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Piperine has been shown to bind to myosin and shift the distribution of conformational states of myosin molecules from the super‐relaxed state to the disordered relaxed state. However, little is known about the implications for muscle force production and potential underlying mechanisms. Muscle contractility experiments were performed using isolated muscles and single fibres from rats and mice. The dose–response effect of piperine on muscle force was assessed at several stimulation frequencies. The potentiation of muscle force was also tested in muscles fatigued by eccentric contractions. Potential mechanisms of force potentiation were assessed by measuring Ca2+ levels during stimulation in enzymatically dissociated muscle fibres, while myofibrillar Ca2+ sensitivity was assessed in chemically skinned muscle fibres. Piperine caused a dose‐dependent increase in low‐frequency force with no effect on high‐frequency force in both slow‐ and fast‐twitch muscle, with similar relative increases in twitch force, rate of force development and relaxation rate. The potentiating effect of piperine on low‐frequency force was reversible, and piperine partially recovered low‐frequency force in fatigued muscle. Piperine had no effect on myoplasmic free [Ca2+] levels in mouse muscle fibres, whereas piperine substantially augmented the force response to submaximal levels of [Ca2+] in rat MyHCII fibres and MyHCI fibres along with a minor increase in maximum Ca2+‐activated force. Piperine enhances low‐frequency force production in both fast‐ and slow‐twitch muscle. The effects are reversible and can counteract muscle fatigue. The primary underlying mechanism appears to be an increase in Ca2+ sensitivity. Key points: Piperine is a plant alkaloid derived from black pepper. It is known to bind to skeletal muscle myosin and enhance resting ATP turnover but its effects on contractility are not well known.We showed for the first time a piperine‐induced force potentiation that was pronounced during low‐frequency electrical stimulation of isolated muscles.The effect of piperine was observed in both slow and fast muscle types, was reversible, and could counteract the force decrements observed after fatiguing muscle contractions.Piperine treatment caused an increase in myofibrillar Ca2+ sensitivity in chemically skinned muscle fibres, while we observed no effect on intracellular Ca2+ concentrations during electrical stimulation in enzymatically dissociated muscle fibres. [ABSTRACT FROM AUTHOR]

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. Key points: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex.In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord.Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord.Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain‐ or spinal‐only conditions, especially at latencies that produced the strongest effects of paired stimulation.Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system. [ABSTRACT FROM AUTHOR]

Seventy years ago, Hodgkin and Huxley published the first mathematical model to describe action potential generation, laying the foundation for modern computational neuroscience. Since then, the field has evolved enormously, with studies spanning from basic neuroscience to clinical applications for neuromodulation. Computer models of neuromodulation have evolved in complexity and personalization, advancing clinical practice and novel neurostimulation therapies, such as spinal cord stimulation. Spinal cord stimulation is a therapy widely used to treat chronic pain, with rapidly expanding indications, such as restoring motor function. In general, simulations contributed dramatically to improve lead designs, stimulation configurations, waveform parameters and programming procedures and provided insight into potential mechanisms of action of electrical stimulation. Although the implementation of neural models are relentlessly increasing in number and complexity, it is reasonable to ask whether this observed increase in complexity is necessary for improved accuracy and, ultimately, for clinical efficacy. With this aim, we performed a systematic literature review and a qualitative meta‐synthesis of the evolution of computational models, with a focus on complexity, personalization and the use of medical imaging to capture realistic anatomy. Our review showed that increased model complexity and personalization improved both mechanistic and translational studies. More specifically, the use of medical imaging enabled the development of patient‐specific models that can help to transform clinical practice in spinal cord stimulation. Finally, we combined our results to provide clear guidelines for standardization and expansion of computational models for spinal cord stimulation. [ABSTRACT FROM AUTHOR]

Activity‐dependent changes in membrane excitability are observed in neurons across brain areas and represent a cell‐autonomous form of plasticity (intrinsic plasticity; IP) that in itself does not involve alterations in synaptic strength (synaptic plasticity; SP). Non‐homeostatic IP may play an essential role in learning, e.g. by changing the action potential threshold near the soma. A computational problem, however, arises from the implication that such amplification does not discriminate between synaptic inputs and therefore may reduce the resolution of input representation. Here, we investigate consequences of IP for the performance of an artificial neural network in (a) the discrimination of unknown input patterns and (b) the recognition of known/learned patterns. While negative changes in threshold potentials in the output layer indeed reduce its ability to discriminate patterns, they benefit the recognition of known but incompletely presented patterns. An analysis of thresholds and IP‐induced threshold changes in published sets of physiological data obtained from whole‐cell patch‐clamp recordings from L2/3 pyramidal neurons in (a) the primary visual cortex (V1) of awake macaques and (b) the primary somatosensory cortex (S1) of mice in vitro, respectively, reveals a difference between resting and threshold potentials of ∼15 mV for V1 and ∼25 mV for S1, and a total plasticity range of ∼10 mV (S1). The most efficient activity pattern to lower threshold is paired cholinergic and electric activation. Our findings show that threshold reduction promotes a shift in neural coding strategies from accurate faithful representation to interpretative assignment of input patterns to learned object categories. Key points: Intrinsic plasticity may change the action potential threshold near the soma of neurons (threshold plasticity), thus altering the input–output function for all synaptic inputs 'upstream' of the plasticity location.A potential problem arising from this shared amplification is that it may reduce the ability to discriminate between different input patterns.Here, we assess the performance of an artificial neural network in the discrimination of unknown input patterns as well as the recognition of known patterns subsequent to changes in the spike threshold.We observe that negative changes in threshold potentials do reduce discrimination performance, but at the same time improve performance in an object recognition task, in particular when patterns are incompletely presented.Analysis of whole‐cell patch‐clamp recordings from pyramidal neurons in the primary somatosensory cortex (S1) of mice reveals that negative threshold changes preferentially result from electric stimulation of neurons paired with the activation of muscarinic acetylcholine receptors. [ABSTRACT FROM AUTHOR]

Fatigue is a common feature of paralysed skeletal muscle, hindering performance when subjected to functional electrical stimulation (ES) for movement. We asked whether (1) 20 Hz ES for 5% of each day (2.5 s on and 2.5 s off for 3 h) increases tibialis anterior and medial gastrocnemius muscle and motor unit (MU) endurance after paralysis by hemisection and deafferentation (HSDA), and (2) muscle length or loading affects their isometric contractile properties. The daily 5% ES increased muscle endurance, largely independent of muscle length or loading, but to a lesser extent than the daily 50% ES (2.5 s on and 2.5 s off for 24 h). The former was effective in counteracting the decline and slowing of muscle force promoted by the 50% ES. The altered muscle properties were confirmed at the MU level in final experiments once the properties had plateaued. Fast‐fatigable MUs were converted to fatigue‐intermediate and ‐resistant MUs that finally comprised ∼80% as compared to ∼10% of the total MU number in the daily 5% ES and the control normal groups, respectively. We conclude that the daily 5% ES regimen counteracts the fatigue of paralysed muscle without compromising contractile force, and thereby, is effective in conditioning muscle for effective movement. Key points: We asked whether 20 Hz electrical stimulation (ES) for 5% of each day (2.5 s on and 2.5 s off for 3 h; 5% ES) preserves medial gastrocnemius and tibialis anterior muscle and MU isometric contractile forces and increases their endurance after paralysis.Daily 5% ES promoted increased muscle endurance irrespective of the muscle length or loading but to a lesser extent than daily 50% ES (20 Hz ES 2.5 s on and 2.5 s off for 24 h).5% ES was effective in counteracting decline and slowing of muscle force that resulted from 50% ES.Motor units (MUs) were converted from fast fatigable to fatigue intermediate and resistant MUs, comprising ∼80% as compared to ∼10% in the control normal groups.We conclude that the 5% ES regimen counteracts the fatigue of paralysed muscle without compromising contractile force, and thereby is effective in conditioning the muscle for effective movement. [ABSTRACT FROM AUTHOR]

Myosin motors in resting muscle are inactivated by folding against the backbone of the myosin filament in an ordered helical array and must be released from that conformation to engage in force generation. Time‐resolved X‐ray diffraction from single fibres of amphibian muscle showed that myosin filament activation could be inhibited by imposing unloaded shortening at the start of stimulation, suggesting that filaments were activated by mechanical stress. Here we improved the signal‐to‐noise ratio of that approach using whole extensor digitorum longus muscles of the mouse contracting tetanically at 28°C. Changes in X‐ray signals associated with myosin filament activation, including the decrease in the first‐order myosin layer line associated with the helical motor array, increase in the spacing of a myosin‐based reflection associated with packing of myosin tails in the filament backbone, and increase in the ratio of the 1,1 and 1,0 equatorial reflections associated with movement of motors away from the backbone, were delayed by imposing 10‐ms unloaded shortening at the start of stimulation. These results show that myosin filaments are predominantly activated by filament stress, as in amphibian muscle. However, a small component of filament activation at zero load was detected, implying an independent mechanism of partial filament activation. X‐ray interference measurements indicated a switch‐like change in myosin motor conformation at the start of force development, accompanied by transient disordering of motors in the regions of the myosin filament near its midpoint, suggesting that filament zonal dynamics also play a role in its activation. Key points: Activation of myosin filaments in extensor digitorum longus muscles of the mouse is delayed by imposing rapid shortening from the start of stimulation.Stress is the major mechanism of myosin filament activation in these muscles, but there is a small component of filament activation during electrical stimulation at zero stress.Myosin motors switch rapidly from the folded inhibited conformation to the actin‐attached force‐generating conformation early in force development. [ABSTRACT FROM AUTHOR]

