UNASSIGNED: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability.
UNASSIGNED: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear.
UNASSIGNED: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

BACKGROUND: Acute lateral ankle sprains (ALAS) are associated with long-term impairments and instability tied to altered neural excitability. Arthrogenic muscle inhibition (AMI) has been observed in this population; however, relationships with injury-related impairments are unclear, potentially due to the resting, prone position in which AMI is typically measured. Assessing AMI during bipedal stance may provide a better understanding of this relationship.
METHODS: AMI was assessed in 38 young adults (19 ALAS within 72 h of injury: 10 males, 21.4 ± 2.7 years; 19 healthy controls: 10 males, 21.9 ± 2.2 years; mean ± SD) using the Hoffmann reflex (H-reflex) during bipedal stance. Electrical stimulation was administered to identify the maximal H-reflex (Hmax) and maximal motor response (Mmax) from the soleus, fibularis longus, and tibialis anterior muscles. The primary outcome measure was the Hmax/Mmax ratio. Secondary outcomes included acute symptoms (pain and swelling), postural control during bipedal stance, and self-reported function.
RESULTS: No significant group-by-limb interactions were observed for any muscle. However, a significant group main effect was observed in the soleus muscle (F(1,35) = 6.82, p = 0.013), indicating significantly lower Hmax/Mmax ratios following ALAS (0.38 ± 0.20) compared to healthy controls (0.53 ± 0.16). Furthermore, lower Hmax/Mmax ratios in the soleus significantly correlated with acute symptoms and self-reported function but not with postural control.
CONCLUSIONS: This study supports previous evidence of AMI in patients with ALAS, providing insight into neurophysiologic impacts of musculoskeletal injury. Our results suggest that assessing AMI in a standing position following acute injury may provide valuable insight into how AMI develops and guide potential therapeutic options to curb and offset the formation of joint instability.

Excitability of hippocampal neurons in subarachnoid hemorrhage (SAH) rats has not been well studied. The rat SAH model was applied in this study to explore the role of nuclear factor E2-related factor (Nrf-2) in the early brain injury of SAH. The neural excitability of CA1 pyramidal cells (PCs) in SAH rats was evaluated by using electrophysiology experiments. Ferroptosis and neuroinflammation were measured by ELISA, transmission electron microscopy and western blotting. Our results indicated that SAH induced neurological deficits, brain edema, ferroptosis, neuroinflammation and neural excitability in rats. Ferrostatin-1 treatment significantly decreased the expression and distribution of IL-1β, IL-6, IL-10, TGF-β and TNF-α. Inhibiting ferroptosis by ferrostatin-1 can attenuate neural excitability, neurological deficits, brain edema and neuroinflammation in SAH rats. Inhibiting the expression of Nrf-2 significantly increased the neural excitability and the levels of IL-1β, IL-6, IL-10, TGF-β and TNF-α in Fer-1-treated SAH rats. Taken together, inhibiting the Nrf-2 induces early brain injury, brain edema and the inflammatory response with increasing of neural excitability in Fer-1-treated SAH rats. These results have indicated that inhibiting ferroptosis, neuroinflammation and neural excitability attenuates early brain injury after SAH by regulating the Nrf-2.

Diabetes mellitus (DM) leads to medical complications, the epidemiologically most important of which is diabetic peripheral neuropathy (DPN). Electrophysiology is a major component of neural functioning and several studies have been undertaken to elucidate the neural electrophysiological alterations caused by DM and their mechanisms of action. Due to the importance of electrophysiology for neuronal function, the review of the studies dealing predominantly with electrophysiological parameters and mechanisms in the neuronal somata of peripheral neural ganglia of diabetic animals during the last 45 years is here undertaken. These studies, using predominantly techniques of electrophysiology, most frequently patch clamp for voltage clamp studies of transmembrane currents through ionic channels, have investigated the experimental DPN. They also have demonstrated that various cellular and molecular mechanisms of action of diabetic physiopathology at the level of biophysical electrical parameters are affected in DPN. Thus, they have demonstrated that several passive and active transmembrane voltage parameters, related to neuronal excitability and neuronal functions, are altered in diabetes. The majority of the studies agreed that DM produces depolarization of the resting membrane potential; alters excitability, increasing and decreasing it in dorsal root ganglia (DRG) and in nodose ganglion, respectively. They have tried to relate these changes to sensorial alterations of DPN. Concerning ionic currents, predominantly studied in DRG, the most frequent finding was increases in Na+, Ca2+, and TRPV1 cation current, and decreases in K+ current. This review concluded that additional studies are needed before an understanding of the hierarchized, time-dependent, and integrated picture of the contribution of neural electrophysiological alterations to the DPN could be reached. DM-induced electrophysiological neuronal alterations that so far have been demonstrated, most of them likely important, are either consistent with the DPN symptomatology or suggest important directions for improvement of the elucidation of DPN physiopathology, which the continuation seems to us very relevant.

