Motor learning changes the axon initial segment of the spinal motoneuron.

We are studying the mechanisms of H-reflex operant conditioning, a simple form of learning. Modelling studies in the literature and our previous data suggested that changes in the axon initial segment (AIS) might contribute. To explore this, we used blinded quantitative histological and immunohistochemical methods to study in adult rats the impact of H-reflex conditioning on the AIS of the spinal motoneuron that produces the reflex. Successful, but not unsuccessful, H-reflex up-conditioning was associated with greater AIS length and distance from soma; greater length correlated with greater H-reflex increase. Modelling studies in the literature suggest that these increases may increase motoneuron excitability, supporting the hypothesis that they may contribute to H-reflex increase. Up-conditioning did not affect AIS ankyrin G (AnkG) immunoreactivity (IR), p-p38 protein kinase IR, or GABAergic terminals. Successful, but not unsuccessful, H-reflex down-conditioning was associated with more GABAergic terminals on the AIS, weaker AnkG-IR, and stronger p-p38-IR. More GABAergic terminals and weaker AnkG-IR correlated with greater H-reflex decrease. These changes might potentially contribute to the positive shift in motoneuron firing threshold underlying H-reflex decrease; they are consistent with modelling suggesting that sodium channel change may be responsible. H-reflex down-conditioning did not affect AIS dimensions. This evidence that AIS plasticity is associated with and might contribute to H-reflex conditioning adds to evidence that motor learning involves both spinal and brain plasticity, and both neuronal and synaptic plasticity. AIS properties of spinal motoneurons are likely to reflect the combined influence of all the motor skills that share these motoneurons. KEY POINTS: Neuronal action potentials normally begin in the axon initial segment (AIS). AIS plasticity affects neuronal excitability in development and disease. Whether it does so in learning is unknown. Operant conditioning of a spinal reflex, a simple learning model, changes the rat spinal motoneuron AIS. Successful, but not unsuccessful, H-reflex up-conditioning is associated with greater AIS length and distance from soma. Successful, but not unsuccessful, down-conditioning is associated with more AIS GABAergic terminals, less ankyrin G, and more p-p38 protein kinase. The associations between AIS plasticity and successful H-reflex conditioning are consistent with those between AIS plasticity and functional changes in development and disease, and with those predicted by modelling studies in the literature. Motor learning changes neurons and synapses in spinal cord and brain. Because spinal motoneurons are the final common pathway for behaviour, their AIS properties probably reflect the combined impact of all the behaviours that use these motoneurons.

Effects of active and sham tDCS on the soleus H-reflex during standing.

Weak transcranial direct current stimulation (tDCS) is known to affect corticospinal excitability and enhance motor skill acquisition, whereas its effects on spinal reflexes in actively contracting muscles are yet to be established. Thus, in this study, we examined the acute effects of Active and Sham tDCS on the soleus H-reflex during standing. In fourteen adults without known neurological conditions, the soleus H-reflex was repeatedly elicited at just above M-wave threshold throughout 30 min of Active (N = 7) or Sham (N = 7) 2-mA tDCS over the primary motor cortex in standing. The maximum H-reflex (Hmax) and M-wave (Mmax) were also measured before and immediately after 30 min of tDCS. The soleus H-reflex amplitudes became significantly larger (by 6%) ≈1 min into Active or Sham tDCS and gradually returned toward the pre-tDCS values, on average, within 15 min. With Active tDCS, the amplitude reduction from the initial increase appeared to occur more swiftly than with Sham tDCS. An acute temporary increase in the soleus H-reflex amplitude within the first minute of Active and Sham tDCS found in this study indicates a previously unreported effect of tDCS on the H-reflex excitability. The present study suggests that neurophysiological characterization of Sham tDCS effects is just as important as investigating Active tDCS effects in understanding and defining acute effects of tDCS on the excitability of spinal reflex pathways.

Heksor: the central nervous system substrate of an adaptive behaviour.