Large trans-sarcolemmal ionic shifts occur with fatiguing exercise or stimulation of isolated muscles. However, it is unknown how resting membrane potential (E M ) and intracellular sodium concentration ([Na + ] i ) change with repeated contractions in living mammals. We investigated (i) whether [Na + ] i (peak, kinetics) can reveal changes of Na + -K + pump activity during brief or fatiguing stimulation and (ii) how resting E M and [Na + ] i change during fatigue and recovery of rat soleus muscle in situ. Muscles of anaesthetised rats were stimulated with brief (10 s) or repeated tetani (60 Hz for 200 ms, every 2 s, for 30 s or 300 s) with isometric force measured. Double-barrelled ion-sensitive microelectrodes were used to quantify resting E M and [Na + ] i . Post-stimulation data were fitted using polynomials and back-extrapolated to time zero recovery. Mean pre-stimulation resting E M (layer 2-7 fibres) was -71 mV (surface fibres were more depolarised), and [Na + ] i was 14 mM. With deeper fibres, 10 s stimulation (2-150 Hz) increased [Na + ] i to 38-46 mM whilst simultaneously causing hyperpolarisations (7.3 mV for 2-90 Hz). Fatiguing stimulation for 30 s or 300 s led to end-stimulation resting E M of -61 to -53 mV, which recovered rapidly (T 1/2 , 8-22 s). Mean end-stimulation [Na + ] i increased to 86-101 mM with both fatigue protocols and the [Na + ] i recovery time-course (T 1/2 , 21-35 s) showed no difference between protocols. These combined findings suggest that brief stimulation hyperpolarises the resting E M , likely via maximum Na + -induced stimulation of the Na + -K + pump. Repeated tetani caused massive depolarisation and elevations of [Na + ] i that together lower force, although they likely interact with other factors to cause fatigue. [Na + ] i recovery kinetics provided no evidence of impaired Na + -K + pump activity with fatigue. KEY POINTS: It is uncertain how resting membrane potential, intracellular sodium concentration ([Na + ] i ), and sodium-potassium (Na + -K + ) pump activity change during repeated muscle contractions in living mammals. For rat soleus muscle fibres in situ, brief tetanic stimulation for 10 s led to raised [Na + ] i , anticipated to evoke maximal Na + -induced stimulation of the Na + -K + pump causing an immediate hyperpolarisation of the sarcolemma. More prolonged stimulation with repeated tetanic contractions causes massive elevations of [Na + ] i , which together with large depolarisations (via K + disturbances) likely reduce force production. These effects occurred without impairment of Na + -K + pump function. Together these findings suggest that rapid activation of the Na + -K + pump occurs with brief stimulation to maintain excitability, whereas more prolonged stimulation causes rundown of the trans-sarcolemmal K + gradient (hence depolarisation) and Na + gradient, which in combination can impair contraction to contribute to fatigue in living mammals., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid‐induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF‐State) or partial suppression (ON‐State) of respiration induced by remifentanil. During the ON‐State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end‐tidal carbon dioxide level compared to pre‐stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre‐stimulation control levels. In the OFF‐State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non‐responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. Key points: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA‐approved method to manage chronic pain.We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low‐dose remifentanil that suppressed respiration (ON‐State) or high‐dose remifentanil that completely inhibited breathing (OFF‐State) during the course of cervical surgery.Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2–C7).Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF‐State, suggesting that cervical EES reversed the opioid‐induced respiratory depression.These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids. [ABSTRACT FROM AUTHOR]

Little is currently known about possible developmental changes in myocardial Na+ handling, which may have impact on cell excitability and Ca2+ content. Resting intracellular Na+ concentration ([Na+]i), measured in freshly isolated rat ventricular myocytes with CoroNa green, was not significantly different in neonates (3–5 days old) and adults, but electrical stimulation caused marked [Na+]i rise only in neonates. Inhibition of L‐type Ca2+ current by CdCl2 abolished not only systolic Ca2+ transients, but also activity‐dependent intracellular Na+ accumulation in immature cells. This indicates that the main Na+ influx pathway during activity is the Na+/Ca2+ exchanger, rather than voltage‐dependent Na+ current (INa), which was not affected by CdCl2. In immature myocytes, INa density was two‐fold greater, inactivation was faster, and the current peak occurred at less negative transmembrane potential (Em) than in adults. Na+ channel steady‐state activation and inactivation curves in neonates showed a rightward shift, which should increase channel availability at diastolic Em, but also require greater depolarization for excitation, which was observed experimentally and reproduced in computer simulations. Ventricular mRNA levels of Nav1.1, Nav1.4 and Nav1.5 pore‐forming isoforms were greater in neonate ventricles, while a decrease was seen for the β1 subunit. Both molecular and biophysical changes in the channel profile may contribute to the differences in INa density and voltage‐dependence, and also to the less negative threshold Em, in neonates compared to adults. The apparently lower excitability in immature ventricle may confer protection against the development of spontaneous activity in this tissue. Key points: Previous studies showed that myocardial preparations from immature rats are less sensitive to electrical field stimulation than adult preparations.Freshly isolated ventricular myocytes from neonatal rats showed lower excitability than adult cells, e.g. less negative threshold membrane potential and greater membrane depolarization required for action potential triggering.In addition to differences in mRNA levels for Na+ channel isoforms and greater Na+ current (INa) density, Na+ channel voltage‐dependence was shifted to the right in immature myocytes, which seems to be sufficient to decrease excitability, according to computer simulations.Only in neonatal myocytes did cyclic activity promote marked cytosolic Na+ accumulation, which was prevented by abolition of systolic Ca2+ transients by blockade of Ca2+ currents.Developmental changes in INa may account for the difference in action potential initiation parameters, but not for cytosolic Na+ accumulation, which seems to be due mainly to Na+/Ca2+ exchanger‐mediated Na+ influx. [ABSTRACT FROM AUTHOR]

Persistent inward currents (PICs) are crucial for initiation, acceleration, and maintenance of motoneuron firing. As PICs are highly sensitive to synaptic inhibition and facilitated by serotonin and noradrenaline, we hypothesised that both reciprocal inhibition (RI) induced by antagonist nerve stimulation and whole‐body relaxation (WBR) would reduce PICs in humans. To test this, we estimated PICs using the well‐established paired motor unit (MU) technique. High‐density surface electromyograms were recorded from gastrocnemius medialis during voluntary, isometric 20‐s ramp, plantarflexor contractions and decomposed into MU discharges to calculate delta frequency (ΔF). Moreover, another technique (VibStim), which evokes involuntary contractions proposed to result from PIC activation, was used. Plantarflexion torque and soleus activity were recorded during 33‐s Achilles tendon vibration and simultaneous 20‐Hz bouts of neuromuscular electrical stimulation (NMES) of triceps surae. ΔF was decreased by RI (n = 15, 5 females) and WBR (n = 15, 7 females). In VibStim, torque during vibration at the end of NMES and sustained post‐vibration torque were reduced by WBR (n = 19, 10 females), while other variables remained unchanged. All VibStim variables remained unaltered in RI (n = 20, 10 females). Analysis of multiple human MUs in this study demonstrates the ability of local, focused inhibition to attenuate the effects of PICs on motoneuron output during voluntary motor control. Moreover, it shows the potential to reduce PICs through non‐pharmacological, neuromodulatory interventions such as WBR. The absence of a consistent effect in VibStim might be explained by a floor effect resulting from low‐magnitude involuntary torque combined with the negative effects of the interventions. Key points: Spinal motoneurons transmit signals to skeletal muscles to regulate their contraction. Motoneuron firing partly depends on their intrinsic properties such as the strength of persistent (long‐lasting) inward currents (PICs) that make motoneurons more responsive to excitatory input.In this study, we demonstrate that both reciprocal inhibition onto motoneurons and whole‐body relaxation reduce the contribution of PICs to human motoneuron firing. This was observed through analysis of the firing of single motor units during voluntary contractions.However, an alternative technique that involves tendon vibration and neuromuscular electrical stimulation to evoke involuntary contractions showed less effect. Thus, it remains unclear whether this alternative technique can be used to estimate PICs under all physiological conditions.These results improve our understanding of the mechanisms of PIC depression in human motoneurons. Potentially, non‐pharmacological interventions such as electrical stimulation or relaxation could attenuate unwanted PIC‐induced muscle contractions in conditions characterised by motoneuron hyperexcitability. [ABSTRACT FROM AUTHOR]

Sound localization involves information analysis in the lateral superior olive (LSO), a conspicuous nucleus in the mammalian auditory brainstem. LSO neurons weigh interaural level differences (ILDs) through precise integration of glutamatergic excitation from the cochlear nucleus (CN) and glycinergic inhibition from the medial nucleus of the trapezoid body (MNTB). Sound sources can be localized even during sustained perception, an accomplishment that requires robust neurotransmission. Virtually nothing is known about the sustained performance and the temporal precision of MNTB–LSO inputs after postnatal day (P)12 (time of hearing onset) and whether acoustic experience guides development. Here we performed whole‐cell patch‐clamp recordings to investigate neurotransmission of single MNTB‐LSO fibres upon sustained electrical stimulation (1–200 Hz/60 s) at P11 and P38 in wild‐type (WT) and deaf otoferlin (Otof) knock‐out (KO) mice. At P11, WT and KO inputs performed remarkably similarly. In WTs, the performance increased drastically between P11 and P38, e.g. manifested by an 8 to 11‐fold higher replenishment rate (RR) of synaptic vesicles and action potential robustness. Together, these changes resulted in reliable and highly precise neurotransmission at frequencies ≤100 Hz. In contrast, KO inputs performed similarly at both ages, implying impaired synaptic maturation. Computational modelling confirmed the empirical observations and established a reduced RR per release site for P38 KOs. In conclusion, acoustic experience appears to contribute massively to the development of reliable neurotransmission, thereby forming the basis for effective ILD detection. Collectively, our results provide novel insights into experience‐dependent maturation of inhibitory neurotransmission and auditory circuits at the synaptic level. Key points: Inhibitory glycinergic inputs from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) are involved in sound localization. This brainstem circuit performs reliably throughout life. How such reliability develops is unknown.Here we investigated the role of acoustic experience on the functional maturation of MNTB‐LSO inputs at juvenile (postnatal day P11) and young adult ages (P38) employing deaf mice lacking otoferlin (KO).We analysed neurotransmission at single MNTB‐LSO fibres in acute brainstem slices employing prolonged high‐frequency stimulation (1–200 Hz/60 s).At P11, KO inputs still performed normally, as manifested by normal synaptic attenuation, fidelity, replenishment rate, temporal precision and action potential robustness. Between P11 and P38, several synaptic parameters increased substantially in wild‐type mice, collectively resulting in high‐fidelity and temporally precise neurotransmission. In contrast, maturation of synaptic fidelity was largely absent in KOs after P11.Collectively, reliable neurotransmission at inhibitory MNTB–LSO inputs develops under the guidance of acoustic experience. [ABSTRACT FROM AUTHOR]

