Lateral epicondylalgia (LE), commonly termed “tennis elbow,” is a prevalent and disabling condition with high rates of symptom chronicity and recurrence. LE has been described as a local insertional tendinopathy, with morphological changes evident in the extensor carpi radialis brevis (ECRB) muscle (9,18,28,34,50). However, sensorimotor dysfunctions present in unilateral LE are frequently bilateral, affect both local and remote upper limb muscles, and persist beyond 6 months (1,4,31). These observations suggest that supraspinal mechanisms may be involved in the motor dysfunction associated with the persistence of LE symptoms. One mechanism that could underpin motor dysfunction and subsequent persistence/recurrence of LE is reorganization of the networks in the motor cortex associated with upper limb muscles.
Preliminary evidence from chronic low back pain suggests loss of discrete motor cortical organization associated with impaired motor control of the back muscles (45,46). That work showed two discrete motor cortical representations, each related to a separate group of back muscles (i.e., short/deep multifidus vs long superficial longissimus), in healthy individuals when the cortical representation is mapped using transcranial magnetic stimulation (TMS). Yet, individuals with chronic low back pain display only one (45). This observation provides evidence of reorganization of the motor cortex, and one interpretation is that there is an overlap or blurring of the motor cortical representations of individual back muscles that may provide a physiological basis for motor dysfunction in chronic musculoskeletal pain. In support of this proposal, it is known that the discrete representation of individual fingers in the primary motor cortex is essential for isolated finger movements (3) and that a lack of discrete cortical representation, as reported in focal hand dystonia, is associated with loss of isolated movement and impaired hand function (39). It would be reasonable to speculate that changes in organization of the cortical representation of the forearm extensors, similar to that occurring in chronic low back pain and focal hand dystonia, could explain observations of sensorimotor dysfunction and underpin persistence and recurrence of symptoms in LE. This possibility has yet to be examined.
As a first step toward identification of cortical changes in LE, we aimed to 1) investigate the excitability and organization of the primary motor cortical territory devoted to ECRB and extensor digitorum (ED) in individuals with LE and in asymptomatic controls and 2) examine the relation between motor cortex parameters and measures of pain severity. Consistent with findings in other musculoskeletal conditions, we hypothesized that motor cortical networks with projections to ECRB would be more excitable and demonstrate less separation between the centers of gravity (CoG) of the cortical representations of ECRB and ED in individuals with LE than asymptomatic controls, and these cortical changes would be associated with pain severity in LE.
MATERIALS AND METHODS
Participants
A convenience sample of 11 individuals with LE (five males, 44 ± 11 yr; mean ± SD) and 11 healthy controls matched for age, gender, and handedness (five males, 42 ± 11 yr) were recruited from local health care practices, community advertisements, and a participant database. Control participants were matched within ±5 yr of the age of individuals with LE (80% matched within ±2 yr). Handedness was assessed by a verbal question. A physiotherapist not otherwise involved in the study screened potential participants with LE using a previously reported telephone interview and clinical examination (10). Participants were included if they reported unilateral elbow pain lasting for longer than 6 wk with pain over the lateral humeral epicondyle provoked by two or more of the following activities: gripping, resisted wrist or middle finger extension, or palpation in conjunction with reduced pain-free grip on the affected side. Individuals with LE were excluded if they reported a concomitant neck or arm pain that prevented participation in usual work or recreational activities, had received conservative treatment in the last 6 months, or had evidence of other sources of elbow pain such as exacerbation of pain with neck movement or manual examination, sensory disturbances, history of fractures, elbow surgery, arthritic or inflammatory disorders, or pain localized to the radiohumeral joint (10,11). In addition, LE and control participants were excluded if they had any contraindications to TMS, such as history or family history of epilepsy, major neurological, respiratory, orthopaedic or circulatory disorders, or if they were pregnant or had a metal in their head or jaw. Participants gave a written informed consent for experimental procedures, which were approved by the institutional human research ethics committee. The study was performed in accordance with the Declaration of Helsinki.