Over the past half-century, the largely hardwired central nervous system (CNS) of 1970 has become the ubiquitously plastic CNS of today, in which change is the rule not the exception. This transformation complicates a central question in neuroscience: how are adaptive behaviours - behaviours that serve the needs of the individual - acquired and maintained through life? It poses a more basic question: how do many adaptive behaviours share the ubiquitously plastic CNS? This question compels neuroscience to adopt a new paradigm. The core of this paradigm is a CNS entity with unique properties, here given the name heksor from the Greek hexis. A heksor is a distributed network of neurons and synapses that changes itself as needed to maintain the key features of an adaptive behaviour, the features that make the behaviour satisfactory. Through their concurrent changes, the numerous heksors that share the CNS negotiate the properties of the neurons and synapses that they all use. Heksors keep the CNS in a state of negotiated equilibrium that enables each heksor to maintain the key features of its behaviour. The new paradigm based on heksors and the negotiated equilibrium they create is supported by animal and human studies of interactions among new and old adaptive behaviours, explains otherwise inexplicable results, and underlies promising new approaches to restoring behaviours impaired by injury or disease. Furthermore, the paradigm offers new and potentially important answers to extant questions, such as the generation and function of spontaneous neuronal activity, the aetiology of muscle synergies, and the control of homeostatic plasticity.

H-reflex conditioning during locomotion in people with spinal cord injury.

KEY POINTS: In people or animals with incomplete spinal cord injury (SCI), changing a spinal reflex through an operant conditioning protocol can improve locomotion. All previous studies conditioned the reflex during steady-state maintenance of a specific posture. By contrast, the present study down-conditioned the reflex during the swing-phase of locomotion in people with hyperreflexia as a result of chronic incomplete SCI. The aim was to modify the functioning of the reflex in a specific phase of a dynamic movement. This novel swing-phase conditioning protocol decreased the reflex much faster and farther than did the steady-state protocol in people or animals with or without SCI, and it also improved locomotion. The reflex decrease persisted for at least 6 months after conditioning ended. The results suggest that conditioning reflex function in a specific phase of a dynamic movement offers a new approach to enhancing and/or accelerating recovery after SCI or in other disorders. ABSTRACT: In animals and people with incomplete spinal cord injury, appropriate operant conditioning of a spinal reflex can improve impaired locomotion. In all previous conditioning studies, the reflex was conditioned during steady-state maintenance of a stable posture; this steady-state protocol aimed to change the excitability of the targeted reflex pathway; reflex size gradually changed over 8-10 weeks. The present study introduces a new protocol, comprising a dynamic protocol that aims to change the functioning of the reflex pathway during a specific phase of a complex movement. Specifically, we down-conditioned the soleus H-reflex during the swing-phase of locomotion in people with hyperreflexia as a result of chronic incomplete SCI. The swing-phase H-reflex, which is absent or very small in neurologically normal individuals, is abnormally large in this patient population. The results were clear. With swing-phase down-conditioning, the H-reflex decreased much faster and farther than did the H-reflex in all previous animal or human studies with the steady-state protocol, and the decrease persisted for at least 6 months after conditioning ended. The H-reflex decrease was accompanied by improvements in walking speed and in the modulation of locomotor electromyograph activity in proximal and distal muscles of both legs. These results provide new insight into the factors controlling spinal reflex conditioning; they suggest that the conditioning protocols targeting reflex function in a specific movement phase provide a promising new opportunity to enhance functional recovery after SCI or in other disorders.

Brain-computer interface use is a skill that user and system acquire together.

A brain-computer interface (BCI) is a computer-based system that acquires, analyzes, and translates brain signals into output commands in real time. Perdikis and colleagues demonstrate superior performance in a Cybathlon BCI race using a system based on "three pillars": machine learning, user training, and application. These results highlight the fact that BCI use is a learned skill and not simply a matter of "mind reading."

Why New Spinal Cord Plasticity Does Not Disrupt Old Motor Behaviors.

