Restoring walking after spinal cord injury: operant conditioning of spinal reflexes can help

Abstract

People with incomplete spinal cord injury (SCI) frequently suffer motor disabilities due to spasticity and poor muscle control, even after conventional therapy. Abnormal spinal reflex activity often contributes to these problems. Operant conditioning of spinal reflexes, which can target plasticity to specific reflex pathways, can enhance recovery. In rats in which a right lateral column lesion had weakened right stance and produced an asymmetrical gait, up-conditioning of the right soleus H-reflex, which increased muscle spindle afferent excitation of soleus, strengthened right stance and eliminated the asymmetry. In people with hyperreflexia due to incomplete SCI, down-conditioning of the soleus H-reflex improved walking speed and symmetry. Furthermore, modulation of electromyographic activity during walking improved bilaterally, indicating that a protocol that targets plasticity to a specific pathway can trigger widespread plasticity that improves recovery far beyond that attributable to the change in the targeted pathway. These improvements were apparent to people in their daily lives. They reported walking faster and farther, and noted less spasticity and better balance. Operant conditioning protocols could be developed to modify other spinal reflexes or corticospinal connections; and could be combined with other therapies to enhance recovery in people with SCI or other neuromuscular disorders.

Keywords: learning; locomotion; spinal cord injury; spinal cord plasticity; spinal reflexes.

© The Author(s) 2014.

Figures

Figure 1

Soleus H-reflex during standing and walking, soleus and tibialis anterior (TA) EMG activity and soleus H-reflex size over the step-cycle in a neurologically normal subject and in two subjects with chronic incomplete SCI. A: Soleus H-reflex sizes during standing and walking in each of 12 equally spaced step-cycle bins versus soleus EMG activity. Each standing H-reflex symbol (x) is the average of 4 responses and each walking H-reflex symbol (o) is the average of 5–10 responses. M-wave sizes are maintained the same within and between tasks. In the normal subjects, the H-reflex at a specific EMG level is clearly smaller during walking than during standing (Capaday and Stein 1986), whereas in subjects with chronic SCI, this task-dependent modulation of H-reflex size between standing and walking is impaired; and H-reflex size does not increase with background EMG level in standing or walking. B: Soleus H-reflex modulation during walking. In the normal subject, the pattern is similar to the soleus EMG pattern (C). In the subjects with SCI (middle and right), H-reflex modulation across the step-cycle is minimal, and hyperactivity of the H-reflex pathway probably contributes to the abnormally low TA activity during the swing phase (D) and to the resulting foot drop. C: Soleus EMG during walking. In the normal subject, soleus EMG activity gradually increases from heel contact to push off, then falls to near zero and remains low for the entire swing phase. In figure subjects with SCI, soleus EMG activity may (middle) or may not (right) be normally modulated. In the subject on the right column, the soleus remains active during the swing phase. D: TA EMG activity during walking. In the normal subject, TA activity typically shows two distinct peaks: one in the early swing phase and another during the swing-stance transition. In subjects with SCI (middle and right), TA activity is often minimal throughout the step-cycle.

Figure 2

H-reflex operant conditioning in rats (A–C) and humans (D–G). A: The soleus H-reflex is elicited in a rat with chronically implanted EMG electrodes and a tibial nerve cuff. Whenever the absolute value of soleus EMG activity stays in a specified range for a 2.3- to 2.7-s period, tibial nerve stimulation through the cuff elicits an M-wave just above threshold and an H-reflex. For the first 10 days (from day −10 to day 0), the rat is exposed to the control mode, in which no reward occurs and the H-reflex is simply measured to determine its initial size. For the next 50 days, the rat is exposed to the up-conditioning (HRup) or down-conditioning (HRdown) mode, in which a food-pellet reward occurs 200 ms after the stimulation whenever the H-reflex is above (HRup) or below (HRdown) a criterion value. B: Average (±SEM) daily H-reflex sizes for 59 successful HRup rats (red upward triangles) and 81 successful HRdown rats (blue downward triangles). C: Average absolute value of post-stimulus EMG activity for representative days from an HRup rat (top) and an HRdown rat (bottom) in the control mode (solid) and near the end of HRup or HRdown conditioning (dashed). (Updated from (Wolpaw 1997). D–G: The subject maintains a natural standing posture and a correct level of soleus EMG activity with the aid of a visual feedback screen (D and E) that shows the current absolute value of soleus EMG activity in relation to a specified range. Whenever the absolute value of soleus EMG activity stays in this range for several sec, tibial nerve stimulation elicits an M-wave just above threshold and an H-reflex. For the first 6 sessions (i.e., baseline sessions, day −14 to day 0), the subject is exposed to the control mode, in which the H-reflex is simply measured to determine its initial size. For the next 24 sessions (i.e., conditioning sessions, days 0–56, 3 sessions/week), the subject is exposed to the HRup or HRdown conditioning mode, in which, after each conditioning trial, the screen provides immediate feedback as to whether the H-reflex was above (HRup) or below (HRdown (shown on screen)) a criterion value (E). The person completes 225 conditioning trials per session. F: Average (±SEM) daily H-reflex sizes for 6 successful HRup people (red upward triangles) and 8 successful HRdown people (blue downward triangles). G: Average peri-stimulus EMG activity from an HRup subject (top) and an HRdown subject (bottom) for a baseline session (i.e., control mode) (solid) and for the last HRup or HRdown conditioning session (dashed). (From (Thompson and others 2009a).)

