Relationship Between Spinal Reflexes and Spastic Movement Disorders

Introduction

Spasticity could affect up to 65–78% of people after SCI^1–3 and impair their sensorimotor control and quality of life^4,5. While different symptoms are likely reported as spasticity in clinical practice, tonic (e.g., hypertonia) and/or phasic (e.g., clonic) hyperactivity of muscles below the injury level^1,6 is often observed in spastic individuals with SCI^7–9. Current common spasticity treatments aim to pharmacologically disable spastic reflex hyperexcitability and/or abnormal muscle contraction (e.g., baclofen, botulinum toxin)^1,10–21; this could, unfortunately, cause an unwanted side effect of muscle weakness^15,22,23. Towards exploring a potential new therapeutic strategy to alleviate spasticity, this chapter will discuss the involvement of spinal reflexes in spastic movement disorders in chronic SCI, focusing on plantarflexors. Spinal reflexes are an effective means to excite or inhibit motoneurons directly or indirectly^24–27. Thus, it is important to understand how spinal reflexes originated from sensory afferents function and contribute to movement generation and motor control^28,29.

During walking, muscle afferents Ia, II, and Ib likely contribute differently to the activation of plantarflexors^{26,27,30–34}. Short latency reflexes originated from Ia excitation triggers corrective reaction to rapid perturbation, whereas feedback from Ib and/or II afferents likely serve as main afferent contributors to the soleus activation in unperturbed steps³⁰. In particular, force sensitive Ib afferent pathways have been indicated as key pathways for activating the plantarflexors during the propulsive force generation phase of walking^26,31–36. The Ia-mediated stretch reflex pathways are accessible on a moment-to-moment basis when there is a need to adjust the plantarflexor activity³⁶ (e.g., in response to an unexpected perturbation), but normally the soleus activation during the stance phase of walking relies on load sensitive afferent mediated pathways³³. While keeping this in mind, this chapter will discuss, primarily, the Ia-mediated stretch reflex pathways in spastic movement caused by SCI.

Modulation of spinal reflexes in normal and spastic movement control

Task- and posture-dependent modulation.

Reflexes are functionally useful and meaningful when the excitability of their pathways and behaviors can be modulated (Figure 1B). Normally, the excitability of spinal reflex pathways is modulated according to the task being performed. For example, the excitability of the soleus H-reflex (a partial electrical analog of the spinal short-latency stretch reflex) pathway decreases from standing to walking to running^37–39, which helps to prevent saturation of this pathway³⁸, and further modulated to more specialized skills such as ballet dancing, jumping and kicking a ball (Figure. 1B) such that this pathway can function appropriately in each of these motor skills and behaviors. In people with chronic SCI, regardless of the activity performed, the excitability of this reflex pathway can be stuck high and not modulated (Figure. 1C), and therefore, the reflex could be detrimental and a part of problematic spasticity.

Figure 1.

Spinal stretch reflex and H-reflex, and their modulation in people without injuries and those with spastic hyperreflexia due to chronic spinal cord injury (SCI). A: Main pathway of the spinal short-latency stretch reflex and the H-reflex. Excitation of Ia (and large II) spindle afferents activates α-motoneurons innervating the same muscle and its synergists largely monosynaptically. If the afferents are excited by muscle stretch, the response is the stretch reflex. If they are stimulated electrically, the response is the H-reflex. The activity of this spinal pathway is strongly affected by excitatory (red) and inhibitory (navy) input of spinal and supraspinal origins. B: In an individual with no injuries, 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 dancing, jumping, and kicking a ball. The gain of the reflex pathway (+ and - in the gray circle) is modulated between the tasks such that the input from muscle spindle afferents contributes appropriately to soleus activity in each of these movement tasks. C: In a person with spasticity due to SCI, task-dependent reflex gain modulation is often impaired, and the pathway could remain hyperactive regardless of the movement tasks, and therefore non-functional. Modified from¹⁰⁷.

Phase-dependent modulation.

During dynamic motion such as locomotion, these reflexes are also phase-dependently modulated. For instance, the soleus H- and stretch reflexes are phase-dependently modulated during walking, in accord with soleus motoneuron excitability level (expressed indirectly through the EMG activity), which is high in the mid-stance phase and little-to-none in the swing phase^40,41. In individuals with SCI, soleus H- and stretch reflexes are unsuppressed or often large in the mid-late swing phase⁴² (Figure 2). This supports the possibility that these reflexes, if not suppressed adequately, would contribute to inappropriate soleus activity in the swing phase and exacerbate foot drop⁴³.

Figure 2.