Sample size
A sample size calculation was performed using data for the variable “map volume” obtained from previous studies on chronic low back pain. These data indicate a minimum difference in means between the patient and control groups of 6.4 mV and an SD of 4.8 mV (45). On the basis of these values, 80% power and alpha 0.05, 11 participants were required in each group.
Clinical measures of LE
The valid and reliable Chronic Pain Grade Questionnaire (CPGQ) was used to classify LE participants into one of four grades (low disability and low pain intensity (I), low disability and high pain intensity (II), high disability and moderate activity limitation (III), and high disability and severe activity limitation (IV)) in the dimensions of pain intensity, disability, and duration (48). Using the CPGQ, participants rated pain intensity at the time of testing (“How would you rate your elbow/arm pain on a 0–10 scale at the present time, that is right now, where 0 is “no pain” and 10 is “pain as bad as it could be?”), worst pain in the past 6 months, and pain-related disability in the past 6 months on an 11-point numerical rating scale from 0 to 10 and reported their duration of pain-related disability in the past 6 months. The CPGQ also includes a pain severity subscore (out of 4), with higher values indicating greater chronicity.
The Patient-Rated Tennis Elbow Evaluation (PRTEE), a reliable, reproducible, and sensitive tool in LE, was used to assess average pain and disability of the affected arm during the week preceding testing (24). Scores for pain (sum of five of 50 items) and function (sum of 10 of 50 items divided by two) were combined to give a total score ranging from 0 (no pain and no functional impairment) to 100 (worst pain imaginable with significant functional impairment).
EMG recording
Surface electrodes were used to record EMG from the ED and ECRB of the elbow using silver–silver chloride disc electrodes (diameter, 10 mm; Grass Telefactor, Warwick, RI). Electrode position was determined after palpation of the ED and ECRB during resisted metacarpophalangeal extension and third finger extension, respectively (15,35). The reference electrode was positioned over the acromion. EMG signals were amplified (CED 1902; Cambridge Electronic Design, Cambridge, United Kingdom), band-pass–filtered between 20 and 1000 Hz, and sampled at 2 kHz using a Power 1401 Data Acquisition System and Signal 3 software (Cambridge Electronic Design, Cambridge, United Kingdom).
TMS
A Magstim 200 stimulator (Magstim Co. Ltd., Dyfed, United Kingdom) was used to deliver single-pulsed TMS to the motor cortex using a figure-of-eight coil (diameter, 7 cm). Before TMS, the participant’s vertex was measured and marked on the scalp, and a Brainsight neuronavigation system (Rogue Research, Inc., Quebec, Canada) was used to register this point. The coil was positioned 45° to the midsagittal plane to preferentially induce a current in a posterior-to-anterior direction in the cortex (5). The scalp site that evoked the largest responses in both the ED and ECRB was located and targeted using the Brainsight software. The distance from this point to the midline and the vertex was measured and recorded. Resting motor threshold (rMT) was determined for the ED and ECRB separately and defined as the minimum stimulator intensity that evoked a response in the target muscle of at least 50 μV for five of 10 stimuli when applied to the optimal scalp position. All TMS procedures adhered to the TMS checklist for methodological quality (8).
Mapping procedure
Participants sat comfortably with their head and neck supported and the test arm (LE group, side of pain; control group, same arm as that tested for the matched LE participant) resting in forearm pronation and elbow flexion on a pillow across the lap. Because there was a difference of less than 2% in rMT between muscles (LE participants: ED = 61 ± 10, ECRB = 59 ± 13; control participants: ED = 56 ± 14, ECRB = 58 ± 15), maps for each muscle were generated concurrently using 120% of ECRB rMT. This procedure for mapping multiple muscles has been used previously (38,39).
TMS was applied every 6 s with a total of five stimuli at each site. Mapping began at the optimal scalp position and moved pseudorandomly over a grid marked with 1 × 1 cm squares until no motor-evoked potential (MEP) was recorded (defined as less than 50 μV peak-to-peak amplitude in all five trials). Participants were instructed to maintain their hand and forearm relaxed throughout the experiment, and this was monitored using visual feedback of EMG.
