SMA is one of the most common neuromuscular disorders ocuring during childhood and is associated with a high morbidity and mortality [20]. It is characterized by degeneration of $\alpha$-MNs in the spinal cord and brainstem (other cell types are also affected; for details see Quinlan et al. 2019 [21]). Approximately 90–95% of SMA cases involve a group of autosomal-recessive disorders caused by loss-of-function mutations in the survival $\alpha$-MN 1 (SMN1) gene on 5q13 [22, 23]. Thus, the majority of SMA cases are caused by low levels, but not the complete absence, of the essential SMN protein. SMN1-associated SMA (5q-SMA) comes in various degress of severity and incidence: severe (type I) has the highest disease incidence, and milder forms including intermediate (type II) and mild (type III) SMA have the higher prevalence. SMA leads to progressive symmetrical muscle atrophy, weakness, and hypotonia, leading to the inability to sit, stand, or walk [24, 25, 26]. Therapy has advanced towards the development of drugs, such as nusinersen, onasemnogene abeparvovec, and risdiplam [20], which when applied presymptomatically, allow affected individuals to achieve normal motor abilities and most other age-based development [26]. Non-SMN1 SMA (or non-5q SMA) is a heterogeneous group of rare neuromuscular disorders associated with autosomal recessive and dominant, as well as X-linked recessive inheritance [22, 27].

Mouse models of SMA have led to deeper insights into the pathophysiology of MN degeneration [28]. However, the precise cellular and molecular mechanisms mediated by SMN deficiency are still unclear. SMA is not a MN autonomous disease [29]. Its’ pathology is not restricted to $\alpha$-MNs and dysfunction is more widespread, particularly within the brainstem and spinal circuits in which the $\alpha$-MNs are located. In a mutant SMN$\mathrm{\Delta }$7 mouse model, $\alpha$-MN degeneration leads to motor deficits, such as weakness and an inability to right themselves, and possible premature death around 2 weeks of age. Additionally, in this model the proximal muscles are more affected than the distal muscles, with the epaxial and hypaxial muscles being more severely weakened [14].

The vulnerability of $\alpha$-MNs and their synaptic connections is further evidenced by the fact that increasing the expression of SMN restricted to $\alpha$-MNs is sufficient to rescue $\alpha$-MN survival, maintain excitatory synapses from sensory afferents onto $\alpha$-MNs, and increase the lifespan in SMN$\mathrm{\Delta }$7 mice. In systemic SMN reduction, deficiencies in other cell types also contribute to SMA pathology (for a more extensive review, see Quinlan et al. 2019 [21]). SMA is likely a non-cell autonomous disease with a critical impact on MN degeneration when considering the pathophysiology of the disease, through the interaction of MNs and other cell types in the nervous system, particularly glial cells [29, 30, 31]. Different glial cells exhibit functions in maintaining MN integrity, including trophic support, minimization of excitotoxicity, synaptic remodeling, and immune surveillance.

ALS is a complex, multi-factorial neurodegenerative disease often associated with pathobiological features of fronto-temporal lobe dementia [36, 37]. About two thirds of patients have the spinal form of the disease, which initially manifests with arm or leg weakness (limb-onset) [38, 39]. Most of the remaining cases are bulbar-onset, which initially manifests with speech and swallowing problems. Most commonly, ALS starts at advanced age (up to 80 years), with a mean age of about 60 years at onset of sporadic disease and about 50 years in familial disease. It presents as progressive muscle weakness and atrophy leading to paralysis, loss of the dexterity, ability to move, talk, eat, breathe, and is often accompanied by spasticity (Sect 3) and pain. Death typically occurs within 3 to 5 years of disease onset [39, 40, 41, 42, 43, 44]. The term ‘lateral sclerosis’ refers to a hardening of the anterior and lateral spinal cord [45], indicating degeneration of mainly the cortico-spinal tract (CST) but also other tracts within antero-lateral spinal white matter [46, 47]. There are two broad classes of etiologies: familial (arround 5–10%) and sporadic (idiopathic). Familial ALS is related to mutations in specific causative genes (C9ORF72, SOD1, TARDBP, FUS, among others), which directly induce $\alpha$-MN degeneration, and sporadic ALS cases are considered to be secondary to the interactions between the individuals’ genetic risk, developmental factors, and environmental conditions [6, 43, 48, 49, 50, 51, 52].

Traditionally, as of the first description by Jean-Martin Charcot in 1869 [45], ALS was considered an $\alpha$-MN disorder characterized by the selective degeneration of upper and lower MNs [38]. More recently, views have changed such that ALS is now considered a multi-system disease in which degenerative pathology has also been detected in the cerebral cortex, cerebellum, basal ganglia, spino-cerebellar tracts, dorsal columns, serotonin-containing neurons in the raphé, noradrenergic neurons in the locus coeruleus, peripheral nervous system, neuromuscular junction, and other synapses, as well as gastrointestinal, autonomic, and vascular systems. This condition has an early and frequent impact on cognition, behavior, sleep, pain, and fatigue [19, 38, 43, 46, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62] (Fig. 1). There is also evidence of immune dysregulation in the pathogenesis of ALS [46, 63, 64, 65].

The underlying pathogenesis and pathophysiology of ALS are complex and incompletely understood, but probably affected by manifold genetic, epigenetic, developmental and environmental factors [37, 49, 50, 51, 52, 66, 67, 68, 69, 70] (Fig. 1).

