Edited by: Mikhail Lebedev, Duke University, United States
Reviewed by: Dobrivoje S. Stokic, Methodist Rehabilitation Center, United States; Rahul Goel, University of Houston, United States; Toshiki Tazoe, University of Miami, United States; Filippo Brighina, University of Palermo, Italy
*Correspondence: Ashlee M. Hendy
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Transcranial magnetic stimulation (TMS) studies have demonstrated that unilateral muscle contractions in the upper limb produce motor cortical activity in both the contralateral and ipsilateral motor cortices. The increase in excitability of the corticomotor pathway activating the resting limb has been termed “cross-activation”, and is of importance due to its involvement in cross-education and rehabilitation. To date, very few studies have investigated cross-activation in the lower limb. Sixteen healthy participants (mean age 29 ± 9 years) took part in this study. To determine the effect of varying contraction intensities in the lower limb, we investigated corticomotor excitability and intracortical inhibition of the right rectus femoris (RF) while the left leg performed isometric extension at 0%, 25%, 50%, 75% and 100% of maximum force output. Contraction intensities of 50% maximal force output and greater produced significant cross-activation of the corticomotor pathway. A reduction in silent period duration was observed during 75% and 100% contractions, while the release of short-interval intracortical inhibition (SICI) was only observed during maximal (100%) contractions. We conclude that increasing isometric contraction intensities produce a monotonic increase in cross-activation, which was greatest during 100% force output. Unilateral training programs designed to induce cross-education of strength in the lower limb should therefore be prescribed at the maximal intensity tolerable.
It is well established that unilateral muscle contractions of the upper limb are associated with bilateral activity of the motor cortex (M1; Carson,
Studies in the upper limb have demonstrated that the magnitude of cross-activation is greatest during high or maximal intensity contractions (Muellbacher et al.,
The majority of research into cross-activation has focused on unilateral movements of the upper limbs, with few studies examining the potential for this effect in the lower limb (Chiou et al.,
It is also possible that the anatomical location of the muscle investigated may influence the magnitude of cross-activation. In animals, ipsilateral projections to the distal forelimb are less pronounced (Soteropoulos et al.,
The primary aim of this study was to determine the effects of unilateral isometric contractions of the non-dominant (left) quadriceps at 25%, 50%, 75% and 100% of MVC, on the cross-activation of the iM1 and corticomotor pathway, as determined from MEPs recorded from the right RF during both resting and low level contractions. It was hypothesized that high intensity isometric contractions would result in an increase in the excitability of the corticomotor pathway of the resting quadriceps along with a subsequent decrease in SICI of the iM1 and reduction in the silent period.
Sixteen right-footed participants (10 males and 6 females; age (mean ± standard deviation (SD) 29 ± 9 years) with no recent lower limb injuries volunteered for the study. A medical questionnaire was used to screen the participants for neurological disorders and contraindications in relation to the application of TMS. This study was carried out in accordance with the recommendations of the Deakin University Human Research Ethics Committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Deakin University Human Research Ethics Committee.
The participants attended a single laboratory session, where they performed isometric contractions with the left quadriceps while corticomotor responses were recorded from the right RF. The participant was seated in the isokinetic dynamometer (Biodex System Pro 4, Shirley, NY, USA) for the duration of the experiment (all measures). The participants were required to contract their left quadriceps at 25%, 50%, 75% and 100% of their predetermined MVC, in a randomized order (see “Voluntary Contractions during Testing” Section for details). While the participants were performing left quadriceps contractions, the corticomotor excitability of the right RF were measured when the right leg was relaxed (
Experiment design. The left quadriceps contracts at five different contraction intensities (0, 25, 50, 75 and 100% MVC) while corticomotor responses of the right rectus femoris (RF) were measured. The measurement order of left quadriceps contraction intensity and transcranial magnetic stimulation (TMS) stimuli intensity were randomized. The entire protocol was first completed for
Maximal voluntary contractions of the left quadriceps was measured using an isokinetic dynamometer (Biodex System Pro 4, Shirley, NY, USA) at the beginning of the experiment. The dynamometer arm was positioned to achieve 45° of knee flexion and was secured to the participants’ ankle with a velcro strap. Participants executed 3–5 submaximal isometric contractions at 10%–50% of their perceived MVC as a warm-up. The participants were then asked to extend with maximum effort, sustaining the isometric contractions for 3 s. All participants performed three trials of MVC separated by 3 min rest, with the highest force output recorded in newton. Verbal encouragement and visual feedback were given for each trial.
