Differential activating effects of thyrotropin-releasing hormone and its analog taltirelin on motor output to the tongue musculature in vivo

Thyrotropin-releasing hormone (TRH) is produced by the hypothalamus but most brain TRH is located elsewhere where it acts as a neuromodulator. TRH-positive neurons project to the hypoglossal motoneuron pool where TRH receptor RNA shows a high degree of differential expression compared with the rest of the brain. Strategies to modulate hypoglossal motor activity are of physiological and clinical interest given the potential for pharmacotherapy for obstructive sleep apnea (OSA), a common and serious respiratory disorder. Here, we identified the effects on tongue motor activity of TRH and a specific analog (taltirelin) applied locally to the hypoglossal motoneuron pool and systemically in vivo. Studies were performed under isoflurane anesthesia and across sleep–wake states in rats. In anesthetized rats, microperfusion of TRH (n = 8) or taltirelin (n = 9) into the hypoglossal motoneuron pool caused dose-dependent increases in tonic and phasic tongue motor activity (both p < 0.001). However, the motor responses to TRH were biphasic, being significantly larger “early” in the response versus at the end of the intervention (p ≤ 0.022). In contrast, responses to taltirelin were similar “early” versus “late” (p ≥ 0.107); i.e. once elicited, the motor responses to taltirelin were sustained and maintained. In freely behaving conscious rats (n = 10), microperfusion of 10 μM taltirelin into the hypoglossal motoneuron pool increased tonic and phasic tongue motor activity in non-rapid-eye-movement (REM) sleep (p ≤ 0.038). Intraperitoneal injection of taltirelin (1 mg/kg, n = 16 rats) also increased tonic tongue motor activity across sleep–wake states (p = 0.010). These findings inform the studies in humans to identify the potential beneficial effects of taltirelin for breathing during sleep and OSA.

Beta-band motor unit coherence and nonlinear surface EMG features of the first dorsal interosseous muscle vary with force

Motor unit firing times are weakly coupled across a range of frequencies during voluntary contractions. Coherent activity within the beta-band (15–35 Hz) has been linked to oscillatory cortical processes, providing evidence of functional connectivity between the motoneuron pool and motor cortex. The aim of this study was to investigate whether beta-band motor unit coherence is altered with increasing abduction force in the first dorsal interosseous muscle. Coherence between motor unit firing times, extracted from decomposed surface electromyography (EMG) signals, was investigated in 17 subjects at 10, 20, 30, and 40% of maximum voluntary contraction. Corresponding changes in nonlinear surface EMG features (specifically sample entropy and determinism, which are sensitive to motor unit synchronization) were also examined. A reduction in beta-band and alpha-band coherence was observed as force increased [ F(3, 151) = 32, P < 0.001 and F(3, 151) = 27, P < 0.001, respectively], accompanied by corresponding changes in nonlinear surface EMG features. A significant relationship between the nonlinear features and motor unit coherence was also detected ( r = −0.43 ± 0.1 and r = 0.45 ± 0.1 for sample entropy and determinism, respectively; both P < 0.001). The reduction in beta-band coherence suggests a change in the relative contribution of correlated and uncorrelated presynaptic inputs to the motoneuron pool, and/or a decrease in the responsiveness of the motoneuron pool to synchronous inputs at higher forces. The study highlights the importance of considering muscle activation when investigating changes in motor unit coherence or nonlinear EMG features and examines other factors that can influence coherence estimation. NEW & NOTEWORTHY Intramuscular alpha- and beta-band coherence decreased as muscle contraction force increased. Beta-band coherence was higher in groups of high-threshold motor units than in simultaneously active lower threshold units. Alterations in motor unit coherence with increases or decreases in force and with the onset of fatigue were accompanied by corresponding changes in surface electromyography sample entropy and determinism. Mixed-model analysis indicated mean firing rate and number of motor units also influenced the coherence estimate.

