Thompson, Aiko K.1,2,3,4; Wolpaw, Jonathan R.1,2,3,4
During the past several decades, the ubiquity of activity-dependent plasticity in the central nervous system (CNS) has become increasingly evident. The traditional view of the CNS as a hard-wired structure that changes only in limited ways and at a few locations has been overturned; it is now clear that plasticity occurs throughout the CNS and throughout life (reviewed in (31,33)). Along with this change has come recognition that the plasticity associated with motor skill acquisition is not limited to the cerebral cortex or even to the entire brain but rather extends all the way down to the spinal cord (reviewed in (31,33,34)). In fact, athletic training or motor skill acquisition induces plasticity in spinal cord pathways (e.g., spinal reflexes). For example, long- and short-distance runners have significantly smaller gastrocnemius H- and T-reflexes than nontrained subjects (13), and ballet dancers have smaller soleus H-reflexes than other highly trained athletes (12). Such training-induced plasticity in spinal reflexes also occurs after spinal cord injury or with other CNS disorders ((7,26) also see Frigon et al. (5,18)).
In sum, extensive training or skill acquisition that repeats certain patterns of peripheral sensory and/or descending inputs to the spinal cord induces plasticity that shapes the activity of spinal reflex pathways and also may affect activity elsewhere in the CNS (reviewed in (31,34)). Thus, to understand the mechanisms of motor skill acquisition, it is important to understand how plasticity is induced and guided at many different sites, including spinal cord pathways, and how these many changes combine to produce the new skill while maintaining existing skills. In this article, we review evidence indicating that operant conditioning of spinal reflexes is an excellent model for elucidating the mechanisms of skill acquisition and that it also can enhance neurorehabilitation by inducing and guiding beneficial plasticity.
ADVANTAGES OF USING A SPINAL REFLEX TO STUDY MOTOR SKILL LEARNING AND MEMORY
Spinal reflexes, the simple behaviors mediated entirely by spinal cord pathways, have unique advantages for studying mechanisms of motor skill acquisition. First, activity-dependent plasticity is abundant in the spinal cord (10,14,17,18,32,33). It is induced and guided by inputs to the spinal cord from the brain and the periphery; these inputs gradually establish and maintain spinal cord circuits in a state that supports the entire roster of motor behaviors (33). This gradual activity-dependent plasticity shapes spinal cord function during development, throughout later life, in response to trauma and disease, and during motor function recovery after CNS or peripheral damage (5,15–18,33,34). Second, the relative simplicity and accessibility of the spinal cord and its distance from the brain facilitate study of individual components of this multisite plasticity. The major neuronal populations and pathways of the spinal cord are well known and accessible to monitoring. Furthermore, the anatomical separation of brain and spinal cord makes it possible to study interactions between supraspinal and spinal plasticity that underlie skill acquisition and maintenance. Finally, and most importantly, spinal cord pathways participate in essentially all behaviors. The spinal cord is the place where multiple supraspinal and peripheral inputs are integrated into the activations of motoneurons (and the resulting muscle contractions) that comprise motor behaviors.
ACQUISITION OF THE SIMPLEST MOTOR SKILL: OPERANT CONDITIONING OF A SPINAL REFLEX
Although spinal reflexes normally function as components of complex skills such as locomotion, they are themselves simple behaviors produced by pathways entirely within the spinal cord (20,35). These pathways are influenced in both the short-term and the long-term by descending inputs from the brain. In the short-term, they undergo task-dependent modulation as the animal or human switches from one behavior to another (20,21). In the long-term, the brain shapes spinal reflex pathways so that they serve new skills and maintain old ones (31,33). Thus, at any given moment, spinal reflex function reflects both short-term task-dependent adaptations and long-term plasticity.
Operant conditioning, in which modification of a behavior is brought about by the consequence of that behavior, is a powerful method to induce learning. Through operant conditioning, even the simplest behaviors, such as spinal reflex behaviors, can be changed. Operant conditioning of a spinal reflex can provide an excellent experimental model for studying learning and memory: its key elements consist of a spinal cord reflex; supraspinal influence over that pathway; and the spinal cord plasticity induced by that influence (32). By basing reward on reflex size, the conditioning protocol operantly conditions the brain to provide supraspinal influence that appropriately affects reflex size.
