Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: A simulation study.

Postinhibitory excitation is a transient overshoot of a neuron's baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model, we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneuron's firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the postinhibitory excitation's strength correlates with the inhibitory stimulus's amplitude and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50% of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition.

Muscle contractile properties directly influence shared synaptic inputs to spinal motor neurons.

Alpha band oscillations in shared synaptic inputs to the alpha motor neuron pool can be considered an involuntary source of noise that hinders precise voluntary force production. This study investigated the impact of changing muscle length on the shared synaptic oscillations to spinal motor neurons, particularly in the physiological tremor band. Fourteen healthy individuals performed low-level dorsiflexion contractions at ankle joint angles of 90° and 130°, while high-density surface electromyography (HDsEMG) was recorded from the tibialis anterior (TA). We decomposed the HDsEMG into motor units spike trains and calculated the motor units' coherence within the delta (1-5 Hz), alpha (5-15 Hz), and beta (15-35 Hz) bands. Additionally, force steadiness and force spectral power within the tremor band were quantified. Results showed no significant differences in force steadiness between 90° and 130°. In contrast, alpha band oscillations in both synaptic inputs and force output decreased as the length of the TA was moved from shorter (90°) to longer (130°), with no changes in delta and beta bands. In a second set of experiments (10 participants), evoked twitches were recorded with the ankle joint at 90° and 130°, revealing longer twitch durations in the longer TA muscle length condition compared to the shorter. These experimental results, supported by a simple computational simulation, suggest that increasing muscle length enhances the muscle's low-pass filtering properties, influencing the oscillations generated by the Ia afferent feedback loop. Therefore, this study provides valuable insights into the interplay between muscle biomechanics and neural oscillations. KEY POINTS: We investigated whether changes in muscle length, achieved by changing joint position, could influence common synaptic oscillations to spinal motor neurons, particularly in the tremor band (5-15 Hz). Our results demonstrate that changing muscle length from shorter to longer induces reductions in the magnitude of alpha band oscillations in common synaptic inputs. Importantly, these reductions were reflected in the oscillations of muscle force output within the alpha band. Longer twitch durations were observed in the longer muscle length condition compared to the shorter, suggesting that increasing muscle length enhances the muscle's low-pass filtering properties. Changes in the peripheral contractile properties of motor units due to changes in muscle length significantly influence the transmission of shared synaptic inputs into muscle force output. These findings prove the interplay between muscle mechanics and neural adaptations.

Voluntary co-contraction of ankle muscles alters motor unit discharge characteristics and reduces estimates of persistent inward currents.

Motoneuronal persistent inward currents (PICs) are facilitated by neuromodulatory inputs but are highly sensitive to local inhibitory circuits. Estimates of PICs are reduced by group Ia reciprocal inhibition, and increased with the diffuse actions of neuromodulators released during remote muscle contraction. However, it remains unknown how motoneurons function in the presence of simultaneous excitatory and inhibitory commands. To probe this topic, we investigated motor unit discharge patterns and estimated PICs during voluntary co-contraction of ankle muscles, which simultaneously demands the contraction of agonist-antagonist pairs. Twenty participants performed triangular ramps of both co-contraction (simultaneous dorsiflexion and plantar flexion) and isometric dorsiflexion to a peak of 30% of their maximum muscle activity from a maximal voluntary contraction. Motor unit spike trains were decomposed from high-density surface EMG activity recorded from tibialis anterior using blind source separation algorithms. Voluntary co-contraction altered motor unit discharge rate characteristics. Discharge rate at recruitment and peak discharge rate were modestly reduced (∼6% change; P < 0.001; d = 0.22) and increased (∼2% change; P = 0.001, d = -0.19), respectively, in the entire dataset but no changes were observed when motor units were tracked across conditions. The largest effects during co-contraction were that estimates of PICs (ΔF) were reduced by ∼20% (4.47 vs. 5.57 pulses per second during isometric dorsiflexion; P < 0.001, d = 0.641). These findings suggest that, during voluntary co-contraction, the inhibitory input from the antagonist muscle overcomes the additional excitatory and neuromodulatory drive that may occur due to the co-contraction of the antagonist muscle, which constrains PIC behaviour. KEY POINTS: Voluntary co-contraction is a unique motor behaviour that concurrently provides excitatory and inhibitory synaptic input to motoneurons. Co-contraction of agonist-antagonist pairs alters agonist motor unit discharge characteristics, consistent with reductions in persistent inward current magnitude.

