ERR2 and ERR3 promote the development of gamma motor neuron functional properties required for proprioceptive movement control.

The ability of terrestrial vertebrates to effectively move on land is integrally linked to the diversification of motor neurons into types that generate muscle force (alpha motor neurons) and types that modulate muscle proprioception, a task that in mammals is chiefly mediated by gamma motor neurons. The diversification of motor neurons into alpha and gamma types and their respective contributions to movement control have been firmly established in the past 7 decades, while recent studies identified gene expression signatures linked to both motor neuron types. However, the mechanisms that promote the specification of gamma motor neurons and/or their unique properties remained unaddressed. Here, we found that upon selective loss of the orphan nuclear receptors ERR2 and ERR3 (also known as ERRß, ERRγ or NR3B2, NR3B3, respectively) in motor neurons in mice, morphologically distinguishable gamma motor neurons are generated but do not acquire characteristic functional properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements. Complementary gain-of-function experiments in chick suggest that ERR2 and ERR3 could operate via transcriptional activation of neural activity modulators to promote a gamma motor neuron biophysical signature of low firing thresholds and high firing rates. Our work identifies a mechanism specifying gamma motor neuron functional properties essential for the regulation of proprioceptive movement control.

Human muscle spindles are wired to function as controllable signal-processing devices.

Muscle spindles are encapsulated sensory organs found in most of our muscles. Prevalent models of sensorimotor control assume the role of spindles is to reliably encode limb posture and movement. Here, I argue that the traditional view of spindles is outdated. Spindle organs can be tuned by spinal γ motor neurons that receive top-down and peripheral input, including from cutaneous afferents. A new model is presented, viewing γ motor activity as an intermediate coordinate transformation that allows multimodal information to converge on spindles, creating flexible coordinate representations at the level of the peripheral nervous system. That is, I propose that spindles play a unique overarching role in the nervous system: that of a peripheral signal-processing device that flexibly facilitates sensorimotor performance, according to task characteristics. This role is compatible with previous findings and supported by recent studies with naturalistically active humans. Such studies have so far shown that spindle tuning enables the independent preparatory control of reflex muscle stiffness, the selective extraction of information during implicit motor adaptation, and for segmental stretch reflexes to operate in joint space. Incorporation of advanced signal-processing at the periphery may well prove a critical step in the evolution of sensorimotor control theories.

Secondary endings of muscle spindles: Structure, reflex action, role in motor control and proprioception.

NEW FINDINGS: What is the topic of this review? We describe the structure and function of secondary sensory endings of muscle spindles, their reflex action and role in motor control and proprioception. What advances does it highlight? In most mammalian skeletal muscles, secondary endings of spindles are more or much more numerous than primary endings but are much less well studied. By focusing on secondary endings in this review, we aim to redress the balance, draw attention to what is not known and stimulate future research. ABSTRACT: Kinaesthesia and the control of bodily movement rely heavily on the sensory input from muscle spindles. Hundreds of these sensory structures are embedded in mammalian muscles. Each spindle has one or more sensory endings and its own complement of small muscle fibres that are activated by the CNS via fusimotor neurons, providing efferent control of sensory responses. Exactly how the CNS wields this influence remains the subject of much fascination and debate. There are two types of sensory endings, primary and secondary, with differing development, morphology, distribution and responsiveness. Spindle primary endings have received more attention than secondaries, although the latter usually outnumber them. This review focuses on the secondary endings. Their location within the spindle, their response properties, the projection of their afferents within the CNS and their reflex actions all suggest that secondaries have certain separate roles from the primaries in proprioception and motor control. Specifically, spindle secondaries seem more adapted than primaries to signalling slow and maintained changes in the relative position of bodily segments, thereby contributing to position sense, postural control and static limb positioning. By highlighting, in this way, the roles of secondary endings, a final aim of the review is to broaden understanding of muscle spindles more generally and of the important contributions they make to both sensory and motor mechanisms.

Feedforward modulation of gamma motor neuron activity can improve motor command accuracy.

Objective. Coactivation of gamma and alpha motor neuron activity ensures that muscle spindle responsiveness is maintained during muscle contractions. However, some evidence suggests that the activity of gamma motor neurons is phase-advanced with respect to that of alpha motor neurons during manual control tasks. We hypothesized that this might be a deliberate control strategy to maximize movement accuracy.Approach. Using a computational model of the neural activation of a muscle and its type Ia sensory feedback to the motor neurons, we systematically investigated the impact of the phase difference between oscillatory descending input to alpha and dynamic gamma motor neurons. Specifically, the amplification of the alpha motor neuron drive to the muscle was investigated as a function of the frequency of the synaptic input (1-9 Hz individually or superimposed) and the alpha-gamma phase difference (0-2π).Main results. Simulation results showed that when the phase advance of the dynamic gamma drive resulted in delays between muscle velocity and type Ia afferent feedback similar to those previously observed experimentally, low-frequency components (1 and 2 Hz) of the motor neuron synaptic input were amplified (gain up to 1.7). On the other hand, synaptic input at higher frequencies was unaffected.Significance. This finding suggests that by imposing a phase advance of the input to dynamic gamma motor neurons, components of the neural drive usually associated with voluntary control are amplified. In this way, our study suggests that this neural strategy increases the control-to-neural-noise ratio of the motor output during movement.