During the past 30 yr, operant conditioning of the simplest spinal cord reflex, the spinal stretch reflex (SSR) (i.e., the “knee-jerk” reflex), or its electrical analog, the Hoffmann (or H-) reflex, has been studied in monkeys, rats, mice, and humans (24,30,32). Figure 1A illustrates this pathway. If the group I (largely 1A) afferents are excited by muscle stretch, the response is the SSR; if they are excited by electrical stimulation of the nerve, the response is the H-reflex (6,8). It should be noted that the SSR and H-reflex do or might differ somewhat in other respects as well: only the SSR is affected by γ-motoneuron-mediated fusimotor control; and the two reflexes are likely to differ in their distributions of active group I afferents (i.e., Ia vs Ib) and/or in the synchrony of afferent excitations (e.g., (9,11)). Nevertheless, both the SSR and H-reflex can be increased or decreased by an operant conditioning protocol (30–32). Regardless of the species (i.e., human, monkey, rat, or mouse), the standard protocol operantly conditions the subject to increase (or decrease) reflex size by rewarding the subject for a larger (or smaller) reflex. The reward contingency ensures that supraspinal influence that increases (or decreases) the reflex is rewarded, whereas influence that decreases (or increases) it is not. As a result, supraspinal influence that increases (or decreases) the reflex becomes more prevalent and gradually changes the spinal cord. For reasons of experimental and clinical practicality, most work has focused and continues to focus on conditioning the H-reflex rather than the SSR.
The rat soleus H-reflex conditioning protocol is summarized briefly here (the monkey and mouse protocols are similar). The rat is implanted chronically with fine-wire electromyography (EMG) electrodes in the soleus muscle and a stimulating cuff on the posterior tibial nerve. The implanted wires connect through a head mount and a flexible tether and commutator to EMG amplifiers and a nerve-cuff simulator. Soleus EMG activity is monitored continuously (24/7) in the freely moving animal. Whenever the absolute soleus EMG activity remains within a specified range for a randomly varying 2.3- to 2.7-s period, a nerve-cuff stimulus elicits the M-wave and the H-reflex. The stimulus level is kept just above M-wave threshold. Typically, the animal provides 2500 to 8000 H-reflex trials per day.
For the first 10 days, the rat is exposed to the control mode, in which no reward occurs and the H-reflex is measured simply to determine its baseline value. For the next 50 days, the rat is exposed to the up-conditioning (HRup) or down-conditioning (HRdown) mode, in which a food reward occurs if the H-reflex is above (HRup) or below (HRdown) a criterion value. Background EMG level and M-wave amplitude remain constant throughout. Because the H-reflex is the earliest possible CNS response to the nerve stimulus, the animal can modify H-reflex size only by being prepared ahead of time, that is, by maintaining mode-appropriate supraspinal influence over the reflex pathway. This influence (most likely exerted by descending corticospinal tract (CST) activity, see the section below) gradually induces activity-dependent plasticity in the spinal cord, resulting in gradual operantly conditioned H-reflex change.
Figure 1C shows the results of operant conditioning in different species. In each species, exposure to the up-(▴) or down-(▾) conditioning paradigm gradually changes the size of the reflex in the correct direction. Successful conditioning (i.e., >20% change in the correct direction (30)) occurs in 75% to 80% of the animals. In the remaining animals, the reflex size remains within 20% of its baseline value. The central finding is that operant conditioning changes the size of the reflex appropriately for the conditioning mode (either up or down) over days and weeks. According to a standard definition of a skill as an adaptive behavior acquired through practice (Compact Oxford English Dictionary 1993), the larger (up-conditioned) or smaller (down-conditioned) reflex created by this operant conditioning protocol is a simple motor skill.
OPERANT CONDITIONING OF THE SOLEUS H-REFLEX IN HUMANS
In humans, reflex operant conditioning was applied first to the biceps brachii stretch reflex (19) and more recently to the soleus H-reflex (24). The human H-reflex conditioning protocol in humans is comparable to that in animals, except for the number of trials; humans perform only 675 trials per week (i.e., only 2%–5% as many as animals), and these trials are confined to three 1-h sessions. The standard protocol is composed of six baseline sessions and 24 conditioning sessions at a rate of three sessions per week and four follow-up sessions for the next 3 months.
In each session, the soleus H-reflex is elicited while the standing subject maintains soleus background EMG at a defined stable level (i.e., natural standing level) (Fig. 2). M-wave size is kept constant for all the H-reflex trials within and between sessions. In each baseline session, three blocks of 75 control H-reflex trials (i.e., 225 H-reflexes) occur. In each conditioning or follow-up session, 20 within-session control H-reflexes are measured as in the baseline sessions and then three blocks of 75 (i.e., 225) conditioned H-reflex trials occur. In these conditioned H-reflex trials, the subject is encouraged to increase (HRup mode) or decrease (HRdown mode) H-reflex size and is given visual feedback after each stimulus (Fig. 2) that indicates whether the H-reflex was larger (HRup mode) or smaller (HRdown mode) than a criterion value. A high frequency of success in satisfying the criterion earns an additional monetary reward. Background EMG and M-wave size are kept stable throughout data collection.