Impairment of several crucial cellular pathways, such as gene-processing disorders, proteostasis, axonal transport impairments, hyperexcitability, excitotoxicity, or functional deficits of surrounding glial cell (with immunological and trophic consequences for the motoneuronal integrity), have been associated with degeneration of $\alpha$-MNs [31, 38, 46, 50, 54] (Fig. 1). In particular, energy homeostasis is compromised in patients with ALS, which has notable clinical implications such as weight loss, hypermetabolism, and hyperlipidaemia. More recently, alterations have been described in all the compounds of the neuro-vascular unit. In addition to MNs, considering the non-cell autonomous pathophysiology of ALS, other cells are considered determinants of ALS onset and progression, such as astrocytes, microglia, oligodendrocytes, Schwann cells, muscle cells, or as contributors, such as lymphocytes, pericytes, and interneurons [31, 38, 46, 54] (Fig. 1).

A number of animal models have been developed to study the genetic and molecular mechanisms of ALS [38, 49, 59, 71, 72, 73]. The first intraspinal changes in ALS appear to differ from those in SMA, at least in mouse models [13, 14]. There are several mouse models, but the one on which most work has been done is the superoxide dismutase SOD1-G93A model. In addition to G93A mutation of SOD1 gene, mice with other mutations of SOD1, such as G37R and G85R, are also commonly used, but to a lesser extent. The SOD1-G93A model survives up to 150 days, longer than the SMN$\mathrm{\Delta }$7 model of SMA. In transgenic mouse models of ALS (expressing mSOD1), PIC amplitudes are altered and may contribute to $\alpha$-MN dysfunction. Na${}^{+}$ PICs are increased and show a rapid recovery from fast inactivation, allowing $\alpha$-MNs to fire at higher rates [33].

A SCI is caused by a primary mechanical insult, e.g., acute compression, sharp injury, missile, laceration, shear etc. This is followed by a secondary injury, comprised of an acute, a sub-acute, and a chronic phase. The primary insult of SCI arises from the loss of directly damaged gray matter and neural pathways, as well as surrounding tissue damage. The acute phase, which occurs within the first 48 hours following primary injury, is associated with spinal ischemia, vasogenic edema, and glutamate excitotoxicity. The sub-acute phase, occuring within the first two weeks following primary injury, involves mitochondrial phosphorylation and neuro-inflammation. The chronic phase then extends from days to years and includes apoptosis, necrosis, acute axonal degeneration, and glia scar formation [106, 107].

At the cellular level, the following changes occur. Immediately after injury, dying neurons release death signals which exacerbate the injury. The immediate tissue damage activates the innate and adaptive immune response [106]. Monocyte-derived macrophages and activated microglia remove the debris from the initial primary insult [108] (Fig. 2). These immune cells remain after debris is removed and continue to release inflammatory cues that initiate secondary injury in areas rostral and caudal to the injury epicenter. Reactive astrocytes limit the spread of inflammation, compensate for a leaky blood-brain barrier, and reduce lesion expansion by forming a glial scar, which may also prevent axonal regeneration through the lesion [108] (Fig. 2). Evidence demonstrates astrocyte-release of growth-promoting factors, such as laminin, however the cumulative effect is detrimental to recovery. Other processes also contribute to the inability of damaged axons to regenerate after injury. Wallerian degeneration of the distal axons and myelin results in debris releasing Nogo (or Rtn4), myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp or Omg), which have all been shown to inhibit regeneration and sprouting. Collectively, these impediments limit the efficacy of spontaneous recovery following a SCI [109, 110].

The acute effect of a complete SCI in humans is a spinal shock in which neither locomotor nor spinal reflexes can be evoked. Muscles are paretic and flaccid [33, 111]. The main reason for spinal shock is the sudden loss of supraspinal influences on spinal networks; that is, the damage of CST glutamatergic signalling, as well as the loss of bulbo-spinal monoaminergic pathways and their powerful descending modulation of spinal excitability [34, 112].

In animals, spinal shock is associated with a dramatic reduction of extensor muscle tone and spinal reflexes, including postural limb reflexes (PLRs). One factor responsible for the reduced efficacy of spinal reflexes is a decrease in the excitability of spinal $\alpha$-MNs. Another factor is a decrease in the activity of most spinal interneurons, including PLR-related interneurons. For example, in decerebrate rabbits in which the head, vertebral column, and pelvis were rigidly fixed, anti-phase flexion/extension movements of the hindlimbs caused by roll tilts of a supporting platform elicited PLRs. Neurons in spinal segments L5–L6, which presumably contribute to the generation of PLRs, can be divided into three groups: F-interneurons activated during flexion of the ipsilateral limb, E-interneurons activated during extension of this limb, and a group of non-modulated interneurons. In decerebrate rabbits acutely spinalized at T12, postural functions were lost, including the disappearance of PLRs in response to roll perturbations of the supporting platform. The three interneuron groups named above reacted differently to spinalization. The proportion of non-modulated interneurons in spinalized rabbits was larger than in controls (33% vs. 18%). This was likely due to the fact that, after elimination of supraspinal drive, part of the modulated interneurons became non-modulated. Spinalization affected the distribution of F- and E-interneurons in segment L5 across the spinal gray matter, causing a significant decrease in their activity, as well as disturbances in processing of posture-related sensory inputs. The decrease in activity (mean frequency, burst frequency, and depth of modulation) of F- and E-interneurons could be caused by three factors: (1) a decrease in excitability of spinal interneurons; (2) a decrease in efficacy of sensory input from limb mechano-receptors; (3) a decrease in the value of sensory input due to a strong reduction in the forces developed by extensor muscles and monitored by load receptors, as well as due to inactivation of $\gamma$-MNs, leading to a decrease in signals from muscle spindles.