Figure 3

Average (±SE) H-reflexes for baseline and conditioning sessions for down-conditioning subjects with SCI (A, N=6, (Thompson and others 2013c)) and for normal subjects (B, N=8, (Thompson and others 2009a)) in whom the H-reflex decreased significantly. Top: Average conditioned H-reflex size. Middle: Average control H-reflex size (i.e., long-term plasticity (see (Thompson and others 2009a) for details). Bottom: Average of conditioned H-reflex size minus control H-reflex size (i.e., task-dependent adaptation (see (Thompson and others 2009a) for details)). In the subjects with SCI (A), the conditioned H-reflex decreases to 69% of the baseline value over the 30 conditioning sessions. This decrease consists of a relatively small task-dependent adaptation (−7%) and a relatively large across-session control reflex decrease (−24%). In neurologically normal subjects (B), the conditioned H-reflex also decreases to 69% of the baseline value over 24 Conditioning sessions. This decrease is the sum of a relatively large task-dependent adaptation (−15%) and a relatively small across-session control reflex decrease (−16%). The asterisks between A and B indicate significant differences (p<0.01) between the groups in final control H-reflex value (middle) and in task-dependent adaptation (bottom).

Figure 4

A: 10-m walking speeds after the 30 conditioning or control sessions (mean±SE % of baseline speed) for subjects with SCI in whom the H-reflex did or did not decrease significantly. B: Step-cycle symmetry before (open bars) and after (shaded bars) after the 30 conditioning or control sessions for subjects with SCI in whom the H-reflex did or did not decrease significantly. Symmetry is measured as the ratio of the time between the nonconditioned leg’s foot contact (nFC) and the conditioned (or simply stimulated in the case of control subjects) and initially more impaired leg’s foot contact (cFC), to the time between cFC and nFC. A ratio of 1 indicates a symmetrical gait. Initially, the ratio is >1. After the 30 conditioning or control sessions, the ratio has decreased toward 1 in the subjects in whom the H-reflex decreased, while it has increased slightly in the subjects in whom the H-reflex did not decrease. C: Successive step cycles before and after conditioning from a subject in whom the H-reflex decreased. Each nFC (●) and cFC (○) is shown. Short vertical dashed lines mark the midpoints between nFCs (i.e., midpoints of the step-cycle), which is when cFC should occur. Before H-reflex conditioning, cFC is too late; after successful conditioning, it is on time.

Figure 5

Rectified soleus EMG activity and locomotor H-reflex size over the step cycle before and after successful H-reflex down-conditioning in a subject with SCI. Successful conditioning results in better EMG and H-reflex modulation. The abnormal tonic EMG activity during the swing phase almost completely disappears after conditioning. The locomotor H-reflex becomes smaller and better modulated after conditioning (i.e., it is lowest during the swing phase). Note also that the step cycle is shorter after conditioning, which translated to an increase in walking speed.

Figure 6

A: In a neurologically normal person, the spinal reflex pathway (center) responsible for the soleus H-reflex participates in many motor behaviors, ranging from standing to walking to running to athletic skills such as ballet, volleyball, and soccer. Each behavior is accompanied by task-dependent adaptation in the gain of the reflex pathway (pluses or minuses in the gray circle), which ensures that input from muscle spindle afferents contributes appropriately to soleus muscle activation during the behavior (Stein and Capaday 1988). B: In a person with spasticity due to SCI, task-dependent adaptation is impaired, and the pathway is hyperactive during sitting, standing, and walking. Down-conditioning of the soleus H-reflex reduces the gain of the reflex pathway for all three tasks, and thereby improves standing and walking.

Figure 7

Spinal and supraspinal plasticity underlies H-reflex conditioning. The shaded ovals indicate the sites of plasticity associated with operant conditioning of the H-reflex. “MN” is the motoneuron, “CST” is the main corticospinal tract, “IN” is a spinal interneuron, and “GABA IN” is a GABAergic spinal interneuron. Dashed pathways imply the possibility of intervening spinal interneurons. The monosynaptic and probably oligosynaptic H-reflex pathway from groups Ia, II, and Ib afferents to the motoneuron is shown. Definite (dark green shade) or probable (light green shade) sites of plasticity include: the motoneuron membrane (i.e., firing threshold and axonal conduction velocity); motor unit properties; GABAergic interneurons; GABAergic terminals and C terminals on the motoneuron; the Ia afferent synaptic connection; terminals conveying oligosynaptic groups I and II inhibition or excitation to the motoneuron; sensorimotor cortex; and cerebellum. The latest data suggest that the reward contingency acts through the inferior olive to guide and maintain plasticity in the cerebellum that guides and maintains plasticity in sensorimotor cortex that (via the CST) guides and maintains plasticity in the spinal cord that is directly responsible for the H-reflex change. (From (Thompson and Wolpaw 2014b).)