Phase-dependent modulation of the soleus H-reflex and stretch reflexes during walking in people without neurological injuries and people with spasticity due to chronic incomplete SCI. A: Examples of the soleus H-reflex during the mid-stance and late-swing phase of and walking in a participant without known neurological injuries (top, black) and in a participant with chronic incomplete SCI (bottom, blue). Height, weight, and age are similar in these two individuals. Each trace is the average of ≥10 EMG sweeps and the time of stimulation is indicated with an arrowhead in each panel. In the participant without injuries, the H-reflex is present in the mid-stance when the soleus is active but completely suppressed in the late-swing phase when the soleus is not active. In the participant with SCI, the H-reflex is not suppressed in the late-swing. B: Amplitudes (mean ± SE) of the soleus EMG, H-reflex, and M1 (soleus short-latency) and M2 (soleus medium-latency) stretch reflexes during walking in participants with chronic incomplete SCI and participants without. For calculating the soleus EMG, >100 unperturbed steps were averaged for each participant. For calculating reflex sizes, for each participant in each of eight equal bins of the step cycle, ≥10 responses were averaged together and normalized to the maximum M-wave (M_max) amplitude measured during standing. Bins 1 to 4 correspond to the stance phase, bin 5 to the stance-swing transition, and bins 6 to 8 to the swing phase. Horizontal lines labeled with “S” in indicate the average maximum H-reflex (H_max) amplitudes during standing. For all panels, statistically significant differences between the groups (red) and between the bins (blue, for the SCI group only) by Student t-test with Bonferroni correction are indicated. Modified from⁴².

Clonus during walking.

Clonus, which is often associated with spastic hyperreflexia^44–46 (however, see also⁴⁷), also impairs walking. As elicitation of stretch reflexes requires only a degree or two of joint rotation⁴⁸, when those reflexes are not suppressed adequately, ground contact that produces a small joint motion perturbation can elicit stretch reflexes, which in turn trigger clonus in individuals with spastic hyperreflexia. Clonus triggered in the late swing to swing-stance transition phase often continues into the stance phase, exaggerates breaking force, reduces forward propulsion, continues into smaller fused push-off bursts and propulsive force generation^49,50, thereby contributing to slow gait⁵¹. Notably, muscle stretch and joint rotation are not the only input sources that trigger clonus; during walking, non-noxious cutaneous nerve stimulation that produces cutaneous sensation around the foot often triggers clonus in the plantarflexors of spastic individuals with chronic SCI (non-published observations by the authors), similarly to dorsiflexion perturbation or H-reflex eliciting posterior tibial nerve stimulation reported previously⁴². The fact that different kinds of afferent input can trigger clonus may further suggest that to some extent, the problems are in the motoneuron (i.e., the final common path for generating motor function and behaviors), multiple spinal interneurons that mediate between the afferents and motoneurons, and/or deprivation of appropriate descending input to the spinal neural circuitry in general.

Abnormal excitability modulation of spinal reflexes in SCI.

Abnormal excitability modulation of spinal reflexes arising from muscle spindle afferent^52–58 is likely be further exacerbated by abnormal reciprocal inhibition between the antagonists^{52,56,59–62}. Reflex abnormalities are also present in other spinal pathways, such as those of Ib inhibition⁶³, recurrent inhibition⁶⁴, and cutaneous reflexes⁶⁵, and are often accompanied by changes in spinal motoneurons and interneurons^66–69. These pathways may also interact with each other^60,70–73. Altogether, in the spinal cord of individuals with chronic SCI, the excitability modulation and function of multiple pathways become impaired, contributing to abnormal motoneuron firing^{66,68,69,74–76} and motor control^12,56,77. Based on these facts, we may view spasticity in chronic SCI as impaired regulation of reflexive excitation of motoneurons and inadequate suppression of motoneuron firing, at least partly.

Spinal reflexes as tools to probe the neural state

Since spinal reflexes are a means of the CNS to excite or inhibit motoneurons, by examining spinal reflexes, we can learn so much about the state of the CNS⁷⁸. In doing so, one should be cognizant of the context in which a reflex is measured and the purpose of measuring a reflex.

Presence/absence and when.

The presence or absence of a reflex indicates whether that specific reflex pathway is available to excite motoneurons in a specific context in which the reflex is measured^37–39. For instance, in individuals without injuries, the soleus H- and stretch reflexes are present during the mid-stance of walking, indicating that these reflex pathways are available to excite soleus motoneurons; whereas during the mid to late swing phase, those reflexes are almost completely absent, indicating that their pathways are not available as the means to excite the same motoneurons (see Figure. 2)^36,37. In spastic individuals with SCI, the H- and stretch reflexes are present in the late-swing phase and can be robust⁴² and trigger clonus that continues into the following stance and leads to a chain of events that impair gait^49–51. A reflex that cannot be turned off when it should be or a reflex whose excitatory/inhibitory action cannot be asserted when it is critical^79,80 would not be useful but detrimental in motor control. Reflexes measured at a specific phase of movement or during a specific task may therefore give insight into normal or abnormal neural control of movements in people with SCI and others.