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Keywords: monoamine; motor unit; nerve stimulation; neuromodulation; reciprocal inhibition EN monoamine motor unit nerve stimulation neuromodulation reciprocal inhibition 3021 3023 3 07/04/22 20220701 NES 220701 Persistent inward currents, neuromodulators and inhibition Activation of a motoneurone occurs when excitatory synaptic input from descending motor pathways, or sensory projections, is sufficient to bring the membrane potential of the motoneurone above its firing threshold. Paired vibration-stimulation activates motoneurones via Ia afferent input to the spinal cord, and this sustained synaptic excitation likely activates PICs to promote motoneurone self-sustained discharge. To study the inhibition of PIC activity in plantar flexor motoneurones, 1 Hz electrical stimuli were applied to the common peroneal nerve and evoked the reciprocal inhibition of plantar flexor motoneurones. [Extracted from the article]

Key points: GABA depolarized sural nerve axons and increased the electrical excitability of C‐fibres via GABAA receptor.Axonal excitability responses to GABA increased monotonically with the rate of action potential firing.Action potential activity in unmyelinated C‐fibres is coupled to Na‐K‐Cl cotransporter type 1 (NKCC1) loading of axonal chloride.Activation of axonal GABAA receptor stabilized C‐fibre excitability during prolonged low frequency (2.5 Hz) firing.NKCC1 maintains intra‐axonal chloride to provide feed‐forward stabilization of C‐fibre excitability and thus support sustained firing. GABAA receptor (GABAAR)‐mediated depolarization of dorsal root ganglia (DRG) axonal projections in the spinal dorsal horn is implicated in pre‐synaptic inhibition. Inhibition, in this case, is predicated on an elevated intra‐axonal chloride concentration and a depolarizing GABA response. In the present study, we report that the peripheral axons of DRG neurons are also depolarized by GABA and this results in an increase in the electrical excitability of unmyelinated C‐fibre axons. GABAAR agonists increased axonal excitability, whereas GABA excitability responses were blocked by GABAAR antagonists and were absent in mice lacking the GABAAR β3 subunit selectively in DRG neurons (AdvillinCre or snsCre). Under control conditions, excitability responses to GABA became larger at higher rates of electrical stimulation (0.5–2.5 Hz). However, during Na‐K‐Cl cotransporter type 1 (NKCC1) blockade, the electrical stimulation rate did not affect GABA response size, suggesting that NKCC1 regulation of axonal chloride is coupled to action potential firing. To examine this, activity‐dependent conduction velocity slowing (activity‐dependent slowing; ADS) was used to quantify C‐fibre excitability loss during a 2.5 Hz challenge. ADS was reduced by GABAAR agonists and exacerbated by either GABAAR antagonists, β3 deletion or NKCC1 blockade. This illustrates that activation of GABAAR stabilizes C‐fibre excitability during sustained firing. We posit that NKCC1 acts in a feed‐forward manner to maintain an elevated intra‐axonal chloride in C‐fibres during ongoing firing. The resulting chloride gradient can be utilized by GABAAR to stabilize axonal excitability. The data imply that therapeutic strategies targeting axonal chloride regulation at peripheral loci of pain and itch may curtail aberrant firing in C‐fibres. Key points: GABA depolarized sural nerve axons and increased the electrical excitability of C‐fibres via GABAA receptor.Axonal excitability responses to GABA increased monotonically with the rate of action potential firing.Action potential activity in unmyelinated C‐fibres is coupled to Na‐K‐Cl cotransporter type 1 (NKCC1) loading of axonal chloride.Activation of axonal GABAA receptor stabilized C‐fibre excitability during prolonged low frequency (2.5 Hz) firing.NKCC1 maintains intra‐axonal chloride to provide feed‐forward stabilization of C‐fibre excitability and thus support sustained firing. [ABSTRACT FROM AUTHOR]

Key points: Motor adaptation is thought to be a strategy to avoid pain.Current experimental pain models do not allow for consistent modulation of pain perception depending on movement.We showed that low‐frequency sinusoidal stimuli delivered at painful intensity result in minimal habituation of pain perception (over 60 s) and minimal stimulation artefacts on electromyographic signals.When the amplitude of the low‐frequency sinusoidal stimuli was modulated based on the vertical force participants applied to the ground with their right leg while standing upright, we demonstrated a strong association between perceived pain and motor adaptation.By enabling task‐relevant modulation of perceived pain intensity and the recording electromyographic signals during electrical painful stimulation, our novel pain model will permit direct experimental testing of the relationship between pain and motor adaptation. Contemporary pain adaptation theories predict that motor adaptation occurs to limit pain. Current experimental pain models, however, do not allow for pain intensity modulation according to one's posture or movements. We developed a task‐relevant experimental pain model using low‐frequency sinusoidal electrical stimuli applied over the infrapatellar fat pad. In fourteen participants, we compared perceived pain habituation and stimulation‐induced artefacts in vastus medialis electromyographic recordings elicited by sinusoidal (4, 10, 20 and 50 Hz) and square electrical waveforms delivered at constant peak stimulation amplitude. Next, we simulated a clinical condition where perceived knee pain intensity is proportional to the load applied on the leg by controlling sinusoidal current amplitude (4 Hz) according to the vertical force the participants applied with their right leg to the ground while standing upright. Pain ratings habituated over a 60 s period for 50 Hz sinusoidal and square waveforms but not for low‐frequency sinusoidal stimuli (P < 0.001). EMG filters removed most stimulation artefacts for low‐frequency sinusoidal stimuli (4 Hz). While balancing upright, participants' pain ratings were correlated with the force applied by the right leg (R2 = 0.65), demonstrating task‐relevant changes in perceived pain intensity. Low‐frequency sinusoidal stimuli can induce knee pain of constant intensity for 60 s with minimal EMG artefacts while enabling task‐relevant pain modulation when controlling current amplitude. By enabling task‐dependent modulation of perceived pain intensity, our novel experimental model replicates key temporal aspects of clinical musculoskeletal pain while allowing quantification of neuromuscular activation during painful electrical stimulation. This approach will enable researchers to test the predicted relationship between movement strategies and pain. Key points: Motor adaptation is thought to be a strategy to avoid pain.Current experimental pain models do not allow for consistent modulation of pain perception depending on movement.We showed that low‐frequency sinusoidal stimuli delivered at painful intensity result in minimal habituation of pain perception (over 60 s) and minimal stimulation artefacts on electromyographic signals.When the amplitude of the low‐frequency sinusoidal stimuli was modulated based on the vertical force participants applied to the ground with their right leg while standing upright, we demonstrated a strong association between perceived pain and motor adaptation.By enabling task‐relevant modulation of perceived pain intensity and the recording electromyographic signals during electrical painful stimulation, our novel pain model will permit direct experimental testing of the relationship between pain and motor adaptation. [ABSTRACT FROM AUTHOR]

The application of neuromuscular electrical stimulation (NMES) to paretic limbs has demonstrated utility for motor rehabilitation following brain injury. When NMES is delivered to a mixed peripheral nerve, typically both efferent and afferent fibres are recruited. Muscle contractions brought about by the excitation of motor neurons are often used to compensate for disability by assisting actions such as the formation of hand aperture, or by preventing others including foot drop. In this context, exogenous stimulation provides a direct substitute for endogenous neural drive. The goal of the present narrative review is to describe the means through which NMES may also promote sustained adaptations within central motor pathways, leading ultimately to increases in (intrinsic) functional capacity. There is an obvious practical motivation, in that detailed knowledge concerning the mechanisms of adaptation has the potential to inform neurorehabilitation practice. In addition, responses to NMES provide a means of studying CNS plasticity at a systems level in humans. We summarize the fundamental aspects of NMES, focusing on the forms that are employed most commonly in clinical and experimental practice. Specific attention is devoted to adjuvant techniques that further promote adaptive responses to NMES thereby offering the prospect of increased therapeutic potential. The emergent theme is that an association with centrally initiated neural activity, whether this is generated in the context of NMES triggered by efferent drive or via indirect methods such as mental imagery, may in some circumstances promote the physiological changes that can be induced through peripheral electrical stimulation. [ABSTRACT FROM AUTHOR]

Key points: C‐nociceptors are generally assumed to have a low maximum discharge frequency of 10–30 Hz. However, only mechano‐insensitive 'silent' C‐nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C‐nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure.Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation.A distinct class of C‐nociceptors with mechanical thresholds >150 mN resembles 'silent' nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. Using extracellular single‐fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5–100 Hz) in different classes of C‐nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano‐sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano‐insensitive C‐nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano‐insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C‐nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C‐fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which possibly contributes to excruciating pain under inflammatory conditions. Key points: C‐nociceptors are generally assumed to have a low maximum discharge frequency of 10–30 Hz. However, only mechano‐insensitive 'silent' C‐nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C‐nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure.Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation.A distinct class of C‐nociceptors with mechanical thresholds >150 mN resembles 'silent' nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. [ABSTRACT FROM AUTHOR]

