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The Evoked Potential Operant Conditioning System (EPOCS): A Research Tool and an Emerging Therapy for Chronic Neuromuscular Disorders

The Evoked Potential Operant Conditioning System (EPOCS) is a software tool that implements protocols for operantly conditioning stimulus-triggered muscle ...

Medical University of South Carolina

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. 

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.

An operant-conditioning protocol that bases reward on the electromyographic response produced by a specific CNS pathway can change that pathway. For example, in both animals and people, an operant-conditioning protocol can increase or decrease the spinal stretch reflex or its electrical analog, the H-reflex. Reflex change is associated with plasticity in the pathway of the reflex as well as elsewhere in the spinal cord and brain. Because these pathways serve many different behaviors, the plasticity produced by this conditioning can change other behaviors. Thus, in animals or people with partial spinal cord injuries, appropriate reflex conditioning can improve locomotion. Furthermore, in people with spinal cord injuries, appropriate reflex conditioning can trigger widespread beneficial plasticity. This wider plasticity appears to reflect an iterative process through which the multiple behaviors in the individual's repertoire negotiate the properties of the spinal neurons and synapses that they all use. Operant-conditioning protocols are a promising new therapeutic method that could complement other rehabilitation methods and enhance functional recovery. Their successful use requires strict adherence to appropriately designed procedures, as well as close attention to accommodating and engaging the individual subject in the conditioning process. 

Targeted neuroplasticity for rehabilitation.

Nothing either good or bad but action makes it so.

People can learn over training sessions to increase or decrease sensorimotor rhythms (SMRs) in the electroencephalogram (EEG). Activity-dependent brain plasticity is thought to guide spinal plasticity during motor skill learning; thus, SMR training may affect spinal reflexes and thereby influence motor control. To test this hypothesis, we investigated the effects of learned mu (8-13 Hz) SMR modulation on the flexor carpi radialis (FCR) H-reflex in 6 subjects with no known neurological conditions and 2 subjects with chronic incomplete spinal cord injury (SCI). All subjects had learned and practiced over more than 10 < 30-min training sessions to increase (SMR-up trials) and decrease (SMR-down trials) mu-rhythm amplitude over the hand/arm area of left sensorimotor cortex with ≥80% accuracy. Right FCR H-reflexes were elicited at random times during SMR-up and SMR-down trials, and in between trials. SMR modulation affected H-reflex size. In all the neurologically normal subjects, the H-reflex was significantly larger [116% ± 6 (mean ± SE)] during SMR-up trials than between trials, and significantly smaller (92% ± 1) during SMR-down trials than between trials ( < 0.05 for both, paired -test). One subject with SCI showed similar H-reflex size dependence (high for SMR-up trials, low for SMR-down trials): the other subject with SCI showed no dependence. These results support the hypothesis that SMR modulation has predictable effects on spinal reflex excitability in people who are neurologically normal; they also suggest that it might be used to enhance therapies that seek to improve functional recovery in some individuals with SCI or other CNS disorders.

Effects of Sensorimotor Rhythm Modulation on the Human Flexor Carpi Radialis H-Reflex.

Damage to the corticospinal pathway often results in weak dorsiflexion of the ankle, thereby limiting the mobility of people with multiple sclerosis (MS). Thus, strengthening corticospinal connectivity may improve locomotion. Here, we investigated the feasibility of tibialis anterior (TA) motor-evoked potential (MEP) operant conditioning and whether it can enhance corticospinal excitability and alleviate locomotor problems in people with chronic stable MS. The protocol consisted of 6 baseline and 24 up-conditioning sessions over 10 weeks. In all sessions, TA MEPs were elicited at 10% above active threshold while the sitting subject provided 30-35% maximum voluntary contraction (MVC) level of TA background EMG. During baseline sessions, MEPs were simply measured. During conditioning trials of the conditioning sessions, the subject was encouraged to increase MEP and was given immediate feedback indicating whether MEP size was above a criterion. In 3/4 subjects, TA MEP increased 32-75%, MVC increased 28-52%, locomotor EMG modulation improved in multiple leg muscles, and foot drop became less severe. In one of them, MEP and MVC increases were maintained throughout 3 years of extensive follow-up sessions. These initial results support a therapeutic possibility of MEP operant conditioning for improving locomotion in people with MS or other CNS disorders, such as spinal cord injury and stroke.

