The current study was the first to report the use of stimulation strategies with customized frequency and intensity modulation for maintaining a targeted isometric force level during repetitive activation of human quadriceps femoris muscles. The major finding of this study was that the combination strategy that began at 30 Hz and first progressively increased the pulse duration and then progressively increased the frequency produced more successful contractions than any of the other stimulation strategies tested. Furthermore, the second best stimulation strategy for maintaining isometric muscle force was fixing the stimulation intensity at the maximum level and progressively increasing only frequency (frequency-modulation-only protocol). Interestingly, the stimulation strategy that fixed the stimulation frequency at the maximum level and progressively increased only intensity (intensity-modulation-only protocol) produced the fewest successful contractions.
We hypothesize 4 different physiological mechanisms that could contribute to the findings of the current study: (1) the force generated by each muscle fiber, (2) the number of pulses delivered during each of the protocols, (3) the extent of low-frequency fatigue (LFF) produced, and (4) the available range for frequency modulation.
The first physiological mechanism—force generation by each muscle fiber—can be used to explain the differences in performance between the frequency-modulation-only and intensity-modulation-only protocols. During the intensity-modulation-only protocol, the frequency was maintained at 60 Hz, and the lowest intensity was used initially (pulse duration at 143.58 microseconds). Thus, a smaller fraction of the motor unit pool was recruited initially. Whenever the muscles failed to generate the targeted peak forces, the pulse duration was progressively increased to recruit more motor units. Motor units that were recruited earlier in the protocol continued to be activated throughout the protocol. Thus, motor units that were recruited early were activated for a longer period of time compared with the motor units that were recruited later in the protocol.
In contrast, during the frequency-modulation-only protocol, the pulse duration was maintained at 600 microseconds throughout the protocol. Thus, because all of the protocols used the same pulse amplitude and had a maximum pulse duration of 600 microseconds, the maximum number of motor units that was recruited within each of the protocols was recruited throughout the frequency-modulation-only protocol.
This allowed the sharing of force generation among a greater number of muscle fibers throughout the protocol. The amount of adenosine triphosphate (ATP) utilized by actin-myosin adenosine triphosphatase (ATPase) is proportional to the force generated by each fiber.26,27
Thus, greater ATP utilization by the actin-myosin ATPase per muscle fiber occurred during the intensity-modulation-only protocol compared with during the frequency-modulation-only protocol.
We, therefore, believe that the frequency-modulation-only protocol produced less fatigue in the recruited motor unit population because of greater motor unit recruitment at the commencement of the protocol, resulting in lower ATP consumption per active muscle fiber by actin-myosin ATPase and consequently improving muscle performance, as evidenced by a greater number of successful contractions. The contribution of greater motor unit recruitment at the commencement of the protocol also could help explain the generally better muscle performance observed during the combination-modulation protocols in which intensity was increased first followed by increasing frequency than the combination-modulation protocols in which frequency was increased first followed by increasing intensity in our preliminary study.
The second physiological mechanism—the number of stimulation pulses—also may have contributed to the large difference between the frequency-modulation-only and intensity-modulation-only protocols. During the intensity-modulation-only protocol, when all of the motor units were always activated at a high frequency of 60 Hz, a greater number of stimulation pulses were delivered to the muscle compared with during the frequency-modulation-only protocol, in which stimulation frequency was progressively increased from a low frequency (~13 Hz). The Ca2+
ATPase and Na+
ATPase reactions in response to each action potential contribute to ATP utilization during muscle force generation.28–31
Because relatively fewer pulses were delivered during the frequency-modulation-only protocol compared with the intensity-modulation-only protocol, less ATP was utilized by the Ca2+
ATPase and Na+
ATPase during the frequency-modulation-only protocol.31,32
Muscle fatigue is related to metabolic demand.33–35
In addition, previous studies16,36,37
showed that higher stimulation frequencies contribute to more rapid muscle fatigue. Thus, the frequency-modulation-only protocol might be less fatiguing than the intensity-modulation-only protocol because it delivers fewer pulses to the muscles. Taken together, compared with the intensity-modulation-only protocols, the frequency-modulation-only protocol appeared to be less fatiguing due to less metabolic demand per recruited muscle fiber by greater motor unit recruitment at the commencement of the protocol and by delivering fewer stimulation pulses, which resulted in better performance during repetitive activation.
The third physiological mechanism—LFF—may help to explain the differences in performance among the 3 combination-modulation protocols. Our results showed that the initial stimulation frequency and intensity combination had a significant effect on the number of successful contractions produced. First described by Edwards and colleagues in 1977,38
LFF is characterized by a preferential loss of force at low stimulation frequencies and a slow recovery over the course of hours or even days (for a review, see Jones39
). The mechanism that causes LFF still is not clear, but both metabolite build-up and the impairment in Ca2+
release from the sarcoplasmic reticulum have been shown to play a role in the development of LFF.40,41
Low-frequency fatigue has been suggested to cause a shift in the normalized force-frequency relationship toward higher frequencies.42,43
Because the majority of the shift in the force-frequency relationship due to LFF occurred at frequencies lower than 30 Hz, the loss in the force responses at 20 Hz would be greater than at 30 Hz. Thus, muscle peak forces would be more difficult to maintain at a targeted level during repetitive activation using 20-Hz stimulation trains. Thus, a faster increment in pulse duration was needed to maintain muscle peak force at the targeted level during the 20-Hz combination-modulation protocol, resulting in fewer successful contractions produced compared with the 30-Hz combination-modulation protocol.