Spinalization affected the contribution of sensory inputs from the ipsilateral and contralateral limbs that modulate F- and E-interneurons. Thus, there was an almost two-fold increase in the proportion of interneurons modulated by sensory input from the ipsilateral limb and a corresponding decrease in the proportion of interneurons with input from the contralateral limb. This was caused by a significant reduction in the efficacy of tilt-related sensory inputs from the contralateral limb to both F- and E-interneurons across the entire gray matter. Most likely, commissural interneurons (CINs) transmitting signals from the contralateral limb are inactivated by acute spinalization. Spinalization differentially affected the efficacy of sensory inputs from the ipsilateral limb to F- and E-interneurons. These changes in the operation of postural networks underlied the loss of postural control after spinalization and represent a starting point for the development of spasticity [113].

After the initial spinal shock, locomotor activity and early spinal reflexes reappear in response to appropriate sensory input. In the subsequent 4–8 months, clinical signs of spasticity appear [111], but deficits in excitation of spinal ɑ-MNs by descending pathways remain and conrtibute to weakness. In incomplete SCI (iSCI), sensory afferent inputs may assume a disproportionately larger influence on volitional activation than in healthy adults, such as during volitional upper extremity tasks, standing, or stepping. After iSCI, specific changes contribute to spasticity, including changes in $\alpha$-MN excitability and sensitivity to serotonin (5-HT) (Sect 4.2.1), decreased reciprocal inhibition (Sect 4.3), recurrent inhibition (Sect 4.4), presynaptic inhibition (Sect 4.5), sprouting of descending (cortico-, bulbo-, and propriospinal) pathways, as well as alterations in interneuronal pattern-generating networks [114]. Beyond these spinal alterations, plasticity in sub-cortical networks and sensory-motor cortices develop, likely to partially compensate for muscle weakness due to loss of whole muscle and muscle fiber size (i.e., atrophy), alterations in fiber phenotype, and increased fatiguability [34].

In patients with iSCI, spinal excitability is increased during the performance of strong voluntary contractions compared to healthy participants with intact spinal cords. In healthy participants, maximal voluntary contractions (MVCs) that fatigue a muscle result in reduced volitional output, but the opposite is observed in SCI patients. In healthy participants, twenty repeated isometric MVCs of the knee extensors resulted in an immediate and sustained decline in peak torque production (~30–35% decrease), while individuals with iSCI produced increased peak torque and electromyographic (EMG) activity by the third contraction (15–20%). In SCI patients, these gains in muscle activation over repeated MVCs were partly due to increased central excitability during maximal contractions, consistent with the presence of PICs (Sect 2.2.1). Thus, in SCI patients, elevated reflex activity typically characterized as spasticity may boost motor performance during both static and dynamic tasks [34].

Spasticity is a long-term symptom of brain and spinal cord damage. It has tradidionally been defined as an augmented resistance of skeletal muscle at rest to passive stretch in a velocity-dependent manner. However, this definition is based on a fast and simple clinical test and not a comprehensive description of spasticty and its underlying mechanisms. In fact, the term spasticity is now mostly used in a wider sense [115].

Spasticity can occur in response to traumatic brain injury, stroke, cerebral palsy, multiple sclerosis (MS), ALS, and SCI [40, 107, 111, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126]. For simplicity, we will focus on SCI-related spasticity, with occasional discussion of stroke-related syndromes. Spasticity goes along with the following chronic symptoms.

Increased muscle tone (hypertonus) with muscle stiffness

Sustained involuntary muscle contractions

Hyperexcitable muscle stretch reflexes associated with velocity-dependent resistance to passive muscle stretch

Increase in short-latency stretch reflexes with enhanced tendon-tap reflexes

Clonus

Clasp-knife reflex

Loss of long-latency reflexes

Synkinesia: co-contraction of normally independently controlled muscles

Long-lasting exaggerated cutaneous reflexes (e.g., flexor or withdrawal reflexes)

Severe uncontrollable muscle spasms

Impaired voluntary activation of multiple muscles

Sensory disturbances such as enhanced abnormal sensation, dysesthesia and pain

Secondary changes in mechanical muscle-fiber properties, collagen tissue, and tendon properties (e.g., loss of sarcomeres, subclinical contractures)

Autonomic and immune dysfunctions

The specific syndromes differ depending on the cause. For example, unilateral stroke in the forebrain may leave various tracts descending to the spinal cord intact. In contrast, a SCI can damage one tract (in iSCI) or all tracts (in complete SCI), and can thus produce primary anatomical and pathophysiological changes and associated secondary changes including neurotoxicity, vascular dysfunction, glial scarring, neuro-inflammation, apoptosis, and demyelination [127]. The effects of SCI also depend on the species, completeness, extent and site of the lesion, and the clinical condition of the animal [33, 122, 128, 129]. One problem elucidating these processes is that they differ considerably between rodents, non-human primates, and humans [130].

Prominent chronic features after SCI are excessive spasms in extensor and flexor muscles with lesser expression of increased muscle tone [120]. This is the opposite pattern than what is observed following a stroke, indicating different underlying mechanisms [33, 107]. Some of these changes have formerly been considered maladaptive, particularly those leading to involuntary motor behaviors, such as spasticity, spasms, and clonus (Sect 4.1.1.2). However, animal models of iSCI and human studies suggest that increased spinal excitability underlying hyperexcitable reflexes may facilitate motor function, particularly when utilized during voluntary tasks [34].

