Despite extensive investigations, the mechanism behind ankle instability remains unclear. The reason for this may be that most of this research had a focus that was far too narrow. Most attention has traditionally gone toward spindle afferents from the peroneal muscles (which are stretched by inversion of the ankle). Typically, stretch reflexes in these muscles were induced in subjects that were standing on a trapdoor that induced ankle inversion. Such methods are reliable when applied in any given laboratory (14), but the results are often inconclusive when it comes to comparing the results of different research groups or when predicting ankle instability. Some studies claim that peroneal reflex latencies are delayed in patients with unstable ankles, whereas others do not find any difference at all even if the patient groups are reasonably similar. Is this because of differences in methods or because the paradigm used has severe limitations? Experimental conditions usually differ, indeed considerably, between groups (e.g., the angle of rotation or the speed of inversion). The onset of the rotation of the platforms is measured with different degrees of accuracy. The analysis techniques are not standardized either. The responses elicited by the inversion are evaluated with widely diverging methods. Some authors use "visual inspection" to determine response onset latency, whereas others use sophisticated automated algorithms for the same purpose. Some authors even express the results in onset latency of the peak of the response. In addition, the experimental paradigm used may have some serious shortcomings.
Whatever the reason, it can be concluded that despite extensive efforts, this field has progressed only minimally, and conclusive evidence is scarce. The question then arises whether the experimental model itself may be too limited and needs to be replaced by newer approaches based on recent research findings. In fact, it is claimed here that this research field has been "getting off on the wrong foot," and it is proposed therefore to abandon some of the older techniques and instead to try new directions.
At this moment, the most common type of experiment uses a small platform with trapdoors that fall to a restricted position (∼30 degrees) while the subjects are standing. Alternatively, subjects are sitting, and a device induces sudden ankle inversions (33). The advantage of these techniques is that they provide reasonably reproducible results in any given laboratory, but there are some drawbacks. The silent assumption made in all these "static" experiments is that the evoked responses are comparable to those obtained under circumstances where ankle sprains occur. This can be questioned, however. First, the physical stimulus may be quite different. During standing, the speed of inversion at the ankle is determined by the weight of the subject. In contrast, under dynamic conditions such as walking and jumping, the impact on the inverting surface is much larger and consequently, the speed of inversion is increased as well. Speeds of inversion while standing can be as low as 50 degrees·s−1 (25), whereas they can be as high as 403 degrees·s−1 during a walking task (27) and 595 degrees·s−1 in a jumping task on inverting surfaces (17). In sports, it is to be expected that speeds are even higher because the laboratory experiments on jumping used jumps from moderate height (30 cm (17)) whereas higher jumps are common in volleyball and basketball.
In addition, reflexes are known to be both task and phase dependent. Task dependency means that the strength of reflexes (the "gain") depends on the task or behavior (e.g., standing, sitting, walking, running, etc.).
The groups of Carpenter and Frank have shown that when people are standing on an elevated platform, their reactions to perturbations differ from those seen for the same perturbations applied when standing on a ground surface. This type of contextual dependency is thought to be caused by descending influences from cortical regions. In fact, it is known that a large proportion of descending fibers does not end on the motoneurons but instead on reflex pathways to these motoneurons. This allows for a high degree of flexibility of reflexes (which goes counter the notion that reflexes are fully stereotyped reactions). In the case of reflexes to ankle inversion, this aspect has received little attention. However, one can assume that patients with unstable ankle are much more afraid when tested on inverting surfaces as compared with control subjects. Hence, any difference that one may find can be biased by this "inversion" fear (similar to the fear of falling of the subjects tested at great height). The modulation is not limited to the same task being performed under different conditions. Indeed, similar modulating influences are thought to play a role in adjusting reflexes when people switch from one task to another. For example, the soleus H-reflex is large during standing but is reduced during walking, even when the exact same stimuli are used under both conditions (2). Inversely, cutaneous reflexes from the sural nerve are larger during walking than during standing (11).
Phase dependency of reflexes means that for the same stimuli, the response may differ depending on the phase in the step cycle when a given stimulus is applied. This is further explained in Figure 1.
For example, in the experiments of Capaday and Stein (2), it was shown that at the onset of stance (when ankle inversion is most likely to occur), the soleus H-reflexes were enhanced. Similarly, cutaneous reflexes are very strongly influenced by phase. In fact, for such reflexes, one can encounter a complete reflex reversal with a change from facilitatory to suppressive responses in some muscles such as tibialis anterior (TA) at end swing and onset of stance (9,36).