When new motor learning changes the spinal cord, old behaviors are not impaired; their key features are preserved by additional compensatory plasticity. To explore the mechanisms responsible for this compensatory plasticity, we transected the spinal dorsal ascending tract before or after female rats acquired a new behavior-operantly conditioned increase or decrease in the right soleus H-reflex-and examined an old behavior-locomotion. Neither spinal dorsal ascending tract transection nor H-reflex conditioning alone impaired locomotion. Nevertheless, when spinal dorsal ascending tract transection and H-reflex conditioning were combined, the rats developed a limp and a tilted posture that correlated in direction and magnitude with the H-reflex change. When the right H-reflex was increased by conditioning, the right step lasted longer than the left and the right hip was higher than the left; when the right H-reflex was decreased by conditioning, the opposite occurred. These results indicate that ascending sensory input guides the compensatory plasticity that normally prevents the plasticity underlying H-reflex change from impairing locomotion. They support the concept of the state of the spinal cord as a negotiated equilibrium that reflects the concurrent influences of all the behaviors in an individual's repertoire; and they support the new therapeutic strategies this concept introduces.SIGNIFICANCE STATEMENT The spinal cord provides a reliable final common pathway for motor behaviors throughout life. Until recently, its reliability was explained by the assumption that it is hardwired; but it is now clear that the spinal cord changes continually as new behaviors are acquired. Nevertheless, old behaviors are preserved. This study shows that their preservation depends on sensory feedback from the spinal cord to the brain: if feedback is removed, the acquisition of a new behavior may disrupt an old behavior. In sum, when a new behavior changes the spinal cord, sensory feedback to the brain guides further change that preserves old behaviors. This finding contributes to a new understanding of spinal cord function and to development of new rehabilitation therapies.

The negotiated equilibrium model of spinal cord function.

The belief that the spinal cord is hardwired is no longer tenable. Like the rest of the CNS, the spinal cord changes during growth and ageing, when new motor behaviours are acquired, and in response to trauma and disease. This paper describes a new model of spinal cord function that reconciles its recently appreciated plasticity with its long-recognized reliability as the final common pathway for behaviour. According to this model, the substrate of each motor behaviour comprises brain and spinal plasticity: the plasticity in the brain induces and maintains the plasticity in the spinal cord. Each time a behaviour occurs, the spinal cord provides the brain with performance information that guides changes in the substrate of the behaviour. All the behaviours in the repertoire undergo this process concurrently; each repeatedly induces plasticity to preserve its key features despite the plasticity induced by other behaviours. The aggregate process is a negotiation among the behaviours: they negotiate the properties of the spinal neurons and synapses that they all use. The ongoing negotiation maintains the spinal cord in an equilibrium - a negotiated equilibrium - that serves all the behaviours. This new model of spinal cord function is supported by laboratory and clinical data, makes predictions borne out by experiment, and underlies a new approach to restoring function to people with neuromuscular disorders. Further studies are needed to test its generality, to determine whether it may apply to other CNS areas such as the cerebral cortex, and to develop its therapeutic implications.

Ablation of the inferior olive prevents H-reflex down-conditioning in rats.

We evaluated the role of the inferior olive (IO) in acquisition of the spinal cord plasticity that underlies H-reflex down-conditioning, a simple motor skill. The IO was chemically ablated before a 50-day exposure to an operant conditioning protocol that rewarded a smaller soleus H-reflex. In normal rats, down-conditioning succeeds (i.e., H-reflex size decreases at least 20%) in 80% of animals. Down-conditioning failed in every IO-ablated rat (P< 0.001 vs. normal rats). IO ablation itself had no long-term effect on H-reflex size. These results indicate that the IO is essential for acquisition of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum enable the cerebellum to guide sensorimotor cortex plasticity that produces and maintains the spinal cord plasticity that underlies the down-conditioned H-reflex. They help to further define H-reflex conditioning as a model for understanding motor learning and as a new approach to enhancing functional recovery after trauma or disease.

The inferior olive is essential for long-term maintenance of a simple motor skill.