It should be emphasised that the disruption of descending tracts also causes a number of autonomic abnormalities, including compromised cardiovascular, respiratory, urinary, gastro-intestinal, thermo-regulatory, and sexual activity. In brief, high thoracic or cervical SCI often causes life-threatening hemodynamics and respiratory dysfunction due to dysregulated sympathetic outflow, while parasympathetic (vagal) control remains intact. With injuries below the 5th thoracic segment, both sympathetic and parasympathetic control of the heart and broncho-pulmonary tree are intact [107, 119, 131, 132]. Moreover, SCI disrupts the neural and humoral control of immune cells. Autonomic dysfunction and impaired neuro-endocrine signalling are instrumental in determining ‘SCI-induced immune deficiency syndrome’, in which mature leukocyte dysfunction plays a sigificant role and the development and mobilization of immune cell precursors in bone marrow are impaired [133].

Without sensory feedback, there can be no upright stance or its maintenance. The important sensory inputs derive from a number of peripheral receptor systems. Here we concentrate on inputs processed at spinal level and their change after SCI. Covarrubias-Escudero et al. [134] used body-worn accelerometers positioned at L5 to measure characteristics of body sway, such as the amplitude, frequency, and smoothness, during quiet upright stance in patients with an iSCI. These patients presented with increased postural sway as measured by altered initial values of jerk (time derivative of acceleration) compared to healthy subjects. Although they were able to generate postural adaptations to environmental challenges, patients with iSCI could not fully compensate for the postural control changes caused by their sensory and motor impairments. It has been argued that iSCI patients might have increased postural sway consequent to deficient motor responses related to timing muscle contractions, which in turn would be the consequence of the diminished motor pathways, thus being insufficient to react and generate appropriate postural adjustments. Postural sway could also increase due to damaged somato-sensory pathways, which are often compromised following a SCI and subsequently reflect noisy somato-sensory feedback from foot pressure, muscle proprioceptors, and joint receptors. Damaged somato-sensory pathways could thus provide inaccurate information about body position in space. Together, these possible consequences of iSCI could generate frequent, abrupt corrections of postural sway direction and might be responsible for higher jerk values as compared to healthy subjects [134].

Due to partial muscle paralysis, iSCI patients tend to have atrophy and weakness in the ankle pantar-flexor muscles and consequently reduced standing balance. A potential compensatory strategy to reduce instability during quiet upright stance is to co-contract ankle plantar-flexor and dorsi-flexor muscles, which increases the ankle-joint stiffness and postural sway. These co-contractions may be a strategy used by older adults as well as subjects with iSCI to compensate for muscle weakness at the ankle joint and their upright posture. Indeed, an iSCI group exhibited more co-contractions than an able-bodied group, and postural sway was larger during ankle muscle co-contractions than during no co-contraction in the SCI-group. It has been hypothesized that the increased co-contraction in the SCI-group may be due to a switch from reciprocal inhibition (Sect 4.3) to facilitation. Both recurrent inhibition (Sect 4.4) and presynaptic inhibition (Sect 4.5) operate incorrectly after SCI which influences reciprocal inhibition. After SCI, reciprocal inhibition has been shown to be replaced with facilitation, which could increase co-contractions of ankle plantar- and flexor muscles [135].

During quiet standing, subjects with iSCI showed larger postural sway than healthy subjects, primarily due to larger ankle-joint acceleration. Also, while in healthy subjects the ankle- and hip-joint accelerations were in anti-phase to minimize the postural sway, this interjoint coordination was not affected in SCI patients, which could therefore not reduce the large center-of-mass (COM) accelerations [136].

In one study, patients with spasticity of different etiologies and degrees of severity, stood quietly upright on a force platform. The body sway measured was not correlated with muscle tone, muscle strength, tendon reflexes, plantar responses, or duration of the disease. On average, compared to healthy subjects, all patient groups showed a forward shift of the center of pressure (COP) under the feet. Moreover, paraparetic, and to a much larger extent hemiparetic patients, showed a lateral shift of COP. Sudden rotations of a supporting platform, in a toe-up or toe-down direction to stretch the soleus muscle or the tibialis anterior (TA) muscle, respectively, evoked short-latency (SLR) and medium-latency (MLR) reflex responses. Evoked SLR responses were assumed to be mediated by muscle-spindle group Ia afferents and MLR responses by group II afferents [137]. Compared to healthy controls, soleus SLR was increased in all patients. TA SLR was observed in both patients with ALS and paraparetic patients, but only rarely in healthy subjects and hemiparetic patients. By contrast, the MLRs of soleus and TA in the affected leg were diminished in hemiparetic patients, which could have contributed to increased body sway. These responses were decreased in size and not modulated by background EMG in the affected leg of hemiparetic patients, suggesting a disturbed control of spinal reflexes fed by spindle group II afferent fibers [138].

In post-stroke patients with spastic hemiparesis standing upright on a force platform, the COP under the feet was shifted toward the unaffected limb. This stance asymmetry could predict deficits in gait resulting from increased time and effort required to shift body weight toward the affected limb [139].