Operant Up-Conditioning of the Tibialis Anterior Motor-Evoked Potential in Multiple Sclerosis: Feasibility Case Studies.

The activity of corticospinal pathways is important in movement control, and its plasticity is essential for motor skill learning and re-learning after central nervous system (CNS) injuries. Therefore, enhancing the corticospinal function may improve motor function recovery after CNS injuries. Operant conditioning of stimulus-induced muscle responses (e.g., reflexes) is known to induce the targeted plasticity in a targeted pathway. Thus, an operant conditioning protocol to target the corticospinal pathways may be able to enhance the corticospinal function. To test this possibility, we investigated whether operant conditioning of the tibialis anterior (TA) motor evoked potential (MEP) to transcranial magnetic stimulation can enhance corticospinal excitability in people with and without chronic incomplete spinal cord injury (SCI). The protocol consisted of 6 baseline and 24 up-conditioning/control sessions over 10 wk. In all sessions, TA MEPs were elicited at 10% above active MEP threshold while the sitting participant provided a fixed preset level of TA background electromyographic activity. During baseline sessions, MEPs were simply measured. During conditioning trials of the conditioning sessions, the participant was encouraged to increase MEP and was given immediate feedback indicating whether MEP size was above a criterion. In 5/8 participants without SCI and 9/10 with SCI, over 24 up-conditioning sessions, MEP size increased significantly to ~150% of the baseline value, whereas the silent period (SP) duration decreased by ~20%. In a control group of participants without SCI, neither MEP nor SP changed. These results indicate that MEP up-conditioning can facilitate corticospinal excitation, which is essential for enhancing motor function recovery after SCI. NEW & NOTEWORTHY We investigated whether operant conditioning of the motor evoked potential (MEP) to transcranial magnetic stimulation can systematically increase corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA) in people with and without chronic incomplete spinal cord injury. We found that up-conditioning can increase the TA MEP while reducing the accompanying silent period (SP) duration. These findings suggest that MEP up-conditioning produces the facilitation of corticospinal excitation as targeted, whereas it suppresses inhibitory mechanisms reflected in SP.

Operant conditioning of the tibialis anterior motor evoked potential in people with and without chronic incomplete spinal cord injury.

Foot drop is very common among people with chronic incomplete spinal cord injury (SCI) and likely stems from SCI that disturbs the corticospinal activation of the ankle dorsiflexor tibialis anterior (TA). Thus, if one can recover or increase the corticospinal excitability reduced by SCI, motor function recovery may be facilitated. Here, we hypothesized that in people suffering from weak dorsiflexion due to chronic incomplete SCI, increasing the TA motor-evoked potential (MEP) through operant up-conditioning can improve dorsiflexion during locomotion, while in people without any injuries, it would have little impact on already normal locomotion. Before and after 24 MEP conditioning or control sessions, locomotor electromyography (EMG) and kinematics were measured. This study reports the results of these locomotor assessments. In participants without SCI, locomotor EMG activity, soleus Hoffmann reflex modulation, and joint kinematics did not change, indicating that MEP up-conditioning or repeated single-pulse transcranial magnetic stimulation (i.e., control protocol) does not influence normal locomotion. In participants with SCI, MEP up-conditioning increased TA activity during the swing-to-swing stance transition phases and ankle joint motion during locomotion in the conditioned leg and increased walking speed consistently. In addition, the swing-phase TA activity and ankle joint motion also improved in the contralateral leg. The results are consistent with our hypothesis. Together with the previous operant conditioning studies in humans and rats, the present study suggests that operant conditioning can be a useful therapeutic tool for enhancing motor function recovery in people with SCI and other central nervous system disorders. NEW & NOTEWORTHY This study examined the functional impact of operant conditioning of motor-evoked potential (MEP) to transcranial magnetic stimulation that aimed to increase corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA). In people with chronic incomplete spinal cord injury (SCI), MEP up-conditioning increased TA activity and improved dorsiflexion during locomotion, while in people without injuries, it had little impact on already normal locomotion. MEP conditioning may potentially be used to enhance motor function recovery after SCI.