We, therefore, believe the findings that fewer successful contractions produced by the intensity-modulation portion of the 20-Hz combination-modulation protocol and the overall better performance by the 30-Hz versus the 20-Hz combination-modulation protocols were primarily due to the greater LFF produced by repetitive stimulation at 20 Hz compared with 30 Hz. However, we unfortunately did not measure the extent of LFF in the current study and, therefore, could not test for differences in the extent of LFF among the protocols.
Finally, the fourth physiological mechanism—the available range for frequency modulation—also can be used to explain the differences in performance among the 3 combination-modulation protocols. Previous studies of human quadriceps femoris muscles have shown a sigmoidal relationship between stimulation frequency and muscle force production, with a steep rising portion generally observed between 5 and 40 Hz and with near-maximal forces produced at approximately 60 Hz.16,43
In the present study, we decided a priori that the maximum stimulation frequency used was 60 Hz. Compared with the 20- and 30-Hz combination-modulation protocols, the 40-Hz combination-modulation protocol had far less capacity to modulate frequency to affect an increase in the force generated. Thus, this limited capacity of the 40-Hz combination-modulation protocol to increase force could explain the fewer successful contractions produced during the frequency-modulation portion of the 40-Hz combination-modulation protocol. Thus, we believe that 30 Hz was the best initial frequency for quadriceps femoris muscle activation because it avoided LFF during the intensity-modulation portion of the protocol and retained a large capacity to increase force during the frequency-modulation portion of the protocol.
This is the first study on human muscles that systematically investigated stimulation strategies involving increase of both the frequency and intensity based on customized modulation steps and real-time feedback of muscle forces. To our knowledge, only a few previous studies have investigated modulation of frequency and intensity on animal muscles to maintain muscle forces19
or have tested the effects of a random modulation (both increase and decrease) of frequency and intensity on muscle fatigue during electrical stimulation.21
Two studies from our laboratory examined the effect on skeletal muscle performance of modulating from a lower frequency to a higher frequency during repetitive electrical stimulation for subjects without impairments or disabilities44
and subjects with spinal cord injuries.45
A more recent study7
compared the effects of progressively increasing the frequency, progressively increasing the intensity, or not changing the stimulation frequency or intensity during repetitive isometric contractions of human quadriceps femoris muscles. However, there were important differences in methodology between the current study and our previous studies. The current study compared the effects of progressively increasing both frequency and intensity on force maintenance during repetitive electrical stimulation. In contrast, Kesar et al7
compared the effects of progressively increasing either frequency alone or intensity alone on the force produced, and Kebaetse and colleagues44,45
only modulated stimulation frequency and only increased from a lower frequency to a higher frequency. In the current study, by progressively increasing the stimulation frequency and intensity based on real-time feedback of muscle forces, muscle peak forces were maintained at a targeted level repetitively, which is similar to functional movements such as walking, in which muscles need to generate targeted forces repetitively. In contrast, previous studies either modulated the stimulation frequency or intensity every 16 contractions regardless of the peak force generated7
or modulated stimulation frequency using only one step and did not try to maintain the muscle’s performance in the protocol.44,45
Another recent study46
showed the enhancement of paralyzed human ankle muscle performance by the use of feedback-controlled stimulation strategies. However, unlike the current study, which investigated effects of modulating both frequency and intensity, only frequency modulation was tested by Shields and colleagues.46
During voluntary contractions, the CNS uses both recruitment and rate coding to modulate muscle forces. When the recruitment is completed at submaximal force levels, higher forces are achieved by using progressively higher activation rates of previously recruited motor units.4,47
Interestingly, our preliminary study comparing stimulation frequency and intensity modulation order found that a similar motor unit activation strategy was needed to improve muscle peak force maintenance during repetitive electrical stimulation. Our results showed that progressively increasing stimulation frequency after reaching the maximum recruitment (600-microsecond pulse duration) (ie, progressively increasing pulse duration intensity followed by progressively increasing stimulation frequency) produced more successful contractions than progressively increasing the intensity after reaching the maximum frequency (60 Hz) (ie, progressively increasing stimulation frequency followed by progressively increasing pulse duration intensity). Current FES systems use a constant frequency (20–40 Hz) and only increase stimulation intensity to maintain muscle force output to overcome fatigue during repetitive activation.6–11
Our findings suggest that, to improve muscle performance during repetitive activation of human skeletal muscle, such as during FES, both frequency and intensity modulation should be used and the modulation should start with progressively increasing intensity as seen in the current approach. After the stimulation intensity reaches the maximum level, progressively increasing frequency could allow the muscle to maintain a targeted force output for a longer period of time.
The current study served as a preliminary work that investigated the effectiveness of using 2 physiological mechanisms—rate coding and recruitment—for skeletal muscle force maintenance during repetitive electrical stimulation. Future studies are needed to confirm the usefulness of the current findings to other muscle groups and paralyzed muscles in patient populations for FES applications.