Thoracic SCI can negatively affect the ability to maintain unsupported sitting. Subjects with high- and low-thoracic SCI swayed more than did able-bodied controls regardless of upper-limb support. The level of injury was correlated with postural performance insofar as those with higher injuries swayed more and faster. Unsupported sitting was more unstable in comparison to supported sitting posture, especially in the anterior-posterior direction. The way subjects with high-thoracic SCI achieved stability was different from that of subjects with low-thoracic SCI, suggesting different postural regulation strategies [140]. Similar reductions in postural stabilty have been observed in subjects with motor-complete thoracic SCI who showed a trunk postural sway constraint to maintain suboptimal unsupported sitting balance [141]. In another study on seated subjects, the SCI group had greater COP sway than the controls, with no difference in the postural sway between the SCI subgroups, suggesting that the impairment in individuals with SCI resulted from disturbed supraspinal and peripheral mechanisms [142].

Many aspects of the specific pathophysiology of spasticity remain unclear. To elucidate the underlying mechanisms, various experimental animal models of spasticity have been developed. These animal models are categorized based on the mechanism of injury into contusion, compression, distraction, dislocation, transection or chemical models [143].

Locomotor rhythms can be generated by spinal central pattern generators (CPGs), which are autogenous in the sense that they do not depend on afferent sensory feedback (fictive locomotion) or spinally descending signals for their basic rhythm-generating function [149]. However, autonomy of the isolated spinal cord for generating locomotor rhythms is far greater in the spinalized rat or cat than in primates, including humans.

Spinal rhythm generation by CPGs require the coordinated activity of many neuron groups that organize the basic rhythmic spinal outputs as well as the spatio-temporal patterns of muscle activities, which must be capable of answering the varying demands of internal goals and the environment. The spatio-temporal patterns include flexion–extension alternation in intra-limb coordination and left–right coordination of different limbs. The underlying neuronal mechanisms have begun to be studied over the past few decades using anatomical, developmental, genetic, molecular, anatomical, and electrophysiological methods, particularly in mice [150, 151, 152, 153, 154, 155, 156, 157] and cats. CPGs most likely occur in humans but are much less undrstood than in mice and other mammals [158, 159, 160].

Sensory inputs have diverse roles in locomotion. Proprioceptive feedback reinforces ongoing motor output, shapes muscle activity, and contributes to timing the transitions between different locomotor step phases. They also play an important role in adjusting basic locomotor rhythm to environmental conditions and compensating for unexpected perturbations. Various sources of sensory feedback change throughout the gait cycle, and all known spinal reflex pathways are modulated during locomotion. These include stretch reflexes, H-reflexes (Sect 4.1), and presynaptic inhibition (Sect 4.5). Sensory information most appropriate for each step phase is gated by CPGs [149, 161, 162, 163, 164, 165]. Presynaptic inhibition is modulated by supraspinal centers and primary afferents in order to filter sensory information, adjust spinal reflex excitability, and ensure smooth movement [166, 167, 168, 169] (Sect 4.5). In SCI animal models and humans with SCI, sensory afferent feedback is important, if not critical, to the locomotor output. The influence of spastic motor behaviors on MN discharge and on different muscles suggests that the altered sensory input-motor output relationships could either facilitate or antagonize the intended motor command [34].

Reach-to-grasp movements to obtain or manipulate objects are synchronous and composed of several observable components, including limb lifting, aiming, and advancing the limb, followed by opening the digits, pronating the wrist, grasping the object, and supinating to orient the object for release. After incomplete or complete SCI at cervical level, this delicately organized sequence is disrupted or impossible, respectively. The consequences of iSCI depend on the site and degree of damage.

In humans, fine motor control of the digits is largely controlled by the descending lateral CST, which decussates and crosses midline at the pyramids in the brainstem, and then continues through the spinal dorso-lateral white matter. These lateral CST fibers synapse in cervical MN pools to control proximal and distal muscles of limbs and digits. The MN pools for the shoulder and arm are located at levels C4-6, and the MN pools of the forearm and digits are located at C7-T1. In addition to CST control in non-human primates, there is evidence of the involvement of descending rubro-spinal and reticulo-spinal tract (RST) fibers in controlling which upper extremity muscles execute the reach and grasp of a target object. Also, direct excitatory projections from the deep cerebellar nuclei to the ipsilateral cervical spinal cord appear to be involved in the control of the reach-to-grasp movement. Mice with silenced ipsilateral cerebello-spinal projection neurons took longer to touch the food pellet and failed to successfully grasp it. After SCI, recovery or compensatory reaching and grasping is mediated by several spared systems that respond after injury. Plasticity of primary sesosry afferent fibers also contribute to improved function post-injury [110].

Muscle stretch reflexes are more complicated than relatively simple tendon-tap responses of manually exerted stretches used by neurologists. They are also more complicated than the phasic H-reflex, which generates a short-latency EMG wave in response to electrical stimulation of group Ia muscle spindle afferents in the parent muscle nerve. After complete SCI, the amplitude of H-reflexes in hindlimb muscles is greatly increased but can be reduced by locomotor training [181].

Augmented stretch reflexes require the consideration of various neuronal networks. Several mechano-receptors and their afferents are involved (Fig. 3, Ref. [120]). For example, group Ia and II afferents from muscle spindles modulated by fusimotor control by $\gamma$-MNs and group Ib afferents from Golgi tendon organs (GTOs) responding particularly to active muscle contraction. Additionally, group III and IV muscle afferents responding in part to mechanical events in muscles (Sect 4.1.2), as well as their complex central connections to $\alpha$-MNs. Important special networks include reciprocal Ia inhibition (Sect 4.3), recurrent inhibition (Sect 4.4), presynaptic inhibition (Sect 4.5), group Ib connections (Sects 4.1.1.3, 4.1.2), and connections from group III and IV afferents (Sect 4.1.1.4; review: Windhorst 2021 [182]).

