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.

A geometric approach to quantifying the neuromodulatory effects of persistent inward currents on individual motor unit discharge patterns.

Objective.All motor commands flow through motoneurons, which entrain control of their innervated muscle fibers, forming a motor unit (MU). Owing to the high fidelity of action potentials within MUs, their discharge profiles detail the organization of ionotropic excitatory/inhibitory as well as metabotropic neuromodulatory commands to motoneurons. Neuromodulatory inputs (e.g. norepinephrine, serotonin) enhance motoneuron excitability and facilitate persistent inward currents (PICs). PICs introduce quantifiable properties in MU discharge profiles by augmenting depolarizing currents upon activation (i.e. PIC amplification) and facilitating discharge at lower levels of excitatory input than required for recruitment (i.e. PIC prolongation).Approach. Here, we introduce a novel geometric approach to estimate neuromodulatory and inhibitory contributions to MU discharge by exploiting discharge non-linearities introduced by PIC amplification during time-varying linear tasks. In specific, we quantify the deviation from linear discharge ('brace height') and the rate of change in discharge (i.e. acceleration slope, attenuation slope, angle). We further characterize these metrics on a simulated motoneuron pool with known excitatory, inhibitory, and neuromodulatory inputs and on human MUs (number of MUs; Tibialis Anterior: 1448, Medial Gastrocnemius: 2100, Soleus: 1062, First Dorsal Interosseus: 2296).Main results. In the simulated motor pool, we found brace height and attenuation slope to consistently indicate changes in neuromodulation and the pattern of inhibition (excitation-inhibition coupling), respectively, whereas the paired MU analysis (ΔF) was dependent on both neuromodulation and inhibition pattern. Furthermore, we provide estimates of these metrics in human MUs and show comparable variability in ΔFand brace height measures for MUs matched across multiple trials.Significance. Spanning both datasets, we found brace height quantification to provide an intuitive method for achieving graded estimates of neuromodulatory and inhibitory drive to individual MUs. This complements common techniques and provides an avenue for decoupling changes in the level of neuromodulatory and pattern of inhibitory motor commands.

Multimodal parameter spaces of a complex multi-channel neuron model.

One of the most common types of models that helps us to understand neuron behavior is based on the Hodgkin-Huxley ion channel formulation (HH model). A major challenge with inferring parameters in HH models is non-uniqueness: many different sets of ion channel parameter values produce similar outputs for the same input stimulus. Such phenomena result in an objective function that exhibits multiple modes (i.e., multiple local minima). This non-uniqueness of local optimality poses challenges for parameter estimation with many algorithmic optimization techniques. HH models additionally have severe non-linearities resulting in further challenges for inferring parameters in an algorithmic fashion. To address these challenges with a tractable method in high-dimensional parameter spaces, we propose using a particular Markov chain Monte Carlo (MCMC) algorithm, which has the advantage of inferring parameters in a Bayesian framework. The Bayesian approach is designed to be suitable for multimodal solutions to inverse problems. We introduce and demonstrate the method using a three-channel HH model. We then focus on the inference of nine parameters in an eight-channel HH model, which we analyze in detail. We explore how the MCMC algorithm can uncover complex relationships between inferred parameters using five injected current levels. The MCMC method provides as a result a nine-dimensional posterior distribution, which we analyze visually with solution maps or landscapes of the possible parameter sets. The visualized solution maps show new complex structures of the multimodal posteriors, and they allow for selection of locally and globally optimal value sets, and they visually expose parameter sensitivities and regions of higher model robustness. We envision these solution maps as enabling experimentalists to improve the design of future experiments, increase scientific productivity and improve on model structure and ideation when the MCMC algorithm is applied to experimental data.

The effects of membrane potential oscillations on the excitability of rat hypoglossal motoneurons.

