au plan des adaptations angulaires compensatoires. Pour ces patients, entre 30 % et 100 % du mouvement du tronc n’a pas été compensé et a été transmis à la position ou trajectoire de l’index. Ces résultats indiqueraient que les influences vestibulaires évoquées par le mouvement de la tête pendant la flexion du tronc jouent un rôle majeur pour garantir l’équivalence motrice dans ces tâches d’atteinte lorsque le nombre de degrés de liberté articulaires varie. Également, ils démontrent que la plasticité de long terme survenant spontanément après une lésion vestibulaire unilatérale complète ne serait pas suffisante pour permettre au SNC de retrouver un niveau d’équivalence motrice normal dans les actions combinant un déplacement du bras et du tronc. Ces tâches de coordination bras-tronc constituent ainsi une approche inédite et sensible pour l’évaluation clinique des déficits vestibulaires. Elles permettent de sonder une dimension fonctionnelle des influences vestibulaires qui n’était pas prise en compte dans les tests cliniques usuels, dont la sensibilité relativement limitée empêche souvent la détection d’insuffisances vestibulaires six mois après une lésion de ces voies. Avec cette première étude, nous avons donc exploré comment le cerveau et les voies descendantes intègrent des degrés de liberté articulaires supplémentaires dans le contrôle du bras. Dans la seconde étude (Raptis et al 2010), notre but était de clarifier la nature des variables spécifiées par les voies descendantes pour le contrôle d’actions motrices réalisées avec ce membre. Nous avons testé l’hypothèse selon laquelle les voies corticospinales contrôlent la position et les mouvements des bras en modulant la position-seuil (position de référence à partir de laquelle les muscles commencent à être activés en réponse à une déviation de cette référence). Selon ce principe, les voies corticospinales ne spécifieraient pas directement les patrons d’activité EMG, ce qui se refléterait par une dissociation entre l’EMG et l’excitabilité corticospinale pour des positions-seuils différentes. Dans un manipulandum, des participants (n=16) ont modifié leur angle du poignet, d’une position de flexion (45°) à une position d’extension (-25°), et vice-versa. Les forces élastiques passives des muscles ont été compensées avec un moteur couple afin que les sujets puissent égaliser leur activité EMG de base dans les deux positions. L’excitabilité motoneuronale dans ces positions a été comparée à travers l’analyse des réponses EMG évoquées à la suite d’étirements brefs. Dans les deux positions, le niveau d’EMG et l’excitabilité motoneuronale étaient semblables. De plus, ces tests ont permis de montrer que le repositionnement du poignet était associé à une translation de la position-seuil. Par contre, malgré la similitude de l’excitabilité motoneuronale dans ces positions, l’excitabilité corticospinale des muscles du poignet était significativement différente : les impulsions de stimulation magnétique transcrânienne (TMS; à 1.2 MT, sur l’aire du poignet de M1) ont provoqué des potentiels moteurs évoqués (MEP) de plus grande amplitude en flexion pour les fléchisseurs comparativement à la position d’extension et vice-versa pour les extenseurs (p<0.005 pour le groupe). Lorsque les mêmes positions étaient établies après une relaxation profonde, les réponses réflexes et les amplitudes des MEPs ont drastiquement diminué. La relation caractéristique observée entre position physique et amplitude des MEPs dans le positionnement actif s’est aussi estompée lorsque les muscles étaient relâchés. Cette étude suggère que la voie corticospinale, en association avec les autres voies descendantes, participerait au contrôle de la position-seuil, un processus qui prédéterminerait le référentiel spatial dans lequel l’activité EMG émerge. Ce contrôle de la « référence » constituerait un principe commun s’appliquant à la fois au contrôle de la force musculaire, de la position, du mouvement et de la relaxation. Nous avons aussi mis en évidence qu’il est nécessaire, dans les prochaines recherches ou applications utilisant la TMS, de prendre en compte la configuration-seuil des articulations, afin de bien interpréter les réponses musculaires (ou leurs changements) évoquées par cette technique; en effet, la configuration-seuil influencerait de manière notable l’excitabilité corticomotrice, qui peut être considérée comme un indicateur non seulement lors d’activités musculaires, mais aussi cognitives, après apprentissages moteurs ou lésions neurologiques causant des déficits moteurs (ex. spasticité, faiblesse). Considérées dans leur ensemble, ces deux études apportent un éclairage inédit sur des principes fondamentaux du contrôle moteur : nous y illustrons de manière plus large le rôle du système vestibulaire dans les tâches d’atteinte exigeant une coordination entre le bras et son « support » (le tronc) et clarifions l’implication des voies corticomotrices dans la spécification de paramètres élémentaires du contrôle moteur du bras. De plus amples recherches sont cependant nécessaires afin de mieux comprendre comment les systèmes sensoriels et descendants (e.g. vestibulo-, réticulo-, rubro-, propriospinal) participent et interagissent avec les signaux corticofugaux afin de spécifier les seuils neuromusculaires dans le contrôle de la posture et du mouvement.

Age-related effects of Ginkgo biloba extract on synaptic plasticity and excitability

EGb 761 is a standardized extract from the Ginkgo biloba leaf and is purported to improve age-related memory impairment. The acute and chronic effect of EGb 761 on synaptic transmission and plasticity in hippocampal slices from young adult (8-12 weeks) and aged (18-24 months) C57B1/6 mice was tested because hippocampal plasticity is believed to be a key component of memory. Acutely applied EGb 761 significantly increased neuronal excitability in slices from aged mice by reducing the population spike threshold and increased the early phase of long-term potentiation, though there was no effect in slices from young adults. In chronically treated mice fed for 30 days with an EGb 761-supplemented diet, EGb 761 significantly increased the population spike threshold and long-term potentiation in slices from aged animals, but had no effect on slices from young adults. The rapid effects of EGb 761 on plasticity indicate a direct interaction with the glutamatergic system and raise interesting implications with respect to a mechanism explaining its effect on cognitive enhancement in human subjects experiencing dementia. (C) 2003 Elsevier Inc. All rights reserved.