Operant conditioning of the motor-evoked potential and locomotion in people with and without chronic incomplete spinal cord injury.

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.

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

In people with spasticity due to chronic incomplete spinal cord injury (SCI), it has been presumed that the abnormal stretch reflex activity impairs gait. However, locomotor stretch reflexes across all phases of walking have not been investigated in people with SCI. Thus, to understand modulation of stretch reflex excitability during spastic gait, we investigated soleus stretch reflexes across the entire gait cycle in nine neurologically normal participants and nine participants with spasticity due to chronic incomplete SCI (2.5-11 year post-injury). While the participant walked on the treadmill at his/her preferred speed, unexpected ankle dorsiflexion perturbations (6° at 250°/s) were imposed every 4-6 steps. The soleus H-reflex was also examined. In participants without SCI, spinal short-latency "M1", spinal medium latency "M2", and long-latency "M3" were clearly modulated throughout the step cycle; the responses were largest in the mid-stance and almost completely suppressed during the stance-swing transition and swing phases. In participants with SCI, M1 and M2 were abnormally large in the mid-late-swing phase, while M3 modulation was similar to that in participants without SCI. The H-reflex was also large in the mid-late-swing phase. Elicitation of H-reflex and stretch reflexes in the late swing often triggered clonus and affected the soleus activity in the following stance. In individuals without SCI, moderate positive correlation was found between H-reflex and stretch reflex sizes across the step cycle, whereas in participants with SCI, such correlation was weak to non-existing, suggesting that H-reflex investigation would not substitute for stretch reflex investigation in individuals after SCI.

Modulation of soleus stretch reflexes during walking in people with chronic incomplete spinal cord injury.

This study investigated effects of ankle joint angle on the Hoffman's reflex (H-reflex) excitability during loaded (weight borne with both legs) and unloaded (full body weight borne with the contralateral leg) standing in people without neurological injuries. Soleus H-reflex/M-wave recruitment curves were examined during upright standing on three different slopes that imposed plantar flexion (-15°), dorsiflexion (+15°), and neutral (0°) angles at the ankle, with the test leg loaded and unloaded. With the leg loaded and unloaded, maximum H-reflex/maximum M-wave ratio of -15° was significantly larger than those of 0° and +15° conditions. The maximum H-reflex/maximum M-wave ratios were 51%, 43%, and 41% with loaded and 56%, 46%, and 44% with unloaded for -15°, 0°, and +15° slope conditions, respectively. Thus, limb loading/unloading had limited impact on the extent of influence that ankle angles exert on the H-reflex excitability. This suggests that task-dependent central nervous system control of reflex excitability may regulate the influence of sensory input on the spinal reflex during standing.

Effect of Ankle Angles on the Soleus H-Reflex Excitability During Standing.

Corticospinal pathway and its function are essential in motor control and motor rehabilitation. Multiple sclerosis (MS) causes damage to the brain and descending connections, and often diminishes corticospinal function. In people with MS, neural plasticity is available, although it does not necessarily remain stable over the course of disease progress. Thus, inducing plasticity to the corticospinal pathway so as to improve its function may lead to motor control improvements, which impact one's mobility, health, and wellness. In order to harness plasticity in people with MS, over the past two decades, non-invasive brain stimulation techniques have been examined for addressing common symptoms, such as cognitive deficits, fatigue, and spasticity. While these methods appear promising, when it comes to motor rehabilitation, just inducing plasticity or having a capacity for it does not guarantee generation of better motor functions. Targeting plasticity to a key pathway, such as the corticospinal pathway, could change what limits one's motor control and improve function. One of such neural training methods is operant conditioning of the motor-evoked potential that aims to train the behavior of the corticospinal-motoneuron pathway. Through up-conditioning training, the person learns to produce the rewarded neuronal behavior/state of increased corticospinal excitability, and through iterative training, the rewarded behavior/state becomes one's habitual, daily motor behavior. This minireview introduces operant conditioning approach for people with MS. Guiding beneficial CNS plasticity on top of continuous disease progress may help to prolong the duration of maintained motor function and quality of life in people living with MS.