Oscillations in membrane potential induced by synaptic inputs and intrinsic ion channel activity play a role in regulating neuronal excitability, but the precise mechanisms underlying their contributions remain largely unknown. Here we used electrophysiological and modeling approaches to investigate the effects of Gaussian white noise injected currents on the membrane properties and discharge characteristics of hypoglossal (HG) motoneurons in P16-21 day old rats. We found that the noise-induced membrane potential oscillations facilitated spike initiation by hyperpolarizing the cells' voltage threshold by 3.1 ± 1.0 mV and reducing the recruitment current for the tonic discharges by 0.26 ± 0.1 nA, on average (n = 59). Further analysis revealed that the noise reduced both recruitment and decruitment currents by 0.26 ± 0.13 and 0.33 ± 0.1 nA, respectively, and prolonged the repetitive firing. The noise also increased the slopes of frequency-current (F-I) relationships by 1.1 ± 0.2 Hz/nA. To investigate the potential mechanisms underlying these findings, we constructed a series of HG motoneuron models based on their electrophysiological properties. The models consisted of five compartments endowed with transient sodium (NaT), delayed-rectify potassium [K(DR)], persistent sodium (NaP), calcium-activated potassium [K(AHP)], L-type calcium (CaL) and H-current channels. In general, all our experimental results could be well fitted by the models, however, a modification of standard Hodgkin-Huxley kinetics was required to reproduce the changes in the F-I relationships and the prolonged discharge firing. This modification, corresponding to the noise generated by the stochastic flicker of voltage-gated ion channels (channel flicker, CF), was an adjustable sinusoidal function added to kinetics of the channels that increased their sensitivity to subthreshold membrane potential oscillations. Models with CF added to NaP and CaL channels mimicked the noise-induced alterations of membrane properties, whereas models with CF added to NaT and K(DR) were particularly effective in reproducing the noise-induced changes for repetitive firing observed in the real motoneurons. Further analysis indicated that the modified channel kinetics enhanced NaP- and CaL-mediated inward currents thus increasing the excitability and output of HG motoneurons, whereas they produced relatively small changes in NaT and K(DR), thus balancing these two currents and triggering variability of repetitive firing. This study provided insight into the types of membrane channel mechanisms that might underlie oscillation-induced alterations of neuronal excitability and motor output in rat HG motoneurons.

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.

Axon initial segment geometry in relation to motoneuron excitability.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Discovery of a natural cyan blue: A unique food-sourced anthocyanin could replace synthetic brilliant blue.

The color of food is critical to the food and beverage industries, as it influences many properties beyond eye-pleasing visuals including flavor, safety, and nutritional value. Blue is one of the rarest colors in nature's food palette-especially a cyan blue-giving scientists few sources for natural blue food colorants. Finding a natural cyan blue dye equivalent to FD&C Blue No. 1 remains an industry-wide challenge and the subject of several research programs worldwide. Computational simulations and large-array spectroscopic techniques were used to determine the 3D chemical structure, color expression, and stability of this previously uncharacterized cyan blue anthocyanin-based colorant. Synthetic biology and computational protein design tools were leveraged to develop an enzymatic transformation of red cabbage anthocyanins into the desired anthocyanin. More broadly, this research demonstrates the power of a multidisciplinary strategy to solve a long-standing challenge in the food industry.

Nonlinear Input-Output Functions of Motoneurons.

All movements are generated by the activation of motoneurons, and hence their input-output properties define the final step in processing of all motor commands. A major challenge to understanding this transformation has been the striking nonlinear behavior of motoneurons conferred by the activation of persistent inward currents (PICs) mediated by their voltage-gated Na+ and Ca2+ channels. In this review, we focus on the contribution that these PICs make to motoneuronal discharge and how the nonlinearities they engender impede the construction of a comprehensive model of motor control.

Impact of parameter selection on estimates of motoneuron excitability using paired motor unit analysis.

OBJECTIVE: Noninvasive estimation of motoneuron excitability in human motoneurons is achieved through a paired motor unit analysis (ΔF) that quantifies hysteresis in the instantaneous firing rates at motor unit recruitment and de-recruitment. The ΔF technique provides insight into the magnitude of neuromodulatory synaptic input and persistent inward currents (PICs). While the ΔF technique is commonly used for estimating motoneuron excitability during voluntary contractions, computational parameters used for the technique vary across studies. A systematic investigation into the relationship between these parameters and ΔF values is necessary. APPROACH: We assessed the sensitivity of the ΔF technique with several criteria commonly used in selecting motor unit pairs for analysis and methods used for smoothing the instantaneous motor unit firing rates. Using high-density surface EMG and convolutive blind source separation, we obtained a large number of motor unit pairs (5409) from the triceps brachii of ten healthy individuals during triangular isometric contractions. MAIN RESULTS: We found an exponential plateau relationship between ΔF and the recruitment time difference between the motor unit pairs and an exponential decay relationship between ΔF and the de-recruitment time difference between the motor unit pairs, with the plateaus occurring at approximately 1 s and 1.5 s, respectively. Reduction or removal of the minimum threshold for rate-rate correlation of the two units did not affect ΔF values or variance. Removing motor unit pairs in which the firing rate of the control unit was saturated had no significant effect on ΔF. Smoothing the filter selection had no substantial effect on ΔF values and ΔF variance; however, filter selection affected the minimum recruitment and de-recruitment time differences. SIGNIFICANCE: Our results offer recommendations for standardized parameters for the ΔF approach and facilitate the interpretation of findings from studies that implement the ΔF analysis but use different computational parameters.

