The purpose of this study was to determine the feasibility of using DQEMG as a means of determining pathophysiological mechanisms associated with motor deficits in compressive neuropathy. A significant aspect of the EMG signal detection protocol was that the subjects were instructed to create constant-intensity as opposed to constant %MVC force contractions. At low to moderate levels of activation, where motor unit firing rates are similar, the constant-intensity protocol results in the activation of similar numbers of motor units across various sets of muscles. The constant-intensity protocol will therefore accentuate changes in motor unit recruitment. For myopathic muscles with fewer and smaller diameter fibres 'early recruitment' (i.e. recruitment of motor units at lower levels of contraction) during constant-intensity protocols will result in reduced %MVC contractions. In contrast, for neurogenic muscle with motor unit loss and collateral reinnervation 'late recruitment' during constant-intensity protocols will result in increased %MVC contractions. In both cases, eliciting the altered recruitment, which occurs to compensate for muscle changes, produces EMG signals that can be more effectively used to detect underlying muscle changes. Because %MVC force measurement is impossible for some muscles and clinically impractical for most while most clinical EMG machines now provide an intensity measure, constant-intensity protocols (albeit at lower levels of intensity than used in this study) are used during clinical needle EMG examinations. In this study, 'late recruitment' resulted in significant changes in the levels of %MVC at which the EMG data was detected for the severe CTS group relative to the mild CTS and healthy groups. In addition, MUP morphology data revealed that individuals with severe CTS had larger amplitude and longer duration MUPs than the other two groups. Both of these differences are consistent with motor unit loss, collateral sprouting and assimilation of orphaned muscle fibers. No differences were seen in SMUP morphology or MUP complexity and stability between the groups. It is not clear whether MUP complexity and stability measures were not sensitive enough to detect differences between the groups, or whether there truly were no differences in MUP complexity and stability between the groups. Both the CMAPs and MUNEs suggested that individuals with severe CTS, who were selected based on evidence of motor deficits obtained from nerve conduction studies, and those with mild CTS who had no nerve conduction study based evidence of motor conduction block or delay (since their CMAPs were within normal limits), had evidence of axonal loss relative to the control subjects. These results indicate that the use of a constant-intensity protocol and DQEMG may provide useful information in the assessment of MUP morphological changes associated with compressive neuropathies and may augment information available from nerve conduction studies. In particular, constant-intensity based use of DQEMG, by virtue of its ability to detect differences in MUP morphology may be useful in determining whether a muscle adapts to a compressive neuropathy by using collateral sprouting as compared to axonal regeneration.
Participants
Subject recruitment for this study proved to be very difficult despite the high prevalence estimates for CTS [
1]. Recruitment was limited particularly by the exclusion criteria that required individuals to be between the ages of 18-60 and to have no other pain complaints or potentially confounding pathology, as well as our decision to target individuals with mild or severe CTS but not moderate CTS. Consequently, the number of subjects who participated in each group was smaller than originally planned; however, the subject numbers are consistent with other published literature. For example, Boe et al. [
10] found differences in MUNEs when they compared data from 10 healthy subjects to 9 patients with amyotrophic lateral sclerosis (ALS). In the present study, although the age and sex distributions were not significantly different among the groups, ideally subjects would have been matched by age and gender. The small number of subjects recruited prevented matching. Nonetheless, the sample in this study revealed significant group differences in many of the measures studied.
The questionnaire data revealed that there were similar symptom severity scores between the severe CTS group and mild CTS group, and that both groups differed from the control group. The severe CTS group had significantly lower functional scores compared to the healthy control group; however the mild CTS group was not significantly different from either the severe CTS group or the healthy control group. This result is not surprising since sensory loss is normally experienced before motor loss in CTS and as such, the sensory losses experienced in subjects with mild CTS would be similar to those sustained by individuals with severe CTS. Despite the fact that individuals with mild CTS showed no nerve conduction study based evidence of motor loss, the functional implications of their sensory loss explains why their functional scores were not different from the individuals with severe CTS. The sensory and functional scores reported in the current study are within one standard deviation, of the mean values of those reported by Levine et al [
18] in patients with CTS who were to undergo surgical repair (Symptom severity: 3.4 ± 0.67; Functional scores: 3.0 ± 0.93).
Evidence of collateral sprouting detected using DQEMG
The shape characteristics of individual MUPs provide insight into the underlying pathophysiology of neuromuscular disease [
5,
6]. For example, in individuals with neuropathy, the classic EMG findings are that MUPs with increased duration and amplitudes indicate that collateral reinnervation is occurring or has occurred [
5]. In these cases, the complexity of the waveform, as measured by the number of turns and/or phases may either be normal or increased [
5]. In the early stages of collateral sprouting, MUP duration and complexity may be increased, whereas in later stages complexity normalizes and amplitude and duration may be unchanged or larger than normal. Stability measurements can also provide useful information regarding what is occurring at the neuromuscular junction, and thus allow inferences about the state of the MUP. Ajiggle measures the amount of shape variation across the selected ensemble of MUP accelerations. Similarly, shimmerCov measures the variation across an ensemble of MUPs. Large values of Ajiggle or shimmerCov may suggest neuromuscular transmission irregularities [
11] and can be indicative of early collateral sprouting. Fibre count represents the number of muscle fibres in close proximity to the electrode [
11] and, similar to Ajiggle and shimmerCov, increases in fibre count are indicative of collateral sprouting. The results of the current study failed to find significant differences between the groups for any stability measures. The lack of significance may be due to the lack of sensitivity of the stability measures used, or perhaps the three groups had stable neuromuscular transmission. Since all of our subjects with CTS had experienced symptoms for at least three months, signs of early collateral sprouting may have been missed [
5]. It should be noted that Ajiggle and ShimmerCov tended to increase with the severity of CTS (Table
4) which might indicate that this study was underpowered in its ability to detect differences in MUP stability in this population.
