In this study, we utilized a position-feedback controlled linear slider for tendon tapping to accurately estimate the stretch reflex thresholds in the dominant arm of control subjects. We then compared our results to reflex thresholds obtained in the spastic and contralateral BB muscle of chronic stroke survivors from a prior study. As reported previously, a significantly lower reflex threshold was observed on the spastic limb of stroke subjects compared to that on the contralateral limb [
18]. The novel result of this study is that the reflex threshold on the contralateral limb was significantly lower than that found in the BB muscle in the dominant arm of age-matched intact subjects.
These statistically significant differences in reflex threshold between the contralateral limb of stroke and the dominant limb of intact subjects support our hypothesis that after stroke there is a bilateral impact on MN excitability in both limbs of our sample of stroke survivors, potentially due to stroke-related damage of bilaterally distributed spinal tracts (such as the RS tract). Besides, correlation analysis of the reflex thresholds between the spastic and contralateral sides showed a clear positive correlation (Fig.
5). This observation suggests that the RS influence is proportional bilaterally, i.e., the reduced threshold on the contralateral side is a function of the excitability on the spastic side.
In previous work, particularly in animal studies, it appears that there is a bilateral near-symmetrical distribution of the RS tract within the spinal cord. It follows that any influence of the RS tract on stretch reflexes should be discernable on both sides after a hemispheric stroke. Axons containing serotonin, originating in neurons within the caudal portion of raphe nucleus [
19], are known to project densely throughout both sides of the cord. These neuromodulatory inputs alter the intrinsic properties of MNs to produce an increase in their excitability by enhancing voltage-gated conductances for sodium (MN soma) and calcium (MN dendrites). Cortical damage in stroke appears to alter the control of these modulating pathways in the brainstem [
18].
Acoustic startle reflex (ASR)
The ASR has been used to estimate the involvement of the RS tract in stroke survivors, and the results suggest a contributing role of the RS tract to spasticity. These studies also report a prevalence of exaggerated startle reflex on the spastic side in stroke survivors compared to the contralateral side during rest [
10,
12]. Jankelowitz and Colebatch also reported a lower latency in the BB of the spastic limb compared to the contralateral limb at rest [
10]. Previously, findings from animal studies have consistently supported the essential role of the caudal pontine reticular nucleus in the startle reflex with a lesion to this area inhibiting the startle reflex [
20]. The ASR circuitry involves the cochlear nucleus, MNs of the brainstem, caudal pontine reticular nuclei, and the spinal cord activated through the medial RS tract [
21]. Exaggerated ASR responses have been observed in the spastic muscle of chronic stroke survivors suggesting that there is RS tract hyperexcitability compared to the contralateral limb of stroke survivors and control subjects [
10,
12]. However in these studies systematic comparisons between the contralateral limbs of hemispheric stroke survivors and control subjects were not performed, thus the bilateral effect of RS tract hyperexcitability has not been documented.
Lateralization of spasticity
Our data supports the contention that RS tract activation, which has bilateral descending influences, is at least partially responsible for increased stretch reflex excitability, post-stroke, as both contralateral and affected sides show increased MN excitability as compared to intact subjects. Still, spasticity, diagnosed routinely only on the affected side, with strongly increased MN excitability on the affected side as compared to the contralateral side (our previous study), may be due to a more strongly lateralized pathway, such as the VS pathway. Below, we highlight possible mechanisms that should further enhance our understanding, including research studies that show unequal distributions of the RS tract.
One plausible explanation of the sharp lateralization of spasticity can be the involvement of the VS tract. Miller et al. found significant differences in the relative amounts of the vestibular drive impacting the MN pools in the spastic and contralateral sides [
22]. These differences have been attributed to the disruption of inhibitory corticobulbar projections to the contralesional vestibular nuclei. However, the role of RS tract in spasticity cannot be fully ignored as the vestibular and reticular complexes do have extensive interconnections [
23]. It has been suggested that acoustic stimuli could also activate ASR through the RS pathways [
8] but results from animal studies show that the lesion to the vestibular nuclei fails to eliminate startle [
20]. Further investigation is necessary to observe the isolated effect of acoustic stimuli to the vestibular nuclei on MN pools in the absence of RS tract influence.
It could be argued that despite being extended bilaterally and substantially affecting the MN excitability on both sides of the cord, the differences in the reflex threshold or the sharp lateralization of spasticity may be due to unequal distribution of the neurons projecting in the RS tract. This could result in increased MN excitability on both sides of the cord as compared to intact subjects, with greater influence on the affected side. Evidence to support this claim originates from studies investigating the anatomical distribution of RS projections [
24,
25]. It is not yet possible to establish the precise anatomical distribution of RS projection in humans using tracing studies, but evidence from animal studies indicates that bilateral distribution of the neurons on the RS tract is not exactly equal to both sides.
For example, Sakai et al. have used bilateral retrograde tracing in non-human primates to show a regional variation in the distribution of RS neurons in the ponto-medullary reticular formation [
24]. Further, they utilized unilateral retrograde tracing to determine the ipsilateral and contralateral contributions of the pontine-medullary reticular formation. They found a dominant proportion (60:40) of the RS cells arising from the ipsilateral gigantocellular reticular nucleus, similar distributions of neurons arising from the Caudal pontine-reticular nucleus (10 times less in number than those found in gigantocellular reticular nuclei), and higher contralateral contributions arising from the Oralis pontine-reticular nucleus. Based on this, it would be a reasonable assumption that despite being bilateral, the distribution of neurons in the RS pathway may have a weak ipsilateral dominance, which could explain the difference in reflex threshold between the contralateral and spastic limbs in this study. However, it is important to mention that the criteria to identify the reticular nuclei are generally made on gross features such as cell size and density, thus the boundaries of these nuclei are not necessarily distinct [
16]. Therefore, we consider it is inconclusive to associate the sharp lateralization of spasticity to the weak ipsilateral dominance of neurons distribution.
Another factor that may contribute to increased MN hyperexcitability on the spastic side is activation of persistent inward currents, due to the possible increase in monoaminergic drive to the spinal cord. The neural circuitry and mechanisms by which this could occur on the spastic side only are yet to be determined. While the role of persistent inward currents in spasticity after spinal level lesions has been well established, there is limited evidence that supports the role of persistent inward currents and monoamines in spasticity after a cerebral lesion [
26].
Clinically practiced methods to objectively measure spasticity, such as MAS evaluation, require minimal time to perform but lack the resolution to identify subtle changes in MN excitability [
27]. While the linear-motor setup is time-consuming, the method used in this paper and previously in [
18,
28] is more reliable in quantifying changes in MN excitability. Further, this method provides a consistent accuracy at the millimeter scale that could be utilized when measuring outcomes over the time course of treatment.