In contrast to the standard animal protocol, this human protocol allows us to distinguish between and track the development of two different components of H-reflex change. The conditioned H-reflexes track the overall development of H-reflex conditioning, the control H-reflexes tracks the development of gradual across-session change, and the within-session differences between the conditioned and control H-reflexes track the development of rapid task-dependent adaptation.
Figure 3 summarizes the results of soleus H-reflex conditioning in neurologically normal subjects. During the 24 conditioning sessions, H-reflex size gradually increased in six of eight HRup subjects and decreased in eight of nine HRdown subjects, resulting in final sizes of 140% (±12% SEM) and 69% (±6%) of baseline size, respectively. In these subjects, the final H-reflex change was the sum of within-session change (i.e., task-dependent adaptation) and across-session (i.e., long-term) change. Task-dependent adaptation appeared within four to six sessions and persisted unchanged thereafter, averaging +13% in HRup subjects and -15% in HRdown subjects. In contrast, long-term change began after 10 to 12 sessions and increased gradually thereafter, reaching +27% in HRup subjects and -16% in HRdown subjects. (See (24) for complete presentation and discussion of task-dependent adaptation and long-term change.)
This study showed that human subjects performing only 225 reflex conditioning trials per day, 3 d wk-1, displayed gradual reflex change similar in course and nearly equal in magnitude to that of animals that performed 20 to 50 times as many trials. This finding shows that H-reflex conditioning is possible in humans, and that it does not require the several thousand trials per day typically completed by animals. (Animals probably do not need that many trials either, but that remains to be determined.) The success rate of 82% (i.e., 14 of 17 subjects changed H-reflex size significantly in the correct direction, whereas H-reflex size did not change significantly in the other three subjects) also was similar to that of animals (24,30).
In addition to its demonstration of H-reflex conditioning in humans, the major significance of this study is that it dissects the course of a simple skill acquisition (i.e., a larger or smaller H-reflex) and thereby distinguishes two phenomena, rapid task-dependent adaptation and gradual long-term change, that constitute the skill. Task-dependent adaptation and long-term change differ in time of onset and rate of development. Task-dependent adaptation can be turned on or off rapidly whereas long-term change occurs gradually and persists for months after conditioning ends. Together with previous animal studies, these findings suggest that task-dependent adaptation reflects supraspinal plasticity (that may change the H-reflex by modifying presynaptic inhibition at the Ia motoneuron synapse) (24,32) and that long-term change reflects plasticity in the spinal cord (e.g., in motoneuron properties) ((27,32) for discussion).
It is worth emphasizing that recognizing the development of each of these two components separately was possible because each conditioning session of the human protocol measured the H-reflex without and with task-dependent adaptation (i.e., the within-session control trials and the conditioning trials, respectively), unlike the animal protocol, which simply imposed the conditioning task for the entire conditioning period. (Although the overall course of reflex change in animals strongly suggested the presence of these two components (32)).
Another recent study examined the impact of H-reflex conditioning on the entire H-reflex recruitment curve (25). Operant conditioning of the human soleus H-reflex changed all or most of the H-reflex recruitment curve. Depending on the individual, the change was an overall positive (with HRup) or negative (with HRdown) shift in the curve (e.g., Fig. 3D) or a leftward (with HRup) or rightward (with HRdown) shift (not shown). Because these H-reflex recruitment curves were measured before the conditioning trials, whereas the subject simply maintained the background EMG level and did not try to change the H-reflex, the H-reflexes changes found in this control situation reflect long-term plasticity produced by the conditioning sessions (24). These results also are consistent with previous data showing that H-reflex conditioning affects the pathway’s participation in other motor behaviors, such as locomotion (32).
THE COMPLEX PLASTICITY ASSOCIATED WITH SPINAL REFLEX CONDITIONING
An ongoing series of animal studies is revealing the complex patterns of spinal and supraspinal plasticity underlying H-reflex conditioning (30–33). A positive shift in motoneuron firing threshold (possibly resulting from a change in the activation voltage of Na+ channels) can account largely for H-reflex down-conditioning (reviewed in (30)). Down-conditioning also is accompanied by marked increases in identifiable GABAergic interneurons in the ventral horn and GABAergic terminals on the soleus motoneuron (32). Additional changes occur in several other synaptic populations on the motoneuron, in motor unit properties, in other spinal interneurons, and even on the contralateral side of the spinal cord (30). Interestingly, up-conditioning and down-conditioning are not mirror images of each other; they seem to have different mechanisms. Up-conditioning may result from plasticity in spinal interneurons (32).