MUP peak-to-peak amplitude is representative of motor unit size [
6]. As such, the larger MUP amplitude in the severe CTS group as compared to the mild CTS and control groups suggests that larger motor units were active during EMG signal detection which in turn may suggest that collateral sprouting may have occurred at some point prior to the study. Similar differences in MUP peak-to-peak amplitude were identified in patients with amyotrophic lateral sclerosis (ALS) using a constant 10% MVC contraction protocol and DQEMG [
10]. However, in contrast to Boe et al. [
10], we used a constant-intensity protocol so that the three test groups activated a similar number of motor units during EMG signal detection. The intensity of the contraction signifies the aggregate number of MUPs per second (pps) seen in the EMG interference pattern and this was not different among the groups. The constant-intensity protocol required the severe CTS group to contract at a higher percentage of their MVC (close to 40%) during EMG data collection than did the control or mild CTS groups (between 10 and 15% MVC). This resulted in the recruitment of larger motor units [
18,
19] and is consistent with motor unit loss. This difference in contraction levels between the severe CTS group and the other groups was not surprising since individuals with severe CTS by definition had motor axonal loss [
20] and thus, in order to generate an EMG interference pattern of a set level of intensity (i.e. recruit and sufficiently activate a sufficiently large set of motor units) a contraction at a higher level of %MVC relative to their pre-disease state would be required.
In order to investigate the impact of the large differences in contraction intensity between the study groups on the resultant MUP amplitudes and durations recorded from the APB, we recruited an additional sample (n = 5) of healthy individuals and had them undergo the EMG data collection procedures previously described while contracting between 10 and 15% MVC and again while contracting at 40% MVC. The DQEMG results indicated that, although the MUP amplitudes tended to be larger for the higher contraction levels, based on one-way ANOVA results, there was no significant difference in the MUP amplitudes between the two contraction levels (F = 2.45; p = 0.156; See Table
5), which were both substantially lower than the amplitudes seen in the severe CTS group in our study. There was also no difference in MUP duration between the contraction levels (F = 0.00; p = 0.96; See Table
5), which again were much smaller than those seen in the severe CTS group. There were large differences in the contraction intensity between the contraction levels (10-15% MVC: 68 pps; 40% MVC: 82 pps) suggesting that more (and therefore larger) MUs were recruited for the higher level contraction.
Table 5
Impact of contraction level on MUP amplitude in a new sample of healthy subjects.
10-15%
| 12.5 (12.5-14.6) | 68 (40-95) | 363.6 (232.5-466.3) | 6.52 (5.33-8.12) |
40
| 42 (38.9-44.7) | 82 (73-137) | 474.3 (277.4-522.8) | 6.30 (5.24-8.19) |
Both MUP and SMUP duration is thought to be influenced by axonal injury, and have been examined previously [
10], however MUP durations are also heavily dependent on the distance of the active motor unit to the recording electrode [
5]. In the current study, the severe CTS group had significantly longer MUP durations as compared to the mild CTS and control groups. The long MUP durations of the severe CTS group relative to the mild and control groups again suggests that the severe group was undergoing or had undergone collateral reinnervation [
5].
The results of the current study offer no evidence that MUPs detected from severe CTS patients have more complexity than those detected from subjects with no motor neuropathy. This might have been related to the high variability inherent in the MUP phase measures [
21‐
23] or again due to a lack of statistical power resulting from the small sample size recruited, since there was a tendency for the severe CTS group to have more phases and turns in their MUP waveforms (Table
3). Other researchers have found low reliably in determining MUP onset and end markers as compared to the high reliability found in determining the peaks [
19,
21,
24]. Calder et al. [
19] recently concluded that MUP duration (ICC: -0.29) and the number of phases in the MUP (ICC: -0.69) had poor within-subject reliability. Also using DQEMG, Boe et al. [
10] failed to find a difference in complexity between healthy individuals and those with ALS. The number of phases in MUP templates may not be sensitive enough to be used in the study of neuromuscular pathology.
Although MUP morphological characteristics offer insight into the size of the active motor units within a muscle, they are influenced by limitations of the needle electrode used to detect them [
22]. Estimating motor unit size and shape using surface EMG electrodes is thought to be a more robust representation, since there is a greater number of muscle fibers per motor unit equally contributing to the surface EMG signal and therefore to the SMUP template [
23], and because the relative distance from the active muscle fibers to the detection electrode is essentially the same for all MUs. Despite the absence of significant differences in SMUP morphology among the groups, the trends in SMUP morphology among the groups were similar in pattern to the group differences seen in the MUP morphology measures. This finding is particularly obvious in the SMUP amplitude and area data presented in Table
3. The lack of statistical significance seen in the SMUP parameters may be attributed to the large within-group variability and the small sample size.