Frequency-dependent deficits in head steadiness in patients with nonspecific neck pain.

Motor control impairments are reported in patients with nonspecific neck pain but the particular deficits in underlying regulatory systems are not known. Head steadiness is controlled both by voluntary and reflex systems that are predominantly effective within different frequency intervals. The aim of the present study was to investigate within which frequency range(s) potential motor control deficits may reside. The ability to keep the head stationary in space in response to unpredictable perturbations was tested in 71 patients with nonspecific neck pain and 17 healthy controls. Participants were exposed to pseudorandom horizontal rotations across 10 superimposed frequencies (0.185-4.115 Hz) by means of an actuated chair in three conditions; with a visual reference, and without vision with, and without a cognitive task. Below 1 Hz, patients kept the head less stable in space compared to healthy controls. Between 1 and 2 Hz, the head was stabilized on the trunk in both groups. Patients kept the head more stable relative to the trunk than relative to space compared to healthy controls. This was interpreted as higher general neck muscle co-activation in patients, which may be explained by altered voluntary control, or/and upregulated gamma motor neuron activity which increases the contribution of reflex-mediated muscle activation. Alternatively, increased muscle activity is secondary to vestibular deficits.

Sympathetic Discharges in intercostal and abdominal nerves.

There are hardly any published data on the characteristics of muscle nerve sympathetic discharges occurring in parallel with the somatic motoneurone discharges in the same nerves. Here, we take advantage of the naturally occurring respiratory activity in recordings of efferent discharges from branches of the intercostal and abdominal nerves in anesthetized cats to make this comparison. The occurrence of efferent spikes with amplitudes below that for alpha motoneurones were analyzed for cardiac modulation, using cross-correlation between the times of the R-wave of the ECG and the efferent spikes. The modulation was observed in nearly all recordings, and for all categories of nerves. It was strongest for the smallest amplitude spikes or spike-like waveforms, which were deduced to comprise postsynaptic sympathetic discharges. New observations were: (1) that the cardiac modulation of these discharges was modest compared to most previous reports for muscle nerves; (2) that the amplitudes of the sympathetic discharges compared to those of the somatic spikes were strongly positively correlated to nerve diameter, such that, for the larger nerves, their amplitudes overlapped considerably with those of gamma motoneurone spikes. This could be explained by random summation of high rates of unit sympathetic spikes. We suggest that under some experimental circumstances this overlap could lead to considerable ambiguity in the identity of the discharges in efferent neurograms.

Functional properties of human muscle spindles.

Muscle spindles are ubiquitous encapsulated mechanoreceptors found in most mammalian muscles. There are two types of endings, primary and secondary, and both are sensitive to changes in muscle length and velocity, with the primary endings having a greater dynamic sensitivity. Unlike other mechanoreceptors in the somatosensory system, muscle spindles are unique in possessing motor innervation, via γ-motoneurons (fusimotor neurons), that control their sensitivity to stretch. Much of what we know about human muscles spindles comes from studying the behavior of their afferents via intraneural microelectrodes (microneurography) inserted into accessible peripheral nerves. We review the functional properties of human muscle spindles, comparing and contrasting with what we know about the functions of muscle spindles studied in experimental animals. As in the cat, many human muscle spindles possess a background discharge that is related to the degree of muscle stretch, but mean firing rates are much lower (~10 Hz). They can faithfully encode changes in muscle fascicle length in passive conditions, but higher level extraction of information is required by the central nervous system to measure changes in muscle length during muscle contraction. Moreover, although there is some evidence supporting independent control of human muscle spindles via fusimotor neurons, any effects are modest compared with the clearly independent control of fusimotor neurons observed in the cat.

Physiological tremor increases when skeletal muscle is shortened: implications for fusimotor control.