Reflex measurements at rest.

In the traditional clinical setting, reflex assessments are often made at rest or made without monitoring pre-stimulus ongoing EMG activity or posture. During such “resting” reflex measurements, the subthreshold level of motoneuron pool’s excitability is unknown and uncontrolled⁸¹. That is, from the surface EMG signal, we cannot know how close or far the motoneuron pool’s excitability is from the firing threshold, and therefore, the variability in subthreshold level of motoneuron pool’s excitability from one reflex measurement to another would be unknown. Thus, when a reflex is measured at rest, a large sample size or a large effect size is likely necessary to overcome such measurement variability. When measuring a reflex at rest, the stimulation rate (for post-activation depression^8,81–83), the agonist and antagonist muscles’ ongoing EMG activity (for motoneuron pool’s excitability, post- and presynaptic inhibition^{61,62 84–87}), and joint posture (for posture-dependent reflex gain modulation^88–91) should be carefully considered in the protocol development. Reflexes are influenced by many factors. At rest, the excitability variability in many spinal neurons including motoneurons is unknown/uncontrolled. Therefore, resting reflexes should be interpretated carefully in association with spasticity and neuromuscular impairments.

Examination of a reflex in dynamic motion to understand its dynamic function.

Abnormal reflex behaviors observed at rest, during static motor tasks, or during isolated joint motion in individuals with SCI^{52–56,66,67,69,92} have encouraged us to assume that spinal reflex abnormalities contribute to spastic movement disorders^93,94. However, in people with spastic hemiparesis due to stroke, stretch reflexes that are hyperexcitable at rest or in passive conditions are near normal or even suppressed during active muscle contractions^95,96, and antispastic medication does not necessarily improve motor function^23,93,97,98. In spastic individuals with chronic SCI, the soleus stretch reflex excitability is elevated during sitting or lying in supine^99,100; the reflex gain and reflex stiffness do not decrease with muscle activation¹⁰⁰; and those reflexes are abnormally large in the mid to late swing phase of walking⁴² (Figure. 2), likely contributing to spastic gait disorders⁵⁰. These observations are reminder that how we measure the reflex matters⁸¹. That is, we can determine whether a reflex functions abnormally and contributes to impaired motion, through its examination in the actual dynamic motion; a reflex characterization measure made at rest would not immediately explain how it functions. In sum, reflexes are useful neural probes of the CNS, as long as we measure them correctly for the intended measurement purposes and apply appropriate interpretation on the gathered observations.

A method to train the CNS to control the excitability of a neural pathway - operant conditioning

In the previous sections, we discussed; (1) reflexes are effective means to excite spinal motoneurons and functionally meaningful when their excitability is adequately modulated; (2) when a reflex is not modulable or its modulation is impaired, it could become a part of spastic movement disorders; and (3) reflexes can be used as robust tools to probe the state of the CNS when the user knows how to use and interpret them. A question that may arise from these facts is “can we train a reflex behavior to improve the CNS function, to improve movement generation and control?” For example, can we train a hyperexcitable reflex to decrease its excitability, thereby making the spastic muscle less spastic and improving spastic movement disorders? Since a spastic limb is not necessarily a strong limb^51,93, removing or reducing the motoneuron’s ability to fire altogether^1,10–21 wouldn’t be ideal. Instead, if we could improve reflexive excitation of motoneurons and motoneuron firing behaviors, that would be preferable. Operant conditioning of spinal reflexes can be one such approach.

Operant conditioning of spinal reflexes.