Data and statistical analysis
Map volume was calculated for each muscle (ED and ECRB) for the assessed hemisphere. For each muscle, the mean peak-to-peak MEP amplitudes at all active sites were summed to calculate the volume. A site was considered “active” if the mean peak-to-peak amplitude (measured between set cursors) of the five MEP evoked at that site was greater than 50 μV. The CoG was defined as the amplitude weighted center of the map (47,49) and was calculated for each muscle using the formula:
;)
where Vi is the mean MEP amplitude at each site with the coordinates Xi, Yi.
The reliability of this mapping procedure for calculating the volume and CoG of representational maps has been previously demonstrated both with the target muscle at rest and during active contraction (25,27,47). Using these data, the distance between the CoG of the maps of the ED and ECRB was calculated using the Pythagoras theorem. Three-dimensional maps of each muscle were created for each participant to allow a qualitative review of the cortical representations.
Statistical analyses were conducted blind to participant group. Data were assessed for normality using the Kolmogorov–Smirnov statistic. CoG separation and ECRB volume required log transformation to meet assumptions of normality and equal variance for the ANOVA. Data were compared between groups (LE vs control) and muscles (ECRB vs ED) using two-way ANOVA for the following map parameters: 1) peak MEP amplitude and 2) map volume. A one-way ANOVA compared CoG separation between groups (LE vs control) and the optimal scalp site for evoking an MEP (combined hotspot vs ECRB vs ED) in each group. Regression lines (first- or second-order polynomial based on the line of best fit) were used to assess the relation between peak MEP amplitude, map volume, CoG separation, and pain severity (at rest at time of testing and worst pain in the last 6 months). Pearson correlation coefficients were then calculated for linear relations, and Spearman rank correlation coefficients were calculated for nonlinear relations. All analyses were performed blind to participant group and, where appropriate, corrected for multiple comparisons using Holm–Sidak post hoc tests. Significance was set at P < 0.05. Unless stated otherwise, all values provided in text are mean ± SD.
RESULTS
The characteristics of the LE participants are summarized in Table 1. The duration of LE symptoms was 9 ± 6 months. At the time of testing, pain severity at rest was 2.7 ± 2.0 on the CPGQ 11-point numerical rating scale. The worst pain in the last 6 months was 6.7 ± 2.3, and in the last week, 6.7 ± 2.4 (2.5 ± 0.7 at rest). The mean CPGQ pain severity subscore for LE participants was 2.5 ± 0.7, and for the PRTEE, 29.3 ± 16.6.
TABLE 1: LE participant characteristics.
Map parameters
Comparison of the combined hotspot used for mapping and the actual hotspot for each muscle revealed no difference in the optimal scalp site (effect of muscle: latitude, P = 0.95; longitude, P = 0.9) in either LE (combined hotspot: latitude = 5.0 ± 0.8, longitude = 0.5 ± 1.4; ECRB: latitude = 5.2 ± 1.2; longitude = 0.8 ± 1.4; ED: latitude = 5.1 ± 1.3, longitude = 0.5 ± 1.5) or control participants (combined hotspot: latitude = 4.6 ± 0.9, longitude = 1.1 ± 1.3; ECRB: latitude = 4.7 ± 1.1, longitude = 1.4 ± 1.4; ED: latitude = 4.7 ± 1.0, longitude = 1.2 ± 1.3). Peak MEP amplitude was greater for both ED and ECRB in individuals with LE (ED, 0.82 ± 0.35; ECRB, 1.3 ± 0.79) than that in healthy controls (ED, 0.64 ± 0.37; ECRB, 0.71 ± 0.46; main effect of group: F1,40 = 5.5, P = 0.024; main effect of muscle: F1,40 = 1.8, P = 0.19; group–muscle interaction: F1,40 = 0.84, P = 0.37). Similarly, map volume was greater for LE participants than that for healthy controls for ED (Fig. 1A and B) (LE, 9.3 ± 5.5; controls, 8.2 ± 5.6) and ECRB (LE, 15.5 ± 13.1; controls, 6.4 ± 4.9; Fig. 1C and 1D; main effect of group: F1,40 = 4.6, P = 0.037; main effect of muscle, F1,40 = 0.15, P = 0.69; group–muscle interaction: F1,40 = 1.1, P = 0.31). Although the difference was small, the distance between the CoG of ECRB and ED was systematically less in individuals with LE (0.11 ± 0.05) than that in healthy participants (0.2 ± 0.1; main effect of group: F1,20 = 7.4, P = 0.013) (Fig. 2A and B).