KEY POINTS: In tonic, isometric, plantarflexion contractions, physiological tremor increases as the ankle joint becomes plantarflexed. Modulation of physiological tremor as a function of muscle stretch differs from that of the stretch reflex amplitude. Amplitude of physiological tremor may be altered as a function of reflex pathway gains. Healthy humans likely increase their γ-static fusimotor drive when muscles shorten. Quantification of physiological tremor by manipulation of joint angle may be a useful experimental probe of afferent gains and/or the integrity of automatic fusimotor control. ABSTRACT: The involuntary force fluctuations associated with physiological (as distinct from pathological) tremor are an unavoidable component of human motor control. While the origins of physiological tremor are known to depend on muscle afferentation, it is possible that the mechanical properties of muscle-tendon systems also affect its generation, amplification and maintenance. In this paper, we investigated the dependence of physiological tremor on muscle length in healthy individuals. We measured physiological tremor during tonic, isometric plantarflexion torque at 30% of maximum at three ankle angles. The amplitude of physiological tremor increased as calf muscles shortened in contrast to the stretch reflex whose amplitude decreases as muscle shortens. We used a published closed-loop simulation model of afferented muscle to explore the mechanisms responsible for this behaviour. We demonstrate that changing muscle lengths does not suffice to explain our experimental findings. Rather, the model consistently required the modulation of  Î³-static fusimotor drive to produce increases in physiological tremor with muscle shortening - while successfully replicating the concomitant reduction in stretch reflex amplitude. This need to control γ-static fusimotor drive explicitly as a function of muscle length has important implications. First, it permits the amplitudes of physiological tremor and stretch reflex to be decoupled. Second, it postulates neuromechanical interactions that require length-dependent γ drive modulation to be independent from α drive to the parent muscle. Lastly, it suggests that physiological tremor can be used as a simple, non-invasive measure of the afferent mechanisms underlying healthy motor function, and their disruption in neurological conditions.

Neuromorphic meets neuromechanics, part II: the role of fusimotor drive.

OBJECTIVE: We studied the fundamentals of muscle afferentation by building a Neuro-mechano-morphic system actuating a cadaveric finger. This system is a faithful implementation of the stretch reflex circuitry. It allowed the systematic exploration of the effects of different fusimotor drives to the muscle spindle on the closed-loop stretch reflex response. APPROACH: As in Part I of this work, sensory neurons conveyed proprioceptive information from muscle spindles (with static and dynamic fusimotor drive) to populations of α-motor neurons (with recruitment and rate coding properties). The motor commands were transformed into tendon forces by a Hill-type muscle model (with activation-contraction dynamics) via brushless DC motors. Two independent afferented muscles emulated the forces of flexor digitorum profundus and the extensor indicis proprius muscles, forming an antagonist pair at the metacarpophalangeal joint of a cadaveric index finger. We measured the physical response to repetitions of bi-directional ramp-and-hold rotational perturbations for 81 combinations of static and dynamic fusimotor drives, across four ramp velocities, and three levels of constant cortical drive to the α-motor neuron pool. MAIN RESULTS: We found that this system produced responses compatible with the physiological literature. Fusimotor and cortical drives had nonlinear effects on the reflex forces. In particular, only cortical drive affected the sensitivity of reflex forces to static fusimotor drive. In contrast, both static fusimotor and cortical drives reduced the sensitivity to dynamic fusimotor drive. Interestingly, realistic signal-dependent motor noise emerged naturally in our system without having been explicitly modeled. SIGNIFICANCE: We demonstrate that these fundamental features of spinal afferentation sufficed to produce muscle function. As such, our Neuro-mechano-morphic system is a viable platform to study the spinal mechanisms for healthy muscle function-and its pathologies such as dystonia and spasticity. In addition, it is a working prototype of a robust biomorphic controller for compliant robotic limbs and exoskeletons.

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS.

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.

The vestibular system does not modulate fusimotor drive to muscle spindles in relaxed leg muscles of subjects in a near-vertical position.

It has been shown that sinusoidal galvanic vestibular stimulation (sGVS) has no effect on the firing of spontaneously active muscle spindles in either relaxed or voluntarily contracting human leg muscles. However, all previous studies have been conducted on subjects in a seated position. Given that independent vestibular control of muscle spindle firing would be more valuable during postural threat, we tested the hypothesis that this modulation would become apparent for subjects in a near-vertical position. Unitary recordings were made from 18 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of awake human subjects laying supine on a motorized tilt table. All recorded spindle afferents were spontaneously active at rest, and each increased its firing rate during a weak static contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (±2 mA, 100 cycles) was applied to the mastoid processes at 0.8 Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock." The subject was then moved into a near-vertical position (75°), and the stimulation repeated. Despite robust vestibular illusions, none of the fusimotor-driven spindles exhibited phase-locked modulation of firing during sinusoidal GVS in either position. We conclude that this dynamic vestibular stimulus was insufficient to modulate the firing of fusimotor neurons in the near-vertical position. However, this does not mean that the vestibular system cannot modulate the sensitivity of muscle spindles via fusimotor neurons in free unsupported standing, when reliance on proprioceptive feedback is higher.