Key points: Muscle contractions increase protein synthesis in a mechanistic target of rapamycin (mTOR)‐dependent manner, yet it is unclear which/how mTOR complexes regulate muscle protein synthesis.We investigated the requirement of mTOR Complex 2 (mTORC2) in contraction‐stimulated muscle protein synthesis.mTORC2 inhibition by muscle‐specific Rictor knockout (Rictor mKO) did not prevent contraction‐induced muscle protein synthesis.Rapamycin prevented contraction‐induced muscle protein synthesis in Rictor mKO but not wild‐type mice. Protein synthesis increases following muscle contractions. Previous studies have shown that inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) suppresses the early but not late muscle protein synthesis response, while inhibition of both mTORC1 and mTORC2 abolishes the two effects. Therefore, we hypothesized that mTORC2 regulates muscle protein synthesis following muscle contractions. To test this, we investigated the effect of mTORC2 inhibition by mouse muscle‐specific Rictor knockout (Rictor mKO) on muscle protein synthesis 3 h after contraction. The right gastrocnemius muscles of Rictor mKO and wild‐type (WT) mice were isometrically contracted using percutaneous electrical stimulation, while the left gastrocnemius muscles served as controls. Vehicle or the mTORC1 inhibitor rapamycin (1.5 mg/kg) was injected intraperitoneally 1 h before contraction. Treatment of WT mice with rapamycin and Rictor mKO lowered protein synthesis in general, but the response to contractions was intact 3 h after contractions in both conditions. Rapamycin treatment in Rictor mKO mice prevented contraction‐stimulated muscle protein synthesis. Notably, signalling traditionally associated with mTORC1 was increased by muscle contractions despite rapamycin treatment. In rapamycin‐treated Rictor mKO mice, the same mTORC1 signalling was blocked following contractions. Our results indicate that although neither rapamycin‐sensitive mTOR/mTORC1 nor mTORC2 is necessary for contraction‐induced muscle protein synthesis, combined inhibition of rapamycin‐sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits contraction‐induced muscle protein synthesis. Key points: Muscle contractions increase protein synthesis in a mechanistic target of rapamycin (mTOR)‐dependent manner, yet it is unclear which/how mTOR complexes regulate muscle protein synthesis.We investigated the requirement of mTOR Complex 2 (mTORC2) in contraction‐stimulated muscle protein synthesis.mTORC2 inhibition by muscle‐specific Rictor knockout (Rictor mKO) did not prevent contraction‐induced muscle protein synthesis.Rapamycin prevented contraction‐induced muscle protein synthesis in Rictor mKO but not wild‐type mice. [ABSTRACT FROM AUTHOR]

By secreting insulin and glucagon, the β‐ and α‐cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP‐regulated potassium (KATP) channels that are regulated by the intracellular ATP/ADP ratio. In β‐cells, KATP channels are active at low (non‐insulin‐releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+]i and initiation of exocytosis of the insulin‐containing secretory granules. The α‐cells are also equipped with KATP channels but they are under strong tonic inhibition at low glucose, explaining why α‐cells are electrically active under hypoglycaemic conditions and generate large Na+‐ and Ca2+‐dependent action potentials. Closure of residual KATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage‐dependent inactivation of the Na+ channels involved in action potential generation. Exocytosis in α‐cells is tightly linked to the opening of voltage‐gated P/Q‐type Ca2+ channels, the activation of which is steeply voltage‐dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion. [ABSTRACT FROM AUTHOR]

Keywords: brain stimulation; electroencephalogram; neuroimaging; transcranial magnetic stimulation EN brain stimulation electroencephalogram neuroimaging transcranial magnetic stimulation 1701 1702 2 05/17/23 20230515 NES 230515 Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is a multi-modal functional neuroimaging approach that has seen growing uptake across basic, cognitive, and clinical neuroscience as a method for safely interrogating cortical physiology I in vivo i . Saying goodbye to an unwelcome guest: towards robust methods for controlling multi-sensory confounds in TMS-EEG research A central finding by Gordon et al. ([3]) was that modulation of GABA SB A sb receptor-mediated neurotransmission via diazepam was able to elicit demonstrable changes on the TMS-EEG record following both active and sham TMS. [Extracted from the article]

Key points: A recent animal study showed that high frequency electrical stimulation (HFS) of C‐fibres induces a gliogenic heterosynaptic long‐term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C‐fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C‐fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C‐fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. Abstract: It has recently been shown that high frequency electrical stimulation (HFS) of C‐fibres induces a gliogenic heterosynaptic long‐term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C‐fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short‐lasting (10 ms) high‐intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2) were applied to the area of increased mechanical pinprick sensitivity at the HFS‐treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0–100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C‐fibre laser‐evoked potentials at the HFS‐treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C‐fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. [ABSTRACT FROM AUTHOR]

Key points: We performed a prospective electrostimulation study, based on 50 operated intact patients, to acquire accurate MNI coordinates of the functional areas of the somatosensory homunculus. In the contralateral BA1, the hand representation displayed not only medial‐to‐lateral, little‐finger‐to‐thumb, but also rostral‐to‐caudal discrete somatotopy, with the tip of each finger located more caudally than the proximal phalanx. The analysis of the MNI body coordinates showed rare inter‐individual variations in the medial‐to‐lateral somatotopic organization in these patients with rather different intensity thresholds needed to elicit sensations in different body parts. We found some similarities but also substantial differences with the previous, seminal works of Penfield and his colleagues. We propose a new drawing of the human somatosensory homunculus according to MNI space. Abstract: In this prospective electrostimulation study, based on 50 operated patients with no sensory deficit and no brain lesion in the postcentral gyrus, we acquired coordinates in the standard MNI space of the functional areas of the somatosensory homunculus. The 3D brain volume of each patient was normalized to that space to obtain the MNI coordinates of the stimulation site locations. For 647 sites stimulated on Brodmann Area 1 (and 1025 in gyri nearby), 258 positive points for somatosensory response (40%) were found in the postcentral gyrus. In the contralateral BA1, the hand representation displayed not only medial‐to‐lateral and little‐finger‐to‐thumb somatotopy, but also rostral‐to‐caudal discrete somatotopy, with the tip of each finger located more caudally than the proximal phalanx. We detected a medial‐to‐lateral, tip‐to‐base tongue organization but no rostral‐to‐caudal functional organization. The analysis of the MNI body coordinates showed rare inter‐individual variations in the medial‐to‐lateral somatotopic organization in these patients with intact somatosensory cortex. Positive stimulations were detected through the ‘on/off’ outbreak effect and discriminative touch sensations were the sensations reported almost exclusively by all patients during stimulation. Mean hand (2.39 mA) and tongue (2.60 mA) positive intensity thresholds were lower (P < 0.05) than the intensities required to elicit sensations in the other parts of the body. Unlike the previous, seminal works of Penfield and colleagues, we detected no sensations such as sense of movement or desire to move, no somatosensory responses outside the postcentral gyrus, and no bilateral responses for face/tongue stimulations. We propose a rationalization of the standard drawing of the somatosensory homunculus according to MNI space. [ABSTRACT FROM AUTHOR]

Keywords: human; OIRD; spinal stimulation EN human OIRD spinal stimulation 2829 2830 2 06/16/22 20220615 NES 220615 Opioid overdoses are a growing problem within the USA and abroad. With this demonstration by Huang et al. in a clinical opioid overdose model, we have the foundations to develop more minimally invasive stimulation methods that could be used by first responders during opioid overdoses. Electroceuticals and respiratory recovery: is there a place for electrical spinal stimulation in opioid-induced respiratory depression?. [Extracted from the article]

Key points It has long been known that the somatosensory cortex gates sensory inputs from the contralateral side of the body. Here, we examined the contribution of the ipsilateral somatosensory cortex (iS1) to sensory gating during index finger voluntary activity., The amplitude of the P25/N33, but not other somatosensory evoked potential (SSEP) components, was reduced during voluntary activity compared with rest. Interhemispheric inhibition between S1s and intracortical inhibition in the S1 modulated the amplitude of the P25/N33. Note that changes in interhemispheric inhibition between S1s correlated with changes in cortical circuits in the ipsilateral motor cortex., Our findings suggest that cortical circuits, probably from somatosensory and motor cortex, contribute to sensory gating in the iS1 during voluntary activity in humans., Abstract An important principle in the organization of the somatosensory cortex is that it processes afferent information from the contralateral side of the body. The role of the ipsilateral somatosensory cortex (iS1) in sensory gating in humans remains largely unknown. Using electroencephalographic (EEG) recordings over the iS1 and electrical stimulation of the ulnar nerve at the wrist, we examined somatosensory evoked potentials (SSEPs; P14/N20, N20/P25 and P25/N33 components) and paired-pulse SSEPs between S1s (interhemispheric inhibition) and within (intracortical inhibition) the iS1 at rest and during tonic index finger voluntary activity. We found that the amplitude of the P25/N33, but not other SSEP components, was reduced during voluntary activity compared with rest. Interhemispheric inhibition increased the amplitude of the P25/N33 and intracortical inhibition reduced the amplitude of the P25/N33, suggesting a cortical origin for this effect. The P25/N33 receives inputs from the motor cortex, so we also examined the contribution of distinct sets of cortical interneurons by testing the effect of ulnar nerve stimulation on motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the ipsilateral motor cortex with the coil in the posterior-anterior (PA) and anterior-posterior (AP) orientation. Afferent input attenuated PA, but not AP, MEPs during voluntary activity compared with rest. Notably, changes in interhemispheric inhibition correlated with changes in PA MEPs. Our novel findings suggest that interhemispheric projections between S1s and intracortical circuits, probably from somatosensory and motor cortex, contribute to sensory gating in the iS1 during voluntary activity in humans. [ABSTRACT FROM AUTHOR]