Can Operant Conditioning of EMG-Evoked Responses Help to Target Corticospinal Plasticity for Improving Motor Function in People With Multiple Sclerosis?

Muscle spindle afferent feedback is modulated during different phases of locomotor tasks in a way that facilitates task goals. However, only a few studies have studied H-reflex modulation during landing. This study aimed to characterize soleus (SOL) H-reflex modulation during the flight and early landing period of drop landings. Since landing presumably involves a massive increase in spindle afferent firing due to rapid SOL muscle stretching, we hypothesized H-reflex size would decrease near landing reflecting neural modulation to prevent excessive motoneuron excitation. The soleus H-reflex was recorded during drop landings from a 30 cm height in nine healthy adults. Electromyography (SOL, tibialis anterior (TA), medial gastrocnemius, and vastus lateralis), ankle and knee joint motion and ground reaction force were recorded during landings. Tibial nerve stimulation was timed to elicit H-reflexes during the flight and early ground contact period (five 30 ms Bins from 90 ms before to 60 ms after landing). The H-reflexes recorded after landing (0-30 and 30-60 ms) were significantly smaller (21-36% less) than that recorded during the flight periods (90-0 ms before ground contact; P ≤ 0.004). The decrease in H-reflex size not occurring until after ground contact indicates a time-critical modulation of reflex gain during the last 30 ms of flight (i.e., time of tibial nerve stimulation). H-reflex size reduction after ground contact supports a probable neural strategy to prevent excessive reflex-mediated muscle activation and thereby facilitates appropriate musculotendon and joint stiffness.

Article	Year
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. Journal of neurophysiology\| PubMed ID: 24944216	2014
Targeted neuroplasticity for rehabilitation. Progress in brain research\| PubMed ID: 25890136	2015
Nothing either good or bad but action makes it so. The Journal of physiology\| PubMed ID: 28198019	2017
Effects of Sensorimotor Rhythm Modulation on the Human Flexor Carpi Radialis H-Reflex. Frontiers in neuroscience\| PubMed ID: 30090056	2018
Operant Up-Conditioning of the Tibialis Anterior Motor-Evoked Potential in Multiple Sclerosis: Feasibility Case Studies. Neural plasticity\| PubMed ID: 30123249	2018
Operant conditioning of the tibialis anterior motor evoked potential in people with and without chronic incomplete spinal cord injury. Journal of neurophysiology\| PubMed ID: 30207863	2018
Operant conditioning of the motor-evoked potential and locomotion in people with and without chronic incomplete spinal cord injury. Journal of neurophysiology\| PubMed ID: 30625010	2019
H-reflex conditioning during locomotion in people with spinal cord injury. The Journal of physiology\| PubMed ID: 31215646	2021
Modulation of soleus stretch reflexes during walking in people with chronic incomplete spinal cord injury. Experimental brain research\| PubMed ID: 31309252	2019
Effect of Ankle Angles on the Soleus H-Reflex Excitability During Standing. Motor control\| PubMed ID: 31899887	2020
Can Operant Conditioning of EMG-Evoked Responses Help to Target Corticospinal Plasticity for Improving Motor Function in People With Multiple Sclerosis? Frontiers in neurology\| PubMed ID: 32765389	2020
Soleus H-reflex modulation during a double-legged drop landing task. Experimental brain research\| PubMed ID: 35122483	2022

Aiko K. Thompson

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