Given these complexities, it is clear that one cannot simply extrapolate the findings from standing to walking or jumping. Some researchers have successfully used a weight-shifting paradigm (34). Others studied landing from a step down or a hop. For example, De Noronha et al. (5) used a landing test in which participants stood on one lower extremity for 3 s on a step, then hopped down onto a force plate and regained postural stability after landing. Participants in the instability group took longer to regain stability (time to stability) after landing, and they displayed greater inversion variability in the prejump period than the control group. Other authors also have stressed the differences in prejump activation between subjects with functional ankle instability versus controls (e.g., for the peroneal muscles (4)).
Although being one step closer to daily life realities, these experiments still have the disadvantage that landing is on a flat surface rather than on a tilted one. Instead, it makes sense to study reflexes directly while stepping or jumping onto inverting surfaces. This has been achieved in recent years. The technique involves a trapdoor on which subjects either jump (Fig. 2 (17,26)) or step (Fig. 3 (19,27)).
From these studies, it was learned that there are both short- and long-latency reflexes (SLR and LLR) in the peroneal muscles, but these responses are too late to have any effect during the ankle inversion movement. Furthermore, the responses are not restricted to the peroneal muscles. The SLR occurred in several leg muscles, whereas the LLR was present even in hip or back muscles. This prompted the hypothesis that the SLR are mostly "local" responses (involving only the stretched muscles) whereas the LLR are part of a global response, involving the whole body, similar to the automated postural responses described after platform perturbations. It thus appears that the peroneus response, which was widely seen as the most prominent defense against ankle inversion, is in fact part of a generalized postural equilibrium response. This is not to claim that the reflex is not important in the prevention of ankle sprain. Indeed, the exact moment of rupture of ligaments in relation to ankle inversion is unknown, and it is possible that the injury occurs after and not during the ankle inversion. In the latter case, the whole-body reaction may be essential in resisting further stretch after the initial ankle inversion. Unloading of the inverted ankle is likely to be a crucial element.
Although it is clear that progress has been made in the laboratory in approaching the experimental conditions closely related to the situations where ankle sprains occur, it also is evident that there still are essential steps to be taken. For example, for safety reasons, the experiments so far have excluded completely unexpected perturbations, although the latter may be an important element in the generation of ankle sprains. Nevertheless, it has been possible to manipulate the level of expectedness, and this has led to the insight that anticipation may indeed play a crucial role. In the experiments of Nieuwenhuijzen and Duysens (27), the subjects were told that a surface, on which they had to step, was never inverting, whereas in another condition, they were informed that the surface could sometimes invert. When no inversion was anticipated, the TA was activated directly at touchdown in conjunction with a near-normal heel strike. Such activity was absent, however, when a possible inversion was expected, even in those trials where there was no inversion occurring (hence, the physical condition was the same in the two situations). Such observations underscore the importance of the level of expectation because the presence of a preactivation may have an effect on the damping at touchdown and on the ensuing reflexes, as well. These complexities are completely overlooked in the traditional paradigm with standing subjects because the foot is in a fixed position. In contrast, during jumps, the ankle angle at landing can be very different depending on the anticipation, thereby allowing for much more variation.
LOAD RECEPTORS AND REFLEXES
From the previous section, it is clear that weight shifts and unloading are crucial elements in the reactions to ankle inversion. However, so far, little attention has been paid to load receptors and their reflexes in the context of ankle inversion presumably because of the predominant focus on group Ia spindle afferents. Nevertheless, it is increasingly clear that sensory feedback about limb loading is of utmost importance in controlling posture and gait (for review, see Duysens et al. (13)). The primary receptors involved are the muscle Golgi tendon organs (GTOs) because they are known to be very sensitive to muscle contraction and loading (20).
In the context of ankle inversion, it has been emphasized that loading of the limb at the onset of stance is a very critical element in the generation of ankle injuries (31). Consequently, it has been proposed that adequate unloading may be a very appropriate strategy to prevent ankle sprains (29). Nevertheless, very few studies have examined the role of loading and unloading in ankle inversion. An important exception is the study of Santos and Liu (29). They used nociceptive electrical stimulation to the lateral aspect of the ankle during standing to induce unloading. The individuals also moved their whole body downward and shifted the body weight to the nonstimulated foot. The authors rightfully point out that the withdrawal reflex has been misrepresented as primarily a flexor response, whereas in fact, the dominant feature may be unloading of extensors. Subjects with functional ankle instability showed increased and faster body weight unloading after stimulation (30). It is tempting to see this as a learned strategy to avoid recurrent sprains. Santos et al. (30) pointed out that this hyperreactivity may partially account for the sensation of the ankle "giving way" in this group.
