Motor cortex excitability is not differentially modulated following skill and strength training

AIM: A single session of skill or strength training can modulate the primary motor cortex (M1), which manifests as increased corticospinal excitability (CSE) and decreased short-latency intra-cortical inhibition (SICI). We tested the hypothesis that both skill and strength training can propagate the neural mechanisms mediating cross-transfer and modulate the ipsilateral M1 (iM1). METHODS: Transcranial magnetic stimulation (TMS) measured baseline CSE and SICI in the contralateral motor cortex (cM1) and iM1. Participants completed 4 sets of unilateral training with their dominant arm, either visuomotor tracking, metronome-paced strength training (MPST), self-paced strength training (SPST) or control. Immediately post training, TMS was repeated in both M1s. RESULTS: Motor-evoked potentials (MEPs) increased and inhibition was reduced for skill and MPST training from baseline in both M1s. Self-paced strength training and control did not produce changes in CSE and SICI when compared to baseline in both M1s. After training, skill and MPST increased CSE and decreased SICI in cM1 compared to SPST and control. Skill and MPST training decreased SICI in iM1 compared to SPST and control post intervention; however, CSE in iM1 was not different across groups post training. CONCLUSION: Both skill training and MPST facilitated an increase in CSE and released SICI in iM1 and cM1 compared to baseline. Our results suggest that synchronizing to an auditory or a visual cue promotes neural adaptations within the iM1, which is thought to mediate cross transfer.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in Parkinson’s disease and is reversed by levodopa

Objectives: In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinson’s disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion–extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa.
Methods: In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min.
Results: In the OFF condition the PECD was absent in the two test muscles after both the MVR and MSR tasks. In the ON condition finger movement kinematics improved and a period of PECD comparable to that in controls was present after both tasks.
Conclusion: The absence of PECD in PD subjects off medication indicates a persisting increase in corticomotor excitability after non-fatiguing repetitive finger movement that is reversed by levodopa.

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.

Exercise training normalizes an increased neuronal excitability of NTS-projecting neurons of the hypothalamic paraventricular nucleus in hypertensive rats

Stern JE, Sonner PM, Son SJ, Silva FC, Jackson K, Michelini LC. Exercise training normalizes an increased neuronal excitability of NTS-projecting neurons of the hypothalamic paraventricular nucleus in hypertensive rats. J Neurophysiol 107: 2912-2921, 2012. First published February 22, 2012; doi:10.1152/jn.00884.2011.-Elevated sympathetic outflow and altered autonomic reflexes, including impaired baroreflex function, are common findings observed in hypertensive disorders. Although a growing body of evidence supports a contribution of preautonomic neurons in the hypothalamic paraventricular nucleus (PVN) to altered autonomic control during hypertension, the precise underlying mechanisms remain unknown. Here, we aimed to determine whether the intrinsic excitability and repetitive firing properties of preautonomic PVN neurons that innervate the nucleus tractus solitarii (PVN-NTS neurons) were altered in spontaneously hypertensive rats (SHR). Moreover, given that exercise training is known to improve and/or correct autonomic deficits in hypertensive conditions, we evaluated whether exercise is an efficient behavioral approach to correct altered neuronal excitability in hypertensive rats. Patch-clamp recordings were obtained from retrogradely labeled PVN-NTS neurons in hypothalamic slices obtained from sedentary (S) and trained (T) Wistar-Kyoto (WKY) and SHR rats. Our results indicate an increased excitability of PVN-NTS neurons in SHR-S rats, reflected by an enhanced input-output function in response to depolarizing stimuli, a hyperpolarizing shift in Na+ spike threshold, and smaller hyperpolarizing afterpotentials. Importantly, we found exercise training in SHR rats to restore all these parameters back to those levels observed in WKY-S rats. In several cases, exercise evoked opposing effects in WKY-S rats compared with SHR-S rats, suggesting that exercise effects on PVN-NTS neurons are state dependent. Taken together, our results suggest that elevated preautonomic PVN-NTS neuronal excitability may contribute to altered autonomic control in SHR rats and that exercise training efficiently corrects these abnormalities.

Modulation of network excitability and epileptiform activity in the hippocampus of immature rats by the activation of GlyRs