Robust and accurate decoding of motoneuron behaviour and prediction of the resulting force output.

KEY POINTS: The spinal alpha motoneuron is the only cell in the human CNS whose discharge can be routinely recorded in humans. We have reengineered motor unit collection and decomposition approaches, originally developed in humans, to measure the neural drive to muscle and estimate muscle force generation in the in vivo cat model. Experimental, computational, and predictive approaches are used to demonstrate the validity of this approach across a wide range of modes to activate the motor pool. The utility of this approach is shown through the ability to track individual motor units across trials, allowing for better predictions of muscle force than the electromyography signal, and providing insights in to the stereotypical discharge characteristics in response to synaptic activation of the motor pool. This approach now allows for a direct link between the intracellular data of single motoneurons, the discharge properties of motoneuron populations, and muscle force generation in the same preparation. ABSTRACT: The discharge of a spinal alpha motoneuron and the resulting contraction of its muscle fibres represents the functional quantum of the motor system. Recent advances in the recording and decomposition of the electromyographic signal allow for the identification of several tens of concurrently active motor units. These detailed population data provide the potential to achieve deep insights into the synaptic organization of motor commands. Yet most of our understanding of the synaptic input to motoneurons is derived from intracellular recordings in animal preparations. Thus, it is necessary to extend the new electrode and decomposition methods to recording of motor unit populations in these same preparations. To achieve this goal, we use high-density electrode arrays and decomposition techniques, analogous to those developed for humans, to record and decompose the activity of tens of concurrently active motor units in a hindlimb muscle in the in vivo cat. Our results showed that the decomposition method in this animal preparation was highly accurate, with conventional two-source validation providing rates of agreement equal to or superior to those found in humans. Multidimensional reconstruction of the motor unit action potential provides the ability to accurately track the same motor unit across multiple contractions. Additionally, correlational analyses demonstrate that the composite spike train provides better estimates of whole muscle force than conventional estimates obtained from the electromyographic signal. Lastly, stark differences are observed between the modes of activation, in particular tendon vibration produced quantal interspike intervals at integer multiples of the vibration period.

Increasing motor neuron excitability to treat weakness in sepsis.

OBJECTIVE: Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. To develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing. METHODS: Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing. RESULTS: Our results suggest alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a U.S. Food and Drug Administration-approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation. INTERPRETATION: Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients. Ann Neurol 2017;82:961-971.

The potential for understanding the synaptic organization of human motor commands via the firing patterns of motoneurons.

Motoneurons are unique in being the only neurons in the CNS whose firing patterns can be easily recorded in human subjects. This is because of the one-to-one relationship between the motoneuron and muscle cell behavior. It has long been appreciated that the connection of motoneurons to their muscle fibers allows their action potentials to be amplified and recorded, but only recently has it become possible to simultaneously record the firing pattern of many motoneurons via array electrodes placed on the skin. These firing patterns contain detailed information about the synaptic organization of motor commands to the motoneurons. This review focuses on parameters in these firing patterns that are directly linked to specific features of this organization. It is now well established that motor commands consist of three components, excitation, inhibition, and neuromodulation; the importance of the third component has become increasingly evident. Firing parameters linked to each of the three components are discussed, along with consideration of potential limitations in their utility for understanding the underlying organization of motor commands. Future work based on realistic computer simulations of motoneurons may allow quantitative "reverse engineering" of human motoneuron firing patterns to provide good estimates of the relative amplitudes and temporal patterns of all three components of motor commands.

Synaptic control of the shape of the motoneuron pool input-output function.