Key points Electrical synapses are modified by various forms of activity, including paired activity in coupled neurons and tetanization of the input to coupled neurons., We show that plasticity of electrical synapses that results from paired spiking activity in coupled neurons depends on calcium influx and calcium-initiated signalling pathways., Plasticity that results from tetanization of input fibres does not depend on calcium influx or dynamics., These results imply that electrically coupled neurons have distinct sets of mechanisms for adjusting coupling according to the specific type of activity they experience., Abstract Recent results have demonstrated modification of electrical synapse strength by varied forms of neuronal activity. However, the mechanisms underlying plasticity induction in central mammalian neurons are unclear. Here we show that the two established inductors of plasticity at electrical synapses in the thalamic reticular nucleus - paired burst spiking in coupled neurons, and mGluR-dependent tetanization of synaptic input - are separate pathways that converge at a common downstream endpoint. Using occlusion experiments and pharmacology in patched pairs of coupled neurons in vitro, we show that burst-induced depression depends on calcium entry via voltage-gated channels, is blocked by BAPTA chelation, and recruits intracellular calcium release on its way to activation of phosphatase activity. In contrast, mGluR-dependent plasticity is independent of calcium entry or calcium dynamics. Together, these results show that the spiking-initiated mechanisms underlying electrical synapse plasticity are similar to those that induce plasticity at chemical synapses, and offer the possibility that calcium-regulated mechanisms may also lead to alternate outcomes, such as potentiation. Because these mechanistic elements are widely found in mature neurons, we expect them to apply broadly to electrical synapses across the brain, acting as the crucial link between neuronal activity and electrical synapse strength. [ABSTRACT FROM AUTHOR]

Key points Golgi tendon organs (GTOs) and associated Ib reflexes contribute to standing balance, but the potential impacts of threats to standing balance on Ib reflexes are unknown., Tendon electrical stimulation to the Achilles' tendon was used to probe changes in Ib inhibition in medial gastrocnemius with postural orientation (lying prone vs. upright standing; experiment 1) and height-induced postural threat (standing at low and high surface heights; experiment 2)., Ib inhibition was reduced while participants stood upright, compared to lying prone (42.2%); and further reduced when standing in the high, compared to low, threat condition (32.4%)., These experiments will impact future research because they demonstrate that tendon electrical stimulation can be used to probe Ib reflexes in muscles engaged in standing balance., These results provide novel evidence that human short-latency GTO-Ib reflexes are dependent upon both task, as evidenced by changes with postural orientation, and context, such as height-induced postural threat during standing., Abstract Golgi tendon organ Ib reflexes are thought to contribute to standing balance control, but it is unknown if they are modulated when people are exposed to a postural threat. We used a novel application of tendon electrical stimulation (TStim) to elicit Ib inhibitory reflexes in the medial gastrocnemius, while actively engaged in upright standing balance, to examine (a) how Ib reflexes to TStim are influenced by upright stance, and (b) the effects of height-induced postural threat on Ib reflexes during standing. TStim evoked short-latency (<47 ms) inhibition apparent in trigger-averaged rectified EMG, which was quantified in terms of area, duration and mean amplitude of inhibition. In order to validate the use of TStim in a standing model, TStim-Ib inhibition was compared from conditions where participants were lying prone vs. standing upright. TStim evoked Ib inhibition in both conditions; however, significant reductions in Ib inhibition area (42.2%) and duration (32.9%) were observed during stance. Postural threat, manipulated by having participants stand at LOW (0.8 m high, 0.6 m from edge) and HIGH (3.2 m, at edge) elevated surfaces, significantly reduced Ib inhibition area (32.4%), duration (16.4%) and amplitude (24.8%) in the HIGH, compared to LOW, threat condition. These results demonstrate TStim is a viable technique for investigating Ib reflexes in standing, and confirm Ib reflexes are modulated with postural orientation. The novel observation of reduced Ib inhibition with elevated postural threat reveals that human Ib reflexes are context dependent, and the human Ib reflex pathways are modulated by threat or emotional processing centres of the CNS. [ABSTRACT FROM AUTHOR]

Key points The vestibular influence on human walking is phase-dependent and modulated across both limbs with changes in locomotor velocity and cadence., Using a split-belt treadmill, we show that vestibular influence on locomotor activity is modulated independently in each limb., The independent vestibular modulation of muscle activity from each limb occurs rapidly at the onset of split-belt walking, over a shorter time course relative to the characteristic split-belt error-correction mechanisms (i.e. muscle activity and kinematics) associated with locomotor adaptation., Together, the present results indicate that the nervous system rapidly modulates the vestibular influence of each limb separately through processes involving ongoing sensory feedback loops., These findings help us understand how vestibular information is used to accommodate the variable and commonplace demands of locomotion, such as turning or navigating irregular terrain., Abstract During walking, the vestibular influence on locomotor activity is phase-dependent and modulated in both limbs with changes in velocity. It is unclear, however, whether this bilateral modulation is due to a coordinated mechanism between both limbs or instead through limb-specific processes that remain masked by the symmetric nature of locomotion. Here, human subjects walked on a split-belt treadmill with one belt moving at 0.4 m s−1 and the other moving at 0.8 m s−1 while exposed to an electrical vestibular stimulus. Muscle activity was recorded bilaterally around the ankles of each limb and used to compare vestibulo-muscular coupling between velocity-matched and unmatched tied-belt walking. In general, response magnitudes decreased by ∼20-50% and occurred ∼13-20% earlier in the stride cycle at the higher belt velocity. This velocity-dependent modulation of vestibular-evoked muscle activity was retained during split-belt walking and was similar, within each limb, to velocity-matched tied-belt walking. These results demonstrate that the vestibular influence on ankle muscles during locomotion can be adapted independently to each limb. Furthermore, modulation of vestibular-evoked muscle responses occurred rapidly (∼13-34 strides) after onset of split-belt walking. This rapid adaptation contrasted with the prolonged adaptation in step length symmetry (∼128 strides) as well as EMG magnitude and timing (∼40-100 and ∼20-70 strides, respectively). These results suggest that vestibular influence on ankle muscle control is adjusted rapidly in sensorimotor control loops as opposed to longer-term error correction mechanisms commonly associated with split-belt adaptation. Rapid limb-specific sensorimotor feedback adaptation may be advantageous for asymmetric overground locomotion, such as navigating irregular terrain or turning. [ABSTRACT FROM AUTHOR]

Key points Myosin filament mechanosensing determines the efficiency of the contraction by adapting the number of switched ON motors to the load., Accordingly, the unloaded shortening velocity ( V0) is already set at the end of latency relaxation (LR), ∼10 ms after the start of stimulation, when the myosin filament is still in the OFF state., Here the number of actin-attached motors per half-myosin filament ( n) during V0 shortening imposed either at the end of LR or at the plateau of the isometric contraction is estimated from the relation between half-sarcomere compliance and force during the force redevelopment after shortening., The value of n decreases progressively with shortening and, during V0 shortening starting at the end of LR, is 1-4., Reduction of n is accounted for by a constant duty ratio of 0.05 and a parallel switching OFF of motors, explaining the very low rate of ATP utilization found during unloaded shortening., Abstract The maximum velocity at which a skeletal muscle can shorten (i.e. the velocity of sliding between the myosin filament and the actin filament under zero load, V0) is already set at the end of the latency relaxation (LR) preceding isometric force generation, ∼10 ms after the start of electrical stimulation in frog muscle fibres at 4°C. At this time, Ca2+-induced activation of the actin filament is maximal, while the myosin filament is in the OFF state characterized by most of the myosin motors lying on helical tracks on the filament surface, making them unavailable for actin binding and ATP hydrolysis. Here, the number of actin-attached motors per half-thick filament during V0 shortening ( n) is estimated by imposing, on tetanized single fibres from Rana esculenta (at 4°C and sarcomere length 2.15 μm), small 4 kHz oscillations and determining the relation between half-sarcomere (hs) compliance and force during the force development following V0 shortening. When V0 shortening is superimposed on the maximum isometric force T0, n decreases progressively with the increase of shortening (range 30-80 nm per hs) and, when V0 shortening is imposed at the end of LR, n can be as low as 1-4. Reduction of n is accounted for by a constant duty ratio of the myosin motor of ∼0.05 and a parallel switching OFF of the thick filament, providing an explanation for the very low rate of ATP utilization during extended V0 shortening. [ABSTRACT FROM AUTHOR]

Suppression of the extensor H-reflex by flexor afferent conditioning is thought to be produced by a long-lasting inhibition of extensor Ia afferent terminals via GABA A receptor-activated primary afferent depolarization (PAD). Given the recent finding that PAD does not produce presynaptic inhibition of Ia afferent terminals, we examined in 28 participants if H-reflex suppression is instead mediated by post-activation depression of the extensor Ia afferents triggered by PAD-evoked spikes and/or by a long-lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H-reflex and the tonic discharge of soleus motor units out to 150 ms following the vibration, suggesting that part of the H-reflex suppression during this period was mediated by postsynaptic inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H-reflex was also suppressed but only when a short-latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short-latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2 + ) neurons produced a large enough PAD to evoke orthodromic spikes in the test Ia afferents, causing post-activation depression of subsequent monosynaptic EPSPs. The long duration of this post-activation depression and related H-reflex suppression (seconds) was similar to rate-dependent depression that is also due to post-activation depression. We conclude that extensor H-reflex inhibition by brief flexor afferent conditioning is produced by both post-activation depression of extensor Ia afferents and long-lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia afferent terminals. KEY POINTS: Suppression of extensor H-reflexes by flexor afferent conditioning was thought to be mediated by GABA A receptor-mediated primary afferent depolarization (PAD) shunting action potentials in the Ia afferent terminal. In line with recent findings that PAD has a facilitatory role in Ia afferent conduction, we show here that when large enough, PAD can evoke orthodromic spikes that travel to the Ia afferent terminal to evoke EPSPs in the motoneuron. These PAD-evoked spikes also produce post-activation depression of Ia afferent terminals and may mediate the short- and long-lasting suppression of extensor H-reflexes in response to flexor afferent conditioning. Our findings highlight that we must re-examine how changes in the activation of GABAergic interneurons and PAD following nervous system injury or disease affects the regulation of Ia afferent transmission to spinal neurons and ultimately motor dysfunction in these disorders., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

An introduction to topics discussed within the issue including the development of myelinating and non-myelinating Schwann cells, the implementation of a low frequency electrical stimulation after surgery in repaired nerves and the contribution of Schwann cells in the repair of spinal cord.