These spinal interneuronal networks are under modulatory influence from various, differentially connected descending tracts [182]. So, any impairment of these descending signals could be expected to derange and shift spinal network functions, including the muscle stretch reflex (Fig. 3). When discussing muscle stretch reflexes, it is important to note that the total mechanical response of a contracting muscle to a stretch is the sum of the response from the passive tissue, the response from the properties of the muscle fibers contracting prior to the stretch (intrinsic properties), and the response from the stretch reflex-mediated contraction of the muscle fibers [183].

$\alpha$-MNs receive multifarious direct or indirect inputs via excitatory recurrent axon collaterals (recurrent facilitation), recurrent inhibition via Renshaw cells (Sect 4.4), reciprocal Ia inhibitory interneurons (Sect 4.3), other spinal interneurons, proprio-spinal neurons, diverse sensory afferents, and several supraspinal structures (Fig. 3). The distribution patterns depend on the species, the muscles innervated (e.g., extensors vs. flexors), and their roles in posture and movement. The supraspinal structures include the cerebral cortex, cerebellum, vestibular nuclei, nucleus ruber, reticular formation, and neuromodulatory structures such as the locus coeruleus and raphé nuclei [182, 213]. Brain lesions may damage different combinations of descending tracts and thus create different pathological pictures.

In human spasticity, $\alpha$-MNs are hyper-excitable. This is indicated by various measures. For example, the latency of the reflex response of single motor unit discharge in the biceps brachii of stroke patients was systematically shorter in the spastic muscle compared to the contralateral muscle [214]. Also, motor units in the resting spastic-paretic biceps brachii muscle showed sustained spontaneous discharges, which increased after voluntary activation on the impaired side [215]. It was suggested that this could be attributed, at least in part, to low-level excitatory synaptic inputs to the resting $\alpha$-MN pool, possibly from regional or supraspinal centers, while less likely to an increase in PIC activation [216]. Nonetheless, in spastic-paretic biceps brachii muscles, the firing rates of motor units during voluntary contractions were abnormally low and their rate modulation was impaired by running into saturation despite increasing force [217].

Such changes may have anatomical causes. For example, after a SCI, the $\alpha$-MN somata and dendritic arbors are reduced, which may explain increases in cell input resistance and decreases in rheobase current, alterations in the input/output relationship and hyper-reflexia. Resting membrane potential and spike threshold may or may not depolarize. Voltage-gated ion channels dramatically change and so does $\alpha$-MN firing after SCI [122]. In part, these changes result from the reduction or complete loss of descending neuromodulation.

It has been shown extensively that spinal networks, such as reciprocal inhibition, recurrent inhibition (Sect 4.4), and presynaptic inhibition (Sect 4.5), are modulated by many descending and sensory inputs [182, 213, 227]. It is evident, therefore, that the operation of these networks are bound to change after the disruption of descending inputs following SCI and probably also by the modification of sensory inputs, for which there is experimental evidence (Fig. 3).

Reciprocal inhibition is important for regulating the actions of antagonist muscles at a joint. It is mediated by reciprocal Ia inhibitory interneurons which inhibit antagonist $\alpha$-MNs and receive their (partial) proprioceptive inputs from group Ia fibers whose inputs they share with agonist $\alpha$-MNs. Moreover, with their corresponding $\alpha$-MNs, these interneurons share many inputs from descending tracts and various sensory afferents [213].

Inhibition of hindlimb $\alpha$-MNs from the CST, rubro-spinal (RuST), reticulo-spinal (ReST), and vestibulo-spinal (VeST) tracts is largely mediated by reciprocal Ia inhibitory interneurons [199, 200, 213, 228, 229]. For example, activation of an extensor $\alpha$-MN pool by the VeST coincides with inhibition of the antagonist flexor $\alpha$-MNs by collaterals of extensor-activating tracts.

Reciprocal inhibition may contribute to adjust ankle-joint stiffness. For instance, when the soleus muscle is stretched, its autogenetic stretch reflex increases its stiffness. At the same time, the antagonist TA $\alpha$-MNs receive increased reciprocal inhibition and their muscle shortens, which reduces the reciprocal inhibition onto soleus and further increases its stiffness, and vice versa [182, 203, 210, 211, 230]. It is more complicated for co-contractions of antagonists. During co-contractions of TA and soleus, reciprocal Ia inhibition is modulated depending on the soleus/TA activity ratio [231].

Changes in reciprocal inhibition after SCI, mostly tested from TA $\alpha$-MNs to soleus $\alpha$-MNs, have been determined many times, and results depend on the site (caudal to rostral), type (contusion, rupture, tumor, section), and extent (complete, incomplete, to what degree) of the lesion. They have been reported as depression or elimination [124, 232, 233] or replacement with facilitation [234, 235, 236].

But if, after iSCI, reciprocal inhibition is replaced with facilitation [135, 235], how then does it change to precisely tune co-contraction for ankle stiffness? In other words: What are the mechanisms to adapt it to the new conditions?

During voluntary ankle dorsi-flexion movements in MS patients, reciprocal inhibition and presynaptic inhibition do not increase at movement onset, as is the case in healthy subjects, which may be responsible for the tendency to elicit unwanted stretch reflex activity and co-contraction of antagonistic muscles [237].