The inferior olive (IO) is essential for operant down-conditioning of the rat soleus H-reflex, a simple motor skill. To evaluate the role of the IO in long-term maintenance of this skill, the H-reflex was down-conditioned over 50 days, the IO was chemically ablated, and down-conditioning continued for up to 102 more days. H-reflex size just before IO ablation averaged 62(±2 SE)% of its initial value (P < 0.001 vs. initial). After IO ablation, H-reflex size rose to 75-80% over ∼10 days, remained there for ∼30 days, rose over 10 days to above its initial value, and averaged 140(±14)% for the final 10 days of study (P < 0.01 vs. initial). This two-stage loss of down-conditioning maintenance correlated with IO neuronal loss (r = 0.75, P < 0.01) and was similar to the loss of down-conditioning that follows ablation of the cerebellar output nuclei dentate and interpositus. In control (i.e., unconditioned) rats, IO ablation has no long-term effect on H-reflex size. These results indicate that the IO is essential for long-term maintenance of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum combine to produce cerebellar plasticity that produces sensorimotor cortex plasticity that produces spinal cord plasticity that produces the smaller H-reflex. H-reflex down-conditioning appears to depend on a hierarchy of plasticity that may be guided by the IO and begin in the cerebellum. Similar hierarchies may underlie other motor learning.

Contribution of the external urethral sphincter to urinary void size in unanesthetized unrestrained rats.

AIMS: In anesthetized rats, voiding is typically associated with phasic activation (bursting) of the external urethral sphincter (EUS). During spontaneous voiding in unanesthetized, unrestrained rats, EUS bursting is the most common form of EUS activity exhibited, but it is not necessary for productive voiding to occur. The aim of the present study was to determine which aspects of EUS activity contributed to void size during bursting and non-bursting voiding in conscious, freely moving rats. METHODS: Female rats were implanted with electrodes adjacent to the EUS for recording electromyographic activity (EMG). EUS EMG recordings were performed during 24-hr sessions in a metabolic cage while voided urine was continuously collected and weighed. RESULTS: Void size was positively correlated with the duration of the intra-burst silent and active periods and variables reflecting the overall intensity and duration of bursting, particularly at lower frequencies within the 3-10 Hz range of EUS bursting. In addition, void size was inversely related to the frequency of bursting and to the average EMG amplitude during voiding, both in voids with and without bursting. CONCLUSIONS: EUS bursting contributes to productive voiding when bursting is present. Lower bursting frequencies elicit more productive voiding than do higher frequencies. In the absence of bursting, the association of increased void size with smaller average EUS EMG amplitude suggests that conscious rats can perform synergic voiding (i.e., bladder contraction with EUS relaxation) that is comparable to that seen in humans and other typically non-bursting species. Neurourol. Urodynam. 35:696-702, 2016. © 2015 Wiley Periodicals, Inc.

Electrocorticographic activity over sensorimotor cortex and motor function in awake behaving rats.

Sensorimotor cortex exerts both short-term and long-term control over the spinal reflex pathways that serve motor behaviors. Better understanding of this control could offer new possibilities for restoring function after central nervous system trauma or disease. We examined the impact of ongoing sensorimotor cortex (SMC) activity on the largely monosynaptic pathway of the H-reflex, the electrical analog of the spinal stretch reflex. In 41 awake adult rats, we measured soleus electromyographic (EMG) activity, the soleus H-reflex, and electrocorticographic activity over the contralateral SMC while rats were producing steady-state soleus EMG activity. Principal component analysis of electrocorticographic frequency spectra before H-reflex elicitation consistently revealed three frequency bands: µß (5-30 Hz), low γ (γ1; 40-85 Hz), and high γ (γ2; 100-200 Hz). Ongoing (i.e., background) soleus EMG amplitude correlated negatively with µß power and positively with γ1 power. In contrast, H-reflex size correlated positively with µß power and negatively with γ1 power, but only when background soleus EMG amplitude was included in the linear model. These results support the hypothesis that increased SMC activation (indicated by decrease in µß power and/or increase in γ1 power) simultaneously potentiates the H-reflex by exciting spinal motoneurons and suppresses it by decreasing the efficacy of the afferent input. They may help guide the development of new rehabilitation methods and of brain-computer interfaces that use SMC activity as a substitute for lost or impaired motor outputs.