During the experiment, the participants performed isometric contraction of the quadriceps at five different intensities with their left leg (0%, 25%, 50%, 75% and 100% MVC). The order of the contraction intensity was randomized for each participant. Online visual feedback of force production was provided to allow participant and researcher to monitor and achieve accurate force production for each trial. The required force output was manually set with a red line using the dynamometer software (Biodex System Pro 4, Shirley, NY, USA), and was visible on a computer screen located 1 m away from the participant at eye level. Participants were instructed to extend the left leg and maintain a constant force to match the red line for at least 2 s. The experimenter applied a TMS stimulus on the left M1 when the required force output was observed on the screen (determined visually by the experimenter). During
Supramaximal electrical stimulation was applied to the left and right femoral nerves to obtain muscle responses (M-waves) from RF using a DS7A constant current electrical stimulator (Digitimer, Hertfordshire, UK), while the participant remained at rest. The back support of the seat was reclined 45° from the upright position to aid in the placement of electrode at the femoral triangle level beneath the inguinal ligament. The optimal intensity of stimulation for recruitment of all RF motor units was determined when the increasing current intensity did not result in any further increase of the EMG response. To ensure a maximal response, the current strength was further increased by another 10%, and five stimuli were delivered with an inter-stimulus period of 6–9 s. The largest peak-to-peak response from each RF (left and right) was reported as
Single and paired-pulse TMS was used to assess the corticomotor excitability and SICI of the motor cortical representation of the right RF muscle. A 110 mm double-cone coil was used to elicit an MEP from the right RF muscle via the left M1 using a BiStim unit attached to two Magstim 2002 stimulators (Magstim Co, Dyfed, UK). The optimal site to elicit the largest and most consistent MEP response in the right RF was determined by exploring the leg representation of left M1 1–3 cm lateral and anterior of the vertex, and was marked with a felt tipped pen to ensure consistent coil placement throughout the experiment. The interval between delivery of each pulse varied based on the participants ability to perform left leg contractions, but was always greater than 10 s. The pre-stimulus rmsEMG activity of the right RF was recorded 50 ms prior to each TMS stimulus to monitor background muscle activity. For
Surface EMG signals were recorded from the right and left RF using bipolar Ag/AgCl surface electrodes. The areas for electrode placement were shaved, scrubbed with an abrasive skin rasp to remove dead skin, and then cleaned with 70% isopropyl alcohol. The electrodes were placed on the muscle belly of the RF, midway between the anterior superior iliac spine and the superior border of the patella, with an inter-electrode distance of 2 cm (center to center). The reference electrode was placed on the right patella. All cables were fastened with tape to reduce movement artifact. The EMG signals, including MEPs and Mwaves, were amplified with a gain of 1000, band-pass filtered (13–1000 Hz), digitized at 2 kHz for 500 ms and recorded for offline analysis using PowerLab 4/35 (ADInstruments, Bella Vista, NSW, Australia).
The rmsEMG present in the right RF for the period 50 ms prior to stimulus delivery was recorded in mV and calculated automatically using the LabChart software. The mean of the five pre-stimulus values was then determined separately for each participant and each contraction intensity during both experiments.