FIGURE 1: Illustration of group mean total map volume (not normalized) obtained for ED (A) and ECRB (C) in LE participants and those obtained for ED (B) and ECRB (D) in healthy controls. Coordinates are referenced to the vertex (0, 0). The average MEP amplitude evoked at each scalp site is indicated by the colored scale (mV) and the vertical Z-axis. Map volume and peak amplitude were greater for ECRB and ED in LE participants than those in controls (both, P < 0.05).
FIGURE 2: Group mean of the position of the CoG for ED (black circles) in LE participants (A) and control participants (C) and ECRB (white circles) in LE participants (B) and control participants (D) superimposed on the mean motor map (not normalized). Coordinates are referenced to the vertex (0, 0). CoG of ECRB (white circle) is transposed onto the maps of ED to highlight intermuscle separation. The distance between the CoG of ECRB and ED was less in LE participants than that in healthy controls (P < 0.05).
Observation and post hoc analysis of the three-dimensional motor maps revealed an additional novel feature that differed systematically between participant groups. This related to the number of sites on the motor cortex over which TMS evoked a relatively discrete “peak” or “hotspot” in each motor representation. As this study is the first to examine cortical organization in LE, this feature has not been previously reported. An additional measure was developed to quantify this feature. Maps for each muscle in each participant were normalized to the maximum MEP amplitude. Discrete peaks were identified if the MEP amplitude at a grid site 1) was greater than 50% of maximum map amplitude, 2) was at least 5% greater than the MEP amplitude of seven of eight surrounding grid sites, and 3) was not adjacent to another identified map peak. Using this definition, 3.2 ± 1.5 (range, 1–6) and 3.4 ± 1.5 (range, 1–6) discrete peaks were identified for the ED and ECRB muscles, respectively, for the healthy controls. The number of discrete peaks in cortical activity within each map (two-way ANOVA; factors, group and muscle) was less in LE participants for both ED and ECRB, with 1.8 ± 1.0 (range, 1–4) and 1.4 ± 0.8 (range, 1–3) peaks identified for ED and ECRB, respectively (Figs. 3 and 4) (main effect of group, F1,40 = 17.9, P < 0.001; main effect of muscle: F1,40 = 0.22, P = 0.64; group–muscle interaction: F1,40 = 0.74, P = 0.39).
FIGURE 3: Three-dimensional representations of motor maps of ED (A) and ECRB (B) in one representative LE participant and ED (C) and ECRB (D) in one representative healthy control participant demonstrating the number of discrete map “peaks” for each muscle. Data are normalized to the maximum MEP amplitude for each participant. Sites colored blue have an amplitude less than the 50% threshold criteria for a peak. Sites that met the criteria for a “peak” are marked with a circle. The number of peaks in the motor maps of both muscles was less in LE participants than that in healthy controls (P < 0.05).
FIGURE 4: Three-dimensional representations of motor maps of ED (A) and ECRB (B) for a second representative LE participant and ED (C) and ECRB (D) in a second representative healthy control participant demonstrating the number of discrete map “peaks” for each muscle. Data are normalized to the maximum MEP amplitude for each participant. Sites colored blue have an amplitude less than the 50% threshold criteria for a peak. Sites that met the criteria for a “peak” are marked with a circle. The number of peaks in the motor maps of both muscles was less in LE participants than that in healthy controls (P < 0.05).