Modulation of gamma and alpha spinal motor neurons activity by trans-spinal direct current stimulation: effects on reflexive actions and locomotor activity.

Spontaneous and evoked spinal activities interact to set the characteristics of emergent motor responses. Gamma motor neurons have feedforward and feedback functions in motor control, which are crucial for transforming motor commands into action. Meanwhile, the intrinsic excitability and functional connectivity of alpha motor neurons determine the accuracy of actions. In this study, we investigated the effects of trans-spinal direct current stimulation (tsDCS) on spontaneous and cortically evoked activity of well-isolated single units of gamma and alpha motor neurons in mice. We also investigated the effects of tsDCS on reflexive and locomotor actions. In general, motor neurons showed increased responses to cathodal tsDCS (c-tsDCS) and decreased responses to anodal tsDCS (a-tsDCS). These effects were observed for cortically evoked discharges and spontaneous firing rates of gamma motor neurons, cortically evoked discharges of larger alpha motor neurons, and spontaneous firing rates of smaller alpha motor neurons. An exception was that spontaneous firing rates of larger alpha motor neurons showed the opposite pattern of reduction by c-tsDCS and increase by a-tsDCS. Reflexive and voluntary behavior were also increased by c-tsDCS and reduced by a-tsDCS. Specifically, the amplitude and duration of crossed and tail pinch reflexes in decerebrate animals and the quality of ground and treadmill walking patterns in healthy awake animals showed this pattern. These polarity-specific changes in behavior could be attributed to polarity-mediated modulation of alpha and gamma motor neuron activity and spinal circuitry. The results reveal an important principle: effects of tsDCS on spinal motor neurons depend on current polarity and cell size.

Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

[The evaluation of hyperkineses in hepatocerebral dystrophy (Wilson-Konovalov disease) from the position of the theory of muscle spindles].

OBJECTIVE: To obtain evidence for the possibility of considering hyperkineses in hepatocerebtal dystrophy from the position of the theory of muscle spindles. MATERIAL AND METHODS: We examined 27 patients: rigid-arrhythmic-hyperkinetic form was diagnosed in 2 patients, trembling-rigid in 8, trembling in 16 and extrapyramidal-cortical in 1. Electromyography of different muscles in resting state and functional loadings taking into account surgical intervention was the main method of the study. RESULTS AND CONCLUSION: An analysis of electrophysiological results based on hyperkinesis variant (torsion dystonic, choreoathetoid etc) revealed a role of the striatal pallidal system in the anomalous control of static and dynamic γ-motorneurons and involvement of spinal reflexes in forced movements. This hypothesis may help to deeply understand the genesis of extrapyramidal dyskinesia and more reasonably select a stereotaxic target in surgical treatment.

On the distribution of information from muscle spindles in the spinal cord; how much does it depend on random factors?

Information forwarded by individual muscle spindles is modulated by the dynamic and static gamma motoneurons in a differentiated way, depending on the coupling between the fusimotor neurons and the various intrafusal muscle fibres. Further modulation of this information at the level of spinal neurons is also differentiated because connections between individual muscle spindles and their spinal target cells are quite variable. This review illustrates this variability with respect to the spinal trajectory of muscle spindle primary afferents and the distribution of their synaptic contacts on motoneurons and other spinal neurons. It also discusses some of the consequences of this variability for the processing of information from proprioceptors.

Muscle spindle and fusimotor activity in locomotion.

Mammals may exhibit different forms of locomotion even within a species. A particular form of locomotion (e.g. walk, run, bound) appears to be selected by supraspinal commands, but the precise pattern, i.e. phasing of limbs and muscles, is generated within the spinal cord by so-called central pattern generators. Peripheral sense organs, particularly the muscle spindle, play a crucial role in modulating the central pattern generator output. In turn, the feedback from muscle spindles is itself modulated by static and dynamic fusimotor (gamma) neurons. The activity of muscle spindle afferents and fusimotor neurons during locomotion in the cat is reviewed here. There is evidence for some alpha-gamma co-activation during locomotion involving static gamma motoneurons. However, both static and dynamic gamma motoneurons show patterns of modulation that are distinct from alpha motoneuron activity. It has been proposed that static gamma activity may drive muscle spindle secondary endings to signal the intended movement to the central nervous system. Dynamic gamma motoneuron drive appears to prime muscle spindle primary endings to signal transitions in phase of the locomotor cycle. These findings come largely from reduced animal preparations (decerebrate) and require confirmation in freely moving intact animals.