Reflex response to airway occlusion in human inspiratory muscles when recruited for breathing and posture

Briefly occluding the airway during inspiration produces a short-latency reflex inhibition in human inspiratory muscles. This occlusion reflex seems specific to respiratory muscles; however, it is not known whether the reflex inhibition has a uniform effect across a motoneuron pool when a muscle is recruited concurrently for breathing and posture. In this study, participants were seated and breathed through a mouthpiece that occluded inspiratory airflow for 250 ms at a volume threshold of 0.2 liters. The reflex response was measured in the scalene and sternocleidomastoid muscles during 1) a control condition with the head supported in space and the muscles recruited for breathing only, 2) a postural condition with the head unsupported and the neck flexors recruited for both breathing and to maintain head posture, and 3) a large-breath condition with the head supported and the volume threshold raised to between 0.8 and 1.0 liters to increase inspiratory muscle activity. When normalized to its preocclusion mean, the reflex response in the scalene muscles was not significantly different between the large-breath and control conditions, whereas concomitant recruitment of these muscles for posture control reduced the reflex response by half compared with the control condition. A reflex response occurred in sternocleidomastoid when it contracted phasically as an accessory muscle for inspiration during the large-breath condition. These results indicate that the occlusion reflex does not produce a uniform effect across the motoneuron pool and that afferent inputs for this reflex most likely act via intersegmental networks of premotoneurons rather than at a motoneuronal level. NEW & NOTEWORTHY In this study, we investigated the effect of nonrespiratory activity on the reflex response to brief sudden airway occlusions in human inspiratory muscles. We show that the reflex inhibition in the scalene muscles was not uniform across the motoneuron pool when the muscle was recruited concurrently for breathing and postural control. The reflex had a larger effect on respiratory-driven motoneurons than those recruited to maintain head posture.

Impact of the localization of dendritic calcium persistent inward current on the input-output properties of spinal motoneuron pool: a computational study

The goal of this study is to investigate how the dendritic Ca-PIC location influences nonlinear input-output properties and depends on the type of motoneurons across the motoneuron pool. A model motoneuron pool consisting of 10 motoneurons was constructed using a recently developed two-compartment modeling approach that reflected key cell type-associated properties experimentally identified. The dendritic excitability and firing output depended systematically on both the PIC location and the motoneuron type. The PIC onset and offset in the current-voltage ( I–V) relationship tended to occur at more hyperpolarized voltages as the path length to the PIC channels from the soma increased and as the cell type shifted from high- to low-threshold motoneurons. At the same time, the firing acceleration and frequency hysteresis in the frequency-current ( F–I) relationship became faster and larger, respectively. However, the PIC onset-offset hysteresis increased as the path length and the recruitment threshold increased. Furthermore, the gain of frequency-current function before full PIC activation was larger for PIC channels located over distal dendritic regions in low- compared with high-threshold motoneurons. When compared with previously published experimental observations, the modeling concurred when Ca-PIC channels were placed closer to the soma in high- than low-threshold motoneurons in the model motoneuron pool. All of these results suggest that the negative relationship of Ca-PIC location and cell recruitment threshold may underlie the systematic variation in I–V and F–I transformation across the motoneuron pool. NEW & NOTEWORTHY How does the dendritic location of calcium persistent inward current (Ca-PIC) influence dendritic excitability and firing behavior across the spinal motoneuron pool? This issue was investigated developing a model motoneuron pool that reflected key motoneuron type-specific properties experimentally identified. The simulation results point out the negative relationship between the distance of Ca-PIC source from the soma and cell recruitment threshold as a basis underlying the systematic variation in input-output properties of motoneurons over the motoneuron pool.

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.

The compensatory interaction between motor unit firing behavior and muscle force during fatigue

Throughout the literature, different observations of motor unit firing behavior during muscle fatigue have been reported and explained with varieties of conjectures. The disagreement amongst previous studies has resulted, in part, from the limited number of available motor units and from the misleading practice of grouping motor unit data across different subjects, contractions, and force levels. To establish a more clear understanding of motor unit control during fatigue, we investigated the firing behavior of motor units from the vastus lateralis muscle of individual subjects during a fatigue protocol of repeated voluntary constant force isometric contractions. Surface electromyographic decomposition technology provided the firings of 1,890 motor unit firing trains. These data revealed that to sustain the contraction force as the muscle fatigued, the following occurred: 1) motor unit firing rates increased; 2) new motor units were recruited; and 3) motor unit recruitment thresholds decreased. Although the degree of these adaptations was subject specific, the behavior was consistent in all subjects. When we compared our empirical observations with those obtained from simulation, we found that the fatigue-induced changes in motor unit firing behavior can be explained by increasing excitation to the motoneuron pool that compensates for the fatigue-induced decrease in muscle force twitch reported in empirical studies. Yet, the fundamental motor unit control scheme remains invariant throughout the development of fatigue. These findings indicate that the central nervous system regulates motor unit firing behavior by adjusting the operating point of the excitation to the motoneuron pool to sustain the contraction force as the muscle fatigues.