In addition, it should be emphasized that here again, the reaction (in this case unloading of the limb) is widespread and involves extensor muscles throughout the whole limb. Evolutionarily, it makes sense to have a system that protects against overloading (the flexor reflex) along with a second system providing reinforcing force feedback (13). Both during mastication and during locomotion, there is evidence for such reinforcing feedback at low force levels whereas suppressive reactions (unloading) are seen above a given load threshold. Lowering this threshold after ankle injury is meaningful because it will lead more easily to protective unloading.
The existence of reinforcing force feedback has received substantial support for years starting from the earlier work on cats (8). In this work, it was shown that GTOs from extensor muscles can be activated by inducing contractions in these muscles (Fig. 4). In addition, it was found that this GTOs firing was associated with a suppression of the activity bursts in antagonist flexor muscles.
In humans, there has been a major effort to identify the role of afferent feedback in the regulation of muscle activations during stance (16). These and other data are compatible with the presence of reinforcing feedback from GTOs (6). In a recent study, the length of muscle fascicles was measured along with responses to stretch (3). The results clearly showed that the stretch responses were hard to understand if they were generated by muscle spindles because the responses increased even when there was no evidence for muscle lengthening. Hence, again, there was evidence for a nonspindle contribution, and the most likely candidate are the Ib afferents from GTOs because they are very fast conducting and therefore can contribute to short-latency responses that are only slightly later than Ia-induced responses.
SKIN AFFERENTS AND CUTANEOUS REFLEXES
Another neglected area includes the skin afferents. Sudden ankle inversions during standing induce stretch in the peroneal muscles, and one may assume that this stretch induces Ia-mediated reflexes, but it also can stretch neighboring skin. There is little doubt that the fastest responses seen in these muscles may indeed be caused by Ia reflexes because Ia afferents provide monosynaptic activation of motor units of the parent muscle. However, the responses described in the literature usually last long enough to be related to other polysynaptic pathways. Hence, it is worthwhile to consider some other possibilities such as skin stretch.
First, there is increased interest in the contribution of skin afferents. This is likely to be caused by the finding that taping is effective in the prevention of ankle sprains (32). Indeed, there is a common belief that this beneficial effect is partly related to increased activation of skin afferents. It is thought that the benefit is not only caused by the larger mechanical stability, but also to an increased afferent input from skin receptors that are stimulated by the traction of the tape (24). Karlsson and Andreasson (21) showed that ankle taping shortened the reaction time significantly in peroneal muscles of unstable ankles. The added exteroceptive function of taping is of special interest because affected kinesthesia and decreased joint position sense are common in subjects with chronically unstable ankles (22). Reduced feedback in these patients may be part of the reason for their recurrent sprains.
Although it is now widely accepted that muscle spindles play a key role in proprioception, there is still no consensus on a similar role for cutaneous afferents. Especially in the hairy skin, slowly adapting Type II receptors are responsive to muscle stretch and therefore provide appropriate proprioceptive signals. These signals can be used to perceive movement (kinesthesia). For example, removal of input from receptors in joint and muscle does not completely eliminate the sense of movement. This is likely related to activity in a population of cutaneous afferents because single afferent microstimulation is not very effective in producing illusions. In addition, the activation of groups of afferents (e.g., by skin stretch) can reliably induce illusions of movement both in the upper limb and in the leg. Similarly, position sense also is likely to depend on cutaneous afferent input. Data from microneurography indicate that cutaneous afferents with receptive fields surrounding the ankle can potentially encode the direction of two-dimensional movements of this joint. One important element however is that in all these studies, the position sense is measured in sitting subjects. This is a severe limitation because one should not extrapolate the findings too easily to conditions of movement. This is because sensations are not the same during rest and during movement, as has been shown in numerous studies. Furthermore, even during movement, the perception of a given stimulus can differ depending on the timing of the stimulus in the step cycle. To give just one example, it was found that the sensation of a cutaneous stimulus at the foot was significantly reduced at the onset of the stance phase of walking as compared with other phases in the step cycle (12).