Operant conditioning is a powerful method for modifying a behavior based on its consequences^78,101–104. Through trial and error, a subject learns to produce a behavior that is rewarded¹⁰¹. Through repetition, a trained neural behavior becomes a habitual behavior¹⁰². With operant conditioning of a spinal reflex, a subject is rewarded for producing a larger (with up-conditioning) or a smaller (with down-conditioning) reflex. Since the amplitude of a reflex reflects the excitability of that reflex pathway at the time of reflex elicitation^{28,81,105,106}, with reflex operant conditioning, we can train the CNS to produce the neural activity that increases (up-conditioning) or decreases (down-conditioning) the excitability of the targeted reflex pathway^{103,104,107–109}. As this is done repeatedly and persistently, over time, the spinal reflex pathway (including spinal interneurons and motoneurons) goes through anatomical and physiological changes^{78,103,104,107,109–122}; and the changes persist after conditioning ends^{78,103,104,107,109,110,117–121,123–125}. Markedly different from conventional pharmacological therapies, reflex operant conditioning does not disable certain connections (e.g., botulinum toxins) or enhance general inhibition (e.g., baclofen), either of which would limit muscle activation and contraction regardless of the motor functions of the person’s intention. When a reflex that underlies spasticity is targeted by down-conditioning^107,109, that reflex’s excitability decreases but preserves motoneuron’s ability to fire in response to voluntary effort¹²⁴ or when it is functionally appropriate (e.g., mid-late stance phase of walking¹²⁶) (Figure 3)^125,127, and thereby helps to improve locomotion in SCI^{104,107,109,119–121,128–135}.

Figure 3.

Soleus H-reflexes in individuals with spastic hyperreflexia due to chronic incomplete SCI, in whom H-reflex size decreased significantly through down-conditioning¹²⁵ and effects of H-reflex down-conditioning on locomotor EMG activity. A: Average H-reflexes for a baseline session (black dotted line) and the last conditioning session (blue solid line) from a participant with SCI. B: Average (±SE) H-reflex size for baseline, conditioning, and 1- and 3-month follow-up sessions. C: Locomotor EMG in the soleus and tibialis anterior (TA) in absolute value before (dashed) and after (solid, green) down-conditioning in an individual whose H-reflex size decreased through down-conditioning. Soleus push-off burst was increased and TA’s co-contraction with the plantarflexors in the stance phase was decreased after conditioning (Modified from¹²⁵). Push-off burst is highlighted by a red oval.

Summary

Spinal reflexes are an effective means of exciting or inhibiting spinal motoneurons. The CNS generates different motor functions, in part, by modulating the excitability of various spinal reflex pathways. Thus, reflexes can serve as tools to probe the CNS state or how it is functioning. During locomotion, spinal reflexes make a meaningful contribution. When a reflex becomes not modulable or its modulation becomes impaired due to injuries and diseases, it becomes a part of spastic gait and other movement disorders. It should be noted that abnormal reflex behaviors observed during chronically impaired locomotion do not necessarily mean that they are the causes of impairments. Hyperexcitable stretch or Ia reflex pathways shaped by the altered descending neural input may be partial underlying causes of spastic gait, or products of compensatory or adaptive plasticity to chronic SCI; nonetheless, they are often part of the post-SCI spastic gait⁴². When considering various features and functions of spinal reflexes, simply removing or suppressing reflex pathways altogether seems far from an optimal solution. Instead, making these pathways more usable by restoring their excitability modulation through neurobehavioral training (e.g., reflex operant conditioning) could be a better solution for enhancing functional recovery in people with spasticity due to SCI or other CNS injuries^{125,127,128,135,136}.

Key Points.

• The central nervous system(CNS) generates various motor functions, in part by modulating the excitability of spinal reflex pathways that drive spinal motoneurons.

• When reflex modulation becomes impaired due to spinal cord lesions or other CNS diseases, it could become a part of spastic movement disorders.

• Particularly for locomotion, in which spinal reflexes make a meaningful contribution, impaired reflexes could become a part of spastic gait and other movement disorders.

• Taking advantage of such features of spinal reflexes, it is possible to operantly condition a reflex to improve the CNS activity and resulting motor function.

Synopsis.

The CNS generates various motor functions, in part by modulating the excitability of spinal reflex pathways, which are effective means of driving spinal motoneurons. When a reflex becomes not modulable or its modulation becomes impaired due to spinal cord lesions or other CNS diseases, it could become a part of spastic movement disorders. For the CNS with or without chronic lesions, thus, reflexes can be used as tools to probe its state. Utilizing such feature of spinal reflexes, it is possible to operantly condition a reflex to improve CNS activity and resulting motor function in spastic individuals with spinal cord lesions.

Consideration in Clinics.

• In the traditional clinical setting, reflex assessments are often made at rest or made without monitoring pre-stimulus ongoing EMG activity or posture. While controlling details of reflex testing procedures could be challenging in the clinic, the clinician or examiner who administers the reflex testing should know the limitations and implications of what they measured in their specific setting.

• A reflex measured at rest could be a useful characterization measure, but it is not a valid explanation for impaired motor function.

• Operant conditioning of a spinal reflex may be used as an effective neurobehavioral training tool to enhance function recovery in people with spasticity due to SCI or other CNS injuries.