The peak-to-peak MEP amplitude from each stimuli was normalized to individual participants’
The SICIratio was used to determine intracortical inhibition. This was calculated by dividing the mean paired-pulse MEP amplitude by the mean single-pulse (120%) MEP amplitude for each participant, and was performed separately for each contraction intensity of the left quadriceps. The SICIratio has an inverse relationship with intracortical inhibition, thus values close to zero represent higher intracortical inhibition, while values closer to one represent lower levels of intracortical inhibition.
In
For each experiment, one-way repeated measure analysis of variances (ANOVAs) were used to detect differences in primary outcome measures for the right RF (corticomotor excitability, SICIratio, silent period,
Thirteen of sixteen participants completed both
Mean values for
Maximal compound waves from the right and left rectus femoris (RF), and pre-stimulus rmsEMG values recorded from the right RF, for both experiments (Mean ± SD).
Experiment 1 | 0% | 25% | 50% | 75% | 100% |
---|---|---|---|---|---|
Left |
5.67 ± 1.66 | 6.01 ± 1.52 | 5.91 ± 1.77 | 6.27 ± 1.81 | 6.11 ± 1.74 |
Right |
5.64 ± 2.01 | 5.43 ± 1.89 | 5.56 ± 1.76 | 5.51 ± 2.01 | 5.46 ± 1.81 |
rmsEMG (mV) | 0.003 ± 0.003 | 0.002 ± 0.001 | 0.003 ± 0.001 | 0.004 ± 0.002 | 0.009* ± 0.006 |
Left |
5.89 ± 1.50 | 5.84 ± 1.62 | 5.93 ± 1.69 | 6.06 ± 1.70 | 5.98 ± 1.63 |
Right |
5.83 ± 2.03 | 5.26 ± 1.60 | 5.25 ± 1.69 | 5.27 ± 1.56 | 5.33 ± 1.43 |
rmsEMG (mV) | 0.024 ± 0.012 | 0.022 ± 0.010 | 0.028 ± 0.014 | 0.036 ± 0.019 | 0.061* ± 0.048 |
Mean values for pre-stimulus rmsEMG recorded from the right RF are displayed in Table
The mean peak-to-peak amplitude of MEPs recorded following stimuli at: (a) 120% RMT; and (b) 150% RMT are displayed in Figure
Mean ± standard deviation (SD) peak-to-peak amplitude of motor evoked potentials (MEPs) delivered at
Motor evoked potential (MEP) amplitudes (%
0% MVC | 25% MVC | 50% MVC | 75% MVC | 100% MVC | |
---|---|---|---|---|---|
120% RMT | 5.01 ± 3.92 | 9.01 ± 9.77 | 9.84 ± 7.54 | 20.04 ± 18.09 | 26.32 ± 15.56 |
150% RMT | 8.9 ± 6.76 | 13.52 ± 12.01 | 14.80 ± 11.99 | 22.69 ± 16.81 | 29.27 ± 16.91 |
SICIratio | 0.23 ± 0.21 | 0.42 ± 0.35 | 0.34 ± 0.22 | 0.40 ± 0.28 | 0.38 ± 0.17 |
The mean SICIratio recorded from the right RF is displayed in Figure
Mean ± SD short-interval intracortical inhibition (SICI)ratio recorded from the resting right RF during isometric contraction of the left quadriceps. *Denotes significant difference in
Mean values for
Mean values for pre-stimulus rmsEMG recorded from the right quadriceps are displayed in Table
The mean peak-to-peak amplitude of MEPs recorded following stimuli at: (a) 120% AMT; and (b) 150% AMT are displayed in Figure
Mean ± SD peak-to-peak amplitude of MEPs delivered at
The mean SICIratio recorded from the right RF is displayed in Figure
Mean ± SD SICIratio recorded from the active right RF during isometric contraction of the left quadriceps.