Operant conditioning of a spinal reflex can improve locomotion after spinal cord injury in humans.

Operant conditioning protocols can modify the activity of specific spinal cord pathways and can thereby affect behaviors that use these pathways. To explore the therapeutic application of these protocols, we studied the impact of down-conditioning the soleus H-reflex in people with impaired locomotion caused by chronic incomplete spinal cord injury. After a baseline period in which soleus H-reflex size was measured and locomotion was assessed, subjects completed either 30 H-reflex down-conditioning sessions (DC subjects) or 30 sessions in which the H-reflex was simply measured [unconditioned (UC) subjects], and locomotion was reassessed. Over the 30 sessions, the soleus H-reflex decreased in two-thirds of the DC subjects (a success rate similar to that in normal subjects) and remained smaller several months later. In these subjects, locomotion became faster and more symmetrical, and the modulation of EMG activity across the step cycle increased bilaterally. Furthermore, beginning about halfway through the conditioning sessions, all of these subjects commented spontaneously that they were walking faster and farther in their daily lives, and several noted less clonus, easier stepping, and/or other improvements. The H-reflex did not decrease in the other DC subjects or in any of the UC subjects; and their locomotion did not improve. These results suggest that reflex-conditioning protocols can enhance recovery of function after incomplete spinal cord injuries and possibly in other disorders as well. Because they are able to target specific spinal pathways, these protocols could be designed to address each individual's particular deficits, and might thereby complement other rehabilitation methods.

Long-term recording of external urethral sphincter EMG activity in unanesthetized, unrestrained rats.

The external urethral sphincter muscle (EUS) plays an important role in urinary function and often contributes to urinary dysfunction. EUS study would benefit from methodology for longitudinal recording of electromyographic activity (EMG) in unanesthetized animals, but this muscle is a poor substrate for chronic intramuscular electrodes, and thus the required methodology has not been available. We describe a method for long-term recording of EUS EMG by implantation of fine wires adjacent to the EUS that are secured to the pubic bone. Wires pass subcutaneously to a skull-mounted plug and connect to the recording apparatus by a flexible cable attached to a commutator. A force transducer-mounted cup under a metabolic cage collected urine, allowing recording of EUS EMG and voided urine weight without anesthesia or restraint. Implant durability permitted EUS EMG recording during repeated (up to 3 times weekly) 24-h sessions for more than 8 wk. EMG and voiding properties were stable over weeks 2-8. The degree of EUS phasic activity (bursting) during voiding was highly variable, with an average of 25% of voids not exhibiting bursting. Electrode implantation adjacent to the EUS yielded stable EMG recordings over extended periods and eliminated the confounding effects of anesthesia, physical restraint, and the potential for dislodgment of the chronically implanted intramuscular electrodes. These results show that micturition in unanesthetized, unrestrained rats is usually, but not always, associated with EUS bursting. This methodology is applicable to studying EUS behavior during progression of gradually evolving disease and injury models and in response to therapeutic interventions.

Persistent beneficial impact of H-reflex conditioning in spinal cord-injured rats.

Operant conditioning of a spinal cord reflex can improve locomotion in rats and humans with incomplete spinal cord injury. This study examined the persistence of its beneficial effects. In rats in which a right lateral column contusion injury had produced asymmetric locomotion, up-conditioning of the right soleus H-reflex eliminated the asymmetry while down-conditioning had no effect. After the 50-day conditioning period ended, the H-reflex was monitored for 100 [±9 (SD)] (range 79-108) more days and locomotion was then reevaluated. After conditioning ended in up-conditioned rats, the H-reflex continued to increase, and locomotion continued to improve. In down-conditioned rats, the H-reflex decrease gradually disappeared after conditioning ended, and locomotion at the end of data collection remained as impaired as it had been before and immediately after down-conditioning. The persistence (and further progression) of H-reflex increase but not H-reflex decrease in these spinal cord-injured rats is consistent with the fact that up-conditioning improved their locomotion while down-conditioning did not. That is, even after up-conditioning ended, the up-conditioned H-reflex pathway remained adaptive because it improved locomotion. The persistence and further enhancement of the locomotor improvement indicates that spinal reflex conditioning protocols might supplement current therapies and enhance neurorehabilitation. They may be especially useful when significant spinal cord regeneration becomes possible and precise methods for retraining the regenerated spinal cord are needed.