Relation between neurophysiological and clinical data
In LE participants, shorter distance between the CoG of ED and ECRB was related to a higher pain severity score at rest (r = 0.64, P = 0.034) and a higher score for “worst pain in the last 6 months” (r = 0.60, P = 0.049). A larger peak MEP in ECRB (ρ = 0.67, P = 0.023) and ED (r = 0.82, P = 0.002) and greater map volume in both muscles (ECRB: ρ = 0.61, P = 0.032; ED: r = 0.64, P = 0.035) was also correlated with a higher “worst pain in the last 6 months” score. Correlations are shown in Figure 5.
FIGURE 5: Correlation in LE participants between the following: the distance between the ED and ECRB CoG and pain severity at rest (A), the distance between the ED and ECRB CoG and worst pain in the last 6 months (B), the maximum MEP amplitude for ECRB and worst pain in the last 6 months (C), the maximum MEP amplitude for ED and worst pain in the last 6 months (D), the total map volume for ECRB and worst pain in the last 6 months (E), and the total map volume for ED and worst pain in the last 6 months (F). Less separation between the ED and ECRB CoG, greater ECRB and ED maximum MEP amplitude, and greater ECRB and ED map volume were associated with higher pain scores in LE participants either at rest or in the last 6 months (P < 0.05).
DISCUSSION
This study demonstrates that the motor cortical organization of the wrist and finger extensor muscles is altered in LE and that specific features of this reorganization are related to pain intensity at rest and/or over the past 6 months. Key observations were a more excitable motor cortical representation of ECRB and ED and a smaller distance between the CoG of the cortical representations of ECRB and ED in individuals with LE than that in asymptomatic controls. Our additional analysis of the number of discrete peaks in the motor map provides particularly novel insight into the reorganization of the motor cortex in our clinical pain group.
Motor cortical reorganization in LE
The organizational structure of the human primary motor cortex relies on a balance between discrete (individual muscle) and distributed (overlapping, within limb) representations, a concept known as functional somatotopy (12,14,44). For instance, cortical representations of the finger and elbow muscles overlap by 14%–35% and maintain somatotopically discrete centers (2,32). This structure is understood to be necessary for integrated, multijoint, and synergistic movements and to allow fine individuated motor control (13,32). Evidence from functional magnetic resonance imaging and intracortical microstimulation studies suggests that this structure is based on variation in the threshold of excitability such that individual muscles have a lower threshold for excitation for key movements (observed as discrete peaks of excitability) whereas movements of adjoining muscles have a higher threshold for excitation (19,32). Consistent with these data, the presence of multiple discrete peaks in excitability in the wrist muscles of healthy individuals in our study can be interpreted to reflect intermuscle coordination required for different functions (19,30,42).
Two features of primary motor cortex organization were altered in LE participants. First, the number of discrete peaks in excitability was reduced. Second, the distance between the CoG of ED and ECRB was decreased. These changes indicate an altered motor cortical organization that may underpin compromised intermuscle coordination and loss of individuated movement in LE. For instance, a reduced number of map peaks may contribute to poor coordination between wrist extensor and finger flexor muscles, leading to maintenance of the wrist in a more flexed position, as is reported in LE (4). Furthermore, a decrease in the distance between the CoG of ED and ECRB has been interpreted to reflect greater overlap and blurring of the spatial territory of the cortical representation for each muscle (25,49) and is consistent with observations in other pain conditions such as focal hand dystonia (39), chronic low back pain (37,45), and phantom limb pain (20). As somatotopically discrete centers are known to be important for fine individuated movement, less separation between the CoG of the cortical representations of wrist muscles could provide a substrate for motor dysfunction, particularly a loss of individuated movement, in LE. However, these aspects of motor control were not measured in the current study. The relation between simplified motor cortical organization and motor dysfunction in LE requires further investigation. Further studies using alternative methods such as functional magnetic resonance imaging would be required to confirm whether the observation of less separation in CoG of the recorded muscles reflects a true overlap of boundaries of cortical maps.