Intrinsic motoneuron properties in typical human development.

Motoneuron properties and their firing patterns undergo significant changes throughout development and in response to neuromodulators such as serotonin. Here, we examined the age-related development of self-sustained firing and general excitability of tibialis anterior motoneurons in a young development (7-17 years), young adult (18-28 years) and adult (32-53 years) group, as well as in a separate group of participants taking selective serotonin reuptake inhibitors (SSRIs, aged 11-28 years). Self-sustained firing, as measured by ΔF, was larger in the young development (∼5.8 Hz, n = 20) compared to the young adult (∼4.9 Hz, n = 13) and adult (∼4.8 Hz, n = 8) groups, consistent with a developmental decrease in self-sustained firing mediated by persistent inward currents (PIC). ΔF was also larger in participants taking SSRIs (∼6.5 Hz, n = 9) compared to their age-matched controls (∼5.3 Hz, n = 26), consistent with increased levels of spinal serotonin facilitating the motoneuron PIC. Participants in the young development and SSRI groups also had higher firing rates and a steeper acceleration in initial firing rates (secondary ranges), consistent with the PIC producing a steeper acceleration in membrane depolarization at the onset of motoneuron firing. In summary, both the young development and SSRI groups exhibited increased intrinsic motoneuron excitability compared to the adults, which, in the young development group, was also associated with a larger unsteadiness in the dorsiflexion torque profiles. We propose several intrinsic and extrinsic factors that affect both motoneuron PICs and cell discharge which vary during development, with a time course similar to the changes in motoneuron firing behaviour observed in the present study. KEY POINTS: Neurons in the spinal cord that activate muscles in the limbs (motoneurons) undergo increases in excitability shortly after birth to help animals stand and walk. We examined whether the excitability of human ankle flexor motoneurons also continues to change from child to adulthood by recording the activity of the muscle fibres they innervate. Motoneurons in children and adolescents aged 7-17 years (young development group) had higher signatures of excitability that included faster firing rates and more self-sustained activity compared to adults aged ≥18 years. Participants aged 11-28 years of age taking serotonin reuptake inhibitors had the highest measures of motoneuron excitability compared to their age-matched controls. The young development group also had more unstable contractions, which might partly be related to the high excitability of the motoneurons.

Foot-dominance does not influence force variability during ankle dorsiflexion and foot adduction.

The aim of our study was to compare the force steadiness and the discharge characteristics of motor units in the tibialis anterior (TA) during ankle dorsiflexion and foot adduction produced by submaximal isometric contractions with the dominant and non-dominant foot. Fifteen young men performed maximal and submaximal contractions at five target forces with both legs, and motor unit activity in TA was recorded using high-density electromyography. Maximal force and the fluctuations in force during submaximal contractions were similar between the two legs (p > 0.05). Motor unit activity was characterized by measures of mean discharge rate (MDR), coefficient of variation for interspike interval (CoV for ISI), and standard deviation of the filtered cumulative spike train (SD of fCST). There were no statistically significant differences in motor unit activity between legs during ankle dorsiflexion. In contrast, the MDR and the CoV for ISI but not the SD of fCST, were greater for the non-dominant foot compared with the dominant foot during foot adduction. Nonetheless, these differences in motor unit activity were not sufficient to influence the force fluctuations during the submaximal contractions. These results indicate that control of the force produced by TA during the two actions was not influenced by limb dominance.

Adaptive HD-sEMG decomposition: towards robust real-time decoding of neural drive.

Objective. Neural interfacing via decomposition of high-density surface electromyography (HD-sEMG) should be robust to signal non-stationarities incurred by changes in joint pose and contraction intensity.Approach. We present an adaptive real-time motor unit decoding algorithm and test it on HD-sEMG collected from the extensor carpi radialis brevis during isometric contractions over a range of wrist angles and contraction intensities. The performance of the algorithm was verified using high-confidence benchmark decompositions derived from concurrently recorded intramuscular electromyography.Main results. In trials where contraction conditions between the initialization and testing data differed, the adaptive decoding algorithm maintained significantly higher decoding accuracies when compared to static decoding methods.Significance. Using "gold standard" verification techniques, we demonstrate the limitations of filter re-use decoding methods and show the necessity of parameter adaptation to achieve robust neural decoding.

More Variability in Tibialis Anterior Function during the Adduction of the Foot than Dorsiflexion of the Ankle.