In healthy subjects, the stretch reflex increases during voluntary muscle contraction, which is attributed in part to the depression of inhibitory mechanisms. In spastic patients, these inhibitory mechanisms are depressed at rest and cannot be depressed any further. This depression may in part explain the occurrence of co-contraction in antagonist muscles. In most normal movements, antagonist muscles should remain silent and maximally relaxed. This is ensured by increasing transmission in several spinal inhibitory pathways. In spastic patients, this control is inadequate, and therefore stretch reflexes in antagonist muscles are easily evoked at the beginning of voluntary movements or in the transition from flexor to extensor muscle activity [238].

In healthy human subjects, the strength of reciprocal Ia inhibition between ankle flexor and extensor muscles can be temporarily increased by electrically stimulating, for 30 min, the common peroneal (CP) nerve with a patterned input (10 pulses at 100 pulses/s every 1.5 s; mimicking Ia afferent discharge during stepping), but not regular pattern at the same average rate (1 pulse every 150 ms). However, this effect is short-lived. Thus, the patterned stimulation induced, but did not maintain, plasticity. Various mechanisms have been suggested to underlie these observations. The glutamatergic group Ia afferent synapses on the reciprocal Ia inhibitory interneurons could be potentiated. Or the inhibitory synapses on $\alpha$-MNs could be potentiated. Alternatively, greater excitability of the reciprocal Ia inhibitory interneuron pool could recruit subliminal interneurons or ‘latent’ inhibitory connections [239].

In cats, spinal recurrent inhibition is mediated by Renshaw cells (RCs), which receive their most important excitatory input from $\alpha$-MNs (and some rarer and weaker effects from $\gamma$-MNs) and in turn inhibit $\alpha$-MNs, reciprocal Ia inhibitory interneurons, $\gamma$-MNs (weaker and rarer effects), other RCs and cells of origin of the ventral spino-cerebellar tract (VSCT) [165, 213, 240, 241, 242, 243, 244, 245, 246, 247].

Recurrent inhibition is further influenced by sensory afferents and signals descending from supraspinal sources, however it is still not well understood [182]. In cats, RCs receive modulating inputs from the motor cortex, cerebellum, nucleus ruber, reticular formation, and vestibular nuclei. These are in part independent of inputs of the same origin to $\alpha$-MNs [182].

Descending influences have also been investigated in humans. In healthy subjects, recurrent inhibition is modulated in various conditions, including stance, locomotion, and voluntary movements. For example, compared to upright stance supported by a wall, recurrent inhibition is enhanced in soleus muscle during unsupported free stance. This has been interpreted as a mechanism to diminish the reciprocal inhibition between antagonistic $\alpha$-MN pools to insure rapid alternating contractions of flexors and extensors for fast stance corrections. Recurrent inhibition is decreased during isolated voluntary plantar ankle flexion carried out by ankle extensor muscles, probably by descending inhibition of RCs. By contrast, recurrent inhibition is increased during co-contraction of plantar- and dorsi-flexors, which might diminish the gain of the stretch reflex and prevent it from falling into oscillations and clonus [227].

In about half of spastic patients, recurrent inhibition is not abnormal, irrespective of lesion site and origin, while in the rest, these factors influence changes in recurrent inhibition. In hemiplegic patients, recurrent inhibition at rest was increased compared to the unaffected side and to healthy subjects. In patients with progressive paraparesis (hereditary spastic paraparesis, ALS), recurrent inhibition was decreased when abnormal. In SCI patients, recurrent inhibition was often increased [227, 248]. In other studies, recurrent inhibition has been reported to change after SCI, but in different ways: increase [249], normal, reduced, or absent [248].

Changes of recurrent inhibition in spasticity are complicated, probably reflecting the different kinds of lesions. If the above results somewhat represent the operations of recurrent inhibition under natural conditions, their effects would not simply be mirrored by changes in reciprocal inhibition because the latter would be additionally determined by inputs other than recurrent inhibition.

Siembab et al. [250] argue that the competition of $\alpha$-MN axon synapses and group Ia afferent synapses on RCs is subtle and specific to VGLUT1 synapses (at central group Ia afferent terminals) and cholinergic VAChT synapses (at $\alpha$-MN axon terminals), but not VGLUT2 synapses (at other glutamatergic afferents). “One intriguing possibility is that the synaptic formation and maintenance of VGLUT1 and motor synapses involve competition for some critical, limited, RC-derived factor (that could be related to electrical activity or not) on which VGLUT2 synapses do not depend”. For example neuregulin-1, neuroligin-1 or gephyrin [250]. The functional rationale for these maturation processes and their underlying mechanisms need to be more fully explored, but they suggest that RCs might play a strong role in ontogenetic plasticity.

In neonatal mice, RCs receive monosynaptic proprioceptive inputs, likely group Ia, which subsequently lose weight because of increasing Renshaw cell dendritic growth [122, 250, 251, 252, 253]. One reason could be that different synaptic inputs on RCs compete. Strengthening of proprioceptive inputs reduces $\alpha$-MN axon synaptic density on RCs. Absent or diminished sensory afferent inputs correlate with increased densities of $\alpha$-MN axon synapses. In contrast, the normal developmental retraction of afferent inputs to RCs and $\alpha$-MNs does not occur after complete SCI, which leaves RCs with few collateral fibers from $\alpha$-MNs [254]. Also, increasing sensory activity with electrical stimulation induces axonal withdrawal and decreases connections of the CST onto $\alpha$-MNs and interneurons. Conversely, a decrease of sensory afferent activity by rhizotomy increases CST connections [255]. Hence, afferent stimulation affects the CST development, and CST stimulation affects the development of sensory afferent inputs [256], indicating that proprioceptive afferents and descending fibers compete for contribution to normal spinal circuitry formation [114, 122].