Neural drive originating in higher brain areas reaches exercising limb muscles through the corticospinal-motoneuronal pathway, which links the motor cortex and spinal motoneurones. The properties of this pathway have frequently been observed to change during fatiguing exercise in ways that could influence the development of central fatigue (i.e. the progressive reduction in voluntary muscle activation). However, based on differences in motor cortical and motoneuronal excitability between exercise modalities (e.g. single-joint vs. locomotor exercise), there is no characteristic response that allows for a categorical conclusion about the effect of these changes on functional impairments and performance limitations. Despite the lack of uniformity in findings during fatigue, there is strong evidence for marked 'inhibition' of motoneurones as a direct result of voluntary drive. Endogenous forms of neuromodulation, such as via serotonin released from neurones, can directly affect motoneuronal output and central fatigue. Exogenous forms of neuromodulation, such as brain stimulation, may achieve a similar effect, although the evidence is weak. Non-invasive transcranial direct current stimulation can cause transient or long-lasting changes in cortical excitability; however, variable results across studies cast doubt on its claimed capacity to enhance performance. Furthermore, with these studies, it is difficult to establish a cause-and-effect relationship between brain responsiveness and exercise performance. This review briefly summarizes changes in the corticomotoneuronal pathway during various types of exercise, and considers the relevance of these changes for the development of central fatigue, as well as the potential of non-invasive brain stimulation to enhance motor cortical excitability, motoneuronal output and, ultimately, exercise performance., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within-train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long-term potentiation, which increases release by LPP terminals, enhanced within-train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3-CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three-pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically. KEY POINTS: The lateral perforant path (LPP)-dentate gyrus (DG) synapse operates as a low-pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed. Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds). Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses. LPP frequency filtering is modified by the unique presynaptic long-term potentiation at this synapse. Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP-DG frequency filtering., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Keywords: electrical stimulation; motor cortex; precentral gyrus; somatotopic organization EN electrical stimulation motor cortex precentral gyrus somatotopic organization 5305 5306 2 12/02/20 20201201 NES 201201 Anyone who has compared Penfield's ultimate motor homunculus (Penfield & Rasmussen, 1950) with some of the original data on which this summary cartoon was based (Penfield & Boldrey, 1937) will be left wondering: Was the ribbon of discrete zones of separate body-part representations an accurate insight envisioned through noisy data? Bringing modern techniques to bear, Roux and colleagues have compiled 14 years of meticulous intraoperative observations to re-examine the human primary motor cortex (M1) in the current issue of the I Journal of Physiology i (Roux I et al i . 2020). Penfield and colleagues evoked movements from many points anterior or posterior to the precentral gyrus I per se i , whereas Roux and colleagues evoked movements almost exclusively from the precentral gyrus. [Extracted from the article]

Key points Application of 2 mA cathodal transcranial direct current stimulation for 20 min results in cortical excitability enhancement instead of inhibition., Longer or more intensive stimulation does not necessarily increase its efficacy., Short intracortical inhibition and facilitation are shifted towards excitability enhancement after both 2 mA anodal and cathodal stimulation., I-waves, input-output curves and cortical silent period are unaffected immediately after 2 mA stimulation., Abstract Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm2 has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI and ICF towards inhibition. No significant changes were observed in the other protocols. Sham tDCS did not induce significant MEP alterations. These results suggest that an enhancement of tDCS intensity does not necessarily increase efficacy of stimulation, but might also shift the direction of excitability alterations. This should be taken into account for applications of the stimulation technique using different intensities and durations in order to achieve stronger or longer lasting after-effects. [ABSTRACT FROM AUTHOR]

Key points Previous studies documented features of corticobulbar projections and of intracortical circuits in the motor cortex innervating lower facial muscles (face M1). However, there have been no studies of the afferent modulation of corticobulbar excitability or of the plasticity of synaptic connections in face M1., Intracortical circuits, sensorimotor integration and plasticity in face M1 were investigated in healthy volunteers using standard protocols of the transcranial magnetic stimulation technique., This study showed, for the first time, that face M1 is prone to plastic changes following paired associative stimulation and that its excitability is modulated by afferent stimulation at long latency (200 ms) but not at short latency (20 ms). Furthermore, contralateral predominance of cortical projection to lower facial muscles was confirmed, and the presence of bilateral intracortical inhibitory and facilitatory mechanisms at rest and during voluntary muscle activation was clarified., These data provide further physiological insight into pathologies affecting the facial motor system., Abstract Previous studies of the cortical control of human facial muscles documented the distribution of corticobulbar projections and the presence of intracortical inhibitory and facilitatory mechanisms. Yet surprisingly, given the importance and precision in control of facial expression, there have been no studies of the afferent modulation of corticobulbar excitability or of the plasticity of synaptic connections in the facial primary motor cortex (face M1). In 25 healthy volunteers, we used standard single- and paired-pulse transcranial magnetic stimulation (TMS) methods to probe motor-evoked potentials (MEPs), short-intracortical inhibition, intracortical facilitation, short-afferent and long-afferent inhibition and paired associative stimulation in relaxed and active depressor anguli oris muscles. Single-pulse TMS evoked bilateral MEPs at rest and during activity that were larger in contralateral muscles, confirming that corticobulbar projection to lower facial muscles is bilateral and asymmetric, with contralateral predominance. Both short-intracortical inhibition and intracortical facilitation were present bilaterally in resting and active conditions. Electrical stimulation of the facial nerve paired with a TMS pulse 5-200 ms later showed no short-afferent inhibition, but long-afferent inhibition was present. Paired associative stimulation tested with an electrical stimulation-TMS interval of 20 ms significantly facilitated MEPs for up to 30 min. The long-term potentiation, evoked for the first time in face M1, demonstrates that excitability of the facial motor cortex is prone to plastic changes after paired associative stimulation. Evaluation of intracortical circuits in both relaxed and active lower facial muscles as well as of plasticity in the facial motor cortex may provide further physiological insight into pathologies affecting the facial motor system. [ABSTRACT FROM AUTHOR]

Key points Rhythmic network activity can be controlled by intracellular signalling pathways but their possible role is largely not yet elucidated., This study is focused on the mechanisms of emergence and maintenance of synchronous rhythmic activity within the preBötzinger complex (preBötC), an essential part of the respiratory network in the brainstem., Depression of the bursting activity by brief hypoxia and electrical stimulation correlated well with ADP-mediated inhibition of TRPM4 channels., Long-lasting increases in calcium during the treatments stimulated calmodulin kinase that facilitated glutamatergic synapses and augmented rhythmic activity., The results will help us better understand how respiratory rhythm is generated and how it is restored in various respiratory disorders, Abstract Emergence of persistent activity in networks can be controlled by intracellular signalling pathways but the mechanisms involved and their role are not yet fully explored. Using calcium imaging and patch-clamp we examined the rhythmic activity in the preBötzinger complex (preBötC) in the lower brainstem that generates the respiratory motor output. In functionally intact acute slices brief hypoxia, electrical stimulation and activation of AMPA receptors transiently depressed bursting activity which then recovered with augmentation. The effects were abrogated after chelation of intracellular calcium, blockade of l-type calcium channels and inhibition of calmodulin (CaM) and CaM kinase (CaMKII). Rhythmic calcium transients and synaptic drive currents in preBötC neurons in the organotypic slices showed similar CaM- and CaMKII-dependent responses. The stimuli increased the amplitude of spontaneous and miniature excitatory synaptic currents indicating postsynaptic changes at glutamatergic synapses. In the acute and organotypic slices, CaM stimulated and ADP inhibited calcium-dependent TRPM4 channels and CaMKII augmented synaptic drive currents. Experimental data and simulations show the role of ADP and CaMKII in the control of bursting activity and its relation to intracellular signalling. I propose that CaMKII-mediated facilitation of glutamatergic transmission strengthens emergent synchronous activity within preBötC that is then maintained by periodic surges of calcium during the bursts. This may find implications in restoration and consolidation of autonomous activity in the respiratory disorders. [ABSTRACT FROM AUTHOR]