Overall, DQEMG appears sensitive enough to determine differences in MUP amplitudes between groups of individuals with and without motor nerve impairment associated with CTS, but in the current study there were no significant differences in measures of MUP stability. The differences in MUP morphology without differences in MUP stability may reflect that collateral sprouting occurred more than three months prior to subjects participating in this study, such that orphaned muscle fibres had been reinnervated and collateral sprouts had matured. In any event, MUP stability measures appear to be of less value in this population.
Evidence of Motor axon loss detected using DQEMG
MUNEs provide information about the number of functioning motor axons in a given motor unit pool [
25‐
27]. This information is useful when evaluating the extent of motor unit loss associated with motor neuron disease or peripheral neuropathy and when assessing the course and outcome of treatment for these disorders. Using constant %MVC protocols and DQEMG, has been found to be a valid, reliable and practical tool for obtaining MUNEs [
8]. However, it has been demonstrated that as the level of contraction used increases the MUNE values decrease [
28]. Boe et al. using a 7%MVC contraction level on average have determined normative MUNE values for the APB muscle using SMUP negative-peak amplitude (269 +/- 104) [
8]. The median MUNE value of the healthy group in the current study, for which the constant-intensity based protocol resulted in a 10%MVC contraction on average, falls within one standard deviation of Boe et al's reported norm for this muscle. The MUNE values for the mild and severe CTS groups are biased to low values because of the higher level of %MVC produced during EMG signal detection and are not anatomically accurate. Nonetheless, they are valid indicators of motor unit loss when compared to the MUNE values of the control group obtained using the same constant-intensity protocol.
In this study there were significant differences in the all the CMAP amplitudes and the MUNEs between the severe CTS and healthy groups as well as the mild CTS and healthy groups. This result occurred despite the mild CTS group being screened before the study to ensure that they had no clinical evidence of motor involvement [
29]. The lack of significant difference found between the mild CTS group and the severe CTS group suggests that at least some individuals in the mild CTS group may have had axonal loss. It is possible, therefore, that MUNEs may provide a more sensitive way to detect motor nerve impairment that is not yet severe enough to be detected using traditional nerve conduction studies. This should be investigated in future studies. The fact that the group with mild CTS did not show evidence of collateral sprouting (increased MUP amplitude and duration relative to the control group) despite having lower MUNEs might indicate that they are at a different stage of the disease process than the severe CTS group.
Unlike other neuropathic conditions such as ALS, where the neuropathy is known to be degenerative in nature, nerve compression injuries can cause both demyelination and axonal loss, both of which can affect the shape characteristics of a CMAP, making it difficult to determine which pathology is most prevalent. Furthermore, it is possible that a portion of the drop in MUNE values is due to reduction in CMAP size due to temporal dispersion of contributing potentials due to conduction slowing which is not accounted for when the mean SMUP is calculated using SMUPs extracted from EMG signal detected during voluntary contractions. Inclusion of a stimulation based MUNE technique might have been informative, but unfortunately was not considered in the design of this experiment. Despite uncertainty in the underlying cause of reduced CMAP size, the consistent trend to increased mean SMUP size across the healthy, mild CTS and severe CTS groups suggest that the amplitude-based MUNE measures are sensitive to differences in the number of healthy or functioning motor units between groups of individuals with and without a given disorder. In this case the severe CTS group (i.e. those with evidence of motor involvement), had lower MUNEs than the mild CTS and control groups.
Limitations
Sensory, motor, and combined nerve conduction studies were used to stratify individuals by severity of CTS such that we had one experimental group with evidence of motor involvement (severe CTS), one group with sensory involvement but no motor involvement (mild CTS), and a control group. Although the specificity of nerve conduction studies is high, the sensitivities of the different tests is quite variable [
3]. The literature suggests that the sensitivities of the motor and mixed nerve conduction studies are lower than those of sensory nerve conduction studies [
3,
30]. Jablecki et al. [
3] reported that the pooled sensitivity (0.85) of the comparison of the median and ulnar sensory conduction between the wrist and the fourth digit proved to be the most sensitive diagnostic test [
3]. By contrast, comparisons of median and ulnar mixed nerve conduction between the wrist and palm and motor conduction studies of median nerve across the wrist were reported to have lower pooled sensitivities (0.71 and 0.63 respectively) [
3]. It is therefore possible, that our stratification based on symptoms and nerve conduction study results may not have been accurate in all subjects. In particular, in the current study the CMAP morphological features were not significantly different between the mild and severe CTS groups despite the fact that subjects were carefully screened according to the standard guidelines [
4].Individuals with mild CTS in the current study may, in fact, have had motor deficits that went undetected based on our criteria. Assessment of abnormal spontaneous activity would have been helpful to rule out motor nerve involvement in our subjects with mild CTS.