Epileptic seizures are the manifestations of epilepsy, which is a major neurological disorder and occurs with a high incidence during early childhood. A fundamental mechanism underlying epileptic seizures is loss of balance between neural excitation and inhibition toward overexcitation. Glycine receptor (GlyR) is ionotropic neurotransmitter receptor that upon binding of glycine opens an anion pore and mediates in the adult nervous system a consistent inhibitory action. While previously it was assumed that GlyRs mediate inhibition mainly in the brain stem and spinal cord, recent studies reported the abundant expression of GlyRs throughout the brain, in particular during neuronal development. But no information is available regarding whether activation of GlyRs modulates neural network excitability and epileptiform activities in the immature central nervous system (CNS). Therefore the study in this thesis addresses the role of GlyRs in the modulation of neuronal excitability and epileptiform activity in the immature rat brain. By using in vitro intact corticohippocampal formation (CHF) of rats at postnatal days 4-7 and electrophysiological methods, a series of pharmacological examinations reveal that GlyRs are directly implicated in the control of hippocampal excitation levels at this age. In this thesis I am able to show that GlyRs are functionally expressed in the immature hippocampus and exhibit the classical pharmacology of GlyR, which can be activated by both glycine and the presumed endogenous agonist taurine. This study also reveals that high concentration of taurine is anticonvulsive, but lower concentration of taurine is proconvulsive. A substantial fraction of both the pro- and anticonvulsive effects of taurine is mediated via GlyRs, although activation of GABAA receptors also considerably contributes to the taurine effects. Similarly, glycine exerts both pro- and anticonvulsive effects at low and high concentrations, respectively. The proconvulsive effects of taurine and glycine depend on NKCC1-mediated Cl- accumulation, as bath application of NKCC1 inhibitor bumetanide completely abolishes proconvulsive effects of low taurine and glycine concentrations. Inhibition of GlyRs with low concentration of strychnine triggers epileptiform activity in the CA3 region of immature CHF, indicating that intrinsically an inhibitory action of GlyRs overwhelms its depolarizing action in the immature hippocampus. Additionally, my study indicates that blocking taurine transporters to accumulate endogenous taurine reduces epileptiform activity via activation of GABAA receptors, but not GlyRs, while blocking glycine transporters has no observable effect on epileptiform activity. From the main results of this study it can be concluded that in the immature rat hippocampus, activation of GlyRs mediates both pro- and anticonvulsive effects, but that a persistent activation of GlyRs is required to prevent intrinic neuronal overexcitability. In summary, this study uncovers an important role of GlyRs in the modulation of neuronal excitability and epileptiform activity in the immature rat hippocampus, and indicates that glycinergic system can potentially be a new therapeutic target against epileptic seizures of children.

Excitability properties of mouse motor axons in the mutant SOD1(G93A) model of amyotrophic lateral sclerosis

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.

Threshold-dependent effects on peripheral nerve in vivo excitability properties in the rat

Various factors, including maturity, have been shown to influence peripheral nerve excitability measures, but little is known about differences in these properties between axons with different stimulation thresholds. Multiple nerve excitability tests were performed on the caudal motor axons of immature and mature female rats, recording from tail muscles at three target compound muscle action potential (CMAP) levels: 10%, 40% ("standard" level), and 60% of the maximum CMAP amplitude. Compared to lower target levels, axons at high target levels have the following characteristics: lower strength-duration time constant, less threshold reduction during depolarizing currents and greater threshold increase to hyperpolarizing currents, most notably to long hyperpolarizing currents in mature rats. Threshold-dependent effects on peripheral nerve excitability properties depend on the maturation stage, especially inward rectification (Ih), which becomes inversely related to threshold level. Performing nerve excitability tests at different target levels is useful in understanding the variation in membrane properties between different axons within a nerve. Because of the threshold effects on nerve excitability and the possibility of increased variability between axons and altered electric recruitment order in disease conditions, excitability parameters measured only at the "standard" target level should be interpreted with caution, especially the responses to hyperpolarizing currents.

Excitability and recruitment patterns of spinal motoneurons in human sleep as assessed by F-wave recordings

This study examines the excitability and recruitment of spinal motoneurons in human sleep. The main objective was to assess whether supraspinal inhibition affects the different subpopulations of the compound spinal motoneuron pool in the same way or rather in a selective fashion in the various sleep stages. To this end, we studied F-conduction velocities (FCV) and F-tacheodispersion alongside F-amplitudes and F-persistence in 22 healthy subjects in sleep stages N2, N3 (slow-wave sleep), REM and in wakefulness. Stimuli were delivered on the ulnar nerve, and F-waves were recorded from the first dorsal interosseus muscle. Repeated sets of stimuli were stored to obtain at least 15 F-waves for each state of vigilance. F-tacheodispersion was calculated based on FCVs using the modified Kimura formula. Confirming the only previous study, excitability of spinal motoneurons was generally decreased in all sleep stages compared with wakefulness as indicated by significantly reduced F-persistence and F-amplitudes. More importantly, F-tacheodispersion showed a narrowed range of FCV in all sleep stages, most prominently in REM. In non-REM, this narrowed range was associated with a shift towards significantly decreased maximal FCV and mean FCV as well as with a trend towards lower minimal FCV. In REM, the lowering of mean FCV was even more pronounced, but contrary to non-REM sleep without a shift of minimal and maximal FCV. Variations in F-tacheodispersion between sleep stages suggest that different supraspinal inhibitory neuronal circuits acting on the spinal motoneuron pool may contribute to muscle hypotonia in human non-REM sleep and to atonia in REM sleep.