Operant conditioning of the soleus H-reflex does not induce long-term changes in the gastrocnemius H-reflexes and does not disturb normal locomotion in humans.

In normal animals, operant conditioning of the spinal stretch reflex or the H-reflex has lesser effects on synergist muscle reflexes. In rats and people with incomplete spinal cord injury (SCI), soleus H-reflex operant conditioning can improve locomotion. We studied in normal humans the impact of soleus H-reflex down-conditioning on medial (MG) and lateral gastrocnemius (LG) H-reflexes and on locomotion. Subjects completed 6 baseline and 30 conditioning sessions. During conditioning trials, the subject was encouraged to decrease soleus H-reflex size with the aid of visual feedback. Every sixth session, MG and LG H-reflexes were measured. Locomotion was assessed before and after conditioning. In successfully conditioned subjects, the soleus H-reflex decreased 27.2%. This was the sum of within-session (task dependent) adaptation (13.2%) and across-session (long term) change (14%). The MG H-reflex decreased 14.5%, due mainly to task-dependent adaptation (13.4%). The LG H-reflex showed no task-dependent adaptation or long-term change. No consistent changes were detected across subjects in locomotor H-reflexes, EMG activity, joint angles, or step symmetry. Thus, in normal humans, soleus H-reflex down-conditioning does not induce long-term changes in MG/LG H-reflexes and does not change locomotion. In these subjects, task-dependent adaptation of the soleus H-reflex is greater than it is in people with SCI, whereas long-term change is less. This difference from results in people with SCI is consistent with the fact that long-term change is beneficial in people with SCI, since it improves locomotion. In contrast, in normal subjects, long-term change is not beneficial and may necessitate compensatory plasticity to preserve satisfactory locomotion.

Locomotor impact of beneficial or nonbeneficial H-reflex conditioning after spinal cord injury.

When new motor learning changes neurons and synapses in the spinal cord, it may affect previously learned behaviors that depend on the same spinal neurons and synapses. To explore these effects, we used operant conditioning to strengthen or weaken the right soleus H-reflex pathway in rats in which a right spinal cord contusion had impaired locomotion. When up-conditioning increased the H-reflex, locomotion improved. Steps became longer, and step-cycle asymmetry (i.e., limping) disappeared. In contrast, when down-conditioning decreased the H-reflex, locomotion did not worsen. Steps did not become shorter, and asymmetry did not increase. Electromyographic and kinematic analyses explained how H-reflex increase improved locomotion and why H-reflex decrease did not further impair it. Although the impact of up-conditioning or down-conditioning on the H-reflex pathway was still present during locomotion, only up-conditioning affected the soleus locomotor burst. Additionally, compensatory plasticity apparently prevented the weaker H-reflex pathway caused by down-conditioning from weakening the locomotor burst and further impairing locomotion. The results support the hypothesis that the state of the spinal cord is a "negotiated equilibrium" that serves all the behaviors that depend on it. When new learning changes the spinal cord, old behaviors undergo concurrent relearning that preserves or improves their key features. Thus, if an old behavior has been impaired by trauma or disease, spinal reflex conditioning, by changing a specific pathway and triggering a new negotiation, may enable recovery beyond that achieved simply by practicing the old behavior. Spinal reflex conditioning protocols might complement other neurorehabilitation methods and enhance recovery.

The simplest motor skill: mechanisms and applications of reflex operant conditioning.