Although motoneurons have often been considered to be fairly linear transducers of synaptic input, recent evidence suggests that strong persistent inward currents (PICs) in motoneurons allow neuromodulatory and inhibitory synaptic inputs to induce large nonlinearities in the relation between the level of excitatory input and motor output. To try to estimate the possible extent of this nonlinearity, we developed a pool of model motoneurons designed to replicate the characteristics of motoneuron input-output properties measured in medial gastrocnemius motoneurons in the decerebrate cat with voltage-clamp and current-clamp techniques. We drove the model pool with a range of synaptic inputs consisting of various mixtures of excitation, inhibition, and neuromodulation. We then looked at the relation between excitatory drive and total pool output. Our results revealed that the PICs not only enhance gain but also induce a strong nonlinearity in the relation between the average firing rate of the motoneuron pool and the level of excitatory input. The relation between the total simulated force output and input was somewhat more linear because of higher force outputs in later-recruited units. We also found that the nonlinearity can be increased by increasing neuromodulatory input and/or balanced inhibitory input and minimized by a reciprocal, push-pull pattern of inhibition. We consider the possibility that a flexible input-output function may allow motor output to be tuned to match the widely varying demands of the normal motor repertoire.NEW & NOTEWORTHY Motoneuron activity is generally considered to reflect the level of excitatory drive. However, the activation of voltage-dependent intrinsic conductances can distort the relation between excitatory drive and the total output of a pool of motoneurons. Using a pool of realistic motoneuron models, we show that pool output can be a highly nonlinear function of synaptic input but linearity can be achieved through adjusting the time course of excitatory and inhibitory synaptic inputs.

Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis.

Contribution of intrinsic motoneuron properties to discharge hysteresis and its estimation based on paired motor unit recordings: a simulation study.

Motoneuron activity is strongly influenced by the activation of persistent inward currents (PICs) mediated by voltage-gated sodium and calcium channels. However, the amount of PIC contribution to the activation of human motoneurons can only be estimated indirectly. Simultaneous recordings of pairs of motor units have been used to provide an estimate of the PIC contribution by using the firing rate of the lower threshold unit to provide an estimate of the common synaptic drive to both units, and the difference in firing rate (ΔF) of this lower threshold unit at recruitment and de-recruitment of the higher threshold unit to estimate the PIC contribution to activation of the higher threshold unit. It has recently been suggested that a number of factors other than PIC can contribute to ΔF values, including mechanisms underlying spike frequency adaptation and spike threshold accommodation. In the present study, we used a set of compartmental models representing a sample of 20 motoneurons with a range of thresholds to investigate how several different intrinsic motoneuron properties can potentially contribute to variations in ΔF values. We drove the models with linearly increasing and decreasing noisy conductance commands of different rate of rise and duration and determined the influence of different intrinsic mechanisms on discharge hysteresis (the difference in excitatory drive at recruitment and de-recruitment) and ΔF. Our results indicate that, although other factors can contribute, variations in discharge hysteresis and ΔF values primarily reflect the contribution of dendritic PICs to motoneuron activation.

Soma size and Cav1.3 channel expression in vulnerable and resistant motoneuron populations of the SOD1G93A mouse model of ALS.

Although the loss of motoneurons is an undisputed feature of amyotrophic lateral sclerosis (ALS) in man and in its animal models (SOD1 mutant mice), how the disease affects the size and excitability of motoneurons prior to their degeneration is not well understood. This study was designed to test the hypothesis that motoneurons in mutant SOD1(G93A) mice exhibit an enlargement of soma size (i.e., cross-sectional area) and an increase in Cav1.3 channel expression at postnatal day 30, well before the manifestation of physiological symptoms that typically occur at p90 (Chiu et al. 1995). We made measurements of spinal and hypoglossal motoneurons vulnerable to degeneration, as well as motoneurons in the oculomotor nucleus that are resistant to degeneration. Overall, we found that the somata of motoneurons in male SOD1(G93A) mutants were larger than those in wild-type transgenic males. When females were included in the two groups, significance was lost. Expression levels of the Cav1.3 channels were not differentiated by genotype, sex, or any interaction of the two. These results raise the intriguing possibility of an interaction between male sex steroid hormones and the SOD1 mutation in the etiopathogenesis of ALS.

Modulation of motoneuron firing by recurrent inhibition in the adult rat in vivo.