Sleep deprivation (SD) is prevalent and impairs motor function; however, little is known about its effect on perceived and performance fatigability, especially in females. To examine the effects of 24 h of SD on these attributes of fatigue, nine females completed a 20-min isometric, sustained elbow flexion contraction, followed by 10 min of recovery. The superimposed twitch (SIT) elicited via transcranial magnetic stimulation (TMS) assessed supraspinal drive. Biceps brachii electromyographic data indicated neural excitability in response to stimulation over the motor cortex (motor evoked potential; MEP), corticospinal tract (cervicomedullary motor evoked potential; CMEP), and brachial plexus (maximal M-wave; Mmax). MEPs and CMEPs were recorded during a TMS-induced silent period. At baseline, ratings of perceived effort (RPE; 2.9 vs. 1.6) and fatigue (RPF; 6.9 vs. 2.9), were higher for SD than control. Across the 20-min contraction, RPE increased from 2.2 to 7.6, SIT and MEP/CMEP increased by 284 and 474%, respectively, whereas maximal voluntary isometric contraction (MVC) torque and CMEP/Mmax decreased by 26 and 57%, respectively. No differences were found across conditions for MVC, SIT, Mmax, CMEP/Mmax, or MEP/CMEP prior to, during, and after the fatiguing task. During recovery, RPE (4.9 vs. 3.4), RPF (7.6 vs. 2.8), and perception of task difficulty (5.5 vs. 4.5) were greater for SD than control. Acute SD does not appear to alter performance fatigability development and subsequent recovery; however, it increases perceptions of fatigue, effort, and task difficulty. Thus, the disconnect between perceived and actual neuromuscular capacity following a sustained, submaximal isometric task is exacerbated by SD.HighlightsSleep deprivation did not alter supraspinal drive or neural excitability during and after a 20-min submaximal elbow flexion contractionSleep deprivation increased perceived fatigue and perception of task difficultyThe disconnect between perceived and performance fatigability is exacerbated in a sleep-deprived state.

Oxygen is critical for neural metabolism, but under most physiological conditions, oxygen levels in the brain are far more than are required. Oxygen levels can be dynamically increased by increases in respiration rate that are tied to the arousal state of the brain and cognition, and not necessarily linked to exertion by the body. Why these changes in respiration occur when oxygen is already adequate has been a long-standing puzzle. In humans, performance on cognitive tasks can be affected by very high or very low oxygen levels, but whether the physiological changes in blood oxygenation produced by respiration have an appreciable effect is an open question. Oxygen has direct effects on potassium channels, increases the degradation rate of nitric oxide, and is rate limiting for the synthesis of some neuromodulators. We discuss whether oxygenation changes due to respiration contribute to neural dynamics associated with attention and arousal.

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

Mono-(2-ethylhexyl) phthalate (MEHP) is one of the main active metabolites of di-(2-ethylhexyl) phthalate (DEHP). In our previous works, by using rat and Drosophila models, we showed a disruption of neural function due to DEHP. However, the exact neural effects of MEHP are still unclear. To explore the effects of MEHP on the central nervous system, the electrophysiological properties of spontaneous action potential (sAP), mini-excitatory postsynaptic currents (mEPSCs), ion channels, including Na+, Ca2+, and K+ channels from rat CA3 hippocampal neurons area were assessed. Our data showed that MEHP (at the concentrations of 100 or 300 μM) decreased the amplitude of sAP and the frequency of mEPSCs. Additionally, MEHP (100 or 300 μM) significantly reduced the peak current density of Ca2+ channels, whereas only the concentration of 300 μM decreased the peak current density of Na+ and K+ channels. Therefore, our results indicate that exposure to MEHP could affect the neuronal excitability and synaptic plasticity of rat CA3 hippocampal neurons by inhibiting ion channels\' activity, implying the distinct role of MEHP in neural transmission.

Ankle injuries can foster maladaptive changes in nervous system function that predisposes patients to subsequent injury. Patients are often placed in a dynamic boot immobilizer (BI) following injury; however, little is known about the effects of this treatment on neuromechanical function.
We aimed to determine the effect of 72 h of BI-use on neural excitability and lower extremity joint motion in a healthy cohort.
Twelve uninjured individuals (20.8 ± 1.4 yrs, 1.7 ± 0.1 m, 75.2 ± 9.9 kg) participated in this crossover study. Neural excitability and lower extremity kinematics were assessed before and after 72 h of BI or compression sock (CS) use. Neural excitability was assessed via the Hoffmann (H) reflex and transcranial magnetic stimulation of the motor cortex by measuring muscle activation at the tibialis anterior, peroneus longus, and soleus of the immobilized extremity. Three-dimensional lower extremity joint angles were assessed while participants walked on a treadmill. Repeated-measures analyses of variance detected changes in neural excitability and peak joint angles across time-points and testing conditions, while statistical parametric mapping (SPM) was implemented to determine continuous joint angle changes (α = 0.05).
Pre-BI to post-BI, HMax:MMax ratio (F = 6.496; p = 0.031) significantly decreased. The BI did not alter resting motor threshold (F = 0.601; p = 0.468), or motor evoked potential amplitudes (F > 2.82; p > 0.608). Significant changes in peak knee and hip angles in the frontal and transverse planes were observed (p < 0.05), with no changes at the ankle. SPM analyses revealed significant hip and knee changes in range of motion (p < 0.05).
Decreased measures of reflex but not corticospinal excitability suggest that BI-use for 72 h unloaded the joint enough to generate peripheral changes, but not the CNS, as has been described in casting models. Further, kinematic changes were observed in proximal lower extremity joints, likely due to swing-phase adaptations while wearing the BI.

Recent studies from the field of interoception have highlighted the link between bodily and neural rhythms during action, perception, and cognition. The mechanisms underlying functional body-brain coupling, however, are poorly understood, as are the ways in which they modulate behavior. We acquired respiration and human magnetoencephalography data from a near-threshold spatial detection task to investigate the trivariate relationship between respiration, neural excitability, and performance. Respiration was found to significantly modulate perceptual sensitivity as well as posterior alpha power (8-13 Hz), a well-established proxy of cortical excitability. In turn, alpha suppression prior to detected versus undetected targets underscored the behavioral benefits of heightened excitability. Notably, respiration-locked excitability changes were maximized at a respiration phase lag of around -30° and thus temporally preceded performance changes. In line with interoceptive inference accounts, these results suggest that respiration actively aligns sampling of sensory information with transient cycles of heightened excitability to facilitate performance.