Possible mechanisms of altered cortical organization
Repetitive afferent input arising from prolonged motor practice plays a key role in the development of maladaptive cortical reorganization. In particular, muscles that repeatedly cocontract or contract nearly simultaneously produce convergent patterns of afferent input that drive the cortical representations for these muscles closer together (29). For instance, electrical stimulation applied simultaneously to two hand muscles in healthy individuals leads to a greater overlap and increased volume in the cortical representations of stimulated muscles (38). Similarly, repetitive movement training in primates produces significant disruption in the primary sensory cortex, characterized by enlargement, overlap, and a loss of differentiation in the cortical hand representation (6,7). Because LE is common in people who perform manual tasks with repeated rapid movements of the wrist and forearm (17,43), it is possible that near-synchronous afferent input generated by repeated wrist extension contributes to the abnormalities reported here.
Although the mechanism underlying altered cortical organization in LE was not examined in the present study, cortical representations are known to be maintained and adjusted by intracortical inhibitory networks through modulation of the γ-aminobutyric acid (GABA) (22). A key function of GABAergic inhibition is to facilitate the contraction of muscles required for execution of a motor task (reduced inhibition) while preventing unwanted movements, muscle overflow, and cocontraction of surrounding muscles (increased inhibition) (23). Thus, this mechanism is essential for the differentiation of motor output from the primary motor cortex and subsequent isolated movement control. Intracortical inhibition is increased in acute pain (36) but reduced in chronic pain (21,26,41), and the magnitude of this reduction is linked to pain severity (40). Because GABAergic inhibition is essential to maintain cortical representations, reduced inhibition is a plausible mechanism to explain increased map volume, greater MEP amplitude, and less separation between the CoG of the cortical representations of the ED and ECRB muscles in LE. If this hypothesis is confirmed in future work, therapies that restore intracortical inhibition may normalize cortical abnormalities and improve pain and function in LE.
Relation between cortical organization and pain
We provide evidence that a shorter distance between the CoG of the cortical representations of ECRB and ED is associated with higher pain severity at rest and/or in the preceding 6 months in LE. Similarly, greater map volume and peak MEP amplitude in ECRB and ED was correlated with the worst pain in the last 6 months. Previous studies have shown a relation between altered sensory cortex representation of the back and pain duration (16), and reorganization of the motor cortex representation of the transversus abdominis muscle in chronic low back pain (increased map volume and posterior–lateral shift of CoG) is associated with later EMG onset of this muscle during rapid limb movements (46). These findings imply that cortical changes may contribute to symptoms of persistent pain and motor dysfunction. However, our study does not permit conclusions about causality. Whether changes in motor dysfunction cause pain or pain causes motor dysfunction remains to be determined. Further investigation using a longitudinal study design is required to disentangle the causal relation between cortical mechanisms and pain and disability in LE.
Limitations and future directions
This study is the first to report a change in the number of discrete cortical peaks in individuals with LE. As a result, the outcome measure used to quantify the number of discrete peaks is novel, and like all measures established post hoc, assessment of the number of discrete peaks in this study is vulnerable to bias. Future research should seek to validate this measure in a large independent sample. In addition, the present study evaluated only the hemisphere corresponding to the “affected” arm in a group of individuals with unilateral LE symptoms. Whether similar cortical abnormalities are present in the “unaffected” hemisphere in unilateral LE and how cortical abnormalities may be altered by the presence of bilateral symptoms are unknown. It should also be noted that pain in our sample of LE participants was assessed using the CPGQ and PRTEE, which are self-report measures that require pain ratings based on memory. Previous studies have shown that pain ratings based on memory, although reliable, may have some inaccuracy, even after very short delays (33). Finally, this study used a small sample size drawn from a convenience sample, and as a result, these findings may not be applicable to the wider LE population. Trials on larger subject numbers are required to confirm the findings of this study.
This work was supported by the National Health and Medical Research Council of Australia (631612 to S. S. and 1002190 to P. H.) and a University of Queensland Early Career Researcher Grant (2009002291 to L. C.).
The authors declare no conflicts of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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