One hypothesis regarding the potential role of $\alpha$-MNs, their proprioceptive inputs, and interneurons including RCs in spinal motor learning has recently been put forward by Brownstone et al. [257]. They suggest that $\alpha$-MNs are controllers effecting muscle contractions and thus posture and movement. Group Ia afferents originating in muscle spindles and contacting $\alpha$-MNs monosynaptically provide ‘instructive’ feedback about the ongoing motor actions. RCs, fed by an efference copy of the $\alpha$-MNs’ outputs, generate a ‘predictive’ feedforward signal reflecting the expected sensory consequences. The instructive and predictive feedback signals are then compared at the level of $\alpha$-MNs that have a hybrid role in being the controllers as well as the comparators that compute a ‘sensory prediction error’ used to adapt system parameters. This arrangement could be regarded as a ‘fundamental learning module’, which “offer(s) the flexibility for both short-term adjustments, and a circuit in which plasticity can lead to long-term changes” [257]. An important point is the balance between the two types of $\alpha$-MN input, group Ia afferents and RCs. If this balance is disturbed, plastic processes should restore it. The model suggested by Brownstone et al. [257] employs supervised learning, as proposed by the authors in reference to cerebellar learning. This hypothesis is important in that it defines an instructive signal initiating the learning process, but the detailed mechanisms are not yet known.

Important progress has been made by targeting RCs by genetic modification. In mice, Enjin et al. [258] used the selective expression of the nicotinic cholinergic receptor2 (Chrna2) to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in RCs. Loss of VIAAT from Chrna2Cre-expressing RCs had the following consequences. In adult mice, the loss of VIAAT had no effect on grip strength, change in gait, or motor coordination. In neonatal mice, the loss of VIAAT did not alter drug-induced fictive locomotion. However, $\alpha$-MNs developed a lower input resistance and an increased number of proprioceptive glutamatergic and calbindin-labeled putative Renshaw cell synapses on their soma and proximal dendrites. Additionally, $\alpha$-MNs received spontaneous inhibitory synaptic input at a reduced frequency and RCs exhibited increased excitability despite receiving a normal number of cholinergic $\alpha$-MN synapses [258].

The above results suggest plastic compensation within the proprioceptive-$\alpha$-MN-Renshaw cell circuit. Surprisingly, the elimination of RCs output elicited distributed plastic changes in proprioceptive-$\alpha$-MN-Renshaw cell function. The precise mechanisms leading to the coordinated plastic changes have yet to be elucidated.

Spinal presynaptic inhibition provides a mechanism by which signal flow from segmental sensory afferents into the CNS may be modulated and regulated at the first central synapse. Presynaptic inhibition is produced predominantly by GABAergic interneurons acting on GABA${}_A$ receptors on primary sensory terminals [166, 167, 168]. GABAergic interneurons depolarize primary sensory afferents of all classes, which can be recorded in the dorsal root as primary afferent depolarizeation (PAD). Presynaptic inhibition shows complicated input-output patterns with a fair degree of functional differentiation that suggests the existence of several interneuronal sub-populations, in part with different locations. Presynaptic inhibition is modulated by a variety of descending and sensory systems. Proprioceptive afferents also regulate the level of their presynaptic GABAergic inhibitory input in an activity-dependent manner. This retrograde influence thus constitutes a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis [259].

Animal and human studies have shown that presynaptic inhibition can be set to different mean levels and modulated dynamically during rest, locomotion, and voluntary movement [149, 162]. For example, inhibition becomes weaker during voluntary contraction [260]. Also, synaptic transmission from group Ia muscle spindle afferents to $\alpha$-MNs is presynaptically inhibited more strongly during stance than rest, more strongly during locomotion than rest, and more strongly during running than walking [169, 261]. In humans, presynaptic inhibition of group Ia afferent terminals on $\alpha$-MNs of voluntarily contracting muscles is decreased, while presynaptic inhibition of group Ia fibers to $\alpha$-MNs of muscles not involved in the contraction is increased. Hence, the control of presynaptic inhibition of group la fibers at the onset of movement may be organized to help achieve selectivity of muscle activation [262].

The disruption of descending tracts should change the operation of presynaptic inhibition. It should be noted that, in humans, presynaptic inhibition suppresses different reflexes differently, where H-reflexes are suppressed strongly and stretch reflexes undergo little supression [263]. SCI has been suggested to lead to hyporeflexia during the ‘spinal shock’ because of an initial increase in the efficacy of presynaptic inhibition. Afterwards, over the time of chronification, presynaptic inhibition of ankle extensor group Ia input declines to levels less than those of control subjects, thereby contributing to enhance spinal reflexes, consistent with the clinical state of ‘spasticity’ [264]. Evidence for this comes from data obtained in paraplegics with bilateral spinal cord lesion sugesting that presynaptic inhibition of soleus group Ia terminals was decreased [1, 265]. More direct evidence for decreased presynaptic inhibition was found in decerebrate rats, in which chronic SCI decreased presynaptic inhibition of the plantar H-reflex through a reduction in primary afferent depolarization (PAD) evoked by stimulation of the posterior biceps-semitendinosus (PBSt) muscle group I afferents [266]. Thus, after SCI, the supraspinal control of interneurons mediating PAD is disengaged, which suggests an augmented role for sensory afferents.