Could cutaneous afferents also play a role in preventing ankle inversion in normal subjects when taping is absent? It has been shown that joint movements (including those from the ankle) not only activate stretched muscles spindles but also stretched skin receptors. Such cutaneous afferent information is potentially used in reflex activations of leg muscles. For example, Fallon et al. (15) used microneurography studies to show that there can be reflex modulation of the firing probability in single motor units by single cutaneous afferents from the foot. These results clearly suggest that there is a strong synaptic coupling between tactile afferents and spinal motoneurons. It remains to be shown though that this also is true for skin that is stretched by ankle inversion.
At least it is known that there is the potential of having afferent firing from stretched skin during gait. Using a technique to record from single afferents during gait in cats, it has been shown that cutaneous afferents from the distal leg fire in particular parts of the step cycle even when the nerve fibers involved are not located in the skin that is in contact with the ground (23) (Fig. 5).
This is best explained by skin stretch induced by locomotor movements. In humans, similar evidence is lacking, but recordings from the sural nerve have indicated that there is massive input from the foot after touchdown (18). Because the sural nerve innervates mostly skin that is not in contact with the ground, it is conceivable that some of this afferent firing is related to skin movement. The area innervated by the sural nerve is of particular interest with respect to ankle inversion because it is this zone in particular which is being stretched during inversion of the ankle (in fact some of this skin could partly overlay the stretched muscles). Damage caused by ankle injury could easily involve this nerve as well. One would predict that this could lead to a loss of proprioception at the ankle, and this in turn could be responsible for altered placement of the foot at landing and during the stance phase. Such abnormalities have indeed been observed in patients with chronic ankle instability (CAI) (7,28). One way of testing these hypotheses is to investigate the effects of sural nerve stimulation in CAI patients. If the nerve is indeed damaged, one would predict that reflexes, normally elicited from that nerve, would be deficient in CAI.
MOVING FROM LOCAL (PERONEAL) TO GLOBAL (FULL-BODY) INVESTIGATION OF REFLEX MODULATION
One striking feature that came out of recent investigations is that most reactions to perturbations involve a widespread activation of muscles rather than just the recruitment of a single muscle group (such as the peroneal muscles in this case). For example, electrical stimulation of sural nerve afferents during gait elicits widespread reflex responses in various muscles of the leg in humans (9,35,36,37). These responses are usually quite specific for the skin area involved, such that stimulation of nerves innervating different parts of the foot activates different sets of muscles (35,37). For the sural nerve area, the responses occur more strongly in the biceps femoris than in the semitendinosus, suggesting that exorotation of the foot could occur (10). In the lower leg, the effects of sural nerve activations may go in the direction of a stabilization of the foot with respect to eversion and inversion. The medial gastrocnemius is more activated than the lateral gastrocnemius (10). Thus, as pointed out by Zehr et al. (37), this can cause eversion of the foot. However, there is simultaneous facilitation in TA that would produce inversion. In addition, sural nerve stimulation produces very consistent reflex suppression in peroneal muscles in the stance phase of walking (1), thereby contributing to foot inversion (Fig. 6). It follows that the net effect may be a stabilization of the ankle because of a mixture of inverting and everting actions.
In conclusion, to advance this field of research into the mechanisms counteracting ankle sprains, it is essential that one should gradually move away from artificial paradigms that have limited extrapolation value toward real sports situations. In addition, recent physiological knowledge should be taken into account and one should consider the possibility that afferents other than Ia muscle spindle afferents could be very important both in the responses to induced ankle inversions and in the evaluation or perception of ankle angle. Finally, the restriction of investigations to the study of the peroneal muscles is too narrow because there is increasing evidence that the whole body participates in reactions to ankle perturbations.
The authors thank Dr. Hamill for the many helpful suggestions to improve the article. The idea for this article came from very stimulating discussions with colleagues F. Staes and W. Helsen. The authors also thank M. Gradussen for secretarial help. This study was supported by grants from bijzonder onderzoeksfonds KU-Leuven (OT/08/034 and IDO/07/012). Note that there is an omission of references from the laboratories of Jim Frank, Mark Carpenter, and Dan Marigold (such as Marigold and Misiaszek, Neuroscientist. 2009;15:36) because of a limitation in number of references.
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