Key points Vasoactive intestinal polypeptide (VIP)-ergic neuromuscular transmission (NMT) was examined in the internal anal sphincter of wild-type mice and compared with that of VIP−/− mice., Relaxation and hyperpolarization during brief trains of electrical field stimulation (EFS; 4 s) were mediated by purinergic and nitrergic NMT., During longer stimulus trains, a non-purinergic, non-nitrergic (NNNP) relaxation and hyperpolarization slowly developed and persisted for several minutes beyond the end of the stimulus train., The NNNP NMT was abolished by VIP receptor antagonists, absent in the VIP−/− mouse internal anal sphincter and mimicked by exogenous VIP., These data suggest that NNNP NMT gives rise to ultraslow relaxation and hyperpolarization that is mediated by VIP. In vivo, this pathway may be activated with larger rectal distensions, leading to a more prolonged anal relaxation., Abstract There is evidence that vasoactive intestinal polypeptide (VIP) participates in inhibitory neuromuscular transmission (NMT) in the internal anal sphincter (IAS). However, specific details concerning VIP-ergic NMT are limited, largely because of difficulties in selectively blocking other inhibitory neural pathways. The present study used the selective P2Y1 receptor antagonist MRS2500 (1 μ m) and the nitric oxide synthase inhibitor NG-nitro- l-arginine ( l-NNA; 100 μ m) to block purinergic and nitrergic NMT to characterize non-purinergic, non-nitrergic (NNNP) inhibitory NMT and the role of VIP in this response. Nerves were stimulated with electrical field stimulation (0.1-20 Hz, 4-60 s) and the associated changes in contractile and electrical activity measured in non-adrenergic, non-cholinergic conditions in the IAS of wild-type and VIP−/− mice. Electrical field stimulation gave rise to frequency-dependent relaxation and hyperpolarization that was blocked by tetrodotoxin. Responses during brief trains of stimuli (4 s) were mediated by purinergic and nitrergic NMT. During longer stimulus trains, an NNNP relaxation and hyperpolarization developed slowly and persisted for several minutes beyond the end of the stimulus train. The NNNP NMT was abolished by VIP6-28 (30 μ m), absent in the VIP−/− mouse and mimicked by exogenous VIP (1-100 n m). Immunoreactivity for VIP was co-localized with neuronal nitric oxide synthase in varicose intramuscular fibres but was not detected in the VIP−/− mouse IAS. In conclusion, this study identified an ultraslow component of inhibitory NMT in the IAS mediated by VIP. In vivo, this pathway may be activated with larger rectal distensions, leading to a more prolonged period of anal relaxation. [ABSTRACT FROM AUTHOR]

Key points Layer V principal neurons of the entorhinal cortex receive the hippocampal output on their proximal and basal dendrites and send their axons to cortical areas, playing a fundamental role in memory processing., The apical dendrites of these neurons are rich in spines and extend to the entorhinal superficial layers, in the proximity of axons from cortical neurons, which could make synapses onto these spines., We stimulated afferent fibres in the superficial layers and recorded depolarizing responses in entorhinal layer V neurons, indicating that they receive excitatory inputs onto their distal dendrites., The responses were completely blocked by glutamatergic receptor antagonists; stimulation of distal afferents could initiate dendritic spikes, which propagated to the soma to generate an action potential., These results show that the distal dendrites of entorhinal layer V neurons have access to information that could affect the integration of the input from the hippocampus., Abstract The entorhinal cortex (EC) has a fundamental function in transferring information between the hippocampus and the neocortex. EC layer V principal neurons are the main recipients of the hippocampal output and send processed information to the neocortex, likely playing an important role in memory processing and consolidation. Most of these neurons have apical dendrites that extend to the superficial layers and are rich in spines, which could be the targets of excitatory inputs from fibres innervating that region. We have used electrical stimulation of afferent fibres coupled with whole-cell patch-clamp somatic recordings to study the features of distal excitatory inputs and compare them with those of proximal ones. The amplitude of putative unitary excitatory responses was ∼1.5 times larger for distal compared with proximal inputs. The responses were purely glutamatergic, as they were abolished by a combination of AMPA and NMDA glutamatergic receptor antagonists. Blockade of Ih by 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) increased temporal summation; the increase was comparable for proximal and distal inputs. Proximal inputs initiated a somatic spike more reliably than distal ones; in some instances, somatic action potentials triggered by distal stimulation were preceded by dendritic spikes that fully propagated to the soma. Altogether, our results show that medial layer V entorhinal neurons receive excitatory synapses at distal dendritic locations, which gives them access to information encoded by inputs to the superficial layers as well as the deep layers. These findings are fundamentally relevant to understanding the role of the EC in the formation and consolidation of episodic memory. [ABSTRACT FROM AUTHOR]

Slowly-adapting type II (SA-II, Ruffini) mechanoreceptive afferents respond well to pressure and stretch, and are regularly encountered in human microneurography studies. Despite an understanding of SA-II response properties, their role in touch perception remains unclear. Specific roles of different myelinated Aβ mechanoreceptive afferents in tactile perception have been revealed using single unit intraneural microstimulation (INMS), via microneurography, recording from and then electrically stimulating individual afferents. This method directly links single afferent artificial activation to perception, where INMS produces specific 'quantal' touch percepts associated with different mechanoreceptive afferent types. However, SA-II afferent stimulation has been ambiguous, producing inconsistent, vague sensations, or no clear percept. We physiologically characterized hundreds of individual Aβ mechanoreceptive afferents in the glabrous hand skin and examined the subsequent percepts evoked by trains of low amplitude INMS current pulses (<10 μA). We present 18 SA-II afferents where INMS resulted in a clear, electrically evoked sensation of large (∼36 mm 2 ) diffuse pressure, which was projected precisely to their physiologically-defined receptive field in the skin. This sensation was felt as natural, distinctive from other afferents, and showed no indications of multi-afferent stimulation. Stimulus frequency modulated sensation intensity and even brief stimuli (4 pulses, 60 ms) were perceived. These results suggest that SA-II afferents contribute to perceived tactile sensations, can signal this rapidly and precisely, and are relevant and important for computational models of touch sensation and artificial prosthetic feedback. KEY POINTS: Slowly adapting type II mechanoreceptors (SA-IIs) are primary sensory neurons in humans that respond to pressure and stretch applied to the skin. To date, no specific conscious correlate of touch has been linked to SA-II activation. Using microneurography and intraneural microstimulation to stimulate single sensory neurons in human subjects, we find a specific sensation linked to the activation of single SA-II afferents. This sensation of touch was reported as gentle pressure and subjects could detect this with a high degree of accuracy. Methods of artificial tactile sensory feedback and computational models of touch should include SA-IIs as meaningful contributors to the conscious sensation of touch., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Key points The muscarinic receptors increase the excitability in spinal cord motoneurons., In the present study, I report the muscarinic modulation of postsynaptic AMPA receptors at glutamatergic synapses on spinal cord motoneurons., The muscarinic modulation acts specifically on synapses originated at the dorsolateral funiculus, which contains supraspinal and spinal intersegmental influences., The present results suggest that the modulatory actions of muscarinic receptors reduce the synaptic weight of excitatory inputs originating at intersegmental and/or supraspinal levels but not at the intrasegmental level., The muscarinic receptor activity might amplify the differences between synaptic weights of inputs with different origins, potentially contributing to the diversity of motor outputs implicating the same muscular groups, as well as to the refinement of locomotor behaviour at early postnatal stages., Abstract A cholinergic synaptic input has been highlighted in recent years as an important modulator of motoneuron excitability. In the present study, it was examined whether, as in other regions, the cholinergic inputs on spinal motoneurons modulate the glutamatergic synaptic activity, evoked by electrical stimulation at the dorsolateral funiculus. The present results show that the pharmacological stimulation of muscarinic receptors produces a selective depression of AMPA-mediated glutamatergic activity in thoracic and lumbar spinal motoneurons. This effect does not involve a change in transmitter release and occurs both on synaptic currents and on AMPA responses evoked by photolysis of MNI-glutamate. Thus, it is concluded that muscarinic modulation occurs at the postsynaptic level. The results suggest that cholinergic inputs contacting motoneurons, which are known to increase motoneuron excitability, also directly interfere with incoming synaptic inputs by changing their amplitudes. [ABSTRACT FROM AUTHOR]

Non-technical summary Individuals with a motor incomplete spinal cord injury (SCI) present clinically with partial control of muscles below the site of the injury, but experience profound weakness which can limit the ability to perform functional tasks such as walking. Interestingly, when individuals with an incomplete SCI are asked to maximally and repeatedly contract their quadriceps muscles, they demonstrate an increase in the peak force generated; individuals without SCI experience a decline in force, or 'fatigue'. Following these repeated maximal efforts, reflex responses to electrical stimulation over the quadriceps muscle elicited amplified and prolonged, involuntary motor activity. Such responses were not observed prior to the maximal contractions, and were not observed in neurologically intact subjects. This finding suggests that increases in spinal excitability following these maximal efforts may enhance force generating capacity, and provides insight into possible novel therapeutic interventions to restore function following SCI. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) refers to a neurosurgical technique where chronically implanted electrodes serve to deliver electrical impulses to highly defined brain regions in neuropsychiatric disorders including Parkinson's disease (PD), depression and obsessive-compulsive disorders. Despite its broad acceptance as a safe and effective treatment for advanced PD, DBS has remained enigmatic with respect to its underlying mechanism(s). In general terms, DBS is capable of reinstating regular electrical activity in the complex neuronal networks that exhibit aberrant firing properties in PD, but how this effect is achieved at the network and cellular level is still highly debated. Our study focuses on a crucial, but hitherto neglected, issue in this controversy, namely the propagation of impulses within and away from the site of electrical stimulation. We propose that DBS overburdens the capacity of axons to transmit signals, thereby filtering and abating the pathological activity in the brain motor loops of PD patients. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) induces modifications of motor cortex excitability depending on the polarity. However, the impact of tDCS applied to lower limb motor cortex on lumbar spinal network excitability has been unknown up to now. This study was performed in order to assess the effects of anodal tDCS compared to sham stimulation on three lumbar spinal circuits, namely reciprocal Ia inhibition, homonymous recurrent inhibition and presynaptic Ia inhibition, in healthy subjects. The results indicate that anodal tDCS modifies the behaviour of 2 of the 3 spinal circuits studied. Effects of anodal tDCS when applied over lower limb motor cortex should be considered with regard not only to cortical circuits but also to spinal motor circuits. The results also suggest that the effects of anodal tDCS on lumbar spinal circuits are similar to those observed during voluntary muscle co-contractions. [ABSTRACT FROM AUTHOR]