Coding of visual space during motor preparation: approaching objects rapidly modulate corticospinal excitability in hand-centered coordinates

Defensive behaviors, such as withdrawing your hand to avoid potentially harmful approaching objects, rely on rapid sensorimotor transformations between visual and motor coordinates. We examined the reference frame for coding visual information about objects approaching the hand during motor preparation. Subjects performed a simple visuomanual task while a task-irrelevant distractor ball rapidly approached a location either near to or far from their hand. After the distractor ball appearance, single pulses of transcranial magnetic stimulation were delivered over the subject's primary motor cortex, eliciting motor evoked potentials (MEPs) in their responding hand. MEP amplitude was reduced when the ball approached near the responding hand, both when the hand was on the left and the right of the midline. Strikingly, this suppression occurred very early, at 70-80ms after ball appearance, and was not modified by visual fixation location. Furthermore, it was selective for approaching balls, since static visual distractors did not modulate MEP amplitude. Together with additional behavioral measurements, we provide converging evidence for automatic hand-centered coding of visual space in the human brain.

Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability

Firing of action potentials in excitable cells accelerates ATP turnover. The voltage-gated potassium channel Kv2.1 regulates action potential frequency in central neurons, whereas the ubiquitous cellular energy sensor AMP-activated protein kinase (AMPK) is activated by ATP depletion and protects cells by switching off energy-consuming processes. We show that treatment of HEK293 cells expressing Kv2.1 with the AMPK activator A-769662 caused hyperpolarizing shifts in the current-voltage relationship for channel activation and inactivation. We identified two sites (S440 and S537) directly phosphorylated on Kv2.1 by AMPK and, using phosphospecific antibodies and quantitative mass spectrometry, show that phosphorylation of both sites increased in A-769662-treated cells. Effects of A-769662 were abolished in cells expressing Kv2.1 with S440A but not with S537A substitutions, suggesting that phosphorylation of S440 was responsible for these effects. Identical shifts in voltage gating were observed after introducing into cells, via the patch pipette, recombinant AMPK rendered active but phosphatase-resistant by thiophosphorylation. Ionomycin caused changes in Kv2.1 gating very similar to those caused by A-769662 but acted via a different mechanism involving Kv2.1 dephosphorylation. In cultured rat hippocampal neurons, A-769662 caused hyperpolarizing shifts in voltage gating similar to those in HEK293 cells, effects that were abolished by intracellular dialysis with Kv2.1 antibodies. When active thiophosphorylated AMPK was introduced into cultured neurons via the patch pipette, a progressive, time-dependent decrease in the frequency of evoked action potentials was observed. Our results suggest that activation of AMPK in neurons during conditions of metabolic stress exerts a protective role by reducing neuronal excitability and thus conserving energy.

Effects of action observation on corticospinal excitability: muscle specificity, direction, and timing of the mirror response

Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity, (2) direction, and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90 ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200 ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour.

Eugenol modifies the excitability of rat sciatic nerve and superior cervical ganglion neurons

Eugenol is a phenylpropene obtained from the essential oils of plants such as clove and basil which has ample use in dentistry. Eugenol possesses analgesic effects that may be related to the inhibition of voltage-dependent Na(+) channels and/or to the activation of TRPV1 receptors or both. In the present study, electrophysiological parameters were taken from the compound action potentials of the isolated rat sciatic nerve and from neurons of the superior cervical ganglion (SCG) impaled with sharp microelectrodes under current-clamp conditions. In the isolated rat sciatic nerve, eugenol inhibited the compound action potential in a concentration-dependent manner. Action potentials recorded from SCG neurons were inhibited by eugenol with an IC(50) of 0.31 mM. At high concentrations (2 mM), during brief applications. eugenol caused significant action potential blockade while it did not interfere with the resting membrane potential or the membrane input resistance. Surprisingly, however, at low eugenol concentrations (0.6 mM), during long time applications, a reversible reduction (by about 50%) in the input membrane resistance was observed, suggesting the possible involvement of a secondary delayed effect of eugenol to reduce neuronal excitability. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations (‘‘TH– Vglut2 Class1’’) also expressed the dopamine transporter (DAT) gene while one did not ("TH–Vglut2 Class2"), and the remaining population did not express TH at all ("TH-Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area

Neuronal excitability level transition induced by electrical stimulation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Increased variability of motor cortical excitability to transcranial magnetic stimulation in migraine: a new clue to an old enigma

Increased, decreased or normal excitability to transcranial magnetic stimulation (TMS) has been reported in the motor (M1) and visual cortices of patients with migraine. Light deprivation (LD) has been reported to modulate M1 excitability in control subjects (CS). Still, effects of LD on M1 excitability compared to exposure to environmental light exposure (EL) had not been previously described in patients with migraine (MP). To further our knowledge about differences between CS and MP, regarding M1 excitability and effects of LD on M1 excitability, we opted for a novel approach by extending measurement conditions. We measured motor thresholds (MTs) to TMS, short-interval intracortical inhibition, and ratios between motor-evoked potential amplitudes and supramaximal M responses in MP and CS on two different days, before and after LD or EL. Motor thresholds significantly increased in MP in LD and EL sessions, and remained stable in CS. There were no significant between-group differences in other measures of TMS. Short-term variation of MTs was greater in MP compared to CS. Fluctuation in excitability over hours or days in MP is an issue that, until now, has been relatively neglected. The results presented here will help to reconcile conflicting observations.