Recent reports show that synaptic inhibition can modulate postsynaptic spike timing without having strong effects on firing rate. Thus synaptic inhibition can achieve multiplicity in neural circuit operation through variable modulation of postsynaptic firing rate vs. timing. We tested this possibility for recurrent inhibition (RI) of spinal motoneurons. In in vivo electrophysiological studies of adult Wistar rats anesthetized by isoflurane, we examined repetitive firing of individual lumbosacral motoneurons recorded in current clamp and modulated by synchronous antidromic electrical stimulation of multiple motor axons and their centrally projecting collateral branches. Antidromic stimulation produced recurrent inhibitory postsynaptic potentials (RIPSPs) having properties similar to those detailed in the cat. Although synchronous RI produced marked short-term modulation of motoneuron spike timing and instantaneous firing rate, there was little or no suppression of average firing rate. The bias in firing modulation of timing over average rate was observed even for high-frequency RI stimulation (100 Hz), perhaps because of the brevity of RIPSPs, which were more than twofold shorter during motoneuron firing compared with rest. These findings demonstrate that RI in the mammalian spinal cord has the capacity to support and not impede heightened motor pool activity, possibly during rapid, forceful movements.

Context-dependent coding in single neurons.

The linear-nonlinear cascade model (LN model) has proven very useful in representing a neural system's encoding properties, but has proven less successful in reproducing the firing patterns of individual neurons whose behavior is strongly dependent on prior firing history. While the cell's behavior can still usefully be considered as feature detection acting on a fluctuating input, some of the coding capacity of the cell is taken up by the increased firing rate due to a constant "driving" direct current (DC) stimulus. Furthermore, both the DC input and the post-spike refractory period generate regular firing, reducing the spike-timing entropy available for encoding time-varying fluctuations. In this paper, we address these issues, focusing on the example of motoneurons in which an afterhyperpolarization (AHP) current plays a dominant role regularizing firing behavior. We explore the accuracy and generalizability of several alternative models for single neurons under changes in DC and variance of the stimulus input. We use a motoneuron simulation to compare coding models in neurons with and without the AHP current. Finally, we quantify the tradeoff between instantaneously encoding information about fluctuations and about the DC.

Changes in motoneuron afterhyperpolarization duration in stroke survivors.

Hemispheric brain injury resulting from a stroke is often accompanied by muscle weakness in limbs contralateral to the lesion. In the present study, we investigated whether weakness in contralesional hand muscle in stroke survivors is partially attributable to alterations in motor unit activation, including alterations in firing rate modulation range. The afterhyperpolarization (AHP) potential of a motoneuron is a primary determinant of motoneuron firing rate. We examined differences in AHP duration in motoneurons innervating paretic and less impaired (contralateral) limb muscles of hemiparetic stroke survivors as well as in control subjects. A novel surface EMG (sEMG) electrode was used to record motor units from the first dorsal interosseous muscle. The sEMG data were subsequently decomposed to derive single-motor unit events, which were then utilized to produce interval (ISI) histograms of the motoneuron discharges. A modified version of interval death rate (IDR) analysis was used to estimate AHP duration. Results from data analyses performed on both arms of 11 stroke subjects and in 7 age-matched control subjects suggest that AHP duration is significantly longer for motor units innervating paretic muscle compared with units in contralateral muscles and in units of intact subjects. These results were supported by a coefficient of variation (CV) analysis showing that paretic motor unit discharges have a lower CV than either contralateral or control units. This study suggests that after stroke biophysical changes occur at the motoneuron level, potentially contributing to lower firing rates and potentially leading to less efficient force production in paretic muscles.

Reduced motoneuron excitability in a rat model of sepsis.

Many critically ill patients in intensive care units suffer from an infection-induced whole body inflammatory state known as sepsis, which causes severe weakness in patients who survive. The mechanisms by which sepsis triggers intensive care unit-acquired weakness (ICUAW) remain unclear. Currently, research into ICUAW is focused on dysfunction of the peripheral nervous system. During electromyographic studies of patients with ICUAW, we noticed that recruitment was limited to few motor units, which fired at low rates. The reduction in motor unit rate modulation suggested that functional impairment within the central nervous system contributes to ICUAW. To understand better the mechanism underlying reduced firing motor unit firing rates, we moved to the rat cecal ligation and puncture model of sepsis. In isoflurane-anesthetized rats, we studied the response of spinal motoneurons to injected current to determine their capacity for initiating and firing action potentials repetitively. Properties of single action potentials and passive membrane properties of motoneurons from septic rats were normal, suggesting excitability was normal. However, motoneurons exhibited striking dysfunction during repetitive firing. The sustained firing that underlies normal motor unit activity and smooth force generation was slower, more erratic, and often intermittent in septic rats. Our data are the first to suggest that reduced excitability of neurons within the central nervous system may contribute to ICUAW.