INTRODUCTION: The aim of the study was to compare maximal force, force steadiness, and the discharge characteristics of motor units in the tibialis anterior (TA) muscle during submaximal isometric contractions for ankle dorsiflexion and adduction of the foot. METHODS: Nineteen active young adults performed maximal and submaximal isometric dorsiflexion and adduction contractions at five target forces (5%, 10%, 20%, 40%, and 60% maximal voluntary contraction [MVC]). The activity of motor units in TA was recorded by high-density EMG. RESULTS: The maximal force was similar between dorsiflexion and adduction, despite EMG amplitude for TA being greater ( P < 0.05) during dorsiflexion than adduction. Τhe coefficient of variation (CV) for force (force steadiness) during dorsiflexion was always less ( P < 0.05) than during adduction, except of 5% MVC force. No differences were observed for mean discharge rate; however, the regression between the changes in discharge rate relative to the change of force was significant for dorsiflexion ( R2 = 0.25, P < 0.05) but not for adduction. Discharge variability, however, was usually less during dorsiflexion. The CV for interspike interval was less ( P < 0.05) at 10%, 20%, and 40% MVC but greater at 60% MVC during dorsiflexion than adduction. Similarly, the SD values of the filtered cumulative spike train of the motor units in TA were less ( P < 0.05) at 5%, 10%, 20%, and 40% MVC during dorsiflexion than adduction. CONCLUSIONS: Although the mean discharge rate of motor units in TA was similar during foot adduction and ankle dorsiflexion, discharge variability was less during dorsiflexion resulting in less accurate performance of the steady adduction contractions. The neural drive to bifunctional muscles differs during their accessory function, which must be considered for training and rehabilitation interventions.

Integrated sustainability assessment of wood building products: The case of larch and chestnut cascading systems in Northern Italy.

Wood is increasingly being appreciated in construction due to its valuable environmental attributes. This paper explores the environmental and market performance of two wood supply chains in Northern Italy. Larch and chestnut wood are extracted and processed to obtain beams, planks, MDF panels and energy. LCA is performed to evaluate the environmental impacts of 1m3 of extracted wood through a cradle-to-gate approach. Then, a biogenic carbon analysis is carried out using the EN 16449:2014 standard including a comparison of different end-of-life treatments. Also, OSB is proposed as an alternative path for wood chips and contrasted to the current energy scenario. Moreover, solid wood beams and planks are compared with engineered wood products (EWPs). Lastly, a market analysis is conducted to assess the market trends of the different wood products studied. The LCA shows similar results for both wood species across most impact categories, with slightly higher values for the chestnut system. Most impacts are related to the production of MDF boards and the energy valorization of wood chips. Biogenic carbon analysis shows a negative balance of emissions with -314 and -205 kg of CO2 eq for larch and chestnut, respectively. It also suggests that OSB manufacturing can be a valuable alternative to the energy use of wood chips and that the end-of-life treatment with better results is recycling. The comparison of beams and planks with engineered wood products supports that solid wood poses a better environmental alternative in similar applications. Market analysis shows stagnation in the apparent consumption of wood products in the European market and a slight growth in the Italian one between 2018 and 2022. Overall, the systems studied suggest that the potential environmental benefits of using wood in construction are not being matched by current market trends.

Voluntary co-contraction of ankle muscles alters motor unit discharge characteristics and reduces estimates of persistent inward currents.

Motoneuronal persistent inward currents (PICs) are both facilitated by neuromodulatory inputs and highly sensitive to local inhibitory circuits (e.g., Ia reciprocal inhibition). Methods aimed to increase group Ia reciprocal inhibition from the antagonistic muscle have been successful in decreasing PICs, and the diffuse actions of neuromodulators released during activation of remote muscles have increased PICs. However, it remains unknown how motoneurons function in the presence of simultaneous excitatory and inhibitory commands. To probe this topic, we investigated motor unit (MU) discharge patterns and estimated PICs during voluntary co-contraction of ankle muscles, which simultaneously demands the contraction of agonist-antagonist pairs. Twenty young adults randomly performed triangular ramps (10s up and down) of both co-contraction (simultaneous dorsiflexion and plantarflexion) and isometric dorsiflexion to a peak of 30% of their maximum muscle activity from a maximal voluntary contraction. Motor unit spike trains were decomposed from high-density surface electromyography recorded over the tibialis anterior (TA) using blind source separation algorithms. Voluntary co-contraction altered motor unit discharge rate characteristics, decreasing estimates of PICs by 20% (4.47 pulses per second (pps) vs 5.57 pps during isometric dorsiflexion). These findings suggest that, during voluntary co-contraction, the inhibitory input from the antagonist muscle overcomes the additional excitatory and neuromodulatory drive that may occur due to the co-contraction of the antagonist muscle, which constrains PIC behavior.