The CST is the only major descending tract essential for H-reflex conditioning (32). Given its rapid development and ability to be turned on and off quickly, task-dependent adaptation (or phase 1 change (32)) in the H-reflex is likely to reflect acute changes in CST activity. This (or related) CST activity is likely to be responsible for gradually inducing the spinal cord plasticity underlying long-term (or phase 2) (24,32)) change in the H-reflex. Furthermore, it is clear that plasticity also occurs in sensorimotor cortex or related brain areas, and that both the cerebellum and the basal ganglia play important roles (32). In sum, the simple skill of a larger or smaller H-reflex rests on a hierarchy of brain and spinal cord plasticity (32). The operant conditioning protocol induces and maintains the plasticity in the brain that produces the CST activity that induces and maintains the spinal cord plasticity that is directly responsible for most of the change in H-reflex size (24,32). Figure 4 summarizes current understanding of the hierarchy of plasticity that underlies H-reflex conditioning.
THE IMPACT OF A NEW SKILL ON OLDER SKILLS
When H-reflex conditioning changes the spinal reflex pathway, it is likely to affect previously acquired behaviors, such as locomotion, that also use this pathway. Indeed, soleus H-reflex conditioning in normal rats changes locomotor EMG activity and kinematics (e.g., ankle angle) (1). Nevertheless, key features of locomotion, such as right/left symmetry in the timing of the step cycle and in hip heights, are preserved (32). These features seem to be preserved by compensatory plasticity that prevents the primary plasticity (i.e., the plasticity directly responsible for soleus H-reflex change) from disrupting locomotion (32). For example, the change in ankle angle associated with the altered soleus H-reflex pathway is accompanied by reciprocal change in hip angle, which prevents change in hip height (1); and a conditioning-induced change in the soleus H-reflex usually is accompanied by an opposite change in the quadriceps H-reflex (1).
These findings support the hypothesis that the functional properties of spinal pathways are maintained in a state of “negotiated equilibrium,” a balance that ensures the satisfactory performance of all the behaviors in the individual’s current repertoire (32). Acquisition of a new behavior (or skill) (e.g., a larger or smaller H-reflex) requires the creation of a new equilibrium that accommodates the H-reflex change and also continues to serve previously acquired skills. Before a new skill acquisition, spinal pathways are in the state of equilibrium that is a product of previous skill acquisitions and serves each of them satisfactorily. When acquisition of a new skill changes spinal pathways and thereby disturbs older skills, it induces compensatory plasticity that preserves the key features of the older skills. The plasticity that preserves each older skill may in turn affect other skills and lead to further plasticity. The culmination of this iterative process, or negotiation, is a new spinal cord equilibrium that satisfies each skill in the expanded repertoire.
THERAPEUTIC APPLICATIONS OF SPINAL REFLEX CONDITIONING
Operant conditioning of a spinal reflex can modify the activity of spinal cord pathways and can thereby affect behaviors that use these pathways. Furthermore, it is now clear that learning the simple skill of a larger or smaller H-reflex creates a hierarchy of complex multisite plasticity from the brain to the spinal cord (31,32). This multisite plasticity involves pathways that play important roles in other behaviors, such as locomotion. Thus, an appropriately designed reflex conditioning protocol might ameliorate movement disabilities caused by CNS damage. Indeed, in rats with abnormal locomotion caused by incomplete spinal cord injury (SCI), appropriate soleus H-reflex conditioning can restore more normal locomotion (32).
In an early study, Segal and Wolf (19) showed that the biceps brachii spinal stretch reflex could be operantly conditioned in people with incomplete SCI. To determine whether reflex conditioning could improve motor function in those with incomplete SCI, we recently studied the feasibility and the functional impact of down-conditioning the soleus H-reflex in people with impaired locomotion caused by chronic incomplete SCI (27).
In people with chronic incomplete SCI, spasticity often is expressed as exaggerated stretch reflexes and abnormal reflex modulation in the ankle extensor muscles (3,22). Normally, spinal reflexes are modulated from standing to walking and, during walking reflexes, are further modulated across the different phases of the step cycle (21,35). However, in people with SCI, modulation of the soleus H-reflex across the step cycle often is absent or diminished greatly (i.e., H-reflex amplitude remains high even in the early stance or swing phase, where the H-reflex is normally very small or absent) (22) and this abnormality seems to affect locomotor EMG activity, contributing to clonus, foot drop, and other disabling problems (3,22). These findings suggest that decreasing reflex excitability in the spastic extensor muscles by operant down-conditioning might alleviate spastic gait in this population.