The mean silent period duration of MEPs evoked at: (a) 120% AMT; and (b) 150% AMT are displayed in Figure
Mean ± SD silent period duration of MEPs evoked at
Our results demonstrate that cross-activation of the iM1 during unilateral contractions of the lower limb occurs at isometric contraction intensities of 50% MVC and above. We observed a linear, monotonic increase in the magnitude of cross-activation as contraction intensity increased, despite randomization of testing order. The effect of isometric contractions on iM1 inhibitory circuits was less pronounced, with significant reductions in SICI only observed during maximal isometric contractions (100% MVC) when the inactive limb was at rest. The reduction in the silent period duration of the right leg observed during 75% and 100% MVC of the left leg suggests that the reduced inhibition along the corticomotor pathway of the inactive limb may also contribute to the cross-activation effect. Unchanged
A linear, monotonic increase in the amplitude of MEPs obtained from the resting right RF was observed as contraction intensity of the left quadriceps increased. This increase in excitability of the corticomotor pathway reached statistical significance at contraction intensities of 50% MVC and above. This relationship between contraction intensity and cross-activation is a novel finding in the lower limb, where the effect of low-intensity contractions has not been previously investigated. In agreement with our findings, one previous study has reported increased excitability of the resting RF and TA during contractions at 75% of maximal EMG (Chiou et al.,
We observed a 65% mean reduction in the SICIratio of the iM1 during isometric unilateral contractions at maximal (100%) intensity, however, submaximal contractions did not produce a significant release of SICI. It should be noted that maximal contractions caused co-contraction of the resting limb, detected via an increase in rmsEMG prior to stimulus delivery, which may have contributed to the reduction in SICI. These findings are in contrast to the majority of evidence obtained from upper-limb studies, where the release of SICI in the iM1 during unilateral contractions appears to be more pronounced (Muellbacher et al.,
Another possible reason for observing a comparatively small effect on SICI of the iM1 in
Interestingly, we observed a linear reduction in silent period duration as contraction intensity in the contralateral limb increased, reaching significance at 75% MVC for MEPs evoked at 150% AMT. A previous study has reported lower levels of variability and greater homoscedasticity in the silent period duration of MEPs evoked at intensities >130% AMT (Damron et al.,
Despite conscious efforts to maintain relaxation (
The increase in background EMG of the resting limb during demanding single limb tasks has been frequently observed in the upper limb, and has been termed “motor irradiation” (Cernacek,
The findings from this study are of importance when developing long-term training protocols to induce cross-education of strength. The use of unilateral training to supplement rehabilitation following single limb immobilization (Pearce et al.,
Muscle fatigue has been shown to increase the magnitude of cross-activation, and increase levels of background EMG in the resting muscle (Arányi and Rösler,
Since transcallosal pathways between the hemispheres contribute to the net corticomotor output of the M1 (Avanzino et al.,
Finally, given our results indicate that reduced inhibition downstream of the iM1 may play a larger role in the increased net corticomotor excitability of the right RF, investigation at segmental levels is required to further elucidate the underpinning mechanisms. Future studies should measure H-reflexes and MEPs elicited at the cervicomedullary junction during unilateral contractions of the lower limb. While such investigation has been conducted in the upper limb (Hortobágyi et al.,
We observed a linear increase in corticomotor excitability of resting RF during increasing isometric contractions of the contralateral limb. Unilateral contraction intensities of 50% MVC and greater result in significant increases in corticomotor output to the resting homologous muscle. These findings suggest that exercise protocols designed to induce cross-education strength gains in the lower limb should be applied at an intensity of at least 50% MVC, with higher intensities preferable in order to maximize stimulus of the corticomotor pathway that activates the resting or unexercised limb. Furthermore, we conclude that a reduction in SICI occurred only during maximal isometric efforts, and may not play a major role in the net output of the iM1 during unilateral contractions. Instead, reductions in the silent period duration during 75% and 100% MVC efforts suggest subcortical and spinal inhibition may contribute to cross-activation of the inactive limb.
AMH and W-PT developed the conceptual basis and experimental design for this study. Data collection and analysis was conducted by AMH and LC. Interpretation of results and manuscript preparation was carried out by AMH.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors wish to thank all participants for their contribution to this study.