Neural Filtering of Physiological Tremor Oscillations to Spinal Motor Neurons Mediates Short-Term Acquisition of a Skill Learning Task.

The acquisition of a motor skill involves adaptations of spinal and supraspinal pathways to alpha motoneurons. In this study, we estimated the shared synaptic contributions of these pathways to understand the neural mechanisms underlying the short-term acquisition of a new force-matching task. High-density surface electromyography (HDsEMG) was acquired from the first dorsal interosseous (FDI; 7 males and 6 females) and tibialis anterior (TA; 7 males and 4 females) during 15 trials of an isometric force-matching task. For two selected trials (pre- and post-skill acquisition), we decomposed the HDsEMG into motor unit spike trains, tracked motor units between trials, and calculated the mean discharge rate and the coefficient of variation of interspike interval (COVISI). We also quantified the post/pre ratio of motor units' coherence within delta, alpha, and beta bands. Force-matching improvements were accompanied by increased mean discharge rate and decreased COVISI for both muscles. Moreover, the area under the curve within alpha band decreased by ∼22% (TA) and ∼13% (FDI), with no delta or beta bands changes. These reductions correlated significantly with increased coupling between force/neural drive and target oscillations. These results suggest that short-term force-matching skill acquisition is mediated by attenuation of physiological tremor oscillations in the shared synaptic inputs. Supported by simulations, a plausible mechanism for alpha band reductions may involve spinal interneuron phase-cancelling descending oscillations. Therefore, during skill learning, the central nervous system acts as a matched filter, adjusting synaptic weights of shared inputs to suppress neural components unrelated to the specific task.

Effect of Direct Acting Antiviral Drugs on the Occurrence and Recurrence of Intra- and Extra-Hepatic Malignancies in Patients with Chronic Hepatitis C Virus Infection.

Introduction: The use of direct-acting antivirals (DAAs) has drastically changed the management of HCV-infected patients by achieving a 95-98% sustained virologic response (SVR) and reducing morbidity and mortality in this population. However, despite their effectiveness, controversy exists concerning the occurrence of oncologic events following DAA therapy. Aims and Methods: A retrospective analysis was conducted on data from the Swiss Hepatitis C Cohort Study, a prospective cohort involving patients with positive HCV viremia upon inclusion, enrolled in various Swiss centers from September 2000 to November 2021. To examine potential differences in the risk of intrahepatic tumor (IHT) occurrence and death among patients treated with direct-acting antivirals (DAAs), untreated patients, and those receiving interferon (IFN)-based therapy, a semiparametric competing risk proportional hazards regression model was used. Results: Among 4082 patients (63.1% male, median age 45 years; genotype 1: 54.1%; cirrhosis: 16.1%), 1026 received exclusive treatment with IFN-based regimens, and 1180 were treated solely with DAAs. Over a median follow-up of 7.8 years (range: 3.8-11.9), 179 patients (4.4%) developed intrahepatic tumors (IHT), and 168 (4.1%) experienced extrahepatic tumors (EHT). The 5-year cumulative incidence of IHT was 1.55% (95% CI 0.96-2.48) for IFN-based therapy, 4.27% (95% CI 2.93-6.2) for DAA and 0.89% (95% CI 0.4-1.99) for untreated patients. There was no statistically significant difference in the risk of developing IHT (HR = 1.34; 95% CI = [0.70; 2.58]; p = 0.380) or death (HR = 0.66; 95% CI = [0.43; 1.03]; p = 0.066) between patients treated with DAAs and those treated with IFN. Conclusions: The DAAs reduced the risk of death and were not associated with an increased risk of extrahepatic tumors (EHT). In the adjusted model, accounting for cirrhosis and high liver stiffness, the DAA treatment was associated with a higher risk of IHT occurrence compared with untreated patients, emphasizing the relevance of implementing standardized hepatocellular carcinoma (HCC) screening post-DAA treatment.

Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis.

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. METHODS: This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. RESULTS: A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. CONCLUSIONS: SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.