In the present study, we examined the role of the neurokinin-1 receptor (NK1R) in the modulation of respiratory rhythm in a functionally identified bradypnoeic region of the ventral respiratory group (VRG) in the in situ arterially perfused juvenile rat preparation. In electrophysiologically and functionally identified bradypnoeic sites corresponding to the Bötzinger complex (BötC), microinjection of the selective NK1R agonist [Sar9-Met(O2)11]-substance P (SSP) produced a significant reduction in phrenic frequency mediated exclusively by an increase in expiratory duration ( TE). The reduction was characterized by a significant increase in postinspiratory (post-I) duration with no effect on either late-expiratory duration (E2) or inspiratory duration ( TI). In contrast, in a functionally identified tachypnoeic region, corresponding to the preBötzinger complex (Pre-BötC), control microinjection of SSP elicited tachypnoea. Pretreatment with the NK1R antagonist CP99994 in the BötC significantly attenuated the bradypnoeic response to SSP injection and blunted the increase in TE duration. This effect of SSP mimicked the extension of TE produced by activation of the Hering-Breuer reflex. Therefore, we hypothesized that activation of NK1Rs in the BötC is requisite for the expiratory-lengthening effect of the Hering-Breuer reflex. Unilateral electrical stimulation of the cervical vagus nerve produced bradypnoea by exclusively extending TE. Ipsilateral blockade of NK1Rs by CP99994 following blockade of the contralateral BötC by the GABAA receptor agonist muscimol significantly reduced the extension of TE produced by vagal stimulation. Results from the present study demonstrate that selective activation of NK1Rs in a functionally identified bradypnoeic region of the VRG can depress respiratory frequency by selectively lengthening post-I duration and provide evidence that endogenous activation of NK1Rs in the BötC appears to be involved in the expiratory-lengthening effect of the Hering-Breuer reflex. In conclusion, our findings demonstrate that selective activation of NK1Rs in discrete regions of the VRG can exert functionally diverse effects on breathing. [ABSTRACT FROM AUTHOR]

Repetitive synaptic stimulation in the stratum radiatum (SR) evokes large amplitude Ca2+ waves in the thick apical dendrites of hippocampal CA1 pyramidal neurons. These waves are initiated by activation of metabotropic glutamate receptors (mGluRs), which mobilize inositol-1,4,5-trisphospate (IP3) and release Ca2+ from intracellular stores. We explored mechanisms that modulate the spatial properties of these waves. Higher stimulus current evoked waves of increasing spatial extent. Most waves did not propagate through the soma; the majority stopped close to the junction of the soma and apical dendrite. Pairing strong stimulation with one electrode and subthreshold stimulation with another (associative activation) extended the waves distally but failed to extend waves into the cell body. Pairing synaptic stimulation with backpropagating action potentials enhanced the likelihood of wave generation but did not extend the waves to the somatic region. Priming the stores with Ca2+ entry through voltage dependent channels modulated wave properties but did not extend them past the dendrites. These results are consistent with propagation failing due to the dilution of synaptically generated IP3 as it diffuses into the large volume of the soma (impedance mismatch). Synaptically activating waves in the presence of low concentrations of carbachol, which probably increased the tonic level of IP3 throughout the cell, enhanced the extent of propagation and generated waves that invaded the soma, as long as low-affinity indicators were used to detect the [Ca2+]i changes. Consistent with this explanation direct injection of IP3 into the soma promoted wave propagation into this region. Ca2+ waves that propagated through the cell body were interesting because they did not fill the volume of the soma, but passed through the centre, often with large amplitude. These waves may be particularly effective in activating gene expression and protein synthesis. [ABSTRACT FROM AUTHOR]

The subthalamic nucleus (STN) plays an important role in movement control by exerting its excitatory influence on the substantia nigra pars reticulata (SNR), a major output structure of the basal ganglia. Moreover, excessive burst firing of SNR neurons seen in Parkinson's disease has been attributed to excessive transmission in the subthalamonigral pathway. Using the ‘blind’ whole-cell patch clamp recording technique in rat brain slices, we found that focal electrical stimulation of the STN evoked complex, long-duration excitatory postsynaptic currents (EPSCs) in SNR neurons. Complex EPSCs lasted 200–500 ms and consisted of an initial monosynaptic EPSC followed by a series of late EPSCs superimposed on a slow inward shift in holding current. Focal stimulation of regions outside the STN failed to evoke complex EPSCs. The late component of complex EPSCs was markedly reduced by ionotropic glutamate receptor antagonists (2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitro-quinoxalone) and by a GABAA receptor agonist (isoguvacine) when these agents were applied directly to the STN using a fast-flow microapplicator. Moreover, the complex EPSC was greatly enhanced by bath application of the GABAA receptor antagonists picrotoxin or bicuculline. These data suggest that recurrent glutamate synapses in the STN generate polysynaptic, complex EPSCs that are under tonic inhibition by GABA. Because complex EPSCs are expected to generate bursts of action potentials in SNR neurons, we suggest that complex EPSCs may contribute to the pathological burst firing that is associated with the symptoms of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Reflex responses are often less pronounced when they are self-induced, but this question has barely been investigated quantitatively. The issue is particularly relevant for locomotion since it has been shown that reflexes elicited during normal gait are important for the regulation of locomotion. The cortex is thought to be involved in the control of reflexes during gait, but it is unclear whether it plays a role in the modulation of these reflexes during the step cycle. During gait, weak electrical stimulation of the sural nerve elicits reflexes in various leg muscles. Are these reflexes different when subjects themselves trigger the stimuli instead of being randomly released by the computer? Cutaneous reflexes were elicited by sural nerve stimulation in 16 phases of the gait cycle in healthy subjects. The stimuli were triggered either by computer or by the subjects themselves. In 6 out of 7 subjects it was observed that the facilitatory responses in leg muscles were smaller and the suppressive responses were more suppressive following self-generated stimuli. In some muscles such as tibialis anterior (TA) both effects were seen (reduced facilitation at end stance and exaggerated suppression at end swing). In all subjects the modulation of anticipatory influences was muscle specific. In the main group of six subjects, the mean reduction in reflex responses was strongest in the TA (max. 30.7%; mean over 16 phases was 12.5%) and weakest in peroneus longus (PL, max. 10.1%; mean over 16 phases was 2.6%). The observation that facilitation is reduced and suppression enhanced in several muscles is taken as evidence that anticipation of self-induced reflex responses reduces the excitatory drive to motoneurones, for example through presynaptic inhibition of facilitatory reflex pathways. [ABSTRACT FROM AUTHOR]

Although cathodal transcranial direct current stimulation (tDCS) decreases cortical excitability, the mechanisms underlying DC-induced changes remain largely unclear. In this study we investigated the effect of cathodal DC stimulation on spontaneous neural activity and on motor responses evoked by stimulation of the central and peripheral nervous system. We studied 17 healthy volunteers. Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the motor area were used to study the effects of cathodal tDCS (1.5 mA, 10 min) on resting motor threshold and motor evoked potentials (MEPs) recorded from the contralateral first dorsal interosseous muscle (FDI). The electroencephalographic (EEG) activity in response to cathodal tDCS was analysed by power spectral density (PSD). Motor axonal excitability changes in response to transcutaneous DC stimulation of the ulnar nerve (0.3 mA, 10 min) were assessed by testing changes in the size of the compound muscle action potential (CMAP) elicited by submaximal nerve stimulation. Cathodal tDCS over the motor area for 10 min increased the motor threshold and decreased the size of MEPs evoked by TMS for at least 60 min after current offset ( t0 71.7 ± 5%, t20 50.8 ± 11%, t40 47.7 ± 7.7%, and t60 39.7 ± 6.4%, P < 0.01). The tDCS also significantly decreased the size of MEPs elicited by TES ( t0 64 ± 16.4%, P= 0.09; t20 67.6 ± 10.8%, P= 0.06; and t40 58.3 ± 9.9%, P < 0.05). At the same time in the EEG the power of delta (2–4 Hz) and theta (4–7 Hz) rhythms increased (delta 181.1 ± 40.2, P < 0.05; and theta 138.7 ± 27.6, P= 0.07). At the peripheral level cathodal DC stimulation increased the size of the ulnar nerve CMAP (175 ± 34.3%, P < 0.05). Our findings demonstrate that the after-effects of tDCS have a non-synaptic mechanism of action based upon changes in neural membrane function. These changes apart from reflecting local changes in ionic concentrations, could arise from alterations in transmembrane proteins and from electrolysis-related changes in [H+] induced by exposure to constant electric field. [ABSTRACT FROM AUTHOR]

Event-related changes of brain electrical rhythms are typically analysed as amplitude modulations of local field potential (LFP) oscillations, like radio amplitude modulation broadcasting. In telecommunications, frequency modulation (FM) is less susceptible to interference than amplitude modulation (AM) and is therefore preferred for high-fidelity transmissions. Here we hypothesized that LFP rhythms detected from deep brain stimulation (DBS) electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease could represent movement-related activity not only in AM but also in FM. By combining adaptive autoregressive identification with spectral power decomposition, we were able to show that FM of low-beta (13–20 Hz) and high-beta (20–35 Hz) rhythms significantly contributes to the involvement of the human STN in movement preparation, execution and recovery, and that the FM patterns are regulated by the dopamine levels in the system. Movement-related FM of beta oscillatory activity in the human subthalamic nucleus therefore provides a novel informational domain for rhythm-based pathophysiological models of cortico-basal ganglia processing. [ABSTRACT FROM AUTHOR]