Our subjects were ambulatory adults with chronic incomplete SCI whose gaits were impaired by ankle extensor spasticity and hyperreflexia. The H-reflex conditioning protocol was the same as the one used in normal subjects (24), except that the number of conditioning sessions was increased from 24 to 30. The six baseline and 30 conditioning sessions occurred at the rate of three sessions per week for 12 wk. Soleus and tibialis anterior background EMG and soleus M-wave size were kept constant throughout the study. After the baseline period in which soleus H-reflex size was measured and locomotion was assessed, the subjects completed either 30 H-reflex down-conditioning sessions (DC subjects) or 30 control sessions in which the H-reflex was measured simply (Unconditioned (UC) subjects), and locomotion was reassessed.
During the 30 sessions, the soleus H-reflex decreased in six of nine DC subjects (Figs. 5 and 6) and remained smaller several months later. In these subjects, locomotion became significantly faster and more symmetrical (Fig. 7), and locomotor EMG modulation 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, less arm weight-bearing, and/or other improvements. The H-reflex did not decrease in the other DC subjects or in any of the UC subjects (Fig. 5A), and their locomotion did not improve. These results indicated that the beneficial impact of H-reflex conditioning extended well beyond the effects that could be ascribed to change in the soleus H-reflex pathway (e.g., locomotor EMG modulation increased in contralateral muscles). In terms of the negotiated equilibrium hypothesis summarized above (32), it seems that the iterative process (i.e., the new negotiation) triggered by the acquisition of the new skill (i.e., a smaller soleus H-reflex) led to a new equilibrium superior to that before H-reflex conditioning (see (32) for discussion). In sum, this initial study suggests that reflex conditioning protocols can enhance motor function recovery after incomplete SCI and possibly in other disorders as well.
There are several compelling reasons to pursue the development of reflex conditioning as a new rehabilitation approach. Because reflexes can be increased or decreased and different reflex pathways can be targeted by these protocols (i.e., not simply the H-reflex pathway), a protocol might be customized for each individual to address his/her motor control problems. For example, in rats with SCI in which locomotion was impaired by weak stance, up-conditioning of the soleus H-reflex strengthened stance and restored gait symmetry (32); in contrast, in people with SCI in whom locomotion was impaired by ankle extensor spasticity, down-conditioning of the soleus H-reflex restored gait symmetry and increased walking speed (27). It also should be possible to design reflex conditioning protocols that complement existing therapeutic training methods, such as treadmill training (4,28) and constraint-induced movement therapy (23,29), to maximize the recovery of useful motor function. Reflex conditioning protocols also might enhance recovery after other kinds of trauma, such as peripheral nerve transection (2).
Furthermore, when CNS regeneration therapy becomes possible, methods such as spinal reflex conditioning could be essential for re-educating newly regenerated connections to function effectively. Without appropriate induction and guidance of activity-dependent plasticity, regenerated connections are likely to display diffuse infantile-like responses and dysfunctional motor outputs (reviewed in (31–33)). As previously mentioned, operant conditioning produces complex patterns of multisite plasticity that extend well beyond the targeted reflex pathway (32). Thus, it is essential to delineate the principles critical for designing reflex conditioning protocols appropriate for individual patients.
Operant conditioning is a powerful method for inducing motor skill learning. Through operant conditioning, even the simplest motor behaviors, such as spinal reflex behaviors, can be changed. Because the spinal cord is relatively simple and technically accessible and is connected to the brain by well-defined pathways, operant conditioning of a spinal reflex provides an excellent experimental model for studying learning and memory: it is possible to identify the critical spinal cord plasticity, to determine its dependence on influence from the brain, and to begin to delineate the hierarchy of brain and spinal cord plasticity underlying the learning. Spinal reflex conditioning affects other behaviors such as locomotion that use the same pathway. Thus, in normal subjects, it induces additional plasticity that preserves the key features of these behaviors. Furthermore, in subjects in whom trauma or disease (e.g., an incomplete SCI) has impaired the key features of a behavior, appropriate reflex conditioning can induce and guide plasticity that improves these features. Reflex conditioning protocols may provide an important new therapeutic approach that can complement other rehabilitation methods and augment recovery of useful function.
This work was supported in part by the New York State Spinal Cord Injury Research Trust (C023685 to A.K. Thompson); the National Institutes of Health (NS069551 to A.K. Thompson, NS22189 to J.R. Wolpaw, and NS061823 to J.R. Wolpaw and Xiang Yang Chen); and the Helen Hayes Hospital Foundation (to A.K. Thompson). The authors recognize the work of other researchers that could not be cited because of the journal’s reference limitations.
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