Operant conditioning protocols can change spinal reflexes gradually, which are the simplest behaviors. This article summarizes the evidence supporting two propositions: that these protocols provide excellent models for defining the substrates of learning and that they can induce and guide plasticity to help restore skills, such as locomotion, that have been impaired by spinal cord injury or other disorders.

Soleus H-reflex operant conditioning changes the H-reflex recruitment curve.

INTRODUCTION: Operant conditioning can gradually change the human soleus H-reflex. The protocol conditions the reflex near M-wave threshold. In this study we examine its impact on the reflexes at other stimulus strengths. METHODS: H-reflex recruitment curves were obtained before and after a 24-session exposure to an up-conditioning (HRup) or a down-conditioning (HRdown) protocol and were compared. RESULTS: In both HRup and HRdown subjects, conditioning affected the entire H-reflex recruitment curve. In 5 of 6 HRup and 3 of 6 HRdown subjects, conditioning elevated (HRup) or depressed (HRdown), respectively, the entire curve. In the other HRup subject or the other 3 HRdown subjects, the curve was shifted to the left or to the right, respectively. CONCLUSIONS: H-reflex conditioning does not simply change the H-reflex to a stimulus of particular strength; it also changes the H-reflexes to stimuli of different strengths. Thus, it is likely to affect many actions in which this pathway participates.

Enhancing neurorehabilitation by targeting beneficial plasticity.

Neurorehabilitation is now one of the most exciting areas in neuroscience. Recognition that the central nervous system (CNS) remains plastic through life, new understanding of skilled behaviors (skills), and novel methods for engaging and guiding beneficial plasticity combine to provide unprecedented opportunities for restoring skills impaired by CNS injury or disease. The substrate of a skill is a distributed network of neurons and synapses that changes continually through life to ensure that skill performance remains satisfactory as new skills are acquired, and as growth, aging, and other life events occur. This substrate can extend from cortex to spinal cord. It has recently been given the name "heksor." In this new context, the primary goal of rehabilitation is to enable damaged heksors to repair themselves so that their skills are once again performed well. Skill-specific practice, the mainstay of standard therapy, often fails to optimally engage the many sites and kinds of plasticity available in the damaged CNS. New noninvasive technology-based interventions can target beneficial plasticity to critical sites in damaged heksors; these interventions may thereby enable much wider beneficial plasticity that enhances skill recovery. Targeted-plasticity interventions include operant conditioning of a spinal reflex or corticospinal motor evoked potential (MEP), paired-pulse facilitation of corticospinal connections, and brain-computer interface (BCI)-based training of electroencephalographic (EEG) sensorimotor rhythms. Initial studies in people with spinal cord injury, stroke, or multiple sclerosis show that these interventions can enhance skill recovery beyond that achieved by skill-specific practice alone. After treatment ends, the repaired heksors maintain the benefits.

Towards clinical application of implantable brain-computer interfaces for people with late-stage ALS: medical and ethical considerations.

Individuals with amyotrophic lateral sclerosis (ALS) frequently develop speech and communication problems in the course of their disease. Currently available augmentative and alternative communication technologies do not present a solution for many people with advanced ALS, because these devices depend on residual and reliable motor activity. Brain-computer interfaces (BCIs) use neural signals for computer control and may allow people with late-stage ALS to communicate even when conventional technology falls short. Recent years have witnessed fast progression in the development and validation of implanted BCIs, which place neural signal recording electrodes in or on the cortex. Eventual widespread clinical application of implanted BCIs as an assistive communication technology for people with ALS will have significant consequences for their daily life, as well as for the clinical management of the disease, among others because of the potential interaction between the BCI and other procedures people with ALS undergo, such as tracheostomy. This article aims to facilitate responsible real-world implementation of implanted BCIs. We review the state of the art of research on implanted BCIs for communication, as well as the medical and ethical implications of the clinical application of this technology. We conclude that the contribution of all BCI stakeholders, including clinicians of the various ALS-related disciplines, will be needed to develop procedures for, and shape the process of, the responsible clinical application of implanted BCIs.